Perioperative Medicine

Perioperative
Medicine
Managing for Outcome
SECOND EDITION

Mark F. Newman, MD
Executive Vice President for Health Affairs
University of Kentucky (UK) Health-care
Professor of Anesthesiology
University of Kentucky College of Medicine
Lexington, Kentucky

Lee A. Fleisher, MD
Robert D. Dripps Professor and Chair
Department of Anesthesiology and Critical Care
Professor of Medicine
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania

Clifford Ko, MD, MS, MSHS, FACS, FASCRS, FASMBS (Hon)

Director of UCLA Center for Surgical Outcomes and Quality
Department of Surgery Professor of Surgery
University of California, Los Angeles
Los Angeles, California

Michael (Monty) Mythen, MBBS, MD, FRCA, FFICM, FCAI (Hon)

Smiths Medical Professor of Anaesthesia and Critical Care
University College London
London, United Kingdom
1600 John F. Kennedy Blvd.
Ste 1600
Philadelphia, PA 19103-2899

PERIOPERATIVE MEDICINE, Second Edition ISBN: 978-0-323-56724-4

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 To our past, current, and future residents, fellows,
and faculty, who, through their dedication,
continue to advance the field of perioperative
medicine and
the care of our patients.

To our families, who have been so supportive:

To my wife, Susan, a partner, a friend, and, most

important, a believer without whom I would be
incomplete.
To my mother and late father, who let me know that
no matter what I accomplished it would be okay.
And to my kids, Sarah, Jack, and Catherine, who
remind me every day of the importance of what
we do and what we learn.
Mark F. Newman

To my wife, Renee, who has been a partner and best

friend for the past 30 years. To my children,
Jessica and Matthew, for their unconditional love
and support and constant reminder about the
important things in life. Finally, to my parents and
grandparents, who instilled in me the desire to
always seek new knowledge.
Lee A. Fleisher

In loving memory of Siobhan Mythen R.I.P.

Monty Mythen

“To my family, friends, and colleagues, thank you for all

you do to make things better”
Clifford Ko
Contributors

Vatche G. Agopian, MD Diana Ayubcha, DO, MS

Associate Professor
Director - Dumont-UCLA Liver Cancer Center
Associate Director - General Surgery Residency
Program, Liver Transplantation and Hepatobiliary
Surgery Department of Surgery
David Geffen School of Medicine at University of California
Los Angeles, California
35 – Solid Organ Transplantation
Assistant Professor
Associate Program Director Neuroscience in Anesthesiology
and Critical Care Fellowship
Department of Anesthesiology and Critical Care
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
5 – Perioperative Cardiac Risk Assessment in Noncardiac
Surgery

Ehab Al-Bizri, MD Angela Bader, MD, MPH

Resident Physician Professor of Anesthesia
Department of Anesthesiology Anesthesiology, Perioperative Medicine and Pain
Stony Brook Medicine Harvard Medical School/Brigham Health;
Stony Brook, New York Vice Chair for Perioperative Medicine
25 – Prevention and Treatment of Gastrointestinal Department of Anesthesiology
Morbidity Perioperative Medicine and Pain
Brigham and Women’s Hospital
Benjamin Y. Andrew, MD, MHS Boston, Massachusetts
Resident Physician 4 – The Value of Preoperative Assessment
Department of Anesthesiology
Duke University Shyamasundar Balasubramanya, MD, FACS, FACC,
Durham, North Carolina FCCP, FAAP
17 – Preservation of Renal Function Health Sciences Assistant Clinical Professor
University of California Los Angeles (UCLA)
Thomas L. Archer, MD, MBA David Geffen School of Medicine
Clinical Professor (retired) Division of Cardiac Surgery
Department of Anesthesiology Ronald Reagan UCLA Medical Center
University of California San Diego Los Angeles, California
La Jolla, California 35 – Solid Organ Transplantation
44 – Economic Analysis of Perioperative Optimization
Peyman Benharash, MD, MS
Gareth L. Ackland, PhD, FRCA, FFICM, FHEA Associate Professor of Surgery and Bioengineering
Translational Medicine & Therapeutics Division of Cardiac Surgery
William Harvey Research Institute David Geffen School of Medicine at UCLA
Barts and The London School of Medicine and Dentistry Los Angeles, California
Queen Mary, University of London 6 – Cardiovascular Risk Assessment in Cardiac Surgery
John Vane Science Centre, Charterhouse Square
London, United Kingdom Miles Berger, MD, PhD
2 – The Inflammatory Response to Surgery Assistant Professor of Anesthesiology
Duke University Medical Center
John G. Augoustides, MD, FASE, FAHA Durham, North Carolina
Professor and Fellowship Director 42 – Postoperative Cognitive Dysfunction and Delirium
Cardiovascular and Thoracic Section
Department of Anesthesiology and Critical Care Muath Bishawi, MD
Perelman School of Medicine Division of Cardiothoracic Surgery
University of Pennsylvania Department of Surgery
Philadelphia, Pennsylvania Duke University
22 – Protecting the Central Nervous System during Durham, North Carolina
Cardiac Surgery 13 – Treatment of Perioperative Ischemia
Infarction, and Ventricular Failure in Cardiac Surgery

vi
 Contributors vii

Victoria Bradford, MD, MBA Benedict Charles Creagh-Brown, BM, FRCP, PhD,
Assistant Professor DICM, FFICM
Anesthesiology Consultant
University of Kentucky Intensive Care Unit
Lexington, Kentucky Royal Surrey County Hospital;
30 – Preservation of Fetal Viability during Noncardiac Reader (Clinical)
Surgery Clinical Medicine
University of Surrey
Thomas Buchheit, MD, CIPS Guildford, United Kingdom
Director of Regenerative Pain Therapies 20 – Prevention and Treatment of Postoperative
Center for Translational Pain Medicine Pulmonary Complications
Department of Anesthesiology
Duke University Jovany Cruz Navarro, MD
Durham, North Carolina Assistant Professor
41 – Improving Pain and Outcomes in the Perioperative Department of Anesthesiology
Setting Department of Neurosurgery
Baylor College of Medicine
Christopher R. Burke, MD Ben Taub General Hospital
Assistant Professor of Cardiac Surgery Houston, Texas
Division of Cardiothoracic Surgery 24 – Perioperative Management of Acute Central Nervous
Associate Program Director System Injury
Cardiothoracic Surgery Residency Programs
University of Washington, James DeBritz, MD
Seattle, Washington Assistant Professor and Director of Orthopedic Trauma
11 – Prevention of Ischemic Injury in Cardiac Surgery Department of Orthopedic Surgery
The George Washington University School of Medicine and
Maurizio Cereda, MD Health Sciences
Associate Professor Washington, D.C.
Co-Director Surgical ICU 34 – Major Orthopedic Surgery
Department of Anesthesiology and Critical Care
University of Pennsylvania Timothy J. Donahue, DO
Philadelphia, Pennsylvania Surgery
9 – Pulmonary Risk Assessment University of Texas
Houston, Texas
Anne Cherry, MD 36 – Multisystem Trauma
Assistant Professor
Department of Anesthesiology Stephen A. Esper, MD, MBA
Duke University School of Medicine Assistant Professor
Durham, North Carolina Director of Center for Perioperative Care
17 – Preservation of Renal Function Department of Anesthesiology and Perioperative Medicine
University of Pittsburgh School of Medicine
Albert T. Cheung, MD Pittsburgh, Pennsylvania
Professor 15 – Prevention and Management of Perioperative
Department of Anesthesiology Dysrhythmias
Stanford University School of Medicine,
Stanford, California; Amanda L. Faulkner, MD, D.ABA
Professor Emeritus Assistant Professor
Department of Anesthesiology Department of Anesthesiology
University of Pennsylvania School of Medicine Duke University
Philadelphia, Pennsylvania Durham, North Carolina
23 – Preservation of Spinal Cord Function 37 – Neurosurgery

Kathleen Claus, MD Duane J. Funk, MD, FRCPC

Assistant Professor, Critical Care Medicine Associate Professor
Department of Anesthesiology Anesthesiology and Medicine
Duke University University of Manitoba
Durham, North Carolina Manitoba, Canada
26 – Prevention and Management of Deep Vein 40 – Endocrine and Electrolyte Disorders
Thrombosis and Pulmonary Embolism
viii Contributors

Robert Gaiser, MD Rachel A. Hadler, MD

Chair and Professor Assistant Professor
Anesthesiology Anesthesiology and Critical Care
University of Kentucky University of Pennsylvania Perelman School of Medicine
Lexington, Kentucky Philadelphia, Pennsylvania
30 – Preservation of Fetal Viability during Noncardiac 43 – Role of Palliative Care
Surgery
Steven Ellis Hill, MD
Tong J. Gan, MD, MBA, MHS, FRCA Professor
Professor and Chairman Anesthesiology and Pain Management
Department of Anesthesiology UT Southwestern Medical Center
Stony Brook University Renaissance School of Medicine Dallas, Texas
Stony Brook, New York 27 – Perioperative Management of Bleeding and
25 – Prevention and Treatment of Gastrointestinal Transfusion
Morbidity
Michael Holmes, MD
Stephen Harrison Gregory, MD Division of Cardiothoracic Anesthesiology and Critical Care
Assistant Professor of Anesthesiology Medicine
Medical Director, Center for Preoperative Assessment Department of Anesthesiology and Pain Medicine
and Planning University of Washington
Washington University in St. Louis School of Medicine Seattle, Washington
St. Louis, Missouri 31 – Cardiac Surgery
12 – Prevention of Ischemic Injury in Noncardiac Surgery
Q. Lina Hu, MD, MS
Michael P.W. Grocott Clinical Scholar in Residence
Anaesthesia and Critical Care Research Area Division of Research and Optimal Patient Care
NIHR Southampton Biomedical Research Centre American College of Surgeons
University Hospital Southampton NHS Foundation Trust; Chicago, Illinois
Integrative Physiology and Critical Illness Group Resident Physician
Clinical and Experimental Sciences, Faculty of Medicine Department of Surgery
University of Southampton University of California, Los Angeles
Southampton, United Kingdom California
46 – Delivering Value Based Care: The UK 28 – Prevention of Perioperative Surgical Site
Perspective Infection

Taras Grosh, MD Peter Inglis, BMBS

Assistant Professor Anesthesia
Regional and Orthopedic Anesthesiology University of Manitoba
Department of Anesthesiology & Critical Care Winnipeg, Canada
Hospital of the University of Pennsylvania & Pennsylvania 40 – Endocrine and Electrolyte Disorders
Presbyterian Medical Center
Philadelphia, Pennsylvania Andrew Iskander, MD
5 – Perioperative Cardiac Risk Assessment in Noncardiac Pediatric Anesthesiologist
Surgery Anesthesiology
New York Medical College
Holden K. Groves, MD, MSc, MAS Valhalla, New York
Assistant Professor of Anesthesiology 25 – Prevention and Treatment of Gastrointestinal
Columbia University Morbidity
New York
19 – Perioperative Management of Renal Failure and Alexander I.R. Jackson
Renal Transplant Anaesthesia and Critical Care Research Area
NIHR Southampton Biomedical Research Centre
Dhanesh K. Gupta, MD, MBA University Hospital Southampton NHS Foundation Trust;
Professor of Anesthesiology Integrative Physiology and Critical Illness Group
Anesthesiology; Clinical and Experimental Sciences, Faculty of Medicine
Chief of Neurosurgical & Spine Anesthesiology University of Southampton
Anesthesiology; Southampton, United Kingdom
Chief of Non-Operating Room Anesthesiology 46 – Delivering Value Based Care: the UK Perspective
Anesthesiology
Duke University, Durham, North Carolina
21 – Carotid and Intracranial Surgery
 Contributors ix

Amir K. Jaffer, MD, MBA, SFHM W. Andrew Kofke, MD, MBA, FCCM, FNCS
Chief Medical Officer Professor, Director Neuroscience in Anesthesiology and
New York, Presbyterian Queens Hospital Critical Care Program
Queens, New York Co-Director Neurocritical Care
47 – Transitions from Hospital to Home Co-Director Perioperative Medicine and Pain Clinical
Research Unit
Michael L. James, MD Department of Anesthesiology and Critical Care
Associate Professor Department of Neurosurgery
Anesthesiology University of Pennsylvania
Neurology Philadelphia, Pennsylvania
Duke University; 24 – Perioperative Management of Acute Central Nervous
Neuroscience Medicine System Injury
Duke Clinical Research Institute
Durham, North Carolina H.T. Lee, MD, PhD
21 – Carotid and Intracranial Surgery Director of Transplant Anesthesiology and Vice Chair for
37 – Neurosurgery Laboratory Research
Professor of Anesthesiology
Timothy F. Jones, BA, MSci, MBBS, MRCS Department of Anesthesiology
Clinical Research Fellow Columbia University
William Harvey Research Institute New York
Barts and The London School of Medicine and Dentistry 19 – Perioperative Management of Renal Failure and
London, United Kingdom Renal Transplant
2 – The Inflammatory Response to Surgery
Jane Lee, MD, PhD
Tammy Ju, MD General Surgeon, General Surgery
Surgery Resident Stephen’s Memorial Hospital
Surgery Norway, Maine;
George Washington University Hospital General Surgeon, General Surgery
Washington, D.C. Maine Medical Center
34 – Major Orthopedic Surgery Portland, Maine
35 – Solid Organ Transplantation
Lillian S. Kao, MD, MS
Professor Jason B. Liu, MD, MS
Surgery Clinical Scholar in Residence
McGovern Medical School Division of Research and Optimal Patient Care
University of Texas Health Science Center at Houston American College of Surgeons;
Houston, Texas Department of Surgery
36 – Multisystem Trauma University of Chicago Medicine
Chicago, Illinois
John A. Kellum, MD, MCCM 45 – Improving Health-Care Quality Through
Professor and Vice Chair Measurement
Department of Critical Care Medicine
University of Pittsburgh Jessica Y. Liu, MD, MS
Pittsburgh, Pennsylvania Resident Physician
18 – Evaluation and Treatment of Acute Oliguria Department of Surgery
Emory University
Miklos D. Kertai, MD, PhD Atlanta, Georgia
Professor of Anesthesiology Clinical Scholar in Residence
Department of Anesthesiology Division of Research and Optimal Patient Care
Vanderbilt University School of Medicine American College of Surgeons
Nashville, Tennessee Chicago, Illinois
8 – Risk Assessment and Perioperative Renal Dysfunction 33 – Major Abdominal Surgery
Clifford Y. Ko, MD, MS, MSHS Alex Macario, MD, MBA
American College of Surgeons Professor
Chicago, Illinois; Department of Anesthesiology
Director of UCLA Center for Surgical Outcomes and Quality Perioperative and Pain Medicine
Department of Surgery Professor of Surgery Stanford University, Stanford, California
University of California, Los Angeles 44 – Economic Analysis of Perioperative Optimization
Los Angeles, California
28 – Prevention of Perioperative Surgical Site
Infection
45 – Improving Health-Care Quality Through Measurement
x Contributors

G. Burkhard Mackensen, MD, PhD, FASE Carmelo A. Milano, MD

Director of Interventional Echocardiography Chief, Section of Adult Cardiac Surgery;
Chief, Division of Cardiothoracic Anesthesiology Surgical Director for LVAD Program;
Adjunct Professor of Medicine Professor of Surgery
UW Medicine Heart Institute Duke University Medical Center
UW Medicine Research & Education Endowed Professor in Durham, North Carolina
Anesthesiology 13 – Treatment of Perioperative Ischemia,
University of Washington Infarction, and Ventricular Failure in Cardiac Surgery
Seattle, Washington
31 – Cardiac Surgery
Richard C. Month, MD
Assistant Professor of Clinical Anesthesiology
Erin Maddy, MD
Department of Anesthesiology and Critical Care
Anesthesiologist
University of Pennsylvania Health System;
Essentia Health
Chief of Obstetrical Anesthesia
Duluth, Minnesota
Hospital of the University of Pennsylvania
44 – Economic Analysis of Perioperative
Philadelphia, Pennsylvania
Optimization
29 – Perioperative Protection of the Pregnant Woman
Aman Mahajan, MD, PhD
Professor and Chair Eugene W. Moretti, MD, MHSc, FASA
Department of Anesthesiology and Perioperative Professor of Anesthesiology
Medicine Department of Anesthesiology
University of Pittsburgh School of Medicine Duke University Medical Center
Pittsburgh, Pennsylvania Durham, North Carolina
15 – Prevention and Management of Perioperative 40 – Endocrine and Electrolyte Disorders
Dysrhythmias

Joseph P. Mathew, MD, MHSc, MBA Rotem Naftalovich, MD, MBA

Professor and Chairman Head of Neurosurgical Anesthesia
Anesthesiology Residency - Assistant Program Director
Duke University Medical Center Department of Anesthesia & Perioperative Care
Durham, North Carolina Rutgers - New Jersey Medical School
14 – Perioperative Management of Valvular Heart Newark, New Jersey
Disease 25 – Prevention and Treatment of Gastrointestinal
42 – Postoperative Cognitive Dysfunction and Morbidity
Delirium
Mark F. Newman, MD
Megan Maxwell, MD Executive Vice President for Health Affairs
Assistant Professor University of Kentucky (UK) Health-Care
Anesthesiology Professor of Anesthesiology
UT Southwestern University of Kentucky Medical College
Dallas, Texas Lexington, Kentucky
7 – Central Nervous System Risk Assessment: Preventing 1 – Implications of Perioperative Morbidity for Long-Term
Postoperative Brain Injury Outcomes
42 – Postoperative Cognitive Dysfunction and Delirium
David L. McDonagh, MD
Departments of Anesthesiology and Pain Management;
Department of Neurology and Neurotherapeutics; Daisuke Francis Nonaka, MD
Department of Neurosurgery; Assistant Professor
UT Southwestern Medical Center Anesthesiology and Pain Management
Dallas, Texas University of Texas Southwestern Medical Center
7 – Central Nervous System Risk Assessment: Preventing Dallas, Texas
Postoperative Brain Injury 27 – Perioperative Management of Bleeding and
Transfusion
Meghan Michael, MD
Assistant Professor Prakash A. Patel, MD, FASE
Anesthesiology and Pain Management Assistant Professor
University of Texas Southwestern Medical Center Anesthesiology and Critical Care
Dallas, Texas University of Pennsylvania
7 – Central Nervous System Risk Assessment: Preventing Philadelphia, Pennsylvania
Postoperative Brain Injury 10 – Hematologic Risk Assessment
 Contributors xi

Jamie R. Privratsky, MD, PhD Babak Sarani, MD

Assistant Professor Professor
Anesthesiology Emergency Medicine
Duke University Surgery
Durham, NC George Washington University
17 – Preservation of Renal Function Washington, D.C.
34 – Major Orthopedic Surgery
Vijay K. Ramaiah, MBBS, MD
Assistant Professor Ryan D. Scully, MD, LCDR, MC, USN
Anesthesiology Department of Orthopaedic Surgery
Duke University Naval Hospital Camp Pendleton
Durham, North Carolina California
21 – Carotid and Intracranial Surgery 34 – Major Orthopedic Surgery

Neil Ray, MD Jyotirmay Sharma, MD, FACS, FACE

Assistant Professor Associate Professor and William C McGarity Chair in
Department of Anesthesiology Surgery
Duke University Vice-Chair for Quality
Durham, North Carolina Patient Safety and Innovation
41 – Improving Pain and Outcomes in the Perioperative Department of Surgery
Setting Emory University School of Medicine
Atlanta, Georgia
Annette Rebel, MD 33 – Major Abdominal Surgery
Professor
Anesthesiology Robert A. Sickeler, MD
Surgery Attending Anesthesiologist
University of Kentucky Anesthesiology
Lexington, Kentucky Stamford Hospital
3 – The Coagulation Cascade in Perioperative Organ Stamford, Connecticut
Injury 8 – Risk Assessment and Perioperative Renal Dysfunction

Lisbi Rivas, MD Martin I. Sigurdsson, MD, PhD

Resident Physician Chief of Anesthesiology and Critical Care
Surgery Department of Anesthesiology and Critical Care
George Washington University Landspitali University Hospital
Washington, DC Professor of Anesthesiology and Critical Care
34 – Major Orthopedic Surgery University of Iceland
Reykjavik, Iceland
Kristen C. Rock, MD 14 – Perioperative Management of Valvular Heart Disease
Assistant Professor
Anesthesia and Critical Care Medicine Mervyn Singer, MBBS, MD, FRCP(Lon), FRCP(Edin),
University of Pennsylvania FFICM
Philadelphia, Pennsylvania Professor of Intensive Care Medicine
1 – Implications of Perioperative Morbidity for Long-Term University College London
Outcomes Director
Bloomsbury Institute of Intensive Care Medicine
Jill S. Sage, MPH Chair, International Sepsis Forum;
American College of Surgeons NIHR Emeritus Senior Investigator
Chicago, Illinois London, United Kingdom
45 – Improving Health-Care Quality Through 38 – Sepsis and Septic Shock
Measurement
Pingping Song, MD
Yas Sanaiha, MD Division of Cardiothoracic Anesthesiology and Critical Care
General Surgery Resident Medicine
General Surgery Department of Anesthesiology and Pain Medicine
David Geffen School of Medicine at UCLA University of Washington
Los Angeles, California Seattle, Washington
6 – Cardiovascular Risk Assessment in Cardiac Surgery 31 – Cardiac Surgery
xii Contributors
Audrey E. Spelde, BA, MD
Critical Care Fellow
Anesthesiology and Critical Care
The University of Pennsylvania
Philadelphia, Pennsylvania
10 – Hematologic Risk Assessment
Mark Stafford-Smith, MD, CM, FRCPC, MBA, FASE
Professor
Department of Anesthesiology
Duke University Medical Center
Durham, North Carolina
17 – Preservation of Renal Function
Kirsten R. Steffner, MD
Clinical Assistant Professor
Department of Anesthesiology
Perioperative & Pain Medicine
Stanford University
Stanford, California
23 – Preservation of Spinal Cord Function
Toby B. Steinberg, MD
Adult Cardiothoracic Anesthesiology Fellow
Department of Anesthesia and Critical Care
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
43 – Role of Palliative Care
Dr. Charlotte Summers, BSc(Hons), BM, PhD, FRCP,
FFICM
University Lecturer in Intensive Care Medicine
Department of Medicine
University of Cambridge
Cambridge, United Kingdom
39 – Acute Respiratory Failure
Ramesh Swamiappan, MBBS
Anesthesiology Critical Care Medicine Fellow
Department of Anesthesiology and Critical Care
University of Pennsylvania
Philadelphia, Pennsylvania
9 – Pulmonary Risk Assessment
Annemarie Thompson, MD
Professor
Anesthesiology and Medicine
Duke University
Durham, North Carolina
12 – Prevention of Ischemic Injury in Noncardiac
Surgery
Rachel E. Thompson, MD, MPH, SFHM
Chief, Hospital Medicine
Medical Director
Clinical Care Transitions
University of Nebraska Medical Center
Lincoln, Nebraska
47 – Transitions from Hospital to Home
Thomas K. Varghese, Jr, MD, MS, FACS
Executive Medical Director & Chief Value Officer –
Huntsman Cancer Institute
Section Chief – General Thoracic Surgery
Program Director – Integrated Thoracic Surgery
Residency & CT Surgery Fellowship Programs
Professor (Tenure Track) of Surgery
University of Utah, Salt Lake City
32 – General Thoracic Surgery
Edward D. Verrier, MD
Merendino Professor of Cardiovascular Surgery
Surgery
University of Washington
Seattle, Washington
11 – Prevention of Ischemic Injury in Cardiac Surgery
Nathan H. Waldron, MD, MHSc
Assistant Professor
Department of Anesthesiology
Duke University School of Medicine
Durham, North Carolina
14 – Perioperative Management of Valvular Heart Disease
Sophie Louisa May Walker, MBBS, BSc
Clinical Research Fellow
William Harvey Research Centre
Queen Mary University of London
London, United Kingdom
2 – The Inflammatory Response to Surgery
Ian J. Welsby, BSc, MBBS
Professor
Anesthesiology and Critical Care
Duke University
Chapel Hill
North Carolina
26 – Prevention and Management of Deep Vein
Thrombosis and Pulmonary Embolism
 Acknowledgment

We wish to express our gratitude to the numerous people multiple steps in the process. We are also indebted to our
who helped in the development and production of our book. publisher and the Elsevier staff who helped in the production
First, the editorial assistants in our offices, Michael Hatfield, of this book.
Kate Musselman, and Cheri Hepfl, were invaluable in

xiii
PART IV

EARLY
POSTOPERATIVE
CARE
PART I

INTRODUCTION
AND BACKGROUND
PART V

CONFLICTING
OUTCOMES VALUE
BASED CARE
PART II

PREOPERATIVE
ASSESSMENT
PART III

PRESERVATION OF
ORGAN FUNCTION
AND PREVENTION
AND MANAGEMENT
OF PERIOPERATIVE
ORGAN
DYSFUNCTION
 1 Implications of Perioperative
Morbidity for Long-Term
Outcomes
KRISTEN C. ROCK, MARK F. NEWMAN, and LEE A. FLEISHER
The practices of anesthesiology, surgery, and critical care
are continuously improving. Through advances in each
field, a number of patients with increasingly severe comor-
bidities are undergoing riskier and more complex operations
and experiencing better outcomes. In recent years, intra-
operative mortality has decreased by a factor of 10.1 None-
theless, perioperative morbidity and mortality remain high.
If perioperative mortality were classified as a disease, it
would be the third leading cause of death in the United
States.2 Thirty-day postoperative mortality after noncardiac
surgery could be as high as 1% and 2% for inpatients in the
United States.3,4 Despite an enhanced ability to effectively
care for this growing high-risk group, these patients remain
at substantial risk for the development of perioperative
organ dysfunction—myocardial, pulmonary, neurologic,
and renal. The degree of dysfunction ranges from mild
(sometimes silent) and even undetected injury to profound
organ injury, coma, or death. The implications of the more
immediate and severe injury occurring in the perioperative
period have long been identified, but only recently has it
been noted that injury thought to be transient may have
long-term consequences. This realization is at the core of
this book. In this chapter, we focus on identifying perioper-
ative morbidity and touch on strategies to prevent or to treat
these complications, many of which will be described fur-
ther in subsequent chapters.
Cardiac Injury
Myocardial injury has long been a dreaded complication
during and after surgery. Each year, over 1 million people
having noncardiac surgery will experience a cardiovascular
complication.5 Although the number of patients with docu-
mented acute myocardial infarctions within 30 days of sur-
gery is significant, the number of patients who likely
experience silent and undetected myocardial injury during
and after surgery is sobering. This injury now has a name:
“MINS” (myocardial injury after noncardiac surgery). MINS
is defined as a peak troponin T of 0.03 ng/mL or greater
judged to be due to myocardial ischemia (i.e., no evidence
of a nonischemic etiology causing the troponin T elevation);
the definition does not require the presence of an ischemic
feature such as electrocardiogram changes or anginal symp-
toms. Due to the common absence of ischemic features, it is
estimated that more than 80% of MINS events will be missed
without routine monitoring of troponin levels after surgery.
2
However, the 30-day mortality increase for patients with
MINS suggests that this is an important perioperative event
with implications for changes in clinical management.6 The
VISION (Vascular Events in Noncardiac Surgery Patients
Cohort Evaluation) trial was a prospective international
study of more than 15,000 patients who received routine
troponin monitoring for 72 hours postoperatively. It demon-
strated that patients with peak troponin T concentrations
less than 0.01 ng/mL had a 1.0% mortality, whereas
patients with concentrations of 0.02 ng/mL, 0.03–0.29
ng/mL, or 0.30 ng/mL or greater had 30-day mortality rates
of 4.0%, 9.3%, or 16.9%, respectively.7 A composite of non-
fatal cardiac arrest, congestive heart failure, stroke, and
death occurred in 18.8% of the MINS cohort and only
2.4% of patients without MINS in the VISION study, an
eightfold increase.7 A similar study in a colorectal surgery
population echoed these results. In this study, mortality of
patients with troponin levels greater than 0.01 ng/mL
within the first 48 hours after surgery was 20%.8
Importantly, the mortality attributed to MINS is not
exclusively cardiac in nature. Nevertheless, recognition of
MINS by the perioperative physician is an opportunity to
improve outcomes. In the colorectal study, 17 of 40 patients
with elevated troponin levels went on to receive an ischemic
evaluation and were started on medical therapy, which may
have prevented worse outcomes.8 Research on whether
instituting medical therapy in MINS will reduce mortality
is ongoing.9
While recognizing and responding to myocardial injury
postoperatively is an important area to target to improve
patient outcomes, preventing myocardial injury in the first
place has been an area of intense study over the past two
decades. Large prospective clinical trials investigating the
ability of pharmaceutical interventions to reduce myocar-
dial injury, morbidity, and mortality were some of the first
trials with adequate power and long-term outcome assess-
ment to lead to an understanding of the implications of peri-
operative injury. The use of perioperative β-blockade to
reduce myocardial injury became popular two decades
ago. The POISE (Perioperative Ischemic Evaluation) trial
in 2008 challenged widespread use of β-blockers, showing
a reduction in ischemic events but an increase in bradycar-
dia, hypotension, strokes, and all-cause mortality for high-
risk patients not receiving a β-blocker prior to surgery.10
A 2014 systemic review of randomized controlled trials
(RCTs) investigating new institution of perioperative
β-blockage supported the POISE trial’s results, suggesting
 1 • Implications of Perioperative Morbidity for Long-Term Outcomes
that the reduction in nonfatal myocardial infarction was off-
set by increases in nonfatal strokes, bradycardia, and
hypotension.11 However, for patients with coronary or
peripheral arterial disease or more than two risk factors
for coronary disease who were maintained on a β-blocker
prior to surgery, perioperative withdrawal of β-blockage
was associated with increased 30-day and 1-year mortal-
ity.12 A Department of Veterans Affairs (VA) study of
angiotensin-converting enzyme (ACE) inhibitors showed
that resumption of the drug within 2 weeks of surgery
was associated with decreased 1-month mortality.13 The
INPRESS (Intraoperative Norepinephrine to Control Arterial
Pressure) study was a multicenter RCT which concluded
that an individualized approach to blood pressure manage-
ment which kept systolic blood pressures within 10% of
baseline blood pressure, as compared with a standard man-
agement strategy, reduced the incidence of postoperative
organ dysfunction by 40% in high-risk surgical patients.14
The good news is that from 2004 to 2013, major adverse
cardiac events decreased from 3.1% to 2.6%, mortality
decreased from 2.0% to 1.3%, and the rate of acute myocar-
dial infarction decreased from 1.0% to 0.8%.15 Regardless of
whether we can distinguish association from causality, we
can, from a prediction standpoint, identify the individuals
who are at greater risk and identify strategies to reduce
the probability of later morbidity and mortality and improve
outcomes for high-risk patients.
Pulmonary Injury
Perhaps the most common perioperative complications, and
possibly the most preventable, are perioperative pulmonary
complications (PPCs), which include respiratory infection,
respiratory failure, pleural effusion, atelectasis, pneumotho-
rax, bronchospasm, aspiration pneumonitis, pulmonary
embolus, and acute respiratory distress syndrome. Though
the incidence of these complications varies widely by study,
the 30-day mortality rate for patients who have one of these
complications is between 14% and 30%.16 A 2017 study
published in JAMA Surgery of 1200 American Society of
Anesthesiologists physical status 3 patients suggested a
PPC rate of 33.4%, with a significant proportion of these
complications being prolonged need for oxygen therapy
and atelectasis. However, any PPC increased early postoper-
ative mortality, intensive care unit (ICU) admission, and ICU
and hospital length of stay.17 The Closed Claims Project
identified 92 claims in which respiratory depression caused
significant harm and concluded that 97% of these events
were preventable.18
Focusing on strategies to optimize nonmodifiable risk fac-
tors and minimize modifiable risk factors can reduce these
numbers. Smoking cessation before major surgery can
reduce postoperative morbidity.19 One study published in
JAMA Surgery suggested that limiting colloid administra-
tion, reducing blood loss and anesthetic duration, and
low-tidal volume ventilation might all reduce the incidence
of PPC.20 A study of 69,235 patients comparing protective
ventilation of less than 10 mL/kg with plateau pressures less
than 30 cm H2O and positive end-expiratory pressure
(PEEP) greater than 5 cm H2O versus nonprotective venti-
lation showed a decrease in a composite of major respiratory
3
complications (adjusted odds ratio, 0.90; 95% confidence
interval [CI], 0.82 to 0.98; P¼ 0.013). A meta-analysis of
15 RCTs of over 2000 general surgery patients showed that
a low-tidal volume ventilation strategy (<8 mL/kg ideal
body weight) reduced PPCs by an adjusted relative risk of
0.64.21 Although less compelling, there is some evidence
suggesting that moderate PEEP of 6–8 cm H2O combined
with low tidal volumes also reduced PPC.22 Inadequate
reversal of neuromuscular blockade is the most common
reason for respiratory failure in the postoperative care unit.
A retrospective observational study of 11,355 patients at
VA hospitals showed an odds ratio of 1.75 for PPC in
patients who did not receive neostigmine reversal as com-
pared with patients who did.23 The POPULAR (Post-
Operative Pulmonary Complications After Use of Muscle
Relaxants in Europe) study was a prospective observational
study of 22,803 patients which suggested that patients
receiving a neuromuscular blocking agent had a 4.4% rel-
ative risk of PPCs as compared with patients receiving gen-
eral anesthesia without neuromuscular blockade. This
increased risk was independent of the use of reversal
agents.24
Patients at high risk for postoperative extubation failure
may be managed successfully with noninvasive ventilation
strategies. A 2009 RCT in 500 cardiac surgery patients
showed that continuous positive airway pressure (CPAP)
of 10 cm H2O for 6 hours after extubation reduced PPCs.25
Multiple studies have found that use of a high-flow nasal
cannula was noninferior to CPAP or bilevel positive airway
pressure for preventing reintubation and respiratory
failure.26,27
Up to 24%–41% of patients presenting for surgery have
obstructive sleep apnea (OSA),28 and many of them are
undiagnosed. These patients are at increased risk of desa-
turation events and respiratory arrest around the time of
surgery. A retrospective case–controlled study of OSA
patients undergoing orthopedic procedures demonstrated
longer hospital stays and 2.5 times the number of postoper-
ative complications for OSA patients (24% vs 9% for control
subjects).29 Those patients who experienced respiratory and
cardiovascular complications had 28-day mortality rates of
26.1% and 17.7%, respectively.30 Improving outcomes for
these patients could be as simple as providing end-tidal car-
bon dioxide monitoring or continuous pulse oximetry for
24 hours after surgery. A meta-analysis of capnography
monitoring reported that it recognized six times more respi-
ratory events than pulse oximetry.31 Perioperative monitor-
ing is recommended until these patients are no longer at risk
for respiratory depression,32 though monitoring has never
been proven to improve outcomes in a clinical trial. The
use of multimodal analgesia and postoperative CPAP also
reduced the risk of apneic events and overall complication
rates.33–35
Neurologic Injury
Perioperative neurologic injury ranges from acute stroke to
a spectrum of neurocognitive disorders (Table 1.1). Stroke is
a leading cause of severe disability today, and perioperative
strokes (estimated to be 15%–20% of all strokes) remain sig-
nificant contributors.36,37 The rate of perioperative stroke in
4 PART I • Introduction and Background

Table 1.1 Summary of Perioperative Cognitive Disorder Nomenclature.

Time period TERM AND DEFINITION Comments
preoperative as in community
Mild NCD Major NCD
Perioperative cognitive disorders

Emergence form Emergence excitation

anaesthesia or delirium
From: Immediately Delirium (postoperative†) Delayed neurocognitive Delayed neurocognitive The time for expected resolution
postoperative OR recovery‡ recovery‡ is based on perioperative conditions,
Until: Expected recovery Delayed neurocognitive e.g., complications/infection/
(to 30 days)∗ recovery prolonged hospitalization
From: Expected recovery Mild NCD Major NCD POCD is an indicator of the temporal
(30 days) postoperative (POCD) postoperative (POCD) associated with the anaesthesia/
Until: 12months surgery/event
Beyond 12 months Mild NCD Major NCD As in community if a new diagnosis
after this time
∗
i.e., the time point from at least 30 days when the effects of anaesthesia and surgery should have resolved. †The postoperative specifier will be applied where
delirium is persistent beyond hospital discharge. ‡Also applies to assessments prior to medical readiness for discharge although it should be noted any decline
prior to readiness for dischrage is unlikely to represent a delay in recovery.
NCD, neurocognitive disorders. POCD, Postoperative neurocognitive disorders.
From Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery 2018. Anesthesiology. 2018;129(5):872-879.
https://doi.org/10.1097/ALN.0000000000002334. ©2020 American Society of Anesthesiologists.

noncardiac surgery has increased from 0.5% to 0.8%, pos-
sibly related to the use of β-blockers.38 However, periopera-
tive neurocognitive dysfunction is increasingly recognized
as a serious, common clinical entity, and its characterization
and prevention are the focus of major research and clinical
initiatives.
Few would question the significance of perioperative
stroke, but perioperative neurocognitive dysfunction has
been thought of historically as a transient process without
substantial long-term implications. However, it is now
known that the incidence of postoperative delirium is signif-
icant and that delirium and delayed neurocognitive recovery
(if mental status remains altered up to 30 days) can lead to
long-lasting cognitive deficits and increased mortality. While
statistics vary widely, the Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition, states that delirium occurs
in 15%–53% of elderly patients and 70%–87% of ICU
patients.39 A 2018 study noted that those patients with
the most severe delirium had three times the rate of cognitive
decline in the 3 years following their surgery.40 Patients with
preexisting cognitive impairment have a synergistically
elevated risk of developing new and worsening cognitive
deficits.41 Regardless of whether the defined association
indicates that more severe perioperative injury causes
greater long-term morbidity and mortality or whether
these individuals were at higher risk for later decline because
the numbers of elderly patients and patients with cognitive
impairment who present for surgery are increasing, this prob-
lem should be a major focus in improving perioperative care.
In 2015, the American Society of Anesthesiologists pro-
posed the Brain Health Initiative as a multidisciplinary
group to “create a low barrier access program to minimize
the impact of pre-existing cognitive deficits, and optimize the
cognitive recovery and perioperative experience for adults
65 years and older undergoing surgery.”42 The initiative
highlights many ways in which care can be improved.
The American Geriatrics Society’s (AGS) Beers criteria list
medications that have an unfavorable risk profile for elderly
patients, many of which can be used during surgery.43 This
list includes avoidance of benzodiazepines, diphenhydra-
mine, and anticholinergics; sparing use of antipsychotics;
and preferential use of dexmedetomidine. Although the
evidence is inconclusive,44 best practice guidelines from
the American College of Surgeons, AGS, and National Sur-
gical Quality Improvement Program suggest preferential
use of regional and neuraxial anesthesia over general anes-
thesia.45 The use of multimodal analgesia and opioid-
sparing techniques, early mobilization and avoidance of
pressure ulcers, aggressive pulmonary hygiene, judicious
use of fluids, and meticulous management of indicated car-
diac medications are other best practice suggestions
(Table 1.2).45 There has been intense interest in the use
of processed electroencephalogram (EEG) monitoring as a
way to reduce anesthetic dosages and delirium. Evidence
is mixed. The 2012 CODA (Cognitive Dysfunction after
Anesthesia) trial was an RCT of bispectral index (BIS)-guided
anesthetic delivery versus usual care for elderly patients,
which concluded that there was a significant reduction in
delirium and postoperative cognitive dysfunction in the
intervention arm. Low intraoperative BIS values, deep anes-
thesia for long periods, and large doses of anesthetic were
predictors of postoperative cognitive dysfunction.46 How-
ever, the results of the ENGAGES (Electroencephalography
Guidance of Anesthesia) trial refute this. This trial was an
RCT of 1232 elderly patients that also looked at processed
EEG-guided management versus usual care and did not find
a reduction in delirium, despite a reduced dose of anesthetic
in the EEG group.47
 1 • Implications of Perioperative Morbidity for Long-Term Outcomes 5

Table 1.2 Immediate preoperative and intraoperative man- Renal Injury

agement consensus recommendations for geriatric patients.
IMMEDIATE PREOPERATIVE MANAGEMENT
▪ Confirm and document patient goals and treatment preferences,
including advance directives.
▪ Confirm and document patient’s health-care proxy or surrogate
decision-maker.
▪ In patients with existing advance directives, discuss new risks
associated with the surgical procedure and an approach for
potentially life-threatening problems consistent with the patient’s
values and preferences (“required reconsideration”).
▪ Consider shortened fluid fast (clear liquids up to 2 hours before
anesthesia).
▪ Adhere to existing best practices regarding antibiotic and venous
thromboembolism prophylaxis.
▪ Ensure nonessential medications have been stopped and essential
medications have been taken.
INTRAOPERATIVE MANAGEMENT
Consideration of regional techniques to avoid postoperative
▪
complications and improve pain control
▪ Directed pain history
▪ Multimodal or opioid-sparing techniques
▪ Postoperative nausea risk stratification and prevention strategies
▪ Strategies to avoid pressure ulcers and nerve damage
▪ Prevention of postoperative pulmonary complications and
hypothermia
▪ Judicious use of intravenous fluids
▪ Appropriate hemodynamic management
▪ Continuation of indicated cardiac medications
With permission from Mohanty S, Rosenthal RA, Russell MM, et al. Optimal
perioperative management of the geriatric patient: a best practices
guideline from the American College of Surgeons NSQIP and the American
Geriatrics Society. J Am Coll Surg. 2016;222:930–947.
Renal injury is a common but often underappreciated peri-
operative complication. From 30% to 40% of documented
acute kidney injuries (AKIs) occur in surgical patients.48
Though chronic kidney disease (CKD) has long been recog-
nized as a risk factor for AKI, AKI has only recently been
appreciated as a risk factor for CKD, with 10%–20% of
patients with AKI eventually progressing to end-stage renal
disease.49,50 In one study of abdominal surgery patients,
those who developed AKI had eight times the mortality risk
as compared with patients with normal renal function.51
Increased mortality rates persist even after renal function
normalizes. In a large retrospective cohort study of over
10,000 patients tracked over a period of 14 years, there
was a direct correlation between survival and severity of
acute kidney injury as defined by the RIFLE criteria
(Fig. 1.1). Even those patients who achieved complete renal
recovery had an adjusted hazard ratio for death of 1.20
(95% CI 1.10-1.31, P < 0.001).52
Perhaps a reason that renal injury was not a focus of peri-
operative care historically was that the prevention and
treatment options were limited. Many risk factors are non-
modifiable. Cardiac, transplant, vascular, large abdominal,
and bariatric surgery have long been recognized to carry
high risk of AKI. Patient factors of obesity, chronic obstruc-
tive pulmonary disease, smoking, metabolic syndrome, car-
diovascular disease, cancer, and hepatobiliary disease are
perhaps even more important than the type of surgical pro-
cedure in risk profiling for AKI.53 However, meticulous
intra- and postoperative management can mitigate these
risks. The type of fluid used is important, with increasing

100
Log-rank p-value < 0.001

90 Trend test p-value < 0.001

80
No AKI
70
Survival (%)

Complete recovery (CR)

60

50

40 Partial recovery (PR)

30
No recovery (NR)
20
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years after Hospital Discharge
Follow Up (years) T=0 T=2 T=4 T=6 T=8 T=10 T=12 T=14

No AKI 7192 6246 5800 4468 3188 2007 955 106

CR 1862 1576 1330 937 606 343 149 18
At risk
(n) PR 1364 1061 886 655 458 281 122 11
NR 98 47 32 17 10 3 2 0

Fig. 1.1 Long-term creatinine clearance values in heart transplant recipients. From Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute
kidney injury during hospitalization after major surgery. Ann Surg. 2009;249(5):851-858. https://doi.org/10.1097/SLA.0b013e3181a40a0b.
6 PART I • Introduction and Background
evidence showing that balanced salt solutions are superior
to normal saline. A 2018 RCT of 15,802 patients random-
ized critically ill patients to saline or balanced crystalloid
administration and showed a reduction in the incidence
of major adverse kidney events, the need for new renal
replacement therapy, and the incidence of persistent renal
dysfunction.1 A retrospective cohort study of patients
undergoing major elective or emergent abdominal surgery
compared those who received either normal saline or Plas-
malyte exclusively as the intraoperative resuscitation fluid.
Reductions in morbidity included postoperative wound
infections, renal failure requiring replacement therapy,
blood transfusions, and electrolyte derangements.54
Starch-containing solutions increase renal injury. The 6S
(Scandinavian Starch for Severe Sepsis/Septic Shock Trial)
trial group conducted a multicenter, modified intention-
to-treat RCT, randomizing roughly 800 patients with severe
sepsis to receive either Tetraspan (6% HES 130/0.42, a
third-generation hydroxyethyl starch [HES]; B. Braun) or
Ringer’s acetate. Patients receiving Tetraspan had an
increased relative risk of death at 90 days and an increased
risk of AKI requiring renal replacement therapy (relative
risk, 1.35; 95% CI, 1.01–1.80; P ¼ 0.04).55 Similar studies
have prompted the US Food and Drug Administration to
issue a black box warning for starch-containing fluids.
Goal-directed fluid therapy as a way to reduce renal
injury has gained footing with the widespread adoption
of enhanced recovery after surgery (ERAS) protocols. Altho-
ugh the exact measurements by which to direct fluid re-
suscitation remain controversial, this is an area of intense
study. Titrating volume resuscitation to intraoperative
urine output does not reduce renal injury.56 At the very
least, avoidance of hypotension is import for renal out-
comes. In a retrospective cohort study of 5100 patients,
the authors showed incremental increases in AKI with
mean arterial pressure (MAP) less than 60 and 55 mmHg
as compared with MAP greater than 65 mmHg. This risk
increased with the duration of hypotension, with risk start-
ing with periods of as little as 10 minutes.57 Avoidance of
nephrotoxic drugs, including contrast, diuretics, angioten-
sin receptor blockers, ACE inhibitors, nonsteroidal anti-
inflammatory drugs, and aminoglycosides, also reduce the
risk of AKI.58
Association Versus Causality
In each of the organ systems discussed, perioperative organ
injury is associated with a greater probability of long-term
morbidity or mortality even if there is intervening recovery
of function. It would be simplest if we could confirm that
perioperative injury causes the morbidity and mortality that
we see in our patients, but it would be difficult to justify this
assertion on the basis of the statistical associations outlined.
The difficulty that we face in recognizing individuals who
have perioperative injury, many of whom recover acutely,
is that this group very likely had significant pathology even
before the procedure. Thus, severity of disease is the com-
mon thread, and the perioperative period is a stressor pre-
dicting a higher probability of long-term morbidity and
mortality. As we look for an association, we need to identify
what part of the increased morbidity and mortality after the
operation is the result of the patient’s own characteristics
and other ongoing risk factors and what part is related to
further injury resulting from perioperative management
decisions.59 Large-scale longitudinal trials in high-risk
patients are needed to illustrate how patient and procedure
interact to define the probability of perioperative organ dys-
function and associated development of morbidity and mor-
tality. For those characteristics that are fixed, these studies
would enrich perioperative decision making. For those char-
acteristics that are modifiable, we can continue to develop
perioperative strategies to improve outcomes. Despite the
difficulty in defining the differences between association
and causality for long-term decline, we must understand
risk of injury if we hope to prevent it.
Conclusion
It has been said that surgery is the ultimate physiologic
stress test. The association between perioperative injury
and long-term outcome has important implications for the
perioperative physician. First, if we identify the incidence
and significance of this injury, we can focus on opportunities
and strategies (as outlined in this book) to reduce that
injury. Second, if we are able to identify the individuals with
injuries who are at greater risk, we may be able to intervene
to reduce the probability that perioperative events will pro-
duce morbidity and mortality and improve the quantity and
quality of life of our patients. Thus, we turn the focus of this
book toward a strategy of perioperative medicine and opti-
mizing outcomes.
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surgery: results from a national data set. Anesthesiology. 2009;110:
505–515.
52. Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and
acute kidney injury during hospitalization after major surgery. Ann
Surg. 2009;249:851–858.
53. Goren O, Matot I. Perioperative acute kidney injury. Br J Anaesth.
2015;115(2):ii3–ii14.
8 PART I • Introduction and Background
54. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications,
mortality, and resource utilization after open abdominal surgery:
0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255(5):
821–829.
55. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/
0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med.
2012;367(2):124–134.
56. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology.
2010;113:470–481.
57. Sun LY, Wijeysundera DN, Tait GA, et al. Association of intraoperative
hypotension with acute kidney injury after elective noncardiac sur-
gery. Anesthesiology. 2015;123:515–523.
58. Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin
converting enzyme inhibitors, and angiotensin receptor blockers with
non-steroidal anti-inflammatory drugs and risk of acute kidney injury:
nested case-control study. BMJ. 2013;346:e852.
59. Mark DB, Newman MF. Protecting the brain in coronary artery bypass
graft surgery. JAMA. 2002;287:1448–1450.
 2 The Inflammatory Response
to Surgery
GARETH L. ACKLAND, SOPHIE LOUISA MAY WALKER, and TIMOTHY F. JONES
Introduction
Tissue damage after surgery triggers a complex inflamma-
tory response termed sterile inflammation characterized by
the release of intracellular molecules into the extracellular
environment leading to receptor-mediated immune signal-
ing cascades. A key feature of this inflammatory response
involves removing necrotic cells and launching a program
of tissue repair. Patients may not only respond differently
to a similar sterile insult because of genetic differences,
but also as a consequence of preexisting disease that can
substantially modify the inflammatory phenotype. The pres-
ence of comorbid diseases frequently fuels an established
dysregulated inflammatory response, which contributes to
organ injury and immunosuppression. Postoperative com-
plications, including (subclinical) organ dysfunction and
infection, increase morbidity and mortality following sur-
gery, even after discharge from hospital. Immune alter-
ations are not only the result of direct tissue injury but
are also influenced by perioperative medications and inter-
ventions. This chapter will discuss the broad current under-
standing of the immune response to tissue damage, the
interaction of this response with comorbid diseases, and
clinical factors that influence perioperative inflammation.
DEFINING ACUTE SYSTEMIC INFLAMMATION
AFTER SURGERY
Although the acute systemic inflammatory response is
widely referred to, defining it objectively in the modern peri-
operative era is rather elusive. Consensus definitions are
lacking, in contrast to sepsis.1 First described by Sir David
Cuthbertson, the classic textbook response entails a biphasic
immune, inflammatory, and metabolic response to
injury.2,3 The first ebb phase, as coined by Cuthbertson,
involves peripheral vasoconstriction, concomitant hypo-
thermia, and shunting of blood and substrates to vital
organs. A transition then occurs (termed flow by Cuthbert-
son), with a hypermetabolic phase ensuing. In the modern
perioperative setting, these classic characteristics are rather
less distinct for several reasons. First, many of the cardiome-
tabolic features following trauma/surgery have been
derived from critical illness, chiefly because these measure-
ments are more attainable in this patient population.
Despite significant morbidity in noncritically ill surgical
patients, it is not clear as to whether this classic temporal
pattern occurs in other patients—particularly in the mod-
ern era of multimorbidity, anesthesia, and surgery. Second,
various clinical measures are nonspecific (e.g., heart rate,
temperature), and are frequently unhelpful in convincingly
differentiating between the systemic inflammatory response
syndrome and alternative pathophysiologic/nonpathologic
etiologies. Third, the interaction between common (treated)
chronic comorbidity and acute systemic inflammation is
poorly defined. Fourth, the nonspecificity of various com-
monly used inflammatory biomarkers cannot distinguish
easily between sterile inflammation and alternative triggers
of the inflammatory response. Table 2.1 summarizes com-
mon clinically used physiologic and biochemical markers
for systemic inflammation after surgery.
Where It All Starts: Cellular Origins of Surgical
Inflammation
The activation of the host response to sterile inflammation
is, unsurprisingly, triggered directly by cellular injury as a
result of surgery. Surgical tissue injury shares many similar-
ities with the immune response to infectious pathogens.
Upon tissue injury, loss of plasma membrane integrity and
cell death (necrosis) leads to the release of danger-associated
molecular patterns (DAMPs) into the extracellular environ-
ment (Fig. 2.1). Pattern recognition receptors (PRRs),
including highly conserved Toll-like receptors (TLRs), are
expressed on a wide range of immune and nonimmune (epi-
thelial, endothelial and fibroblasts) cells. PRRs recognize
both pathogen-associated molecular patterns (PAMPs)
and DAMPs (also known as alarmins) following tissue
injury.10 Thus host innate immune surveillance monitors
endogenous (self) markers of tissue damage as well as non-
self antigens, such as bacterial infection—a process known
as the “danger hypothesis.”11 Receptors and downstream
signaling pathways common to both sterile and pathogenic
stimuli, such as nuclear factor-ĸβ and mitogen-activated
protein kinase, lead to similar patterns of cytokine release
and cellular activation.12 A diverse array of stimuli synon-
ymous with surgical tissue trauma activate the ubiquitous
NLRP3 inflammasome, including multiple microbial prod-
ucts, endogenous molecules, and particulate matter.13
The biochemical function of inflammasomes is to activate
caspase-1, which leads to the maturation and release of
interleukin 1β (IL-1β) and IL-18, and induction of pyroptosis
(a form of cell death) fueling the release of other inflamma-
tory mediators.14 Human monocytes (unlike tissue resident
macrophages) can release mature IL-1β in response to
TLR ligands alone, but most microbial stimuli appear to
prime the NLRP3 inflammasome for activation.14 Clinically,
sterile and pathogenic inflammatory responses are fre-
quently indistinguishable.15 DAMPs implicated in generat-
ing inflammation and organ dysfunction after surgery
9
10 PART I • Introduction and Background

Table 2.1 Clinical and biochemical measures of systemic inflammation after surgery.
Type Marker Description Associations References
Clinical Systemic SIRS diagnosed if 2 + criteria are met without Length of duration of SIRS associated with Haga et al.4
inflammatory evidence of an infectious source: increased mortality and complication rate after Shepherd
response gastrointestinal and vascular surgery and trauma. et al.5
syndrome (SIRS) Temperature <36°C (96.8°F) or >38°C
(100.4°F);
Heart rate > 90 min 1;
Respiratory rate > 20 min 1 or PaCO2 < 4.3
kPa;
White cell count < 4  109 L 1 or > 12 
109 L 1 or >10% immature
neutrophilic bands.
Sequential Combined total of scores (0-4) in each of six Increasing score associated with increased Bota et al.6
Organ Failure organ systems (nervous, respiratory, mortality after elective gastrointestinal and cardiac
Assessment cardiovascular, hepatic, renal, and surgery.
(SOFA) coagulation).
Biochemical Neutrophil- The ratio of neutrophils to lymphocytes in Increased ratio associated with adverse events in Malietzis
lymphocyte blood. cardiac, vascular, gastrointestinal, and orthopedic et al.7
ratio (NLR) surgery.
C-reactive Acute phase protein synthesized in the liver Increased levels correlated with the degree of Rettig
protein and produced largely in response to tissue trauma caused by orthopedic surgery and et al.8
interleukin-6. with anastomotic leak rate after upper
gastrointestinal resection.
Albumin Family of abundant globular proteins Hypoalbuminemia associated with increased rates Neumayer
representing the majority of protein present of wound infection, need for further surgery, and et al.9
in plasma. respiratory complications.

Key references pertaining to the perioperative/trauma population are cited.

(Table 2.2) include mitochondrial DNA, which activate
innate inflammation via TRLs.15,16
PAMPS MAY ALSO CONTRIBUTE TO SYSTEMIC
INFLAMMATION AFTER SURGERY
TLRs were first characterized for their recognition of PAMPs
derived from microbial organisms. Gut microbes may also
contribute to systemic inflammation following surgery, par-
ticularly when hypoperfusion of the gastrointestinal tract
occurs as a result of hypovolemia.21 Breakdown of the epi-
thelial mucosa may promote the release of enterically
derived bacterial endotoxin—termed bacterial transloca-
tion.22 Gram-negative bacteria also activate the NLRP3
inflammasome through the transport of lipopolysaccharide
into the cell, which activates caspase-11 and release of IL-
1β. In patients, endogenous antibodies to endotoxin appear
to be associated with protection from endotoxin-mediated
toxicity.23 Bacterial infection is also an early risk, as features
of immunosuppression appear rapidly within hours of sur-
gery. The cellular features of the immunosuppressive
response include a rapid decrease in monocyte human leu-
cocyte antigen-DR (HLA-DR) expression24 and an expan-
sion of myeloid-derived suppressor-like cells that impair
adaptive immune responses.25 Both of these features persist
for several days and are associated with postoperative infec-
tion and delayed recovery. The underlying mechanism is
likely to be multifactorial but may be partially attributed
to high levels of circulating catecholamines.26
Systemic Processes Triggered by DAMPs/PAMPs
The onset of inflammation heralds a chain of events that in
many patients results in organ dysfunction, much of which
is subclinical. Typically, different morbidities cluster, as
reflected by various clinical measures of subclinical organ
dysfunction.27 For example, many clinicians would over-
look a decline in serum albumin that occurs after the vast
majority of surgery types, yet there are compelling adverse
clinical outcomes linked to this phenomenon that are driven
by pivotal inflammatory mechanisms, including endothelial
damage. The release of DAMPs triggers a stereotypical
response characterized by a dramatic change in circulating
blood leukocyte subsets, following the peripheral redistribu-
tion of white blood cells to sites of injury and/or lymph
nodes. For example, a striking feature of this early phase
is a typical doubling of the number of neutrophils in the
blood.28 This process is driven, in part, by autonomic and
neuroendocrine activation. Given the changing landscape
of modern surgery, both in terms of surgical techniques
and increasingly physiologically challenging patients with
multiple comorbidities, the classic stress/inflammatory
response, as discussed before, is likely to be a gross oversim-
plification of the broad (rather classic) descriptions that
follow.
Autonomic Changes
Profound changes in autonomic function accompany sur-
gery, even in the absence of shock. In part, this is triggered
 2 • The Inflammatory Response to Surgery 11

Surgery Trauma

Tissue injury

DAMPs
Endotoxin
HMGB1 mtDNA Histones ATP Uric acid

PRRs

TLRs Inflammasomes

Cytokine release

Autonomic dysfunction Anesthesia Neuroendocrine changes

Analgesia
Sympathetic > Parasympathetic - Catecholamines Ç
- Cortisol Ç
- Vasopressin Ç

Exogenous steroid Blood transfusion

Celluar effects Physiologic effects

Lymphocyte contraction Myeloid expansion Muscle mass È Total protein È Water retention È
ROS production Antigen presentation È

Organ dysfunction

Fig. 2.1 An overview of the molecular, cellular, and physiologic responses to tissue injury leading to organ dysfunction. Both surgery and trauma are
characterized by tissue damage that disrupts cellular integrity and releases intracellular contents into the extracellular space. The release of certain
intracellular components (DAMPs) can be detected by the host via pattern recognition receptors. The ligation of PRRs results in cytokine release as the
body attempts to amplify danger signals that initiate protection and repair mechanisms. Cytokine production has direct cellular effects but also on the
endocrine and autonomic nervous systems. Cytokine production is further promoted iatrogenically through the administration of common periop-
erative medications and blood transfusion. ATP, Adenosine triphosphate; DAMP, damage-associated molecular pattern; HMGB1, high mobility group
box 1 protein; mtDNA, mitochondrial deoxyribonucleic acid; PRR, pattern recognition receptor; ROS, reactive oxygen species; TLR, Toll-like receptor.

Table 2.2 Damage-associated molecular patterns with potential roles in organ dysfunction after surgery.
Molecule Physiologic function Location Receptor Reference
HMGB1 Chromatin regulation Nucleus of immune cells TLR4 Andersson et al.17
Histones Nucleosome structure Nucleus TLR2/4/9 and NLRP3 Silk et al.18
Mitochondrial DNA Mitochondrial genome Mitochondria TLR9 / NLRP3 Zhang et al.15
ATP Cellular energy source Mitochondria P2RX7 / NLRP3 Gombault et al.19
Uric acid Byproduct of purine metabolism Cytoplasm NLRP3 Hughes and O’Neill20

ATP, Adenosine triphosphate; HMGB1, high-mobility group box 1 protein; NLRP3, NACHT, LRR and PYD domains containing protein 3 inflammasome; P2RX7, P2X
purinoreceptor 7; TLR, Toll-like receptor.
12 PART I • Introduction and Background
by inflammatory mediators that are sensed by afferent
nerves hardwired to detect inflammatory mediators.29 In
concert with this, the inevitable hemodynamic changes that
follow both general and regional anesthesia challenge the
arterial baroreflex mechanism, which buffers acute fluctua-
tions in blood pressure.30 In health, small increases in blood
pressure result in increased parasympathetic activity that,
via the vagus nerve, slows the heart. Conversely, falls in
arterial blood pressure lead to central neural activation of
the sympathetic nervous system and consequent catechol-
amine release (epinephrine and norepinephrine). However,
reduced baroreceptor sensitivity is common (e.g., in patients
with chronic hypertension) and associated with excess mor-
bidity.31 Stereotypical autonomic features of surgery are
activation of the sympathetic, yet relative loss of parasym-
pathetic, neural activity.32 Heightened sympathetic activity
leads to increased release of catecholamines that spill over
into the circulation.33,34 Concomitantly, the neuroendo-
crine release of vasopressin and angiotensin, among other
neurohormones beyond the scope of this short introduction,
occurs to counteract relative, redistributive hypovolemia.
Inflammatory mediators may also directly trigger neuroen-
docrine activation, acting via areas of the brain devoid of the
blood barrier.35 Preexisting autonomic dysfunction is
common in many patients prior to surgery and likely to
exacerbate the early features of the inflammatory response
through both cardiovascular and noncardiovascular
mechanisms.36
Neuroendocrine Response
Shortly after tissue trauma/surgery, increased production
and secretion of catecholamines, antidiuretic hormone
(vasopressin), cortisol, insulin, glucagon, and growth hor-
mone occur, leading to a catabolic, relatively hypermeta-
bolic, inflammatory state.37 The interplay between these
neurohormones is complex, with many directly modulating
the inflammatory response.38 For example, cortisol increases
blood glucose levels through antagonizing the actions of
insulin, while dampening immune responses. Hyperglyce-
mia is common in the postoperative setting in both diabetics
and nondiabetics, as a result of catecholamine-, cortisol-,
glucagon-, and cytokine-induced antagonism of peripheral
insulin activity and impaired peripheral glucose uptake.38
During acute stress, the rate of hepatic cortisol extraction
from the blood is decreased and the plasma half-life of cortisol
is increased.38a Additionally, cortisol-binding globulin con-
centration and binding affinity for cortisol are decreased,
resulting in increased free and biologically active cortisol
concentrations, prolonged elevations of which may be dele-
terious through promotion of immunosuppression.37
The metabolic response is characterized by the mobiliza-
tion of hepatic glycogen stores (glycogenolysis), together
with gluconeogenesis fueled by the liver and, to varying
degrees, skeletal and visceral muscle breakdown, plus lipol-
ysis and mobilization of free fatty acids.38 Modern studies of
the classic “hypermetabolic” responses are lacking, so some
caution is required regarding whether this is typical of
patients with comorbidities characterized by established
metabolic derangement. However, after major tissue
trauma, total body protein and skeletal muscle mass cer-
tainly appear to decline, in concert with weight gain chiefly
attributable to the accumulation of water. The extent to
which the latter is due to iatrogenic reasons is considered
elsewhere in this book.
Host Influences on Perioperative Inflammatory
Response
Multiple host factors are likely to influence the inflamma-
tory response after surgery that may, in part, explain the
heterogenous outcomes observed after noncardiac surgery
and the recognition that preoperative factors may be more
influential in shaping longer-term outcomes.39,40 However,
broadly similar pathologic mechanisms are shared between
apparently disparate comorbidities, largely because of com-
mon cellular pathways mediating much of the inflamma-
tory response driven by tissue trauma. Nevertheless, it is
worth bearing in mind that many common comorbidities
have not been systematically examined in the perioperative
setting. Here, we have focused on the commonest endotypes
associated with higher rates of perioperative organ dysfunc-
tion and framed this association by focusing on their conver-
gent, dysregulated inflammatory features (Fig. 2.2).
AGE
As a consequence of the aging population, the number of
elderly patients undergoing major surgery is increasing year
on year. Increased age and/or frailty are consistently asso-
ciated with higher risk of postoperative morbidity and mor-
tality.41 The cause of this increased postoperative risk is
likely multifactorial, but age-associated dysregulation of
the inflammatory response appears to be a significant con-
tributor. “Inflamm-aging” is an core component of the
aging process, and describes a persistent proinflammatory
state that coexists with the inability to mount an efficient
innate and adaptive immune response.42 Identified mecha-
nisms that contribute to inflamm-aging include altered
immune cell number and function, changes in pattern rec-
ognition receptor expression, and activation by endogenous
mediators that lead to chronic low-grade systemic inflam-
mation.43 Older individuals often exhibit higher levels of
non–cell-associated DNA, released from senescent and
necrotic cells into the circulation that in turn may activate
the NLRP3 inflammasome.43 These DAMPs stimulate an
innate immune response, contributing to increased baseline
inflammation seen in older patients. Consequently, older
adults have higher basal levels of proinflammatory cyto-
kines such as IL-6, as well as clotting factors and acute
phase reactants. Several human studies have found an asso-
ciation between increased levels of these proinflammatory
cytokines and long-term mortality and morbidity.44 Levels
of TNF and IL-6 produced in response to TLR1/TLR2 stim-
ulation, however, are reduced from monocytes of older
adults.45 The propensity with age to sustain more infectious
complications, in part, is further attributable to impaired
neutrophil chemotaxis and phagocytosis of pathogens.46
CHRONIC KIDNEY DISEASE
Chronic kidney disease (estimated glomerular filtration rate
[eGFR] <60 mL/min per 1.73 m2) is present in 15% of
surgical patients and independently associated with higher
rates of perioperative morbidity and mortality.47 In addition,
 2 • The Inflammatory Response to Surgery 13

CKD
Aging Type 2
Renal clearance
Cellular senescence Diabetes
Uremic toxins
±necrosis CRP
Non–cell- Hyperglycemia
associated DNA ROS production
Obesity
Clotting factors Circulating dietary
free fatty acids
Acute phase reactants

DAMPs

NLRP3 Inflammasome Activation

Type 2
Diabetes
Aging
Hyperglycemia
Circulating Hypercytokinemia
androgens
 TNF-␣  IL-1␤
 IL-6
CKD
Fig. 2.2 The contribution of comorbidity to Renal clearance
inflammation and impaired immune function.
Common comorbidities in the surgical patient
are increased age, chronic kidney disease, and Myeloid cells
diabetes mellitus. All three conditions are Impaired:
characterized by the release of DAMPs, cyto- Chemotaxis
kine release, and the consequent activation of Phagocytosis
inflammation. The effect of this immune dis- Cytokine production
turbance is impaired function, and clinically
this is manifest as postoperative infection and
delayed wound healing. CKD, chronic kidney
disease; ROS, reactive oxygen species. Delayed wound healing Postoperative infections

to the cardiometabolic disease that is highly prevalent in this proinflammatory cytokines and impairs the ability of innate
population, dysregulated inflammation contributes to fur- immune cells to migrate to, and kill bacteria at, sites of
ther renal and extra renal organ dysfunction.48 Decreased trauma/infection.53
renal clearance leads to high levels of circulating cytokines
and low-molecular-weight proteins that promote defective PERIOPERATIVE MODULATION OF THE
chemotaxis and impaired bacterial killing.49
INFLAMMATORY RESPONSE

DIABETES MELLITUS Several perioperative treatments/drugs modulate the

The health-care burden of type 2 diabetes mellitus (T2DM)
is becoming more prevalent worldwide, increasingly as a
result of obesity.50 An individual with diabetes is more
likely to undergo surgery, yet is also more likely to sustain
perioperative morbidity.51 Chronic inflammation is a hall-
mark of diabetes, in part attributable to the deleterious
consequences of high glucose levels.52 Oxidative stress
induced by hyperglycemia promotes higher levels of
inflammatory response to tissue damage that may affect
organ injury significantly.
Anesthesia and Analgesia
Inhalational and intravenous anesthetic agents modulate
essential biologic features of lymphocytes, neutrophils,
and mononuclear cells.54 Leucocytes, including T lympho-
cytes, natural killer cells, and antigen-presenting cells,
express opioid receptors; exogenous opioids produce
14 PART I • Introduction and Background
immunosuppression after surgery, which may impact on
cancer recurrence and postoperative infections.55
Blood Transfusion
Blood transfusion, which is frequently used to correct ane-
mia or treat hemorrhage, is associated with significant
immunomodulation, termed transfusion-related immuno-
modulation (TRIM). Observational studies in human
cohorts have shown allogeneic blood transfusion to be asso-
ciated with immunosuppressive cytokine profiles in elective
surgical patients.56 Blood transfusion may be immunomod-
ulatory through a number of mechanisms, including
deficient natural killer cell function, altered antigen presen-
tation, and impaired macrophage phagocytosis.57-59
Whether these immune changes alter the inflammatory
profile and increase the risk of infection24 and/or recurrence
of cancer remain controversial.60 These associations may
merely reflect patient comorbidity and/or intraoperative
hemorrhage.
Steroids
The steroid dexamethasone is principally administered peri-
operatively to reduce nausea and vomiting. A single dose of
dexamethasone in healthy volunteers suppresses cortisol <
5% of baseline value up to 24 hours after administration.61
In a double-blind, randomized controlled trial of females
undergoing laparoscopic surgery, dexamethasone at induc-
tion had no effect on systemic inflammation (IL-6 levels) or
hyperglycemia, but substantial alterations in lymphocyte
subsets were observed.62 Whether exogenous glucocorti-
coid therapy alters the risk of organ injury or infection
remains unclear.63
Conclusions
While the onset of the inflammatory response triggered by
surgery is predictable, the interaction between acute and
chronic inflammation with underlying cardiometabolic dys-
function plays a crucial role in determining the magnitude
of organ injury. With an aging population characterized
by complex multimorbidity, the classic ebb and flow model
following tissue trauma is increasingly untenable. Under-
standing how the inflammatory response may be modulated
in different patient endotypes to influence better outcomes
remains worthy of exploration.
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39. Khuri SF, Henderson WG, DePalma RG, et al. Determinants of long-
term survival after major surgery and the adverse effect of postopera-
tive complications. Ann Surg. 2005;242:326–341, discussion 41–43.
40. Moonesinghe SR, Harris S, Mythen MG, et al. Survival after postoper-
ative morbidity: a longitudinal observational cohort study. Br J
Anaesth. 2014;113:977–984.
41. Lin HS, Watts JN, Peel NM, et al. Frailty and post-operative outcomes in
older surgical patients: a systematic review. BMC Geriatr.
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42. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregula-
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45. Duin D, Mohanty S, Thomas V, et al. Age-associated defect in human
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2 • The Inflammatory Response to Surgery 15
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221–230.
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 3 The Coagulation Cascade
in Perioperative Organ Injury
ANNETTE REBEL
Significance of Perioperative
Organ Injury
Although anesthesia-related complications have decreased
in the last two decades, perioperative mortality has not.
The leading precursor to death after surgery is acute organ
injury progressing to single-organ or multiorgan failure.1,2
The failure of two or more vital organs has been termed
“multiorgan dysfunction syndrome” (MODS). The common
trigger for development of organ dysfunction or acute organ
injury is the systemic inflammatory response. The patho-
physiology of MODS involves an indiscriminate activation
of the inflammation response by hostile stimuli, including
sepsis, hypovolemia, trauma, or other circumstances involv-
ing significant tissue damage.3,4 Several organ systems are
more at risk for perioperative organ injury.2 The acute stress
response related to surgery has been shown to create a
hypercoagulable state and to impair neuroprotective mech-
anisms, forming a potential for cerebral ischemia or stroke.5
Postoperative pulmonary and renal complications are sim-
ilarly seen as an exacerbation of inflammatory pathways
unless related to direct surgical trauma.2
Recent advances in the understanding of the pathogene-
sis of organ dysfunction in sepsis indicate that coagulation
abnormalities contribute strongly to its evolution.6 With a
less organ-based but more histological approach, the sys-
temic endothelial injury appears to be central for the devel-
opment of organ failure.7 Shock-induced sympathoadrenal
activation with excessive catecholamine levels induces sys-
temic injury to endothelium and microcirculation of all
organs.8 The natural anticoagulation protection of the
endothelium is provided primarily by the heparinoid-rich
glycocalyx, the tissue factor pathway inhibitor (TFPI), and
the protein C/thrombomodulin system.9 In the case of tissue
ischemia or inflammatory stress, the degradation/shedding
of glycocalyx combined with coagulation activation and
profibrinolytic factors from the injured endothelium may
result in profound coagulation imbalance.10 Major surgery
has been shown to induce a patient-specific inflammatory
acute stress response contributing to the imbalance of the
coagulation system, and the inflammatory environment
may contribute to hypo- and hypercoagulability.11–13
The coagulation factor activation, and indeed the entire
coagulation cascade, extend beyond the clotting function.
Relevant to perioperative stress, the coagulation proteins
are connected to numerous proinflammatory signaling
pathways.14–16 The overall state of coagulation in the circu-
lation depends on the balance between pro- and anticoagu-
lant mechanisms. When the balance is disturbed in favor of
16
a procoagulant state, the proinflammatory signals of the
coagulation proteins may be more dominant. Alternatively,
disruption of coagulation ability may lead to bleeding,
which has major clinical importance in the operative set-
ting. Impaired coagulation ability and the consequences
of bleeding in the operative setting are well recognized.
Several mechanisms contribute to the organ injury
related to the activation of coagulation system, including
extravascular fibrin deposition, small-vessel obstruction by
thrombosis, and amplification of cellular inflammatory
pathways.17 The procoagulant state has been shown to
be especially important in the pathogenesis of sepsis-
associated MODS.6 Similar mechanisms are probably perti-
nent to organ dysfunction in the perioperative period, when
multiple proteins intermingle to alter the balance between
procoagulant and anticoagulant.18,19 Attributing organ
dysfunction solely to a specific type of surgical procedure
is difficult, because the true incidence of perioperative organ
dysfunction is unknown, and perioperative organ dysfunc-
tion severity appears to vary between surgical sites and pro-
cedures. Perioperative complications include postoperative
sepsis and shock, which may produce coagulation abnor-
malities and organ dysfunction that are difficult to disasso-
ciate from the surgical event. The following paragraphs
cover the basic coagulation and fibrinolytic functions and
discuss alterations of these functions in the perioperative
period.
Current Understanding of
Coagulation and the Fibrinolytic
Process
The traditional understanding of the coagulation cascade is
that the coagulation is initiated by a sequential activation of
several serine proteases, leading to a polymerization of the
fibrin clot. The extrinsic pathway of the coagulation cascade
is initiated by cell surface expression of tissue factor (TF),
which binds to activated factor VII (FVIIa) to form a com-
plex. The intrinsic pathway is initiated by contact activa-
tion. The TF–FVIIa complex converts factor X to factor
Xa, which converts prothrombin to thrombin. Thrombin
cleaves fibrinogen to fibrin. The cross-linking of fibrin gen-
erates the mechanical durable fibrin clot.
Focusing on a more in vivo understanding of coagulation,
a cell-based model of the coagulation cascade was intro-
duced by Hoffman and colleagues in 2003.20 The cell-based
coagulation model operates on the notion that the “intrin-
sic” and “extrinsic” pathways are operating in parallel on
 3 • The Coagulation Cascade in Perioperative Organ Injury 17

different cell surfaces. The model describes four overlapping
stages of coagulation: initiation, amplification, propagation,
and stabilization. In the initiation phase, TF is expressed,
and the extravascular TF binds to FVII, leading to FVII acti-
vation and forming the activated TF–FVIIa complex, which
leads to the thrombin generation as described before. In the
amplification phase, the small amount of thrombin pro-
duced by the TF–FVIIa complex allows platelet adhesion
and activation. Thrombin is a very potent in vivo platelet
activator. The activated platelets bind von Willebrand fac-
tor, cleave FVIII and activate it to FVIIIa. The propagation
phase begins when FVa and FVIIIa are bound on the platelet
surface. Large numbers of platelets are engaged to the site of
injury, and surface FXa binds to FVa to produce a burst of
thrombin generation for clot formation. During the stabili-
zation phase, the formation of fibrin monomer and sufficient
thrombin amount activate FXIII, which cross-links the
fibrin into a stable fibrin clot (Fig. 3.1).
The endothelium plays a pivotal role in the activation of
the extrinsic coagulation pathway because injury to the
endothelial glycocalyx exposes TF. Under normal condi-
tions, natural anticoagulant systems protect the endothe-
lium to limit fibrin generation and deposition to the
specific injury site. The negatively charged glycocalyx is rich
in heparinoids and interacts with antithrombin. Other nat-
ural anticoagulants include TFPI, proteins C and S, and anti-
thrombin III (ATIII).
Fibrinolytic proteins function to regulate fibrin accumula-
tion. Tissue and urokinase plasminogen activators initiate
the plasminogen conversion to plasmin, which directly
degrades fibrin. The fibrinolytic system is controlled by
plasminogen activator inhibitors (PAIs). Increased PAI
expression has been reported in several pathological situa-
tions, impairing fibrinolysis and therefore creating a hyper-
coagulable environment.21 To control the vascular injury in
a normal host, surgical trauma generally promotes a more
procoagulant state.
How Does Inflammation Interfere
With/Change the Coagulation
Process?
In addition to endothelial TF exposure secondary to surgi-
cal trauma, injured cells release endogenous molecules to
communicate the cell injury to other pathways.22 TF
activates immunologically active cells (monocytes and
neutrophils).13 The TF activation leads to excess fibrin
deposition. Natural anticoagulation mechanisms (includ-
ing TFPI, antithrombin, protein C) are reduced or dysfunc-
tional secondary to inflammation or tissue hypoperfusion.6
Protease-jactivated receptors (PARs) establish the link
between coagulation and inflammation on the molecular
level. Of the four PAR subtypes identified, PAR1 is partic-
ularly relevant in inflammatory pathophysiology.6 The
cytoprotective effect of PAR1 is stimulated by activated
protein C (APC) or a low amount of thrombin. When acti-
vated by high-dose thrombin, PAR1 has a more disruptive
effect on the endothelial barrier.23
The observation that a patient in septic shock had low
APC levels and that microvascular thrombosis was partially
responsible for impaired tissue oxygenation became the
rationale for exploring APC in septic shock to improve

FXI Thrombin

FXIa Fibrinogen
B
Thrombin
Fibrinogen

Fibrin clot
Thrombin Thrombin
Thrombin
C D
FXIa FXI FVIIIa FVa
FIXa FXa
FX FII

FVa Thrombin
Activated Platelet
FVIIIa FXIa FXIII
FXa
A Platelet FV
C
FVIII/vWF FX
FIX
FVIII FVIIa

TF
vWF
Vascular Endothelium

Fig. 3.1 The cell-based coagulation model integrated with the coagulation cascade. The coagulation process is activated in vivo by endothelial
exposure of tissue factor (TF) binding to activated factor VII (FVIIa), which then activates FIX and FX (A, initiation phase). The small amount of generated
thrombin activates FV, FVIII, and FIX and increases the thrombin generation in a feedback loop (B, amplification). The increasing thrombin generation
produces large amounts of FXa and conversion of platelets to activated platelets and FVa, increasing the clot formation (C, propagation). The fibrin
monomer formation and sufficient amount of thrombin activate FXIII, which cross-links the fibrin into a stable fibrin clot (D, stabilization). vWF, von
Willebrand factor. (Modified with permission from Bombeli T, Spahn DR. Updates in perioperative coagulation: physiology and management of
thromboembolism and haemorrhage. Br J Anaesth. 2004;93(2):275-287 and Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis.
2003;16:17-20.)
18 PART I • Introduction and Background
TEG analysis 27
Coagulation
Kinetics
of clot
development
Angle
R K
Reaction time, Achievement
first significant of certain clot
clot formation firmness
Fig. 3.2 Thromboelastographic analysis. K, K-value; LY30, time at 30 minutes; MA, maximum amplitude; R, R-value = reaction time. (With permission from
MacIvor D, Rebel A, Hassan ZU. How do we integrate thromboelastography with perioperative transfusion management? Transfusion. 2013;53:1386-1392.)
patient outcome.24 Clinical trials failed to demonstrate a
treatment benefit of APC or protein C zymogen but was
associated with increased bleeding.25,26
Perioperative Monitoring
of Coagulation
Due to the complexity of the coagulation abnormalities in
the perioperative period, conventional coagulation assess-
ment with prothrombin time (PT), activated partial throm-
boplastin time (aPTT), and fibrinogen levels may not be
sufficient or timely enough. The long turnaround times
may render laboratory test results irrelevant before the
information is available. In the operating room or in the
intensive care unit, activated clotting time is a periopera-
tively available point-of-care test. The most concerning lim-
itation of coagulation monitoring is its artificial nature,
assessing isolated components of the coagulation system
under artificial laboratory conditions. Recent publications
are favoring perioperative coagulation monitoring using
viscoelastic point-of-care testing such as thromboelastogra-
phy (TEG) or rotational thromboelastometry (ROTEM).
Although the technology is still FF and artificial, it more
closely reflects the in vivo coagulation status.27,28 There
are different variants of this technique currently available:
TEG (Haemonetics Corp., Braintree, MA), ROTEM (Tem
International GmbH, Munich, Germany), and Sonoclot
(Sienco, Inc, Arvada, CO). The information obtained using
this technology has been shown to be helpful for clinical
decision-making during high-blood loss surgical procedures
(trauma, cardiac surgery, and liver surgery) and for coagu-
lation assessment during pregnancy.29–32
Information obtained from TEG and ROTEM indicates
(1) time to initiation of clot formation (R), (2) speed or rate
Fibrinolysis
LY
LY30
MA
Percent lysis
30 minutes
after MA
Maximum amplitude-
maximum strength of
clot
of clot propagation (a), and (3) clot strength (amplitude A,
or shear elastic modulus G) (Fig. 3.2). The test takes into
account both platelet function and fibrin–platelet interaction.
Modifications of the method use inhibitors of platelet–fibrin
interaction and inhibitors of platelet aggregation, and they
can distinguish coagulation factors from platelet contribu-
tions to the clot formation.27 Viscoelasticity-based coagula-
tion assessment and treatment have been shown to be
helpful in multiple clinical situations with complex coagulo-
pathies (trauma, liver transplantation, sepsis, and cardiopul-
monary bypass).29,33,34 A test to assess not only platelet
quantity but also quality is the platelet function analyzer
(PFA-100; Dade International Inc., Miami, FL), which mea-
sures platelet aggregation or plug time. D-dimer assays are
widely available to detect fibrin degradation products, and
the presence of these products indicates activation of fibrino-
lysis, but the D-dimer is not necessarily a marker of increased
fibrin formation.
Alteration of Coagulation Status
During Perioperative Period
Surgical procedures and surgical stress commonly unbal-
ance this elaborate arrangement, therefore causing hypo-
or hypercoagulability. In addition to direct surgical injury
to vascular structures and blood loss, fluid therapy-induced
dilution of coagulation components, hypothermia, or tissue
acidosis may promote hypocoagulability and bleeding.17
Surgical stress and tissue trauma release of TF may activate
the coagulation process. The stress response also results in a
downregulation of the anticoagulant response.13 The result
of decreased anticoagulant activity, in combination with
immobility and other patient factors (malignancy, drugs,
and comorbidities), may be hypercoagulability.

During the perioperative period, the function of the coag-
ulation system is altered by activation of the procoagulant
mechanisms and depression of the anticoagulant and fibri-
nolytic mechanisms. The primary outcomes and events
measured for perioperative activation of coagulation are
vascular thrombotic complications, including stroke, myo-
cardial infarction, and venous thromboembolism.2 Specific
pathways and mechanisms have been implicated in
surgery-associated hypercoagulability. Extrinsic coagula-
tion is activated by vascular injuries that expose or upregu-
late TF on the endothelial surfaces and by platelet thrombi at
sites of injury that also generate fibrin clot formation.35
Other surgical responses include increased levels of coagu-
lation factors, decreased levels and activity of endogenous
anticoagulants such as APC and ATIII, and inhibition of
fibrinolytic function.17,19
Several variables related to the surgical procedures and
concurrent interventions affect the coagulation function
in the perioperative period. Although several specific vari-
ables have been studied with respect to activation of the
coagulation response, identifying the role of individual fac-
tors in the complexity of the whole surgical setting has been
difficult. Variables that have been implicated include the
pain or stress response, the mode of anesthesia, the type
and quantity of intravenous fluid administration, body
temperature, and the site of surgery.
INTRAOPERATIVE ACTIVATION OF COAGULATION
Stress Response or Pain
Hypercoagulability has been reported as part of a complex
stress or pain response.19,36 Enhanced coagulability devel-
oped over 15 minutes after insertion of a peripheral intrave-
nous line in patients in the operative theater before
undergoing elective cesarean section.36 This observation
may be related to the stress response. This has also been
inferred from other studies addressing effects of pain on coag-
ulation parameters (see Pain Control, later).
Site of Surgery
Surgery itself puts the patient at risk for thrombotic compli-
cations resulting from immobilization, although some pro-
cedures seem to have especially high rates of clot
formation. With the true incidence of venous thromboem-
bolism unknown, it is estimated that 25% of in-hospital sur-
gical patients are affected by venous thromboembolic
events.37 In addition to patient-related factors (age, sex, obe-
sity, and malignancy), the highest incidence is seen in
orthopedic, abdominal, neurosurgical, and gynecological
procedures.17,38 Although an increased likelihood of throm-
botic complications is certainly influenced by the degree of
immobilization required by the procedure, it may also reflect
differential activation of coagulation related to operative
location. Coagulation abnormalities have been demon-
strated after a number of different types of surgical
procedures. In certain surgical settings (cardiovascular,
trauma, and obstetric surgical settings), the primary cause
of bleeding may be more anatomical than pathophysiolog-
ical. Acquired coagulopathy may occur secondary to blood
loss, hemodilution, and loss or consumption of coagulation
factors. After major abdominal surgery, such as the Whipple
3 • The Coagulation Cascade in Perioperative Organ Injury 19
procedure or pancreatic, gastric, or rectal resections, multi-
ple signs of activation of both coagulation and fibrinolysis
can be demonstrated by the end of the procedure, including
decreased ATIII and fibrinogen.39 In addition, D-dimer and
platelet aggregation are elevated several hours after surgery
and continue to be elevated on the first postoperative day.
Although the available literature has not compared coagu-
lation parameters between different procedures, certain sites
of surgery may be more apt to activate coagulation. For
example, the brain is highly enriched in TF, and the release
of TF during parenchymal manipulation may explain an
apparent increased susceptibility to thrombosis in neurosur-
gical patients undergoing craniotomy.40 In the era before
routine deep venous thrombosis (DVT) prophylaxis, such
patients had a 29%–42% incidence of thrombotic complica-
tions. Vascular procedures are also likely to activate coagu-
lation because of intravascular stimulation of TF exposure.
Minimally invasive surgical techniques may have less
impact on the coagulation system. Comparisons of open ver-
sus laparoscopic procedures have shown that open surgery
was associated with higher levels of thrombin–antithrom-
bin complexes and prothrombin fragments postopera-
tively.41 Other studies have found more prothrombotic
coagulation changes in patients after laparoscopic proce-
dures.42 Although several observational studies have
documented changes in coagulation profile related to lapa-
roscopic versus open technique, it is currently unclear if
these laboratory changes have clinical significance.43,44
The influence of surgical technique on coagulation may
be related to surgical procedure, surgical duration (venosta-
sis), and patient factors (e.g., comorbidities, malignancy).43
Anesthesia-related factors (neuraxial technique for postop-
erative analgesia, fluid management, and anesthesia
agents) may contribute as well.
Mode of Anesthesia
On the basis of several studies, epidural anesthesia reduces
the incidence of thrombotic events and is associated with
beneficial effects on postoperative outcome compared with
general anesthesia.18,45,46 Patients receiving epidural or
spinal (neuraxial) anesthesia show diminished elaboration
of procoagulants compared with those undergoing general
anesthesia.18 Other investigations have shown that after
epidural anesthesia, patients appear to maintain adequate
fibrinolysis, as evidenced by lower release of PAI-126 and
enhanced release of plasminogen activators.18,45 In addi-
tion, it is proposed that certain local anesthetic agents, such
as lidocaine, may have anti-inflammatory actions, which
could potentially attenuate recruitment of procoagulant
mechanisms.47,48 In a meta-analysis of studies of complica-
tions comparing general anesthesia alone with neuraxial
anesthesia (epidural or spinal anesthesia), it was reported
that in addition to having an overall benefit, concomitant
neuraxial blockade reduced the odds of thrombotic compli-
cations, including DVT and pulmonary embolism, by 44%
and 55%, respectively.49 This meta-analysis is confounded
by the inclusion of studies of multiple surgical procedures
and sites, which limits the conclusions. Moreover, in some
of the studies reviewed, the use of general anesthesia was
combined with neuraxial blockade for postoperative pain
control. Thus, the effect of pain on coagulation was a
confounding variable in the analysis.
20 PART I • Introduction and Background
Regional anesthesia and adequate pain control are core
principles of all enhanced recovery after surgery (ERAS)
guidelines, providing supportive evidence of the potential
impact of these techniques of controlling the inflammatory
response and therefore improving outcomes.
Intravenous Fluid Management
The amount and quality of intraoperative fluid therapy may
have an impact on the coagulation system during the peri-
operative period. Obviously, an excessive amount of crystal-
loid or colloid intravenous fluid can have a dilutional effect
and cause an acquired coagulopathy.
Large-volume crystalloid administration and dilutional
coagulopathy in trauma is associated with poor outcome.50
Because intravenous solutions do not contain coagulation
factors, the dilutional coagulopathy is nonspecific to the
solution used. However, specific anticoagulant effects are
specific to the agent used. Intravenous fluid replacement
is undertaken with crystalloid, such as 0.9% sodium chlo-
ride, lactated Ringer, or synthetic colloids. Colloid plasma
substitutes are thought to lead to hemostatic derangement
independent of effects on hemodilution. A meta-analysis of
studies of colloids and hemostatic function concluded
that these fluids are most likely to result in impaired coa-
gulation when given in large volumes.51 Colloids used in
the perioperative period are hydroxyethyl starch (HES),
dextran, gelatins, and albumin. The different HES solutions
are slowly degradable HES (heta-, hexa-, and pentastarch) or
rapidly degradable HES (tetrastarch). The specific anticoa-
gulant effect differs between colloids (dextran > hetastarch >
tetrastarch, gelatins > albumin).52 The anticoagulant activity
is caused by transient decrease in FVIII and von Willebrand
factor levels, impaired thrombin–fibrinogen interaction,
impaired thrombus generation, impaired FXIII–fibrin
polymer interaction, and enhanced fibrinolytic activity. Plate-
let reactivity is reduced because of diminished glycoprotein
IIb-IIIa availability and decreased platelet aggregability/
adhesion.52
Viscoelastic coagulation assessment has been shown to
be helpful if non–blood component therapy is used for major
fluid loss replacement in the perioperative period to assess
the severity of the acquired coagulopathy.53 Advanced
coagulation assessment is needed to use physiological trans-
fusion triggers and allow more restrictive blood component
therapy practice.
Body Temperature
Hypothermia is encountered during surgical procedures,
particularly following shock and massive resuscitation.
Decreased body temperature may alter the coagulation and
clotting function responses outlined earlier. Starting at a core
temperature of less than 36°C (mild-moderate hypothermia
<36–33°C), coagulation ability is impaired by decreased
platelet aggregation and adhesion and decreased TF activ-
ity.54 Hypothermia contributes to the trauma coagulopathy
described earlier.55 Surgical procedures with a wide range of
temperature fluctuations (e.g., hyperthermic intraperitoneal
chemotherapy, cardiopulmonary bypass) are prone to display
complex coagulation abnormalities. Various studies docu-
mented temperature-related abnormal coagulation tests (PT,
aPTT) but also objective reduction in coagulation factor acti-
vity (ATIII, fibrinogen, FXIII, and thrombocytopenia).56,57
Perioperative monitoring with TEG is encouraged if complex
perioperative coagulation abnormalities are expected or
suspected.
Trauma Coagulopathy
Recent reviews have described the current understanding of
the complex coagulation disorder occurring after massive
trauma when hypoperfusion, shock, and vascular damage
are present.50,58 In addition to significant blood loss and
hemodilution, the tissue injury triggers an endogenous
coagulation response that is amplified by hypothermia
and acidemia.55 Although the increased catecholamine
levels initiate endothelial changes, as described earlier,7
the endogenous response entails increased APC, fibrinogen
depletion via fibrinolysis, and platelet dysfunction.59,60 APC
and fibrinolysis have a critical role in the pathophysiology of
trauma-induced coagulopathy. Protein C is a serine prote-
ase with anticoagulant and inflammation-modulating func-
tions.61 Initiated by tissue injury and hypoperfusion,
elevated endothelial and circulating thrombomodulin bind
thrombin to form a thrombomodulin–thrombin complex,
which subsequently activates protein C.55 APC inhibits clot
formation by deactivating FV and FVIII and depleting PAIs.
The reduced activity of thrombin-activated fibrinolysis
inhibitors further exacerbates the process. The result is
unopposed fibrinolysis.62
The dilutional and consumptive characteristics of the
trauma-induced coagulopathy are not easily identified
using conventional in vitro testing. Early recognition and
a hemostatic resuscitation approach (damage control resus-
citation) are critical to improving patient outcomes.63–65
Perioperatively, point-of-care monitoring based on visco-
elastic properties (TEG or ROTEM) has been used in manage-
ment of trauma patients and has been shown to improve
blood component therapy use.66,67 Point-of-care TEG may
be useful to guide the use of antifibrinolytic therapy in
trauma patients.68
Postoperative Activation
of Coagulation
Several important variables in the postoperative course
have an impact on coagulation function and the possible
risk of organ dysfunction. Increased coagulation parameters
have been found to continue into the postoperative
period.46,57 Complications (such as sepsis and hypotension)
and requirements for further fluid resuscitation appear to be
major factors that perpetuate coagulation abnormalities
during this time.
PAIN CONTROL
Pain is one very important variable that is determined to
contribute to coagulation abnormalities.46 As mentioned
previously (see Mode of Anesthesia section earlier), it has
been suggested that local anesthetic agents may have bio-
chemical effects that alter coagulation. Improved pain con-
trol may have a beneficial effect on coagulation state by
reducing perioperative stress, but available studies do not
allow these effects to be delineated clearly.18 One study

compared postoperative pain control using epidural anes-
thesia with narcotic analgesia in patients undergoing major
surgery for peripheral vascular disease under general anes-
thesia. Patients in the epidural analgesia group had lower
activation of coagulation, as evidenced by both thromboe-
lastography and number of vascular events, including
venous thromboembolism, myocardial infarction, and
thrombosis of the vascular graft.46 However, another group
showed that in a large number of patients undergoing
abdominal aortic surgery, there was no difference between
the number of major organ failures in patients treated inten-
sively with neuraxial pain control and those treated with
narcotic analgesia.69
Interesting research developments are the influences of
opioids and propofol on patient outcomes after oncologic
procedures.70 On the basis of current understanding of
how surgical stress and anesthesia may interfere with
immune response, it may not be unreasonable to stipulate
a connection between the immune system and the coagula-
tion system, with an important impact on outcomes.
Consequences of Dysregulated
Coagulation
When coagulation balance is disrupted to favor procoagu-
lant mechanisms, organ dysfunction is elicited by the depo-
sition of fibrin in the vessel lumen and tissue parenchyma as
well as by proinflammatory actions of coagulation proteins.
The association between activation of coagulation and
organ dysfunction is established in sepsis and other systemic
inflammatory states.2,6 The following paragraphs briefly
review these mechanisms and point out their potential rel-
evance in perioperative organ dysfunction, which remains
largely unexplored.
PROINFLAMMATORY ACTIONS OF COAGULATION
PROTEASES
Several key proteins in the extrinsic coagulation system are
capable of generating intracellular signals. TF is an integral
membrane glycoprotein with structural features of a class 2
cytokine receptor. TF is expressed on monocytes or macro-
phages and on endothelial cell surfaces, and after binding by
circulating FVIIa, its interaction with other cell receptors or
direct intracellular action leads to increased oxidant produc-
tion, protein tyrosine phosphorylation, and calcium oscilla-
tions in human cells. Signal transduction pathways
activated by the FVIIa/TF complex include p44/42 (extra-
cellular signal-regulated kinase) and p38 mitogen-activated
protein kinase.14–16 These signaling pathways activate
inflammatory transcription factors and expression of pro-
teins, such as interleukin-6 and vascular endothelial growth
factor, that further amplify inflammation and may promote
capillary leak.
FXa and thrombin are serine protease components of the
coagulation cascade downstream from TF-based initiation
that have independent inflammatory signaling functions.
As previously discussed, FXa attaches to a cell surface–based
3 • The Coagulation Cascade in Perioperative Organ Injury 21
receptor, effector cell protease receptor-1 (EPR-1),
and thrombin binds to PAR1.14–16 Multiple proinflamma-
tory roles of EPR-1 and PAR1 have been demonstrated,
including nuclear factor-κB activation. Proliferative and
proinflammatory responses to thrombin have been demon-
strated in endothelial cells and macrophages, respectively.
Summary and Recommendations
Anesthesiologists have a crucial role in improving the out-
comes of surgical patients. Improving understanding of the
pathophysiology of perioperative organ injury should facili-
tate the development of preventive or therapeutic strategies.
The pathophysiology of coagulation abnormalities leading to
perioperative organ dysfunction is an area of ongoing inves-
tigation. This understanding has been well accepted in organ
injury related to sepsis and trauma, and it is quite likely rel-
evant to perioperative conditions when coagulation abnor-
malities are present. In addition to the effects of surgical
trauma, many other variables are known to affect the evolu-
tion of coagulation abnormalities, including pain, fluid
replacement, and anesthetic regimen. Of special interest as
possible therapeutic targets are procoagulant aspects of
hemodilution and anticoagulant effects of colloids and anti-
inflammatory and anticoagulant effects of propofol, opioids,
non–opioid-based analgesics, and local anesthetic agents.
These factors correlate with changes in coagulation status,
but much work remains to be done to connect them causally
to less obvious effects such as organ dysfunction. Further-
more, true incidences of organ dysfunction remain to be
defined, as do special aspects related to the surgical proce-
dure, surgical technique, and perioperative care. Care
paradigm changes such as ERAS guidelines may influence
patient outcomes, partially due to changes in coagulation
activation. Finally, much of the available data were obtained
prior to or without regard to standard practices of postoper-
ative thromboembolism prophylaxis. A modern approach to
coagulation abnormalities in the postoperative setting needs
to be developed to evaluate their effects on outcome, espe-
cially involving postoperative infection and organ failure.
Recommendations for thromboembolism prophylaxis should
be followed rigorously and organ function closely monitored
in all postoperative patients at high risk for complications of
hypercoagulability.
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 4 The Value of Preoperative
Assessment
ANGELA BADER
Describing the value of preoperative assessment resembles
the fable of six blind men trying to describe an elephant:
Each comes across different parts and creates his own ver-
sion of reality from that limited experience and perspective.
Therefore, a clear definition of both value and preoperative
assessment is necessary to inform the following discussion.
Value
The pursuit of value in health-care is an increasingly impor-
tant focus of health policy discourse. At a basic level, value is
defined as health outcomes that matter to the patient,
divided by cost.1 As Porter wrote,1 “value” is not a code
word for cost reduction. Value depends on results, not just
inputs, and cannot be measured by considering only the cost
or volume of services delivered. Frequently hospital admin-
istrators focus only on increasing procedural volume as a
measure of operating room “success”with little attention
paid to both the short- and long-term metrics, lasting well
beyond day of discharge, that determine the actual value
that the procedure provided. Current commonly used mea-
sures are also a problem. Although 30-day morbidity and
mortality are important, the patient would certainly hope
that the results of a procedure are of far more benefit than
just avoiding death and complications.
The shift from volume to value is hopefully at a tipping
point but will be difficult to achieve if budgets are siloed
and the overall impact of a procedure across patients’
health-care trajectories in terms of outcomes achieved for
resources expended is not considered. Administrators who
remain focused on siloed budgets may cite the “expense”
of providing preoperative assessment services that could
maximally impact value for the patients undergoing proce-
dures at their institutions. The total expenses for the full
cycle of care for each patient’s condition must be included.
Preoperative services should be available that will maximize
the value of the overall cycle of care, rather than attempting
to reduce costs in individual siloed budgets. Lowering costs
in siloed budgets could actually increase overall costs of the
surgical episode if downstream impact is not considered.
High-value interventions offer the patient benefits more
than harm, based on high-quality preoperative risk assess-
ment and shared decision-making. Risk–benefit analysis
has never been straightforward, but it has become even
more complex with recognition that the appropriateness
of care depends on patient-specific preferences and goals.
The task of ensuring high-value preoperative assessment
is therefore inextricable from the process of developing
patient-centered, shared decision-making processes in the
26
preoperative setting. In addition to undermining value,
inappropriate care is a threat to the ethical integrity of sur-
gical practice.
Preoperative Assessment
Elements
Preoperative assessment is done after the decision to per-
form a procedure is made; it is defined as a set of multidisci-
plinary tasks that must be completed prior to beginning any
procedure. These steps cannot be eliminated, but they can
be done in different ways at different institutions, based
on patient acuity and risk of surgery performed. As an
example, Table 4.1 lists the clinical and regulatory elements
of preoperative assessment and how these are achieved at
Brigham and Women’s Hospital. Each institution should
evaluate a similar list of preoperative elements and decide
where and by whom each is performed, with an eye toward
maximizing value throughout the continuum of care. A
careful analysis will determine how best to provide preoper-
ative care at individual institutions. For example, at Brig-
ham and Women’s Hospital, most patients having in-
person preoperative assessment visits are classified as Amer-
ican Society of Anesthesiologists physical status III and IV,
generally having higher-risk procedures. Patients who are
deemed healthier by an internal algorithm and who are
having lower-risk surgery are screened by phone, with
the anesthesia assessment and anesthesia consent done
immediately prior to the procedure. Regardless of whether
phone or in-person assessment is done, metrics must reflect
that completion of all required elements occurs. Shifting
some of these elements to the day of the procedure may give
a false impression that eliminating preoperative clinic func-
tions saves cost. Unless the cost of the portion of day-of-
surgery resources devoted to what could have been done
preoperatively is contained separately in the overall operat-
ing room budget, however, these costs are not actually
being eliminated; they are just hidden within the operating
room budget costs. In addition, the cost per minute of clinic
time is much less than the cost per minute of operating room
time, so any tasks done on the day of the procedure will cost
proportionately more. The cost of day-of-surgery delays and
cancelations must be considered as well.
For example, institutions without robust preoperative
assessment systems usually have nursing resources
assigned on the day of surgery just to perform nursing func-
tions that could have been done in the preoperative clinic.
Patients may be inconvenienced because these institutions

Table 4.1 Elements of preoperative visit.
1. Surgical history and physical examination (JC states must be done
within 30 days of procedure)
Confirm correctness of OR booking; side and procedure
2. Nursing assessment (JC)
a. Falls assessment; email if >45, place on precautions (JC)
b. Skin integrity and wound assessment; email if <18 (never events for
nonpayment) (CMS)
c. Advance directives on all patients (JC)
d. All patient preoperative instructions; this includes giving bowel
prep materials and bowel prep instructions when appropriate
e. ERAS pathway instituted, ClearFast drink (ClearFast, Cardiff by the
Sea, CA) given
f. All patient teaching regarding hospitalization and recovery
g. Coordinate special needs for OR (e.g., latex allergies, MRSA or VRE
[antibiotic resistant organisms]), request special equipment as
needed, and notify anesthesia team of difficult intubation history
h. Instruct regarding Hibiclens scrub (M€ olnlycke Health-Care,
Norcross, GA) at home preoperatively (per infection control),
Hibiclens given to patient
i. Hospital-acquired infections education documentation (JC)
j. Domestic abuse/social work referral questions (JC)
k. Pain assessment status/history (JC)
l. Venous thromboembolism risk assessment (JC)
3. Electronic medication documentation (medicine reconciliation) (JC)
4. Anesthesia assessment
a. Includes assessment for anesthesia based on above information,
patient education regarding anesthesia options, and discussion
of risk/benefit
5. Resolution of medical issues
a. Resolve all medical issues and identify issues that require follow-up
postvisit, provide antiplatelet and anticoagulation
recommendations, etc. Discussion with anesthesia attending to
each patient, review of ECG, etc.
b. Scheduling tests as indicated
c. Contact surgeon, anesthesia team, or nursing regarding specific
issues; coordinate need for postoperative pain service
d. Implement protocols when appropriate (ERAS, diabetes, geriatric)
6. Blood tests and electrocardiogram
Ensure evidence-based laboratory testing and review/act on results
as indicated
7. Unresolved problems identified
a. Retrieval and review of additional information when appropriate
b. Final review to ensure all issues are addressed
c. Final OR checklist with completed elements and task list if
anything is needed on day of surgery
CMS, Centers for Medicare and Medicaid Services requirement; ECG,
electrocardiogram; ERAS, enhanced recovery after surgery; JC, Joint
Commission requirement; MRSA, methicillin-resistant Staphylococcus
aureus; VRE, vancomycin-resistant enterococci.
have them arrive hours earlier than they might have needed
to otherwise, so that operating rooms can start on time.
Anesthesiologists may discover clinical issues and medica-
tion errors that result in delays, cancelations, or at worst
proceeding with a case that would otherwise not have been
done if sufficient time had been available to address these
issues. Perhaps thinking about reassigning resources cur-
rently used on the day of surgery to perform preoperative
assessment functions would shift resources with a positive
financial impact. Hospitals with robust preoperative systems
can perform all of these functions prior to the day of the pro-
cedure; nursing as well as anesthesia and surgical staff can
spend much less time per patient on their surgical day.
4 • The Value of Preoperative Assessment 27
Goals of Preoperative Assessment
Good preoperative assessment systems include performing
surgical population management, ensuring that resources
are focused throughout the care cycle to obtain the highest
possible value from the procedure. This requires triaging
populations preoperatively to perioperative care pathways.
An understanding of the intended goals of a well-designed
preoperative assessment system is essential. Protocols and
pathways need to be evidence based as much as possible,
with regular review and modification as evidence evolves.
In addition, institutional strategies that result in new surgi-
cal or procedural service lines need to be analyzed to deter-
mine the impact of additional volume on preoperative
resources and the need to modify pathways and protocols.
Good preoperative assessment systems are never static or
generic.
An understanding of the intended goals of a well-designed
preoperative assessment system is essential.
Overall goals are outlined here and will be discussed in
detail in the following sections.
1. Ensuring appropriateness of procedure and high-quality
shared decision-making
2. Completion of surgical, anesthesia, and nursing assess-
ments to ensure proper risk assessment and optimization;
need to ensure optimization of old issues and diagnosis of
new issues that could impact outcomes
3. Population management assigning patients in specific
groups to appropriate perioperative pathways to ensure
high-value care; examples include enhanced recovery
after surgery (ERAS), patients at risk for significant pain
issues post procedure, and geriatric patients deemed to be
frail and/or cognitively impaired
4. Completion of regulatory requirements
5. Completion and review of testing deemed necessary to
ensure proper assessment and optimization
6. Documentation and transmission of all important
information to downstream providers, including infor-
mation impacting setup of the operating room (e.g., latex
allergy), assignment of the teams (e.g., Jehovah’s Wit-
nesses members, difficult airways), and issues reflecting
patient goals and values, (e.g., do not resuscitate/do
not intubate [DNR/DNI] statements, advance care direc-
tives, health-care proxies)
7. Patient and family education
ENSURING HIGH-QUALITY SHARED DECISION-
MAKING AND APPROPRIATENESS OF CARE
Beyond outcomes, appropriateness also encompasses con-
siderations of cost/risk. A high-value procedure offers a
favorable outcome at a cost considered to be worthwhile
based on the degree of likely benefit.2 Existing methods of
ensuring the appropriateness of surgical care have
attempted to maximize benefit and minimize harm by incor-
porating clinical evidence, surgeon qualifications, and hos-
pital certification. Notably absent from these approaches is
attention to whether the procedure is consistent with the
patient’s overall preferences and values (Fig. 4.1). Ensuring
high-quality shared decision-making as a part of
28 PART II • Preoperative Assessment

Right operation
Procedure is the best surgical
treatment for the diagnosis

Right patient High-Quality Right provider

Complete risk/benefit discussed Shared The surgeon has the requisite
and procedure reflects patient Decision-Making skills/certification/privileges
goals and values

Right place
The health-care facility chosen
has all necessary resources

Fig. 4.1 Concepts defining high-quality surgical shared decision-making.

preoperative assessment also assumes appropriate discus-
sion of additional risk attributable to comorbidities, review-
ing advance care directives and assignment of health-care
proxy, and discussion of special requests such as DNR/
DNI statements and refusal of blood products. These discus-
sions are critical to complete effectively as part of the preop-
erative assessment process.
At what point during the preoperative assessment period
should shared decision-making discussions be held? Is this
the responsibility of the referring physician, surgeon, proce-
duralist, or anesthesiologist? The patient should be making
the final decision on the basis of the results of these discus-
sions. As Fig. 4.1 suggests, high-quality shared decision-
making may be best performed as a multistep process.
The surgeon has the expertise to make the clinical decision
regarding which operation is best for the patient’s diagnosis
and can speak best to risks/benefits in this area. However,
the impact of the patient’s comorbidities on the likelihood
of achieving beneficial outcomes may be best addressed by
anesthesiologists with expertise in perioperative medicine.
The discussion incorporating specific patient goals and
values should be done in this holistic context. All too often,
the presence of a signed surgical consent obviates further
discussion on whether a truly informed decision has been
made or whether issues such as those noted earlier have
been discussed preoperatively. Consent for anesthesia may
be similarly uninformed. Regardless of opinion regarding
where this responsibility lies, there is good evidence that
the quality of current practice falls short in the domains
of patient understanding, incorporation of patient values,
and advance care planning, despite the presence of signed
surgical consent at the time of the preoperative assessment.
In a study of over 1000 preoperative patients, 8% could not
identify their diagnosis, 10% could not identify their proce-
dure, and 7% reported that they did not know the risks and
benefits of different options.3 Half of those in this study
scheduled for postoperative intensive care unit recovery
were unaware of this need for the intensive care unit.
In the absence of high-quality shared decision-making in
the preoperative period, patients fail to develop a clear sense
of which risks and benefits are most important to them, and
some remain unsure of which option is therefore best. Such
deficits in decision-making may help account for intensity
and cost of care at the end of life; nearly one-third of elderly
Americans undergo surgery in the last year of life, most
within the last month of life.4
The data describing advance care planning during preop-
erative assessment are similarly discouraging. One study
indicated that medical patients were 22 times more likely
than surgical patients to have notes relating to end-of-life
care.5 Another study of advance care planning before elec-
tive surgery found that nearly two-thirds of patients seen in
the preoperative clinic after the surgical office visit had not
completed an advance directive, and even among the
patients who had completed one, nearly one-third were
missing from the chart. Roughly one-half had a health-care
proxy on file, and almost one-third reported a desire to talk
further about advance care planning.3 Surgeons performing
high-risk operations rarely discuss the potential need for
prolonged mechanical ventilation/intensive care or elicit
patient preferences about postoperative treatments6; having
a patient sign anesthesia consent without these discussions
preoperatively is problematic. This current pattern is at odds
with the American Society of Anesthesiology and American
College of Surgeons guidelines recommending preoperative
discussion regarding implications of advance directives on
intraoperative and postoperative care.7,8
Although clinicians and our professional societies may
agree with the importance of preoperative assessment incor-
porating discussions to address these issues and ensure
high-quality shared decision-making, these lofty goals are
difficult to achieve routinely. These deficits reflect several
factors.
First, surgical and anesthesia training is generally lacking
in these skills; a minority of residents express feeling
comfortable performing key tasks such as conducting these

preoperative discussions regarding advance care direc-
tives, patient goals and values, and perioperative code sta-
tus.9 There are also cultural issues that may have
narrowed discussion of anesthesia and surgical practice.
For example, “Even with 4 years of medical school educa-
tion and 4 years of residency training, most anesthesiolo-
gists are not (nor want to be) trained to deal with issues
outside the immediate perioperative area.”10
Second, the time it takes to incorporate these high-value
discussions into preoperative assessment programs takes
clinical resources. Hospital administrators may fail to realize
the impact of allowing time to ensure high-quality decision-
making on improving value by reducing inappropriate care
that is not aligned with patient goals and values. In addition,
ensuring an adequate discussion of risk/benefit may result
in better patient selection for high-risk procedures, hopefully
resulting in fewer patients likely to have complications that
result in increased long-term health-care costs. As newer
payment models such as bundled payments and account-
able care organizations become more prevalent, there will
be increasing emphasis on ensuring appropriate care and
good patient selection to improve outcomes and reduce
overall health-care costs.11 Until recognition of the impor-
tance of these discussions on value is widespread, it may
be difficult to get the educational and clinical resources nec-
essary to ensure these discussions occur routinely as a crit-
ical part of preoperative assessment.
Third, and finally, it is difficult to ensure that high-quality
shared decision-making has occurred during preoperative
assessment because there are currently no widely accepted
metrics. There are, of course, standards for informed con-
sent, as described by Joint Commission and Centers for Medi-
care and Medicaid Services (CMS) guidelines, which focus
on description of the surgery and anesthesia, clinical risks
and benefits, and treatment alternatives.12 However, met-
rics currently do not exist to ensure that these minimal stan-
dards, as well as incorporation of patient goals and values,
are met. As demonstrated, signed consent does not equal
high-quality shared surgical decision-making. Developing
measures of decisional quality during preoperative
assessment is an essential task for several reasons. First,
measurement is necessary to evaluate the effectiveness of
innovations intended to enhance shared decision-making.
Second, it can facilitate use of payment incentives to drive
implementation of evidence-based strategies. Finally, mea-
surement tools will be necessary to identify populations at
risk of experiencing low-quality decision-making processes
and their negative sequelae. Despite its importance in guid-
ing innovation, the process of developing and validating
tools for measurement of preoperative decision quality is
in its infancy.
PREOPERATIVE ASSESSMENT SHOULD ENSURE
APPROPRIATE RISK ASSESSMENT AND
OPTIMIZATION
Completion of surgical, anesthesia, and nursing preopera-
tive assessments should ensure proper risk assessment
and optimization. This includes optimization of old issues
and diagnosis of new issues that could impact outcomes.
Appropriate risk assessment and optimization are necessary
4 • The Value of Preoperative Assessment 29
for optimal throughput and use of the operating room and
procedural areas to occur.
The evolution of preoperative assessment systems shows
increasing benefits from risk assessment and optimization.
Outpatient preoperative assessment clinics initially were
constructed to replace preoperative inpatient admission
days when payment systems changed to eliminate addi-
tional revenue for increasing length of stay. Additional ben-
efits became apparent over the ensuing years, as recently
summarized in an article describing well-known landmarks
in preoperative clinic achievements.13 Computerized preop-
erative clinic evaluations were shown to identify patients
with increasing risk.14 Preoperative clinic assessment was
associated with reductions in unnecessary laboratory test-
ing and reduced cancelations and delays on the day of the
procedure, as well as reduced length of stay.15,16 These ben-
efits have resulted in significant cost savings. In addition to
optimizing known comorbidities, preoperative clinic assess-
ment has been shown to diagnose and manage a significant
number of new medical issues that could have significant
impact on patient outcome and day-of-surgery efficiency.17
Most recently, in matched cohorts, in-person preoperative
clinic evaluations have been shown to significantly decrease
postoperative inpatient mortality.18
To achieve the benefits described requires multidisciplin-
ary coordinated development of preoperative systems best
suited for institutions. To be successful, overall medical
direction by a clinician with expertise in perioperative med-
icine as well as operations management is essential. Devel-
oping a value-based business plan supported by evidence-
based clinical protocols is needed. Sufficient resources
should be provided to diagnose and manage comorbidities,
involving outside consultants as needed. The return on
investment in terms of ensuring high-value care should
be documented and metrics established for review by collab-
orative multidisciplinary administrative leadership. Cost of
preoperative services is not an outcome metric; value of pre-
operative services is. Routine preoperative assessment done
by surgery and anesthesia clinicians, as well as routine pre-
operative care provided by the hospital, is already bundled
into the payments received by clinicians and the hospital.
Additional billing therefore cannot be done for routine pre-
operative services because that would be considered double
billing. Administrators who say that preoperative services
do not generate revenue may be uninformed about the cur-
rent state of payment for these tasks. Institutions are, in fact,
being paid for these services. Routine pre- and postoperative
care services are part of the payment already received in the
payments sent to the hospital, surgeon, and anesthesiologist
performing the procedure. Additional consultative and
management services that go beyond routine care can be
billed for, but they require a referral for a specific reason.
Routine history and physical examinations cannot be billed
for separately, whether done by a surgeon, an anesthesiol-
ogist, a hospitalist, or a primary care specialist. Institutions
need to learn how to provide the elements needed efficiently
for routine services and not to eliminate them because they
cannot bill for them separately. There are many elements
required for routine care that cannot be billed for separately,
such as maintenance of an electronic medical record and
salaries of administrators who do not generate clinical bill-
ing. Institutions accept that these are necessary cost centers
30 PART II • Preoperative Assessment
for overall success; preoperative services need to be consid-
ered in a similar manner. Of course, management of more
complex patients can generate separate billing, and the
details of the business case for preoperative services are cov-
ered in a separate chapter.
Risk assessment and optimization require transfer of all
important documentation so that downstream providers
receive high-quality handoffs. Good preoperative assess-
ment systems can ensure this by coordinating informa-
tion that may be fragmented across different providers
and domains. This provides information that is critical
to effective use of the operating rooms as well as patient
safety.
Specifically, in the perioperative setting, authors of a
review of surgical malpractice claims related to communica-
tion breakdowns reported that 43% involved handoffs and
38% of these occurred preoperatively.19 Chow et al20
showed that standardized communication to downstream
providers after preoperative assessment improves multiple
domains, including medical optimization, provider commu-
nication, patient satisfaction, clinical planning, postopera-
tive care, operating room efficiency, and patient safety.
Fig. 4.2 lists some elements impacted by preoperative clinic
handoffs with specific examples. It is very likely that robust
preoperative risk assessment prevents many near misses, as
review of Chow et al.’s publication reveals. The role of pre-
operative assessment in communication across the periop-
erative continuum can be critical, and perioperative
leadership should develop and monitor standardized com-
munication processes.
Domains of Perioperative Care Impacted by
Communication From the
Preoperative Assessment Team
Cross-disciplinary communication
Perioperative care plan
Day of surgery throughput
Postoperative care plan
Patient safety
Patient requests
Fig. 4.2 Downstream impact of preoperative evaluation. ACD, Advance care directive; DDAVP, desmopressin; DNR/DNI, do not resuscitate/do not
intubate order; HCP, home care package; ICU, intensive care unit; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant
enterococci.
Preoperative risk assessment is often discussed in the
setting of specific algorithms. There are a number of algo-
rithms commonly used to define risk and to identify
patients who may benefit from further optimization; these
are discussed in detail in other chapters dealing with peri-
operative physiology. Adult preoperative assessment is
heavily focused on cardiac risk, and commonly used
cardiac risk algorithms have well-known advantages
and disadvantages. Specific pulmonary, hepatic, and
other risk assessment systems are well described. More
generalized risk assessment tools include the National
Surgical Quality Improvement Program, which provides
a risk assessment calculator that is readily available via
the internet and incorporates clinical and demographic
factors to determine risk of postoperative surgical morbid-
ity and mortality.
The problem with using these established risk calculators
is that although they may be validated for their specific use,
risk assessment cannot be measured solely by known algo-
rithms. These algorithms are often geared toward tradi-
tional postoperative metrics, such as in-hospital or 30-day
morbidity and mortality. A patient who dies on day 31 will
not be entered into the 30-day mortality statistic. Is this a
more successful outcome than if the patient had died on
day 30? The value of a procedure should go far beyond these
traditional metrics, and there is in fact an increasing
focus on more patient-centered outcomes. Preoperative
assessment is most valuable when it goes beyond traditional
tools to ensure a holistic approach to assessment. For exam-
ple, traditional surgical calculators may not incorporate
Specific Examples
• Important updates on clinical condition, integrating input from
specialists as needed. Ensuring alignment of team regarding risk
optimization, eliminating positional discussions on day of surgery
• Transmission of information on previous difficult intubation
• Anticoagulation/antiplatelet plans, especially if regional is
considered
• Requirements for specific operating room equipment
• Pretreatment for specific conditions ensured (e.g., DDAVP)
• Orders written for needed day-of-surgery labs
• Need for ICU bed if not currently booked based on comorbidities
• Acute pain service involvement
• VRE, MRSA planning
• Allergies/ sensitivities (e.g., antibiotics, latex, metal)
• Discussion of DNR/DNI documentation
• Ensuring completion of HCP/ACD so downstream teams are
aware

important factors such as frailty and perioperative cognitive
dysfunction that are not routinely measured in most current
preoperative assessment systems.
Because risk assessment of other systems is commonly
used and well described, here the focus is on the areas of risk
assessment that are not commonly used. There has been an
increasing interest in the impact of brain health on periop-
erative outcomes, as well as the importance of routinely
incorporating preoperative cognitive evaluation to obtain
the highest value from preoperative assessment.21
Although the relationship between preoperative cognitive
dysfunction and postoperative complications, including
delirium, is well known, most institutions do not currently
do routine cognitive screening as a part of preoperative
assessment. Culley et al22 validated the use of the Mini-
Cog test for routine preoperative screening for patients over
age 70, showing a significant prevalence of previously
undiagnosed abnormal cognitive stratification that
increases with age. In this study, 24% of patients assessed
had probable cognitive impairment. An analysis of these
patients comparing them with a cohort without preopera-
tive cognitive impairment showed a significant negative
impact on surgical outcomes.23 Those with cognitive
impairment were more likely to experience postoperative
delirium (21% v 7%), had a longer length of stay by
1.12 days, and were more likely to have a nonhome dis-
charge location (67% v 34%). Knowing that patients with
previously undiagnosed cognitive impairment have worse
outcomes strongly supports preoperative cognitive screen-
ing of geriatric patients to identify those at increased risk.
Clinicians can easily be trained to perform this short assess-
ment with good reliability and without impacting clinical
efficiency.24 Preoperative assessment systems need to
include cognitive screening as well as to develop periopera-
tive pathways to mitigate risk associated with abnormal
cognitive stratification to truly achieve risk assessment
and optimization in the geriatric surgical population. The
additional resources that would be required to implement
these pathways should result in a significant return on
investment by preventing complications that can add signif-
icant cost to surgical care. For example, the additional cost
to the surgical encounter of a case of delirium is reported to
be in the range of $15,000 to $60,000.25 The impact of
delirium on the postoperative long-term health-care
trajectory is often significantly negative, adding to overall
health-care costs and worsening long-term patient out-
comes.26 We hope that it is easy to see how the costs of
instituting preoperative cognitive screening as well as im-
plementing a comanagement pathway to reduce
complications such as delirium would be small compared
with the overall costs if these complications were not pre-
vented. In addition, a patient who has not been cognitively
screened preoperatively and is, in fact, in the group that
stratifies as abnormal has been misinformed in terms of
expected risk because it has now been documented that
this is associated with worse outcomes.23 This would there-
fore seem to be an ethical issue as well. Not screening
patients or screening and not informing patients who
stratify as abnormal of these risks because the institution
does not have a good way to mitigate them seems
inherently wrong.
4 • The Value of Preoperative Assessment 31
PREOPERATIVE ASSESSMENT AND POPULATION
MANAGEMENT
Surgery is a public health issue, although it is not frequently
thought of in this way. Appropriate perioperative manage-
ment should identify at-risk groups, whether for clinical
issues or disparity issues, that would benefit from triage to
specific treatments. Preoperative assessment provides signif-
icant value when it includes development and implementa-
tion of perioperative care pathways that appropriately
assign specific patient groups to allocated resources. This
population management throughout the perioperative care
cycle will ensure optimization and mitigation of risk, as well
as cost savings from decreased complications and improved
postoperative health-care trajectories. There are many
pathways that can be used to improve value, and institu-
tions vary in their ability to make use of these pathways
effectively. ERAS is a common example of such a perioper-
ative pathway, requiring a multidisciplinary bundle of peri-
operative care elements used longitudinally that has been
strongly associated with reduced length of stay and fewer
postoperative complications.27 Institutions are establishing
perioperative pathways for patients with diabetes, geriatric
patients, patients with anemia, and patients with risk fac-
tors likely to result in significant pain issues post proce-
dure.28 Now that previously undiagnosed cognitive
dysfunction is known to be a significant predictor of adverse
postoperative outcomes, pathways to mitigate these effects
need to be implemented as well.
Although changing the framework of traditional preoper-
ative assessment systems for population management may
seem daunting, there is increasing evidence in the literature
that implementation and development are clinically and
financially feasible and can have a significant impact on
increasing the value of preoperative assessment. The main
requirement is a perioperative leadership group that is will-
ing to become knowledgeable on these issues, understand
the impact on value for both the patient and the institution,
and willing to redefine resource allocation and metrics to
achieve these results. Unfortunately there are few institu-
tions with enlightened leadership in this area, leaving peri-
operative clinicians fighting an uphill battle to achieve these
clinical models. A recent publication in New England Journal
of Medicine Catalyst highlights the difficulties with this trans-
formation.29 The authors of the publication noted remark-
able gaps in the alignment deemed necessary between key
stakeholders. Although 91% of respondents say it is
extremely necessary for frontline clinicians and top execu-
tives to be aligned, only 30% believe this to be the case at
their own institution. Only 5% reported alignment as a
financial model that provides an incentive for providers
and executives to move toward common goals. Alignment
between executive goals and patient goals is also important;
surgical volume is not a measure of success for patients
receiving surgery, although this is often used as a measure
of success by hospital executives.
Fortunately, there are leaders and mentors guiding the
way in surgical population management. Aronson et al.30
recently described in depth the successful development
and implementation at Duke of a perioperative medicine
model for population health. This publication described
32 PART II • Preoperative Assessment
Phone screen
Preoperative
Referral
from PCP Surgeon’s Triage
or self office visit algorithms
Chart review:
Second surgery by
same service w/i
30 days
Fig. 4.3 Perioperative continuum of care. DNR/DNI, Do not resuscitate/do not intubate order; ERAS, enhanced recovery after surgery; PCP, primary care
physician; SDM, shared decision-making.
the multiple perioperative risk evaluation and optimization
programs at Duke listing modifiable risk and an operational
timeline. Surgical population management must include
preoperative assessment and begins as soon as the decision
for surgery is even contemplated. “Going forward, payment
for health-care delivery will increasingly be based on ser-
vices that contribute to individual and/or population health
value, and funds … will be increasingly vulnerable to com-
petitive markets.”30 To be competitive, institutions must
develop “a sustainable population health strategy … that
includes perioperative medicine as an essential compo-
nent.”30 Fig. 4.3 outlines this process from surgery contem-
plation to post discharge. Once surgery is considered,
patients are triaged to the appropriate level of assessment
so that resources can be assigned on the basis of individual
patient characteristics. The workflow diagram demon-
strates that overall coordination of these resources is part
of preoperative assessment; patients may be assigned to be
low risk and triaged just to preoperative phone screening,
or they may have additional optimization via comanage-
ment pathways such as geriatrics, anemia, and ERAS. This
is required to achieve maximum value for the perioperative
care cycle. Institutional budgets will need to recognize the
importance of assigning resources to implement and main-
tain these pathways to achieve optimal outcomes and
reduce cost. Ensuring that specific pathway-related metrics
are established and monitored and that pathways are
adjusted as evidence evolves will be critical. There is ever-
increasing information in the published literature on the
development and implementation successes of these various
pathways.31
These pathways are not limited to adult surgical care.
Pediatric patients with complex chronic comorbidities can
also benefit from perioperative pathways coordinated
through preoperative assessment systems.32 The prevalence
of children in the United States with special health-care
needs now represents 15.1% of the population less than
18 years of age.32 Additional perioperative pathways will
need to be developed for children with congenital and
acquired chronic diseases and associated special needs that
Triage
clinic visit algor ithms
1. Routine preop visit Documentation
(including SDM) with
2. Pathway assignment handoff
1. ERAS communication
2. Geriatric/cognitive transition of care
3. Diabetes
4. Anemia
5. Pain
6. Antiplatelet/anticoagulation
management
7. Special issue requiring specific
discussion (DNR/DNI, etc.)
will differ from those in the adult population. Perioperative
pathways incorporating holistic preoperative assessment
and coordination of care have been reported to reduce
intensive care unit length of stay and improve outcomes
after pediatric pectus excavatum repair,33 and use of a pedi-
atric adenoidectomy pathway that included protocolizing
care, collaborating among care providers, and educating
families resulted in a significant number of children who
were previously admitted being able to be discharged to
home on the same day as surgery.34
To achieve these goals will require a cultural change on
the part of all the various clinicians who work in this
space and emphasis on the importance of multidisciplinary
perioperative collaborative care and high-value preoperative
assessment to ensure coordination of this care. This agenda
introduces an expanded role for anesthesiologists in achie-
ving key health-care metrics beyond the intraoperative
phase of surgical care, a role that will become increa-
singly important in the setting of pay for performance
and value-based purchasing payment models.35,36
Unfortunately, there are no current mandates to ensure
that this concept occurs during training in any of the disci-
plines involved.
PREOPERATIVE ASSESSMENT AND REGULATORY
ISSUES
A good preoperative assessment system will ensure comple-
tion of all appropriate regulatory requirements. As an exam-
ple, Table 4.1 highlights the measures completed during an
assessment at Brigham and Women’s Hospital. In addition,
regulatory agencies such as CMS will penalize payments to
hospitals that perform poorly compared with their peers in
terms of hospital-acquired conditions.37 Good preoperative
assessment systems can document the presence prior to
admission of certain conditions, such as areas of skin break-
down and pressure ulcers, to avoid payment penalties. Pre-
operative reporting of patients with increased fall risk can
ensure that precautions are put into place to prevent in-
hospital falls.

Regulatory agencies also require that appropriate surgi-
cal and anesthesia consent be obtained, and the day of pro-
cedure is not an ideal time to discuss in detail associated
risks and benefits and attempt to ensure alignment with
patient values and goals. As discussed, the quality of the
shared decision-making in current practice is not ideal,
and no metrics are currently in place.
At a minimum, hospitals must develop informed consent
policies to adhere to regulatory standards outlined by the
CMS and the Joint Commission.38 Institutions must also
be attentive to their own states’ standards for obtaining
and documenting informed consent.
Though necessary, documentation of informed consent is
not sufficient to ensure that decision-making processes
include adequate assessment of patient understanding or
integration of patient values. The next step will entail over-
coming known barriers to shared decision-making such as
provider attitudes, inadequate training, and perhaps most
important time pressure and competing demands on
clinicians’ time.
Preoperative assessment should also ensure that all infor-
mation necessary from a regulatory perspective is correctly
documented for appropriate billing. Incomplete assessment
and incorrect risk stratification can impact not only pay-
ment but also hospital metrics as far as risk adjustment,
overestimating the prevalence of complications because cor-
rect risk adjustment has not been performed. An examina-
tion of the metrics for comorbidities, billing impact, and risk
adjustment at an individual institution may reveal that min-
imizing preoperative assessment resources is resulting in a
significant negative financial impact.
PREOPERATIVE ASSESSMENT SHOULD ENSURE
APPROPRIATE USE OF TESTING
Evidence supporting the impact of preoperative assessment
on reducing inappropriate testing and consultation has
been in the literature for decades.15,17 More recently, the
Choosing Wisely program has reinforced this.39 The pro-
gram’s website provides the most recent information on
appropriate testing by society, and preoperative testing
can be found under the recommendations of the American
Society of Anesthesiology and the American College of Sur-
gery in the Choosing Wisely program.39 Clinicians should
base their institutional laboratory ordering practices on
these recommendations, institute standardized protocols,
and ensure provider education. This website is continually
updated as practices change and should provide a good
long-term reference base for this area of preoperative
assessment.
DOCUMENTATION AND TRANSMISSION OF ALL
IMPORTANT INFORMATION TO DOWNSTREAM
PROVIDERS
High-value preoperative assessment systems can help pre-
vent the fragmentation of perioperative care that often
exists, thereby not exposing patients to unnecessary risks
and handoff errors. Recent work demonstrated the impact
of preoperative assessment on improving documentation
and transmission of important information to operating
4 • The Value of Preoperative Assessment 33
room staff and downstream clinical providers. As discussed
in a previous section on goals of preoperative assessment,
Fig. 4.2 provides a list of affected domains and examples.
Errors in transmission of these issues risk negatively impact-
ing patient safety, operating room efficiency, and potential
failure to act on specific patient issues and requests. For
example, the ubiquitous “presumed full code” is often a part
of electronic medical records when patients in fact have a
DNI/DNR statement on file; although this may have been
discussed as a part of preoperative assessment, appropriate
documentation was not done. This can lead to errors in
handoffs and transitions of care that could have significant
impact during recovery. Unanticipated complications may
occur and decisions may be made that conflict with patient
wishes that are documented elsewhere in the medical
record. Obviously, effective documentation and transmis-
sion of all clinical issues assessed preoperatively are critical.
Verbal or email communication between perioperative pro-
viders without good documentation preoperatively can lead
to significant issues in clinical care. Malpractice claims
reveal that communication breakdowns are among the
most frequent contributors to adverse events in medicine,
resulting in serious injury to patients.19 Communication
and documentation are critical to surgical safety, and preop-
erative assessment should ensure that this occurs appropri-
ately during the transition from preoperative to procedural
areas. Preoperative assessment allows a pause to occur
when discussion can take place among patient, family mem-
bers, and clinical providers to ensure alignment. Documen-
tation in the electronic medical record should reflect the
results of this communication and final recommendations.
This will avoid difficult and positional discussions on the
day of the procedure, which are stressful for patients as well
as caregivers if alignment has not been reached as a part of
preoperative assessment.
PATIENT/FAMILY EDUCATION AND DISCHARGE
PLANNING
Patient education and engagement during preoperative
assessment are becoming even more important because
these are key components of successful perioperative path-
ways and enhanced recovery programs.40 This will support
recovery by improving adherence to processes of care that
must be completed by the patient to achieve optimal out-
comes. For example, education regarding elements of preha-
bilitation, including exercise, as well as nutritional uptake,
adherence to medication instructions, and facilitation of
postdischarge follow-up has the potential to improve out-
comes. In addition, appropriate patient assessment can help
predict those who are more likely to require nonhome dis-
charge. Part of the preoperative assessment can include dis-
cussions with care coordination and physical therapy
services when indicated so that preprocedural planning will
set patient and family expectations appropriately and start
the discharge-planning process as part of the preoperative
assessment. This should help to reduce length of stay by
identifying early in the preoperative process patients in need
of these services. Patient education during preoperative
assessment goes far beyond discussion of risks and benefits
and should clearly outline expectations, ensure prepared-
ness, and empower the patient and family to become
34 PART II • Preoperative Assessment
activated as key stakeholders in the process and positively
impact their own health-care.41
Preoperative assessment is also an opportunity to ensure
that surrogates and health-care proxies, who are often fam-
ily members, understand what the patient would want if
decisions need to be made during a time the patient is unable
to make them. Alignment between surrogate and patient is
often not addressed because the patient may never have dis-
cussed these issues with the person whose name is listed on
the health-care proxy form. Time for this discussion should
be included during preoperative assessment, especially for
seriously ill or elderly patients facing high-risk procedures.
Conclusions
High-value preoperative assessment provides a pause point
when completion of all the elements described in this chap-
ter can be assured. We have now incorporated the use of
surgical safety checklists into routine care,42 and implemen-
tation science suggests that innovations such as checklists
need to be inserted at a natural “pause point” during the
workflow to promote sustainability. The period just before
induction has been identified as a natural pause point when
all involved disciplines can perform the checklist, but we
acknowledge that learning about critical issues just prior
to induction using these checklists may not be the ideal
time. High-value preoperative assessment provides a pause
point when completion of all the elements described can be
assured. Perhaps an additional checklist reflecting comple-
tion of preoperative assessment elements should be added
upstream to ensure completion of all factors related to per-
formance of high-value preoperative assessment.
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4 • The Value of Preoperative Assessment 35
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 5 Perioperative Cardiac Risk
Assessment in Noncardiac
Surgery
DIANA AYUBCHA, TARAS GROSH, and LEE A. FLEISHER
Introduction
Anesthesia has become increasingly safer.1 According to
the Anesthesia Quality Institute’s National Anesthesia Clin-
ical Outcomes Registry, comprising over 30 million cases,
perioperative mortality has significantly decreased in
high-income countries despite a population increasingly
burdened by severe comorbidities.2 Nevertheless, cardiac
complications are still common after noncardiac surgery,
with myocardial infarction (MI) being the single most com-
mon cause of death.3 Annually, 4% of the world’s popula-
tion will undergo a surgical procedure, and 30% of those
patients have at least one cardiovascular risk factor. The
30-day mortality of patients with at least one cardiovascular
risk factor is 0.5%–2%.4 Many efforts have been made to
quantify risk through indices and algorithms in multivariate
analyses. However, although cardiac risk can be measured,
interventions are often not performed in a timely manner.
This chapter’s focus is to assist the physician responsible
for the well-being of the patient scheduled for surgery to
do the following: (1) clinically assess the patient’s current
medical status and provide a clinical risk profile, (2) decide
whether further cardiac testing is indicated prior to surgery,
and (3) make recommendations concerning the risk of peri-
operative cardiac complications and alter management
with the purpose of lowering that risk.
Preoperative History and Physical
Examination
Once a patient decides to undergo a surgical procedure, an
entire care team is dedicated to ensuring that there are min-
imal complications during the perioperative process. The
perioperative evaluation is a multidisciplinary effort with
good communication between the patient, primary care
physician, anesthesiologist, cardiologist, and surgeon. For
elective procedures, patients should schedule an appoint-
ment with their primary care physician in order to undergo
initial presurgical screening. The primary care evaluation
will consist of a detailed history, physical examination,
and review of pertinent laboratory data. A thorough review
of the medical record is done to identify any previous cardiac
examination or workup: electrocardiogram (ECG), echocar-
diography, stress testing, or cardiac catheterization. As part
36
of the physical examination, physicians should assess for
signs or symptoms of cardiopulmonary dysfunction and
any associated comorbidities. The overall goal is to identify
active cardiac conditions that may have developed in the
months preceding noncardiac surgery. The aim of appropri-
ate preoperative evaluation and therapy in individuals with
established coronary artery disease (CAD) is not only to
improve immediate perioperative outcome but also to
improve the long-term clinical outcome.
The severity, frequency, and duration of symptoms, as
well as treatments initiated, should be recorded. A detailed
physical examination of the cardiovascular system is per-
formed, looking for evidence of heart disease (Table 5.1).
In addition to the physical examination findings, a detailed
review of the history can identify clinical predictors of car-
diovascular risk. Table 5.2 lists the clinical predictors of peri-
operative cardiovascular risk. Major risk factors require
immediate attention, whether through testing or cardiology
consultation, in order to lower the long-term risk, regardless
of the need for surgery. In emergent nonelective cases, the
benefits of proceeding with surgery frequently outweigh the
risk of waiting for additional testing. In such situations, phy-
sicians must be ready to manage cardiovascular complica-
tions intraoperatively as well as postoperatively in at-risk
patients. It is worth mentioning that abnormal findings of
a physical examination as well as extracted from the
patient’s history may justifiably warrant postponing the
scheduled surgical procedure.
ECG
Unless the patient is undergoing a low-risk surgery, an ECG
is obtained in patients with cardiovascular disease, arrhyth-
mias, or structural heart disease, as recommended by 2014
guidelines of the American College of Cardiology/American
Heart Association (ACC/AHA) and the European Society of
Cardiology/European Society of Anaesthesiology (ESC/
ESA).5 Although ECG abnormalities have an inconsistent
prognostic factor, they serve as a baseline in the event that
perioperative complications arise. The ECG should be evalu-
ated for the presence of Q waves, significant ST-segment ele-
vations and depressions, ischemia, infarction, left
ventricular (LV) hypertrophy, QTc prolongation, bundle
branch block, or arrhythmia.6
 5 • Perioperative Cardiac Risk Assessment in Noncardiac Surgery 37

Table 5.1 Signs and symptoms of cardiac disease. Table 5.2 Clinical predictors of increased perioperative car-
diovascular risk.a
Location Signs Symptoms Complaints
Major Intermediate Minor
Hands Clubbing Heart failure Dyspnea
Splinter Orthopnea b
Unstable ACS Mild angina Advanced age
hemorrhages Tachypnea
Asthma MI within 60 days Prior MI: pathologic Abnormal ECG
unresponsive to Q waves (LVH, LBBB, ST-T
bronchodilator abnormality)

Radial Rate/rhythm/ Arrhythmia Palpitations Unstable anginab Compensated/prior Rhythm other

pulse volume Dizziness heart failure than sinus
Character/ Syncope Decompensated heart Diabetes mellitus Low functional
contour Orthostatic failure capacity
Bruits
Symmetry High-grade arrhythmia History CVA
Blood Systolic + Coronary Angina Severe valvular disease Uncontrolled
pressure diastolic artery Dyspnea systemic HTN
Hypertension disease
Hypotension SVT with uncontrolled Obesity
ventricular response
Carotid Volume Auscultation: New systolic +
pulse Character cardiac diastolic murmurs ACS, Acute coronary syndrome; CVA, cerebrovascular accident; ECG,
Bruit S3 heart sounds electrocardiogram; HTN, hypertension; LVH, left ventricular hypertrophy;
LBBB, left bundle branch block; MI, myocardial infarction; SVT,
Jugular Height Auscultation: Rales/rhonchi supraventricular tachycardia.
venous Waveform lungs crackles/wheeze a
Risk includes myocardial infarction, congestive heart failure, and death.
pressure b
May include stable angina in unusually sedentary patients.
Face Pallor Abdomen Hepatomegaly Reprinted with permission from Fleisher LA, Fleischmann KE, Auerbach AD, et al:
Mouth Central Ascites 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and
Eyes cyanosis Aortic aneurysm management of patients undergoing noncardiac surgery: Executive summary:
Malar flush bruit A report of the American college of cardiology/American heart association task
Dental caries force on practice guidelines. Reprinted with permission Circulation 2014;130
Fundi (24):2215–2245. © 2014 American Heart Association, Inc.

Precordium Apical Legs Peripheral pulses

impulse Edema
Thrills/ Calf pain
heaves
Scar
Skin Skin temperature
Sweating
Urine output
Created by Taras Grosh, MD
Metabolic Equivalents
Part of the history and physical is an assessment of func-
tional capacity based on the number of metabolic equiva-
lents (METs) that a patient can perform. METs are
determined on the basis of a set of questions administered
by the physician to the patient. The Duke Activity Status
Index (DASI) is a 12-item questionnaire that uses self-
reported physical work capacity to estimate peak METs
and has been shown to be a valid measurement of functional
capacity.7 One MET is defined as 3.5 mL/kg/min of oxygen
uptake, the equivalent of sitting at rest.8 Table 5.3 lists activ-
ities and their corresponding METs. Those patients able to do
more than 4 METs are largely said to be at low risk for a car-
diovascular complication. Unfortunately, subjective assess-
ment of functional capacity has limitations when
compared with formal objective testing. The researchers
in the Measurement of Exercise Tolerance before Surgery
(METS) study reported that when comparing formal indices
and questionnaires (DASI) and formal cardiopulmonary
exercise testing (CPET), subjective interpretation of METs
did not accurately identify patients with poor cardiovascular
fitness or predict postoperative morbidity and mortality.9 Of
the 1401 patients included in the study, subjective assess-
ment only identified 16% correctly as being able to achieve
less than 4 METs.9 Moreover, high-risk patients were fre-
quently misclassified as being at low risk. Importantly, there
are characteristics of CPET that predict all-cause mortality
and can be useful in determining fitness for surgery. A
key part of the 2014 ACC/AHA algorithm—subjective
assessment of functional capacity—is important in order
to avoid missing severely deconditioned individuals.
Risk Assessment
All patients scheduled to undergo noncardiac surgery
should have an assessment of the risk of a perioperative car-
diac event done by their primary care physician using the
ACC/AHA perioperative cardiovascular evaluation algo-
rithm (Fig. 5.1). The algorithm combines the patient-specific
risk factors obtained from the history, physical examination,
and 12-lead ECG, with surgical risk factors to determine the
overall risk of experiencing a cardiac event. In the past, pre-
operative cardiac risk stratification practices grouped oper-
ations into broad categories, which might inadequately
consider the intrinsic cardiac risks of individual operations.
Using high-quality clinical data from more than 3.2 million
patients, Liu et al10 empirically derived the intrinsic risk of
individual operations for perioperative cardiac events, as
shown in Table 5.4.
Once all data are available, the algorithm is used by
health-care providers to weigh the surgical risks and bene-
fits, optimize the timing of the surgery, and discuss possible
alternatives to surgery. Low-risk patients undergoing low-
risk procedures as well as patients requiring emergent
38 PART II • Preoperative Assessment

Patient scheduled for

surgery with known or risk
factors for CAD (step 1)

Emergency

No Yes

ACS (step 2) Clinical risk stratification

and proceed to surgery

No Yes

Estimated perioperative Evaluate and treat

risk of MACE based according to GDMT
on combined clinical/
surgical risk
(step 3)

Low risk (< 1%) Elevated risk

(stepl 4) (step 5)

No further testing Moderate or greater

(Class III: NB) ( ⱖ4 METs) functional capacity

Proceed to surgery No or Moderate/good Excellent

unknown ( ⱖ4–10 METs) (<10 METs)

Poor OR unknown functional No further testing No further testing

capacity (<4 METs): (Class IIb) (class IIA)
Will further testing impact
decision making OR
perioperative care? (step 6) Proceed to surgery

No Yes

Proceed to surgery according Pharamacologic

to GDMT OR alternate strategies If normal stress testing
(noninvasive treatment, palliation) (class IIa)
(step 7)

If abnormal

Coronary revascularization
according to existing
CPGs (class I)

Fig. 5.1 Stepwise approach to perioperative cardiac assessment for coronary artery disease (CAD). ACS, Acute coronary syndrome; CPG, clinical practice
guideline; GDMT, guideline-directed medical therapy; MACE, major adverse cardiac events; METs, metabolic equivalents; NB, no benefit. (Reprinted with
permission from Fleisher LA, Fleischmann KE, Auerbach AD, et al: 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of
patients undergoing noncardiac surgery: Executive summary: A report of the American college of cardiology/American heart association task force on practice
guidelines. Reprinted with permission Circulation 2014;130(24):2215–2245. © 2014 American Heart Association, Inc.)

interventions will proceed to surgery without further test-
ing. Patients with poor or unknown functional capacity
may require a formal consultation with a cardiologist, phar-
macologic stress testing, and/or coronary revascularization
in order to reduce the risk of major adverse cardiac events
because it is well established that patients with CAD and
prior percutaneous coronary intervention (PCI) who
undergo noncardiac surgery have a significantly increased
risk of postoperative adverse events compared with the gen-
eral population.11
 5 • Perioperative Cardiac Risk Assessment in Noncardiac Surgery 39

Pateints age ≥45 years or 18–44 years with known significant cardiovascular disease*
Pateints undergoing noncardiac surgery requiring overnight hospital admission

Timing of
Emergency surgery Urgent/semiurgent surgery Elective surgery
surgery‡

Proceed to surgery; only Assessment of perioperative cardiac risk

undertake preoperative Risk stratification with RCRI§
Proceed to surgery
cardiac assessment if
without additional
unstable cardiac condition or
preoperative
suspected undiagnosed If a pateint’s age ≥65 years, RCRI ≥1, or age
cardiac assessment
Preoperative severe PHTN or obstructive 45–64 years with significant cardiovasular
assessment cadriac disease£ disease* → order NT-proBNP/BNP

Positive Negative
NT-proBNP or
NT-proBNP NT=proBNP
If patient’s age ≥65 years or 18–64 years with significant BNP
300mg/L or <300 mg/L or
cardiovascular disease* not available
BNP ≥92 mg/L BNP <92 mg/L

No additional
Measure troponin daily x 48–72 hrs
Postoperative routine
Obtain ECG in PACU
monitoring postoperative
Consider in-hospital shared-care management**
monitoring

Fig. 5.2 Preoperative risk assessment and postoperative monitoring flow diagram provides an overview of the Canadian Cardiovascular Society (CCS)
approach to preoperative cardiac risk assessment and perioperative cardiac monitoring. The CCS divided surgeries into three categories on the basis of
the timing of surgery (i.e., emergent, urgent/semiurgent, and elective), and these categories influenced the recommendations regarding preoperative
cardiac risk assessment. BNP, Brain natriuretic peptide; ECG, electrocardiogram; NT-proBNP, N-terminal probrain natriuretic peptide; PACU, posta-
nesthesia care unit; PHTN, pulmonary hypertension; RCRI, Revised Cardiac Risk Index. *Significant cardiovascular disease includes known history of
coronary artery disease, cerebral vascular disease, peripheral artery disease, congestive heart failure, severe PHTN, or a severe obstructive intracardiac
abnormality (e.g., severe aortic stenosis, severe mitral stenosis, or severe hypertrophic obstructive cardiomyopathy). ‡Timing of surgery refers to
emergency surgery (e.g., severe trauma, ruptured aortic aneurysm), urgent surgery (e.g., hip fracture, bowel obstruction), semiurgent surgery (e.g.,
cancer with potential to metastasize), or elective surgery (e.g., knee arthroplasty). £If physical examination suggests there is an unknown severe
obstructive intracardiac abnormality (e.g., severe aortic stenosis, severe mitral stenosis, or severe hypertrophic obstructive cardiomyopathy) or severe
PHTN, then obtain an echocardiogram before surgery to inform the anesthesiologist, surgeon, and medical team of the type and degree of disease. If
the history suggests the patient has an unstable cardiac condition (e.g., unstable angina), then discussion with the patient and surgical/medical team is
required to decide whether to delay, cancel, or proceed with surgery. §RCRI score (each worth 1 point): history of coronary artery disease, cerebro-
vascular disease, congestive heart failure, preoperative insulin use, preoperative creatinine greater than 177 μmol/L, and high-risk surgery (i.e., intra-
peritoneal, intrathoracic, or suprainguinal vascular surgery). **Shared-care management refers to a multidisciplinary approach to inpatient
postoperative care; this includes the surgeon and a medical specialist (e.g., internist, cardiologist, gerontologist), who will help with perioperative
monitoring and management of cardiovascular complications. (With permission from Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular
Society guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery. Can J Cardiol. 2017;33:17-32..)

Table 5.3 Metabolic equivalents (METs). Table 5.4 Surgical risk factor chart.
METs Activity Estimated
cardiac risk
1 At rest of
3-4 Introduction to pilates ORa hypothetical
Light housework Description (95% CI) patientb (%) Reliabilityc
Golf (carrying clubs) Low intrinsic cardiac
4-5 Weightlifting, vigorous risk
Climbing flight of stairs Partial mastectomy 0.22 (0.15–0.31) 0.05 1.00
6 Moving furniture (lumpectomy)

8 Basketball Arthroscopic rotator 0.32 (0.19–0.54) 0.07 1.00

cuff repair
10 Competitive soccer
Simple mastectomy 0.37 (0.26–0.50) 0.08 1.00
Adapted with permission from Coutinho-Myrrha MA, Fernandes AA, Araújo (complete breast)
CG, et al. Duke Activity Status Index for cardiovascular diseases: validation of
the Portuguese translation. Arq Bras Cardiol. 2014;102:383-390. Continued
40 PART II • Preoperative Assessment

Table 5.4 Surgical risk factor chart—cont’d This systematic evaluation is useful for identifying poten-
tial medical problems patients may unknowingly possess.
Estimated Regardless of whether the patient proceeds with surgery,
cardiac risk
of
the medical problems identified need to be treated.
OR hypothetical
Description (95% CI) patient (%) Reliability
Risk Models
Laparoscopic 0.45 (0.33–0.62) 0.10 1.00
appendectomy Although many models exist to estimate cardiovascular
Laparoscopic 0.62 (0.53–0.72) 0.14 1.00 risk, each has its limitations. The Revised Cardiac Risk Index
cholecystectomy (RCRI), also known as the Lee index, and the American
Intermediate College of Surgeons National Surgical Quality Improvement
intrinsic cardiac risk Program (NSQIP) risk model calculator are two models
Transurethral 0.85 (0.61–1.20) 0.19 0.94
frequently used to estimate cardiovascular risk in noncar-
resection of bladder diac surgery. Table 5.5 lists the risk factors and models cur-
tumor, large rently used to predict the likelihood of a cardiovascular
Laparoscopic 0.88 (0.69–1.12) 0.19 1.00
complication. Although atrial fibrillation and obesity are
prostatectomy not included as characteristics in the abovementioned pre-
dictive models, the presence of either carries higher risk of
Open 0.95 (0.51–1.75) 0.21 0.96
appendectomy
cardiovascular complications.12,13
We define perioperative risk as the likelihood that a patient
Total hip 0.95 (0.83–1.08) 0.21 1.00 will experience a cardiac complication at the time of surgery.
arthroplasty
The Dripps–American Surgical Association (ASA) classifi-
Laparoscopic radial 1.05 (0.57–1.94) 0.23 0.96 cation was initially developed and used through the late
hysterectomy with 1970s for the preoperative assessment of surgical risk.14
bilateral salpingo-
oophorectomy
High intrinsic cardiac
risk
Table 5.5 Risk factors used in risk prediction models.

Laparoscopic total 1.50 (0.92–2.44) 0.33 0.95 RISK FACTOR MODELS

abdominal AUB-POCES
colectomy with NSQIP RCRI CVRI VSG-CRI
ileostomy
a
Type of surgery Type of Age Increased
Breast 1.52 (0.81–2.86) 0.33 0.97 surgerya >75 years age
reconstruction with
free flap Increased History of History of Insulin-
age ischemic heart heart disease dependent
Open 1.55 (1.25–1.92) 0.34 0.95 disease diabetes
cholecystectomy
American Society of History of Symptoms of Coronary
Open ventral hernia 1.78 (1.29–2.44) 0.39 0.95 Anesthesiologists heart failure angina/ artery
repair, incarcerated physical status dyspnea disease
or strangulated, classification
recurrent
Perioperative History of Hgb Congestive
Whipple procedure, 4.70 (4.00–5.53) 1.02 0.86
functional status heart failure <12 mg/dL heart failure
pylorus-sparing
Perioperative serum Insulin- Vascular Abnormal
See Supplemental Table 1, Supplemental Digital Content (http://links.lww. creatinine dependent surgery cardiac
com/ALN/B593) for a comprehensive list. >1.5 mg/dL DM stress test
CI, Confidence interval; OR, odds ratio.
a Perioperative Emergency Long-term
ORs are relative to the statistically estimated average procedure. Values
greater than 1.0 represent higher-than-average risk for perioperative serum surgery β-blocker
adverse cardiac events, whereas values less than 1.0 represent lower-than- creatinine therapy
average risk for perioperative adverse cardiac events. >2.0 mg/dL
b
The hypothetical patient used to estimate numerical risk values across all
COPD
operations for comparison was a 67-year-old white female with
hypertension, diabetes requiring oral therapy, and a body mass index of Creatinine
32 kg/m2 (class I obesity), who is functionally independent, does not smoke, >1.8 mg/dL
and has American Society of Anesthesiologists physical status II
classification. AUB-POCES CVRI, American University of Beirut Pre-Operative Cardiovascular
c
Statistical reliability represents the confidence in the rank of the Common Evaluation Study Cardiovascular Risk Index; COPD, chronic obstructive
Procedural Terminology (CPT) code. Conceptually, it is the signal-to-noise pulmonary disease; DM, diabetes mellitus; Hgb, hemoglobin; NSQIP,
ratio. Reliability is a continuous number ranging from 0 to 1, where CPT American College of Surgeons National Surgical Quality Improvement
codes with values closer to 1 mean CPT codes are appropriately ranked and Program; RCRI, Revised Cardiac Risk Index; VSG-CRI, Vascular Study Group of
the OR can be considered reliable. New England Cardiac Risk Index.
a
With permission from Liu JB, Liu Y, Cohen ME, et al. Defining the intrinsic Cardiac death or nonfatal myocardial infarction: high-risk procedure >5%,
cardiac risks of operations to improve preoperative cardiac risk intermediate-risk procedure 1%–5%, low-risk procedure <1%.
assessments. Anesthesiology. 2018;128:283-292. Created by Taras Grosh, MD
 5 • Perioperative Cardiac Risk Assessment in Noncardiac Surgery
The Dripps-ASA classification stratified patients into five
classes based on general medical history and physical status,
but it did not direct attention to elements of the patient
history that were specific for different types of perioperative
complications. The ASA classification gave clinicians a
measure of predictive power for noncardiac perioperative
complications, but it was found to be less reliable in helping
anticipate the development of cardiac-specific adverse
events.
Risk models such as the Goldman cardiac risk index,
Detsky modified risk index, and Eagle criteria were also used
at one time, but they have been replaced by newer, more
reliable models. Although new models still have limitations
in predictive ability, they are more reflective of the current
population. Physicians are urged to familiarize themselves
and learn one of the following risk models: Lee RCRI, NSQIP,
Gupta Perioperative Risk for Myocardial Infarction or Car-
diac Arrest calculator, and the newer online NSQIP Surgical
Risk Calculator.15–17
The NSQIP index was validated in 2008 and developed
from a database of over 200,000 patients who experienced
an intraoperative or postoperative MI or cardiac arrest; the
NSQIP index outperforms the RCRI.16 The RCRI was pub-
lished in 1999 from a database of nearly 3000 patients
undergoing noncardiac surgery and evaluated those subse-
quently experiencing major cardiac complications.15 In
2009, a systematic review identified that the model per-
formed well at distinguishing low- from high-risk patients
undergoing noncardiac surgery, but the model did not per-
form well in predicting all-cause mortality or risk specifically
in vascular surgery.18 A simplified (five vs six factors) recon-
structed RCRI excluded diabetes and insulin treatment and
resulted in superior predictive ability for major cardiac com-
plications.19 The rates of cardiac death, nonfatal MI, nonfa-
tal cardiac arrest, MI, pulmonary edema, ventricular
fibrillation, primary cardiac arrest, and complete heart block
are directly proportional to the number of risk factors, as
shown in Table 5.6.
Table 5.6 Revised Cardiac Risk Index: rate of complications.
RATE OF CARDIAC DEATH, NONFATAL MYOCARDIAL INFARCTION,
AND NONFATAL CARDIAC ARREST
No risk factors 0.4% (95% CI, 0.1–0.8)
One risk factor 1.0% (95% CI, 0.5–1.4)
Two risk factors 2.4% (95% CI, 1.3–3.5)
Three or more risk factors 5.4% (95% CI, 2.8–7.9)
RATE OF MYOCARDIAL INFARCTION, PULMONARY EDEMA,
VENTRICULAR FIBRILLATION, PRIMARY CARDIAC ARREST, AND
COMPLETE HEART BLOCK
No risk factors 0.5% (95% CI, 0.2–1.1)
One risk factor 1.3% (95% CI, 0.7–2.1)
Two risk factors 3.6% (95% CI, 2.1–5.6)
Three or more risk factors 9.1% (95% CI, 5.5–13.8)
CI, Confidence interval.
Adapted with permission from Davis C, Tait G, Carroll J, et al. The revised
cardiac risk index in the new millennium: a single-centre prospective cohort
re-evaluation of the original variables in 9,519 consecutive elective surgical
patients. Can J Anaesth. 2013;60:855-863. Created by Taras Grosh, MD
41
The 2019 American University of Beirut (AUB) Pre-
Operative Cardiovascular Evaluation Study is a prospective
study that enrolled consecutive adult patients (aged 40 years
and older) scheduled for noncardiac surgery at AUB
between July 1, 2016, and December 30, 2017.20 The pres-
ence of four specific data elements was recorded for each
patient (aged 75 years or older, history of heart disease,
symptoms of angina or dyspnea, and vascular surgery).
Each patient was assigned a Cardiovascular Risk Index
(CVRI) of 0, 1, 2, or  3, based on the number of data ele-
ments present. Patients were followed for 30 days after sur-
gery. The primary outcome measure was death, MI, or
stroke. The CVRI performed better than RCRI at predicting
all-cause mortality; has strong discriminatory power; and
can effectively stratify patients into very low–, low-,
intermediate-, and high-risk groups. Although promising,
additional validation is still needed.
The Vascular Study Group of New England created a risk
index specifically for patients undergoing vascular surgery
using increasing age, smoking, insulin-dependent diabetes
mellitus, CAD, congestive heart failure (CHF), abnormal stress
test, long-term β-blocker therapy, chronic obstructive pul-
monary disease, and creatinine > 1.8 mg/dL.21 The RCRI
substantially underestimates in-hospital cardiac events in
patients undergoing elective or urgent vascular surgery,
especially after lower-extremity bypass, endovascular
abdominal aortic aneurysm repair, and open abdominal
aortic aneurysm repair. The Vascular Study Group of
New England Cardiac Risk Index more accurately predicts
in-hospital cardiac events after vascular surgery and repre-
sents an important tool for clinical decision-making.
Patients classified as being at low risk have an estimated
risk of death less than 1% and can proceed to surgery; high-
risk patients have a risk of death greater than 1% and
require further CPET, such as stress testing, echocardiogra-
phy, or coronary revascularization, only if it is indicated
even in the absence of said surgery. Additional testing in
the absence of an indication has not been shown to improve
surgical outcomes. Evaluation of high-risk patients is based
on the 2014 ACC/AHA algorithm.
Despite the collaborative efforts between the ACC/AHA
and ESC/ESA to minimize discrepancies in recommen-
dations, the Canadian Cardiovascular Society (CCS) Guide-
lines Committee and key Canadian opinion leaders created a
separate set of guidelines for the perioperative evaluation of
patients for noncardiac surgery in October 2016
(Fig. 5.2).22 The ACC/AHA and ESC/ESA guidelines rely
on stress testing to elicit cardiac symptoms in those with
questionable functional capacity, whereas the CCS guide-
lines make a strong recommendation against performing
pharmacologic stress testing preoperatively for enhancing
perioperative cardiovascular risk estimation, citing limita-
tions in study methodology. Instead, the CCS focuses more
on biomarkers, claiming higher quality of evidence but also
because of the lower cost and rapidity of results. Moreover,
the CCS claims the cascade of events after a positive stress
test may delay elective surgery for up to 1 year, significantly
impacting a patient’s quality of life. The CCS list of strong
recommendations included the following22:
1. Measuring brain natriuretic peptide (BNP) or N-terminal
fragment of proBNP (NT-proBNP) before surgery to
enhance perioperative cardiac risk estimation in patients
42 PART II • Preoperative Assessment
who are 65 years of age or older, are 45–64 years of age
with significant cardiovascular disease, or have an RCRI
score  1;
2. Not performing preoperative resting echocardiography,
coronary computed tomographic angiography, exercise
testing or CPET, pharmacologic stress echocardiography,
or radionuclide imaging to enhance perioperative car-
diac risk estimation;
3. Not initiating or continuing acetylsalicylic acid for the
prevention of perioperative cardiac events, except in
patients with a recent coronary artery stent or who will
undergo carotid endarterectomy;
4. Not initiating α2-agonist or β-blocker therapy within
24 hours before surgery;
5. Withholding angiotensin-converting enzyme inhibitor
and angiotensin II receptor blocker therapy starting
24 hours before surgery;
6. Facilitating smoking cessation before surgery;
7. Measuring daily troponin for 48–72 hours after surgery
in patients with an elevated NT-proBNP/BNP measure-
ment before surgery or if there is no NT-proBNP/BNP
measurement before surgery, in those who have an RCRI
score  1, are aged 45–64 years with significant cardio-
vascular disease, or are aged 65 years or older; and
8. Initiating long-term acetylsalicylic acid and statin ther-
apy in patients who experience myocardial injury/infarc-
tion after surgery
CARDIAC TESTING
Multiple modalities of noninvasive cardiac testing are avail-
able for the clinician performing a preoperative cardiovascu-
lar evaluation of a patient who is to undergo noncardiac
surgery. Tests can be done to study cardiac function under
resting conditions or in settings of increased stress and oxy-
gen demand. Patients who report a high capacity for exer-
cise tolerance in their daily activities usually gain little from
additional testing.23 Routine screening with noninvasive
stress testing is not considered useful for patients at low risk
for noncardiac surgery and is considered a class III indica-
tion according to the latest ACC/AHA recommendations.5
Stress testing is recommended as a class IIb indication for
patients with an increased risk and unknown functional
capacity to assess for functional capacity if it may alter
management.5
Resting echocardiography is not indicated in the perioper-
ative patient unless there is another indication: evaluation of
valve function in patients with a murmur or evaluation of LV
systolic function in patients with CHF or dyspnea. Tradition-
ally, measurements of the left ventricular ejection fraction
(LVEF) were thought to help identify patients at increased risk
of postoperative cardiac complications. Multiple retrospective
and prospective studies looked at the correlation between pre-
operative LV systolic function and the risk of postoperative
cardiac morbidity and mortality.24–27 The shared conclusion
of these studies was that the greatest incidence of postopera-
tive cardiac complications occurred in patients with an LVEF
less than 35%, linking poor ejection fraction to a higher inci-
dence of postoperative ischemia, CHF, and death. Despite
these data, a resting echocardiogram has never been
unequivocally demonstrated to be a reliable predictor of peri-
operative ischemic events.28,29
Stress testing can be considered for patients undergoing
major vascular procedures; otherwise, it is not indicated in
the perioperative patient solely on the basis of an upcoming
noncardiac surgery.30,31 Interestingly, although a direct
correlation exists between the degree of myocardial ische-
mia and prognosis, prophylactic revascularization to
prevent perioperative ischemia does not improve out-
comes.31 In ambulatory patients, exercise stress testing
is usually preferred over pharmacologic stress testing
because it gives the physician an idea of functional capac-
ity as well as a global picture of exercise tolerance. Limita-
tions may be encountered when attempting to administer
exercise testing to patients at high risk for perioperative
events. About half of the patients fail to achieve the age-
predicted target heart rates necessary to rule out myocar-
dial ischemia because of effort limitations or pharmaco-
logic alterations from β-blockers/calcium channel blockers.
Some patients are unable to exercise because of the primary
disease that the noncardiac surgical procedure seeks to
address, such as claudication in patients with vascular prob-
lems and severe degenerative joint disease in the orthopedic
population. If an exercise stress test is performed, obtaining
the details of the examination is critical. Peak heart rate, sys-
tolic blood pressure, number of METs achieved, predicted tar-
get heart rate, and presence of ECG changes or symptoms
provide a better clinical picture to the physician than a simple
“normal” or “abnormal” determination. If ischemia is identi-
fied, noting the heart rate and blood pressure at which it
occurred may be useful for intraoperative and postoperative
management.
Patients unable to exercise need pharmacologic evalua-
tion with either dipyridamole/adenosine (coronary vasodi-
latory effects) or dobutamine (increase in oxygen demand)
paired with nuclear imaging to look for changes in myocar-
dial perfusion effected by these vasodilatory agents.
Twenty-four–hour ambulatory monitoring is not other-
wise recommended for perioperative diagnostic or prognos-
tic purposes, because its use has not been shown to improve
outcomes in the surgical setting. Indications for 24-hour
ambulatory monitoring are primarily syncope—significant
bradycardia or tachycardia if not previously evaluated.
Mangano et al.,32 through multivariate analysis, showed
no perioperative variable to be independently associated
with ischemic events, including cardiac risk index, a history
of previous MI or CHF, or the occurrence of ischemia before
or during surgery.
Interventions: Preoperative
Coronary Revascularization
Patients in need of coronary revascularization, regardless of
the upcoming surgery, should have the procedure per-
formed only if clinically warranted.33 The 2014 ACC/
AHA guideline on perioperative cardiovascular evaluation
and management of patients undergoing noncardiac sur-
gery, based on all available evidence, stated that it is not
recommended that routine coronary revascularization be
performed before noncardiac surgery exclusively to reduce
perioperative cardiac events, and in fact the guideline gives
it a class III recommendation.5
 5 • Perioperative Cardiac Risk Assessment in Noncardiac Surgery
Percutaneous Coronary
Intervention
The 2014 ACC/AHA guidelines state that the role of preop-
erative PCI in reducing untoward perioperative cardiac
complications is uncertain, given the available data. Per-
forming PCI before noncardiac surgery should be limited
to (1) patients with left main coronary artery disease whose
comorbidities preclude bypass surgery without undue risk
and (2) patients with unstable CAD who would be appropri-
ate candidates for emergent or urgent revascularization.5
Review of various studies with 50 patients or more under-
going noncardiac surgery after percutaneous transluminal
coronary angioplasty demonstrated rates of perioperative
mortality and MI that were not significantly better than
rates in control subjects.5 Another study showed a lower
30-day rate of cardiac complications in patients who
received their PCI at least 90 days prior to noncardiac sur-
gery, but this benefit was lost if the intervention was done
within 90 days, suggesting that a prophylactic angioplasty
does not necessarily improve postoperative outcome.34 The
placement of coronary stents carries an even higher risk of
postprocedural complications when combined with noncar-
diac surgery. One study observed that 40 patients who
received PCI and stents placed less than 6 weeks before
an elective noncardiac surgery had high rates of periopera-
tive mortality, MI, and bleeding.35 The majority of patients
with catastrophic outcomes had had stents placed less than
14 days prior to surgery. Death was chiefly attributed to
stent thrombosis in the first 2 weeks after placement. Wilson
et al.36 reexamined this question and suggested that surgery
should be delayed at least 6 weeks after stent placement,
providing optimal time for coronary endothelial healing
and the discontinuation of required antiplatelet agents.
Patients with ST-elevation MI or non–ST-elevation acute
coronary syndrome benefit from early invasive manage-
ment. In patients in whom noncardiac surgery is time sen-
sitive despite an increased risk in the perioperative period, a
strategy of balloon angioplasty or bare metal stent (BMS)
implant should be considered.5 Elective noncardiac surgery
should be delayed 14 days after balloon angioplasty (level C
evidence) and 30 days after BMS implant.5 Patients who
have drug-eluting stents must remain on antiplatelet agents
for at least 6 months after the intervention to avoid
restenosis.
There are no prospective randomized controlled trials
(RCTs) supporting coronary revascularization, by either
coronary artery bypass grafting (CABG) or PCI, before non-
cardiac surgery to decrease intraoperative and postopera-
tive cardiac events. In the largest RCT, CARP (Coronary
Artery Revascularization Prophylaxis),37 there were no dif-
ferences in perioperative and long-term cardiac outcomes
with or without preoperative coronary revascularization
by CABG or PCI in patients with documented CAD, with
the exclusion of those with left main coronary artery dis-
ease, an LVEF less than 20%, and severe aortic stenosis.
The CARP study randomly assigned patients at increased
risk for perioperative cardiac complications and clinically
significant CAD to undergo either revascularization or no
revascularization before elective major vascular surgery.37
At 2.7 years after randomization, mortality was 22% in
43
the revascularization group and 23% in the no-
revascularization group (relative risk, 0.98; 95% confidence
interval, 0.70–1.37; P ¼ 0.92). Within 30 days after the
vascular operation, a postoperative MI, defined by elevated
troponin levels, occurred in 12% of the revascularization
group and 14% of the no-revascularization group (P ¼
0.37). Overall, coronary artery revascularization before
elective vascular surgery did not significantly alter the
long-term outcome. On the basis of these data, a strategy
of coronary artery revascularization before elective vascular
surgery among patients with stable cardiac symptoms was
not recommended by the authors.37 A follow-up analysis
reported improved outcomes in the subset of patients who
underwent CABG compared with those who underwent
PCI.38 In an additional analysis of the database of patients
who underwent coronary angiography in both the random-
ized and nonrandomized portions of the CARP trial, only the
subset of patients with unprotected left main coronary
artery disease showed a benefit from preoperative coronary
artery revascularization.
Coronary Artery Bypass Grafting
Retrospective data hinted at a possible benefit of revascular-
ization in patients undergoing vascular surgery, including
improvement in long-term outcomes.31,33 One study
showed some benefits in patients receiving preoperative
CABG compared with those with equally severe, uncor-
rected disease (1.5% vs 3%–14%); however, when coupled
with the operative mortality of CABG alone, no short-term
benefit was gained. The CASS (Coronary Artery Surgery
Study) registry was a large database that enrolled patients
from 1978 to 1981. It provided some of the strongest non-
randomized study evidence for the possible benefit of preop-
erative CABG in patients scheduled for elective vascular
surgery. Initial studies of this patient database suggested a
significant reduction of perioperative cardiac death, but
there was no change in number of MIs between the patients
who underwent preoperative CABG and those in the nonre-
vascularized group.39 Another review of the CASS database
revealed a lower rate of both death and perioperative MI in
revascularized patients undergoing higher-risk noncardiac
procedures, such as major vascular surgery.
Patients who received lower-risk noncardiac procedures
(skin, breast, urologic, minor orthopedic procedures) did
not appear to benefit from preoperative CABG, given the
already low rates of perioperative cardiac adverse events.
A protective benefit does exist for patients with a previous
CABG who now are scheduled for noncardiac surgery.
Assuming that the patient remains medically stable after
revascularization, this protective effect is optimal over the
first 4–6 years after CABG and then diminishes beyond
this point.
Summary
Successful preoperative evaluation of high-risk cardiac
patients who are undergoing noncardiac surgery requires
an organized and logical approach. This requires careful
attention and clear communication between the physicians
44 PART II • Preoperative Assessment
involved in the patient’s perioperative care, including the
primary care physician, anesthesiologist, consultants, and
surgeon. A focused algorithm should be based on the grow-
ing body of evidence that better defines the indications and
benefits of specific modes of perioperative testing and treat-
ment for specific subsets of patients. A single style of preop-
erative cardiovascular testing and risk assessment can no
longer be applied to all patients scheduled for major surgery.
It is increasingly evident that the potential benefits of car-
diac ischemic stress testing and revascularization are appli-
cable to a shrinking subset of symptomatic patients; this
knowledge helps eliminate an unnecessary workup while
generating an accurate and useful cardiac risk profile for
any individual who may undergo noncardiac surgery. Com-
bined with selective testing, intervention with optimal med-
ical therapy may provide an ideal model of evaluation for the
reduction of not only cardiac risk but also other forms of
perioperative morbidity and mortality.
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 6 Cardiovascular Risk Assessment
in Cardiac Surgery
YAS SANAIHA and PEYMAN BENHARASH
Despite significant advancements in surgical and periopera-
tive technology, cardiac surgery remains associated with sig-
nificant risk of morbidity and mortality. Over the last
30 years, at least 20 risk models have been developed to
account for variations in patient comorbidities, operations
subtypes, and statistical techniques. The utility of risk models
is intimately related to the characteristics of the population
used to generate them. Therefore, currently accepted and
prominent risk calculators based on data from the 1990s
and early 2000s require further attention to ensure accu-
rately informed patient and provider decision-making. Fur-
thermore, risk assessment in cardiac surgery has evolved
from a primary focus on mortality to other measures of peri-
operative morbidity, approaching the currently unattainable
standard of assessment quality-of-life measures and patient
satisfaction with high-risk surgical interventions.
Purpose of Risk Assessment
Before Cardiac Surgery
In 1986, publication of poorly adjusted institutional mortal-
ity data for coronary bypass surgery by the federal govern-
ment spurred the creation of the Society of Thoracic
Surgeons (STS) database to create a fair and unbiased reg-
istry for public reporting. Risk modeling has become an inte-
gral instrument in the current health-care environment
driven by value-based care. Furthermore, risk adjustment
allows cardiac surgery programs, hospitals, and regions to
be benchmarked in mortality and morbidity performance
reflecting variations in the patient population better than
unadjusted comparisons. Several studies have shown that
dissemination of risk-adjusted outcomes has resulted in
improved mortality and morbidity within a health-care sys-
tem.1–4 Appropriate risk adjustment has become increasingly
emphasized, given pay-for-performance reimbursement pro-
grams. Finally, appropriate patient counseling is reliant on
the integrity of preoperative risk modeling. Nonetheless, risk
calculation mandates the recognition of strengths and limita-
tions of a designated model in order to prevent misinterpreta-
tion of derived endpoints.
Outcome Measurement in Cardiac
Surgery
With major improvements in myocardial protection and
rapid dissemination of cardiac surgery in the late 1970s,
institutional, regional, and national databases facilitated
46
outcome reporting and risk prediction. Though some
efforts were motivated in response to government reports
thought to inaccurately depict operative outcomes, the
majority of efforts were scholarly and voluntary. Although
many efforts used administrative data, prospectively col-
lected clinical data gathered by objective clinicians has
become the mainstay of national databases and quality
outcome initiatives.
Development of Perioperative
Risk Assessment for Cardiac
Surgery
Regardless of collection method, accuracy of data elements
is critical to the validity of any prediction model. Moreover,
responsible stewardship of statistical methodology and
choice of sound statistical techniques enhance the ultimate
utility of risk models. Among the various perioperative risk
calculators, patient characteristics, operation types (all car-
diac surgery, coronary artery bypass grafting [CABG], valve,
CABG + valve), institutional structure and location, and sta-
tistical methods impact the predictive capability. Inclusion
of emergent and urgent operations will further bias the
results of risk assessment tools. Models are often forced to
lump heterogeneous operations (such as valve repair/
replacement) in order to achieve improved discriminatory
power of relatively rare events such as death. Regardless
of these considerations, risk scores based on retrospective
observational data are inherently biased because of the inev-
itable impact of the surgeon’s selection bias. Furthermore,
model development requires balanced inclusion of patient
and hospital characteristics.
Features of a risk assessment scale include discrimina-
tion and ability for calibration. Discrimination can be
defined as a model’s ability to distinguish between patients
suffering from a specific adverse event such as mortality
and/or major morbidity and those who do not.5 Most
models measure discriminatory power using the C-statistic
obtained from the area under the receiver operating char-
acteristic curve (AUC). Calibration of models has also been
described as a crucial part of accurate model develop-
ment.5 Without calibration, a risk calculator cannot be
expected to provide accurate predictions of patient risk.
Historic techniques for assessing model calibration have
included the Hosmer-Lemeshow goodness of fit.6 More
recently, many have proposed replacement of Hosmer-
Lemeshow model calibration with risk-adjusted mortality
 6 • Cardiovascular Risk Assessment in Cardiac Surgery 47

using observed/predicted ratios.7 Bhatti and colleagues Established Risk Assessment

have also suggested performing chi-square tests to com-
pare the observed to expected mortality as a means to bet-
ter fit the model to actual data.8 While availability of a
validation cohort to perform model discrimination and cal-
ibration is critical, several currently available risk assess-
ment scores, including the European System for Cardiac
Operative Risk Evaluation (EuroSCORE), were calibrated
using only the derivation dataset.9
Currently, most risk algorithms are based on logistic
regression analysis with a priori assumptions of linear rela-
tionships. Current risk prediction can be improved by using
complex techniques such as an artificial neural network,
which has the advantage of the capacity to model complex,
nonlinear relationships and is relatively robust and tolerant
of missing data.9
Models in Cardiac Surgery
Over the last 30 years, over 20 cardiac surgery risk stratifi-
cation models have been devised (Table 6.1). The character-
istics included vary for each unique patient population; the
most commonly used models are compared in Table 6.2.10
Discussed in more detail in this section are the Parsonnet;
EuroSCORE; age, creatinine, and ejection fraction (ACEF);
and STS mortality and morbidity scores.
PARSONNET
In 1989, Victor Parsonnet popularized the first risk score in
cardiac surgery mortality prognostication, based on 14

Table 6.1 A summary of cardiac surgery risk stratification models.10

Model Region Years of data collection Year of publication Number of patients (centers) Risk variables

Amphiascore The Netherlands 1997–2001 2003 7282 (1) 8

Cabdeal Finland 1990–1991 1996 386 (1) 7
Cleveland Clinic USA 1986–1988 1992 5051 (1) 13
EuroSCORE (additive) Europe 1995 1999 13,302 (128) 17
EuroSCORE (logistic) Europe 1995 1999 13,302 (128) 17
French score France 1993 1995 7181 (42) 13
Magovern USA 1991–1992 1996 1567 (1) 18
NYS USA 1998 2001 18,814 (33) 14
NNE USA 1996–1998 1999 7290 (N/A) 8
Ontario Canada 1991–1993 1995 6213 (9) 6
Parsonnet USA 1982–1987 1989 3500 (1) 16
Parsonnet (modified) France 1992–1993 1997 6649 (42) 41
Pons Spain 1994 1997 1309 (7) 11
STS risk calculatora USA 2002–2006 2007 774,881 (819) 49
isolated CABG 109,759 50
valve procedures 101,661 50
CABG and valve
Toronto Canada 1993–1996 1999 7491 (2) 9
Toronto (modified) Canada 1996–1997 2000 1904 (1) 9
Tremblay Canada 1989–1990 1993 2029 (1) 8
Tuman USA N/A 1992 3156 (1) 10
UK national score UK 1995–1996 1998 1774 (2) 19
Veterans Affairs USA 1987–1990 1993 12,715 (43) 10
a
The STS risk calculator of seven risk prediction models in three main categories, namely isolated CABG, valve procedures, and combined CABG and valve
procedures. Data represented for the STS risk calculator reflect the number of patients and risk variable captured in the database used for the latest models
developed (version 2.61).
CABG, Coronary artery bypass grafting surgery; EuroSCORE, European System for Cardiac Operative Risk Evaluation; NNE, Northern New England; NYS, New York
State; STS, Society of Thoracic Surgeons.
With permission from Mayer EK, Sevdalis N, Rout S, et al: Surgical checklist implementation project. Ann Surg 2016;263(1):58-63. doi:10.1097/
SLA.0000000000001185; and Afilalo J, Eisenberg MJ, Morin JF, et al: Gait speed as an incremental predictor of mortality and major morbidity in elderly patients
undergoing cardiac surgery. J Am Coll Cardiol 2010;56(20):1668-1676. doi:10.1016/J.JACC.2010.06.039.
48 PART II • Preoperative Assessment

Table 6.2 A comparison of common cardiac surgery risk calculators.11

Preoperative risk factor EuroSCORE STS Initial parsonnet Cleveland clinic NNE (CABG only) Complex bayes (CABG only)
Age X X X X X X
Sex X X X X
Race X
Weight/BSA X X X X X
IABP/inotropes X X X
LV function X X X X X X
Renal disease X X X X X X
Lung disease X X X X X
PVD X X X X
Diabetes X X X X X
Neurologic dysfunction X X X X
Active endocarditis X
Unstable angina or recent MI X X X
Previous cardiac surgery X X X X X X
Combined surgery X X X NA NA
Aortic involvement X X NA NA
Valve surgery X X X X NA NA
Emergency surgery X X X X X X

BSA, Body surface area; CABG, coronary artery bypass grafting; EuroSCORE, European System for Cardiac Operative Risk Evaluation; IABP, intra-aortic balloon pump;
LV, left ventricular; MI, myocardial infarction; NA, not applicable; NNE, Northern New England; PVD, peripheral vascular disease; STS, Society of Thoracic Surgeons.

variables derived from a single institution.12 While the
model has been criticized because of advancement of surgi-
cal techniques compared with the original era in which the
score was devised, the scoring methodology holds reason-
able discriminatory power nearly 30 years later. Some of
the criticism is associated with inclusion of too few variables
and certain variables that are thought to be arbitrary and
could significantly influence the calculated risk (e.g., cata-
strophic states and other rare circumstances).10 The Par-
sonnet score divides patients into five risk groups based
on the score accumulated from 16 different preoperative
variables. Later iterations of this scale, namely the 2000
Bernstein-Parsonnet logistic regression–based additive risk
model, have been shown to be comparable to the Euro-
SCORE in prediction of mortality.13,14 Despite this modifica-
tion, the Parsonnet score is still not favored, given that it is
based on data that are very old and predate many advances
in state-of-the-art cardiac surgery.
EUROSCORE
The EuroSCORE was developed in the late 1990s in response
to the need for an objective scoring system representative of
a diverse population of cardiac surgery patients.16 In con-
trast to earlier scoring systems such as the Parsonnet score
and the Cleveland Clinic Risk Score, which were developed
on the basis of individual institutional experience, the Euro-
SCORE was derived from and validated on the basis of
20,014 consecutive patients from 132 hospitals in eight
European countries. The score was developed using 97 risk
factors to generate the EuroSCORE calculation, which can
be calculated by the additive method or more complex, logis-
tic model.16 The original cohort had a mean age of
62.5 years, with 10% of patients being older than 75 years
of age and only 28% being female. The derivation cohort
featured 0.5% dialysis dependence; 13.7% had chronic car-
diac insufficiency, while only 1% of cases were reported as
emergent.16 The additive method has been found to overes-
timate the chance of mortality for patients at the lower end
of the risk spectrum while underestimating this parameter
in the very high-risk patient groups.17,18 Thus mortality
estimates transition from over to under at the 12% margin
pivot point.18 Further limitations of the EuroSCORE include
lower and upper limits of risk (0 and 22%) as well as
reported maximal sensitivity of 64% and specificity of
87%.18 In a study by Nashef and colleagues, the EuroSCORE
was validated in the North American population using STS
data from 1995 to 1999.19 A comparison of the two scales
found that the EuroSCORE had satisfactory discriminatory
power in various subsets of patients across several years
of data despite differences in baseline demographics, risk
levels, and surgical characteristics between the European
and American cohorts.19
ACEF
Creation of the ACEF score was motivated by the fact that
internationally used risk calculators were based on large
populations for low event rates, including emergent and
nonemergent cases.20 If these published risk calculators
 6 • Cardiovascular Risk Assessment in Cardiac Surgery 49

were applied to centers with low annual operative volume
and special patient populations, they may no longer be
valid, given limited power for most of the covariates. Thus
Ranucci and colleagues attempted to evaluate the discrim-
inatory power of a parsimonious mortality calculator with
only three factors.20 The ACEF score was based on 8648
patients undergoing elective operations and calculated by
dividing patient age by left ventricular ejection fraction
and adding 1 if serum preoperative creatinine was >2.0
mg/dL. Patients’ predicted mortality was calculated on
the basis of the nomogram shown in Fig. 6.1. Compared
with the EuroSCORE and several regional risk scores, ACEF
performed best in predicting mortality after an isolated
CABG and only second to the Cleveland Clinic Score
overall.21
SOCIETY OF THORACIC SURGERY
The STS Adult Cardiac Surgery Database, established in
1989, represents the first attempt by a large professional
society to gather nationally representative data and
provide benchmarks for various institutions.21 Over the
ensuing 30 years, the STS database progressively grew
to encompass nearly 6 million operations and various
procedure types beyond CABG. An important feature of
the STS database is the regular refitting that is done to
the dataset in order to provide up-to-date risk prediction
and quality metrics for individual institutions. Using
feedback methodology with the voluntarily participating
centers, data fields are periodically changed in order to
reflect the most important predictors of risk. While over
200 preoperative and operative elements exist for CABG
patients, over 1300 are available for all other subtypes,
which suffer from variable completion (Table 6.3). The
STS provides separate risk scores for various operation
types and is currently the most commonly used score in
the United States. In their most recent release of data,
Shahian and colleagues reported the C-statistic for mor-
tality prediction of the model to be 0.82 for isolated CABG,
0.72 for CABG/valve, and 0.76–0.84 for isolated valve/
replacement.23–25 Owing to the large number of patients
in the database, the STS model is also able to predict the
risk for serious adverse postoperative events such as
stroke, deep sternal wound infection, reoperation, and
prolonged mechanical ventilation.22–24
Sophistication of the STS risk prediction algorithm has
diametric real-world implications. Reporting data to the
STS is resource-intensive and generally requires dedicated

72
70 Age (years)
68 ACEF score = + 1 (if serum creatinine ≥ 2 mg/dL)
66 EF (%)
64
62
60
58
56
54
52
50
48
Predicted mortality rate (%)

46
44
42
40
38
36
34
32
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2

ACEF score
Fig. 6.1 Univariate association (logistic regression) between age, creatinine, and ejection fraction (ACEF) score and mortality risk.21 EF, Ejection fraction.
 Table 6.3 A list of candidate variables and their coding for Society of Thoracic Surgeons valve plus coronoary artery bypass
grafting models.24
Candidate variables Coding
CONTINUOUS VARIABLES
Agea Linear spline truncated from below at 50 with knot at 75
Ejection fraction Linear; values >50 mapped to 50
Body surface areaa Quadratic polynomial modeled separately for males and females. Note: BSA <1.4 and >2.6 were
mapped to those values, respectively.
Creatinine Linear (only for patients not on dialysis). Note: Creatinine <0.5 and >5.0 mapped to those values,
respectively.
Time trenda Ordinal categorical variable with separate category for each 6-month harvest interval. Modeled as
linear across the categories.
BINARY VARIABLES
Active infectious endocarditis Yes/no
Dialysis Yes/no
Preoperative atrial fibrillation Yes/no
Shock Yes/no
a
Female Yes/no
Hypertension Yes/no
Immunosuppressive treatment Yes/no
Preoperative IABP or inotropes Yes/no
Peripheral vascular disease Yes/no
Unstable angina (no MI <7 days) Yes/no
Left main disease Yes/no
Aortic stenosis Yes/no
Mitral stenosis Yes/no
Aortic insufficiency Defined as at least moderate (yes/no)
Mitral insufficiency Defined as at least moderate (yes/no)
Tricuspid insufficiency Defined as at least moderate (yes/no)

CATEGORICAL VARIABLES
Surgery type Three groups: AVR + CABG, MVR + CABG, MV repair + CABG
Chronic lung disease Modeled as linear across categories (none, mild, moderate, severe)
CVD/CVA Three groups: no CVD, CVD no CVA, CVD + CVA
Diabetes mellitus Three groups: insulin diabetes, noninsulin diabetes, other or no diabetes
No. of diseased coronary vessels Three groups: <2-vessel disease; 2-vessel disease; 3-vessel disease. Modeled as linear across the
categories.
MI Three groups: <24 hours, 1–21 days, >21 days or no MI. Note: Groups 1 and 2 were subsequently
collapsed for some models.
Race Three groups: black, Hispanic, other including white
Status Four groups: elective, urgent, emergent no resuscitation, salvage, or emergent with resuscitation
Previous cardiovascular operations Three groups: 0 previous, 1 previous, 2 previous
CHF and NYHA class Three groups: No CHF, CHF not NYHA IV, CHF and NYHA IV

INTERACTION TERMS
Age by reoperationa
Age by emergent statusa
Surgery type by each of the following: Age, diabetes, dialysis, creatinine, reoperation, endocarditis, emergent status, CLD, CHF, EF, sex,
shock, IABP/inotropes, mitral insufficiency, aortic insufficiency, mitral stenosis, aortic stenosis.

AVR, Aortic valve replacement; BSA, body surface area; CABG, coronary artery bypass grafting; CHF, congestive heart failure; CLD, chronic lung disease;
CVA, cerebrovascular accident; CVD, cardiovascular disease; EF, ejection fraction; IABP, intra-aortic balloon pump; MI, myocardial infarction; MVR, mitral
valve replacement; NYHA, New York Heart Association classification.

staff to accurately abstract data and complete the electronic
fields. However, the calibration and discriminatory power of
the STS model has validated its use in determination of can-
didacy for alternative procedures such as transcatheter aor-
tic valve replacement (AVR) or MitraClip (Abbott). This has
further popularized the use of the STS database’s congenital
and thoracic registries. Additionally, hospital- and surgeon-
level metrics of performance are expected to be used in pay-
for-performance methodologies and to have a wider impact
on regionalization and risk mitigation strategies.
FRAILTY VERSUS AGE
While elderly patients have historically been shown to ben-
efit from cardiac surgery, they often present with more
extensive coronary artery calcifications and concurrent val-
vular abnormalities, and they are more likely to require
urgent/emergent interventions.25 Age alone is often a
marker of comorbid conditions and weighs heavily in risk
models. Outcomes for elderly patients undergoing cardiac
surgery are difficult to study, given the additive impact of
morbidities, disabilities, and disease severity that cannot
always be discerned by administrative risk factors and even
clinical data. Large multicenter clinical series examining
octogenarians have found that in older patients with mini-
mal morbidity, the mortality associated with CABG and
CABG/AVR approaches the mortality of younger cohorts.
Furthermore, these studies found that predictors of mortal-
ity after cardiac surgery are similar between young and old
cohorts.26 Given that older patients account for nearly half
of the cardiac operations and 80% of all postoperative
complications and deaths in North America, dedicated pre-
operative risk assessment in the elderly is needed.23 Further-
more, long-term survival of octogenarians undergoing
cardiac operations was satisfactory despite substantial rates
of complications and deaths.27 However, combined opera-
tions such as CABG/valve add to mortality risk, with
CABG/mitral valve replacement associated with even
higher mortality risk than CABG/AVR.
Commonly used mortality prediction calculators such as
the EuroSCORE are prone to overestimating mortality for
the elderly, given that these scores were generated from
younger cohorts. Given the increasing proportion of the
population over the age of 75 undergoing cardiac surgery,
examination of the unique factors that impact mortality risk
for this older population is warranted.28
Another observational study comparing patients less
than and greater than 75 years old undergoing non-
emergent CABG showed that while the proportion of
patients in the elderly cohort increased, mortality decreased.
An analysis of age-adjusted EuroSCORE (subtracted age
from original EuroSCORE) demonstrated similar risks
despite an increasing proportion of elderly patients undergo-
ing cardiac surgery, suggesting plateauing of comorbidities
with increasing age.25 Ultimately, these observational stud-
ies are limited by treatment selection bias. Furthermore,
a patient’s “physiologic age” cannot be quantified and inte-
grated within existing models, and a more nuanced risk
calculation for the aged is needed.
More recently, frailty, defined as a condition of decreased
resiliency and reserve to respond to physiologic stressors,
6 • Cardiovascular Risk Assessment in Cardiac Surgery 51
has become a topic of great interest in cardiovascular med-
icine.29 Frailty appears to be distinct from age, disability,
and other comorbidities.30 Several scales are used to assess
the degree of patient frailty and disability, including the “get
up and go,” grip strength, Cardiovascular Health Study
(CHS) criteria, and Edmonton Frail Scale. Slower gait speed
has been shown in separate analyses to incrementally
increase risk of mortality and major comorbidity after car-
diac surgery.30
Beyond correlation between comorbidity-based scores
and frailty assessment, addition of frailty measures to preop-
erative risk assessment has significantly increased discrimi-
natory power of existing models.31 Afilalo and colleagues
showed that the number of impairments in activities of daily
living were not different among patients with and without
adverse postoperative events.31 Instead, combination of
the Parsonnet score with slow 5-meter gait speed
(6 seconds) and Nagi scale score (at least three impair-
ments in Nagi scale) yielded the greatest predictive power
and association with significantly increased risk of mortal-
ity.31 Addition of 5-meter gait speed and Nagi scale score
increased the C-statistic of the STS predicted risk of mortality
and morbidity (STS-PROMM) from 0.68 to 0.73. Interest-
ingly, the ACEF score yielded the lowest AUC when com-
pared with frailty scales and was not a significant
predictor of mortality in this multicenter study.31
Several additional studies have shown the association
with frailty and outcomes after cardiac surgery in the elderly
population. In a report of 131 patients, gait speed, measured
using a nonstandardized method, was an independent pre-
dictor of mortality or major morbidity and discharge to a
convalescent care facility after accounting for STS-PROMM
score.30 A study from the Leipzig Heart Center demonstrated
the significant power of the CHS frailty score in predicting
mortality its low to moderate correlation with the STS score
and EuroSCORE.32 Data from the Maritime Heart Center
Cardiac Surgery Registry (Halifax, NS, Canada) also demon-
strated that frailty as defined by the Katz Index of Indepen-
dence in Activities of Daily Living scale, was an independent
predictor of in-hospital mortality, institutional discharge,
and midterm mortality.33 Though obesity can be protective
against physiologic stressors, recognized as the “obesity par-
adox,” obese patients can also be frail due to “sarcopenic
obesity.”34 Given the growing body of evidence, rigorous
testing of these scales in predicting mortality for elderly
patients is warranted. Integration of such frailty scales into
existing risk models may allow selection of optimal therapies
and patient stratification for more intensive preoperative
and post-discharge interventions.
CONGENITAL HEART SURGERY
Patients with congenital heart disease represent an espe-
cially vulnerable cohort with a diverse burden of disease.
Complexity of congenital lesions, low blood volume, and
the common need for repeat sternotomy make surgery for
congenital heart defects challenging. The earliest tool for
case mix adjustment was the Aristotle Basic Complexity
score reported by Lacour-Gayet and colleagues in 2003.35
Developed using an expert international panel of surgeons
and a three-component score, including potential for mor-
tality, morbidity, and technical difficulty, was generated
52 PART II • Preoperative Assessment
for 145 distinct congenital heart operations. A separate
method for predicting short-term mortality within the pedi-
atric population, Risk Adjustment for Congenital Heart
Surgery (RACHS-1), was also created by a consensus panel
of pediatric cardiologists and surgeons and included proce-
dure type (six categories), age, history of prematurity, and
concurrent major noncardiac developmental anomalies.36
The Aristotle score, the RACHS-1 appears to have improved
discrimination for predicting mortality.37 The RACHS-1 has
been used in assessing the ratio of observed/expected mortal-
ity adjusted for case mix complexity between peer institu-
tions. Integration of RACHS-1 variables in multivariable
logistic regression also facilitates analysis of patient-level fac-
tors regarding in-hospital mortality. Criticisms of RACHS-1
have included significant data reduction by categorizing
diverse anatomic abnormalities and repairs into an ordinal
scale. While these groupings allow sufficient sample sizes to
perform risk modeling, loss of anatomic granularity and case
mix specificity remains a weakness of this predictive tool. This
tool also excludes patients undergoing cardiac transplant and
patients with significant morbidity from noncardiac surgical
causes.38 Furthermore, with increased survival of children
with congenital heart disease into adulthood, the RACHS-1
scoring system, derived from operations on children less than
18 years old, is perhaps less applicable to adult congenital
operations.38
Similar to the RACHS-1 score, the STS-Congenital Heart
Surgery Database (STS-CHSD) accounts for procedural mor-
tality using risk categories. Using the STS–European Associ-
ation for Cardio-Thoracic Surgery (EACTS) Congenital
Heart Surgery Mortality Categories (STAT-Mortality) cate-
gories, operations are assigned a risk of death on a scale
of 1–5.37 These categories were defined on the basis of data
compiled from the EACTS Congenital Heart Database and
STS-CHSD, representing over 77,294 operations from
2002 to 2007. Each procedure was assigned an STS-EACTS
score based on estimated mortality rate and was grouped in
an STS-EACTS category. On the basis of a separate valida-
tion cohort, the STS-EACTS score was found to have
improved discrimination compared with STS-EACTS cate-
gories. These models were superior to both the RACHS-1
and Aristotle Basic Complexity score for procedures with
more than 40 occurrences.37
The most recent iteration of the STS-CHSD risk model,
based on 52,224 patients from 2010 to 2013, demonstrated
that inclusion of patient factors improved discriminatory
power and reduced bias in risk-adjusted hospital mortality
comparisons.39 Despite its tremendous growth since its
launch in 2004, several preoperative patient factors con-
tinue to be excluded from the STS database due to insuffi-
cient reporting. Furthermore, the most recent STS-CHSD
does not account for effects of interactions among several
patient factors, such as age and operation, on the odds of
mortality.
As mortality associated with pediatric heart surgery
has decreased, reduction of operative morbidity and
improved quality of survival remain significant priorities
for pediatricians and surgeons alike. Focused on physio-
logic factors that instigate the path to intensive care unit
admission, the Pediatric Risk of Mortality score has been
recognized as a reliable predictor of mortality and morbid-
ity. Addition of operative complexity scoring with RACHS
and STS-STAT categories did not improve discrimination
of mortality and new functional morbidity. Thus, risk pre-
diction is shifting from dependence on operation type to
physiologic data. Furthermore, risk models for congenital
cardiac surgery that include data from various points of
the patient’s perioperative course may help to delineate
targets for quality improvement across the continuum
of care.41
Regardless of these considerations, the 2800 adults
with congenital heart disease per 1 million population of
adult survivors of congenital heart disease remain a distinct
category not well captured within adult or pediatric risk pre-
diction models.41 The increased risk of reoperation in adult
congenital heart disease patients is largely related to the
risks associated with repeat sternotomies and the presence
of aortic pulmonary collaterals.42,43 Adult risk assessment
models such as the Parsonnet, EuroSCORE, and STS include
prior cardiac surgery, without a separate designation for
congenital anomalies, which undeniably may impact
patient mortality and morbidity.
EXTRACORPOREAL MECHANICAL SUPPORT
As extracorporeal membrane oxygenation (ECMO) out-
comes have improved, judicious administration of this
technology in acute situations of cardiopulmonary col-
lapse have prompted efforts to achieve rapid identification
of appropriate candidates. For example, the ENCOURAGE
(prEdictioN of Cardiogenic shock OUtcome foR AMI
patients salvaGed by venoarterial extracorporeal mem-
brane oxygenation) score is comprised of seven pre-ECMO
characteristics with improved ability to predict survival
compared with other algorithms, including the Survival
After Veno-arterial ECMO (SAVE), Simplified Acute
Physiology Score II, and Sepsis-related Organ Failure
Assessment.44,45
For patients with isolated, potentially reversible acute
respiratory failure, the Conventional Ventilatory Support
versus Extracorporeal Membrane Oxygenation for Severe
Adult Respiratory Failure (CESAR) trial demonstrated
early venovenous (VV) ECMO use to enhance survival
without significant morbidity at 6 months.46 Since the
publication of this multi-institutional randomized con-
trolled trial, several groups have attempted to optimize
patient selection using mortality prediction models. One
such score is the Prediction of Survival on ECMO Therapy
Score (PRESET-Score) developed by Hilder and colleagues
in response to the previously published ECMOnet and
Respiratory Extracorporeal Membrane Oxygenation Sur-
vival Prediction (RESP) scores.47–49 Both ECMOnet and
RESP scores were moderately capable of discriminating
survivors (AUCs of 0.69 and 0.64, respectively). However,
inclusion of extrapulmonary variables with the PRESET
score revealed improved internal and external validation
cohort discrimination (AUCs of 0.85 and 0.70, respec-
tively). Regardless, both the ECMO-NET and PRESET scores
are derived from limited institutional cohorts, while the
RESP score may be representative of a larger VV-ECMO
experience (Table 6.4). Currently, the relatively poor
discriminatory power of existing risk scores precludes
physicians from making absolute judgments about with-
holding ECMO from patients in critical condition.
 6 • Cardiovascular Risk Assessment in Cardiac Surgery 53

Table 6.4 Comparison of venovenous extracorporeal membrane oxygenation mortality risk calculators.
ECMO-NET47 RESP48 PRESET49
Derivation cohort 60 Patients with H1N1, ARDS 2355 Patients in ELSO database 82 Consecutive patients with ARDS
receiving VV-ECMO from 2010 to 2012 receiving VV-ECMO
External validation cohort 74 ARDS because of H1N1 patients 140 Multicenter French patients 59 ARDS VV-ECMO patients at
in other countries separate German institution
Age ✓
Pre-ECMO hospital LOS (days) ✓ ✓
Bilirubin (mg/dL) ✓
Creatinine (mg/dL) ✓
Hematocrit (%) ✓
Mean arterial pressure (mmHg) ✓ ✓
Immunocompromised status ✓
Mechanic ventilation prior to ✓
initiation of ECMO (h)
Acute respiratory diagnosis ✓
CNS dysfunction ✓
Acute nonpulmonary infections ✓
Neuromuscular blockade agents ✓
before ECMO
Nitric oxide use before ECMO ✓
Bicarbonate infusion before ✓
ECMO
Cardiac arrest before ECMO ✓
PaCO₂, mmHg ✓
Peak inspiratory pressure, cm ✓
H₂O
Lactate concentration ✓
pHa ✓
Platelet concentration ✓

ARDS, Acute respiratory distress syndrome; CNS, central nervous system; ECMO, extracorporeal membrane oxygenation; ECMO-NET, International ECMO Network;
ELSO, Extracorporeal Life Support Organization; LOS, length of stay; PaCO2, partial pressure of carbon dioxide; pHa, arterial pH; PRESET, Prediction of Survival on
ECMO Therapy; RESP, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction; VV, venovenous.

VENTRICULAR ASSIST DEVICES Registry for Mechanically Assisted Circulatory Support

For patients with end-stage heart failure, mechanical assist
devices have served as a bridge-to-transplant and destina-
tion therapy. However, selection of patients who will receive
the greatest benefit is crucial to preventing futile care. Pre-
viously established survival calculators for pulsatile flow left
ventricular assist device (LVAD) implantation have included
factors such as age, malnutrition, thrombocytopenia, renal
dysfunction, and elevated international normalized ratio as
increasing risk of short-term mortality at 90 days after
implantation (Table 6.5). Patient selection and survival will
likely continue to evolve with LVAD technology and char-
acteristics of the heart failure population, because organ
shortages persist and more patients are requiring mechan-
ical support.50–53 While several risk scores are available for
predicting mortality in patients receiving LVADs, clinician
and team judgment remains paramount. Undoubtedly, data
accumulating in large registries such as the Interagency
will be needed to devise appropriate risk scores for modern
ventricular assist device technologies.
BEYOND MORTALITY
Efforts to achieve accurate prediction of mortality in cardiac
surgery continue to evolve in parallel with advancements in
surgical technique and perioperative management. Both the
EuroSCORE and latest STS risk calculators have been
adopted to predict events such as permanent stroke, renal
failure, prolonged ventilation, and mediastinitis. The Euro-
SCORE has been found to correlate with nearly all adverse
events except myocardial infarction and incidence of
bleeding.54 The STS calculators for major morbidity have
reached satisfactory discriminatory power, ranging from
0.62 to 0.79, depending on operation type and adverse
event. Risk scores are now used beyond their original intent
54 PART II • Preoperative Assessment

Table 6.5 Comparison of left ventricular assist device survival prediction models.
Lietz Score52 HeartMate II Risk Score (HMRS)53 Penn-Columbia Risk Score54
VAD type HeartMate XVE HeartMate II Heartmate II and HVAD (Heartware)
VAD flow type Pulsatile Continuous Continuous
Derivation cohort REMATCH trial, 222 patients, HMII trial, 583 patients, 2005–2010 210 Patients, 2006–2014
2001–2005
Validation cohort Not performed HMII trial, 539 patients, 2005-2010 260 Patients, at Columbia
Survival analysis 90-Day and 1-year 90-Day and long-term survival 1-Year survival
Age ✓ ✓
3
Platelet count 148  10 /μL ✓
Serum albumin ✓ ✓
Hematocrit 34 ✓
AST >45 U/mL ✓
INR ✓ ✓
Vasodilator therapy ✓
No intravenous inotropes ✓
Blood urea nitrogen >51 U/dL ✓
Creatinine ✓ ✓
Total bilirubin ✓
Body mass index ✓
RV dysfunction ✓
Aortic insufficiency ✓
Center LVAD volume ✓

AST, Aspartate aminotransferase; INR, international normalized ratio; LVAD, left ventricular assist device; RV, right ventricular; VAD, ventricular assist device.

and are used to provide quality benchmarks for institutions
and surgeons. Formal integration of significant patient char-
acteristics such as frailty will enhance the discriminatory
power of current models. Finally, reliance on risk scores will
enable practitioners to choose from among the ever-
expanding armamentarium of surgical and interventional
technologies to treat patients with heart disease safely.
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athoracsur.2009.01.057.
29. Abdullahi YS, Athanasopoulos LV, Casula RP, et al. Systematic review
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30. Afilalo J, Eisenberg MJ, Morin JF, et al. Gait speed as an incremental
predictor of mortality and major morbidity in elderly patients undergo-
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tality or major morbidity. Circ Cardiovasc Qual Outcomes. 2012;5
(2):222–228. https://doi.org/10.1161/CIRCOUTCOMES.111.963157.
32. S€undermann S, Dademasch A, Praetorius J, et al. Comprehensive
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org/10.1016/j.ejcts.2010.04.013.
33. Lee DH, Buth KJ, Martin B-J, et al. Frail patients are at increased risk
for mortality and prolonged institutional care after cardiac surgery.
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jtcvs.2018.01.103.
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35. Lacour-Gayet F, Clarke D, Jacobs J, et al. The Aristotle score: a
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56 PART II • Preoperative Assessment

53. Birati EY, Hanff TC, Maldonado D, et al. Predicting long term outcome 54. Hirose H, Inaba H, Noguchi C, et al. EuroSCORE predicts postoperative
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 7 Central Nervous System Risk
Assessment: Preventing
Postoperative Brain Injury
MEGAN MAXWELL, MEGHAN MICHAEL, and DAVID L. MCDONAGH
Perioperative complications involving the central nervous
system (CNS) are common. However, these issues have gen-
erally received little attention in the presurgical assessment
process. New data allow us to better guide physicians and
patients regarding perioperative CNS risk and ways to mit-
igate that risk (Fig. 7.1).
Postoperative Delirium
DEFINITION
Postoperative delirium (POD) is an acute confusional syn-
drome that is frequently encountered in the postoperative
setting. In fact, it is the most common surgical complication
among older adults, with an incidence ranging from 15% to
50% in this population, depending on the procedure.1 Delir-
ium can be defined as an acute, fluctuating, multifactorial
disorder characterized by a decline of attention, cognition,
and awareness,2,3 and it is a distinct disorder that is separate
from dementia or chronic cognitive decline.4 Three subtypes
of delirium exist: hyperactive, hypoactive, and mixed.
Despite hypoactive being the most frequent subtype,
patients who have hypoactive delirium are less frequently
diagnosed and have poorer prognoses than those with
hyperactive delirium.1,5 Unfortunately, a diagnosis of delir-
ium carries many implications for a patient because those
diagnosed with delirium have increased morbidity, mortal-
ity, loss of independence, likelihood of subsequent institu-
tionalization, and health-care costs.2
Establishing a diagnosis of delirium requires that the
patient’s baseline mental status be defined with a preopera-
tive screen or by a knowledgeable informant. Once this is
established, a cognitive screening test may be used to deter-
mine what, if any, change from baseline the patient is
experiencing.6 There are many different diagnostic tools
and severity scales for delirium, with two of the most com-
mon being the Confusion Assessment Method (CAM) and
CAM-ICU, which is a derivative of the CAM that is intended
for mechanically ventilated patients in the intensive care
unit (ICU) (Fig. 7.2).7,8
RISK FACTORS
The pathophysiologic mechanisms underlying delirium are
poorly understood and may include neurotransmitter
imbalance and/or neuroinflammation.1,2,5,9 Despite the
lack of a definite cause of delirium, multiple predisposing
and precipitating factors for delirium have been elucidated
(Table 7.1).10 The summation of predisposing and precipi-
tating factors will determine a patient’s likelihood of devel-
oping delirium; a higher burden of predisposing factors will
necessitate a lower number of precipitating factors.11 Mul-
tiple drugs have been shown to increase the probability of
delirium in the geriatric population and should be avoided
in the perioperative period if possible. These include benzo-
diazepines, anticholinergics, diphenhydramine, hydroxy-
zine, meperidine, histamine-2 antagonists, and sedative
hypnotics.12
INTRAOPERATIVE MANAGEMENT
Currently, optimal intraoperative management of patients
at risk for delirium is not yet well defined. The only intra-
operative delirium-reducing interventions for which strong
recommendations exist are avoidance of predisposing drugs
and adequate pain control, with nonopioid medications and
regional anesthesia being a consideration when possible or
appropriate.12 However, several interventions are currently
being investigated. Some studies have shown that deeper
levels of anesthesia are associated with increased incidence
of POD and that bispectral index (BIS)-guided anesthetics
are associated with a lower incidence of POD.14–16 It has
been hypothesized that BIS-guided anesthetics may have
fewer periods of electroencephalogram (EEG) burst suppres-
sion.16 However, the increased burden of burst suppression
and other EEG patterns identified in patients with POD may
simply be a marker of fragility and not a causative factor.
The largest randomized trial to date, the ENGAGES [Electro-
encephalography Guidance of Anesthesia] trial,17 random-
ized over 1200 patients to EEG-guided anesthesia or control
and found no difference in the incidence of POD. Other stud-
ies are ongoing.
Another intervention that has been investigated in recent
years is the use of dexmedetomidine. Recent studies have
shown that dexmedetomidine administered perioperatively
as a low-dose prophylactic infusion may decrease not only
POD but also the rates of stroke and both operative and
in-hospital mortality.18–20 These findings may be explained
in part by evidence that dexmedetomidine acts via the
JAK2/STAT3 pathway to attenuate isoflurane-induced neu-
rocognitive deficits in senile mice.21 However, other studies
have been unable to replicate these findings and have found
that dexmedetomidine does not decrease POD.22,23 A recent
report found that low-dose nocturnal dexmedetomidine
57
58 PART II • Preoperative Assessment

Risk for Postoperative Delirium: Risk for Postoperative Cognitive Decline:

• Geriatric medicine • Consider pros/cons of purely elective surgery
consultation preoperatively • Geriatric medicine consultation preoperatively
• Multimodal analgesia, early • Avoidance and/or prompt treatment of delirium,
mobilization, sleep hygiene. etc. pain, or infection in the postop period.

Parkinson Disease: Red Flags: Risk for Perioperative

• Develop a plan for continued
anti-parkinsonian therapy
throughout the perioperative
period
Prior Stroke:
• Delay purely elective surgery
for 9 months
• Stroke medicine consultation
to establish perioperative risk
• Close attention to
blood pressure
• Advanced Age Seizures:
• Cognitive Problems • Maintain antiepileptic
• Seizure Disorder drug therapy
• Previous Stroke • Avoid tranexamic acid (TXA)
• Chronic Neurologic Disease and aminocaproic acid.
• Recent Concussion
• Planned Cardiovascular Surgery
• Implanted CNS Devices
Risk for Hypoxic Brain
Injury or Ischemic Stroke:
• Protocol for targeted
Recent Concussion: temperature management
• Delay elective surgery • Acute stroke team
until recovery • Endovascular thrombectomy
treatment plan

CNS Device:
• Vagal nerve stimulator, deep brain Risk for Spinal Cord Injury:
stimulator, spinal cord stimulator • Intraoperative neuromonitoring
• Alert the OR team • CSF drainage in aortic
• Arrange for device management surgery
(deactivation, reactivation, interrogation)
• ECT requires careful preoperative
planning in these patients
• Evaluate the safety of any

Fig. 7.1 Recommendations for management of at-risk central nervous system (CNS) conditions. CSF, Cerebrospinal fluid; ECT, Electroconvulsive
therapy; OR, operating room.

The Confusion Assessment Method for the Intensive Table 7.1 Predisposing and precipitating risk factors for
Care Unit (CAM-ICU) postoperative delirium.10,12,13
Factors known to Factors known to precipitate
Acute Onset or predispose to delirium delirium
AND Inattention
Fluctuating Course
Older age Drugs (benzodiazepines,
PLUS Baseline dementia anticholinergics, meperidine, opioids,
Functional disability diphenhydramine, hydroxyzine,
High burden of coexisting histamine-2 antagonists, sedative
Disorganized Altered Level of disease hypnotics)
OR Male sex Major surgery
Thinking Consciousness
Poor vision Anesthesia
Poor hearing Pain
Depressive symptoms Anemia
Mild cognitive impairment Infection
Fig. 7.2 The confusion assessment method for diagnosis of delirium in Laboratory abnormalities Acute illness
the intensive care unit (CAM-ICU). Data from Ely EW, Inouye SK, Bernard Alcohol abuse Acute exacerbation of chronic illness
GR, et al. Delirium in mechanically ventilated patients: validity and reli- Depression
ability of the confusion assessment method for the intensive care unit
(CAM-ICU). JAMA 2001;286(21):2703-2710.

reduced POD in the ICU, but this awaits validation in larger

trials.24 As the data are conflicting at this time, it would be
reasonable for the anesthesiologist to consider the perioper-
ative use of dexmedetomidine in the at-risk patient if it is
considered clinically feasible/appropriate. It remains
unclear whether intraoperative, postoperative, or combined
dosing is most effective.
Much like dexmedetomidine, ketamine showed initial
promise as an intraoperative intervention to prevent
POD.25 However, a recent study was unable to replicate this
result, and patients receiving ketamine experienced higher
incidences of hallucinations and nightmares (but not delir-
ium).26 Although ketamine does show benefit in decreasing
delirium in children,27,28 there are still relatively few studies
examining ketamine in adult delirium prevention. Ketamine
may allow lower perioperative opioid doses to be used, and
the anesthesiologist may still consider ketamine use in at-
risk patients as part of a multimodal anesthetic.
 7 • Central Nervous System Risk Assessment: Preventing Postoperative Brain Injury
Finally, both cholinesterase inhibitors such as rivastig-
mine and antipsychotics such as haloperidol administered
perioperatively in a preventative capacity have been inves-
tigated. Cholinesterase inhibitors have not been found to
decrease delirium incidence and furthermore may be asso-
ciated with increased adverse effects, including mortality.12
It is not recommended that patients not taking preoperative
cholinesterase inhibitors be started on one in the perioper-
ative setting.12 Data on prophylactic perioperative use of
antipsychotics are less conclusive but generally do not favor
their use, owing to mixed results on delirium prevention, no
decrease in mortality, and a high rate of adverse effects.12,29
Emergence Delirium
Emergence delirium is an acute, short-lived phenomenon
that occurs in the early/immediate postoperative period
after the patient has awakened. These patients experience
a short-term impairment in consciousness that may mani-
fest as disorientation, hallucinations, confusion, restless-
ness, and hyperactive behavior that may be violent or
harmful to the patient or hospital staff.30 The incidence is
reported to range from 3% to 21%,30,31 and these patients
experience longer recovery periods, use more resources, and
pose a greater risk for harm to themselves and hospital
staff.32
Emergence delirium is not as well investigated in the
adult population as it is in the pediatric population. How-
ever, some risk factors that have been identified for adults
include preoperative benzodiazepine administration, post-
traumatic stress disorder, breast surgery, abdominal sur-
gery, long duration of surgery, young age, presence of an
endotracheal tube and/or urinary catheter, sevoflurane
anesthesia, recent smoking, and postoperative pain 5 on
the numerical rating scale.32–34
Treatment of emergence delirium is also not well studied,
but there are some case reports and case series describing
the effective use of dexmedetomidine, both as an intraopera-
tive infusion in patients with a history of emergence delir-
ium and via intravenous bolus dosing as rescue therapy
for patients after extubation.35,36 It is therefore reasonable
to consider use of dexmedetomidine in patients who have
a history of emergence delirium, who have risk factors for
emergence delirium, or who experience significant delirium
upon awakening from their anesthetic.
Treatment of Postoperative
Delirium After the Immediate
Recovery Period
As up to 40% of delirium has been shown to be prevent-
able,37,38 the best treatment for delirium is the prevention
of its occurrence altogether. Currently recommended
preventative strategies include cognitive reorientation,
sleep enhancement with nonpharmacologic sleep protocols
and hygiene, adaptations for visual and hearing impair-
ment, early mobility, nutrition and fluid repletion, avoid-
ance of precipitating medications, adequate oxygenation,
59
prevention of constipation, pain management, education
of health-care professionals, and use of an interdisciplinary
team.12
If a patient does develop delirium, the aforementioned
nonpharmacologic therapies should be implemented as
first-line treatment if not already in place. In addition, the
patient should be evaluated for the presence of any precip-
itating factors (such as a urinary tract infection or poorly
controlled pain) that warrant intervention.12 In the event
that the above interventions are ineffective and the patient
is experiencing hyperactive delirium that is posing a threat
to him-/herself and/or hospital staff, antipsychotics may be
used. It is recommended that the lowest possible dose be
used for the shortest possible time.12 Benzodiazepines are
not recommended unless medically indicated, such as in
the instance of alcohol or benzodiazepine withdrawal.12
Action Plan:
1. Identify patients with predisposing and/or precipitating
risk factors for POD.
2. In patients at risk for POD, consider regional anesthesia,
multimodal analgesia, and the use of dexmedetomidine.
3. EEG-guided anesthesia does not prevent POD but may
be desirable in allowing optimization of anesthetic
dosing.
4. Avoid precipitating medications, such as preoperative
benzodiazepines, when possible in high-risk patients.
5. Implement multidisciplinary, nonpharmacologic
measures, such as geriatrics consultation, to both pre-
vent and treat POD.
6. Use low-dose, short-course antipsychotics or dexmede-
tomidine for delirious patients at risk of harm to them-
selves or others. Reserve benzodiazepines for patients
withdrawing from alcohol or benzodiazepines.
Postoperative Cognitive
Dysfunction
DEFINITION
Postoperative cognitive dysfunction (POCD) describes a syn-
drome of prolonged impairment or deterioration of cognitive
function with onset usually occurring weeks to months after
surgery.39,40 Assessment of decline is made with preopera-
tive and postoperative testing. Features include limitations
in memory, intellectual ability, and executive function.39,40
A standardized approach to the identification and study of
POCD has been limited by the lack of consensus diagnostic
criteria.39,40 In general, the diagnosis involves identifying a
worsening in postoperative formal neurocognitive testing
relative to preoperative levels and is hence difficult outside
of a research protocol.41 The International Study of Postop-
erative Cognitive Dysfunction (ISPOCD) made the diagnosis
of POCD based on a combined Z-score >2 (i.e., 2 standard
deviations from the mean) across a multitude of individual
cognitive tests or at least two Z-scores >2 for single test
parameters.40,42 Other investigators have looked at changes
in cognitive domains such as memory and executive func-
tion, based on similar individual neurocognitive tests, rela-
tive to the patient’s baseline or to a control group.43
60 PART II • Preoperative Assessment
Although a consensus definition remains elusive, most
investigators agree the morbidity of cognitive decline is sig-
nificant. POCD is associated with longer hospital stays and
cost, premature withdrawal from the workforce, and greater
1-year mortality, and it may possibly cause a change in the
trajectory toward dementia.40,44–46
Attention to preoperative recognition of patients at risk
for POCD has increased in recent years in the hope that iden-
tification, preoperative counseling, risk factor modification,
and possible interventional strategies can help mitigate the
untoward effects of POCD on individual patients and health-
care systems as a whole.40,44
INCIDENCE
Since 1955, with the publication of “Adverse Cerebral
Effects of Anaesthesia on Old People” in The Lancet, clinicians
have observed cognitive decline after surgery that can per-
sist for months or even years.47 These early observations
inspired research into the phenomenon of cognitive decline
and the frequency with which it occurs. Current studies
report an incidence ranging between 10% and 80% due
to different patient populations and approaches to measur-
ing POCD.40,48
Initial investigations focused on cognitive impairment
after cardiac surgery. A higher prevalence of POCD was
originally described following coronary artery bypass graft-
ing surgery than after noncardiac surgery, with rates as
high as 24% at 6 months and 42% at 5 years.49 More recent
work suggests underlying coronary artery disease and asso-
ciated risk factors may contribute to cognitive decline more
than cardiac surgery and anesthesia; ongoing research is
necessary to dissect out the contribution of each of these risk
factors.50
It soon became clear that POCD was present after noncar-
diac surgery as well as after cardiac surgery.40 The ISPOCD
was a series of multicenter, prospective, case control studies
on POCD in noncardiac surgery.51–57 The ISPOCD1 study
(mean age, 68 years) found POCD in 25% of patients at
1 week, in 10% at 3 months, and in 1% at 1 year.52 Subse-
quent work looking at young, middle-aged, and elderly
groups found an increased rate of POCD (12.7%) in the older
age group (mean age, 70 years) at 3 months, compared with
5.7% in the young and 5.6% in the middle-aged group.45 In
fact, those with POCD at both discharge and 3 months were
five times more likely than those without POCD to die in the
first year after surgery.45
RISK FACTORS
Risk factors for POCD are comprised of both modifiable
(extrinsic) and nonmodifiable (intrinsic) factors
(Table 7.2).40,58 It is important to screen for intrinsic risk
factors, even though these variables are difficult or impossi-
ble to modify, because this may impact decisions on purely
elective surgery. Intrinsic risk factors include increasing
age, preexisting cognitive impairment, lower education
level, and comorbid conditions.40,58 Extrinsic factors, such
as hemodynamic instability, metabolic derangements, or
pain control, can more easily be addressed and optimized
Table 7.2 Risk factors for postoperative cognitive
dysfunction.40,51,55
Nonmodifiable Potentially modifiable
Advanced age Major surgery
Fewer years of education Increased duration of anesthesia
Preexisting cognitive Hemodynamic instability
impairment Metabolic derangements
Declined functional status Uncontrolled postoperative pain
Alcohol abuse Postoperative infections
Frailty Postoperative respiratory
Medical comorbidities complications
Prior stroke Postoperative delirium
Repeat operations
Polypharmacy
Depression
Anemia
in the perioperative period in an effort to reduce the inci-
dence of POCD.40,58
More definitively linked to POD,59 the contribution of
intraoperative hypotension and hypoxia to POCD is less
clear. Early studies such as the ISPOCD1 study found that
mild, brief hypoxemia and hypotension were independent
risk factors for the development of POCD.51 Newer evidence
indicates low blood pressure may accelerate cognitive
decline in elderly patients.60 More research is needed in
the perioperative arena.
SCREENING TOOLS
Although there is consensus that testing for preoperative
cognitive dysfunction should be performed, there is not con-
sensus on how we should be testing or what tool we should
use. A standard, validated tool that is both thorough and
practical has not yet been developed. However, POCD is
hard to diagnose and quantify without documentation of
baseline status.44
The 2012 American College of Surgeons National Surgi-
cal Quality Improvement Program/American Geriatrics
Society Best Practice Guidelines for Optimal Preoperative
Assessment of the Geriatric Surgical Patient recommend
early cognitive testing of any patient older than age 65,
which should include an interview with spouse or family
members to supplement evaluation. Also recommended is
referral to a geriatrician for perioperative management,
should cognitive dysfunction be present. These guidelines
recommend use of the Mini-Cog tool (which consists of a
three-item recall test and clock drawing exercise); however,
other tools exist throughout the POCD literature
(Table 7.3).61
PATHOPHYSIOLOGY AND ASSOCIATION
WITH ANESTHESIA
The underlying pathogenesis of POCD remains unclear.
Most sources agree that cognitive decline is likely multifac-
torial in etiology, with suspected contributors including sys-
temic inflammation, surgical stress, sleep disturbances,
uncontrolled pain, hypoperfusion, and possibly direct neu-
rotoxic effects from anesthetic agents.40,65
 7 • Central Nervous System Risk Assessment: Preventing Postoperative Brain Injury
Table 7.3 Screening tools for preoperative cognitive dysfunction.4,62–64
Tool Pros
Mini-Cog ▪ Can be performed in 2–3 minutes
▪ Recommended by
the ACS/AGS
▪ Tested in
perioperative environment
MoCA ▪ Widely used
(Montreal Cognitive ▪ High sensitivity
Assessment)
MMSE ▪ Most widely used
(Mini Mental State ▪ High specificity
Examination)
SLUMS ▪ Content emphasizes executive functioning and episodic
(Saint Louis University memory, allowing earlier detection of subtle deficits
Mental Status Exam) ▪ Can be administered in approximately 10 min
ACS, American College of Surgeons; AGS, American Geriatrics Society.
Evidence does exist to suggest that the risk of dementia
is increased with repeated surgery coupled with general
anesthesia.46,66 However, questions remain regarding
to what extent various anesthetic drugs and techniques
are to blame. Although clear evidence regarding the
effect of anesthesia on the adult human brain is lacking,
animal studies have demonstrated anesthetic neurotoxic-
ity.67–70 Because of this proposed neurotoxicity, many
hoped avoidance of general anesthesia might lead to neu-
roprotective effects. Unfortunately, available studies have
not demonstrated improved cognitive outcomes with
regional or neuraxial anesthetic techniques. Wu et al.
provided a comprehensive review in 2004 that concluded
the choice of anesthesia does not influence the incidence
of POCD.71 This was confirmed by a 2011 meta-analysis
that compared general and regional anesthesia and
did not find that general anesthesia was independently
associated with POCD.72 Short-term POCD, diagnosed
approximately 1 week after surgery, may be more com-
mon after general anesthesia, as might intuitively make
sense due to proximity to the surgery.54,73 More research
is needed to clearly define any link between anesthetics
drugs and POCD.
INTERVENTIONS
Preoperative recognition of patients who appear to be at
high risk for developing POCD and referral to a geriatric spe-
cialist who may be able to optimize modifiable risk factors
should be considered.74 Counseling patients and families
on the risk of cognitive decline should also be included in
the preoperative interview. The decision to proceed with
purely elective surgery should only occur after a multispeci-
alty assessment in high-risk patients.
Although links are not clearly defined, minimizing sur-
gical invasiveness; length of operative time; and, in turn,
time under anesthesia may mitigate the risk of POCD. Con-
sideration should be given for monitoring of anesthetic
depth and cerebral oxygenation in high-risk patients.67,75
Avoidance of hemodynamic instability is also important.
61
Cons
▪ Screening tool only; if abnormal, further
evaluation needed for more definitive diagnosis
▪ Takes about 10 min to administer
▪ Low specificity
▪ Not very sensitive for mild impairments
▪ Age/education level
biases
▪ Takes 7–10 min to
administer
▪ Takes about 7 min to complete
▪ Limited research in
the perioperative arena
Postoperatively, since it is known that delirium can be a
risk factor for the development of POCD,76 prompt identi-
fication and treatment of delirium is important. Careful
treatment of pain and medical complications may help
improve the cognitive trajectory.40,65
Action Plan:
1. Identify patients at high risk for POCD and consider
preoperative cognitive testing and/or referral to a geri-
atric specialist.
2. Optimize modifiable risk factors.
3. Minimize surgical invasiveness and time under
anesthesia.
4. Consider monitoring depth of anesthesia and cerebral
oximetry in high-risk patients (so-called optimized ane-
sthesia).
5. Avoid hemodynamic instability.
6. Ensure early diagnosis and treatment of delirium, pain,
and infection in the postoperative period.
7. Correct any modifiable risk factors.
8. Minimize operative time, consider less invasive surgical
approaches, and reduce length of exposure to anesthe-
sia as much as possible.
9. Avoid prolonged periods of hemodynamic instability.
10. Promptly identify and treat delirium if applicable.
11. Carry out postoperative cognitive testing or refer to
geriatric specialist.
Seizure Disorders and Epilepsy
Patients with preexisting seizure disorders/epilepsy are at
elevated risk for seizures in the perioperative period primar-
ily due to the following:
1. Discontinuation of antiepileptic drug (AED) therapy:
Decrease in serum levels allows recrudescence of previ-
ously controlled seizures.
2. Seizures induced by certain medications, most com-
monly the lysine analogs, epsilon-aminocaproic acid and
62 PART II • Preoperative Assessment
tranexamic acid. Patients with seizure disorders should
not receive these medications, if possible, or they should
be given the lowest therapeutic dose.
Action Plan:
1. Continue AEDs throughout the perioperative period. If
the enteral route is off limits, develop an intravenous
administration plan; this may include using agents other
than what the patient takes at home.
2. Avoid aminocaproic acid and tranexamic acid if possible.
These lysine analogs act as γ-aminobutyric acid type A
antagonists and promote CNS hyperexcitability.77
Recent Concussion
Concussion is the occurrence of transient neurologic dys-
function (often cognitive) following traumatic head injury;
routine neuroimaging studies are normal. There is little evi-
dence to guide anesthetic practice in these patients.78 The
theoretical concern is that the concussed brain may be more
susceptible to secondary injury in the setting of anesthesia
and surgery.
Action Plan:
1. A commonsense approach is to delay purely elective
surgery until the patient has resumed full normal activ-
ities without restrictions.
Stroke Risk
There are procedural factors and patient factors in assessing
stroke risk. Certain surgical procedures (open and endovas-
cular), including cardiovascular, aortic, and neurovascular
procedures, carry a significant risk for stroke.79 Medical cen-
ters performing these procedures must have a pathway for
acute perioperative stroke care, typically involving a multi-
disciplinary stroke team. Thrombolysis and endovascular
thrombectomy should be available. Alternatively, in non-
cardiovascular surgery, perioperative ischemic stroke is
uncommon. A recent analysis of 150,198 cases from Mas-
sachusetts General Hospital and two affiliated hospitals
found a 0.5% incidence of ischemic stroke within 30 days
of surgery.80 Interestingly, patients with a preoperatively
diagnosed patent foramen ovale (PFO; n¼ 1540), were at
higher risk, with 3.2% suffering a perioperative stroke. In
adjusted analyses, estimated stroke risk was 5.9 per 1000
patients with a PFO versus 2.2 per 1000 patients without
a PFO.
Patient factors include prior stroke (discussed below),
atrial fibrillation, hypercoagulable states, PFOs, and pros-
thetic heart valves. Routine screening of all patients for a
PFO is not recommended currently, but more research is
needed. Thoughtful management of anticoagulation, used
for stroke prophylaxis in patients with atrial fibrillation or
prosthetic valves, and antiplatelet agents, used for stroke
prophylaxis in patients with cerebrovascular disease,
require cardiology and/or neurology input regarding timing
of stopping and restarting perioperatively.
Action Plan for High Stroke Risk Procedures or
Patients:
1. Each medical center needs a specific plan for acute post-
operative stroke care, even if that only involves emergent
transfer to a nearby comprehensive stroke center.
2. Preoperative plan regarding management of chronic
anticoagulant or antiplatelet drugs used as stroke prophy-
laxis (usually requires cardiology and/or neurology input)
3. “Stroke code” team availability
4. Noncontrast computed tomography (stat) with com-
puted tomographic angiography to rule out large-vessel
occlusion
5. Ability to administer intravenous alteplase and to
perform endovascular thrombectomy (interventional
neuroradiology)
6. Neurosurgical support (for hemorrhagic complications)
Prior Stroke
Patients with a prior stroke are at a greatly elevated risk for
postoperative stroke, as well as for the postoperative cogni-
tive syndromes discussed above. Currently, best evidence for
recurrent perioperative stroke risk comes from retrospective
analyses of the Danish National Registry. Christiansen et al.
analyzed 146,694 emergency surgeries in Danish patients
from 2005 to 2011, 7496 (5%) of whom had prior stroke.81
Thirty-day major adverse cardiovascular events (MACE;
acute myocardial infarction, ischemic stroke, and cardiovas-
cular death) occurred in 2.3% of patients with no previous
stroke, 20.7% of patients with stroke in the preceding
3 months, 10.3% of patients with stroke in the previous
3–9 months, and 8.8% of patients with stroke more than
9 months prior to the emergency surgery.
Jorgensen and colleagues performed a similar analysis of
the Danish National Registry for patients undergoing elec-
tive surgery.82 A total of 474,046 patients without prior
stroke were compared with 7137 patients with prior
stroke. Thirty-day MACE occurred in 0.4% of patients
without prior stroke. Those with prior stroke <3 months
before the elective surgery had a 17.7% 30-day incidence
of MACE; the rates were 7.2% for those with strokes 3–
6 months prior, 4.1% for those with strokes 6–12 months
prior, and 3.4% for patients with stroke 12 months prior
to the surgery. The authors concluded, on the basis of cubic
regression splines for the patients with prior stroke, that
the odds ratios for MACE, all-cause mortality, and ischemic
stroke leveled off at approximately 9 months. Therefore
best evidence currently indicates that purely elective pro-
cedures should be delayed for 9 months after an ischemic
stroke.
In patients with recent nondevastating stroke or transient
ischemic attack (TIA) due to symptomatic carotid disease,
corrective surgery (carotid stent or endarterectomy) should
be performed early, typically less than 2 weeks after the
stroke or TIA. Available evidence suggests that acute endar-
terectomy is safer than carotid artery stenting during the
first 7 days after symptom onset.83
In accordance with recommendations from the Society
of Neuroscience in Anesthesiology and Critical Care,74
 7 • Central Nervous System Risk Assessment: Preventing Postoperative Brain Injury 63

intraoperative and postoperative blood pressure should target
maintenance of baseline blood pressure levels and avoidance
of hypotension. Beta-blockade, started preoperatively, may
increase the risk of stroke in noncardiac surgery.74
It must be emphasized that “stroke” is a broad term
encompassing large- and small-vessel ischemic stroke, hem-
orrhagic stroke, and subarachnoid hemorrhage. An under-
standing of the etiology is essential in order to risk-stratify
the patient appropriately. For example, patients with occlu-
sive cerebrovascular disease may be very perfusion pressure
dependent and need relatively high blood pressure through-
out the perioperative period, while those with prior hemor-
rhagic stroke or subarachnoid hemorrhage (and potentially
unprotected aneurysms) may need careful avoidance of
hypertension.
Action Plan:
1. Delay purely elective surgery for 9 months after ischemic
stroke.
2. Maintain blood pressure at preoperative levels (maintain
cerebral perfusion pressure).
3. Use extreme caution if starting beta-blockers
preoperatively.
4. In patients with recent minor/nondisabling stroke or TIA
due to symptomatic carotid atherosclerosis, carotid sur-
gery should be performed early after the stroke or TIA.
5. Consider the individualized risk to the patient from
hypotension versus hypertension in conjunction with
the stroke neurologist or neurovascular specialist.
6. Patients with a PFO carry a higher risk for perioperative
stroke. Screening for PFO in all patients is not currently
recommended.
Risk for Hypoxic-Ischemic Injury
High-risk procedures include cardiac surgery, aortic sur-
gery, percutaneous coronary interventions, and possibly
interventional electrophysiologic procedures. Anoxic brain
insults in the setting of periprocedural cardiac arrest should
be treated with targeted temperature management. Rapid
induction of therapeutic hypothermia or tightly controlled
normothermia is standard of care.84
Action Plan:
1. Medical centers conducting these surgical procedures
should have specific plans for the critical care of the

Table 7.4 Summary of action plans for perioperative central nervous system risk assessment and modification.
Condition Concern Action plan
Delirium Elderly and cognitively impaired patients at high risk for ▪ Prevent when possible with nonpharmacologic measures
postoperative delirium ▪ Avoid precipitating medications
▪ Use multimodal approach to pain control
▪ Consider dexmedetomidine
▪ Treat with dexmedetomidine or antipsychotics as appropriate
▪ Reserve benzodiazepines for alcohol/benzodiazepine
withdrawal states
POCD Elderly and cognitively impaired patients at high risk for ▪ Identify patients at risk with preoperative screening and
postoperative cognitive decline counseling
▪ Optimize modifiable risk factors
▪ Consider depth of anesthesia and cerebral desaturation
monitoring in high-risk patients
▪ Avoid postoperative delirium
▪ Individuals with preexisting and/or postoperative cognitive
dysfunction may benefit from management by a geriatrician
Prior stroke Perioperative recurrent stroke in a patient with prior ▪ Delay purely elective surgery 9 months
stroke ▪ Maintain blood pressure perioperatively
▪ Recent minor stroke or TIA due to carotid disease; early carotid
surgery (CEA or stent)
Risk for hypoxic- Cardiothoracic surgery ▪ Ability to implement therapeutic hypothermia or TTM
ischemic injury Interventional cardiology ▪ Consider cerebral oximetry monitoring
Risk for ischemic Cardiothoracic surgery ▪ Acute stroke care team available
stroke Endoaortic procedures (cardiac catheterization) ▪ CT/CT angiography available
Interventional or open cerebrovascular surgery ▪ Ability to give IV alteplase
▪ Ability to deliver endovascular thrombectomy
Implanted Deep brain stimulators, spinal cord stimulators, vagal ▪ May need preoperative disabling and/or postoperative
neurostimulator nerve stimulators, and intrathecal pumps interrogation
devices ▪ Position grounding pad away from device
▪ Avoid electrocautery near device/leads
Seizure disorders Disruption of AED therapy ▪ Maintain antiepileptic drug therapy (IV if necessary)
Use of antifibrinolytics ▪ Avoid tranexamic acid and aminocaproic acid
Recent concussion Delayed recovery or exacerbation of brain injury ▪ Delay elective surgery until concussive symptoms resolve and/
or activity restrictions are lifted

AED, Antiepileptic drug; CEA, carotid endarterectomy; CT, computed tomography; IV, intravenous; POCD, postoperative cognitive dysfunction; TIA, transient
ischemic attack; TTM, targeted temperature management.
64 PART II • Preoperative Assessment
patient with hypoxic-ischemic brain injury (i.e., thera-
peutic hypothermia or targeted temperature manage-
ment) in accordance with American Heart Association
guidelines.84
Implanted Neurostimulator and
Other Devices
These devices include deep brain stimulators for movement
disorders or other indications, spinal cord stimulators for
chronic pain, vagal nerve stimulators for epilepsy, and intra-
thecal pumps for pain or spasticity (opioid or baclofen).85
Surgery with electrocautery, electrical stimulation (such
as evoked potentials in spine surgery), or magnetic stimula-
tion require careful planning to avoid excessive energy
transfer to brain, spinal cord, or neural tissue or damage
to the device.
Action Plan:
1. Consider the need for preoperative inactivation and/or
postoperative interrogation, usually with neurology,
neurosurgery, or pain management consultation.
2. Know the location of the device and wire leads.
3. Position the electrocautery grounding pad away from
the device.
4. Procedures such as electroconvulsive therapy require
multispecialty assessment and planning. Similarly,
motor evoked potential monitoring in spine surgery
may be contraindicated, depending on the location of
the stimulator (such as with a deep brain stimulator).
See Table 7.4 for a summary of action plans for perioper-
ative CNS risk assessment and modification.
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47. Bedford PD. Adverse cerebral effects of anaesthesia on old people.
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48. Rudolph JL, Schreiber KA, Culley DJ, et al. Measurement of post-
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51. Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative
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56. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. Long-
term consequences of postoperative cognitive dysfunction. Anesthesiol-
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57. Steinmetz J, Siersma V, Kessing LV, Rasmussen LS. Is postoperative
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66 PART II • Preoperative Assessment
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 8 Risk Assessment and
Perioperative Renal Dysfunction
ROBERT A. SICKELER and MIKLOS D. KERTAI
All patients undergoing surgery—from simple surgery to an
extremely complex operative procedure—suffer some per-
turbation in oxygen delivery to the kidneys. Postoperative
acute kidney injury (AKI) portends an increase in overall
morbidity, mortality, and hospital resource use. Thus the
identification of patients with an increased risk for postoper-
ative AKI is critical. The prognosis of postoperative AKI for a
particular patient scheduled for a specific operative inter-
vention may (1) assist the patient and the family in the deci-
sion to undergo a particular type of surgical procedure and
(2) allow optimization of preoperative, intraoperative, and
postoperative renal homeostasis. Several investigations sug-
gest that the anticipation of postoperative AKI and its timely
diagnosis are critical to the effective treatment of postoper-
ative AKI, and this has potential to minimize the risk for
temporary or chronic renal replacement therapies. Patient
characteristics (e.g., advanced age, diabetes mellitus [DM],
vascular disease), the type of operative procedure (e.g.,
endoscopic cholecystectomy versus aortic arch replace-
ment), and intraoperative characteristics (e.g., the duration
of hypotension or suprarenal cross-clamp placement, circu-
latory arrest), as well as medications and/or interventions
that are known risk factors for AKI (aminoglycoside or
radiocontrast dye), all affect the risk of developing postoper-
ative AKI (Box 8.1)
Several chapters in this book address the association
between the surgery and postoperative AKI; however, the
specific goal of this chapter is to provide clinicians with
methods to identify patients at increased risk for postopera-
tive AKI. First, we outline the intrinsic effects of surgery and
anesthesia on renal physiology that illustrate why all
patients are at potential risk for postoperative AKI. Second,
we discuss patient characteristics that are associated with
an increase in risk for postoperative AKI. Third, we detail
three types of surgical intervention—extracorporeal circu-
lation, profound hypothermic circulatory arrest (HCA),
and suprarenal aortic occlusion—that mechanically and
profoundly reduce normal renal perfusion during an opera-
tive procedure and thus pose a significant risk for postoper-
ative AKI. (Although this is not an exhaustive list of the
mechanical perturbations that can affect renal blood flow
[RBF] during an operative procedure, these interventions
are chosen because they are used in a number of surgical
procedures.) Fourth, because preexisting renal impairment
is associated with an increased risk for postoperative AKI,
we present strategies to identify patients with preexisting
kidney disease or to quantify the severity of preexisting
chronic kidney disease. Fifth, we conclude the chapter with
a review of existing scoring systems for quantifying the risk
for postoperative AKI and their respective utilities.
Influence of Surgery and
Anesthesia on Renal Perfusion
The kidney is an elegant system of integrated processes that
maintain fluid homeostasis and eliminate waste products.
Although the kidney requires only 10% of the total corpo-
real oxygen consumption, the renal cortex receives 90%
of the total RBF and extracts only 18% of the oxygen deliv-
ered. In contrast, the renal medulla receives only 10% of the
RBF to the kidney, and it is the site of the costly energy- and
oxygen-consuming processes that are responsible for reab-
sorbing tubular sodium and water. In the medulla, 79%
of the oxygen delivered is extracted, resulting in a high arte-
riovenous oxygen gradient in the medulla of the kidney.
Thus the medulla is exquisitely sensitive to reductions in
RBF. A 40% reduction in RBF may lead to acute tubular
necrosis, especially in the presence of other renal insults.
Interventions that improve RBF (increased cardiac output
[CO], fluid replacement) or decrease medullary oxygen con-
sumption can potentially improve the tolerance to intermit-
tent periods of ischemia. Other conditions, including
exposure to radiocontrast dyes and an increased bilirubin
concentration or myoglobinuria, can exacerbate the
adverse response to renal hypoxia by increasing the osmotic
load to the nephron and further increasing oxygen
requirements.
Several types of drugs have been shown to be nephrotoxic
through a variety of mechanisms. The perioperative use of
aminoglycosides or non-steroidal anti-inflammatory drugs
may precipitate AKI in the hypoxic kidney. The chronic
use of angiotensin-converting enzyme (ACE) inhibitors
may lead to an attenuation of the normal compensatory
response to a decrease in renal perfusion. Aprotinin, which
is an anti-inflammatory serine protease inhibitor that was
used intraoperatively to reduce blood loss, is concentrated
in the kidney, and as previous studies suggested, its use
was associated with postoperative AKI and renal failure
requiring renal replacement therapy.1–3 Further, a combi-
nation of ACE inhibitors and aprotinin can have a synergis-
tic adverse effect on renal function in patients undergoing
cardiac surgery with cardiopulmonary bypass (CPB).4
AKI itself is defined by an abrupt loss of kidney function,
resulting in the accumulation of metabolic waste and
67
68 PART II • Preoperative Assessment
Box 8.1 Factors associated with an increased risk of postoperative acute
kidney injury.
Patient characteristics
Advanced age
▪ ▪
▪ Diabetes mellitus
▪ Left ventricular dysfunction
▪ Peripheral vascular disease
Renovascular disease
▪ ▪
▪ Sepsis
Hepatic failure
▪ ▪
Operative procedure
Aortic surgery
▪ ▪
▪ Cardiopulmonary bypass
▪ Trauma surgery
byproducts and the loss of fluid and electrolyte regulation.
There has been a shift from terms such as “renal dysfunc-
tion” and “renal failure” to the more accepted term of “kid-
ney injury” to better reflect the knowledge that a small
degree of renal dysfunction may not necessarily result in
complete organ failure but still have profound physiologic
consequences and can result in significant morbidity and
increased mortality. There are many—over 30—definitions
of AKI using various clinical criteria. Indeed, the lack of con-
sensus of a single clear and universally accepted definition of
AKI has been a source of controversy and confusion in the
field, as well as a barrier to research of the disease and
advancement in knowledge of AKI.
Three of the most well-known definitions are the Acute
Dialysis Quality Initiative RIFLE criteria,5 the Acute Kidney
Injury Network (AKIN) criteria,6 and the Kidney Disease:
Improving Global Outcomes (KDIGO) criteria,7 which have
been developed over years as knowledge of AKI has
improved. RIFLE criteria used the idea of stages of kidney
injury, known as “risk,” “injury,” “failure,” “loss of kidney
function,” and “end-stage renal disease,” from which the
acronym was derived, and used increases in creatinine
(Cr) and decreases in urine output (UO) as metrics. The
AKIN criteria were developed later and revised the RIFLE
criteria, removing the “loss of kidney function” and “end-
stage renal disease” stages and simplifying the names of
the first three stages to stages 1, 2, and 3. They also modified
the time scale over which these perturbations occur, reduc-
ing the time to 48 hours from the RIFLE criteria’s original 7-
day window. The KDIGO criteria are the most recent and
allow correction of volume status and obstructive causes
of AKI before classification. The KDIGO definition of AKI
involves an increase in serum creatinine (sCr) by 0.3 mg/
dL or more within 48 hours, or an increase in sCr to 1.5
times baseline or more within the prior 7 days, or UO less
than 0.5 mL/kg/h for 6 hours. Further criteria are then used
to stage AKI.
Anesthesia (both general and regional) and surgery,
independently and synergistically, could impair renal
homeostasis during operative procedures. Both types of
anesthesia are associated with peripheral vasodilation,
thus leading to a reduction of circulating blood volume
▪ Liver transplant
▪ Renal transplant
Lung transplant
Perioperative renal insults
▪ Prolonged dehydration
Prolonged bladder obstruction
▪ Hypoxia
Hypotension
▪ Aminoglycoside exposure
▪ Myoglobin or hemoglobinuria
Intravenous contrast dyes
and renal perfusion. Vasodilation and the resultant reduc-
tion in RBF are particularly a concern in a patient who
has been nil per os (NPO) for 8 or more hours, was pre-
scribed a chronic diuretic or an ACE inhibitor, has suffered
recent vomiting or diarrhea, has undergone a recent
bowel preparation, or is actively bleeding. No studies have
demonstrated that general anesthesia is superior to
regional anesthesia in limiting the likelihood for postoper-
ative AKI.8
Regarding general anesthesia in particular, there have
been investigations into the possible adverse renal effects
of inhalational anesthetics and their fluoride ion meta-
bolic byproducts. Of the clinically used inhalational
agents, sevoflurane and enflurane release the greatest
number of fluoride moieties. However, the pharmacoki-
netics of these volatile agents greatly limits the likelihood
of renal dysfunction secondary to fluoride exposure.
Choice of an inhalational agent has been found to have
little relevance for inducing postoperative AKI, as it was
reflected by a lack of elevation of AKI biomarkers in the
patients who underwent elective cardiac surgery.9 An
interaction between sevoflurane and soda lime or barium
hydroxyl carbon dioxide could also pose a potential risk
for producing a potentially nephrotoxic haloalkene
known as “compound A.” However, the metabolic path-
ways for this compound in humans limit the likelihood
of compound A–induced nephrotoxicity. Indeed, there
are no published reports of AKI induced by exposure to
sevoflurane in surgical patients.
Patient Characteristics and the
Risk of Postoperative Acute
Kidney Injury
Patient-specific factors (identifiable in the preoperative
period) that are associated with postoperative AKI fall gen-
erally into one of three categories: (1) patient characteristics
suggesting impaired renal functional reserve, (2) physio-
logic findings associated with impaired renal perfusion, or
(3) pathophysiologic processes that cause renal injury.
 8 • Risk Assessment and Perioperative Renal Dysfunction 69

CR CL < 60
No Yes

Prior heart IABP

surgery
No Yes No Yes

39/409
valve NYHA IV cardiomegaly 9.5%

No Yes No Yes No Yes

109/24673 29/2228 48/1724

0.4% 1.3% 2.8% PVD NYHA IV

NYHA IV No Yes No Yes

No Yes 53/4943 30/1311 48/969

1.1% 2.3% 5.0%
34/3659 20/948
0.9% 2.1% valve

No Yes

36/1678 14/231
2.1% 6.1%
Fig. 8.1 Preoperative renal risk algorithm. Classification tree based on recursive partitioning analysis. Next to the solid boxes are the risk categories. CR
CL, Creatinine clearance; IABP, intra-aortic balloon pump; NYHA, New York Heart Association; PVD, peripheral vascular disease. (Adapted with permission
from Chertow GM, Lazarus JM, Christiansen CL, et al 1997.)

Potential risk factors include advanced age; abnormal sCr
values; DM; and any sign, symptom, or factor indicative
of a reduced CO and thus compromised renal perfusion
(Fig. 8.1). However, the low incidence of postoperative
AKI necessitating renal replacement therapy (<2.0% even
in high-risk populations) and the lack of sensitive, routine
laboratory studies that identify AKI even when it does not
result in an increase in Cr or blood urea nitrogen (BUN) have
challenged investigators to identify factors that are associ-
ated with postoperative AKI.
PATIENT CHARACTERISTICS ASSOCIATED WITH
REDUCED RENAL RESERVE
Renal mass and overall renal function decrease with
advancing age. By age 70 years, the number of functioning
nephrons is reduced by half. Novis and colleagues10
reviewed 28 studies evaluating risk factors for postoperative
AKI. Four of the five largest studies identified advanced age
as a risk for postoperative AKI. In a study of 2400 patients
undergoing elective coronary artery bypass grafting (CABG)
surgery, Mangano and colleagues11 found that patients
between 70 and 80 years old and those over 80 years old
suffered a twofold and fourfold increase in the risk for post-
operative AKI, respectively. Similarly, Chertow and col-
leagues,12 in their study of 42,723 US Department of
Veterans Affairs (VA) cardiac surgery patients, found that
1.5% and 1.8% of CABG surgery patients between 70 and
80 years old and older than 80 years, respectively, required
postoperative dialysis. In comparison, only 0.5% and 0.9%
of patients 50 to 59 and 60 to 69 years of age, respectively,
required renal replacement therapy. However, after adjust-
ing for peripheral vascular disease, prior cardiac surgery,
and other related variables, advanced age no longer
remained a significant predictor of renal replacement
therapy.
Patients with DM, especially those suffering from long-
standing disease managed with insulin, tend to have
reduced renal reserve. Type 1 DM and preoperative glucose
values greater than 300 mg/dL were significantly and
independently associated with postoperative AKI in the
study of Mangano and colleagues.11 Those patients with
type 1 DM and those with hyperglycemia were 1.8 and
3.7 times more likely, respectively, than patients without
type 1 DM to develop postoperative AKI. Although some
investigators have failed to demonstrate an independent
association between DM and postoperative AKI, many
other investigators have been able to develop risk indices
that included DM as a significant predictor of postoperative
AKI.13
Recent research has focused on the role of obesity and its
association with increased risk of postoperative AKI. Several
studies have shown a two- to threefold increase in the rate of
postoperative AKI in patients with obesity,14 and a poten-
tially larger increase in risk when other components of met-
abolic syndrome were also present. This relationship has
been seen in both cardiac and noncardiac surgery
patients.15 Interestingly, some studies have found a para-
doxical effect between obesity and improved outcomes,
which has been ascribed to several possible metabolic and
70 PART II • Preoperative Assessment
Table 8.1 Risk of renal dysfunction according to renal reserve.
Remaining Glomerular filtration
Renal reserve nephron (%) rate (mL/min)
Normal >50 125
Decreased renal 40 50–80
reserve
Renal 20–40 20–50
insufficiency
Uremia 5–10 <20
BUN, Blood urea nitrogen.
With permission from Prough DS, Foreman AS. Anesthesia and the renal system. In: Barash PG, Stoelting RK, Cullen BF, eds. Clinical Anesthesia. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 1992:1125-1156.
pathophysiologic mechanisms, all of which unfortunately
remain poorly studied and therefore poorly understood.16,17
Reduced renal functional reserve is best identified by mea-
suring glomerular filtration rate (GFR). However, most stud-
ies rely on sCr values as a potential measure of renal reserve.
Because Cr values are substantially affected by nonrenal fac-
tors (e.g., age, sex, muscle mass), they cannot be considered
adequate measures of GFR. Some studies have used the
Cockcroft-Gault equation to estimate GFR.18 Studies using
sCr values, derived values for GFR, or true creatinine clear-
ance (CrCl) assessments have almost uniformly identified
reduced preoperative renal reserve, manifested as an
increase in Cr or as a reduction in GFR, as the most common
and one of the most important patient characteristics asso-
ciated with postoperative AKI (Table 8.1).
Several studies have emphasized the additive risk associ-
ated with even mild preoperative kidney disease on postop-
erative AKI. Weerasinghe and colleagues studied 1427
patients with no known kidney disease who were scheduled
for elective primary CABG surgery.19 They reported that
patients with a minimal elevation in Cr values (Cr
>130 μmol/L) were at a substantial risk for postoperative
renal failure requiring renal replacement therapy.
PATIENT CHARACTERISTICS SUGGESTING REDUCED
RENAL BLOOD FLOW
Many patients presenting for surgery—particularly cardiac
or major vascular surgery—have signs and symptoms that
suggest a reduced CO and thus reduced RBF. Such signs and
symptoms include rales, rhonchi, edema, jugular venous
distention, abnormal heart sounds, a need for pharmaco-
logic or mechanical ventricular support, and echocardio-
graphic evidence of a significantly reduced ejection
fraction (<35%). Even in the absence of apparent preexist-
ing renal dysfunction (i.e., with normal Cr values), these
patients may have a greatly reduced ability to maintain nor-
mal GFR and fluid homeostasis, especially with the addi-
tional insults of surgery and other interventions.
The study by Chertow and colleagues12 of 43,642 cardiac
surgery patients and the report by Thakar and colleagues20
of 33,217 cardiac surgery patients both emphasize the
prognostic value of signs, symptoms, interventions, and
Signs/ Risk of dysfunction
symptoms Laboratory abnormalities or failure
None None Minimal
None None Mild
Nocturia Moderate increase in BUN/creatinine, Moderate
unless stressed
Uremic Multiple Severe
syndrome
laboratory assessments indicating reduced left ventricular
function and thus compromised renal perfusion. The preop-
erative presence of any of these factors usually indicates that
there is an increased risk for postoperative AKI.
Recent studies have further explored the association
between preoperative hemodynamic compromise and post-
operative AKI. A meta-analysis by Brienza and colleagues21
that included 20 studies with a total of 4220 patients sug-
gested that perioperative hemodynamic optimization may
reduce the risk of postoperative AKI. Adequate fluid resus-
citation combined with inotropic support in the preopera-
tive period could potentially be an effective way to
minimize the risk for postoperative AKI, particularly in
higher-risk patients.
Several studies assessed the association of postoperative
AKI with factors that might be expected to be associated
with reduced RBF, such as renal artery stenosis.22,23 In
one of the studies, Conlon and colleagues assessed the asso-
ciation of preexisting renal artery stenosis (>50% stenosis)
with postoperative AKI, but they found no significant asso-
ciation between preexisting renal artery stenosis and post-
operative AKI.22
OTHER PREOPERATIVE PATIENT VARIABLES
ASSOCIATED WITH KIDNEY INJURY
A patient may suffer various pathophysiologic processes in
the preoperative period that expose the kidney to toxic
insults, such as increased levels of metabolic byproducts
or naturally occurring biomolecules, thus putting additional
stress on renal function. These phenomena cause an
increase in renal oxygen demand. For example, hepatic fail-
ure or obstruction leads to an increase in bilirubin and other
incompletely metabolized moieties. As these metabolites
accumulate, the renal parenchyma compensates for hepatic
insufficiency and must detoxify, excrete, concentrate, or
secrete these toxic substances. This often requires an
increase in oxygen demand, and thus, it may limit the kid-
ney’s ability to withstand any further renal insults that are
inflicted during the perioperative period. Similarly, patients
suffering massive trauma, hemorrhage, or extensive burn
injuries have increased renal oxygen requirements, as the
 8 • Risk Assessment and Perioperative Renal Dysfunction 71

kidneys must filter increased plasma levels of myoglobin and
hemoglobin. Both sepsis and gut ischemia are associated
with endotoxin release and may lead to a reduction in renal
perfusion, and perhaps more important, an accelerated
inflammatory response reaction. During the acute inflam-
matory phase, the kidney is recruited to help manage many
of the inflammatory kinins, and it is exposed to activated
leukocytes. Filtered inflammatory mediators may be tubulo-
toxic. Hypotension reduces GFR, and efferent arterioles con-
strict to compensate. Ultimately, the hypotension, the
medullary ischemia, and the sludging of activated neutro-
phils lead to an increased neutrophil adhesion potential.
Adherent neutrophils release vasoconstrictive and tubulo-
toxic mediators, further increasing renal oxygen demand
and reducing oxygen delivery.24
OTHER PREOPERATIVE PATIENT FACTORS
ASSOCIATED WITH POSTOPERATIVE RENAL
DYSFUNCTION
Other patient factors, including previous cardiac surgery,
peripheral vascular disease, hypertension, and chronic
obstructive pulmonary disease, have been identified as
potential risk factors for postoperative AKI. These factors,
which have not been uniformly accepted as risk factors,
are discussed in the following section.
Surgical Interventions Associated
With Substantial Intraoperative
Renal Ischemia
CARDIOPULMONARY BYPASS
The incidence of postoperative AKI after cardiac surgery
ranges from 2% to 50%, with approximately 0.4%–4.7%
of patients who develop postoperative AKI requiring dialysis
(Table 8.2). In a landmark study of 42,773 patients by Cher-
tow and colleagues, dialysis-dependent postoperative AKI
occurred in 1.1% of patients with a 63.7% associated mor-
tality—striking when compared with the 4.3% mortality
among those who did not require dialysis after cardiac sur-
gery.12 Postoperative AKI heralds a poor prognosis with
increasing complications and mortality, especially for
patients with postoperative respiratory failure, hypotensive
episodes, bleeding, atrial fibrillation, or other end-organ dys-
function.11,12,25–27
These patients remain in the intensive care unit and hos-
pital for greater durations and are more likely to require spe-
cialized long-term care.11,12,19,20 The overall mortality for
patients who developed postoperative AKI requiring renal
replacement therapy ranges from 27% to 100%. The eco-
nomic impact of postoperative AKI in cardiac surgery

Table 8.2 Studies of renal dysfunction after cardiopulmonary bypass surgery.

NONDIALYSIS OUTCOME DIALYSIS OUTCOME
Number of Definition of renal Incidence Mortality Incidence Mortality
Author (ref. no.) patients Study design dysfunction (%) (%) (%) (%)
Yeboah et al.28 428 — — 26 38 4.7 70
29
Abel et al. 500 Prospective Cr >1.5 mmol/L 21.6 13.8 3 100
30 a
Bhat et al. 490 Retrospective Cr 1.6 mmol/L 28.1 10.9 2.2 45
31
McLeish et al. 1542 Retrospective — Not reported Not reported 1.3 35
Hilberman et al.32 204 Case control BUN 30 mmol/Lb 2.5 60 2.5 60c
Gailiunas et al.33 752 Retrospective Cr >1.5 mmol/L 17 Not reported 1.5 27
34
Lange et al. 2959 — — Not reported Not reported 1.2 53
35
Corwin et al. 572 Case control Crpostop 1.5 Crpreop 6.3 Not reported 1 33
Slogoff et al.36 504 — Cr 1.5 mmol/Ld 2.4 0.2 0.4 0
37
Zanardo et al. 775 Prospective Cr 1.5 mmol/L 15.1 9.5 0.5 44
11
Mangano et al. 2417 Prospective Cr 2.0 mmol/L 7.7 19 1.4 40
38 2e
Abrahamov et al. 2214 Retrospective CrCl <40 mL/min/1.73 m 2.1 Not reported 1% 30
Grayson et al.39 5132 Retrospective Cr >2.0 mmol/L 2 Not reported 0.9 32.9 or 46.2f
Antunes et al.40 2455 Prospective Cr 2.1 mmol/Lg 5.6 5.8 0.6 33.3
Oprea et al.41 6130 Retrospective Cr 0.3 mmol/dL 58 30.7 Not reported Not reported

BUN, Blood urea nitrogen; Cr, creatinine; CrCl, creatinine clearance; Crpostop, postoperative creatinine; Crpreop, preoperative creatinine; V, valve.
a
Also, Crpostop - Crpreop  0.4 mmol/L (mg/dL).
b
Or inulin or creatinine clearance 50 mL/min/1.73 m2.
c
Mortality is combined for dialysis and nondialysis patients.
d
And fractional excretion of sodium >1% or total urinary sodium >20 μg/L or urine with casts, epithelial cells, or cellular debris.
e
Creatinine clearance at least a 15-mL/min decline from preoperative level.
f
Depending on the type of surgery (32.9% after coronary artery bypass grafting [CABG]; 46.2% after valve operation with or without CABG).
g
Plus an increased creatinine level of 0.9 mmol/L from preoperative to maximum postoperative values.
72 PART II • Preoperative Assessment
patients is considerable. In fact, it is estimated that nation-
ally, the direct hospital cost of caring for patients with post-
CPB renal failure is approaching $645 million.42
Postoperative AKI after cardiac surgery with CPB in
patients with advanced age can sometimes be the result
of acute renal ischemia superimposed on preexisting limited
renal reserve.11,43 Predictive risk factors indicative of
compromised renal perfusion, such as advanced age
(>70 years old), preoperative left ventricular dysfunction,
atherosclerotic vascular disease, decreased renal reserve,
DM, prior myocardial revascularization, a longer duration
of CPB time (>3 hours), type of operation (e.g., valvular sur-
gery), perioperative use of nephrotoxic agents (e.g., radio-
contrast dyes), and postoperative low CO, all have been
associated with an increased risk for postoperative
AKI.11,28–48
Historically, extracorporeal circulation was thought to be
associated with multiple perturbations in renal physiology
and function. During CPB, there are substantive decreases
(25%–75%) in RBF and GFR and increases in renal vascular
resistance. These physiologic perturbations are likely
sequelae of the loss of pulsatile blood flow,49 increases in cir-
culating catecholamines and inflammatory mediators,50
macroembolic and microembolic insults to the kidneys
(organic and inorganic debris),51 release of free hemoglobin
from traumatized red blood cells,52 and decrease in flow
rates and mean arterial pressure during CPB.28,29 In addi-
tion, extreme hemodilution and deep HCA have been asso-
ciated with a significantly greater likelihood of postoperative
AKI.53 However, several studies have found no effects of
hypothermia without circulatory arrest,54,55 pulsatile per-
fusion,56 pH-stat management,56 or type of membrane oxy-
genators57 on renal function after CPB. Lema and
colleagues studied the GFR and effective renal plasma flow
of patients with a Cr level of less than 1.5 mg/dL undergoing
hypothermic CPB and found that renal function was not
adversely affected by CPB.46
The off-pump coronary artery bypass approach to coro-
nary revascularization was expected to substantially
reduce the incidence of end-organ dysfunction (e.g., renal,
cerebral) observed in patients undergoing CABG surgery
with CPB. However, a substantial number of retrospective
and prospective studies comparing the incidence of adverse
outcomes associated with off- versus on-pump CABG sur-
gery have failed to indicate that off-pump CABG surgery
was associated with a lower risk for postoperative compli-
cations. Although studies of patients undergoing off-pump
CABG surgery revealed significantly fewer changes in
microalbuminuria, fractional extraction of sodium, free
water clearance, free hemoglobin, and N-acetyl-β-D-gluco-
saminidase,58 this was not associated with a significant
reduction in postoperative AKI.59–61 In patients with pre-
operative non–dialysis-dependent AKI, however, off-pump
CABG surgery appears to lower the incidence of postoper-
ative renal failure, need for renal replacement therapy, and
mortality.62–64 A recent meta-analysis indicated some
potential benefit of off-pump CABG surgery for the reduc-
tion in the incidence of postoperative AKI; however, there
was no difference found in need for dialysis or mortality.65
In contrast, Lamy and colleagues failed to show a differ-
ence between new-onset renal failure requiring dialysis
at either 30 days, 1 year, or 5 years after on- or off-pump
CABG surgery.66,67 Additional studies68–70 have found
similar results with respect to postoperative AKI. Finally,
McCreath and colleagues suggested that a minimally inva-
sive cardiac surgical approach such as the port access
minithoracotomy approach to mitral valve surgery may
confer a reduction in the incidence of postoperative AKI
when compared with a standard median sternotomy
approach.71
PHARMACOLOGIC MANAGEMENT OF
POST–CARDIOPULMONARY BYPASS AKI
Pharmacologic approaches to reduce postoperative AKI
have been studied extensively in recent years. Although
most of these pharmacologic agents appeared to promote
UO in the perioperative period, intraoperative UO had no
correlation with postoperative renal function, especially
when diuretics were used intraoperatively.32 Dopamine
(DA) at low doses activates the DA-1 receptor and has the
theoretical benefits of renal artery dilation, natriuresis,
and diuresis. Although DA was once shown to increase
renal plasma flow, GFR, and urinary sodium excretion,72
these dopaminergic effects were not observed in patients
with impaired renal function (GFR <50 mL/min/1.73 m2),
probably because of a lack of renal reserve capacity in
response to the effects of DA.73 Randomized controlled trials
with cardiac surgery patients have not demonstrated that
prophylactic low-dose DA can preserve renal function,
reduce the development of AKI,74–76 and decrease mortal-
ity. In addition, the positive inotropic and chronotropic
effects of DA could lead to the development of perioperative
arrhythmias and an increase in myocardial oxygen con-
sumption that are potentially deleterious to cardiac surgery
patients.77 Furthermore, the use of DA to promote diuresis
in patients who are hypovolemic is likely to exacerbate renal
failure.78 In view of the lack of proven benefits and the
potential harm, routine use of DA to promote diuresis in
the perioperative setting is not recommended.
Mannitol is a hyperosmotic agent that increases GFR dur-
ing periods of renal hypoperfusion, augments renal cortical
and medullary blood flow, and promotes scavenging of reac-
tive hydroxyl free radicals. It reduces renal oxygen con-
sumption during periods of ischemia and enhances
diuresis of intraluminal debris. However, the prophylactic
use of mannitol in patients undergoing CPB has not pro-
duced convincing improvement in renal function and mor-
tality outcome.79,80
Loop diuretics such as furosemide offer benefits similar to
those of mannitol in reducing oxygen consumption and
improving diuresis by preventing the accumulation of
obstructive casts. In two separate prospective randomized
studies, the use of furosemide during and after CPB was
found to have no clinical benefits and to be potentially det-
rimental to renal function.74,81 Although DA, mannitol,
and furosemide can convert oliguric to nonoliguric renal
failure and facilitate management of fluid balance and elec-
trolytes, in the absence of evidence that forced diuresis
translates to survival benefit, the routine use of these
medications is not encouraged.

A selective DA-1 receptor agonist, fenoldopam, has the
theoretical advantages of decreasing renal vascular resis-
tance and increasing RBF and GFR.82 Caimmi and col-
leagues studied patients with a preoperative Cr level of
greater than 1.5 mg/dL and found that infusion of fenoldo-
pam (0.1–0.3 μg/kg/min) during CPB and in the early post-
operative period was associated with an improvement in
postoperative Cr level and CrCl.83 In a prospective multicen-
ter cohort study of high-risk cardiac surgery patients with
renal failure, prophylactic infusion of fenoldopam was asso-
ciated with a 50% reduction of AKI and a decrease in mor-
tality from 15.7% to 6.5%.84 These clinical benefits were
based on a preliminary experience with fenoldopam and will
have to be confirmed by larger-scale prospective randomized
clinical trials before it is used routinely.
Vasodilators such as calcium channel blockers (e.g.,
nifedipine, diltiazem) have been shown to improve GFR in
patients undergoing cardiac surgery with CPB.85–88 How-
ever, clinically significant decreases in morbidity and mor-
tality outcomes are lacking to advocate their routine use
for the prevention and treatment of postoperative AKI.
Clonidine is a nonselective α-adrenergic agonist that may
prevent renal hypoperfusion by inhibiting stress-induced
catecholamine–mediated vasoconstriction. Kulka and col-
leagues found that in patients without an elevated risk for
postoperative AKI, clonidine at 4 μg/kg prevented the dete-
rioration of CrCl after cardiac surgery compared with pla-
cebo.89 However, the long-term benefit of clonidine
infusion for reduction of mortality in high-risk patients
has not been fully evaluated.
Atrial natriuretic peptide (ANP) is important in intravas-
cular fluid and circulatory regulation. It promotes diuresis
and natriuresis, increases GFR, reverses afferent renal vaso-
constriction and efferent renal dilation, and inhibits sodium
reabsorption.90 Intraoperative volume loading has been
shown to regulate ANP release, and its concentrations
may predict long-term outcomes after CABG surgery.91
Intraoperative infusion of ANP has been shown to decrease
central venous pressure, pulmonary capillary wedge pres-
sure, pulmonary vascular resistance, peripheral vascular
resistance, and the renin-angiotensin-aldosterone system,
and its use was associated with increasing RBF, GFR, and
diuresis.92–94 The precise effects of ANP on post-CPB renal
function and their potential role in curtailing renal failure
and its associated mortality will have to be determined by
future clinical trials.95,96
Two studies that examined the institution of early renal
replacement therapy in the form of continuous venovenous
hemodiafiltration in patients with established postoperative
AKI found a statistically significant reduction in the overall
rate of mortality.97,98 Even outside the setting of the periop-
erative period, a debate exists on the optimal timing of renal
replacement therapy for AKI in critically ill patients.99–101
In summary, the effects of CPB on the kidneys have sig-
nificant impacts on patient management and outcomes.
However, despite intensive investigation into the pathogen-
esis and prevention of postoperative AKI, there has been
only limited progress in the development of effective protec-
tive strategies. As intravascular volume depletion and hypo-
perfusion can lead to exacerbation of renal ischemia and
accentuate the risk for postoperative AKI, avoidance of
8 • Risk Assessment and Perioperative Renal Dysfunction 73
nephrotoxic agents and close attention to maintenance of
intravascular volume, blood pressure, and CO are key in
the effort to reduce the occurrence of postoperative AKI
after cardiac surgery.102 Identification of patients with
genetic variants of specific inflammatory markers
(interleukin-6 [IL-6] gene promoter polymorphism, apolipo-
protein E) to determine predisposition for postoperative AKI
may be an additional means of identifying patients at risk for
postoperative AKI.103,104 In recent years, kidney-specific
biomarkers measured perioperatively have been correlated
with prolonged CPB time and may help predict AKI after
CPB.105
MAJOR AORTIC SURGERY
Patients undergoing major aortic surgery with or without
HCA are particularly vulnerable to postoperative AKI. These
patients are typically of advanced age and have atheroscle-
rotic disease of the large arterial vessels and end-organ vas-
cular beds (e.g., of the heart, brain, and kidney). Thus
vascular surgery patients have many of the characteristics
that are prognostic for postoperative AKI in cardiac surgery
patients. Review of the literature suggests that the presence
of preoperative AKI is the most consistent predictor for
postoperative AKI following major vascular surgery.106–115
However, because each type of major vascular surgery
procedure is associated with a significant mechanical per-
turbation that interferes with RBF—cross-clamping of the
aorta, left-heart bypass, renal artery reimplantation or
surgery, or CPB with or without HCA—the type and
duration of the particular mechanical intervention render
other potential variables less important predictors of
postoperative AKI.
The reported incidences of AKI and dialysis after major
aortic surgery vary substantially (Table 8.3).111–127 The
reported incidences of postoperative AKI range between
5% and 29% and between 1.6% and 22.2%, respectively.
This reflects the nonuniform definitions of preoperative
and postoperative AKI but also, and perhaps more impor-
tant, the underlying potential for significant, potentially
life-threatening differences in patient characteristics and
management strategies in this group of patients.
Most clinicians caring for patients with an abdominal
aortic aneurysm (AAA) recognize the critical nature of
the decision regarding the intraoperative position of the
aortic cross-clamp. Cardiovascular anesthesiologists
encourage their surgical colleagues to consider infrarenal
cross-clamp placement (if at all possible) in patients under-
going AAA surgery. Studies by Breckwoldt and col-
leagues116 and Johnston and colleagues117 emphasize
the importance of infrarenal versus suprarenal cross-
clamp placement regarding the development of postopera-
tive AKI (Table 8.4). In a study of 205 patients with AAA,
Breckwoldt and colleagues found that in patients in whom
aortic clamp was applied infrarenally (n ¼ 39), there were
fewer who were at risk for developing postoperative AKI
than there were among the patients requiring suprarenal
occlusion of the aorta (n ¼ 166).116 The multicenter study
by Johnston and colleagues117 included 666 patients
managed with an infrarenal versus suprarenal aortic
74 PART II • Preoperative Assessment

Table 8.3 Studies of renal dysfunction after vascular surgery.

Postoperative Postoperative
Study author renal dialysis
Surgery (ref. no.) dysfunction (%) required (%) Risk factors for renal failure
Infrarenal Powell et al.128 - 8–9a Preoperative RD
116
Infrarenal vs. Breckwoldt et al. Infrarenal 13.9 1.80 No single factor
suprarenal
Suprarenal 38.5 2.60
AAA infrarenal + Johnston117 5.0–33.0 0.4–6.0 Preoperative RD, AX site, RV ligation, RA bypass
suprarenal
Shepard et al.129 14 1.18
130
Renal involvement Hallett et al. 22 9.0–35.0 —
118
Chaikof et al. 4.0 18.3 Preoperative RD
110
Nypaver et al. 16.98 5.66 RA bypass/endarterectomy, any postoperative complication
Allen et al.119 12.3 3.08 Preoperative RD
120
Cambria et al. 9.0 15.0 Preoperative RD
121 a
Acher et al. 19.0 2.0–71.0 Preoperative RD
122
Aortic rupture Panneton et al. 27.7 6.3 Preoperative RD
Bauer et al.123 29.0 — AX time/site, preoperative RD, age, hypotension
Hajarizadeh et al.124 11.43 18.1 -
125
Berisa et al. 16.0 84.0 Preoperative RD
113
Thoracoabdominal Crawford et al. - 5.0–17.0 Preoperative renal dysfunction
Schepens et al.111 - 11.9–14.1 Age, preoperative creatinine, CAD, DM
Svensson et al.112 15.87 13 Repair of visceral artery, preoperative RD, and postoperative
complication
Godet131 17.26 8 Age >50 y, preoperative RD, LRA, ischemic time, transfusion
114
Safi et al. 2.5 15 LRA reattachment, preoperative RD, visceral perfusion, simple
cross-clamp technique
Endovascular White et al.126 14.29 21.43 —
Sharma et al.127 3.7a 11.1a Aortoiliac source of embolus

AAA, Abdominal aortic aneurysm; AX, aortic cross-clamp; CAD, coronary artery disease; DM, diabetes mellitus; LRA, left renal artery; RA, renal artery; RD, non–dialysis-
dependent renal failure; RV, renal vein.
a
If preoperative CR >1.5 mg%.

Table 8.4 Comparisona of methods for determination of cross-clamp, and they also found that infrarenal aortic
glomerular filtration rate.
cross-clamping was associated with a lower risk for post-
Testing Clinical operative AKI (see Fig. 8.1).
Clearance method complexity Accuracy usefulness Surgical patients with thoracoabdominal aneurysmal dis-
Classic insulin clearance ++++ ++++ + ease may suffer the greatest perturbations in perioperative
1
renal homeostasis. A variety of approaches are used to limit
Radioisotope clearance +++ + + + /2 ++ the ischemic time and overall insult to the kidneys; HCA, left
Radioisotope plasma +++ +++ ++ heart bypass, and renal “plegia” are measures to reduce
disappearance renal metabolism or limit actual interruption of
Creatinine clearance ++ ++ +++ RBF.111–116 However, most patients continue to be at risk
1 1 for profound AKI because several common intraoperative
Nomogram creatinine + /2 + /2 +++
clearance
events further negatively impact renal metabolism. Sub-
stantial blood loss, visceral ischemia and endotoxemia,
Serum creatinine + + ++++ requirements for massive blood product transfusions, and
a
Rated from high (+ + + +) to low (+). renal ischemia all portend postoperative AKI.
With permission from Mehta RL, Chertow GM. Acute renal failure definitions There is debate in the surgical community about the
and classification: time for change? J Am Soc Nephrol 2003;14(8):2178-2187. optimal set of approaches for operative management of
 8 • Risk Assessment and Perioperative Renal Dysfunction 75

extensive thoracoabdominal aortic disease. Some clinicians the morbid intraoperative events (cross-clamp placement,
claim that HCA is superior to left-heart bypass in preserving HCA, left-heart bypass) associated with these vascular pro-
renal function. Soukiasian and colleagues reviewed all of cedures is likely to be the greatest determinant of perioper-
their cases of patients undergoing thoracoabdominal ative risk for renal adverse events.
aneurysm repair in a 12-year period.132 Their practice
underwent a modification to use circulatory arrest rather
than left-heart bypass. In the first group of 20 patients, Perioperative Testing of Renal
the rate of renal failure was 15%, and it was 0% in the
39 patients managed with HCA. Comments published
Function
with the article essentially dismissed these findings and
Although the ability to identify patients at risk for postoper-
quoted work by Crawford, Cosseli, and others that coun-
ative AKI has improved, the methods to detect and quantify
tered these findings.113 Importantly, this high-risk group
both deterioration and subsequent improvement in renal
of patients is managed differently by different surgeons function require further refinement.
and in different institutions. As such, it is difficult to identify
Although many renal function tests are available and
many of the potential risk factors for postoperative AKI.
each examines a different aspect of the kidney’s physiologic
Indeed, prospective randomized studies to define the risk fac- function (Box 8.2),8 GFR remains the most reliable indicator
tors associated with AKI are lacking. However, most studies
of renal function. GFR is most frequently estimated by
suggest that preexisting AKI, aortic rupture, and the
CrCl, a value obtained from a 24-hour urine collection
requirement for renal arterial reconstruction are associated
(see Table 8.4).138 Although some authors have investi-
with an increase in risk for postoperative AKI and subse-
gated a CrCl estimate based on a 2-hour standard, a 24-hour
quent mortality.
CrCl estimate of GFR is currently the best predictive marker
One of the most promising developments in the manage-
of changes in renal function and the potential development
ment of aortic disease is the introduction of stent
of postoperative AKI.
grafts,133–137 and the techniques are rapidly evolving. Sev-
Historically, sCr and UO have been the most clinically
eral types of grafts are approved for use in the descending
accessible means to assess and follow renal function. In spite
thoracic and abdominal aorta. Some centers use multiple of their practicality, they are highly variable predictors. Nor-
stent grafts to reconstruct the thoracoabdominal aorta.
mal sCr values vary as a function of age, sex, race, body hab-
One such technique uses a combined “open-and-closed”
itus, and diet.139 Changes in sCr are not specific and do not
approach in which open access is achieved (limiting the
reveal the etiology, site, and extent of injury. Also, sCr
source of one of the most common adverse events associated
changes are insensitive to changes in GFR and may be
with stent grafts) and a stent is used where adequate “land-
delayed for several days. UO and sCr may be altered by
ing zones” can be identified.136
diuretics and dialysis as well as other preventative and treat-
Black and colleagues reported their findings in 29 consec-
ment modalities. Furthermore, many studies have shown a
utive patients treated with endovascular occlusion and open
variable correlation between sCr and UO and the risk of
visceral revascularization for management of thoracoab-
developing perioperative AKI. There is also no clear associ-
dominal aneurysms.137 Five of the patients had known ation between changes in sCr and morbidity or the progno-
renal insufficiency. Postoperatively, four patients suffered
sis for long-term recovery. Additionally, definitions of AKI
AKI, with two requiring temporary dialysis. The group
based on initial and subsequent changes in sCr have varied
concluded that they would manage all Crawford types I, widely.138
II, and III thoracoabdominal aneurysms with this approach.
Much of the recent literature has focused on the applica-
As in other work in the surgical management of thoracoab-
tion of the modified Cockcroft-Gault equation to estimate
dominal aortic disease, no prospective randomized studies
CrCl, which is an alternative measure of renal function with
have defined the difference in risk between open and stent
improved accuracy and estimation of renal reserve.18 The
graft repairs in regard to a number of adverse outcomes,
equations in men and women are as follows:
including AKI.
In summary, vascular surgery patients represent a
group of patients with multiple intrinsic and extrinsic CrCl (in men) ¼ ([140 - age]  weight  1.2)  sCr
potential risk factors for AKI. However, the magnitude of CrCl (in women) ¼ ([140 - age]  weight)  sCr

Box 8.2 Renal function tests available for clinical use.

▪ Urine volume ▪ Urinary sodium excretion
▪ Urine specific gravity ▪ Fractional excretion of sodium
▪ Urine osmolality ▪ Free water clearance
▪ Serum creatinine and blood urea nitrogen ▪ Creatinine clearance
▪ Urine-to-plasma creatinine ratio ▪ Renal blood flow
▪ Urine-to-plasma urea ratio

With permission from Sear JW. Kidney dysfunction in the postoperative period. Br J Anaesth 2005;95(1):20-32.
76 PART II • Preoperative Assessment
Wijeysundera and colleagues found that a combination of
sCr and CrCl allowed identification of patients they desig-
nated as having occult renal insufficiency, defined as a nor-
mal sCr with a CrCl of 60 mL/min or less.140 They found that
approximately 13% of patients with a normal sCr had occult
renal insufficiency, which was independently associated
with the need for postoperative renal replacement therapy
in cardiac surgery patients.
A more recent method of estimating GFR involves mea-
surement of serum cystatin C, an alkaline nonglycosylated
protein.140,141 Cystatin C is produced by virtually all nucle-
ated cells and is freely filtered through the glomerular mem-
brane and nearly completely reabsorbed and degraded by
the proximal tubular cells. The reference range values for
cystatin C are the same for men, women, and children,
and they are not dependent on muscle mass or diet. A recent
meta-analysis by Dharnidharka and colleagues, which com-
pared serum cystatin C levels with CrCl values, suggested
that cystatin C is a better surrogate of GFR and one that
reflects changes in GFR more rapidly.142
Recent elucidations of the pathophysiology of AKI have
revealed the need for earlier detection of both deterioration
and improvement in renal function. Newer techniques are
now being investigated that could provide more detailed
assessment of both the nature and timing of injury. These
could allow for earlier diagnosis, identification of specific
time points for intervention, and quantifiable measurements
for therapeutic effectiveness.
One emerging field is urinary proteomics. Clinical proteo-
mics, or urinary protein profiling, has brought about the dis-
covery of novel protein biomarkers for renal diseases.143
One application of urinary proteomics involves the use of
surface-enhanced laser desorption/ionization time-of-flight
mass spectrometry (SELDI-TOF-MS), which has emerged
as one of the preferred methods of urinary protein profiling.
SELDI-TOF-MS allows rapid profiling of multiple urine sam-
ples and detects low-molecular-weight biomarkers that are
often missed by other methods.143
Several other new techniques are also being investigated
and are ready to be adapted for human studies. KIM-1 (kid-
ney injury marker 1) may be an early marker for renal
tubule injury, and a cysteine-rich protein (CYP 61) has been
found in the urine after ischemia-reperfusion injury. Newer
contrast agents used with magnetic resonance imaging are
being tested in experimental AKI models and may provide
insight into intrarenal hemodynamics, the level and extent
of proximal tubule injury, and the presence of inflamma-
tion.138 Additional biomarkers continue to be investigated
with the objective of identifying methods to diagnose post-
operative AKI earlier and more accurately than using UO
or sCr levels. There is an extensive list of such biomarkers
that continue to be discovered and developed, including
NGAL (neutrophil gelatinase-associated lipocalin), IL-18,
liver-type fatty acid–binding protein, TIMP2 (tissue inhibi-
tor of metalloproteinase 2), IGFBP7 (insulin-like growth fac-
tor–binding protein 7), among others.144,145 Unfortunately,
the routine use of many of these markers is still cost
prohibitive; these markers only target certain mechanisms
of AKI; or these markers have various other limitations
(e.g., poorly understood mechanisms and limited data on
kinetics) that prevent more extensive research into them
and their ultimate widespread adoption into routine clinical
practice.
Perioperative Renal Risk Scoring
Algorithms
The development of numerous scoring systems based on
well-defined risk factors has provided greater insight into
which patients are at greatest risk for perioperative AKI.
Most of the indices include many of the risk factors discussed
in this chapter.
The algorithm proposed by Chertow and colleagues to
predict postoperative renal failure and dialysis after cardiac
surgery was developed in a robust database of 43,642 VA
patients.12 Chertow and colleagues identified 10 clinical
variables related to baseline cardiovascular disease and
renal function (Box 8.3). On the basis of these variables,
they divided renal risk into three categories—low risk
(<0.4%), medium risk (0.9%–2.8%), and high risk
(>5.0%). They used recursive partitioning to identify 11
separate groups of patients based on interactions among
key discriminating variables. For example, primary CABG
surgery patients with essentially normal preoperative renal
function have a less than 0.4% risk of requiring postopera-
tive dialysis. In contrast, valvular heart surgery patients
with preoperative renal dysfunction, class IV heart failure,
and intra-aortic balloon pump counterpulsation support
have a greater than 5.0% risk for postoperative renal failure
and dialysis (see Fig. 8.1).
Thakar and colleagues created an AKI score for postoper-
ative dialysis based on 33,217 patients who underwent car-
diac surgery at the Cleveland Clinic Foundation
(Table 8.5).20 This score included 13 preoperative variables
assigned point values of 1 or 2. Patients could have a score of
zero to a maximum of 17. The four risk categories were
assigned point values of 0–2, 3–5, 6–8, and 9–13, respec-
tively (Fig. 8.2). The frequency of dialysis ranged between
0.5% and 21.1%. The model was consistent for both the test
and validation data sets, with an area under the curve of
0.82 in both cases.
Mangano and the McSPI (Multicenter Study of Perioper-
ative Ischemia) research group11 reported probabilities for
Box 8.3 Nonrenal variables affecting serum
creatinine and blood urea nitrogen levels.
▪ Increased nitrogen absorption
▪ Tissue breakdown
▪ Body mass
▪ Diet
Activity
▪
▪ Hepatic disease
Diabetic ketoacidosis
▪
▪ Large hematoma
▪ Gastrointestinal bleeding
▪ Drug or steroid use
 8 • Risk Assessment and Perioperative Renal Dysfunction 77

Table 8.5 Acute renal failure score.a
Risk factor
Female sex
Congestive heart failure
Left ventricular ejection fraction <35%
Preoperative use of IABP
COPD
Insulin-dependent diabetes
Previous cardiac surgery
Emergency surgery
Valve surgery only (compared with CABG)
CABG + valve surgery (compared with CABG)
Other cardiac surgeries
Preoperative creatinine 1.2 to <2.1 mg/dL (compared
with 1.2)
Preoperative creatinine 2.1 mg/dL (compared with 1.2)
CABG, Coronary artery bypass grafting; COPD, chronic obstructive pulmonary
disease; IABP, intra-aortic balloon pump.
a
Minimum total score, 0; maximum total score, 17.
With permission from Thakar CV, Arrigain S, Worley S, et al. A clinical score to
predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005;16
(1):162-168.
developing postoperative AKI based on their multivariate
logistic model of preoperative risk factors (Table 8.6). For
example, patients 70–79 years of age who had preoperative
heart failure, preexisting renal dysfunction, and a previous
CABG had a 33.3% chance of developing postoperative AKI.
Their data set was not sufficiently robust to develop a risk
score for the 1.7% of the patients in their study who required
postoperative renal replacement therapy. Interestingly, the
incidence for dialysis after heart surgery in the studies by
Chertow,12 Thakar,20 Mangano,11 and Aronson146 were
equal (all approximately 1.7%).
Points Newer scoring systems continue to be developed, vali-
1 dated, and optimized. The Mehta score147 and the Wijey-
sundera Simplified Renal Index Score148 show promise in
1
identifying patients at risk for postoperative AKI who will
1 require dialysis. Birnie and colleagues developed a scoring
2 system that accounted for all stages (Stage I, risk; Stage
II, injury; Stage III, failure) of AKI, not just severe AKI.149
1 Additional scoring systems have incorporated novel bio-
1 markers such as urine IL-18 and urine NGAL into their
1
algorithms, with promising results. While there has yet to
be a definitive consensus on the optimal renal risk scoring
2 system, these new developments hold promise for a system
1 that allows enhanced clinical decision making leading to
improved patient outcomes.
2
A scoring system cannot provide a specific answer regard-
2 ing whether a particular patient should undergo a cardiac
2 procedure given the predicted risk for postoperative AKI.
However, it provides an objective assessment of the risk of
5 developing a morbid event that will be associated with a pro-
tracted hospital stay and that will place the patient at an
increased risk for perioperative death. Although some pre-
operative risk factors (e.g., advanced age, previous cardiac
surgery) cannot be altered, others might be controlled or
ameliorated. Preventative or therapeutic strategies can be
focused on patients most likely to need them. Cardiac func-
tion should be optimized and renal perfusion enhanced.
Hyperglycemia should be treated aggressively. Therapy
with nephrotoxic medications should be avoided or mini-
mized. Identification of a high-risk group of patients allows
individuals and their families a more comprehensive
informed consent about their decision to pursue health-care
alternatives. Additionally, effective and validated scoring
systems facilitate research into postoperative AKI by identi-
fying and stratifying patient populations with different
degrees of AKI risk.

30

Test data
25 Validation data
95% CI

20
% ARF-Dialysis

15

10

0
Risk category 0-2 3-5 6-8 9-13
Test N 8,416 6,097 1,181 144
Validation N 8,519 5,978 1,173 169
Fig. 8.2 The acute kidney injury risk categories. ARF, Acute renal failure; CI, confidence interval. (Adapted with permission from Thakar CV, Arrigain S,
Worley S, et al. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005;16(1):162-168.)
 Table 8.6 Preoperative risk factors and predicted probabilities of renal dysfunction.
RISK FACTOR AGE <70 YEARS AGE 70–79 YEARS AGE 80–95 YEARS
Preoperative
Congestive creatinine
heart Redo Type 1 level Predicted Predicted Predicted
Number of risk factors failure CABG diabetes >124 mmol/L Observed (95% CI) Observed (95% CI) Observed (95% CI)
n (%) % n (%) % n (%) %
0 No No No No 909 (1.9) 3.0 (2.3–4.0) 330 (7.0) 5.3 (3.9–7.2) 68 (11.8) 9.9 (6.1–15.6)
1 No No No Yes 80 (5.0) 6.7 (4.5–9.8) 76 (18.4) 11.5 (8.0–16.3) 16 (12.5) 20.3 (12.6–31.1)
No No Yes No 68 (5.9) 6.0 (3.8–9.5) 21 (4.8) 10.5 (6.4–16.8) 1 (0.0) 18.6 (10.1–31.8)
No Yes No No 130 (6.2) 7.8 (5.4–11.1) 56 (14.3) 13.3 (9.2–18.9) 4 (25.0) 23.1 (13.9–36.0)
Yes No No No 144 (7.6) 7.3 (5.1–10.2) 73 (12.3) 12.5 (8.8–17.4) 17 (29.4) 21.8 (13.7–32.8)
2 No No Yes Yes 9 (22.2) 13.0 (7.9–20.7) 7 (0.0) 21.4 (13.3–32.6) 0 —
No Yes No Yes 25 (20.0) 16.4 (10.8–24.1) 13 (30.8) 26.3 (18.3–36.4) 0 —
No Yes Yes No 8 (37.5) 15.0 (9.0–24.0) 3 (33.3) 24.3 (14.7–37.5) 1 (0.0) 38.6 (21.9–58.4)
Yes No No Yes 19 (47.4) 15.4 (10.3–22.4) 26 (7.7) 24.9 (17.8–33.7) 9 (44.4) 39.3 (26.5–53.8)
Yes No Yes No 27 (25.9) 14.1 (9.0–21.3) 11 (18.2) 23.0 (14.7–33.9) 0 —
Yes Yes No No 19 (31.6) 17.7 (11.9–25.6) 14 (7.1) 28.1 (19.5–38.7) 1 (100.0) 43.3 (28.3–59.7)
3 No Yes Yes Yes 1 (100.0) 29.1 (17.9–43.6) 1 (100.0) 42.8 (28.1–58.8) 0 —
Yes No Yes Yes 12 (8.3) 27.6 (18.0–39.8) 4 (25.0) 40.9 (28.4–54.8) 1 (0.0) 57.5 (39.9–73.5)
Yes Yes No Yes 2 (0.0) 33.3 (22.8–45.9) 9 (33.3) 47.6 (35.5–60.1) 2 (0.0) 64.0 (47.4–77.8)
Yes Yes Yes No 3 (33.3) 31.0 (19.8–45.0) 0 — 0 —
4 Yes Yes Yes Yes 2 (50.0) 51.1 (35.7–66.3) 0 — 0 —

For “Observed” columns, n ¼ observed number of patients with risk factor combinations and % ¼ observed proportion of patients with renal dysfunction among those with the specified risk factor combination. For
the “Predicted” columns, % ¼ predicted probability of renal dysfunction derived from the multivariate logistic regression model of preoperative factors.
CABG, Coronary artery bypass grafting.
With permission from Mangano CM, Diamondstone LS, Ramsay JG, et al. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998;128
(3):194-203.

Conclusion
The incidence of postoperative AKI, as well as its potential
impact on use of health-care resources after major cardiac
and vascular surgery, is likely to increase in the next decade.
Patients presenting for surgery are increasingly older, have
multiple comorbidities, and are more likely to have a preex-
isting decrement in renal function, further increasing their
risk and vulnerability to serious adverse renal events after
an operative procedure. Furthermore, physicians are more
willing to pursue treatment of life-threatening illnesses
(major aortic pathology, poor myocardial performance),
whereas patients expect advanced and/or novel surgical
approaches and treatment options. Although the majority
of predictors of postoperative AKI are nonmodifiable, a
few of the risk factors, such as preexisting and postoperative
anemia, adequate fluid management,21,150 and inclusion
and exclusion of several perioperative medications, that
can be modified may mitigate the occurrence of AKI after
cardiac and noncardiac surgery.
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147. Mehta RH, Grab JD, O’Brien SM, et al. Bedside tool for predicting the
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148. Wijeysundera DN, Karkouti K, Dupuis JY, et al. Derivation and val-
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149. Birnie K, Verheyden V, Pagano D, et al. Predictive models for Kidney
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 9 Pulmonary Risk Assessment
RAMESH SWAMIAPPAN and MAURIZIO CEREDA
Introduction
Postoperative pulmonary complications (PPCs) have unde-
niable clinical relevance because they are frequent and
impose a significant burden of perioperative morbidity and
mortality. The reported incidence of PPCs varies consider-
ably among studies, from 2% to 40%, with several risk fac-
tors identified (Table 9.1). Ambiguities in the definition of
PPCs and lack of systematic studies have created more chal-
lenges to the perioperative pulmonary risk evaluation. How-
ever, in the last decade, definitions were improved and risk
factors were comprehensively analyzed and included in val-
idated outcome prediction models.1–6
Epidemiology
Approximately 1 million surgical patients have PPCs each
year in the United States.10 Studies have shown that PPCs
occur in 2%–12% of nonthoracic surgeries and in up to 38%
of thoracic surgeries.6,10 In patients after major abdominal
surgery, the incidence of PPCs was around 6%.2
In a multicenter study, the 30-day mortality was esti-
mated to be 19.5% in those with PPC as opposed to 0.5%
in those without a PPC.6 A prospective cohort study on
patients undergoing nonthoracic surgery showed that
patients who developed a PPC had a mean hospital stay
of 27.9 days as opposed to a mean value of 4.5 days in
patients who did not have a PPC.10
A study on US Medicare beneficiaries showed that pneu-
monia and respiratory failure respectively account for 2.8%
and 1.4%, respectively, of causes of rehospitalization after
surgery.21 The American College of Surgeons National Surgi-
cal Quality Improvement Program (ACS-NSQIP) analyzed
Medicare inpatient claims and found that preventing postop-
erative complications would avoid 41,846 readmissions and
save $620 million of public health expense every year.22
Definition
Early studies lumped events with questionable clinical rele-
vance, such as intraoperative bronchospasm or low-grade
fever, together with more significant complications, such
as pneumonia and respiratory failure.23 A more systematic
approach should evaluate only those complications that are
likely to affect mortality, prolong hospital stay, or require
specific treatment. These clinical entities should be defined
by criteria as stringent and univocal as possible, such as
the criteria for nosocomial pneumonia.24 However, the
reported rate of pulmonary complications is variable even
when stricter criteria for the diagnosis of PPCs are used,
probably due to the heterogeneity of the populations studied
and of the surgical procedures performed (Table 9.2). The
large variability among studies is also due to difficulty in dis-
criminating each of the complications because they have
interdependent pathways.
Pneumonia is probably the single most important PPC
because it has a definitive impact on outcomes. Postopera-
tive pneumonia has been detected in 18.6% of 140 patients
undergoing major surgery25 and is associated with mortal-
ity rates as high as 21%.12 Perioperative bronchospasm
seems to occur in a surprisingly small portion of the popu-
lation, even when patients with asthma are considered.26
However, bronchospasm was the most frequent complica-
tion in smokers with evidence of airway obstruction by spi-
rometry.27 Recently, the European Perioperative Clinical
Outcome definitions included a universal definition of PPCs
with a comprehensive list of components (Table 9.3).28
Etiology and Pathophysiology
The mechanisms leading to PPCs are complex and only
partially understood. Factors related to preexisting dis-
eases, surgical trauma, and anesthesia interact in predis-
posing a patient to the development of PPC (Fig. 9.1).
Perioperative loss of lung volumes with consequent forma-
tion of atelectasis is widely accepted as one of the most
important mechanisms leading to PPC. Atelectasis is initi-
ated during anesthesia and mechanical ventilation and
deteriorates gas exchange intraoperatively and in the early
postoperative period.30 Using computed tomographic
scans of the chest, Hedenstierna et al. observed small areas
of alveolar collapse shortly after the induction of general
anesthesia in healthy subjects31 but could not demonstrate
the same phenomenon in patients receiving epidural anes-
thesia.32 The causes of the formation of atelectasis during
general anesthesia are multiple. Lung tissue has a natural
tendency to display gravity-dependent alveolar collapse
during mechanical ventilation, as suggested by the fact
that atelectasis is located in the recumbent parts of the
lungs (Fig. 9.2).33 Mechanical ventilation and muscle
relaxation cause cephalad displacement and decreased
respiratory excursion of the posterior part of the dia-
phragm, a finding that explains the dominant caudal dis-
tribution of the areas of atelectasis (Fig. 9.3).34,35 High
fraction of inspired oxygen and lower pulmonary distend-
ing pressures predispose to dependent airway closure and
subsequent absorption atelectasis. The three mechanisms
83
84 PART II • Preoperative Assessment

Table 9.1 Risk factors for postoperative pulmonary complications.

Strong evidencea Fair evidencea Indeterminate
Patient-related factors Advanced age History of smoking Respiratory infection in the last month6
ASA class >2 Impaired sensorium GERD7
Congestive heart failure Weight loss Alcohol use7,8
Functional dependence Alcohol use Diabetes mellitus7,8
COPD Weight loss8
Obesity8
Moderate/severe obstructive sleep apnea9
Hypertension8
Liver disease1,8
Cancer8
Sepsis5,8
Asthma10
Renal failure11
Ascites2
Diabetes mellitus7,8
Preoperative shock2
Procedure-related factors Aortic aneurysm Transfusion Prolonged hospitalization8
Thoracic Procedures with a high risk for ALI/ARDS7
Abdominal Procedures with a risk for UEPI8
Upper abdominal Perioperative nasogastric tube12,13
Neurosurgery Use of long-acting neuromuscular blockers14
Prolonged surgery (>3 hours) Mechanical ventilation strategy11
Head and neck Open abdominal surgery (vs. laparoscopic)15
Emergency Neostigmine16
Vascular Failure to use peripheral nerve stimulator16
General anesthesia
Blood transfusion
Lab/preoperative testing Low serum albumin Chest radiograph Positive cough test6,10
Blood urea Low preoperative oxygen saturation6
Anemia 6
Generic variations17
Increased creatinine18
Abnormal liver function test results8
Predicted maximal oxygen uptake19
FEV1/FVC <0.7 and FEV1 <80% of predicted15

ACP, American College of Physicians; ALI/ARDS, acute lung injury/acute respiratory distress syndrome; ASA, American Society of Anesthesiologists; COPD, chronic
obstructive pulmonary disease; GERD, gastroesophageal reflux disease; PPCs, postoperative pulmonary complications; SpO2, oxygen saturation as measured by
pulse oximetry; UEPI, unanticipated early postoperative intubation.
a
Adapted from Smetana GW, Lawrence VA, Cornell JE. American College of Physicians: Preoperative pulmonary risk stratification for noncardiothoracic surgery:
systematic review for the American College of Physicians. Ann Intern Med 2006;144(8):581.

postulated for atelectasis during general anesthesia are
compression of lung tissue, absorption atelectasis, and loss
of surfactant.36
Functional residual capacity declines after surgery, and
the observed changes are bigger when the site of surgical
incision is closer to the diaphragm.38 Pain and surgical
trauma lead to limitation of inspiratory excursion and are
important contributors to postoperative lung volume loss.
Pain in the immediate postoperative period causes spinal
reflex inhibition of the phrenic nerve due to nociceptive
 9 • Pulmonary Risk Assessment 85

Table 9.2 Reported rates of postoperative pulmonary Table 9.3 Definitions of postoperative pulmonary
complications with various procedure-related factors. complications.—cont’d
Procedure-related risk Adjusted OR for PPCs PPC ratea Definition by Canet
factor (95% CI) (%) Measure et al. 2010 Other definition
Surgical site Atelectasis Suggested by lung Requires
opacification with shift intervention
Aorta 6.90 (2.74–17.36) – of the mediastinum, (bronchoscopy,
Vascular (aortic) 2.10 (0.81–5.42 25.5 hilum, or postural therapy)
hemidiaphragm toward
Head and neck 2.21 (1.82–2.68) 10.3 the affected area and
compensatory
Thorax 4.24 (2.89–6.23) – overinflation in the
Esophagectomy – 18.9 adjacent nonatelectatic
lung
Upper abdomen – 19.7
Aspiration Respiratory failure after
Hip – 5.1 pneumonitis the inhalation of
regurgitated gastric
Lower abdomen – 7.7 contests
Neurosurgery 2.53 (1.84–3.47) – Pneumothorax Air in the pleural space Requires drainage
Gynecologic and – 1.8 with no vascular bed
urologic surrounding the visceral
pleura
Prolonged surgeryb 2.26 (1.47–3.47) –
Pleural effusion Chest radiograph Requires drainage
Emergency surgery 2.52 (1.69–3.75) – demonstrating blunting
of the costophrenic
General anesthesia 2.35 (1.77–3.12) –
angle, loss of the sharp
silhouette of the
CI, Confidence interval; OR, odds ratio.
a ipsilateral
After multivariable adjustment for other patient-related and procedure-
hemidiaphragm
related risk factors.
b
Most commonly defined as >3 hours. Bronchospasm Newly detected Requires
Adapted with permission from Smetana GW, Lawrence VA, Cornell JE. expiratory wheezing bronchodilator
American College of Physicians: Preoperative pulmonary risk stratification treated with therapy
for noncardiothoracic surgery: systematic review for the American College bronchodilators
of Physicians. Ann Intern Med 2006;144(8):581.
ARDS Acute onset
<1 week, bilateral
infiltrates on CXR,
Table 9.3 Definitions of postoperative pulmonary hypoxemia as
complications. evidenced by PaO2/
FiO2 <300, minimal
Definition by Canet evidence of left atrial
Measure et al. 20106 Other definition fluid overload, PCWP
<18 cm H2O
Respiratory failure Postoperative PaO2 Requires invasive or
<60 mmHg on room noninvasive Tracheobronchitis Purulent sputum
air, a ratio of PaO2 to mechanical with normal chest
FiO2 <300, or arterial ventilation radiograph, no IV
oxyhemoglobin antibiotics
saturation measured
Pulmonary Pulmonary
with pulse oximetry
edema congestion/
<90% and requiring
hypostasis, acute
oxygen therapy
edema of lung,
Suspected Treatment with Clinical diagnostic congestive heart
pulmonary antibiotics for a criteria for failure
infection respiratory infection, nosocomial
plus at least one of the Exacerbation of Not further defined
pneumonia
following criteria: preexisting lung
New or changed disease
sputum Pulmonary Not further defined
New or changed embolism
lung opacities on a
clinically indicated ARDS, Acute respiratory distress syndrome; CXR, chest x-ray; FiO2, fraction of
chest radiograph inspired oxygen; IV, intravenous; PaO2, partial pressure of oxygen; PCWP,
Temperature pulmonary capillary wedge pressure.
>38.3°C Adapted with permission from Miskovic A, Lumb AB. Postoperative pulmonary
Leukocyte count complications. Br J Anaesth 2017;118(3):317-334.
>12,000/mm3
Continued
86 PART II • Preoperative Assessment

undemonstrated. Experimental data showed limited bacte-

ANESTHESIA rial growth following alveolar recruitment in an animal
Airway irritation model of pneumonia, suggesting that collapsed lung pro-
Mucous secretion/transport
vides a favorable environment for infection.41
Increased In addition to volume loss, other factors play a role in the
airway genesis of PPC and of postoperative pneumonia. An impor-
resistance tant factor is probably mucous retention caused by
decreased coughing resulting from pain and medications
SURGICAL TRAUMA
and by dysfunction of mucociliary transport in the airway
Decreased Hypoxemia mucosa. Mucociliary transport is an important mechanism
Pain
FRC Ventilatory of pulmonary defense, and its velocity is decreased by anes-
Abnormal resp. pattern
Atelectasis Failure
Resp. muscle dysfunction thesia and by endotracheal intubation with a cuffed
tube.42,43 Smokers have a decreased mucociliary transport
velocity during anesthesia compared with nonsmokers, a
Pneumonia finding that may help to explain the high rate of PPC in
these patients. It is not clear how long this functional
impairment of mucous transport lasts after the end of anes-
PREEXISTING DISEASE thesia and extubation.
Respiratory mechanics Aspiration of contaminated oropharyngeal secretions is
Gas exchange thought to be a prominent mechanism leading to nosoco-
mial and postoperative pneumonia.25 Residual subclinical
Fig. 9.1 Mechanisms that lead to pulmonary complications in the muscle relaxation has been detected in patients who
surgical patient. FRC, Functional residual capacity.
received long-acting muscle relaxants, and it was associ-
ated with an increased rate of pulmonary complica-
tions.14 Residual effects of neuromuscular blockers
cause atelectasis in the postanesthesia care unit. Residual
blockade is defined as a train-of-four ratio of <0.9, which
is associated with lower values of forced vital capacity and
of peak expiratory flow rate as measured by pulmonary
function testing (PFT).44 Poor airway protection and aspi-
ration of secretions are probably even more common after
certain procedures, such as transhiatal esophagectomy,
explaining the 28.5% rate of PPCs observed after this
surgery.45
Finally, chronic obstructive pulmonary disease (COPD)
causes gas exchange and respiratory mechanics abnor-
malities that reduce the patients’ ability to tolerate
superimposed acute lung disease and render them prone
to respiratory failure. Additionally, patients with COPD
have dysfunction of the respiratory muscles due to chest
wall deformation and to myopathy.46 These patients
may be unable to withstand the increased ventilatory
demand and the higher work of breathing required in
the postoperative period and may require ventilatory
support earlier than patients with normal muscle
Fig. 9.2 Three-dimensional reconstruction of chest computed tomo-
graphic scans in an anesthetized and paralyzed human. (With permis- function.
sion from Hedenstierna G. Alveolar collapse and closure of airways: regular
effects of anaesthesia. Clin Physiol Funct Imaging 2003;23(3):123-129.)

inputs to ventral and ventrolateral horns of the spinal cord,
which affect the diaphragm function.39 There is also
evidence that surgical manipulation of upper abdominal vis-
cera results in a reflex dysfunction of the diaphragm muscle
that is not related to pain, as shown in patients
after laparoscopic cholecystectomy.40 Atelectasis is consid-
ered a relevant complication in itself, because it can cause
hypoxemia and respiratory failure and also because it
could predispose to pneumonia. However, a causative
link between atelectasis and pneumonia remains
Preoperative Pulmonary
Evaluation for Nonthoracic
Surgery
The preoperative pulmonary evaluation is an integral part
of the general preoperative risk assessment. The evaluation
should start by collecting information on the patient’s over-
all health status, then focus on the respiratory system and
include a careful exam.
The majority of patients undergoing nonthoracic proce-
dures are less likely to benefit from instrumental testing.
They should proceed to have surgery, have it postponed,
 9 • Pulmonary Risk Assessment 87

A B

C D
Fig. 9.3 Lateral views of the diaphragm at end inspiration (stippled line) and at end expiration (thick line) in a healthy subject during spontaneous
breathing (A and B) and during mechanical ventilation (C and D). The area between the two lines represents diaphragm excursion. Inspirations with
baseline tidal volumes (A and C) and with large tidal volumes (B and D) are shown. Overall diaphragm excursion was reduced during mechanical
ventilation at both tidal volumes. The posterior (inferior parts of the pictures) portion of the diaphragm had the greatest reduction in tidal excursion.
(With permission from Kleinman BS, Frey K, VanDrunen M, et al. Motion of the diaphragm in patients with chronic obstructive pulmonary disease while
spontaneously breathing versus during positive pressure breathing after anesthesia and neuromuscular blockade. Anesthesiology. 2002;97(2):298–305.)

or have it denied without further evaluation. This approach
should be the same, regardless of the type of planned sur-
gery, and differs from the evaluation of the patient candidate
for pulmonary resection, which is discussed later in this
chapter.
For better understanding, the risk factors for PPC are
grouped into patient factors and operative factors. Patient
factors include pulmonary and extrapulmonary factors,
while the operative factors include anesthesia and surgical
factors, which are discussed separately.
Patient Factors
PULMONARY FACTORS
After an evaluation of the overall health status, history tak-
ing should elicit specific pulmonary risk factors, such as
chronic or acute pulmonary diseases, smoking history,
and sleep-related breathing disorders.
The presence of COPD was associated with an increased
risk of PPCs in multiple studies.10,47–49 In the NSQIP popu-
lation, a previous diagnosis of COPD was an independent
risk factor for postoperative pneumonia (odds ratio [OR],
1.71), reintubation (OR 1.54), and failure to wean from
the ventilator (OR, 1.45).49 Even when a history of COPD
is not documented, its presence should be suspected on
the basis of elements of the history, such as elevated sputum
production. In a prospective study on 148 veterans under-
going nonthoracic surgery, the presence of elevated preop-
erative sputum production was an independent predictor of
PPC by multivariate analysis.50 A systematic review by
Smetana et al. in COPD patients undergoing nonthoracic
surgery showed that the OR for PPCs attributable to COPD
was 2.36.20
It is unclear whether a history of asthma is associated
with increased rates of clinically significant PPCs. In a
review of records of 706 patients with asthma undergoing
surgery, Warner et al. reported a small incidence (1.7%)
of bronchospasm during or after surgery. The rate of this
event was higher in patients who had a recent asthma exac-
erbation.26 However, the incidence of more severe compli-
cations and postoperative respiratory failure (PRF) was
negligible in this study. In both prospective studies by McAl-
ister et al., a history of asthma was not associated with a
higher risk of PPCs.10,47
A history of recent acute pulmonary process or exacerba-
tion of preexisting lung disease is a high-yield finding
because these patients are prone to airway hyperreactivity
and to altered immune responses, which are often related to
antibiotic use or to the infection itself. Such history is con-
sidered a risk factor for developing PPCs and is thought to be
an adequate reason to postpone elective surgery. In the
88 PART II • Preoperative Assessment
NSQIP study, the presence of preexisting pneumonia had an
OR of 1.7 for developing PRF.51 For patients who have had a
recent or have an ongoing upper respiratory infection, post-
poning the operation is probably appropriate in the setting
of elective surgery, but the evidence supporting this decision
is relatively weak. Studies reported more frequent episodes
of oxygen desaturation but no major pulmonary complica-
tions or morbidity. For example, a recent upper respiratory
infection significantly complicated the postoperative course
in children after cardiac surgery,52 but there is little evi-
dence that this problem also occurs in adults. In the study
by Warner et al., asthmatic patients with recent upper respi-
ratory infections were not at increased risk of PPC compared
with the rest of the population.26 In a prospective study, a
history of upper or lower respiratory infection was not asso-
ciated with a higher risk of PPC.53 Similarly, recent upper
respiratory infections were not associated with PPCs in both
studies by McAlister et al.10,47 Recently, however, Canet
et al. included in their study patients who had recent upper
and lower respiratory tract infections with a history of fever
and recent antibiotic use. They found that 17.2% of the
study population (n ¼ 2464) developed one or more PPCs,6
and recent respiratory infection was an independent
risk factor.
The presence of dyspnea and exercise intolerance should
be investigated during the preoperative evaluation because
these symptoms have been related to the risk of PPCs. The
association between dyspnea and PPCs was not confirmed
in the previous studies.10 In fact, this was not a criterion
in the risk index proposed by Arozullah. However, dyspnea
was included in the Assess Respiratory Risk in Surgical
Patients in Catalonia (ARISCAT) risk score model proposed
by Canet et al., which was validated in a prospective multi-
center observational cohort study.1
Having a history of tobacco use is probably the most solid
risk factor for PPC, because smoking has been established
to be an independent predictor of PPC by several stud-
ies.10,12,26,27,31,47,50,51,53 In patients who are not current
smokers, the risk of contracting a PPC decreases with time
from smoking cessation, but it is unclear how much time is
required for this risk to decrease optimally. Warner et al.
reported that patients who quit smoking less than 8 weeks
prior to surgery had a higher rate of PPC than patients who
quit earlier.54 However, a longer smoke-free period seems
to be needed to reduce the risk of PPCs to the level of the
nonsmoking population, as suggested by the study by Aro-
zullah et al., which showed that having smoked within
1 year before surgery increased the risk of pneumonia12
compared with the remaining patients. On the basis of
study results, it has been suggested that smokers who do
not quit entirely or who quit less than 8 weeks before sur-
gery54 may have an increased risk of PPC not only com-
pared with the nonsmoking population but also
compared with patients who did continue to smoke. The
results of the studies by McAlister et al.10 suggested that
the extent of previous tobacco consumption may be a more
important risk factor for PPCs than the timing of smoking
cessation. Canet et al. observed that the PPC was related to
the number of pack-years smoked and that history of
smoking more than 40 pack-years was associated with
PPCs in bivariate analysis.6 In a recent meta-analysis, pre-
operative smoking was found to be associated with PPCs
(relative risk [RR]¼ 1.73; 95% confidence interval [CI],
1.35–2.23) but not with postoperative mortality.55
Obstructive sleep apnea (OSA) is a sleep-related breathing
disorder with a relatively high prevalence in the population
and with a significant impact on health. The prevalence of
symptomatic OSA has been estimated to be around 5%,
while the prevalence of asymptomatic OSA is likely to be
near 20%.56 Sleep-related breathing disorders are diagnosed
and graded by measuring the apnea–hypopnea index by
polysomnography. However, only a minority of patients
with OSA present with a previous instrumental diagnosis.
Finkel et al. screened surgical patients who were at high risk
of OSA and noted that 81% of patients were unaware that
they had sleep apnea prior to surgery.57
The presence of sleep apnea may be associated with an
increased rate of perioperative complications. In fact, OSA
is accompanied by a cluster of comorbidities that can affect
surgical outcomes. These include systemic hypertension
and pulmonary hypertension (PH), right heart failure, dia-
betes, obesity, and stroke.58 However, it is also a common
perception that OSA per se may independently increase
the risk of complications of surgery and anesthesia. Patients
with sleep-related breathing disorders have decreased con-
trol of airway muscle tone and of ventilation during sleep,
which is exacerbated by long-acting narcotics and by resid-
ual anesthetic effects in the postoperative period.59 Airway
problems, postoperative hypoxemia, and ventilatory failure
occur in a severity-dependent manner in OSA patients
undergoing upper airway surgery. However, there is limited
evidence that OSA is associated with morbidity in other
types of surgery. Memtsoudis et al.60 analyzed a national
database to evaluate the effect of sleep-disordered breathing
on pulmonary outcomes in orthopedic and general surgical
populations and found an increased risk of worse pulmonary
outcomes, including aspiration pneumonia, acute respira-
tory distress syndrome (ARDS), and emergent endotracheal
intubation, but not pulmonary embolism.
STOP-BANG QUESTIONNAIRE
In a Canadian study of surgical patients,61 a STOP-Bang
score of 5–8 identified patients with high probability of mod-
erate/severe OSA with high specificity (Table 9.4). The
American Society of Anesthesiologists (ASA) task force
recommendations62 are as follows:
▪ Continuous positive airway pressure should be initiated
in patients with severe OSA preoperatively.
▪ There is insufficient literature to offer guidance regarding
which patients with OSA can be safely managed on an
inpatient versus outpatient basis. It should be a com-
bined decision between the surgeon and anesthesiolo-
gist, individualized to the patient.
▪ A routine sleep study for all patients with OSA was not
recommended.
▪ In patients who have had corrective airway surgery,
such as uvulopalatopharyngoplasty or surgical man-
dibular advancement, it should be assumed that they
remain at risk of OSA complications unless proven
otherwise by a normal sleep study or reversal of
symptoms.
 9 • Pulmonary Risk Assessment 89

Table 9.4 STOP-BANG score. Table 9.5 Physical findings associated with increased risk of
postoperative pulmonary complications.
1. Snoring Do you snore loudly (louder than talking or
loud enough to be heard through closed Odds ratio
doors)? Finding Technique (95% CI) P value
2. Tired Do you often feel tired, fatigued, or sleepy Positive Coughing once after 4.3 (1.5–12.3) a
0.01
during daytime? cough test deep inspiration 3.84 (1.51–9.80)b 0.01
triggers recurrent
3. Observed apnea Has anyone observed you stop breathing
coughing
during your sleep?
Positive Wheezing after five 3.4 (1.2–9.4)a 0.04
4. Blood pressure Do you have or are you treated for high
wheeze test deep inspirations/ 0.94 (0.12–7.08)b 1.00
blood pressure?
expirations
5. BMI Is it more than a 35 kg/m2?
Forced Duration of forced 5.7 (2.3–14.2)a 0.0002
6. Age Age over 50 years old? expiratory exhalation after one 4.28 (1.22–15.02)b 0.04
time deep inspiration
7. Neck circumference Neck circumference greater than 40 cm? 9 seconds
8. Gender Gender male? Maximum Distance between 6.9 (2.7–17.4)a <0.0001
laryngeal the sternal notch 1.17 (0.44–3.12)b 0.79
Score 1 point for each positive outcome.
height and the top of the
Interpretation: 0–2 ¼ low risk; 3–4 ¼ medium risk; 5–8 ¼ 4 cm thyroid cartilage at
high risk for OSA end expiration
Wheezing Presence or absence 3.1 (0.9–10.0)a 0.13
BMI, Body mass index.
on standard of wheezing on 2.39 (0.54–10.51)b 0.23
Adapted with permission from Chung F, Yegneswaran B, Liao P, et al. STOP
auscultation standard thoracic
questionnaire: a tool to screen patients for obstructive sleep apnea.
exam
Anesthesiology. 2008;108(5):812–821.
CI, Confidence interval.
a
Data from McAlister FA, Khan NA, Straus SE, et al. Accuracy of the
preoperative assessment in predicting pulmonary risk after nonthoracic
surgery. Am J Respir Crit Care Med 2003;167(5):741-744.
b
Data from McAlister FA, Bertsch K, Man J, et al. Incidence of and risk factors for
pulmonary complications after nonthoracic surgery. Am J Respir Crit Care
Med 2005;171(5):514-517.
Physical Examination
Physical examination is another essential tool in the preop-
erative evaluation of the patient’s pulmonary status because EXTRAPULMONARY FACTORS
it allows the detection of unrecognized pulmonary disease.
Although the diagnosis of chronic lung disease is often made A review of the patient’s general history is important to
by instrumental testing, a combination of data from patient increase the accuracy of the preoperative pulmonary eval-
history and from physical exam has reasonable accuracy in uation because several extrapulmonary factors correlate
predicting the presence of COPD.63 Lawrence et al. docu- with the probability of PPCs. Advanced age is probably an
mented that having an abnormal thoracic physical exam important risk factor. Early studies did not include multivar-
result was an independent predictor of PPCs. However, iate analysis to account for the presence of coexisting dis-
the exact abnormalities detected were not specified, thus eases in older patients and were probably flawed.23 Later
decreasing the applicability of their results.64 The studies studies that did account for the other conditions confirmed
by McAlister et al.10,47 are more informative because they that an association between age and PPC exists. Li et al.
rigorously evaluated specific physical findings and detected found the association of age as an independent risk factor
significant correlations between these and the risk of PPCs for postoperative complications in patients undergoing
(Table 9.5). In these studies, multiple physical findings cor- abdominal aortic aneurysm (AAA) repair.13 Similar results
related with the incidence of PPCs, and two of them were were shown in two studies in patients undergoing nonthor-
independent predictors of complications: decreased laryn- acic surgery.10,47 Arozullah et al. detected an independent
geal height and positive cough test. The presence of wheez- association of advanced age with both postoperative venti-
ing on standard auscultation is usually considered an latory failure and postoperative pneumonia.12,51 Patients
important physical sign, but it was not significantly associ- older than 80 years of age are 5.1 times more likely to have
ated with a higher risk of PPCs in these studies. This result is PPCs than patients who are younger than 50 years of age.6
in agreement with a previous study where decreased laryn- These studies used multivariate analysis and fulfilled the cri-
geal height was an independent predictor of the presence of teria of a high-quality design for the evaluation of prognostic
COPD diagnosed by spirometry, while wheezing was not.63 variables. This aspect is relevant here in the context of
These studies suggest that simple findings obtained through increasing rate of surgeries in elderly patients.
a methodical physical exam may help in the prediction of Other nonpulmonary factors are associated with the risk
the probability of PPCs. However, none of the physical of PPCs. Arozullah et al. reported that indexes of a poor
examination parameters have been added in the current nutritional status, such as a low serum albumin concen-
risk prediction models, which were mostly derived from tration and a history of weight loss, and indexes of an
medical record data. altered blood volume status, such as abnormal blood urea
90 PART II • Preoperative Assessment
nitrogen concentration, were all associated with PRF and
with pneumonia.12,51 In these same studies, an increased
probability of PPCs was also observed in patients who had
a history of dependent functional status, recent alcohol
use, diabetes, congestive heart failure, and renal failure.
Preoperative neurologic impairment and history of stroke
have also been reported to be independent predictors of
PPCs in more than one study,12,51 probably due to an
increased occurrence of aspiration of gastric or pharyngeal
secretions. Evidence suggests that congestive heart failure
is one of the significant risk factor for PPCs (OR, 2.93; CI,
1.02–8.43).65
The ASA classification is a reasonable instrument to
evaluate the patient’s overall physical condition, and its
score is related to the incidence of postoperative complica-
tions. Multiple studies have detected a correlation of the
ASA score with PPCs. An ASA score higher than 2 was
predictive of PPCs after abdominal surgery. In a prospec-
tive longitudinal study,48 the coexistence of advanced
age and ASA score >2 identified the majority (88%) of
the patients who developed any PPC. Gupta et al. analyzed
NSQIP data and studied the preoperative variables associ-
ated with PPCs. After multivariate analysis, patients in the
ASA class IV had an OR of 1.28 (CI, 1.04–1.57) for PPCs.
Recently, ASA was included as a component of the PRF
risk index proposed by Gupta et al.5
Other health classification systems that are not specifi-
cally focused on the respiratory system may be useful in
the pulmonary evaluation. Both the Goldman cardiac risk
index and the Charlson comorbidity index have been
reported to be associated with the incidence of PPCs.50 Pre-
operative functional dependence and altered sensorium
were shown to be risk factors.66 Preoperative anemia as
defined by hemoglobin <10g% was shown to be associated
with a threefold higher risk for developing PPC.6 At the
same time, there is no clear evidence to show that preoper-
ative transfusion eliminates the risk.
Other risk factors are supported by equivocal evidence,
including gastroesophageal reflux, alcohol abuse,8 weight
loss, diagnosis of cancer or sepsis,8 and a positive cough
test.6,10 There is no strong evidence to state whether exer-
cise ability, diabetes, and human immunodeficiency virus
infection are independent risk factors for PPCs.
It is common to assume that patients who are obese are at
high risk of having PPCs, but this belief has been questioned
on the basis of studies that failed to detect correlations
between obesity and PPCs. For example, a study on patients
undergoing thoracotomy67 did not find a higher risk of PPCs
in obese patients. However, factors related to the type of sur-
gery and to patient selection in these studies might explain
these results, because other studies did detect a correlation
between obesity and PPCs. In fact, an elevated body mass
index (BMI) was an independent predictor of PPCs by mul-
tivariate analysis in at least two studies.48,53 In the prospec-
tive blinded study by McAlister et al., a BMI >30 kg/m2 was
associated with increased risk for PPCs by univariate anal-
ysis,10 although the correlation was not significant by mul-
tivariate analysis. The guidelines of the American College of
Physicians (ACP) state that obesity is not a significant risk
factor for PPCs and should not affect patient selection for
otherwise high-risk procedures. This statement is true even
for a morbidly obese patient.65
Surgical Factors
Multiple studies reported correlations between surgical fac-
tors and incidence of PPCs (Table 9.6), both the type of sur-
gery and the location of the incision are key contributors to
this pulmonary risk. In the studies by Arozullah et al., abdom-
inal aortic, thoracic, and upper abdominal surgery were the
strongest of all independent predictors of PPC because they
had the highest ORs for respiratory failure and pneumo-
nia.12,51 Other studies reported increased risk of PPCs during
abdominal surgery68 and particularly after upper abdominal
incisions. In fact, the risk of PPCs is higher when the incision
is closer to the diaphragm.48,53 McAlister et al. detected a cor-
relation between the rate of PPCs and abdominal surgery,10
although this was not confirmed by univariate analysis. This
discrepancy with previous studies may be explained by the
fact that only a minority of the study patients underwent
upper abdominal surgery in McAlister’s study. Emergent sur-
gery was associated with higher risk of PPC.12,51,68 In the
NSQIP studies, both neurologic and neck surgery were asso-
ciated with increased risk of respiratory failure and
Table 9.6 Independent predictors of postoperative
pulmonary complications obtained from intraoperative data.
Intraoperative
risk factor Significance
Duration of OR (CI), 4.9 (2.4–10.1) with >2 hours and 9.7
anesthesia or (4.7–19.9) when >3 hours6
surgery
Type of RA reduces the 30-day mortality, risk ratio (CI), 0.71
anesthesia (0.53–0.94)69
Type of Laparoscopy vs. open surgery reported to have
surgery fewer complications (effect of increased IAP on
atelectasis)
Emergency surgery: higher complications versus
planned
Site of Long acting NMBs during GA: risk factor
surgery
Neck, thorax, upper abdominal surgeries,
neurological surgery and abdominal aortic
aneurysm surgery
Distance of incision from diaphragm inversely
proportional to the incidence of complications
Upper abdominal surgeries complications increase
by a factor of 1.5
Blood More than 4 units12
transfusion
Mechanical Risk predictor of VALI
ventilation
>48 hours
NGT Presence associated with VAP and PP selective
rather than routine NGT placement advocated70
GA, General anesthesia; IAP, intra-abdominal pressure; NGT, nasogastric tube;
NMBs, neuromuscular blockers; PP, postoperative pneumonia; PPC,
postoperative pulmonary complication; RA, regional anesthesia; TRALI,
transfusion-related acute lung injury; VALI, ventilator-associated lung injury;
VAP, ventilator-associated pneumonia.

pneumonia, suggesting a role of poor airway protection in the
genesis of PPC, although the ORs were not as high as for thor-
acoabdominal surgery.12,51
The choice of surgical approach may significantly affect the
risk of PPCs. There is some evidence that performing laparo-
scopic surgery is associated with decreased PPCs, as shown
by Hall et al.71 In a randomized study, patients undergoing
laparoscopic fundoplication had better respiratory function
and shorter hospital stay than patients who had an open pro-
cedure.72 But it is unclear whether reduced pulmonary dys-
function translated into clinically important differences in
PPC rates.66 The advent of endovascular aneurysm repair
is likely going to affect the rate of PPCs. In fact, a recent Euro-
pean study analyzed a nationwide vascular registry of
patients undergoing open repair vs. endovascular abdominal
aortic aneurysm repair, detecting a significantly smaller risk
of severe PPCs in the patients who received the endovascular
repair (1.0% vs. 6.9%).73 Laparoscopic cholecystectomy was
associated with shorter recovery times, less reduction in post-
operative lung volumes, and less postoperative pain than
open cholecystectomy, with incidence of PPCs around
2.7% and 17.2%, respectively (P < 0.05).20
Among intraoperative factors, the duration of anesthesia
and surgery is probably one of the reliable predictors of PPCs,
and this association has been detected by more than one
study.53,58 McAlister et al. reported that duration of anesthe-
sia longer than 2.5 hours was an independent predictor of
PPCs, with an OR of 3.3.10 Duration of anesthesia was an
independent risk factor for PPCs also in a prospective study
by Mitchell et al.50 It is not clear, though, whether the dura-
tion of the procedure has an effect on PPCs independently of
the complexity and type of procedure. In a population-based
cohort study,6 duration of surgery of more than 3 hours was
associated with a PPC rate of 21% as opposed to 2.5% if the
duration was shorter than 2 hours. This correlation was
maintained in the multivariate analysis.
Concerning the anesthetic technique, the evidence on the
importance of the type of anesthesia is ambiguous. In the
NSQIP studies, general anesthesia was associated with
higher risks of ventilatory failure and of pneumonia, with
ORs of 1.91 and 1.56, respectively.12,51 However, in both
studies by McAlister et al., general anesthesia did not corre-
late with the risk of PPCs.10 The evaluation of the type of
anesthesia as a risk factor for PPCs through observational
studies is complicated by the fact that the effect of anesthesia
is not easily distinguishable from the effect of the site of sur-
gery. In fact, general anesthesia is more frequent in surger-
ies at high risk of PPCs, such as thoracoabdominal surgery,
and relatively less frequently selected in peripheral surgery.
In a review of data on COPD patients from the NSQIP data-
base (2005–2010), patients who received regional anesthe-
sia as compared with patients who received general
anesthesia had a lower incidence of postoperative pneumo-
nia (0.3% vs. 1.3%; P ¼ 0.03) with absolute risk reduction
of 1.0%. In this analysis, prolonged ventilator dependence
(2.1% vs. 0.9%; P ¼ 0.0008) and unplanned postoperative
intubation (2.6% vs. 1.8%; P ¼ 0.04) were more frequent in
general vs. regional anesthesia.74 The evaluation of anes-
thesia choice as a strategy to reduce the risk of PPCs will
be discussed in Chapter 20.
The use of a perioperative gastric tube is probably a risk fac-
tor for the development of PPCs. At least two prospective
9 • Pulmonary Risk Assessment 91
studies10,50 reported that the perioperative use of nasogastric
tubes was an independent predictor of PPCs. This correlation
was confirmed by multivariate analysis,75 which suggests
that gastric suctioning per se, and not its use in high-risk pro-
cedures, causes PPCs. The mechanism of causation of PPCs
by a nasogastric tube is probably due to decreased airway
reflexes and aspiration of oropharyngeal secretions.
Preoperative Tests
Preoperative testing is valuable only if it provides data that
cannot be obtained from history and physical exam and if it
helps to determine the probability of a complication in
patients who are known to have risk factors. Preoperative
tests that are typically ordered for pulmonary risk assess-
ment include PFTs, arterial blood gases, chest radiographs,
and, less commonly, exercise testing and echocardiography.
However, it is unclear which ones add useful information to
the preoperative evaluation.
PFTs have been used to screen for unknown pulmonary
disease and to risk-stratify patients, assuming a relationship
between the severity of PFT abnormalities and the probabil-
ity of PPCs. On the basis of currently available evidence,
PFTs are unlikely to fulfill either one of these purposes. PFTs
are probably not indispensable for the identification of
patients with pulmonary disease, as suggested by the studies
where history taking and physical exam had a reasonable
accuracy in the diagnosis of COPD.63 More rigorous studies
either failed to demonstrate a correlation between PFTs and
the incidence of PPCs or could not confirm by multivariate
analysis that PFT data are independent predictors of PPCs.
In a case control study by Lawrence et al.,64 comorbidity
indexes and abnormal chest examination were indepen-
dently associated with PPCs, while PFT results were not.
Mitchell et al.50 showed that, in patients undergoing gen-
eral elective surgery, PFT results had no significant correla-
tion with PPCs, unlike preoperative sputum production,
duration of the procedure, and use of nasogastric tubes. A
possible explanation of these results is that other factors,
such as the overall physical status and nonpulmonary
comorbidities, may be more important than the degree of
airway obstruction in predisposing to PPCs. Other studies
also suggest that pulmonary and nonpulmonary data col-
lected through clinical evaluation contain most of the infor-
mation necessary to make a risk prediction, rendering the
information obtained from PFTs superfluous. In the studies
by McAlister et al.,47 PFT data were significantly associated
with the incidence of PPCs. However, none of the PFT vari-
ables were found to be independent predictors of PPCs by
multivariate analysis, while variables such as smoking his-
tory, duration of anesthesia, and selected physical exam
findings were independently related with PPCs. These
results imply that no information is added by routinely per-
forming PFTs in the clinical evaluation of patients undergo-
ing nonthoracic surgery. Therefore PFTs should only be
used within the context of a diagnostic workup to confirm
a diagnosis of pulmonary disease in patients who have find-
ings suggesting its presence or in patients with known
chronic pulmonary disease whose symptoms suggest a
superimposed exacerbation. The 1990 consensus statement
of the ACP limited the use of PFTs in nonthoracic surgery to
92 PART II • Preoperative Assessment
patients undergoing upper abdominal surgery who had a
history of smoking or dyspnea and to patients undergoing
more peripheral surgeries who had unexplained pulmonary
symptoms. In 1995, it was estimated that 39% of preoper-
ative PFTs performed did not fulfill the ACP recommenda-
tions. Based on this estimate, a cost analysis performed in
1997 described an annual excess expenditure of several mil-
lion dollars due to unneeded PFTs.76 It is possible that com-
pliance with ACP guidelines has improved in the past few
years, with substantial financial savings. However, it may
be argued that the use of PFTs should be even more
restricted than suggested by the ACP. There is no strong evi-
dence available supporting the routine use of preoperative
PFTs for high-risk nonthoracic surgeries and in high-risk
patients. In a study by Warner et al., 135 patients with mod-
erate to severe flow limitation by PFTs were compared with
a group of patients with similar characteristics but without
obstructive disease.27 The group with obstructive disease
had increased frequency of bronchospasm, but the rate of
more significant complications was similar between the
two groups. In particular, there was no difference in the
incidence of prolonged intubation. In a study by Wong
et al., patients with severe COPD had a high (37%) risk of
developing any PPCs.68 By multivariate analysis, it was pos-
sible to determine that, although a lower forced expiratory
volume in 1 second (FEV1) was associated with PPCs, non-
pulmonary factors such as anesthesia duration and scoring
systems such as the ASA were better predictors.
Similar to PFTs, arterial blood gases have been used in the
past for the preoperative evaluation of nonthoracic surgery
patients without strong evidence suggesting their value.
Hypercapnia with partial pressure of carbon dioxide higher
than 45 mmHg has been considered an important risk fac-
tor for PPCs and mortality.77 Similarly, arterial hypoxemia
has been considered an important risk factor for PPCs and a
contraindication for surgery. These blood gas alterations
may help in the risk versus benefit assessment of a certain
procedure because their presence is associated with signifi-
cantly shortened life expectancy in patients with COPD.
However, neither hypercapnia nor hypoxemia has been
shown to be an independent predictor of the risk of
PPCs.10,47 More recently, low preoperative oxygen satura-
tion on room air was included as a component in the ARIS-
CAT score, and recent evidence has externally validated this
score in surgical population.4
Chest radiographs are still routinely performed preopera-
tively in older patients, in patients with known pulmonary
disease, and in patients who smoke. Although this practice
is deeply radicated, there is little or no evidence that routine
chest radiographs affect the perioperative management or
outcomes in any way.78 In patients who are asymptomatic
or have no risk factor for pulmonary disease, chest radio-
graphs are unlikely to reveal new information,79 and they
are likely to lead to unnecessary further testing in case of
false-positive results. Patients who have risk factors for pul-
monary disease are more likely to have abnormal findings.
However, it is not clear whether chest radiographs adds any
information to the pulmonary risk stratification in patients
who have stable symptoms or no symptoms at all.78 The
only appropriate use of chest radiology may be in the case
of patients with new or unexplained pulmonary symptoms,
in whom radiography may uncover unknown pulmonary
disease requiring further workup or an acute process, such
as pneumonia, due to which it may be prudent to postpone
elective surgery.
Limited evidence supports exercise testing as a useful tool
to identify patients at risk for PPCs in nonthoracic surgery.
Girish et al. performed exercise testing prior to high-risk sur-
geries, including also thoracotomy, by simply measuring the
number of flights of stairs that the patients were capable of
climbing. A poor performance on this simple test was an
independent risk factor for combined cardiopulmonary com-
plications, while PFT results, age, weight, and preexisting
pulmonary disease were not. The inability to climb more
than two flights of stairs had a positive predictive value of
0.8 and a negative predictive value of 0.82 for postoperative
cardiopulmonary complications. This study suggests that
this simple test of exercise tolerance may be adopted in
the clinical evaluation of patients scheduled to undergo
high-risk surgeries.80 However, there is inadequate evi-
dence to recommend routine exercise testing for the preop-
erative assessment of nonthoracic surgery patients.65
A form of exercise testing that can be easily tested in an
office setting is the 6-minute walk test. In thoracic or upper
abdominal surgery patients, 6-minute walk distance was
shown to have a negative correlation with the rates and
severity of postoperative complications as a whole but not
limited to PPCs.81
PH is relatively common in patients with COPD or with
other types of chronic pulmonary diseases. PH is defined
by a mean pulmonary artery pressure of greater than or
equal to 25 mmHg at rest. According to the American Col-
lege of Cardiology/American Heart Association guide-
lines,82 PH is not currently listed as an independent risk
factor for patients undergoing noncardiac surgery, though
there are reports of unanticipated deaths in the periopera-
tive period. The prevalence of PH in severe COPD patients
ranges between 5% and 10%.83 Its detection in such popu-
lations has important prognostic value and may help in
patient selection, because this condition is associated with
significantly shorter lifespan in COPD. In thoracic surgery,
PH is used as a criterion to deny certain procedures, such
as lung reduction surgery.84 PH and right ventricular fail-
ure can significantly complicate intraoperative and postop-
erative management of patients undergoing high-risk
surgeries, and it can be hypothesized that patients who tol-
erate moderate hypertension at rest may become acutely
decompensated in the perioperative period. There should
be at least awareness of the possible presence of these con-
ditions when evaluating patients who have chronic pulmo-
nary diseases and who need to undergo major surgery.
Their existence can be suspected on the basis of clinical eval-
uation, but the accuracy of the history and physical exam in
the diagnosis of PH is probably low. Echocardiography is
commonly used in the assessment of patients with suspected
right ventricular compromise or PH. As per the guidelines of
the American Society of Echocardiography, pulmonary
artery systolic pressure can be reasonably estimated by mea-
suring the tricuspid regurgitation velocity and using the
simplified Bernoulli equation. The diastolic pressure can
be estimated from the end-diastolic pulmonary regurgita-
tion velocity. Mean pressure can be estimated by the pulmo-
nary artery acceleration time or derived from the systolic
and diastolic pressures.85 Although there is limited support-
ing evidence for routine echocardiography, it is reasonable
to obtain studies in those patients with severe lung disease
 9 • Pulmonary Risk Assessment 93

who have signs compatible with right heart dysfunction or of surgery, laboratory results, functional status, history of
who have significant exercise intolerance. Lai et al.86 stud- COPD, and age. The type of surgery was the strongest pre-
ied 62 patients with severe PH who underwent noncardiac dictor also in the pneumonia index (Table 9.8), together
surgery and reported postoperative morbidity and mortality with age and functional status. On the basis of final risk
of 24% and 9.7%, respectively. Major morbidities were scores, patients were assigned to five risk classes, and for
delayed extubation (21%), heart failure (9.7%), and major each of these, the accuracy of risk prediction was validated
arrhythmias (3.2%). Again, there was no separate analysis in independent cohorts of patients, confirming that the
between cardiac and pulmonary causes in this study. CPET models had adequate performance (Table 9.9). Due to the
is one of the common tests done preoperatively, in some number of parameters needed for the prediction, these scor-
European countries. It could be used as a risk stratification ing systems are complicated for use in clinical practice,
tool to predict PPC. In the United States, CPET is not per- although they have been used in the research setting.
formed routinely. Patients who have borderline PFT are fur- Another limitation of these studies is that the NSQIP data-
ther evaluated with CPET. There are new tools such as the base used to derive the model included mostly male subjects.
Duke Activity Status Index (DASI) questionnaire, which has The fact that neither blood gases nor PFTs were included in
been evaluated to identify patients with poor functional
capacity but yet to be validated in wider surgical population.
Table 9.8 Postoperative pneumonia risk index.
Preoperative risk factor Point value
Risk Prediction Scores
Type of surgery
Risk scores can be useful clinical tools if they provide a rea- Abdominal aortic 15
sonably accurate estimate of the probability of complications
Thoracic 14
and if the information can be used to guide therapeutic
choices. Additionally, risk scores can provide some insight Upper abdominal 10
into the most important factors contributing to the genesis Neck 8
of a certain outcome. Although cardiac risk scores such as
the Goldman index87 have been in use for several years, pul- Neurosurgery 8
monary evaluation has lacked a valid risk index. Vascular 3
In two companion cohort studies, Arozullah et al. built Age (years)
and validated multifactorial risk score systems to predict
postoperative pneumonia12 and respiratory failure.51 The >80 17
studies used patient data from the Department of Veteran 70–79 13
Affairs NSQIP. Study patients underwent a variety of non-
60–69 9
cardiac procedures, including lung resection.
The Arozullah respiratory failure index (Table 9.7) pre- 50–59 4
dicts the incidence of PRF (mechanical ventilation for Functional status
48 hours) on the basis of several factors, including type
Totally dependent 10
Partially dependent 6
Table 9.7 Respiratory failure risk index.
Weight loss >10% in past 6 months 7
Preoperative predictor Point value
History of COPD 5
Type of surgery
General anesthesia 4
Abdominal 27
Impaired sensorium 4
Thoracic 21
History of cerebrovascular accident 4
Neurosurgery, upper abdominal, peripheral vascular 14
Blood urea nitrogen level
Neck 11
<8 mg/dL 4
Emergency surgery 11
22–30 mg/dL 2
Albumin <3 g/dL 9
>30 mg/dL 3
Blood urea nitrogen >30 mg/dL 8
Transfusion >4 units 3
Partially or fully dependent functional status 7
Emergency surgery 3
History of chronic obstructive pulmonary disease 6
Steroid use for chronic condition 3
Age (years)
Current smoker within 1 year 3
>70 6
Alcohol intake >2 drinks/d in past 2 weeks 2
60–69 4
Modified with permission from Arozullah AM, Khuri SF, Henderson WG, et al.
Modified with permission from Arozullah AM, Daley J, Henderson WG, et al. Participants in the National Veterans Affairs Surgical Quality Improvement
National Veterans Administration Surgical Quality Improvement Program. Program. Development and validation of a multifactorial risk index for
Multifactorial risk index for predicting postoperative respiratory failure in predicting postoperative pneumonia after major noncardiac surgery. Ann
men after major noncardiac surgery. Ann Surg 2000;232(2):242-253. Intern Med 2001;135(10):847-857.
94 PART II • Preoperative Assessment

Table 9.9 Risk categories for respiratory failure and pneumonia.

Postoperative respiratory failure Probability of respiratory Postoperative pneumonia Probability of
Class risk index (point total) failure (%) risk index (point total) pneumonia (%)
1 0–10 0.5 0–15 0.2
2 11–19 2.2 16–25 1.2
3 20–27 5.0 26–40 4.0
4 28–40 11.6 41–55 9.4
5 >40 30.5 >55 15.3

Modified with permission from Arozullah AM, Khuri SF, Henderson WG, et al. Participants in the National Veterans Affairs Surgical Quality Improvement Program.
Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med 2001;135
(10):847-857; Arozullah AM, Daley J, Henderson WG, et al. National Veterans Administration Surgical Quality Improvement Program. Multifactorial risk index for
predicting postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 2000;232(2):242-253.

the models due to difficulties in obtaining these data may be Table 9.10a Independent predictors of risk for PPCs
considered another weakness of the study. identified in the logistic regression model.
Canet et al.6 avoided sampling bias by prospectively study-
ing a heterogeneous group of patients and derived a new pre- Multivariate
analysis OR
diction model called the “ARISCAT score” (Tables 9.10a and (95% CI) Risk
9.10b). This included the following components: n 5 1,624* β Coefficient score†

1. Advanced age Age, yr

2. Upper abdominal or thoracic surgery  50 1
3. Surgery lasting more than 2 hours
51–80 1.4 (0.6–3.3) 0.331 3
4. Emergency surgery
5. Low preoperative oxygen saturation > 80 5.1 (1.9–13.3) 1.619 16
6. Respiratory infection within the past month Preoperative Spo2, %
7. Preoperative anemia
 96 1
The last three variables were not included in previous pre- 91–95 2.2 (1.2–4.2) 0.802 8
diction systems or ACP guidelines.65 The incidence of PPCs
in patients with scores categorized as mild, moderate, and  90 10.7 (4.1–28.1) 2.375 24
severe risk were estimated to be 1.6%, 13.3%, and 42.2%, Respiratory infection
respectively. Recently, the ARISCAT score was externally in the last month 5.5 (2.6–11.5) 1.698 17
validated in a European population cohort called PERI- Preoperative anemia
SCOPE (Prospective Evaluation of a RIsk Score for postoper- (10 g/dl) 3.0 (1.4–6.5) 1.105 11
ative pulmonary COmPlications in Europe) with good Surgical incision
discrimination and C-statistic 0.80 (CI, 0.78–0.82).4
The PRF index (Table 9.11) by Gupta et al. used multiple Peripheral 1
preoperative factors to predict the risk of failure to wean Upper abdominal 4.4 (2.3–8.5) 1.480 15
from mechanical ventilation within 48 hours of surgery
Intrathoracic 11.4 (4.9–26.0) 2.431 24
and unplanned postoperative intubation and reintubation.
The risk calculator includes variables such as sepsis and sep- Duration of surgery, h
tic shock in addition to the Arozullah index mentioned pre- 2 1
viously. It is derived from the NSQIP data set using logistic
> 2 to 3 4.9 (2.4–10.1) 1.593 16
regression techniques.5 Again, this score has been validated
using the PERISCOPE cohort population in Europe.1 >3 9.7 (4.7–19.9) 2.268 23
Kor et al. derived a surgical lung injury prediction model Emergency
(Tables 9.12a and 9.12b) in patients who underwent major procedure 2.2 (1.0–4.5) 0.768 8
surgery and received mechanical ventilation for >3 hours
and found that cardiac/thoracic/vascular surgery, COPD, CI, confidence interval; OR, odds ratio; PPC, postoperative pulmonary
complications; Spo2, oxyhemoglobin saturation by pulse oximetry
alcoholism, diabetes, and gastroesophageal reflux disease breathing air in supine position.
were predictors of PPC.7 This model is developed to differen- *Because of a missing value for some variables, three patients were excluded.
tiate patients who have high risk for developing acute lung Logistic regression model constructed with the development subsample,
injury/ARDS with an area under the receiver operating char- c-index ¼ 0.90; Hosmer-Lemeshow chi-square test ¼ 7.862; P ¼ 0.447.
†
The simplified risk score was the sum of each β logistic regression coefficient
acteristic curve (95% CI) of 0.82 (0.78–0.86). However, this multiplied by 10, after rounding off its value.
model has not been externally validated yet.
 9 • Pulmonary Risk Assessment 95

Table 9.10b PPC Risk score: distribution of patients and rates by intervals.
Risk score intervals*
Low risk <26 Points Intermediate risk 26–44 points High risk ≥45 points
†
Development subsample, No. (%) of patients 1,238 (76.2) 288 (17.7) 98 (6.0)
Validation subsample, No. (%) of patients 645 (77.1) 135 (16.1) 57 (6.8)
PPC rate, development subsample, % (95% CI) 0.7 (0.2–1.2) 6.3 (3.5–9.1) 44.9 (35.1–54.7)
PPC rate, validation subsample, % (95% CI) 1.6 (0.6–2.6) 13.3 (7.6–19.0) 42.1 (29.3–54.9)

CI, confidence interval; PPC, postoperative pulmonary complication.

*Risk intervals were based on division of the development subsample into optimal risk intervals, according to the simplified risk score and applying the minimum
description length principle.
†
Three patients were excluded because of a missing value in some variable.

Table 9.11 Postoperative pneumonia risk calculator. Table 9.11 Postoperative pneumonia risk calculator—cont’d
Measure Score Measure Score
Procedure Anorectal 1 Sepsis Patients with preoperative systemic 3
inflammatory
Aortic 2
Patients with preoperative septic shock 2
Bariatric 3
Patients with preoperative sepsis 1
Brain 4
Without 0
Breast 5
Smoking Smoking within the year prior to surgery 1
Cardiac 6
Without smoking 0
ENT (except thyroid/parathyroid) 7
ASA, American Society of Anesthesiologists; COPD, chronic obstructive
Foregut/hepatopancreatobiliary 8
pulmonary disease; ENT, ear, nose, and throat; GOLD, Global Initiative for
Gallbladder, appendix, adrenal, and spleen 9 Chronic Obstructive Lung Disease.
With permission from Gupta H, Gupta PK, Fang X, et al. Development and
Hernia (ventral, inguinal, femoral) 10 validation of a risk calculator predicting postoperative respiratory failure.
Intestinal 11 Chest 2011;140(5):1207-1215.

Neck (thyroid and parathyroid) 12

Obstetric/gynecologic 13 Table 9.12a Parameter estimates for ALI risk predictors in
a multivariate logistic regression analysis (n ¼ 4,280).
Orthopedic and nonvascular extremity 14
Parameter Odds ratio
Other abdominal 15 Risk predictor estimate (95% CI) P Value
Peripheral vascular 16 Demographics
Skin 17 Age* 0.010 1.01 (0.99–1.03) 0.25
Spine 18 Sex, male –0.071 0.93 (0.61–1.45) 0.75
Nonesophageal thoracic 19 Procedural factors
Vein 20 6.39
Urology 21 High-risk cardiac 1.854 (3.87–10.87) <0.01

ASA class I–V 1 to 5 High-risk 26.46

vascular 3.276 (8.52–73.63) <0.01
Age Age in years 1 to 100
Low-risk
COPD GOLD stages 2–4 COPD 1 vascular 0.542 1.72 (0.39–5.23) 0.39
Without GOLD 0 High-risk
thoracic 1.486 4.42 (1.86–9.67) <0.01
Functional Patients with totally dependent funcional 2
status status Comorbidities
Patients who have partially dependent Diabetes
functional status 1 mellitus 0.588 1.80 (1.13–2.80) 0.01
Patients who are totally independent 0 COPD 0.761 2.14 (1.22–3.63) <0.01
Continued Continued
96 PART II • Preoperative Assessment

Table 9.12a Parameter estimates for ALI risk predictors in

Nonthoracic Surgery Algorithm
a multivariate logistic regression analysis (n ¼ 4,280)—cont’d
Parameter Odds ratio
Risk predictor estimate (95% CI) P Value Has patient had
any signs of Yes
Restrictive lung current or Postpone elective
disease 0.510 1.66 (0.73–3.40) 0.19 recent surgery for at least 2–3
GERD 0.619 1.86 (1.23–2.82) <0.01 respiratory weeks
infection?
Modifying conditions
Tobacco use
History of lung disease
Former 0.063 1.07 (0.66–1.73) 0.79
Reduced exercise tolerance
Active 0.473 1.60 (0.86–2.95) 0.13 smoke Hx > 40py
No
Abnormal physical exam
Alcohol abuse 1.050 2.86 (1.85–4.38) <0.01 Proceed with
Wheezing
surgery
Recent Thyrostemal < 4 cm
chemotherapy† 0.667 1.95 (0.55–6.25) 0.27
Prolonged expiry > 9 sec
Amiodarone 0.312 1.37 (0.73–2.44) 0.31 Positive couch test
Statins 0.154 1.17 (0.77–1.78) 0.47

ALI, acute lung injury; COPD, chronic obstructive pulmonary disease; GERD,
gastroesophageal reflux disease. Yes
*Age, for each additional year.
†
Within 6 months of the surgical procedure; only in patients undergoing
esophagectomy or lung resection for cancer. Consider
Any recent CXR
worsening in PFTs
symptoms Pulmonary consult
Yes
Table 9.12b SLIP scoring criteria (n ¼ 4,328). (increased Steroid pulse
sputum, DOE, Antibiotic if infection
Predictor variables Parameter estimate SLIP Points fever, etc.)? Aggressive
High-risk surgical procedure bronchodilation

Cardiac 1.88 19
No Consider modifying
Vascular 3.21 32
surgical approach
Thoracic 1.60 16 (i.e., laparoscopic)
Comorbidities
High-risk
Diabetes mellitus 0.62 6 Yes Consider regional
surgery?
anesthesia if
COPD 0.95 10
applicable
GERD 0.72 7 Consider epidural
analgesia
Modifying conditions
Alcohol abuse 1.13 11
Consider perioperative
COPD, chronic obstructive pulmonary disease; GERD, gastro-esophageal reflux risk reduction
disease; SLIP, surgical lung injury prediction. strategies (chest PT,
incentive spirometry,
bronchodilators)
Evaluation Paradigm for Fig. 9.4 Approach to nonthoracic surgery for a patient with lung dis-
Nonthoracic Surgery ease. CXR, Chest x-ray; DOE, dyspnea on exertion; Hx, history; PFTs,
pulmonary function tests; PT, physical therapypy, pack-years.

A thorough history and a physical exam should be obtained,

with particular attention to pulmonary and nonpulmonary
factors as described previously (Fig. 9.4). In patients who
have recent or ongoing respiratory infections, delay of sur-
gery for 2–3 weeks should be considered if acceptable from
the surgical point of view. Patients with known chronic
lung disease and with worse symptoms or patients who
have no known respiratory disease but who have new-onset
symptoms should receive further evaluation, and involve-
ment of a pulmonary specialist may be considered. Chest
radiography and PFTs may be considered, too. In patients
who have stable pulmonary symptoms but who are under-
going a high-risk procedure (upper abdominal surgery,
major vascular, probable duration longer than 2.5 hours,
likely use of gastric suctioning), a further attempt at risk
stratification using the ARISCAT (see Table 9.10) or Gupta
(see Table 9.11) score can be made. In patients with a high
score and with a high probability of PPCs, risk reduction
strategies, alternative surgical approaches, or nonsurgical
management may be considered, depending on surgical
indication and patient preferences.

Evaluation of the Lung Resection
Candidate
The goal of the preoperative evaluation is not only to assess
the risk of PPCs but also to determine whether a patient is a
candidate for surgery and to establish the amount of pulmo-
nary tissue that can be resected without causing intolerable
functional impairment. Unlike nonthoracic surgery, the pre-
operative assessment of lung resection candidates relies on
instrumental testing. The evaluation paradigms for thoracic
surgery include tests that are supported by adequate clinical
evidence and place particular emphasis on the prediction of
postoperative pulmonary function and on the use of exercise
testing.
The mortality reported in the general thoracic surgery
databases is 1.6%–2.3% after lobectomy and 3.7%–6.7%
after pneumonectomy.88 These outcomes have improved
over the years, although they remain substantial. Thus
selection criteria that were considered valid in the past
are now questioned. For example, advanced age used to
be considered a major contraindication to extensive lung
resection. However, recent guidelines indicate that
patients with lung cancer who are potential candidates
for curative surgical resection should be evaluated regard-
less of age.89
The preoperative evaluation for lung resection should
start with the identification of pulmonary and nonpulmon-
ary risk factors for PPCs by physical exam and by history
taking, as discussed for nonthoracic surgery. Factors that
have been shown to be related to PPCs in thoracic surgery
patients include cardiovascular diseases, smoking history,
and ASA status.90 Intraoperative factors that have been
shown to affect the rate of PPCs in lung resection patients
are duration of procedure, blood loss, and the amount of
intravenous fluids administered.91
All lung resection candidates should receive spirometry in
their initial evaluation. Previously, it was recommended92
that surgery be performed with no further evaluation in
pneumonectomy patients who have an FEV1 >2 L or
>80% predicted and in lobectomy patients who have
FEV1 >1.5 L. The most recent update was provided by
the American College of Chest Physicians (ACCP).
In patients with lung cancer being considered for surgery,
it is recommended that predicted postoperative (PPO) values
of both FEV1 and diffusing capacity of the lung for carbon
monoxide (DLCO) be calculated.89 These are estimated from
the preoperative values and the planned extent of the lung
resection. The latter can be determined using radionuclide
lung perfusion scans or simply by adding the segments that
will be removed. The use of perfusion scans to predict
postoperative lung function is recommended for pneumo-
nectomies, while for lobectomies, using the segment count
method is probably sufficiently accurate.93 However,
acceptable mortality and morbidity rates have been reported
even in patients who had low PPO pulmonary function.
Additionally, it has been suggested that preoperative PFTs
overestimate postoperative loss in exercise ability, particu-
larly after lobectomy.94 Therefore further evaluation
through exercise testing in patients with poor PPO lung
function is needed. Exercise testing is valuable for this pur-
pose because it provides a reasonably accurate assessment
9 • Pulmonary Risk Assessment 97
of a patient’s cardiopulmonary functional status and of
his/her ability to tolerate perioperative stress.
In the United States, there is a wide difference among sur-
geons' adherence to CPET as a modality for preoperative
thoracic surgery. The main variables used in CPET are
anaerobic threshold (AT) and peak oxygen uptake
(VO2peak) and ventilatory equivalent of carbon dioxide
(VE/VCO2).
The AT is a measure of submaximal or sustainable exer-
cise capacity and is defined as the oxygen uptake above
which the lactate production exceeds resting levels persis-
tently. It is associated with metabolic acidosis. Values less
than 10 mL/kg/min predicts the risk. VO2 peak is different
from VO2 max, and it is defined as the peak oxygen uptake
while performing an incremental exercise testing.
(VE/VCO2) is a measure to evaluate the efficiency of gas
exchange. If this is measured at AT, then it has been shown
to predict the morbidity and mortality in variety of surgical
patients.
Of note, a three-by-three assembly of specifically arranged
graphical display called the 9-panel plot is commonly
used.97
Exercise ability can be evaluated by calculating the max-
imal oxygen consumption (VO2max). Exercise testing can
be combined with radionuclide lung scanning to obtain
PPO VO2max.
The ACCP has recommended guidelines for physiologic
evaluation of a patient with lung carcinoma who is
considered for a thoracotomy with lung resection surgery
(lobectomy or more).89 The algorithm is shown in Fig. 9.5.
▪ If the PPO FEV1 and PPO DLCO are more than 60% of
predicted value, the patient is deemed as low risk for the
surgical procedure.
▪ If either the PPO FEV1 or PPO DLCO is less than 60% but
more than 30% of the predicted value, then the patient
should undergo either stair climb or shuttle walk test.
These are considered as low-technology exercise testing,
as opposed to the standard CPET.
▪ If the PPO FEV1 is less than 30% predicted or a PPO DLCO
is less than 30% predicted, then the patient should be
subjected to CPET with calculation of VO2max.
▪ When undergoing the low-technology tests, patients
who perform <25 shuttles (or <400 m) on the shuttle
walk test or climb <22 m at symptom-limited stair-
climbing test should be again subjected to CPET with
measurement of VO2max.
▪ In CPET, VO2max values should be carefully interpreted.
If the predicted value is less than 10 mL/kg/min or
<35% predicted, patients are deemed as being in the
high-risk category, and they should be counseled about
minimally invasive surgery, sublobar resection, or non-
operative treatment options.
▪ Patients whose VO2max is 10–20 mL/kg/min or 35%–
75% of predicted value from CPET testing are deemed as
being in the moderate risk category.
▪ Values of VO2max of 10–15 mL/kg/min are still con-
sidered to imply increased risk of mortality, taking into
account other factors, such as PPO FEV1 and DLCO as
well as patient comorbidities.
98 PART II • Preoperative Assessment

Positive low risk of negative

cardiac evaluation

ppoFEV1%
ppoDLCO%

ppoFEV1 and ppoFEV1 or ppoFEV1 or

ppoDLCO >60% ppoDLCO <60% ppoDLCO <30%
and BOTH >30%

Stair climb or SCT <22m or Positive high-risk

CPET
shuttle walk SWT <400m cardiac evaluation

VO2max VO2max VO2max

SCT >22m or >20ml/kg/min 20ml/kg/min <10ml/kg/min
SWT >400m or > 75% or 35%–75% or <35%

Low risk Moderate

High risk
risk

Fig. 9.5 Physiologic evaluation of a patient who is considered for a thoracotomy with lung resection surgery more than a lobectomy. CPET, Cardio-
pulmonary exercise testing; DLCO, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in 1 second; PPO, predicted postoperative value; SCT,
stair climbing test; SWT, shuttle walk test; VO2max, maximum oxygen consumption. (Adapted with permission from Brunelli A, Kim AW, Berger KI, et al.
Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: diagnosis and management of lung cancer, 3rd ed: American
College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e166S-e190S.)

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Newer models to predict PPCs are relatively simple and easy
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 10 Hematologic Risk Assessment
AUDREY E. SPELDE, DONAT R. SPAHN*, and PRAKASH A. PATEL
Hematologic risk assessment (HRA) involves evaluating and
managing needs for red blood cell (RBC) transfusion as well
as the integrity of a patient’s coagulation ability, including
intrinsic bleeding disorders or coagulopathies and anticoag-
ulant or antiplatelet medications. HRA is an essential com-
ponent of preoperative assessment for virtually all patients
undergoing surgery, but it is particularly critical for those
refusing blood and blood products, in patients for whom
an insufficient number of RBC units is available, in patients
with a history of a bleeding disorder, in those with preoper-
ative laboratory evidence of compromised blood coagula-
tion, and in patients on anticoagulant or antiplatelet
drugs (Box 10.1). The goal of HRA is to minimize transfu-
sion needs and prevent complications such as hemorrhage
and thrombosis. Efficient collaboration and communication
among surgeons, anesthesiologists, and at times other spe-
cialists, such as hematology consultants, are prerequisites to
successful perioperative management of patients at elevated
risk. This chapter covers the following topics: the preopera-
tive assessment for RBC transfusion needs and mitigation of
RBC transfusion risk, preoperative assessment of coagula-
tion abnormalities, and perioperative management of anti-
platelet and anticoagulant medications.
Red Blood Cell Transfusion
Hemoglobin (Hgb) contained within RBCs is the primary
transport mechanism of oxygen throughout the circulatory
system, responsible for maintaining systemic tissue oxygen-
ation. Thus, decreases in Hgb content of the blood, termed
“anemia,” can lead to decreased oxygen delivery (DO2) and
end-organ ischemia. DO2 is dependent on the following
equation:
DO2 ¼ cardiac output ðCOÞ
 arterial oxygen content ðCaO2 Þ
and
CaO2 ¼ ð1:34  ½HgbŠ  SaO2 Þ + ð0:003  PaO2 Þ,
where SaO2 is arterial oxygen saturation and PaO2 is partial
pressure of oxygen dissolved in arterial blood.
DO2 and subsequent extraction must be equal to or
greater than oxygen consumption; otherwise, a deficit
exists, resulting in tissue ischemia. As can be seen in the
previous equation, under physiologic conditions, arterial
oxygen content is primarily dependent on Hgb concentra-
tion, with only a small fraction relying on dissolved oxy-
gen.1 Therefore, the rationale for RBC transfusion is to
*Inactive on 5e.
maintain an adequate Hgb concentration for systemic
DO2. In healthy, resting volunteers, acute isovolemic ane-
mia was tolerated to an Hgb of 5 g/dL, and this is primarily
compensated by increases in heart rate, stroke volume, and
cardiac index,2 as well as increased oxygen extraction.
However, in a study of 1958 patients who declined blood
transfusion for religious reasons, odds of death rose
inversely with declining preoperative Hgb, demonstrating
the deleterious effects of anemia during the physiologic
stress of the perioperative period, which was especially evi-
dent in patients with underlying cardiovascular disease.3
The appropriate Hgb target within the surgical population
continues to be debated in randomized clinical trials. The
TRICC (Transfusion Requirements in Critical Care) trial
was one such randomized clinical trial in critically ill
patients. That trial compared a restrictive (Hgb <7 g/dL)
versus liberal (Hgb <10 g/dL) transfusion trigger.
Although the TRICC trial did not find a statistically signif-
icant difference between the two groups, it found a trend
toward lower 30-day mortality in the restrictive group,
and subgroup analyses found a statistically significant
decrease in 30-day mortality among the less critically ill
and those older than age 55 years.4 However, the appro-
priate Hgb target likely differs among patients in varying
comorbidities and in surgical subpopulations. In a recent
meta-analysis comparing critically ill versus surgical
patients, while a restrictive transfusion strategy resulted
in reduced 30-day mortality among critically ill patients,
the opposite effect was found among surgical patients.5
In the face of the available evidence, the American Society
of Anesthesiologists Task Force on Blood Component Ther-
apy concluded that no single Hgb trigger should dictate
transfusion decisions, instead using individual patient risks
for complications. The transfusion target for most patients
likely falls somewhere in the range of an Hgb of 7–9 g/dL,
with transfusion being rarely indicated for Hgb concentra-
tions greater than 10 g/dL and almost always indicated
when Hgb falls below 6 g/dL.6
RBC transfusion is not without risks. These include
transfusion-transmissible infection (viral, bacterial, and prion
disease), allergic and immunologic reactions (e.g., febrile
transfusion reaction, hemolytic reactions, alloimmunization,
and autoimmunization), mistransfusion, transfusion-related
acute lung injury, and transfusion-associated circulatory
overload.1 According to 2016 US Food and Drug Administra-
tion data on fatalities reported following blood collection
and transfusion, the highest number of fatalities related to
transfusion was due to transfusion-associated circulatory
overload.7
In addition to the inherent risks of transfusion, for reli-
gious reasons or otherwise, not all patients are accepting
of RBC transfusion. A common example is the patient
101
102 PART II • Preoperative Assessment

Box 10.1 Situations requiring hematologic risk Table 10.1 Procedural bleeding risk.
assessment. High (2-day risk of major bleed Low (2-day risk of major bleed
2%–4%) 0%–2%)
Patients refusing allogeneic red blood cell (RBC) transfusions
No or insufficient number of allogeneic RBCs available Heart valve replacement Cholecystectomy
Patients with a history of a bleeding disorder Coronary artery bypass Abdominal hysterectomy
Patients with a prolonged prothrombin time (PT)
Patients with a prolonged activated partial thromboplastin time Abdominal aortic aneurysm Gastrointestinal endoscopy 
(aPTT) repair biopsy, enteroscopy, biliary/
Patients with a low platelet count pancreatic stent without
sphincterotomy,
Patients with a platelet function defect endosonography without fine-
Patients on antiplatelet drugs needle aspiration
Patients on anticoagulant medications
Neurosurgical/urologic/head and Pacemaker and cardiac
neck/abdominal/breast cancer defibrillator insertion and
surgery electrophysiologic testing
Bilateral knee replacement Simple dental extractions
who is a Jehovah’s Witness. While it is important to clarify
with each individual patient which, if any, blood products Laminectomy Carpal tunnel repair
they are willing to accept, Jehovah’s Witnesses generally Transurethral prostate resection Knee/hip replacement and
refuse the transfusion of whole blood, blood cells, and shoulder/foot/hand surgery and
plasma,8 stemming from strict obedience to the belief that arthroscopy
the soul abides in the blood. The refusal or acceptance of Kidney biopsy Dilation and curettage
“minor” components of the blood (such as albumin and
Polypectomy, variceal treatment, Skin cancer excision
coagulation factors) is left up to the individual patient, biliary sphincterectomy,
and substances produced by genetic engineering are gener- pneumatic dilation
ally accepted. Moreover, the integrity of the vascular tree is
PEG placement Abdominal hernia repair
paramount because Jehovah’s Witnesses believe the soul
cannot remain outside the body. Therefore, cardiopulmo- Endoscopically guided fine- Hemorrhoidal surgery
nary bypass or normovolemic hemodilution is accepted as needle aspiration
long as the continuity of the blood circulation is preserved. Multiple tooth extractions Axillary node dissection
Patients who have received transfusions in the past may
Vascular and general surgery Hydrocele repair
develop antibodies directed against relevant red cell surface
antigens, leading to incompatibilities with future transfu- Any major operation (procedure Cataract and noncataract eye
sions. Some patients raise a high level of a clinically impor- duration >45 minutes) surgery
tant alloantibody that is directed against a very common Noncoronary angiography
antigen (e.g., present in > 90% of individuals). It might then Bronchoscopy  biopsy
become almost impossible to find blood units to which they
do not react, or not enough for a proposed surgery. Central venous catheter removal
In these situations in a patient refusing RBC transfu- Cutaneous and bladder/prostate/
sion or for whom there is insufficient availability of com- thyroid/breast/lymph node
patible RBC units, prior to proceeding with surgery, it biopsies
becomes necessary to evaluate the patient’s maximum PEG, percutaneous endoscopic gastrostomy.
allowable blood loss (mABL), the periprocedural bleeding Adapted with permission from Spyropoulos AC, Douketis JD. How I treat
risk (Table 10.1), and any alternatives to transfusion anticoagulated patients undergoing an elective procedure or surgery.
(Fig. 10.1). For patients undergoing procedures with Blood. 2012;120(15):2954-2962.
elevated bleeding risk, the mABL can be calculated using
the following formula, assuming that normovolemia is
maintained9: perioperative blood loss rather than the intraoperative blood
mABL ¼ ½EBV  ðHgbi Hgbf ފ=Hgbi , loss, accounting for potentially significant postoperative
blood loss.10 If the mABL is considerably greater than the
where historical perioperative blood loss, no further measures
are necessary and the surgery can be performed safely, even
EBV ¼ body weight ðkgÞ  average blood volume ðmL=kgÞ,
in the absence of RBCs. However, if the mABL is similar to or
with EBV being estimated blood volume, Hgbi being initial smaller than the expected perioperative blood loss, addi-
hemoglobin, and Hgbf being final hemoglobin (transfusion tional measures are required.
trigger). Blood volume in nonobese patients is calculated As previously described, blood conservation strategies
as 70–75 mL/kg in adult males and 60–65 mL/kg in adult can be used for reasons including patient refusal of blood
females. Blood volume is 80 mL/kg in infants, 85 mL/kg in products or lack of blood availability, but the end goal is
full-term neonates, and 95 mL/kg in premature neonates. the same: to avoid allogeneic RBC transfusion. The preoper-
The next step is to compare the mABL with the perioper- ative assessment of these patients is particularly important
ative bleeding risk and the historical perioperative blood loss and aims at optimizing Hgb concentration at the time of sur-
for the planned operation performed by the local surgical gery and planning for blood conservation measures to be
team. This comparison should be with the historical employed intraoperatively.
 10 • Hematologic Risk Assessment 103

Preoperative
screening
(4 weeks prior to
elective surgery)

Hg < 12 g/dL (females)

Hg < 13 g/dL (males

GFR < 60: chronic

kidney disease.
Consider referral
to nephrologist Low vitamin B
Iron status? TSAT > 20% Serum creatinine/GFR or folic acid
levels: Start therapy
Measure vitamin B
GFR > 60 and folate levels

Normal vitamin B
or folic acid levels
Iron deficiency Start oral iron therapy.
(consider referral to If Gl intolerance to oral If no response
TSAT < 20%
gastroenterologist to iron or short time before to iron therapy:
rule out malignancy) therapy, consider IV iron.

Anemia of
chronic disease.
Start erythopoiesis
stimulating agent.

Fig. 10.1 Algorithm for evaluation and management of anemia. GFR, Glomerular filtration rate; GI, gastrointestinal; Hg, hemoglobin; IV, intravenous;
TSAT, transferrin saturation. (Adapted with permission from Shander A, Goodnough LT, Javidroozi M, et al. Iron deficiency anemia—bridging the knowledge
and practice gap. Transfus Med Rev. 2014;28(3):156–166.)

Ideally, a baseline Hgb should be measured 4 weeks in

advance of all elective procedures aside from minor surgery Box 10.2 Blood-sparing strategies.
with low risk of blood loss. Anemia has been found to be an Preoperative pharmacologic preparation
independent risk factor for morbidity, mortality, longer hos- ▪ Erythropoietin (EPO), 150–300 IU/kg, six doses in 3 weeks
pital stay, and reduced quality of life and should be (alternative: 600 IU/kg, three doses in 7–10 days)
addressed for all patients.11 Shander et al. proposed an algo- ▪ Iron, 100–300 mg/day, intravenous or oral
rithm for evaluation and management of anemia ▪ Folic acid, 5 mg/day
(see Fig. 10.1).12 For anemic patients, Hgb should be ▪ Vitamin B12, 15–30 μg/day
increased by preoperative iron therapy, vitamin B12, folic Preoperative autologous blood donation (PABD)
acid, or erythropoietin if time allows (Box 10.2), with the Intraoperative alternatives to blood transfusions
goal of therapy being to increase Hgb levels by 1 g/dL each ▪ Acute normovolemic hemodilution
week. This reduces the need for allogeneic blood transfusion, ▪ Cell salvage and retransfusion techniques (Cell-Saver)
Anesthetic technique
allows preoperative autologous blood donation (PABD)
despite anemia,13 and increases the amount of blood col-
▪ Intraoperative normothermia
▪ Maintained normovolemia with crystalloids  colloids
lected by intraoperative isovolemic hemodilution.14 Eryth- ▪ Hyperoxic ventilation (inspired oxygen 100%)
ropoietin and iron therapy have been used successfully in ▪ Deep anesthesia with muscle relaxation
individual cases where blood transfusion was refused or Pharmacologic treatment
impossible. ▪ Antifibrinolytic substances (aprotinin, ε-aminocaproic acid,
PABD should be considered only if large blood losses are tranexamic acid)
expected (>2000 mL) and if the likelihood of transfusion ▪ Desmopressin
exceeds 50%.15 In many cases, PABD is effectively hemodilu- ▪ Coagulation factors (fresh frozen plasma; fibrinogen; factors
II, VII, IX, and X)
tion because only a fraction of the donated erythrocytes are
regenerated preoperatively.16 To maximize the advantages of ▪ Recombinant factor VIIa
Acceptance of minimal hemoglobin values
PABD, a longer interval before surgery or the use of erythro- ▪ 6 g/dL in healthy individuals
poietin and iron is required to allow regenerative erythropoi- ▪ 8 g/dL in aged or compromised patients
esis. If PABD is not an option, or if the patient does not Adaptation of surgical procedure
respond to iron and/or erythropoietin, preoperative acute
104 PART II • Preoperative Assessment
normovolemic hemodilution (ANH) and cell saving should be
considered (see Fig. 10.1).17,18 ANH can be performed until
the lowest acceptable Hgb is reached; most often, however, it
is performed only to Hgb levels of 8 to 9 g/dL.19 Similar to cal-
culating mABL, the Hgb that is mass harvested during ANH
(HgMANH) can be calculated as follows20:
HgbMANH ¼ ½EBV  ðHgbi =Hgbf ފ=Hgbavg
where EBV is the patient’s estimated blood volume, Hgbi is
the Hgb concentration prior to ANH, Hgbf is the Hgb con-
centration after ANH (target Hgb), and Hgbavg is the arith-
metical average between the starting and final Hgb. After
ANH, any further blood loss occurs from a lower starting
Hgb, and thus mABL should be recalculated.
Accepting a lower minimal Hgb in otherwise healthy
individuals will also help to avoid the need for transfusion,
but this approach should be taken cautiously. Hyperoxic
ventilation will increase DO2 and has been shown to
decrease myocardial ischemia and cognitive dysfunction
due to ANH.21,22 However, the lower the Hgb, the more
important it is to maintain normovolemia (see Box 10.2).
Only at normovolemia are physiologic compensatory mech-
anisms maximally efficacious.23 Therefore, crystalloid
replacement should be given at a 1:3 ratio and colloid given
at 1:1. In addition, maintaining normothermia and avoid-
ing hypothermia are of great importance in decreasing over-
all blood loss.24
If preoperative treatment cannot augment RBC mass
sufficiently, and despite use of ANH and cell-saving tech-
niques the expected blood loss becomes greater than
mABL, alternative treatment strategies, including less
invasive and nonsurgical treatment modalities, must be
considered (see Box 10.2).
PT aPTT
TF VIIa
IXa
IX
TF VIIa
Ca++ X Ca++
Phospholipids
Xa
Va Xa
Ca++
PT and aPTT Phospholipids
Fig. 10.2 Coagulation pathways and specificity of different coagulation assays. aPTT, Activated partial thromboplastin time; PT, prothrombin time; TF,
tissue factor.
Hemostasis
Hemostasis is a complex mechanism involving the vessel
wall, circulating cellular elements (particularly platelets),
and circulating soluble factors such as coagulation factors.
The characteristics of blood flow (laminar vs turbulent, flow
velocity, pressure gradients, wall tension, and elasticity)
define vascular bed specificity, which describes how differ-
ent aspects of hemostasis can be relevant in different vascu-
lar beds. Hemostasis in general can be described as
occurring in four phases:
1. Vasoconstriction: When the vessel wall is damaged, the
vessel diameter reduces, thereby diminishing the size of
the breach and bringing the circulating elements of
coagulation into proximity of the endothelium.
2. Primary hemostasis: Circulating platelets adhere to sub-
endothelial collagen via von llebrand factor (vWF) and the
platelets’ receptor glycoprotein (GP) Ib. Activated platelets
subsequently change from discoid to spherical; form pseu-
dopods, exposing procoagulant receptors to form a pri-
mary hemostatic plug; and release the contents of their
granules, secreting multiple factors that enhance further
platelet activation and coagulation. Platelets’ GPIIb/IIIa
receptors and negatively charged phospholipids are the
anchors by which platelets adhere to one another.25
3. Secondary hemostasis: The various coagulation factors
and cofactors interact on the platelets’ surfaces to form
insoluble fibrin strands (Fig. 10.2) that will mediate clot
retraction and result in formation of a stable thrombus.
The traditional division of this reaction into an extrinsic,
an intrinsic, and a common pathway is a simplification of
a complex series of interactions. The simplification is
Activator Activator
XIIa XII
XIa XI
IX
X IXa VIIIa
Phospholipids
Insoluble fibrin
Xa XIIIa
Soluble fibrin
II
IIa
Fibrin monomer
Fibrinogen

useful to illustrate the underlying mechanisms of com-
mon coagulation tests (e.g., prothrombin time [PT]
and activated partial thromboplastin time [aPTT]). Sev-
eral enzymes inhibit the coagulation cascade: activation
of protein C, which is initiated by the coagulation cas-
cade itself, tissue factor pathway inhibitor, and
antithrombin.
4. Recanalization: After the endothelial continuity has been
reestablished, the blood clot is broken down by the fibri-
nolytic system, which is catalyzed by plasmin, and blood
flow is restored through the vessel. Plasminogen, the pre-
cursor of plasmin, circulates freely in plasma and is acti-
vated by tissue plasminogen activator and urokinase-
type plasminogen activator, which are secreted by
vascular cells.
Preoperative Risk Assessment
Strong emphasis is placed on preoperative evaluation to
identify risk factors for requiring blood transfusion or adju-
vant therapies. This evaluation should include review of
medical records, patient or family interview, physical exam-
ination, review of existing laboratory results, and ordering
additional laboratory tests when indicated.26 Multiple stud-
ies have demonstrated that routine preoperative hemostatic
testing is of low clinical value, is not predictive of postoper-
ative complications, and is not cost effective.27–29 Further,
the surgical procedure itself does not constitute an indica-
tion for coagulation testing in both cardiac and noncardiac
surgery.30–33
Rather, laboratory testing should be ordered on an
individual-patient basis (see “Medical History and Physical
Examination” section). Patients identified as being at risk
Patient history and physical examination
Negative
Hemorhagic surgery
Hepatic surgery
Extracorporeal circulation
No Yes
Negative
Proceed to surgery
Fig. 10.3 Strategy for preoperative screening of bleeding diathesis. aPTT, Activated partial thromboplastin time; PC, platelet count; PFA, platelet
function analyzer; PT, prothrombin time; VWF-Ag, von Willebrand factor antigen.
10 • Hematologic Risk Assessment 105
should then undergo further laboratory testing, which
may include PT, aPTT, platelet count (PC), platelet function
testing using a platelet function analyzer (PFA-100; Sie-
mens Medical Solutions, Malvern, PA), and a functional
vWF assay. This strategy of testing the at-risk subpopulation
(Fig. 10.3) was shown to reduce transfusion needs when
applied in combination with a standardized therapeutic reg-
imen and is consistent with the practice guidelines issued by
the American Society of Anesthesiologists.26
MEDICAL HISTORY AND PHYSICAL EXAMINATION
Clinical evaluation is one of the best tools to identify patients
at risk for bleeding.34 The patient’s personal and family his-
tory can provide important clues to the presence and type of
bleeding disorder. Several questionnaires have been pub-
lished. The Koscielny questionnaire (Box 10.3) was estab-
lished retrospectively and later validated in a prospective
study, each study including more than 5000 patients.35,36
On the basis of this questionnaire, 5021 (88.8%) of 5649
patients were identified as having a negative bleeding his-
tory, of which the only laboratory test abnormality found
was a prolonged aPTT in 9 patients (0.2%) due to lupus
anticoagulant.36 No other test identified a bleeding disorder
in the patients with a negative bleeding history, highlight-
ing the utility of clinical history.
If a positive family history is present, the patient should be
asked about the intensity and type of bleeding and the
hereditary pattern. If a bleeding tendency is present, recent
medication that might interfere with normal coagulation
(e.g., non-steroidal anti-inflammatory drugs, aspirin) or
measures that may have been taken to stop the bleeding
(e.g., nasal tamponade, vitamin K), recent illnesses, and
recent transfusion should all be asked about. Concomitant
Positive
PT, aPTT, PC, PFA, and VWF-Ag
Positive
Explore and treat
106 PART II • Preoperative Assessment
Box 10.3 Questionnaire for detecting an
increased bleeding risk.
1. Have you ever experienced strong nose bleeding without
prior reason?
2. Did you ever have—without trauma—“blue spots” (hema-
toma) or “small bleeding” (at the torso or other unusual
regions of the body)?
3. Did you ever have bleeding of the gums without apparent
reason?
4. How often do you have bleeding or “blue spots” (hematoma):
more than one or two times per week or just one or two times
per week?
5. Do you have the impression that you have prolonged bleeding
after minor wounds (e.g., razor cuts)?
6. Did you have prolonged or grave bleeding during or after
operations (e.g., tonsillectomy, appendectomy, or during
labor)?
7. Did you ever have prolonged or grave bleeding after a tooth
extraction?
8. Did you ever receive blood packs or blood products during an
operation? If so, please define the operation(s).
9. Is there a history of bleeding disorders in your family?
10. Do you take analgesic drugs or drugs against rheumatic dis-
ease? If so, please specify.
11. Do you take other drugs? If so, please specify.
12. Do you have the impression that you have prolonged men-
struation (>7 days) or a high frequency of tampon change? [to
be answered only by women]
With permission from Koscielny J, Ziemer S, Radtke H, et al. A practical
concept for preoperative identification of patients with impaired pri-
mary hemostasis. Clin Appl Thromb Hemost. 2004;10(3):195-204.
liver or renal disease, hypersplenism, hypothyroidism,
excessive alcohol use, connective tissue disorders, malig-
nancy, and hematologic diseases also influence hemostasis
and should be investigated. Physical signs that can indicate
pathologic states associated with increased bleeding include
purpura, hematomas, jaundice, hepatomegaly, splenomeg-
aly, and adenopathy.
The clinical presentation of bleeding diatheses varies, and
different signs can be related to different disorders. The most
frequent manifestations are cutaneous and mucosal bleed-
ing. Oozing, hemarthrosis, and muscular hematomas are
other types of bleeding that can be found in several bleeding
disorders. The clinical presentations of the major bleeding
disorders are listed in Table 10.2.
Petechiae, lesions less than 2 mm in diameter, are
mainly caused by thrombocytopenia. Purpura are 3 to
6 mm in diameter and most frequently caused by Henoch-
Sch€ onlein purpura and cryoglobulinemia. Ecchymoses
are large dermal extravasations of blood exceeding 6 to
7 mm. They appear most often on exposed body parts
and are caused by thrombocytopenia, cortisone therapy,
or erythrocyte autosensitization. Easy bruising defines
the tendency to have variable skin lesions, such as
ecchymoses and hematomas, after minor trauma that
the patient is often unable to recall. Usually, there is
an underlying thrombocytopenia or coagulation disor-
der. Senile vessel fragility and Cushing syndrome can
also cause easy bruising of the skin. Oozing is a special
feature of cutaneous bleeding. It can be defined by the
continuing loss of blood at puncture sites or wounds.
The underlying disorder can be hypofibrinogenemia,
Table 10.2 Clinical presentation of major bleeding disorders.
Disorder Findings
Conjunctival ecchymosis Hypertension
Thrombocytopenia
Circulating anticoagulants
Petechiae Thrombocytopenia
Mucosal Osler-Weber-Rendu syndrome
Von Willebrand disease
Platelet disorders
Hematomas Single-factor congenital deficiency
Circulating anticoagulants
Traumas
Hemarthrosis Hemophilia A and B
FII, FVII, FX deficiency
Easy bruising Thrombocytopenia
Cushing disease
FII, Factor II; FVII, factor VII; FX, factor X.
With permission from Girolami A, Luzzatto G, Varvarikis C, et al. Main clinical
manifestations of a bleeding diathesis: an often disregarded aspect of
medical and surgical history taking. Haemophilia. 2005;11(3):193–202.
hyperfibrinolysis, thrombocytopenia, or factor XIII defi-
ciency. Newborns with factor XIII deficiency or afibrino-
genemia often present with oozing at the umbilical stump.
Mucosal bleeding can occur at any organ covered with
mucosa: the gastrointestinal, respiratory, urinary, and uter-
ovaginal tracts and the eyes. It is frequently seen in cases of
thrombocytopenia and von Willebrand disease (vWD). It
also can be caused by a variety of non–coagulation-related
disorders, such as Osler-Weber-Rendu syndrome, gastroin-
testinal ulcers, malignancies, infections, and varicose veins.
Menorrhagia and metrorrhagia are frequent in thrombocy-
topenia and vWD. Minor uterovaginal bleeding (“break-
through bleeding”) is often the result of hormonal
imbalance, but it may be caused by congenital factor defi-
ciencies (factors II, V, and X). Conjunctival ecchymosis
can be found in hypertension, thrombocytopenia, and anti-
coagulant use. Hematuria is most often caused by non–
coagulation-related disorders.
Intramuscular and intra-articular bleeding occur fre-
quently in patients with hemophilia. Hemarthrosis has also
been described in patients with factors II, VII, and X deficien-
cies. These patients are particularly prone to intracerebral
hemorrhages.
Despite a negative bleeding history, there are still
instances when it is appropriate to order laboratory tests
for hemostasis37:
• Unreliable historian: The patient is unable to recall a sur-
gical or trauma history or does not recognize the history
as abnormal.
• Inadequate provocation: The patient has not been exposed
to a significant bleeding risk such as trauma, major sur-
gery, or dental extraction.
• Acquired disorder: The disorder is not heritable and was
developed later in life after the patient was exposed to a
significant bleeding risk.

Laboratory Testing
If clinical assessment of the patient suggests the presence of
a bleeding disorder, screening tests should be performed,
including PT, aPTT, and PC. If bleeding history is abnormal
but not suggestive of a particular bleeding disorder, addi-
tional testing should be obtained as well, including complete
blood count, creatinine, and liver function studies. Other
studies, such as specific factor assays, platelet function stud-
ies, and vWF, can be ordered on the basis of clinical suspi-
cion. If initial testing does not reveal an explanation for
abnormal bleeding history, hematology consultation should
be obtained.
TESTS OF PRIMARY HEMOSTASIS: PLATELET COUNT
AND FUNCTION
Absolute preoperative PC is a highly reliable and reproduc-
ible test, but it gives information only regarding the number
of circulating platelets, not about function. Alone it is not an
efficient predictor of perioperative bleeding, but in conjunc-
tion with other tests, it is included by many authors in a pre-
operative screening regimen.36,38 A patient presenting with
a PC of less than 100,000/μL should be investigated. The
main causes for low PC are listed in Box 10.4.
Pseudothrombocytopenia is the result of agglutination of
thrombocytes in vitro, causing a falsely low PC without the
clinical bleeding tendency. It occurs in 0.2% of the general
population and in 1.9% of hospitalized patients, and it
accounts for up to 15% of low PCs in hospital laborato-
ries.39–41 An antibody with affinity for antigens on
in vitro thrombocytes is the cause and is strongly enhanced
by the anticoagulant ethylenediaminetetraacetic acid used
in test tubes. The GPIIb/IIIa inhibitor abciximab can induce
an antibody-mediated clinically important thrombocytope-
nia and has been shown to induce pseudothrombocytopenia
Box 10.4 Causes of low platelet count.
Pseudothrombocytopenia
Impaired production
▪ Congenital thrombocytopenia
▪ Acute leukemia
▪ Myelodysplasia
Osteopetrosis
▪ 100,000/μL be respected.46 Platelet transfusion may be
▪ Toxins (e.g., chemotherapy, alcohol)
▪ Infection (e.g., human immunodeficiency virus)
Peripheral consumption
▪ Autoimmune
▪ Primary (e.g., idiopathic thrombocytopenic purpura)
▪ Secondary
▪ Disseminated intravascular coagulation
▪ Thrombotic thrombocytopenic purpura
▪ Hemolytic uremic syndrome
Redistribution and dilution
▪ Massive transfusion
▪ Splenomegaly
10 • Hematologic Risk Assessment 107
in 2% of patients undergoing coronary interventions
through a related mechanism.
True thrombocytopenia can be congenital or acquired,
caused by low platelet production, peripheral platelet
destruction, or dilution. The perioperative management
for different types of thrombocytopenia is depicted in
Fig. 10.4. The use of antiplatelet drugs is the most frequent
cause of platelet dysfunction and is addressed later (see
“Management of Patients Under Antiplatelet Therapy”
section).
Congenital thrombocytopenia (CTP) accounts for a very
small number of the low PCs encountered. CTP is a hetero-
geneous group of disorders with variable bleeding tenden-
cies with ill-defined management strategies. The available
options include desmopressin (DDAVP), antifibrinolytics,
platelet transfusion, and recombinant factor VIIa.42
Immune thrombocytopenia is caused by antibodies to cir-
culating platelets. It can be a primary autoimmune disorder,
known as “idiopathic thrombocytopenic purpura” (ITP), or
secondary to infections (e.g., human immunodeficiency
virus infection), systemic lupus erythematosus, antipho-
spholipid syndrome, and B-cell malignancies. ITP is treated
with steroids and immunoglobulins (intravenous [IV]
immunoglobulin, anti-D, anti-CD20) if PC is less than
20,000/μL.43
Heparin-induced thrombocytopenia (HIT) is a particular
form of immune thrombocytopenia related to prolonged
(minimum 5 days) or prior heparin therapy.44 Its pathogen-
esis is based on the binding of the heparin molecule with cir-
culating platelet factor 4 (PF4), a protein stored in platelet α-
granules. These heparin–PF4 complexes induce production
of antibodies that form immune complexes and activate
platelets, leading to release of additional PF4 and enhanced
formation of immune complexes. HIT is a serious complica-
tion of heparin therapy leading to thrombocytopenia and a
prothrombotic state that should be suspected in patients
with a 50% drop in platelets being treated with heparin.45
HIT is treated by discontinuing heparin and administering
an alternative anticoagulant such as argatroban, bivaliru-
din, or fondaparinux.45
A PC between 20,000/μL and 100,000/μL may lead to
increased surgical or traumatic hemorrhage but normally
does not result in spontaneous bleeding, the risk of which
increases below 20,000/μL.25 If platelet function is normal,
a count greater than 50,000/μL is considered sufficient for a
patient to undergo nearly any kind of surgery, including
cardiac surgery. Only in procedures in which minimal
bleeding can have deleterious consequences (e.g., neurosur-
gery and ophthalmic surgery) should the lower limit of
indicated if PC is less than 100,000/μL and intraoperative
or postoperative microvascular bleeding is present.17 In
obstetrics, gestational thrombocytopenia is a benign condi-
tion that does not require platelet transfusion.47 Thrombo-
cytopenia associated with preeclampsia and hemolysis,
elevated liver enzymes, and low platelets (HELLP syndrome),
however, requires close follow-up and transfusion of plate-
lets if the count drops to less than 30,000/μL for a vaginal
delivery or to less than 50,000/μL in the case of a cesarean
section.46 For spinal anesthesia, a lower limit of 50,000/μL
is advocated, whereas for epidural anesthesia, a PC of
80,000/μL has been recommended because of the higher
risk for spinal hematoma.46
108 PART II • Preoperative Assessment
Normal HIT ITP PTCP
PFA100@
• DDAVP • Stop heparin • Steroids No treatment
• Antifibrinolytics • Antithrombin • Immune globulin necessary
• FVII/VWF agents
• Estrogens
Fig. 10.4 Strategies for thrombocytopenia. This category contains exclusively pediatric patients undergoing lumbar puncture for intrathecal
chemotherapy. Lumbar puncture for other reasons or spinal anesthesia requires 50,000 /μL. DDAVP, Desmopressin; HIT, heparin-induced thrombo-
cytopenia; ITP, idiopathic thrombocytopenic purpura; PFA, platelet function analyzer; PTCP, pseudothrombocytopenia; rFVIIa, recombinant activated
factor VII; TCP, thrombocytopenia; VWF, von Willebrand factor.
While bleeding time was historically used to test platelet
function, it has poor discriminating power in predicting
operative blood loss,48,49 and it is poorly related to PC.50
In 1998, the American Society of Pathologists stated that
bleeding time cannot be used as a predictor for surgical hem-
orrhage, that a normal bleeding time does not exclude
excessive hemorrhage, and that bleeding time cannot reli-
ably distinguish between patients who have recently
ingested aspirin and those who have not.51 Bleeding time
is thus abandoned as a preoperative test to evaluate bleeding
tendency or to predict surgical blood loss.
Light transmission aggregometry (LTA) was developed in
the 1960s and remains the gold standard for assessing the
various platelet functions. LTA is the most widely employed
method for detecting platelet function disorders, including
vWD and monitoring antiplatelet therapies; however, it is
time consuming, requires a high degree of skill to perform
and interpret, requires an ongoing standardization process,
and typically requires further, more specific confirmatory
testing.52 Alternative screening strategies include PFA-
100, a point-of-care (POC) in vitro test sensitive for platelet
function and vWF activity in which whole blood is exposed
to high shear through a collagen-coated membrane in the
presence of an agonist.53 Closure time or the time for the
aperture to close as a result of platelet aggregation is
Platelet count
Congenital TCP with TCP with normal
normal function function
Lumbar puncture for
10,000 µL IT chemotherapy
30,000 µL Vaginal delivery
• Surgery
50,000 µL
• Spinal anesthesia
80,000 µL Epidural anesthesia
• DDAVP • Intracranial and
• Antifibrinolytics 100,000 µL medullar surgery
• rFVIIa • Ophthalmic surgery
measured and compared with control values. PFA-100
has been shown to be more sensitive than bleeding time
in diagnosing vWD and platelet function defects.52
Other methods available to assess platelet function
include impedance platelet aggregation, global thrombosis
test, flow cytometry, immunoassays, the Plateletworks ana-
lyzer (Helena Laboratories, Beaumont, TX), the Impact-R
cone and plate analyzer system (Matis Medical, Beersel, Bel-
gium), the VerifyNow system (Accriva, San Diego, CA),
thromboelastography (TEG) with platelet mapping (Haemo-
netics, Braintree, MA), and the rotational thromboelastome-
try (ROTEM) platelet system (TEM Innovations, Munich,
Germany) (see “Point-of-Care Testing” section).52 These lat-
ter assays continue to undergo further prospective study.
TESTS OF SECONDARY HEMOSTASIS: PT AND APTT
As mentioned previously, routine hemostatic testing has not
been shown to predict hemorrhagic complications, nor
have unexpected laboratory abnormalities been shown to
result in adverse surgical or anesthetic consequences.54,55
This is true across surgical specialties, with evidence existing
for cardiac surgery,56 gynecologic oncology surgery,57
abdominal and thyroid surgery,58 tonsillectomy,59,60 prostate
surgery,61 dental surgery,62 liver biopsy,63 thoracentesis and

paracentesis,64,65 transbronchial lung biopsy,66 renal
biopsy,67 angiographic procedures,68 and central venous
catheter insertion.67,69 At best, routine use of these tests leads
to confusing results, repetition of tests, and unjustified cancel-
ation or postponement of surgery.
However, in an at-risk population such as the one identi-
fied by the Koscielny algorithm, such tests may prove useful
in identifying patients with underlying bleeding disorders.
Additionally, when coagulation abnormalities are expected
as a result of the surgical procedure itself (major hepatic sur-
gery, extracorporeal circulation, massive blood loss and
transfusion), preoperative baseline PT and aPTT values
should be obtained to be able to interpret intraoperative
and postoperative values.
The PT and aPTT are in vitro coagulation tests designed
to detect deficiencies of coagulation factors. In the PT, tissue
factor and calcium are added to citrated plasma, and the
time needed for a clot to form is measured and compared
with control values. In the aPTT, an activator of factor
PT, aPTT
aPTT prolonged PT and aPTT prolonged
Vit K deficiency
Liver disease
FII, FV, FX fibrinogen
deficiency
DIC
FXII deficiency
VWD
FVIII deficiency (hemophilia A)
FIX deficiency (hemophilia B)
FXI deficiency
Lupus anticoagulant
Heparin
Fig. 10.5 Strategies for the treatment of coagulation disorders. *The correction of coagulation disorders by the administration of vitamin K takes 2 to
3 days. If urgent correction is necessary, prothrombin complex concentrate or fresh frozen plasma (FFP) is necessary. aPTT, Activated partial throm-
boplastin time; DDAVP, desmopressin; DIC, disseminated intravascular coagulation; F, factor; PT, prothrombin time; rF, recombinant factor; Vit K, vitamin
K; VWF, von Willebrand factor.
10 • Hematologic Risk Assessment 109
XII is added to plasma, and time to clot formation is
expressed in seconds. Thus, PT specifically tests the integrity
of the extrinsic pathway (used to monitor warfarin therapy),
and aPTT tests the intrinsic pathway (sensitive to changes
in all factors other than VII and XIII; used to monitor hep-
arin therapy). Both tests are abnormal if the coagulopathy
impairs the common pathway (see Fig. 10.2). Clotting times
are prolonged in the presence of disseminated intravascular
coagulation (DIC), vitamin K antagonists, direct thrombin
inhibitor or factor Xa inhibitor therapy, heparin therapy,
vitamin K deficiency, congenital or acquired (i.e., liver dis-
ease) factor deficiencies, dysfibrinogenemia or hypofibrino-
genemia, factor VIII deficiency secondary to vWD, or
lupus anticoagulant or anticardiolipins. These different
states and their influence on clotting tests are discussed
later. Strategies for perioperative care in these patients are
depicted in Fig. 10.5.
DIC is a severe coagulopathy associated with advanced
disease states such as sepsis, burns, massive transfusion,
PT prolonged
Prothrombin complex concentrate*
Vit K Coumarin
FFP FVII deficiency
Cryoprecipitate
No treatment
DDAVP
FVIII/VWF concentrate
rFVIIIa
rFIX
FFP
Thrombosis prophylaxis
Protamine
110 PART II • Preoperative Assessment
and shock. It is unlikely that prolonged PT or aPTT will
uncover an otherwise unsuspected DIC. Liver disease has
to be in an advanced and clinically apparent state before
the reduced hepatic production of coagulation factors leads
to coagulopathies. Factors V, VII, and X have to fall below
50% of normal values and prothrombin levels have to be less
than 30% before the PT prolongs. The aPTT stays within
normal limits until the activity of the factors of the intrinsic
pathway is less than 30%.25
Vitamin K deficiency can be suspected in cases of malnu-
trition or malabsorption, but it may be uncovered by a path-
ologic PT or, if very severe, a prolonged aPTT. Congenital
factor VII deficiency leads to a prolongation of PT without
affecting aPTT; it is a very rare condition that leads to var-
iable bleeding tendency, from mild to life threatening. Defi-
ciencies in the factors II, V, and X lead to abnormal PT and
aPTT, but these are very rare,25,70 and the cost to detect
these conditions by routine testing of the surgical popula-
tion is unjustifiable.
Dysfibrinogenemia is caused by a variety of structural
abnormalities in the fibrinogen molecule.71 It can be inher-
ited or acquired. The prevalence of the inherited forms is
unknown; its hereditary pattern is usually autosomal dom-
inant, and the clinical presentation can be either a bleeding
or a thrombosis tendency. Both features can be present in
the same patient, and most patients are asymptomatic.
The disease is suspected on the basis of a bleeding or throm-
bosis tendency that is not explained by other more common
entities and by a pathologic PT that may be prolonged or
shortened. Other tests, such as reptilase time and fibrinogen
analysis, are needed for confirmation. Acquired dysfibrino-
genemia is caused by diseases of the liver or biliary tract (cir-
rhosis, liver failure, acetaminophen overdose, obstructive
jaundice). It can also be a paraneoplastic phenomenon in
the case of hepatoma or renal malignancies. It is unknown
if acquired dysfibrinogenemia is an independent risk factor
for bleeding or thrombosis. Hypofibrinogenemia can be
caused by liver disease resulting in decreased fibrinogen
levels or by consumptive processes such as DIC or coagulo-
pathy of acute trauma.
The aPTT is prolonged by deficiencies of factors XII, XI,
IX, and VIII; by lupus anticoagulant; and by vWD. Congen-
ital factor XII deficiency is relatively frequent in Asians, but
it does not lead to increased bleeding, even in the total
absence of the factor. Factor XI deficiency is generally a rare
disorder (1 in 1 million), except among Ashkenazi Jews, in
whom the prevalence is 12%.72 It is an autosomal recessive
bleeding disorder detectable by a prolongation of aPTT char-
acterized by injury-related hemorrhage.73 It is one of the
very few conditions that may go unnoticed until excessive
bleeding during surgery occurs. Preoperative transfusion
of fresh frozen plasma (FFP) can prevent hemorrhage. Defi-
ciencies of factors VIII and IX are known as hemophilia A
and B, respectively. These patients have a long-standing his-
tory of bleeding complications and are extremely unlikely to
be first diagnosed by a routine preoperative screening.
vWD leads to factor VIII deficiency, because vWF serves
as a carrier protein for this factor and prevents it from
destruction by circulating inhibitors. vWD results in a pro-
longed aPTT, with variable bleeding tendency, depending
on the amount and function of circulating vWF.74 It is
the most frequent inherited bleeding disorder, with a
prevalence as high as 2% in the general population accord-
ing to some studies.75 On the basis of patients referred for
bleeding, however, the prevalence has been estimated to
be 30 to 100 cases per 1 million.74 In types 1 and 2, the
bleeding tendency varies strongly and may even go unno-
ticed; in type 3 (complete or near-complete absence of the
factor), bleeding is severe and presents in the very early
stages of life.
Lupus anticoagulant can cause a prolongation of the
aPTT but normally does not affect PT.25 Paradoxically,
these patients have an increased risk for thrombotic compli-
cations and do not show increased bleeding risk unless
thrombocytopenia or decreased thrombin levels are present.
In this case, the PT is also prolonged.
POINT-OF-CARE TESTING
Standard laboratory tests (Hgb concentration, PT/aPTT, PC,
fibrinogen concentration) typically take at least 45 minutes
for processing and reporting, limiting their utility in an
intraoperative setting. Several POC tests are available,
allowing rapid estimates of Hgb and hematocrit and overall
hemostatic function using viscoelastic testing. In general,
POC tests for Hgb are not as accurate as standard laboratory
tests76 but can be used as an estimate for calculating intrao-
perative blood loss and can help guide intraoperative trans-
fusion decisions.
Viscoelastic POC testing includes methods such as
TEG (Haemonetics, Braintree, MA) and ROTEM (TEM
Innovations, Munich, Germany), which allow rapid
assessment of coagulation status and response to inter-
ventions such as blood product transfusion. TEG and
ROTEM are whole-blood assessments of the whole coag-
ulation process from initiation through fibrinolysis and
clot degradation, taking into account contributions from
platelets, clotting factors, and RBCs. Different types of
assays exist that use different activators, making mea-
surements not directly comparable; however, similar var-
iables with different nomenclature are obtained from
each assay (Box 10.5). The result of the assay produces
a tracing with different measurements indicating the dif-
ferent components of hemostasis.
A standard TEG tracing is seen in Fig. 10.6. Standard TEG
uses kaolin as a clotting activator, allowing measurement of
mostly intrinsic and common pathways. Reaction time, or R
Box 10.5 Measurements obtained by
thromboelastography and rotational
thromboelastometry.
TEG values ROTEM values
R value (reaction time) Clotting time (CT)
K value and α angle α Angle and clot formation time
(CFT)
Maximum amplitude Maximum clot firmness (MCF)
(MA)
Lysis 30 (LY30) Clot lysis (CL)
ROTEM, Rotational thromboelastometry; TEG, thromboelastography.

Alpha
angle MA
R K LY30
Coagulation Fibrinolysis
Fig. 10.6 Thromboelastographic tracing. (K: Kinetic time; LY30: lysis 30
minutes after MA; MA: maximum amplitude; R: reaction time. With per-
mission from O’Keeffe T, Joseph B. Coagulopathy in the critically ill patient.
In: Cameron JL, Cameron AM. Current Surgical Therapy. 12th ed. Phila-
delphia: Elsevier; 2017:1459–1466.)
value, represents time until the first measurable clot is
formed and represents enzymatic clotting activation. Pro-
longed R time is treated in most cases with FFP. K value
measures the interval from reaction time to a fixed value
of clot firmness, of the point at which the amplitude reaches
20 mm, reflecting cleavage of fibrinogen to fibrin by throm-
bin. The alpha angle measures the tangential line between
baseline and the beginning of the cross-linking process, also
dependent on conversion of fibrinogen to fibrin. Low K value
or alpha angle should be treated in most cases with cryopre-
cipitate or fibrinogen concentrates. Maximum amplitude is
a measure of overall clot strength resulting from maximal
platelet and fibrin interaction. Decreased maximum ampli-
tude is treated with platelets, cryoprecipitate for low fibrin-
ogen levels, or both. Finally, lysis 30 measures the degree of
clot lysis at 30 minutes. Above-normal values indicate
hyperfibrinolysis and can be treated with epsilon-
aminocaproic acid or tranexamic acid.77 The addition of
platelet mapping can determine the degree to which platelet
function is inhibited by aspirin or clopidogrel by measuring
reactivity of platelet activators with GPIIb/IIIa and adeno-
sine diphosphate (ADP) receptors.
TEG and ROTEM have been found to decrease blood prod-
uct transfusion, particularly when used with a transfusion
algorithm, which promotes rapid decision making,
decreases practice variability, and reduces unnecessary
transfusions.78–80 Particularly in the cardiac surgery and
liver transplant population, data show a reduction in blood
product use when using a transfusion algorithm,81 though
data on mortality outcomes are mixed. TEG has also been
shown to be helpful in the management of coagulopathy
in acute trauma.82 Additionally, case reports indicate the
utility of viscoelastic testing in following and correcting coa-
gulopathy for procedures such as epidural catheter and spi-
nal drain placement and removal, but these tests have not
yet been validated for these purposes.83–85
Management of Patients Under
Antiplatelet Therapy
Antiplatelet drugs offer a high degree of protection against
myocardial infarction, stroke, and peripheral vascular
occlusion. Interruption of antiplatelet agents, particularly
in the inflammation-inducing perioperative period, places
10 • Hematologic Risk Assessment 111
patients at high risk of thrombotic events and must be
weighed against the risk of increased surgical bleeding. Dual
antiplatelet therapy (DAPT) has become a key component in
the treatment of coronary artery disease (CAD), and a large
number of patients are maintained on varying combinations
of antiplatelet medications for variable durations. While the
indications and recommendations for antiplatelet therapy
are outside the scope of this chapter, we discuss common
medications and their perioperative implications.
Common antiplatelet medications include aspirin; dipyr-
idamole; cilostazol; thienopyridines such as clopidogrel, pra-
sugrel, and ticagrelor; nonthienopyridine P2Y12 receptor
antagonists such as IV cangrelor; and IV GP IIb/IIIa recep-
tor antagonists such as abciximab, eptifibatide, and
tirofiban.37
• Aspirin irreversibly acetylates platelet cyclooxygenase-1
(COX-1), inhibiting the synthesis of the potent platelet
aggregator and vasoconstrictor thromboxane A2. Resto-
ration of platelet COX-1 activity depends on the genera-
tion of new platelets. There is no antidote to aspirin
except platelet transfusion. However, platelet replace-
ment is rarely indicated, because aspirin induces only
a weak inhibition of platelet function.
• Dipyridamole (inhibitor of adenosine deaminase and
phosphodiesterase) and cilostazol (phosphodiesterase III
inhibitor) both increase intracellular cyclic adenosine
monophosphate, inhibiting platelet aggregation via
increased protein kinase A.
• Thienopyridines block the P2Y12 component of ADP
receptors on platelets, preventing activation of the
GPIIb/IIIa receptor complex and subsequent platelet acti-
vation and aggregation. Unlike the irreversible inhibition
caused by clopidogrel and prasugrel, ticagrelor is a revers-
ible, noncompetitive antagonist of the P2Y12 receptor.
• Cangrelor is a reversible, nonthienopyridine P2Y12
receptor antagonist with a very short half-life. After dis-
continuation of a continuous infusion, platelet function
returns to normal within 1 hour.
• The GPIIb/IIIa receptor antagonists target the final common
pathway of platelet aggregation. These potent antiplatelet
agents are usually administered intravenously for patients
undergoing percutaneous coronary interventions (PCIs) to
prevent early acute stent thrombosis. All GPIIb/IIIa antago-
nists are reversible, varying in their half-lives and affinity for
the GPIIb/IIIa receptor. Abciximab has a half-life of 23 hours;
its molecules are redistributed among circulating, newly
formed, and probably transfused platelets. Eptifibatide and
tirofiban have considerably lower receptor affinity with rapid
plasma clearance; platelet function returns to near baseline
after 4 to 8 hours of drug cessation.
ASPIRIN
Unless otherwise contraindicated, lifelong aspirin is recom-
mended for all patients with CAD, cerebrovascular disease,
peripheral occlusive disease, or prior venous thromboembo-
lism (VTE).86,87 Withdrawal of aspirin in patients with sta-
ble CAD has been shown to be associated with a fourfold
increase in the rate of death compared with patients appro-
priately treated,88 with aspirin withdrawal preceding 10%
112 PART II • Preoperative Assessment
of all acute cardiovascular syndromes.89 In a meta-analysis
of 135,000 high-risk patients, aspirin was associated with a
22% reduction in vascular deaths.90 Data supporting aspi-
rin use for primary prevention, however, is less robust,
showing a modest reduction in risk of myocardial infarction,
stroke, and colon cancer but increased rates of gastrointes-
tinal bleeding and hemorrhagic stroke.91
The POISE-2 trial (PeriOperative ISchemic Evaluation-2
Trial) found increased rates of major bleeding without
decreased rates of cardiovascular events or mortality among
patients undergoing noncardiac surgery randomized to take
perioperative aspirin.92 However, methodologic issues make
it difficult to draw conclusions regarding aspirin discontin-
uation in patients at high risk of adverse perioperative car-
diovascular events.87 The 2014 American College of
Cardiology/American Heart Association (ACC/AHA) guide-
lines recommend, for nonstented patients with high risk for
CAD or cerebrovascular disease, that it may be reasonable to
continue aspirin when the risk of potential increased cardiac
events outweighs the risk of increased bleeding.93 For
patients with prior acute coronary syndrome (ACS) or
PCI, aspirin monotherapy should not be stopped in the peri-
operative period.94
DUAL ANTIPLATELET THERAPY
There are currently five medications available for com-
bined use in DAPT: aspirin, clopidogrel, prasugrel, ticagre-
lor, and cangrelor.95 Multiple studies have shown the
superiority of DAPT over aspirin therapy alone in decreas-
ing risk of stroke, myocardial infarction, and mortality fol-
lowing ACS and PCI.95 Cessation of antiplatelet therapy is
the major independent predictor of stent occlusion. It is
associated with a two- to fivefold increase in mortality
and infarction rate, a 20% incidence of thrombosis in those
with uncoated stents, and 20% to 45% mortality in
patients with drug-eluting stents (DESs).96–98 Following
PCI, DAPT duration is determined by the type of stent
placed: 6–12 months for DESs and at least 1 month for bare
metal stents.99 However, studies of the newer-generation
DESs suggest they may require a shorter minimum dura-
tion of DAPT, with multiple studies investigating optimal
treatment length.
For elective noncardiac surgery, the prior recommenda-
tion to delay surgery for 1 year following DES placement
has been modified to “optimally at least 6 months delayed”
to avoid the need to disrupt DAPT.99 Similarly, the recom-
mendation that elective noncardiac surgery in patients trea-
ted with DES may be considered after 180 days has been
modified to “after 3 months.”99 Figure 10.7 shows the treat-
ment algorithm for timing of elective noncardiac surgery in
patients with DESs. For patients receiving DAPT, if P2Y12
therapy needs to be held, aspirin should be continued
throughout the perioperative period if possible, and P2Y12
therapy should be restarted postoperatively as soon as pos-
sible. There has been no convincing clinical evidence sug-
gesting a benefit to “bridging” patients through the
perioperative period on IV antiplatelet agents when DAPT
must be temporarily discontinued.99 It has been standard
practice to discontinue therapy 7–10 days before surgery
to allow regeneration of new platelets and minimize periop-
erative blood loss.100
The decisions regarding surgical timing and discontinua-
tion of DAPT are complex and involve weighing the risks of
the surgical procedure, risk of delaying surgery, risks of
ischemia and stent thrombosis, and the risk and conse-
quences of bleeding. This highly individualized decision is
best made by involving the surgeon, anesthesiologist, cardi-
ologist, and patient.99
In the setting of urgent or emergent surgery following
recent PCI before completion of DAPT, an interdisciplinary
approach is mandatory, keeping in mind the same consider-
ations described previously. For low bleeding risk, DAPT can
be continued, whereas DAPT should be discontinued for
intermediate to high bleeding risk procedures while con-
tinuing aspirin monotherapy if possible.95 Platelet transfu-
sion may be necessary in this situation if DAPT cannot be
stopped soon enough prior to surgery.
In patients undergoing cardiac surgery on cardiopulmo-
nary bypass and systemic heparinization, continuation of
DAPT was found to increase surgical bleeding, chest tube
output, transfusion rate, and length of hospital stay by
about 50%.101 According to the 2011 ACC/AHA guidelines
for coronary artery bypass grafting (CABG), patients on
DAPT undergoing elective CABG should be continued on
preoperative aspirin with discontinuation of clopidogrel
and ticagrelor at least 5 days prior to surgery and discontin-
uation of prasugrel at least 7 days prior to surgery. For
urgent CABG, clopidogrel and ticagrelor should be discon-
tinued at least 24 hours prior to surgery to reduce major
bleeding complications. For patients on GPIIb/IIIa inhibitors
referred for CABG, eptifibatide and tirofiban should be dis-
continued at least 2–4 hours prior to surgery, and abcixi-
mab should be discontinued at least 12 hours prior to
surgery.102
Management of Patients on
Anticoagulation Therapy
As the population ages, increasing numbers of patients in
the United States are being placed on anticoagulation ther-
apy. Of patients aged 65 years and older, an estimated 9%
have atrial fibrillation and require evaluation for lifelong
anticoagulation.103 Other common indications include
VTE and mechanical heart valves. In addition to warfarin,
the historical mainstay of therapy, a new class of direct oral
anticoagulants (DOACs) is expanding,104 with each agent
and indication conferring its own considerations for periop-
erative management. We discuss the management of the
different anticoagulation agents during the perioperative
period. Similar to antiplatelet medications, the management
of these medications commonly involves close communica-
tion between anesthesiologist, surgeon, and cardiologist or
hematologist.
Common anticoagulants include vitamin K antagonists
(warfarin); unfractionated heparin (UFH); low-molecular-
weight heparins (LWMHs) such as dalteparin, enoxaparin,
and fondaparinux; direct factor Xa inhibitors such as rivar-
oxaban, apixaban, edoxaban, and betrixaban; and direct
thrombin inhibitors such as lepirudin, bivalirudin, argatro-
ban, and dabigatran. Of these agents, the most common oral
agents used for long-term outpatient anticoagulation are
warfarin, dabigatran, rivaroxaban, and apixaban.
 10 • Hematologic Risk Assessment 113

Pateints treated with PCI undergoing

elective noncardiac surgery

BMS treated DES treated

with DAPT with DAPT

0d

<30 d ≥30 d
30 d since BMS since BMS
implantation implantation

Class I:
Class III: Harm <3 mo since DES
Proceed with
delay surgery implantation
surgery
3 mo
3–6 mo since DES
implantation,
Class III: Harm
discontinue DAPT;
delay surgery
delayed surgery risk is
great than stent
thrombosis risk
6 mo ≥6 mo
Class IIb: since DES
Proceeding with implantation,
surgery may be discontinue
considered DAPT

Class I:
Proceed with
surgery
Fig. 10.7 Coronary stent management. (With permission from Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of
dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on
Clinical Practice Guidelines. J Thorac Cardiovasc Surg. 2016;152(5):1243–1275.) BMS: Bare-metal stent; DAPT: dual antiplatelet therapy; DES: drug-eluting stent;
PCI: percutaneous coronary intervention.

UFH works by accelerating the activity of antithrombin.
UFH is commonly used as an IV infusion titrated to a goal
PTT for inpatients, as a bridging therapy, or in subcutane-
ous dosing for VTE prophylaxis. Heparin, a highly negatively
charged molecule, is readily reversed by protamine, a highly
positively charged molecule, making it ideal for treating
inpatients with a potential need for anticoagulation rever-
sal. Therapeutic dosing of UFH is typically administered
intravenously, making it impractical for use as a long-term
anticoagulant.104 Subcutaneously dosed LMWHs can be
used therapeutically in an outpatient setting but are not
ideal for long-term anticoagulation with the exception of
use in cancer-related thrombosis, where it has been shown
to be superior to warfarin.104
Warfarin works by competitively inhibiting vitamin K
reductase, leading to decreased amounts of reduced vitamin
K, the active form of vitamin K necessary for synthesis of
coagulation factors II, VII, IX, and X. Warfarin effect is mea-
sured via international normalized ratio (INR), a derivative
of PT, with an INR of 2–3 corresponding to approximately
10%–20% of coagulation factor activity.104 Due to a narrow
therapeutic window and varying effects of factors such as
diet, studies estimate that the time patients spend in the
therapeutic window is approximately 60% at best.104 While
the long-term bleeding risk of warfarin is cited at 3% per
year, it is also readily reversed with vitamin K, FFP, and pro-
thrombin complex concentrate (PCC).
The DOACs work by reversibly binding to the active site of
specific coagulation factors, currently factor IIa or Xa. These
agents were designed to eliminate the need for monitoring,
and while they will affect PT and PTT testing, the effect
occurs in a nonlinear relationship, making traditional coag-
ulation testing unusable for monitoring.
Dabigatran was the first DOAC in use and targets factor
IIa, causing dose-dependent thrombin inhibition. Dosing is
twice daily, and it is largely cleared renally; a creatinine
clearance <30 mL/min nearly doubles its half-life from
12–15 hours to >24 hours. While routine thrombin time
114 PART II • Preoperative Assessment
cannot be used to monitor therapeutic effect, a negative
thrombin time does indicate that clinically significant blood
levels of dabigatran are not present for the purposes of sur-
gical clearance.104
Rivaroxaban works by targeting factor Xa and is dosed
once daily. Drug excretion is two-thirds renal and one-third
hepatobiliary. A rivaroxaban-calibrated anti-Xa activity
assay can be used to measure rivaroxaban concentration.
However, the absence of anti-Xa activity on a standard
assay serves as a reasonable indicator of clinically significant
drug absence for surgical clearance.104
Apixaban is also a factor Xa inhibitor, but it is dosed twice
daily. Similar to rivaroxaban, an apixaban-calibrated anti-
Xa assay can be used for anti-Xa monitoring. Drug elimina-
tion is 25% renal and 75% hepatobiliary, making it better
tolerated by patients with renal impairment.104
While the newer DOACs have certain advantages, such
as fast onset (1–4 hours), ease of use, and freedom from lab-
oratory testing, they also come with the disadvantages of
difficulty in monitoring with traditional coagulation tests,
difficulty in managing bleeding, and challenges with periop-
erative management.104,105
Similar to patients on antiplatelet medications, perioper-
ative management of patients on anticoagulants involves
balancing the risks of surgical bleeding with the risks of
thromboembolism in the face of holding antithrombotics.
While minor surgeries may be able to be performed without
interrupting therapy, continuation of anticoagulants signif-
icantly increases the risk of major bleeding, thus necessitat-
ing careful planning regarding need for and timing of
discontinuation and determining the need for bridging
therapy.
The American College of Chest Physicians (ACCP) has
published evidence-based guidelines for the perioperative
management of antithrombotic medications.100 General
recommendations are that patients at moderate to high risk
of thromboembolism should receive bridging therapy,
whereas low-risk patients do not require bridging. Further,
Table 10.3 Suggested risk stratification for perioperative thromboembolism.
INDICATION FOR WARFARIN THERAPY
Risk
stratum Mechanical heart valve
High - Any mechanical prosthesis
- Any caged-ball or tilting disc aortic valve
prosthesis
- Recent (within 6 months) stroke or transient
ischemic attack
Moderate - Bileaflet aortic valve prosthesis and one or more
of the following risk factors: atrial fibrillation,
prior stroke or transient ischemic attack,
hypertension, diabetes, congestive heart failure,
age >75 years
Low - Bileaflet aortic valve prosthesis without atrial
fibrillation and no other risk factors for stroke
CHADS2, Congestive heart failure, hypertension, age 75 years, diabetes mellitus, and stroke or transient ischemic attack; VTE, venous thromboembolism.
With permission from Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S–e350S.
resumption of antithrombotic therapy should occur
24 hours postoperatively in patients at low bleeding risk,
whereas those at high bleeding risk should wait 48–
72 hours.100
The ACCP guidelines suggest a risk stratification table
(Table 10.3) based on patients with mechanical heart
valves, chronic atrial fibrillation, and history of VTE. These
guidelines define high risk as >10% annual risk for throm-
boembolism, moderate risk as 5%–10% annual risk, and low
risk as <5% annual risk for thromboembolism.100 The
ACCP recommendations for perioperative management of
warfarin therapy are summarized here100:
• Discontinue warfarin 5 days prior to surgery
• Assess INR 1–2 days prior to surgery; if INR is >1.5,
consider 1–2 mg oral vitamin K
• For high thromboembolism risk patients, bridge with
therapeutic subcutaneous LMWH (preferred) or IV UFH.
The last dose of LMWH should be given 24 hours preop-
eratively at half the daily dose. UFH should be discontin-
ued 4–6 hours preoperatively.
• For moderate thromboembolism risk patients, the decision
for bridging therapy is made on the basis of an assessment
of individual-patient and surgery-related factors.
• For low thromboembolism risk patients, no bridging
is needed.
• In the case of urgent or emergent surgery, consider 2.5–
5 mg oral or IV vitamin K. For immediate reversal, con-
sider FFP or PCC.
• Resume warfarin therapy approximately 12–24 hours
after surgery (evening of the day of surgery or the next
morning) and when there is adequate hemostasis.
• In patients who are receiving bridging therapy with
therapeutic LMWH and undergoing a high bleeding risk
surgery, resume the therapeutic dose of LMWH 48–
72 hours after surgery when adequate hemostasis has
been achieved.
• In patients receiving bridging therapy with UFH
undergoing high bleeding risk surgery, IV UFH should
Atrial fibrillation VTE
- CHADS2 score of 5 or 6 - Recent (within 3 months) VTE
- Recent (within 6 months) - Severe thrombophilia (e.g., deficiency of
stroke or transient protein C, protein S, or antithrombin;
ischemic attack antiphospholipid antibodies; multiple
- Rheumatic valvular heart abnormalities)
disease
- CHADS2 score of 3 or 4 - VTE within the past 3–12 months
- Nonsevere thrombophilia (e.g., heterozygous
factor V Leiden or prothrombin gene mutation)
- Recurrent VTE
- Active cancer (treated within 6 months or
palliative)
- CHADS2 score of 0 to 2 - VTE >12 months previous and no other risk
(assuming no prior factors
stroke or transient
ischemic attack)
 10 • Hematologic Risk Assessment 115

be resumed without a bolus dose at the same infusion rate Table 10.5 Postoperative resumption of direct oral
as was used preoperatively 48–72 hours after surgery anticoagulants: a suggested approach.
when adequate hemostasis has been achieved.
Low bleeding risk High bleeding risk
On the basis of bleeding risk (see Table 10.1), drug half- Drug surgery surgery
life, and creatinine clearance, Spyropoulos and Douketis Dabigatran Resume on postoperative Resume on
proposed a strategy for preoperative drug withdrawal of day 1 (24 hours postoperative day 2-3
DOACs (Table 10.4).106 Their recommendations are based postoperatively), 150 mg (48–72 hours
on aiming for mild to moderate residual anticoagulation twice daily postoperatively),
150 mg twice dailya
at the time of surgery (<12%–25%) for low bleeding risk
patients and no to minimal residual anticoagulation at Rivaroxaban Resume on postoperative Resume on
the time of surgery (<3%–6%) for high bleeding risk day 1 (24 hours postoperative days 2–3
postoperatively), 20 mg (48–72 hours
patients.106 While specific reversal agents exist for both oral daily postoperatively), 20 mg
direct thrombin inhibitors and oral factor Xa inhibitors, dailyb
these are not recommended for the patient presenting for
Apixaban Resume on postoperative Resume on
elective surgery and therefore are not discussed here. day 1 (24 hours postoperative days 2–3
Resumption of anticoagulation following surgery must postoperatively), 5 mg (48–72 hours
consider bleeding risk associated with the procedure and twice daily postoperatively), 5 mg
the risk of thrombosis. This decision should be made in con- twice dailyb
junction with the surgical team. A suggested strategy by a
For patients at high risk of thromboembolism, consider administering a
Spyropoulos and Douketis for resuming DOACs is found in reduced dose of dabigatran (e.g., 110–150 mg once/day) on the evening
Table 10.5.106 The previous recommendations are largely after surgery and on the next day after surgery (first postoperative day).
b
based on indirect evidence and clinical experience but are Consider reduced dose (such as rivaroxaban 10 mg once/day or apixaban
meant to provide general guidance. Patient management 2.5 mg twice/day) on first 2 days postoperative in patients at high risk for
thromboembolism.
Adapted with permission from Spyropoulos AC, Douketis JD. How I treat
anticoagulated patients undergoing an elective procedure or surgery.
Table 10.4 Direct oral anticoagulant half-lives and Blood. 2012;120(15):2954–2962.
recommendations for preoperative hold.
Drug may vary on an individual basis using clinical judgment,
(dose)/ Patient renal Low bleeding High bleeding depending on patient characteristics, planned procedure,
half-life function risk risk
and patient values and preferences.
DABIGATRAN (150 MG TWICE DAILY)
T1/2 ¼ 14– Normal or mild Last dose: 2 days Last dose: 3 days NEURAXIAL BLOCKADE
17 hours impairment preoperatively preoperatively
(CrCl > (skip 2 doses) (skip 4 doses) Patients on antiplatelet or anticoagulant medications
50 mL/min)
require special consideration when planning neuraxial
T1/2 ¼ 16– Moderate Last dose: 3 days Last dose: blockade as part of anesthesia. Neuraxial techniques, defined
18 hours impairment preoperatively 4–5 days as spinal, epidural, or combined spinal-epidural procedures,
(CrCl 30– (skip 4 doses) preoperatively
50 mL/min) (skip 6–8 doses)
can be used as a primary anesthetic, for postoperative pain,
and in the management of chronic pain. Inappropriate man-
RIVAROXABAN (20 MG ONCE DAILY) agement of antiplatelet and anticoagulant medications
T1/2 ¼ Normal or mild Last dose: 2 days Last dose: 3 days increases the risk of complications associated with neuraxial
8–9 hours impairment preoperatively preoperatively procedures, the most important being epidural hematoma.
(CrCl > (skip 1 dose) (skip 2 doses) Epidural hematoma, while rare, is a potentially catastrophic
50 mL/min)
complication caused by spinal cord or cauda equina com-
T1/2 ¼ Moderate Last dose: 2 days Last dose: 3 days pression and ischemia from expanding hematoma, poten-
9 hours impairment preoperatively preoperatively tially leading to severe neurologic injury and paraplegia.
(CrCl 30– (skip 1 dose) (skip 2 doses)
50 mL/min) To reduce the risk of bleeding, timing of neuraxial tech-
niques and/or catheter removal should be coordinated with
T1/2 ¼ 9–10 Severe impairment Last dose: 3 days Last dose: 4 days appropriate discontinuation of medications and normaliza-
hours (CrCl 15– preoperatively preoperatively
29.9 mL/min) (skip 2 doses) (skip 3 doses) tion of hemostasis. Planning should include the specific med-
ication, dosing regimen, and timing of last dose with
APIXABAN (5 MG TWICE DAILY)
guidelines provided by the American Society of Regional
T1/2 ¼ 7–8 Normal or mild Last dose: 2 days Last dose: 3 days Anesthesia and Pain Medicine (Table 10.6).107
hours impairment preoperatively preoperatively
(CrCl > (skip 2 doses) (skip 4 doses)
For thrombocytopenic patients, no “safe” lower limit has
50 mL/min) been identified for performing neuraxial techniques.108
Rather, case series have informed the understanding of
T1/2 ¼ 17– Moderate Last dose: 3 days Last dose: 4 days
18 hours impairment preoperatively preoperatively the increasing risk of epidural hematoma associated with
(CrCl 30– (skip 4 doses) (skip 6 doses) falling PCs. In a review of 1525 patients, the upper bound
50 mL/min) of the 95% confidence interval for risk of epidural hematoma
was 0.2% for PCs of 70,000–100,000/μL, 3% for PCs of
CrCl, Creatinine clearance; T1/2, half-life.
Adapted with permission from Spyropoulos AC, Douketis JD. How I treat
50,000–69,000/μL, and 11% for PCs less than 49,000/μL,
anticoagulated patients undergoing an elective procedure or surgery. thus demonstrating the increasing risk associated with
Blood. 2012;120(15):2954–2962. lower PCs.109 Additionally, epidural techniques present a
116 PART II • Preoperative Assessment

Table 10.6 Recommended time intervals and laboratory tests before and after neuraxial puncture or catheter removal.a
Time to hold Time before restarting Time before
medication before medication after Time to hold restarting medication
puncture/catheter puncture/catheter medication before after catheter Laboratory
placement placement catheter removal removal tests

SC UFH (for 4–6 hours Immediately 4–6 hours Immediately Platelets during
prophylaxis, 12 hours (and Unknown risk. Assess risk/ Unknown risk. Assess Immediately treatment for
15,000 IU/day) assess coagulation) benefit. risk/benefit >5 days
SC UFH (for
prophylaxis,
>15,000 IU/day)
UFH (for IV 4–6 hours and normal 1 hour 4–6 hours and normal 1 hours aPTT, ACT,
treatment) coagulation status Not recommended coagulation status Immediately platelets
SC 24 hours and normal during indwelling Not recommended
coagulation status catheter during indwelling
catheter
Daily LMWH (for 12 hours At least 12 hours 12 hours At least 4 hours, no Platelets during
prophylaxis) earlier than 12 hours treatment for
after needle/catheter >5 days
placement
LMWH twice 12 hours No earlier than 12 hours Remove catheter prior to At least 4 hours, No Platelets during
daily (for following needle restarting earlier than 12 hours treatment for
prophylaxis) placement after needle/catheter >5 days
Remove catheter prior to placement
restarting
LMWH (for 24 hours 24–72 hours Remove catheter prior to 4 hours Platelets during
treatment) 24 hours for low bleeding restarting treatment for
risk surgery; 48–72 hours >5 days
after high bleeding risk
surgery
Remove catheter prior
to restarting
Fondaparinux 36–42 hours 6–12 hours Avoid medication with 6 hours Anti-factor Xa,
Avoid medication with indwelling catheter standardized for
indwelling catheter specific agent
Rivaroxaban 72 hours 6 hours 22–26 hours or check 6 hours Anti-factor Xa,
Remove indwelling anti-factor Xa assay standardized for
catheters before (if unanticipated dose specific agent
restarting given with indwelling
catheter)
Apixaban 72 hours 6 hours 26–30 hours or check 6 hours Anti-factor Xa,
Remove indwelling anti-factor Xa assay standardized for
catheters before (if unanticipated dose specific agent
restarting given with indwelling
catheter)
Dabigatran 72 hours 6 hours 34–36 hours or 6 hours Thrombin time
(up to 120 hours if Remove indwelling dTT/ECT testing or dilute
CrCl 30–49 mL/min) catheters before (if unanticipated dose thrombin time
restarting given with indwelling
catheter)
Warfarin 5 days and INR within No delay INR <1.5: remove No delay INR
normal range For patients on low dose 12–24 hours after Continue neurologic
therapy, monitor INR daily dose given assessment at least
Routinely perform 1.5 < INR < 3.0: 24 hours following
neurologic evaluations Indwelling catheter may
be maintained with
caution
INR >3.0: hold warfarin
or reduce dose
Hirudins Avoid neuraxial aPTT
(desirudin/ techniques
bivalirudin)
Argatroban Avoid neuraxial aPTT, ACT
techniques
Aspirin No restriction No restrictions No restrictions No restrictions
 Table 10.6 Recommended time intervals and laboratory tests before and after neuraxial puncture or catheter removal—cont’d
Time to hold Time before restarting
medication before medication after
puncture/catheter puncture/catheter
placement placement
Clopidogrel 5–7 days Immediately, if no loading
dose and 24 hours
postoperatively
If loading dose required,
wait 6 hours after needle
placement
Ticlopidine 10 days Immediately, if no
loading dose and
24 hours postop
If loading dose required,
6 hours after needle
placement
Prasugrel 7–10 days Immediately, if no loading
dose and 24 hours
postoperatively
If loading dose required,
6 hours after catheter
removal
Remove catheter prior to
restarting
Ticagrelor 5–7 days Immediately, if no
loading dose and
24 hours postop
If loading dose
required, 6 hours
after catheter removal
Remove catheter prior to
restarting
Cangrelor At least 3 hours 8 hours
Remove catheter prior to
restarting
Abciximab 24–48 hours Avoid (contraindicated
within 4 weeks of surgery)
Dipyridamole 24 hours 6 hours
Remove catheter prior to
restarting
Cilostazol 48 hours 6 hours
Remove catheter prior to
restarting
NSAIDs No restrictions No restrictions
dTT, Dilute thrombin time; ECT, ecarin clotting time; SC, subcutaneous. ACT: Activated clotting time; aPTT: activated partial thromboplastin time; CrCl: creatinine
clearance; INR: international normalized ratio; IV, intravenous; LMWH: low-molecular-weight heparin; NSAID: nonsteroidal antiinflammatory drug;
UFH: unfractionated heparin.
a
All time intervals refer to patients with normal renal function. Prolonged time interval in patients with hepatic insufficiency.
Adapted with permission from Horlocker TT, Vandermeuelen E, Kopp SL, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy:
American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Fourth Edition). Reg Anesth Pain Med. 2018;43(3):263–309.
higher risk of significant bleeding than spinal techniques.
The decision to proceed with neuraxial techniques in throm-
bocytopenia must be individualized, particularly as PC falls
below 70,000/μL and the risk of complications increases,
taking into account the risks of the procedure versus
alternatives.
Summary
Assessment of hematologic risk must be considered on an
individual-patient basis, taking into account a patient’s risk
for bleeding and thrombosis, need for RBC transfusion,
intrinsic hemostatic ability, and management of antiplatelet
and/or antithrombotic medications. The goal of HRA is to
minimize transfusion needs and prevent complications such
Time before
Time to hold restarting medication
medication before after catheter Laboratory
catheter removal removal tests
Catheter may be Immediately if no
maintained 1–2 days loading dose
after restarting if no If loading dose
loading dose used required, wait 6 hours
after catheter removal
Catheter may be Immediately if no
maintained 1–2 days loading dose
after restarting if no If loading dose
loading dose used required, wait 6 hours
after catheter removal
Avoid medication while Immediately if no
catheter in place loading dose
If loading dose, wait
6 hours after catheter
removal
Avoid medication while Immediately if no
catheter in place loading dose
If loading dose, wait
6 hours after catheter
removal
Avoid medication while 8 hours
catheter in place
Avoid Avoid
Avoid 6 hours
Avoid medication while 6 hours
catheter in place
No restrictions No restrictions
as hemorrhage and thrombosis. This essential component of
the preoperative assessment often involves close communi-
cation with the patient as well as the surgical team, cardi-
ologist, hematologist, or primary care provider to coordinate
preoperative optimization and medication management.
Fortunately, guidelines and recommendations exist to help
patients and clinicians navigate the perioperative course
while minimizing risk.
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 11 Prevention of Ischemic Injury
in Cardiac Surgery
CHRISTOPHER R. BURKE and EDWARD D. VERRIER
The development of the heart-lung machine by John and
Mary Gibbon over a half-century ago ushered in the modern
era of cardiac surgery. Prior to 1953, the emerging field of
heart surgery was limited primarily to brief operations con-
ducted on the aorta, great vessels, pericardium, and cardiac
surface, all of which were performed without interrupting car-
diac function; valvular repairs were often performed with a
blind sweep of the surgeon’s finger. The introduction of the
Gibbon oxygenator made possible the bloodless, motionless
field necessary to perform anything beyond the simplest of
cardiac repairs.1–3 In the previous decades, advances in the
commercial production of the natural anticoagulant heparin
had made that drug safe, inexpensive, reversible, and readily
available. Together, these two developments provided the
foundation for the modern surgical treatment of cardiovascu-
lar disease.4
Interestingly, despite his initial success with extracorporeal
oxygenation (repair of an atrial septal defect in an 18-year-old
woman),1 Gibbon’s next three patients all died, and he never
again used the machine. Clearly, oxygenating blood was only
one piece of the puzzle, and strategies needed to be developed to
keep the patient safe while on the heart-lung machine. This
chapter attempts to summarize the major developments in
myocardial protection. Some, such as hypothermia, trace their
history back to the early days of the field. Others, such as del
Nido cardioplegia, can trace their roots to congenital cardiac
surgery prior to receiving widespread acceptance into adult
cardiac surgery. Still others, such as ischemic preconditioning
(IPC), have largely fallen out of favor. Taken together, these
strategies have led to tremendous decreases in the morbidity
and mortality associated with heart surgery, and they have
enabled cardiac surgery, particularly coronary artery bypass
grafting (CABG), to become one of the most widely and
successfully performed procedures in the world.
Despite the myriad advancements in the prevention of
ischemia during cardiac surgery, no universally applicable
myocardial protection technique has been identified,5 and
the ideal method for myocardial protection remains to be
established.6 In part, this may be due to the overall success
of four generations of cardiac surgeons in reducing the mor-
bidity and mortality associated with cardiac surgery to very
low levels, which makes demonstrating a significant differ-
ence between one technique and another more challenging.
To a greater extent, the explanation stems from our relatively
recent acknowledgment of the fact that each cardiac surgery
patient is unique, and thus a given patient’s response to car-
diac surgery, including, in particular, cardiopulmonary
bypass (CPB), reflects individual biological variability. Thus,
no single intervention or strategy or protocol in isolation
can be expected to succeed for every patient.7
Another explanation for the many ongoing controversies
in myocardial protection is the uniqueness of each operating
surgeon. In the past 2 decades, medical societies and institu-
tions the world over have attempted a paradigm shift in
which practice patterns are grounded in evidence-based med-
icine. This model deemphasizes intuition and unsystematic
clinical experience as sufficient grounds for clinical decision
making and stresses the examination of evidence from ratio-
nal, hypothesis-driven clinical and experimental research.8
However, recent surveys of practice patterns in the United
States9 and Great Britain10 belie the fact that, to a great
degree, cardiac surgery is still as much an art as it is a science.
Indeed, a cursory review of the Cochrane Library, an interna-
tionally recognized, evidence-based health-care database,
reveals minimal information on CABG. Similarly, Bartels
and colleagues recently conducted a study of the scientific evi-
dence supporting 48 major principles that are currently
applied for CABG performance, and their evaluation found
that the data concerning the effectiveness and safety of every
one of these key principles was insufficient in both amount and
quality to serve as a basis for practical, evidence-based guide-
lines.11 With the recent introduction of larger databases such
as the Society of Thoracic Surgeons cardiovascular database,
and even more recently the interest in artificial intelligence,
we can expect more clarity in the future in terms of informa-
tion moving toward knowledge and stricter guidelines.
Nevertheless, despite the significant variation that exists
between different countries, different institutions, and even
different individuals within institutions, some universally
accepted tenets can be identified. Recognizing that an
efficiently executed and technically superior operation per-
formed on an appropriate patient under the right circum-
stances is perhaps the greatest form of myocardial
protection, in this chapter we attempt to highlight these pro-
tective strategies, and the data (or lack thereof) supporting
them, in an effort to develop an evidence-based approach to
prevention of ischemic injury during cardiac surgery.
Perioperative Ischemia
Prevention Strategies
The success of any operation requires a coordinated plan
of care that begins prior to the patient entering the operat-
ing room and continues throughout the postoperative
period. As with any surgical intervention, the ideal medical
management of stable and unstable coronary artery dis-
ease, heart failure, and acute myocardial infarction (MI)
continues to evolve and improve, as does the care of the
postoperative cardiac patient. The appropriate use of
123
124 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
medicines such as beta-blockers, afterload-reducing agents,
statins, and antiplatelet agents is essential, but pharmaco-
therapy is just one facet of cardiac care. Appropriate vigi-
lance must be directed toward patient-controlled factors
such as dietary modification, smoking cessation, glucose
control, and exercise, because these factors may doom
a technically perfect operation, hastening the onset of
graft failure and the recurrence of ischemia. Numerous
large, well-conducted clinical trials are available to guide
the internist, cardiologist, or intensive care specialist who
may be primarily responsible for directing care of the car-
diac patient outside of the operating room, and a detailed
discussion of the perioperative management of ischemic
heart disease is beyond the scope of this chapter. However,
there are strategies in which the surgical team plays a cen-
tral role and which therefore merit brief discussion here.
OPTIMAL TIMING OF CARDIAC SURGERY AFTER
ACUTE MYOCARDIAL INFARCTION
The appropriate timing of revascularization surgery in the
setting of acute MI has been the subject of uncertainty since
the earliest days of CABG. In contrast to the patient with sta-
ble coronary artery disease or unstable angina, to whom the
general rule of “sooner is better” applies, the traditional
dogma for patients who have experienced MI is to delay sur-
gical intervention if possible. For patients with evidence of
valvular or papillary muscle dysfunction, ongoing ischemia
despite maximal medical therapy, or cardiogenic shock,
high mortality in the absence of surgery warrants the risk
of immediate surgical intervention, either CABG or implan-
tation of a ventricular assist device (see Chapter 14). Less
clear is the best course of action with a relatively stable
patient who has recently experienced an acute MI.
Over the past half-century, numerous attempts have been
made to identify the appropriate timing of operative inter-
vention after MI. In 1974, Cooley and colleagues noted a
striking temporal association with in-hospital mortality of
CABG patients after MI. When CABG was performed within
7 days of MI, mortality was 38%; when performed 31 to
60 days after MI, mortality fell to 6%.12 This study, along
with several others performed in the 1970s with similar out-
comes,13,14 led a generation of cardiac surgeons to delay
operative management of the acute MI patient. As the man-
agement of acute MI evolved in the 1980s and 1990s, par-
ticularly with the advent of new thrombolytic therapy,
platelet inhibitors, percutaneous transluminal coronary
angioplasty, coronary stenting, and intra-aortic balloon
pumps (IABPs), a number of investigators attempted to
readdress this question of timing of CABG after MI. Although
contemporary data suggest that perhaps such a long delay
between MI and CABG is not necessary, few of these studies
were randomized, and results have been disparate.15–20
Several large retrospective analyses have been used to create
risk models to suggest that, when possible, waiting 7 days
after MI may lead to improved outcomes.21–23 Other investi-
gators have argued that, in the setting of a nontransmural
(non–Q-wave) MI, patients may undergo CABG relatively
safely at any time, and that even in the case of a transmural
(Q-wave) infarct, a delay of only 48 to 72 hours may be suf-
ficient.24–26 Early revascularization after transmural MI with
impaired regional or global ventricular function has been
shown consistently to have a higher operative mortality
and worse long-term benefits in survival. Therefore, no firm
conclusion can be made regarding the optimal timing of
CABG in the setting of acute MI; the available evidence sug-
gests that a delay of 3 to 7 days is appropriate, especially with
impaired ventricular function. As mechanical assist devices
increase physicians’ abilities to manage the sequelae of MI,
particularly cardiogenic shock, new questions have arisen
as to whether the initial surgical intervention should be defin-
itive revascularization or insertion of a temporary assist
device to lengthen the window of time between MI and
surgery.
Intraoperative Ischemia-
Prevention Strategies
NONOPERATIVE STRATEGIES
Anesthesia Considerations
The concept of cardiac anesthesia has been in development
since the introduction of the CPB machine in the 1950s, and
the modern cardiac anesthesiologist is an invaluable mem-
ber of the cardiac surgery team. Because the focus of the car-
diac surgeon while in the operating room must be devoted to
the performance of a technically superior operation, the car-
diac anesthesiologist, whose tasks include surveying
numerous monitors and ongoing laboratory results, is in
perhaps the best position to identify the subtle changes in
a patient’s status that may signify myocardial injury or
other impending complications. We will now review a num-
ber of the specific tools that may be used to identify ischemia,
as well as some of the nonoperative remedies employed to
prevent or treat ischemia in the setting of cardiac surgery.
Monitoring for ischemia. Routine intraoperative moni-
toring during cardiac surgery includes temperature, pulse
oximetry, capnography, surface electrocardiography, and
noninvasive blood pressure monitoring. More invasive
methods typically employed during cardiac surgery include
an arterial line for continuous blood pressure monitoring
and repeated blood sampling, a central venous catheter to
measure central venous pressure, and use of a Swan-Ganz
pulmonary artery catheter (PAC). Transesophageal echo-
cardiography (TEE) is also an invaluable adjunct in the oper-
ating room, especially with valvular surgery.
The PAC provides potentially valuable information
regarding pulmonary arterial pressure, pulmonary capillary
wedge pressure (a surrogate of left-sided filling pressure),
cardiac output, mixed venous saturation, and both systemic
and pulmonary vascular resistance, all of which can be used
to guide management directed at improving perfusion or
optimizing hemodynamic performance after cardiotomy.27
Nevertheless, use of the PAC has been a topic of great debate
ever since its introduction into clinical practice, and the con-
troversy continues to rage today.28 Almost 20 years ago,
several published studies failed to detect a benefit from the
use of PACs in the setting of acute myocardial ischemia/
infarction.29,30 Similarly, in 1989, Tuman and colleagues
published their study showing no differences in outcome
when PACs were used during CABG.31,32 In 1996, the

SUPPORT trial (Study to Understand Prognoses and Prefer-
ences for Outcomes and Risks of Treatments) reported that
PAC use was associated with longer hospital and intensive
care unit (ICU) stays, significantly increased costs, and
increased mortality, including a 1.5-fold increase in the rel-
ative risk of death in postoperative patients.33 In the ensuing
discussions, some called for a moratorium on continued use
of the PAC.34 However, attachment to the device by most
practitioners proved strong, and, with evidence that the
PAC was a useful tool for identifying perioperative ische-
mia,35,36 a more measured approach was adopted. Never-
theless, even the staunchest of PAC supporters recognized
that nonselective, routine use of the PAC was not justified.27
Today, the decision to place a PAC preoperatively should be
made between the surgical and anesthetic teams, and
important factors such as the type of operation and baseline
cardiac function will help guide this decision. TEE provides
important data on valvular and cardiac function and is a
common adjunct used in the cardiac operating room. Advo-
cates of TEE point to the fact that it is generally safe and
can provide nearly all the same data as the PAC, plus
additional information on wall motion, ejection fraction,
stroke volume, volume status, and valvular function not
ascertainable by any other method.37 Small, nonrando-
mized studies of TEE in the setting of CABG have shown
that TEE may be more important than PAC in guiding inter-
ventions involving fluid administration, vasoactive medica-
tions, and other anti-ischemia therapies,38 and that among
high-risk patients undergoing CABG, data provided by
TEE affected anesthetic or surgical management 50% of
the time.39
The reported safety and benefits of TEE notwithstanding,
debate similar to that surrounding the PAC has emerged.
Critics of TEE point to studies suggesting that unsuspected
TEE findings of major significance occur in less than 2%
of cases,40 that intraoperative interpretation by cardiac
anesthesiologists is widely variable and often does not con-
cur with later interpretation by cardiologists,38,41 and that,
like PAC, TEE has not been shown to improve outcomes.42
Critics also point to the fact that performing TEE may divert
the anesthesiologist from performing other critical tasks; in
one study, anesthesiologists’ response time to an alarm light
was 10 times slower when performing TEE than during
monitor observation.43
In sum, a range of modalities to detect ischemia are avail-
able to the modern cardiac anesthesiologist, and the wealth
of information provided by them is vast. In valvular cardiac
surgery, the importance of TEE is well established. However,
in the setting of myocardial revascularization, serious ques-
tions remain unanswered as to whether the information
these devices provide, and the way that clinical care is
guided by that information, is helpful as determined by mea-
suring important outcome variables such as morbidity, mor-
tality, and cost. Thus, judicious rather than routine use is
warranted.
Anesthetic agents. The goals of cardiac anesthesia are to
maintain hemodynamic stability and myocardial oxygen
balance, minimize the incidence and severity of ischemic
episodes, and facilitate prompt and uncomplicated separa-
tion from CPB and assisted ventilation.44 Throughout the
relatively short history of cardiac surgery, numerous
11 • Prevention of Ischemic Injury in Cardiac Surgery 125
anesthetic regimens have been developed, each with its
own proponents and each with purported advantages and
shortcomings. To date, however, no evidence exists that
any one technique can be claimed to be superior for patients
with cardiovascular disease.45
Anesthesia during the early years of cardiac surgery con-
sisted primarily of high-dose opioids, first morphine and later
synthetic opioids. In the 1970s, fentanyl gained widespread
acceptance for both induction and maintenance of anesthe-
sia because of its improved hemodynamic stability. Because
opiate-alone anesthesia was associated with an unaccept-
ably high risk of patient awareness (which can lead to
hypertension, tachycardia, and an attendant increase in
myocardial oxygen consumption), benzodiazepines were
added. More recently, propofol and volatile anesthetics have
become a mainstay in both the induction and maintenance
of cardiac anesthesia. Although some centers have gone
to an all-intravenous anesthetic technique, the reported
preconditioning protection provided by inhaled anes-
thetics46,47 has led some to advocate their continued and
routine use. In practice, the importance of anesthesia in
minimizing ischemic risk is perhaps most evident during
induction, when the potentially wide variation in blood
pressure may put overwhelming strain on an already
stressed heart. Standard therapy in the modern era, there-
fore, may include preinduction use of beta-blockade in addi-
tion to anxiolytics. Typical induction agents include a
combination of paralytic, analgesic, and anesthetic agents.
Anesthesia is maintained with a combination of analgesics
and anesthetic agents.
Metabolic Considerations
Systemic temperature. With the passing of Wilfred Gor-
don Bigelow in 2005, cardiac surgery lost the man referred
to as “the father of heart surgery in Canada.”48 After train-
ing at Johns Hopkins, Bigelow returned to the University of
Toronto and the Banting Research Institute in 1947, where
over the next 2 decades, he and his colleagues performed
much of the initial research that identified hypothermia
as a practical means by which the body could be protected
during the brief periods of circulatory arrest required for rel-
atively simple cardiac repairs. Prior to his investigations,
heart surgery was performed in an environment approach-
ing normothermia. The early CPB circuits did not include a
heat exchanger, and most of the temperature change that
did occur was passive. Indeed, if any attempt was made to
regulate the patient’s body temperature, it was to maintain
normothermia. Hypothermia was seen as detrimental to the
sick and wounded patients because of its adverse effects on
coagulation and because metabolic rates were actually
known to increase as patients got colder, largely caused
by shivering. Bigelow’s systematic studies of surface-
induced hypothermia, primarily using a canine model, were
the first to show that with shivering minimized by adequate
anesthesia, metabolism actually decreased in a linear rela-
tionship to core body temperature, with each 10°C temper-
ature drop corresponding to a roughly 50% reduction in
oxygen consumption.49–51
Although metabolism could be essentially halted at low-
enough temperatures, providing excellent protection for the
brain, temperatures below 28°C to 32°C led to cardiac and
pulmonary failure, limiting the early use of hypothermic
126 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
protection alone to cases requiring only very brief periods of
cardiac arrest. With the advent of CPB, however, tempera-
tures could be reduced to 10°C, thereby lengthening the
window of protection. Following these early observations
on systemic hypothermia, numerous others expanded on
the use of hypothermia and its application in cardiac sur-
gery. Shumway and colleagues soon demonstrated the addi-
tional benefit gained by topical cooling of the heart using
ice-cold saline lavage.52,53 This topical effect probably had
more impact on the more anteriorly situated, thinner-
walled right ventricle more prone to rewarming under the
operative lights and ambient room temperature than the
thicker left ventricle better protected by intravascular pro-
tection strategies. Other advances, including introduction
of the heat exchanger in the CPB circuit, made hypothermia
a mainstay of myocardial protection during the early years
of cardiac surgery.
Despite significant advances in our understanding of the
molecular processes involved in tissue metabolism, hypo-
thermia continues to be a central component of myocardial
protection strategies, particularly in the transplant
realm.54,55 The use of hypothermia, however, remains rel-
atively individualized between surgeons and institutions.
Some centers routinely actively cool during CPB; others sim-
ply let the patient’s temperature drift downward. Almost all
centers use topical cooling of the heart, although since the
early 1990s, a few investigators have advocated “warm
heart surgery.”56–58
Although significant debate persists, consensus is build-
ing that rather than the creation of severe hypothermia
or active maintenance of normothermia, the appropriate
temperature for the systemic circulation may be mild to
moderate hypothermia (approximately 28°C to 34°C). A
number of studies suggest that such a tepid strategy pro-
vides the best level of myocardial protection without the
consequences of deep hypothermia.59–69
Myocardial acid–base management. The influence of
intraoperative systemic pH status on CABG outcomes has
been studied primarily in relation to its influence on neuro-
protection. Most cardiac surgeons, and certainly cardiac
anesthesiologists, are familiar with the concept of α-stat ver-
sus pH-stat management strategies, a detailed discussion of
which is beyond the scope of this chapter. Less well under-
stood is the relationship between ischemia, myocardial
acid–base management, and non-neurologic outcomes.
Normal myocardial pH (7.2) is lower than systemic pH,70
and various studies have demonstrated that mild acidosis
(6.8 to 7.0) may actually protect the myocardium
during ischemia by decreasing cardiomyocyte energy
demands.71,72 However, myocardial acidosis during CABG
may be much more severe, with typical measurements of
pH 6.5 or lower, and may trigger cell death via apopto-
sis.73,74 Decreased myocardial pH is a consequence of inad-
equate coronary blood flow, which results in decreased
oxygen delivery, decreased washout of hydrogen ions, and
an attendant rise in myocardial tissue partial pressure of
carbon dioxide, and as such, it may be used as a surrogate
marker for myocardial ischemia. During cardiac surgery,
low coronary flow may occur as a result of preexisting
severe coronary artery stenosis, ineffective cardioplegia dur-
ing CPB, or inadequate revascularization.75 Myocardial
acidosis may be the sentinel event in a potentially devastat-
ing cycle in which inadequate oxygen delivery leads to
depressed myocardial function. This in turn necessitates
the use of inotropes, which themselves can lead to increased
myocardial oxygen consumption.76 If not reversed, irrevers-
ible cardiac injury can occur. As an indicator of underlying
ischemia, measurement of myocardial acidosis represents a
potentially valuable monitoring tool for guiding the care of
the cardiac surgery patient. Regular, repeated arterial blood
gas measurements are standard practice in cardiac surgery,
but they represent only static images of a constantly chang-
ing landscape and may not accurately reflect the condition
of the myocardium. Current myocardial protection strate-
gies based on these intermittent measurements may be
insufficient.77 Several attempts have therefore been made
to develop real-time, continuous myocardial pH-measuring
devices.78 Continuous blood gas monitors, for example,
have been credited with decreasing the need for intraopera-
tive pacing and cardioversion, decreasing the length of post-
operative mechanical ventilation, and decreasing the length
of ICU stay.79
In a series of studies over the past 30 years, Khuri and col-
leagues have increased our understanding of the potential
importance of intramyocardial pH management. These
investigators have developed a system using electrodes
implanted in the ventricular wall that allows continuous
pH measurements to monitor for regional myocardial ische-
mia and decreased coronary perfusion. Their retrospective
analyses conclude that low myocardial pH can predict clin-
ically relevant outcomes ranging from an increased need for
inotropic support,76 to an increased risk of 30-day adverse
events,80 and finally to decreased long-term survival.75
On the basis of their findings, they have developed a series
of recommendations aimed at keeping myocardial pH in a
safe range throughout all aspects of any cardiac surgery
procedure.70 Though compelling, these data and recom-
mendations require prospective, randomized examination,
and little external validation has ever been done; therefore,
widespread adoption of intramyocardial pH monitoring has
not become widely accepted in clinical practice.
Blood glucose. Diabetes mellitus has long been considered
an established risk factor both for the development of cardio-
vascular disease81 and for significant perioperative morbid-
ity and mortality associated with cardiac surgery.82–86 Even
after adjusting for other confounding risk factors, such as
age, hypertension, hypercholesterolemia, and smoking, dia-
betes has been shown in numerous studies to be a signifi-
cant independent predictor of both short- and long-term
survival after CABG.87–90 The data are not all consistent,
as some studies have not identified diabetes as an indepen-
dent predictor of mortality.91 Nevertheless, because diabetes
now affects almost one-third of patients undergoing bypass
surgery, optimal perioperative glucose management must
be a priority for all cardiac surgeons.
Although the mechanism of diabetes-related cardiac
pathophysiology is multifactorial, patients with more
severe forms of the disease (i.e., those who require preoper-
ative insulin therapy), and by extension those with higher
blood glucose levels (poor control), have a poorer progno-
sis.88 Both acute and chronic hyperglycemia increase
the risk of ischemic myocardial injury through a number

of mechanisms, all of which may play a role around the time
of cardiac surgery. These include a decrease in coronary col-
lateral blood flow, endothelial dysfunction, and attenuation
of the protective effects of inhaled anesthetics and other
pharmacologic preconditioning agents.92,93 The association
of higher blood glucose with increased morbidity and mor-
tality has shifted the focus of research in this area away from
characterizing the risk from diabetes per se to the role of ele-
vated blood glucose in cardiac pathophysiology. In the
absence of intervention, serum glucose concentrations in
the intraoperative and perioperative periods often become
elevated far above the normal range, even in nondiabetic
patients. The cause of this elevation, which is similar to that
which occurs in other forms of surgery and is in response to
stress such as trauma or infection, reflects a combination of
acute glucose intolerance in the form of insulin suppression,
stress-hormone–induced gluconeogenesis, and impaired
glucose excretion as a consequence of enhanced renal tubu-
lar resorption.94 The metabolic effects of diabetes and ele-
vated blood glucose have been shown to be similarly wide
ranging and include a higher incidence of left ventricular
dysfunction, more diffuse coronary artery disease, altered
endothelial function, and abnormal fibrinolytic and platelet
function.95
Maintenance of normal glucose levels during the intrao-
perative and perioperative periods is difficult, even in
nondiabetic patients, and carries with it the risk for poten-
tially life-threatening iatrogenic hypoglycemia.96 Neverthe-
less, Furnary and colleagues performed a series of studies
investigating the feasibility of tight perioperative glycemic
control and its effects on the important outcomes of sternal
wound infection and death.97 An initial study of 1585 dia-
betic patients undergoing cardiac surgery demonstrated
that elevated blood glucose levels (>200 mg/dL) on the first
and second postoperative days were associated with a
higher incidence of deep sternal wound infection, and the
average blood glucose level over those 2 days was the stron-
gest predictor of deep sternal wound infection in a diabetic
patient.97 On the basis of these findings, these investigators
hypothesized that tight glycemic control would decrease the
incidence of postoperative sternal wound infections. A pro-
spective study of 2467 diabetic patients undergoing cardiac
surgery was performed in which maintaining serum glucose
at a level of less than 200 mg/dL was the goal. The control
group (968 patients) was treated with intermittent doses of
subcutaneous insulin, with administration based on a slid-
ing scale; the study group (1499 patients) was treated with
a continuous intravenous insulin infusion in an attempt to
maintain a blood glucose level of less than 200 mg/dL. Con-
tinuous intravenous insulin infusion resulted in better gly-
cemic control and a significant reduction in the incidence
of deep sternal wound infection (0.8%) compared with
the intermittent subcutaneous insulin injection group
(2.0%; P < .01).98 A subsequent retrospective review of
3554 diabetic patients undergoing isolated CABG demon-
strated that continuous insulin infusion resulted in better
glycemic control. Furthermore, tight glycemic control led
to a 57% reduction in mortality, with this reduction being
accounted for by cardiac-related deaths.99 On the basis of
these results, the authors concluded that diabetes mellitus
per se is not a true risk factor for death after CABG and that
continuous insulin infusion should become the standard of
11 • Prevention of Ischemic Injury in Cardiac Surgery 127
care for glucose control in diabetic patients undergoing
CABG. After review of the available data, other investigators
have also reached similar conclusions, namely that poor
glycemic control, not a diagnosis of diabetes per se, signifi-
cantly increases the risk of adverse clinical outcomes, pro-
longed hospitalizations, and increased health-care costs
following cardiac surgery.100 Additional evidence comes
from a prospective study involving 1548 critically ill
patients in the surgical ICU, in which even tighter control
(a serum glucose level goal of between 80 and 110 mg/dL
versus 180 to 200 mg/dL) was associated with significantly
improved mortality (4.6% versus 8.0%; P < .04).101 On the
basis of these data, it is reasonable to conclude that tight gly-
cemic control is likely beneficial for all patients undergoing
cardiac surgery, and this has become a current standard of
practice.
Transfusion strategy. Despite the development of nation-
al consensus guidelines for blood transfusion in the
1980s,102–104 in 2002 it was estimated that some 20% of
all allogeneic blood transfusions in the United States were
associated with cardiac surgery.105 Despite established guide-
lines, a number of studies have demonstrated that transfusion
practices vary dramatically across institutions, with some
centers transfusing less than 5% of patients and others trans-
fusing nearly all patients.106–109 Different transfusion prac-
tices even within the same institution110 highlight the lack
of widespread accepted transfusion thresholds. Furthermore,
a recent analysis of cardiac surgery patients undergoing car-
diac surgery found that red blood cell transfusion appears to
be associated more closely with morbidity and mortality
than with preoperative anemia; therefore, efforts to minimize
unnecessary blood transfusion are justified.111
The myocardium relies on either increased blood flow or
increased oxygen content to satisfy increased oxygen
demand.112 One of the primary rationales for blood transfu-
sions in the setting of cardiac ischemia, therefore, is to
increase oxygen delivery to the stressed myocardium.
Unfortunately, very little evidence exists to support this
rationale. On the contrary, some degree of anemia is
required during hypothermic CPB to reduce blood viscosity
and allow adequate flow without excessive arterial blood
pressure. Furthermore, a number of large studies have con-
cluded that blood transfusion is associated with increased
short- and long-term mortality,113,114 including transfu-
sions in the setting of CABG.115
Decreased hematocrit is one of the prime drivers of the
decision to transfuse, but management of hematocrit during
CPB is controversial. Numerous studies have demonstrated
that normovolemic anemia is well tolerated in cardiac
patients, even at levels as low as 14%.116 Spiess and col-
leagues analyzed more than 2200 bypass patients and found
that high hematocrit (34% or greater) upon entry to the
ICU was associated with a significantly higher rate of MI
than was a low hematocrit (less than 24%), leading the
authors to conclude that low hematocrit might be protec-
tive against perioperative MI.117 In contrast, Klass and col-
leagues performed a study of 500 CABG patients and found
no association between perioperative MI rate and hematocrit
value on entry into the ICU.118 Habib and colleagues exam-
ined 5000 operations using CPB and found that a number of
clinically significant outcomes, including stroke, MI, cardiac
128 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
failure, renal failure, pulmonary failure, and mortality, were
all increased if the intraoperative hematocrit nadir was less
than 22%.119 Similarly, DeFoe and colleagues demonstrated
that low hematocrit during CABG is associated with periop-
erative cardiac failure and increased in-hospital mortal-
ity.120 Each of these studies is limited by its retrospective
design, and significant differences in patient populations
and other key factors make direct comparisons difficult. Until
a well-designed prospective study is performed, the optimal
hematocrit value for CPB will remain undetermined, leaving
the evaluation of this key indicator of the need to transfuse to
the discretion of the physician.
Although the optimal hematocrit during CABG surgery is
the subject of continued debate, data are accumulating on
the deleterious effects of blood transfusion. Several studies
have demonstrated the proinflammatory properties of trans-
fused blood.121,122 In addition, the immunomodulatory
effects of transfusion have been known for more than 2
decades,123 and blood transfusion has been associated with
increased risk of bacterial as well as viral infection.124–127
A number of blood conservation strategies have been
designed with the specific intent of decreasing the need
for transfusion, including technical modifications to the
bypass circuit and the use of various cell salvage techniques,
such as autologous blood transfusion and Cell-Saver use. For
those patients in whom transfusion cannot be avoided, the
use of leukoreduced blood is gaining favor as a method of
minimizing the detrimental effects of transfused blood.
A national universal leukoreduction program in Canada
has been credited with decreasing mortality and antibiotic
use in high-risk patients.128 In the setting of CABG, the role
of transfusing leukoreduced blood is unsettled. At least two
studies have shown that leukoreduction is not associated
with a decrease in postoperative infections.129,130 However,
in a well-conducted, prospective trial, Furnary and col-
leagues showed that transfusing leukoreduced blood confers
a survival advantage that is present at 1 month and persists
up to 1 year.130
In sum, despite the regular occurrence of blood transfu-
sion in cardiac surgery patients, the indications, goals, effec-
tiveness, and safety of this common clinical practice remain
uncertain. Clinician preference and habit therefore continue
to be the prime determinants of many blood transfusion
strategies.131 Data on transfusion practices in cardiac sur-
gery are mixed, but as one prominent expert in the field
has concluded, the predominance of data regarding red
blood cell transfusion does not support the premise that it
improves outcome.132 Thus, until the appropriate patients
and circumstances of transfusion are better defined, it is a
practice to be used judiciously.
OPERATIVE STRATEGIES TO PREVENT ISCHEMIA
AND ISCHEMIA-REPERFUSION INJURY
For an operation that is performed safely more than 1 mil-
lion times annually worldwide, CABG is an incredibly com-
plex procedure. Accordingly, strategies aimed at minimizing
the morbidity and mortality associated with heart surgery
are equally broad in scope. Although overlap exists, concep-
tually one may divide these efforts into two broad categories:
strategies to protect the myocardium itself and strategies to
protect against the effects of CPB. In addition, a third cate-
gory is emerging that includes newer techniques which are
a combination of the two and thus do not fall easily into
either of the first two categories.
Myocardial Protection Strategies
Cardioplegia. Generally agreed-on characteristics of the
ideal cardioplegia solution are that it will (1) achieve a rapid
and sustained diastolic arrest, (2) minimize energy require-
ments while the heart is arrested, (3) prevent damage
caused by the absence of coronary blood flow, and (4) pre-
vent ischemia-reperfusion (I/R) injury when blood flow is
restored.133 The earliest cardioplegia solutions contained
a high (2.5%) concentration of potassium citrate.134,135
Although this solution was effective in achieving chemical
cardiac arrest, it was abandoned after only several years
when the high potassium concentration was shown to
induce myocardial necrosis.136 In the mid-1960s, several
new cardioplegia solutions were introduced, and they were
the forerunners of solutions still in use today. The most pop-
ular of these were Bretschneider’s intracellular crystalloid
solution,137–139 St. Thomas’ Hospital extracellular crystal-
loid solution,140 and several solutions developed by Ameri-
can researchers.141–144 These new solutions continued to
rely on potassium to induce cardiac arrest, although at
much lower levels than previous solutions. By the late
1970s, use of potassium-based cold crystalloid cardioplegia
had become common practice in the United States. Since
that time, efforts to improve on cardioplegia have focused
on composition of the solution, temperature, the route of
delivery, and the use of special additives.
CARDIOPLEGIA COMPOSITION: BLOOD VERSUS CRYSTALLOID.
Asanguineous crystalloid solutions have been shown to pro-
vide good protection against ischemia, even in cases with
prolonged bypass times;145 however, their poor oxygen-
carrying capacity may give rise to myocardial oxygen debt.
This problem may be overcome, in part, by reducing myo-
cardial metabolism via hypothermia, by oxygenating the
crystalloid solution,146 or by using blood as the cardioplegia
vehicle.
Potassium-based blood cardioplegia, introduced in the
late 1970s, was shown experimentally to provide better
protection than either blood alone or crystalloid cardiople-
gia.147 Work by Buckberg and colleagues demonstrated
that blood cardioplegia could be performed safely in humans
and with good results.148,149 Laks and associates provided
similar positive results in 1979.150 Since that time, a num-
ber of studies have shown that blood cardioplegia may lead
to decreased creatine kinase-MB enzyme release and
improved postoperative ventricular function151,152 and that
it may be of particular benefit to patients with unstable
angina153 or reduced left ventricular function.154,155
The preponderance of evidence suggests that use of blood
cardioplegia is superior to use of crystalloid; however, no
large-scale, randomized trial has ever been undertaken to
provide a more definitive answer. Despite these limitations,
over the past 20 years blood cardioplegia has become the
preferred means of myocardial protection for most cardiac
surgeons.156
CARDIOPLEGIA SOLUTIONS: SINGLE DOSE. Del Nido cardioplegia
was developed mainly for use in the congenital cardiac pop-
ulation in the mid-1990s as a way to address the inability of

the immature myocardium to tolerate high levels of intra-
cellular calcium influx. As opposed to Buckberg cardioplegia
and other whole-blood (WB) solutions, del Nido solution is
not glucose based; instead, it is a calcium-free, potassium-
rich solution intended to have an electrolyte composition
close to the extracellular fluid. It also contains lidocaine,
which blocks sodium channels maintaining depolarization
and limits intracellular calcium influx.
Del Nido cardioplegia solution is typically mixed with cold
blood in a 4:1 ratio (as opposed to Buckberg solution, mixed
in a 1:4 ratio). It is usually delivered as a single dose for
straightforward cardiac operations, as its safety up to
90 minutes of myocardial ischemic time has been described.
This may improve the efficiency and flow of the operation, as
other WB-based cardioplegia solutions are typically redosed
every 20 minutes.
Over the past decade, del Nido cardioplegia solution has
gained increasing favor among adult cardiac surgeons
and in many institutions now represents the cardioplegia
solution of choice. Potential benefits include its single-dose
use for many cases (typical redosing interval around
60 minutes), decreased cost, decreased postoperative glu-
cose perturbations, and possible improved myocardial pro-
tection. Mick and colleagues evaluated del Nido and
Buckberg use among patients undergoing isolated valve
replacement.157 They found shorter CPB, aortic cross-
clamping, and total operative times associated with the
use of del Nido solution. Postoperative insulin requirements
were also lower in the del Nido group.
Ad and colleagues performed a prospective randomized
trial comparing del Nido with WB cardioplegia.158 They
found that the use of del Nido was associated with a lower
troponin level 24 hours after surgery. Patients receiving del
Nido solution also had a higher return to spontaneous
rhythm, and fewer patients in the del Nido group required
postoperative inotropic support. These results favor at least
equivalent myocardial protection between del Nido and tra-
ditional WB solutions and possibly point toward superior
myocardial protection with del Nido.
Some have questioned the safety of del Nido cardioplegia
in complex adult cardiac operations, including patients with
significant multivessel coronary artery disease. Theoretical
concerns with single-dose cardioplegia include maldistribu-
tion of delivery and inadequate myocardial protection. Sev-
eral studies have evaluated del Nido solution in these
higher-risk patient populations. Yerebakan and colleagues
evaluated del Nido use in patients undergoing CABG during
an acute MI and found no difference in outcome between del
Nido and WB cardioplegia.159 A recent propensity-matched
study looked at CABG with del Nido cardioplegia versus
Buckberg.160 Del Nido was found to provide equivalent
myocardial protection while requiring significantly fewer
doses, was associated with decreased aortic cross-clamping
time, and had lower postoperative glucose levels. Del Nido
has also been found to be effective in reoperative cardiac sur-
gery as well, including given in a continuous retrograde
fashion during redo CABG with patent left internal mam-
mary artery (LIMA).161–162
Del Nido cardioplegia likely provides myocardial protec-
tion at least equivalent to that of WB solutions, and there
may be a signal among published reports that del Nido in
fact provides superior myocardial protection during adult
11 • Prevention of Ischemic Injury in Cardiac Surgery 129
cardiac surgery. This is accompanied by its ease of use
and potential for increased efficiency during the operation,
with corresponding shorter operative times. Previous con-
cerns regarding patients with significant coronary artery
disease are probably overstated; however, continued inves-
tigation is needed to prove del Nido solutions’ safety in these
complex patients.
CARDIOPLEGIA TEMPERATURE: WARM VERSUS COLD. For 4 decades,
hypothermia was considered a fundamental requirement in
cardiac surgery. However, in the early 1990s, Lichtenstein
and colleagues published the earliest reports describing the
use of retrograde continuous normothermic cardiople-
gia.56,57 This study compared 121 consecutive patients
undergoing CABG with normothermic cardioplegia
with 133 historical control subjects, and it showed signifi-
cant improvement in perioperative MI rate (1.7% versus
6.8%; P < .05), decreased use of IABP (0.9% versus
9.0%; P < .005), and decreased prevalence of low output
syndrome (3.3% versus 13.5%; P < .005).56 In 1994,
the Warm Heart Investigators Trial reported the initial
results of a study involving more than 1700 patients ran-
domized either to continuous warm-blood cardioplegia
(systemic temperature 33°C to 37°C) or to cold-blood cardi-
oplegia (systemic temperature 25°C to 30°C). This study
again demonstrated decreased evidence of enzymatic MI
using normothermia (warm 12.3% versus cold 17.3%;
P < .001) and decreased incidence of postoperative
low-output syndrome in warm patients (6.1% versus
9.3%; P < .01).58 A subsequent prospectively designed sub-
analysis of this study demonstrated that warm cardioplegia
significantly reduced the overall prevalence of morbidity
and mortality (warm 15.9% versus cold 25.2%; P < .01);
this protection was seen across all risk groups.163 However,
given the historical precedent of hypothermia being a
critical adjunct to myocardial protection, larger studies
comparing normothermic and hypothermic cardioplegia
strategies will be needed until large-scale practice patterns
evolve. Cold blood cardioplegia remains the current gold
standard for protection during cardiac arrest.
CARDIOPLEGIA ROUTE OF DELIVERY: ANTEGRADE VERSUS RETROGRADE.
Antegrade administration of cardioplegia represents the
most physiologic method for delivery and is the workhorse
method in a majority of cases. However, retrograde deliv-
ery of cardioplegia offers a number of potential advan-
tages over antegrade perfusion, including the ability to
perfuse regions of the myocardium that would not be
reached via antegrade infusion because of occlusion of
coronary arteries164–166 and the ability to maintain con-
tinuous cardioplegia. Disadvantages include the fact that
it is technically more difficult than cannulation of the
aorta, that retrograde flow provides less homogeneous dis-
tribution of cardioplegic solution,167 and that the right
ventricle and posterior ventricular septum receive inferior
protection.168–170 Despite these limitations, a number of
investigators have demonstrated good outcomes using
retrograde cardioplegia.171–173 Numerous attempts have
been made to determine whether antegrade or retrograde
cardioplegia provides superior protection. No definitive
conclusion has been reached, but many investigators
have determined that a combined approach is likely to
yield the greatest success and that high-risk patients
with severe coronary artery occlusion and/or left
130 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
ventricular dysfunction or patients undergoing repeat
coronary revascularization stand to benefit the most from
retrograde delivery of cardioplegia.155,174–176
Noncardioplegia myocardial protection strategies.
HYPOTHERMIA. Of all the non–cardioplegia-based myocar-
dial protection strategies, hypothermia has been used most
widely and has had the most consistent benefit. As we have
learned more about the potential negative consequences of
lowered body temperature, and as other protection strate-
gies have been developed, the role of systemic hypothermia
has become less central in myocardial protection. Neverthe-
less, its importance in the history of cardiac surgery cannot
be overemphasized, and even today deep systemic hypother-
mia, as well as topical hypothermia (i.e., slush), may be the
complementary strategy or the strategy of choice in special
situations.177
ARREST VARIATIONS. Cardiac arrest serves the dual purpose of
greatly reducing the metabolic demand of the myocardium
while providing the motionless field necessary to complete
many operations. As discussed earlier, potassium-based
depolarizing chemical cardioplegia has been the mainstay
of cardiac arrest mechanisms since the late 1960s. How-
ever, a number of alternative techniques have been
employed, many of which may be used in conjunction with
chemical cardioplegia. These include hypothermia49,52 and
intermittent aortic cross-clamping with electrically induced
ventricular fibrillation.178 Newer strategies such as polar-
ized arrest179 and “electroplegia”180 have yet to be tested
in large clinical studies. Of the alternative accepted arrest
techniques, cold crystalloid cardioplegia and intermittent
aortic cross-clamping are used most widely. Proponents of
intermittent cross-clamping cite its simplicity and the
reduced cumulative ischemia in comparison with cardiople-
gia, but head-to-head comparative studies have failed to
demonstrate the superiority of either strategy.181–183
HYPOTHERMIC FIBRILLATORY ARREST. Hypothermic fibrillatory
arrest (without aortic cross-clamping) is used with increas-
ing frequency in alternative access cardiac surgery, and in
particular has been championed in minimally invasive valve
surgery, with excellent results.184 This technique generally
involves CPB with systemic cooling to 26–30°C. The heart is
appropriately vented or the left atrium opened directly (in
the case of mitral valve surgery) once the patient begins
to fibrillate. Obvious limitations are significant aortic insuf-
ficiency, which must be dealt with using the optimal surgi-
cal visualization. Upon conclusion of the operation using
this technique, the importance of meticulous de-airing
techniques cannot be overemphasized. These include use
of aortic root vents as well as direct venting of the left ven-
tricle while closing the left atrium (in the case of mitral valve
surgery). In the appropriate patient, this represents a pow-
erful tool and should be in the arsenal of the cardiac surgeon
caring for complex patients as well as performing alternative
access surgery.
CANNULATION TECHNIQUES. The modern technique of placing a
patient on CPB is remarkably similar to the technique
employed by pioneers in the field 50 years ago.185 Both
the venous and arterial systems are cannulated as they
enter and exit the heart, respectively. When the venae
cavae and aorta are then clamped, blood flow is diverted
to the bypass machine, effectively excluding the heart and
lungs. Cardiac venting is typically required to remove blood
that enters the heart from noncoronary collateral flow, such
as the bronchial arteries and Thebesian veins. In addition to
improving operative visibility, effective drainage prevents
distention of the ventricles. Alternatives to the most com-
mon forms of venous drainage (right atrial two-stage and
bicaval cannulation) and arterial perfusion (ascending aor-
tic cannulation) exist and may be particularly useful in cer-
tain circumstances, but no technique has been
demonstrated to have a significant impact on prevention
of ischemic or inflammatory injury.
CPB circuit modifications. Since its introduction, the
CPB circuit has undergone numerous advances, each of
which has contributed to declining morbidity and mortality
associated with cardiac surgery. The many challenges posed
by use of CPB has made it one of the most researched areas
of cardiovascular medicine.186
HEPARIN-BONDED CIRCUITS. To minimize the systemic inflam-
matory response to the CPB circuit, a number of strategies
have been implemented in an attempt to make the circuit
more biocompatible. By far the best studied molecule used
in these modified circuits is heparin. In theory, a layer of
heparin molecules lining the CPB circuitry may mimic the
heparan sulfate that coats endothelial cells in vivo, thereby
reducing the pathophysiologic response that occurs when
blood cells come into contact with the foreign surface.187
Gott and colleagues first reported the binding of heparin
to artificial surfaces in 1963.188 Since then, heparin-bonded
circuits have been tested extensively, and abundant exper-
imental and clinical evidence suggests that, during CPB,
heparin-bonded circuits do in fact attenuate the activation
of leukocytes,189,190 platelets,191 and complement;192–194
decrease release of inflammatory cytokines;195 and diminish
the formation of thromboembolic debris.196 Although evi-
dence exists that heparin-bonded circuits may not actually
decrease thrombogenesis,197 several controlled studies
suggest that the level of anticoagulation can be safely
decreased when heparin-bonded circuits are used.198–200
Work from our institution has demonstrated that a strategy
that combines heparin-bonded circuits and low-dose
heparinization as part of a comprehensive blood conserva-
tion strategy decreases the inflammatory response and
need for transfusion more than any single measure in
isolation.201
CARDIOTOMY SUCTIONING. The possible negative conse-
quences of infusion of cardiotomy suction blood have been
recognized for decades. As early as 1963, it was demon-
strated that neurologic complications associated with CPB
could be ameliorated by discarding shed blood rather than
returning it to the patient,202 and diffuse cerebral intravas-
cular fat emboli have been observed in patients who die of
neurologic complications in the perioperative period.203
To minimize this potentially disastrous complication, a
defoaming chamber is incorporated into the cardiotomy res-
ervoir, and various filtration systems have been developed.
Recent evidence suggests that use of cell salvage techniques
may be an even more effective method of recycling shed
mediastinal blood. Cell savers have been shown to reduce
the lipid burden from shed blood before it is returned to
the patient and to reduce the number of lipid microem-
boli.204,205 An additional advantage of a cell saver is that
it removes leukocytes from the shed blood, which may help
to minimize the inflammatory reaction.

Less readily apparent than the threat of embolism but
perhaps equally detrimental are the significant metabolic
and proinflammatory effects that are associated with rein-
fusion of cardiotomy suction blood. Paradoxically,
attempts to minimize transfusion requirements by salvag-
ing shed mediastinal blood may be offset by heightened
inflammation, vasomotor dysfunction, and altered coagu-
lation. In an observational study involving 12 academic
medical centers and more than 600 patients, Body and col-
leagues concluded that autotransfusion of shed mediasti-
nal blood was ineffective as a blood conservation
strategy and that it may be associated with an increased
risk of wound infection.206 Further refinements to the
CPB cardiotomy circuit are likely needed to reduce both
the embolic and proinflammatory component of recircula-
tion of shed blood.
OPEN VERSUS CLOSED CIRCUIT. Contact with air and filters is
known to contribute to blood activation. The conventional
CPB circuit includes an open venous reservoir (“hard
shell”), which collects both venous return and cardiotomy
blood; blood in this open reservoir is exposed to the air
and must pass through an integrated filter. A closed reser-
voir (“soft shell”) is independent from the cardiotomy reser-
voir, is never exposed to the air, and does not require a filter.
Use of closed reservoirs has been shown to decrease fibrin
deposition207 and decrease the expression of a number of
inflammatory mediators, including complement levels, the
proinflammatory cytokine interleukin (IL)-8, thromboxane,
elastase, and tissue plasminogen activator antigen.208,209
More importantly, closed reservoirs have been shown to
decrease blood loss, decrease the need for blood transfusion,
and decrease the length of stay.208,210 Although limited to
only a few studies, these data are promising, and use of
closed reservoirs should be expected to increase in the com-
ing years as a result of solid evidence of their efficacy. How-
ever, closed shells are slightly limited in their ability to
incorporate vacuum-assisted drainage, and therefore may
not be the best choice for certain high-risk situations.
PUMP TYPE. Currently, two types of pumps, roller and cen-
trifugal, are used in the vast majority of cardiac surgery
cases with CPB. For many years, CPB was performed exclu-
sively with continuous roller pumps. Hemolysis, the risk of
pumping large volumes of air, and spallation (the release of
particles from the tubing surface) are known consequences
of the roller pump;185 however, its simplicity of design and
implementation, as well as relatively low cost, are used to
justify its continued use. Reported advantages of a centrifu-
gal pump are improved blood handling, elimination of the
risk of over pressurization, and decreased spallation.211,212
In vitro analysis has demonstrated reduced hemolysis using
centrifugal pumps;213 however, two small studies have
shown that terminal complement levels, the proinflamma-
tory cytokines IL-6 and IL-8, neutrophil count, and elastase
levels are all higher when using centrifugal pumps.214,215
Clinical outcomes, including chest tube drainage, transfu-
sion requirements, and length of hospital stay may be
improved through the use of centrifugal pumps,216
although clinical benefit has not been shown in all
studies.217,218
Both roller and centrifugal pumps generate continuous,
nonpulsatile blood circulation. In the 1950s, Wesolowski
and Welch published a series of reports based on more than
20 years spent developing an artificial pump.219 Their
11 • Prevention of Ischemic Injury in Cardiac Surgery 131
studies, using a canine model, indicated that a short period
(up to 6 hours) of nonpulsatile flow had no apparent effect
on pulmonary, cardiac, renal, or central nervous system
physiology. Limited evidence accumulated since that time
suggests that the flow characteristics do have physiologic
consequences,220 and small studies have demonstrated that
pulsatile CPB may reduce endothelial damage, suppress
cytokine activation, and prevent increases in endogenous
endotoxin levels.221,222 Taylor and coworkers have sug-
gested that pulsatile flow may provide significant clinical
benefit, including improved postoperative ventricular func-
tion and reduced mortality.223 However, these positive find-
ings have not been universal.224 The effects of pulsatility
have been the subject of several recent reviews.225–227 In
short, the impact of nonpulsatile flow is not fully known.
Furthermore, by extrapolating from the success of durable
left ventricular assist devices, exposing patients to long-term
nonpulsatile flow, this probably has minimal impact during
surgery.
BLOOD FILTRATION: LEUKOCYTE DEPLETION. The central role of
leukocytes, particularly neutrophils, in the inflammatory
response to CPB and I/R injury is well established. Like
many other strategies, leukocyte depletion seems to be fairly
effective in reducing inflammatory cells and mediators
involved in the response to CPB,228–234 but clinically
relevant data have been inconclusive.235–242 A number
of investigators have noted that leukocyte depletion
may be beneficial only in certain populations, such as
children,243,244 patients with impaired cardiac func-
tion,230,233,245–247 and patients undergoing emergent
CABG.248
Pharmacologic protection strategies. Just as numerous
modifications to the CPB circuit have been devised to com-
bat the complexity of the endogenous response to cardiac
surgery, numerous pharmacologic interventions have been
studied as well. Taking a broad view of the data regarding
pharmacologic anti-inflammatory strategies, two conclu-
sions emerge. First, a common feature of many of these
drugs is that although experimentally each may signifi-
cantly reduce the biochemical markers of infection, their
clinical utility has been questionable. Most have not under-
gone the sort of large, prospective, double-blind, randomized
trial that would enable some measure of certainty on their
efficacy. Second, as more is learned about the inflammatory
mechanisms initiated by cardiac surgery and the unique
response of each cardiac surgery patient to those mecha-
nisms, it is becoming clear that no single therapy, in isola-
tion, is effective or appropriate for all situations in all
patients. Thus, future investigations must be designed to
determine the most beneficial combination of anti-
inflammatory strategies, so that treatment can be tailored
accordingly.
CORTICOSTEROIDS. Experimentally, corticosteroids have been
shown to decrease the levels of numerous proinflammatory
cytokines and chemokines; to reduce complement levels; to
prevent the production of thromboxane and prostaglandins;
and to inhibit the activation of inflammatory cells, including
macrophages and neutrophils.249,250 The effectiveness of
corticosteroids in the setting of CPB has been studied by a
number of investigators. General agreement exists that at
the molecular level, corticosteroids are effective in minimiz-
ing the inflammatory response to CPB. Various studies have
132 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
demonstrated reductions in the release of proinflammatory
cytokines IL-6 and IL-8,251–253 complement levels,254,255
tumor necrosis factor-α (TNF-α),253,256–258 cellular adhe-
sion molecules,258,259 and neutrophil activation and
sequestration.260,261 At the same time, the anti-
inflammatory cytokine IL-10 has been shown to increase
with the use of corticosteroids.262–264
In terms of clinical efficacy, the data regarding use of cor-
ticosteroids have been far less consistent. Dietzman and col-
leagues reported some of the first observational studies on
the use of corticosteroids in the setting of human CPB sur-
gery. On the basis of their findings, they determined that ste-
roids might lead to decreased vasoconstriction, resulting in
improvements in both pulmonary and cardiac function.265–
267
These positive outcomes were soon called into question
by the findings of another small study which found that ste-
roid use led to increased blood loss, decreased cardiac func-
tion, and an increased requirement for postoperative
mechanical ventilation.268 In the 3 decades since that time,
numerous small, randomized trials have been published, but
the results have been conflicting.269–277
These contradictory clinical findings have fueled great
controversy on the appropriateness of steroid use in cardiac
surgery.278,279 Proponents point to data which suggest that
steroid use is associated with fewer arrhythmias274 and
improved pulmonary function.273 Limited data indicate that
steroids may directly protect the myocardium against ische-
mic injury as well.280 Those who advocate against the use of
glucocorticoids argue that the existing data do not ade-
quately prove any clinically significant benefit. Because of
the lack of proven benefit, and in light of evidence that cor-
ticosteroids may prolong mechanical ventilation,272,281
suppress T-cell function,282 and decrease glucose toler-
ance,273,275,282,283 thereby increasing the risk of wound
disruption284,285 and infection,97 the potential risk is not
justified.
After reviewing the extant data, a joint task force of the
American College of Cardiology and American Heart Asso-
ciation published guidelines in which they supported the
“liberal prophylactic use” of corticosteroids in the setting
of surgery with CPB—notably, except for diabetic
patients.5 In the absence of more definitive data, the pre-
sent authors arrive at a different conclusion. Although
the weight of the evidence strongly supports the notion
that corticosteroids are effective in ameliorating the proin-
flammatory response to CPB at molecular and cellular
levels, conclusive evidence that corticosteroids lead to clin-
ically significant benefit is lacking. At the same time, the
evidence that corticosteroids are harmful is equally insuf-
ficient. Until appropriately designed, large, randomized,
controlled trials are carried out, expansion of use does
not seem warranted at present.
HEMOSTATIC AGENTS. Several drugs are used to decrease
bleeding associated with CPB in the effort to mitigate
transfusion-related morbidity. These agents include the
lysine analogs tranexamic acid and epsilon-aminocaproic
acid, which reduce bleeding by inhibiting the conversion
of plasminogen to plasmin (the serine protease responsible
for breaking down fibrinogen); and desmopressin, a vaso-
pressin analog that induces release of the contents of endo-
thelial cell–associated Weibel-Palade bodies, including von
Willebrand factor and associated coagulation factor VIII,
leading to potentiation of primary hemostasis.286–291 Sev-
eral meta-analyses suggest that tranexamic acid and
epsilon-aminocaproic acid may be similarly effective in pre-
venting perioperative bleeding and the risk of transfusion in
cardiac surgery patients; desmopressin does not seem to pro-
vide as much benefit.292–294 Data concerning the clinical
outcomes associated with the use of these drugs are insuffi-
cient to allow conclusive recommendations to be made
regarding their use.
Recombinant factor VIIa, which may produce its hemo-
static effects by activating platelets in the absence of tissue
factor to activate factors IX and X and thus enhance throm-
bin generation295 or by directly interacting with tissue fac-
tor at the site of injury to initiate thrombin generation,296
has only recently been introduced to cardiac surgery. Cur-
rently, this drug is being used primarily as a measure of
last resort to treat uncontrollable hemorrhage rather
than as routine therapy.297–302 Several other factor concen-
trates are available for salvage situations during intense
coagulopathy.
As cardiac surgery patients become increasingly complex
and higher risk, the need for multiple pharmacologic options
to decrease bleeding will only grow.303
ANTIOXIDANTS. The generation of reactive oxygen species is
a major component of the I/R response to cardiac sur-
gery.304–306 Oxygen radicals are primarily produced by acti-
vated neutrophils and may exert their deleterious effects by
the peroxidation of membrane lipids and the oxidation of
protective proteins. The body’s innate antioxidant defenses,
including α-tocopherol (vitamin E) and ascorbic acid (vita-
min C), are critical in preventing free radical–mediated dam-
age. Indeed, studies have shown an inverse epidemiologic
correlation between plasma vitamin E levels and mortality
due to ischemic heart disease.307 CPB induces simultaneous
increases in both reactive oxygen species and the body’s
own antioxidant defense mechanisms; however, these
endogenously produced free-radical scavengers may not
be able to compensate fully,308 leading to subsequent tissue
destruction. For this reason, a number of investigators have
attempted to determine whether administration of exoge-
nous antioxidants is beneficial in CPB.
In animal models, supplementation of vitamin E and vita-
min C has been demonstrated to decrease the molecular dam-
age caused by reactive oxygen species;309–312 the free-radical
scavengers superoxide dismutase (SOD) and catalase resulted
in significantly better recovery of left ventricular function
after reperfusion; and SOD and allopurinol have been shown
to reduce significantly the extent of myocardial necrosis that
developed after reversible coronary arterial branch occlu-
sion.313 The same biochemical protection provided by antiox-
idants has been seen in humans undergoing cardiac
surgery;314 however, in a number of small trials, clinically
relevant effects have been minor,312,315,316 nonexistent,311
or even potentially harmful.317
Alternative Approaches to Myocardial Protection
Previously in this chapter, we discussed protective strategies
that are focused either on direct protection of the myocar-
dium or on ameliorating the inflammatory response and
I/R injury that are caused by CPB. In these final paragraphs,
we shall examine two protective strategies that do not easily
fit into either of those categories.

Bypassing CPB: off-pump CABG. Myocardial revascular-
ization without the use of CPB is not a novel concept.
Indeed, many of the landmark events in the early years of
cardiothoracic surgery, including the first CABG, were per-
formed without the aid of the bypass circuit. Although this
technique fell out of favor in the late 1960s with the rise of
CPB and cardioplegia, the development of new stabilizing
devices and the use of a left anterior thoracotomy rather
than median sternotomy contributed to their reintroduction
into clinical practice in the early 1990s,318–320 in large part
because both off-pump CABG (OPCAB) and minimally inva-
sive direct CABG offer the theoretical advantage of eliminat-
ing CPB-associated morbidity altogether. With the
exception of the short duration of regional myocardial ische-
mia created when the anastomoses are being performed,
blood flow to the beating heart is uninterrupted, thereby
minimizing ischemic injury. In addition to avoiding the del-
eterious effects of CPB, OPCAB has other supposed advan-
tages, including decreased surgical trauma, quicker
recovery time, and shorter hospital stays.
A number of studies have attempted to compare the
inflammatory response of OPCAB with standard CABG
(CABG with CPB). The majority of reported studies are small
and nonrandomized, but most have demonstrated that
OPCAB is associated with decreased markers of inflamma-
tion when compared with standard CABG. For example, leu-
kocyte, neutrophil, and monocyte activation are greater
with the use of CPB.321 Complement levels (C3a, C5a),
TNF-α, IL-1, IL-6, IL-8, and IL-10 are all increased with
CPB.321–330 An important confounding factor in most of
these studies is that surgical access (i.e., median sternotomy
in standard CABG versus anterolateral thoracotomy for
OPCAB) has been demonstrated to play an important role
in cytokine release;327,328,331 indeed, some authors believe
that alternative surgical approaches may have a greater
effect on the inflammatory response than does the use of
CPB.332 In addition, many of the early studies comparing
OPCAB with standard CABG did not incorporate the newer
drugs and technical modifications (described earlier) that
have been specifically designed to ameliorate the effects of
CPB. Thus, for example, study protocols that have incorpo-
rated normothermia, heparin-bonded circuits, complement
inhibitors, and elimination of cardiotomy suction blood from
the CPB circuit have yielded results which suggest that sur-
gical trauma, rather than CPB, may prove to be a more sig-
nificant driver of inflammation than CPB.322,329,330,333 In
low-risk patients, differences in markers of inflammation
may be indistinguishable.329
A final consideration regarding the role of OPCAB in min-
imizing inflammation is that although global myocardial
ischemia may be avoided, regional myocardial ischemia
continues to occur. When the anastomoses are complete
and blood flow is restored, all the same factors are in play
in terms of I/R injury. The preservation of regional myocar-
dial perfusion by using coronary shunts may preserve left
ventricular function334–336 and prevent severe hemody-
namic consequences,337 but the ability of shunts to prevent
I/R injury has not been adequately examined. Thus,
although ischemic myocardial damage may be lessened
by OPCAB,338,339 it is not eliminated,340 nor is I/R injury.
The ROOBY (Randomized On/Off Bypass) trial was a ran-
domized controlled trial comparing on-pump CABG and
11 • Prevention of Ischemic Injury in Cardiac Surgery 133
OPCAB.341 A total of 2203 patients were included in the
analysis. No difference was observed in early mortality.
However, at 1 year, the OPCAB has significantly inferior
graft patency compared with the on-pump CABG cohort
(82.5% versus 87.8%; P < .01). Furthermore, patients in
the OPCAB had fewer grafts performed. Critics of this trial
will point to the inclusion of operations where surgical res-
idents were involved, pointing toward the steep learning
curve of the procedure. Regardless, OPCAB remains a viable
option in experienced hands and in certain clinical settings
(i.e., porcelain aorta). However, the superiority over on-
pump CABG remains to be settled.
Myocardial conditioning. As investigation into the
molecular machinery of I/R injury enters its fourth decade,
we understand that adaptive, protective cellular mecha-
nisms exist. Much current research is aimed at understand-
ing the key receptors, transduction pathways, and
molecular mediators involved so that we may develop
methods to modify gene expression in order to shift cellular
machinery toward a protective phenotype. The phenome-
non of myocardial conditioning is reputed to provide the
most powerful protection against ischemic injury yet
demonstrated.
PRECONDITIONING. In 1986, Murry and colleagues reported
their somewhat paradoxical findings that brief, nonsustained
periods of I/R could actually diminish the effects of a sub-
sequent prolonged I/R event.342 This phenomenon, termed
ischemic preconditioning, leads not only to smaller infarct
size342 but also to fewer I/R-induced arrhythmias,343
improved postischemic contractile recovery,344 reduced
ventricular remodeling,345 and improved survival. Later
research established that the protection afforded by precondi-
tioning occurs in two phases, with an early period of
protection beginning within minutes of the preconditioning
event and lasting several hours (“classical” or “early”
preconditioning),346 and a later period of protection begin-
ning approximately 24 hours after the preconditioning
regimen and lasting as long as 3 to 4 days (“delayed
preconditioning”).347,348
Since the initial description by Murry using a canine
model, the beneficial effects of IPC have been demonst-
rated experimentally in multiple species,349–354 including
humans.355–358 In addition to myocardial ischemia, other
physiologic and pharmacologic stimuli have been shown
to trigger preconditioning, including remote ischemia,359
rapid atrial pacing,360 heat shock,347 adenosine,361 opi-
oids,362 volatile anesthetics,363,364 endotoxin,365 and many
others. Extensive research has significantly advanced our
understanding of the molecular mechanisms underlying
both IPC and I/R.366
Unfortunately, efforts to translate these promising labora-
tory findings into clinical therapies have proven disappoint-
ing, as recently highlighted by a Working Group of the
National Heart, Lung, and Blood Institute.367 One of the dif-
ficulties in translating the gains made in our basic science
understanding of the preconditioning phenomenon into
clinical practice is that the onset of the ischemic event
(e.g., in the case of acute coronary syndromes) is often
unpredictable. Although certain at-risk patients may one
day benefit from pharmacologic strategies aimed at harnes-
sing the protective power of delayed preconditioning, early
134 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
preconditioning–focused strategies will be less applicable in
these unforeseeable events. On the other hand, cardiac sur-
gery and transplantation are two examples of instances in
which the nature and timing of the I/R event are predictable
and controllable, and thus surgical I/R is very amenable to
strategies aimed at exploiting the resistance to injury pro-
vided by early preconditioning.355,356,368,369
Unfortunately, despite the wealth of supporting labora-
tory data, results in humans in the clinical setting have been
mixed.370–372 In fact, a large randomized trial comparing
remote ischemic preconditioning (RIPC) with controls prior
to cardiac surgery found no difference in outcomes between
groups.373 Furthermore, a recent meta-analysis of RIPC
found that this technique offered no benefit in morbidity
or mortality in patients undergoing cardiac surgery.374
Therefore, this technique has largely been abandoned in
contemporary practice.
POSTCONDITIONING. The beneficial effects of modified reperfu-
sion have been known for many years375,376 and have been
demonstrated in the clinical setting.377 In 2003, Zhao,
Vinten-Johansen, and colleagues at Emory published the
first study describing a variation of controlled reperfusion
they entitled postconditioning.378 Using an open-chest
canine model, they demonstrated that by briefly interrupt-
ing reperfusion in a repetitive fashion at the onset of coro-
nary reflow, infarct size was greatly diminished. These
intriguing findings have since been achieved in other ani-
mal models, with a degree of protection comparable to that
seen with preconditioning.379,380 In addition to decreasing
infarct size, protection against life-threatening arrhythmias
has also been shown.381
Although the mechanisms of postconditioning protection
are undefined, possibilities include an attenuation of injury
caused by reactive oxygen species,378 the prevention of car-
diomyocyte hypercontracture,296 a reduction in ischemia-
induced swelling,382 and activation and “cross-talk” of var-
ious “cell survival” pathways.380,383,384 Some of the key
mediators involved in preconditioning have been studied
in postconditioning protocols. In addition to ischemia, anes-
thetics,385 adenosine,386,387 bradykinin,388 and insulin389
are protective when given immediately before or at the time
of reperfusion. Important effectors include mitochondrial
adenosine triphosphate-regulated potassium (KATP) chan-
nels,380 the mitochondrial permeability transition pore,390
and phosphoinositide 3-kinase-Akt.385,387,391
Although still in its infancy, the field of postconditioning
has tremendous appeal because of its potential therapeutic
impact.378 As noted earlier, one of the great difficulties in
applying preconditioning strategies in the clinical setting
is that the ischemic event is frequently unpredictable. In
postconditioning, by contrast, any proposed intervention
comes at the time of reperfusion, the manner and timing
of which is under the control of the physician. Furthermore,
in cases of planned I/R (e.g., CABG or organ transplant), a
combination of preconditioning and postconditioning strat-
egies may yield protection superior to either alone.380
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activation. Basic Res Cardiol. 2005;100:57–63.
388. Bell RM, Yellon DM. Bradykinin limits infarction when administered
as an adjunct to reperfusion in mouse heart: The role of PI3K, Akt and
eNOS. J Mol Cell Cardiol. 2003;35:185–193.
389. Jonassen AK, Sack MN, Mjos OD, et al. Myocardial protection by insu-
lin at reperfusion requires early administration and is mediated via
Akt and p70s6 kinase cell-survival signaling. Circ Res. 2001;89:
1191–1198.
390. Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibits
mitochondrial permeability transition. Circulation. 2005;111:194–197.
391. Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning: A form
of “modified reperfusion” protects the myocardium by activating
the phosphatidylinositol 3-kinase-Akt pathway. Circ Res. 2004;95:
230–232.
 12 Prevention of Ischemic Injury
in Noncardiac Surgery
ANNEMARIE THOMPSON and STEPHEN HARRISON GREGORY
Introduction
Perioperative myocardial infarction (MI) is the most com-
mon cause of death in the early postoperative period.1 Peri-
operative ischemia can be caused by either acute coronary
thrombosis or by a mismatch between myocardial oxygen
supply and demand.1 While the inflammatory response to
surgery itself may be responsible for precipitating acute pla-
que rupture and MI, other hemodynamic disturbances,
including hypertension/hypotension, tachycardia, acute
blood loss, and anemia, may be also lead to ischemic events
in vulnerable patients.2,3
A comprehensive approach to the evaluation and man-
agement of patients at risk for major adverse cardiac events
(MACE) in the perioperative period is essential to optimize
outcomes in this population. In this chapter, we discuss
the perioperative management of patients at risk of MI,
including preoperative medical optimization, intraoperative
management, and anesthetic selection. We also discuss
emerging concepts in ischemia prevention. Emphasis is
placed on current American College of Cardiology/Ameri-
can Heart Association (ACC/AHA) guidelines for periopera-
tive management and the European Society of Cardiology/
European Society of Anaesthesiology (ESC/ESA) guidelines
on noncardiac surgery.4,5
Pathophysiology and Natural
History of Perioperative Ischemia
The pathophysiology of perioperative MI is complex and
variable. Generally, there are two subtypes of perioperative
ischemia: acute coronary syndrome from thrombotic occlu-
sion of a coronary artery and demand ischemia. Demand
ischemia is far more prevalent than acute coronary syn-
drome as the etiology of perioperative MI.1 Perioperative
MI typically occurs in the first 4 postoperative days,
although it can occur at any point during hospitalization
(Fig. 12.1).6
In contrast to medical patients presenting with MI, who
primarily die of thrombotic coronary occlusion, angio-
graphic studies of patients who had a fatal perioperative
MI showed a much lower rate of plaque rupture.6–8 This
suggests that myocardial oxygen supply and demand mis-
match play a much more prominent role in perioperative
MI. Predictably, patients with a high burden of coronary
artery disease preoperatively are at elevated risk for periop-
erative MI. The number and severity of lesions is correlated
with the risk of perioperative mortality in vascular surgery
patients, and the presence of a chronic total occlusion of a
coronary artery with collateralization is common in patients
experiencing perioperative MI.9
The incidence of perioperative MI varies, depending on
the definition used, but even a minor increase in serum tro-
ponin is associated with a significant increase in 30-day
mortality, although a cause-and-effect relationship has
not been firmly established.10 Importantly, studies suggest
the majority of patients with perioperative MI will not pre-
sent with symptoms of ischemia, and there should be a low
threshold to initiate an ischemic workup in postoperative
patients who demonstrate evidence of clinical decompensa-
tion. Ultimately, patients who develop perioperative MI are
at a significantly increased risk of mortality, with the largest
cohort to date examining outcomes in this patient popula-
tion showing a fivefold increase in 30-day mortality in
patients with perioperative MI.11
Preoperative Optimization
SCREENING AND RISK STRATIFICATION
A detailed discussion of preoperative cardiac assessment can
be found in Chapter 5. In general, risk stratification for non-
cardiac surgery is performed by assessing functional status
and for the presence of comorbidities that predict an
increased risk of MACE. Functional status can be deter-
mined formally, via exercise testing or a number of existing
validated activity indices, or informally, by assessing activ-
ities of daily living. Patients who are unable to perform
greater than 4 metabolic equivalents of activity are at
increased risk of MACE, independent of other comorbid-
ities.12 Similarly, elderly patients who have significant
frailty, as defined by a number of scoring systems, are at
increased risk of adverse perioperative events.13
Assessment of preexisting comorbidities is also useful for
defining perioperative risk, and there are a number of tools
that can be used to help assess for risk of MACE. The revised
cardiac risk index is a straightforward and easy method of
estimating the risk of MACE. Patients are assessed for six cri-
teria: (1) ischemic heart disease, (2) cerebrovascular dis-
ease, (3) serum creatinine >2 mg/dL, (4) congestive heart
failure, (5) insulin-dependent diabetes mellitus, and (6)
high-risk surgery.14 Patients with zero or one criterion
are at low risk for MACE, and patients who meet two or
more criteria are at increased risk.4 While this algorithm
played a central role in directing preoperative cardiac
assessment in the 2007 AHA/ACC preoperative testing
guidelines, its utility has been deemphasized in the 2014
143
144 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
100%
90%
80%
70%
60%
50%
40%
30%
25% 25%
20% 16%
12%
10%
5% 3%
1% 1%
0%
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Fig. 12.1 Cumulative (gray) and proportional (black) presentation per
day of perioperative myocardial infarction. (With permission from Bic-
card BM, Rodseth RN. The pathophysiology of peri-operative myocardial
infarction. Anaesthesia. 2010;65(7):733–741.)
edition of the guidelines in favor of more sophisticated indi-
ces of preoperative risk assessment, such as the American
College of Surgeons National Surgical Quality Improvement
Program, Myocardial Infarction or Cardiac Arrest, and sur-
gical risk calculators.4,15 The current algorithm from the
ACC/AHA guidelines for preoperative assessment detailing
decision making for preoperative cardiac testing can be
found in Fig. 12.2.
MYOCARDIAL REVASCULARIZATION
The role of preoperative myocardial revascularization in the
patient with significant coronary artery disease remains
controversial, and current literature is conflicting as to its
clinical benefit.16 Most large studies evaluating the utility
of preoperative revascularization have been performed in
the high-risk vascular surgery population. In 2004, the
CARP (Coronary Artery Revascularization Prophylaxis)
trial demonstrated no significant mortality benefit and no
reduction in 30-day MI in patients who underwent preop-
erative revascularization with either percutaneous coro-
nary intervention (PCI) or coronary artery bypass grafting
(CABG).17
The management of the patient undergoing preoperative
evaluation who is found to have significant coronary artery
disease depends on (1) the urgency of the surgery, (2) the
anatomic distribution of their coronary artery disease, and
(3) their degree of clinical symptoms. The most recent rec-
ommendations suggest that patients scheduled for an
elevated-risk surgical procedure who are found to have cor-
onary artery disease for which CABG is indicated should
undergo CABG prior to proceeding with their originally
scheduled procedure if the procedure is not of a time-
sensitive nature. The role of PCI is less clear in the perioper-
ative setting and should only be performed in those patients
with left main coronary artery disease who are not candi-
dates for CABG or patients with unstable angina or MI.4
Importantly, patients presenting for elective surgery
with a significant burden of coronary artery disease should
be involved in the surgical decision-making process, with
consideration for cancelation or delay of surgery if
perioperative risk is felt to be high. Perioperative manage-
ment and decisions regarding preoperative revasculariza-
tion should be made with input from a multidisciplinary
team, including the patient’s cardiologist, surgical team,
and anesthesiologist.
MEDICATION OPTIMIZATION
Preoperative medication optimization has remained a major
focus in the anesthetic literature, with numerous major
clinical trials attempting to ascertain the potential of various
medications to prevent perioperative ischemic events.
Although a number of medications have been evaluated,
determining the optimal medical regimen for preventing
perioperative ischemic events remains under investigation.
Here, we review the current evidence for common medica-
tions, as well as the current guidelines for perioperative
medication management.4,5
BETA-BLOCKADE
The use of beta-adrenergic blocking agents in the periop-
erative period has been a subject of intense clinical inves-
tigation. In general, research into the management of
beta-blockers in the perioperative period has focused on
the management of patients already taking beta-blockers
with examination of the effect of beta-blocker discontinu-
ation and on patients who are not taking beta-blockers
preoperatively but are deemed to be at elevated risk of
perioperative MACE.
The continuation of beta-blockade in patients previously
taking beta-blockers is a core measure in the Surgical Care
Improvement Project, with a Class I recommendation in the
current ACC/AHA guidelines. Interestingly, despite an
extensive body of prospective literature examining initiation
of beta-blockade in the perioperative period, the evidence for
beta-blocker continuation is still evolving. A 2001 study of
140 vascular surgical patients showed a 50% mortality rate
in patients who had beta-blockers discontinued in the early
postoperative period, but this group only constituted 8
patients out of a cohort of 140.18 Hoeks and colleagues
examined a similar cohort of 711 vascular surgery patients
and found an increase in 1-year mortality in patients who
had their beta-blockers discontinued perioperatively.19
These two studies formed the basis for the initial recommen-
dation for beta-blocker continuation in the 2007 ACC/AHA
guidelines.15 More recent studies examining larger cohorts
showed a less dramatic difference but collectively concluded
that continuation of beta-blockers was associated with a
lower overall risk of cardiovascular events and mortality
in patients receiving them preoperatively.20,21
With regard to the initiation of beta-blockade in the peri-
operative period, the available evidence suggests that initi-
ation on the day of surgery may potentially be detrimental.
The largest study to date evaluating perioperative beta-
blocker administration was the POISE (PeriOperative ISche-
mic Evaluation) trial. This trial prospectively randomized
over 8000 patients to high-dose, extended-release metopro-
lol or placebo beginning on the morning of surgery and con-
tinuing for 30 days.22 While the administration of
metoprolol was found to be associated with a lower risk of
 12 • Prevention of Ischemic Injury in Noncardiac Surgery 145

*See sections 2.2, 2.4, and 2.5

Patient scheduled for surgery with in the full-text CPG for
known or risk factors for CAD* recommendations for patients
(Step 1) with symptomatic HF, VHD, or
arrhythmias.

†SeeUA/NSTEMI and STEMI

CPGs (Table 2).
Clinical risk stratification
Emergency Yes and proceed to surgery

No

ACS† Evaluate and treat

Yes
(step 2) according to GDMT†

No

Estimated perioperative risk of MACE No further

based on combined clinical/surgical risk testing
(step 3) (Class IIa)

Excellent
(>10 METs)

Low risk (< 1%) Elevated risk Moderate or greater Proceed to

(Step 4) (Step 5) (≥4 METs) functional surgery
capacity
Moderate/Good
( 4–10 METs)

No further
No further testing
No or
testing (Class IIb)
Unknown
(Class III:NB)

Proceed to Poor OR unknown

surgery functional capacity
(<4 METs): Pharamacologic
will further testing impact Yes stress testing
decision making OR (class IIa)
perioperative care?
(Step 6)
If If
normal abnormal

No Coronary
revascularization
Proceed to surgery according to existing
according to GDMT OR CPGs (Class I)
alternate strategies
(noninvasive treatment,
palliation)
(Step 7)
Fig. 12.2 Algorithm for perioperative decision making, risk stratification, and preoperative cardiac evaluation. ACS, Acute coronary syndrome;
CAD, coronary artery disease; CPG, clinical practice guidelines; GDMT, guideline-directed medical therapy; HF, heart failure; MACE, major adverse cardiac
events; MET, metabolic equivalents; VHD, valvular heart disease. (With permission from 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-e137.)
146 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
MI, there was an overall increase in the risk of stroke and
mortality. In 2014, the ACC/AHA Task Force on Practice
Guidelines issued a systematic review specific to periopera-
tive beta-blocker therapy.23 Consistent with the POISE trial,
this systematic review examining over 12,000 patients
demonstrated that the initiation of beta-blocker therapy
within 1 day of surgery was associated with an overall
decrease in the incidence of MI but an increase in stroke,
hypotension, and bradycardia. This study also suggested a
possible increase in cardiac and all-cause mortality in this
population. To date, the effect of initiating beta-blocking
medications days to weeks in advance of an operation has
not been rigorously evaluated and remains a focus of contin-
ued investigation.
Current Recommendations
The 2014 ACC/AHA guidelines for patients undergoing
noncardiac surgery suggest that patients receiving beta-
blockers preoperatively should be continued on them in
the perioperative period (Class I). Patients who are deemed
to be at high risk of perioperative MACE may benefit from
the initiation of beta-blockers prior to surgery, but there
should be adequate time to assess the safety and tolerability
of beta-blockade (Class IIB). The guidelines caution against
the initiation of beta-blocker therapy on the day of surgery
(Class III).4
The 2014 ESC/ESA guidelines also emphasize the utility
of beta-blocker continuation in patients receiving them pre-
operatively (Class I) and advocate for the initiation of beta-
blockers in patients scheduled for high-risk surgery with at
least two clinical risk factors or American Society of Anes-
thesiologists physical status >3 or patients with known
ischemic heart disease (Class IIB). However, these guidelines
advocate for consideration of atenolol or bisoprolol as a first-
choice beta-blocker (Class IIB), in contrast to the ACC/AHA
guidelines, which do not specify which specific beta-blocker
should be used. The guidelines recommend against periop-
erative initiation of high-dose beta-blockers or initiation in
patients having low-risk surgery (Class III).5
STATINS
Until recently, evidence for the perioperative use of statin
therapy for prevention of MACE was limited to high-risk
patients undergoing vascular or cardiothoracic surgery,
with guidelines primarily emphasizing the utility of statin
continuation in patients treated with preoperative statin
therapy.4,15,24,25 Recently, London and colleagues per-
formed a large, retrospective, observational review on over
180,000 patients undergoing noncardiac surgery whose
information is recorded in the Veterans Affairs (VA) Surgical
Quality Improvement Database. They found that exposure
to statins on the day of or day after surgery was associated
with a significant reduction in 30-day mortality as well as
cardiac, respiratory, renal, and infectious complications.25
The benefit of initiating statin therapy in patients not pre-
viously on a statin is less well defined. A 2015 systematic
review examined 16 randomized controlled trials that eval-
uated preoperative initiation of statin therapy on morbidity
and mortality. Of note, 13 of 16 trials looked exclusively at
patients having CABG. The authors demonstrated a
reduction in mortality, MI, atrial fibrillation, and hospital
length of stay, concluding with a recommendation that
the initiation of statin therapy should be considered in
statin-naïve patients having cardiac surgery, although they
were unable to make recommendations based on their sub-
group analysis in the noncardiac surgical population.24 In
contrast, a 2013 Cochrane systematic review concluded
that statin therapy was not associated in any significant
reduction in mortality, cardiovascular-specific mortality,
or MI, although it should be noted that the sample reviewed
in this analysis was quite small.26 Unfortunately, as the
authors of this analysis noted, the use of statin medications
in the population at risk for MACE is already ubiquitous,
making large randomized controlled trials difficult to
perform.
Current Recommendations
The current ACC/AHA guidelines recommend the continu-
ation of statins during the perioperative period in patients
who are already taking them preoperatively (Class I). The
guidelines also suggest that preoperative initiation of statins
is reasonable in patients who are undergoing vascular sur-
gery (Class IIA) and potentially other elevated-risk proce-
dures, if risk factors for perioperative MACE are present
(Class IIB).4 The ESC/ESA guidelines mirror the ACC/AHA
guidelines for statin use.5
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/
ANGIOTENSIN RECEPTOR BLOCKERS
Angiotensin-converting enzyme (ACE) inhibitors and angio-
tensin receptor blockers (ARBs) are commonly prescribed
medications for the management of hypertension and heart
failure. Despite the ubiquity of these medications, they have
not been the subject of a large number of randomized con-
trolled trials, as beta-adrenergic blocking drugs have.
Instead, investigation of the perioperative management of
ACE/ARB medications has proceeded primarily through
large retrospective cohort analyses. Current research has
focused on (1) whether to continue or stop ACE inhibitors
and ARBs in the perioperative period and (2) the benefits
of early resumption of therapy following surgery.27–29
Although the current ACC/AHA guidelines recommend
continuation of ACE inhibitors or ARBs during the perioper-
ative period, recent evidence suggests that the discontinua-
tion of these medications may actually be associated with a
lower risk of death or postoperative vascular complica-
tions.30 This analysis retrospectively analyzed 4802
patients taking an ACE inhibitor or an ARB who underwent
noncardiac surgery. The 1245 patients who discontinued
their ACE inhibitor/ARB prior to surgery had a lower inci-
dence of death, stroke, and myocardial ischemia, as well
as less intraoperative hypotension. This study is in contrast
to a 2012 study by Turan and colleagues demonstrating no
increase in perioperative morbidity or mortality in patients
taking ACE inhibitors and ARBs in the perioperative
period.29
The utility of early postoperative resumption of ACE
inhibitor therapy was investigated in a large retrospective
cohort study of VA patients undergoing noncardiac surgery.
In this study, the authors demonstrated that failing to

resume ACE inhibitor therapy within the first 14 postoper-
ative days is associated with a large increase in 30-day post-
operative mortality (hazard ratio, 3.44). Although this
retrospective analysis of patients does not establish a causal
relationship between failure to resume ACE inhibitors in the
postoperative period and eventual mortality, this large study
formed the basis for recommendations for early resumption
of therapy in the current ACC/AHA guidelines.4,27
Current Recommendations
The current ACC/AHA guidelines suggest that it is appropri-
ate to continue ACE inhibitors and ARBs during the periop-
erative period (Class IIA). In patients in whom ACE/ARB
medications are discontinued, the guidelines recommend
early resumption of therapy (Class IIA).
The ESC/ESA guidelines also recommend continuation of
ACE inhibitors and ARBs in patients with stable heart failure
or left ventricular dysfunction (Class IIA), but they suggest
that temporary discontinuation in patients taking ACE
inhibitors or ARBs for hypertension may be appropriate
(Class IIA). The ESC/ESA guidelines also recommend the ini-
tiation of ACE inhibitors or ARBs at least 1 week prior to sur-
gery in patients with heart failure or ventricular dysfunction
(Class IIA). However, as discussed above, discontinuation of
ACE inhibitors and ARBs in the perioperative period should
be considered, given new clinical data.
ALPHA-2 AGONISTS
Alpha-2 agonists are widely used for control of hyperten-
sion, and their sympatholytic properties make them poten-
tial candidates to prevent perioperative MI. There was initial
enthusiasm for the use of alpha-2 agonists for myocardial
protection based on early studies showing potential benefit
in reducing perioperative morbidity and myocardial ische-
mia in vascular surgery patients.31 This conceptually
formed the basis for the POISE-2 trial examining the utility
of both aspirin and clonidine in preventing perioperative MI.
The POISE-2 trial randomized over 10,000 patients to
receive either clonidine or placebo with or without aspirin
in a 2-by-2 design. Unfortunately, neither clonidine nor
aspirin reduced the incidence of MI or death within 30 days
of surgery.32 A subsequent analysis examined the potential
ability of clonidine or aspirin to prevent acute kidney injury
following noncardiac surgery and again found no benefit.33
Current Recommendations
Starting or administering alpha-2 agonists to prevent peri-
operative MACE is not recommended in the current ACC/
AHA guidelines (Class III) or ESC/ESA guidelines.
ASPIRIN AND ANTIPLATELET AGENTS
A substantial number of patients at risk for perioperative MI
present for surgery taking one of more antiplatelet agents.
These patients can be separated into several groups, which
will be discussed here: (1) patients who are on aspirin for pri-
mary prevention of cardiovascular events, (2) patients with
a history of coronary artery disease and prior bare metal
12 • Prevention of Ischemic Injury in Noncardiac Surgery 147
stent, (3) patients with a history of coronary artery disease
and prior drug-eluting stent, and (4) patients who have
undergone recent CABG.
As discussed previously, the initiation or continuation of
aspirin therapy to prevent perioperative MI was investigated
as part of the POISE-2 trial. This study demonstrated no sig-
nificant reduction in perioperative ischemic events but did
show a significant increase in the risk of major bleeding
in patients receiving aspirin compared with placebo.34 Over-
all, this trial suggests that the continuation of aspirin in
patients without recent coronary artery stenting to prevent
perioperative MI is probably not beneficial and may be
harmful. There are a number of important patient popula-
tions excluded in this trial, most notably patients with
recent drug-eluting stent or bare metal stent placement,
in whom the management of antiplatelet agents deserves
special consideration.
Patients with recent stent placement are at increased risk
of in-stent thrombosis, especially with the discontinuation of
antiplatelet therapy.35,36 However, the optimal approach to
the management of dual antiplatelet therapy in these
patients in the perioperative period remains unclear. A
recent ACC/AHA guideline update on the management of
dual antiplatelet therapy advocates a more nuanced
approach to antiplatelet therapy in patients with coronary
artery disease, with therapy duration based on the type of
stent placed, whether the patient presented with stable
ischemic heart disease or an acute coronary syndrome,
and an assessment of the patient’s overall bleeding risk.37
In patients who have stable ischemic heart disease and a
high bleeding risk, the guidelines suggest that it may be
appropriate to discontinue clopidogrel as early as 3 months
following drug-eluting stent placement. The association
between stent indication and perioperative MACE was
recently investigated as part of a large retrospective analysis
of VA patients in the United States undergoing noncardiac
surgery.38 In this study, patients who had a stent placed for
MI were at significantly increased risk of perioperative
MACE, regardless of the type of stent that was placed.
Although these data and recommendations have not yet
been incorporated into guidelines for perioperative manage-
ment, it seems likely that a more selective approach to anti-
platelet agent discontinuation may be forthcoming. In these
recommendations, patients undergoing CABG also have
stratified recommendations based on their presentation,
with a Class I recommendation for the use of a P2Y12 inhib-
itor in patients with acute coronary syndrome who have
CABG and a Class IIB recommendation for 12 months of
P2Y12 inhibitor therapy in patients presenting with stable
ischemic heart disease.
Ultimately, a patient presenting for noncardiac surgery
on antiplatelet therapy should undergo a comprehensive
risk assessment with involvement of the patient’s cardiolo-
gist, anesthesiologist, and surgical team to discuss the rela-
tive risks of surgical bleeding and perioperative cardiac
events. Discontinuation of antiplatelet therapy, especially
in patients with recent cardiac stent placement, may
increase the risk of in-stent thrombosis/stenosis and periop-
erative MI. Depending on the urgency of the operation, it
may be appropriate to delay surgery to attempt to reduce
the potential risk of antiplatelet therapy discontinuation.
148 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Current Recommendations
The current ACC/AHA guidelines recommend continuation
of dual antiplatelet therapy in any patient undergoing non-
cardiac surgery in the first 4–6 weeks following either bare
metal stent or drug-eluting stent placement. If it is necessary
to discontinue the patient’s P2Y12 inhibitor, aspirin should
be continued and the P2Y12 inhibitor should be restarted as
soon as is safe following the surgical procedure (Class I). In
patients without prior coronary stenting, clinicians may
continue aspirin when the risk of bleeding is outweighed
by the risk of cardiac events (Class IIb), but the initiation
or continuation of aspirin is not beneficial in elective non-
cardiac surgery that does not involve carotid artery inter-
vention (Class III) (Fig. 12.3).4
The ESC/ESA guidelines also recommend continuation of
aspirin for a minimum of 4 weeks after bare metal stent
placement or 3–12 months after drug-eluting stent place-
ment, unless the risk of life-threatening hemorrhage is
deemed to be inappropriately high (Class I) with a similar
time course for patients taking P2Y12 inhibitors (Class
IIA). Outside of these time periods, the management of
patients taking aspirin or P2Y12 inhibitors should be made
with consideration of the potential risk of hemorrhage bal-
anced with the patient’s risk of perioperative MACE.5
With regard to the timing of elective surgery after stent
placement, the ACC/AHA guidelines recommend a delay
of 14 days following balloon angioplasty, 30 days following
bare metal stent placement, and 365 days following drug-
eluting stent placement (Class I), although elective surgery
can be considered at 180 days following drug-eluting stent
placement (Class IIB). Elective noncardiac surgery should
not be performed within 30 days of bare metal stent place-
ment or 365 days of drug-eluting stent placement if the peri-
operative discontinuation of dual antiplatelet therapy is
required.4 This timing is consistent with that outlined in
the ESC/ESA guidelines.5
Intraoperative Management
ANESTHETIC SELECTION
Despite a large quantity of evidence examining the relative
benefits of neuraxial, regional, and general anesthesia in
patients at risk of adverse perioperative outcomes, the
“ideal” anesthetic technique for this patient population
remains elusive.39–44 A large Cochrane systematic review
of prior systematic reviews examined trials evaluating the
utility of neuraxial versus general anesthesia in improving
perioperative outcomes. In this trial, the authors demon-
strated an overall reduction in mortality (7.9% vs 5.2%)
and postoperative pneumonia (16.8% vs 7.6%) in the
neuraxial anesthesia group, but there was no difference
in perioperative MI. In contrast, the addition of a neuraxial
technique to a general anesthetic did not appear to
improve perioperative mortality or cardiovascular morbid-
ity, but it did still show benefit in preventing perioperative
pneumonia.43
The utility of volatile versus intravenous anesthesia also
remains uncertain. Based on existing literature, the 2007
ACC/AHA guidelines recommended consideration for the
use of volatile anesthesia over intravenous anesthesia in
patients at risk for perioperative myocardial ischemia,
although data at the time of publication were primarily lim-
ited to the cardiac surgery population, with extrapolation to
noncardiac surgery patients.15 Further research in the non-
cardiac surgery population has not demonstrated any
advantage from volatile over intravenous anesthesia.45,46
In light of recent evidence, the 2014 ACC/AHA guidelines
no longer recommend the use of volatile anesthesia as a
means to mitigate myocardial ischemia in noncardiac
surgery.4
MONITORING FOR ISCHEMIA
Intraoperative assessment for myocardial ischemia is an
important responsibility of the anesthesiologist caring for
the patient in the operating room. By far, the most common
method of monitoring for myocardial ischemia in the peri-
operative period is via routine electrocardiography
(ECG).47 ECG monitoring is an American Society of Anes-
thesiologists standard monitor and is used in virtually every
anesthetic administered in the United States. Typically, a
five-lead ECG is used to allow for the monitoring of multiple
leads during the anesthetic, thus increasing the sensitivity of
the ECG for myocardial ischemia.48 Unfortunately, surgical
constraints (altering lead placement), filtering, and artifact
may all result in a suboptimal ECG signal, reducing the sen-
sitivity of the ECG for MI.
Pulmonary artery catheterization can also provide evi-
dence of evolving myocardial ischemia, although its use out-
side of the cardiac surgical operating room is becoming
increasingly rare.49 Myocardial ischemia may manifest as
an acute decrease in cardiac index, typically with a concom-
itant increase in pulmonary capillary wedge pressure.47,49
A large Cochrane review examining the potential utility
of the pulmonary artery catheter in the critical care setting
demonstrated no significant change in mortality, length of
stay, or cost, although it could be argued that the use of a
pulmonary artery catheter as a monitor would not neces-
sarily be expected to lead to improvements in clinical out-
come.50 Regardless of these considerations, pulmonary
artery catheterization outside of cardiac surgery and liver
transplantation is typically reserved for the exceptionally
high-risk patient.
Transesophageal echocardiography (TEE) is another use-
ful and sensitive modality for the detection of perioperative
myocardial ischemia that is being used more frequently in
noncardiac surgery.51,52 The presence of a new regional
wall motion abnormality on TEE is typically the earliest indi-
cator of new-onset myocardial ischemia.52 Interestingly,
there is a striking lack of concordance between TEE and
ECG, suggesting that they are complementary modalities
for the evaluation of perioperative ischemia.51 The use of
TEE in cardiac surgery is well established, with clinical prac-
tice guidelines suggesting its use in all patients undergoing
open-heart or thoracic aortic surgery.53 In contrast, guide-
lines for the use of TEE in noncardiac surgery are less well
defined. The 2010 Practice Guidelines for Perioperative
Transesophageal Echocardiography suggest that TEE
should be used when the planned surgery or patient pathol-
ogy may result in severe hemodynamic, respiratory, or
 12 • Prevention of Ischemic Injury in Noncardiac Surgery 149

Patient with coronary stent

Delay surgery until

Stent
after optimal period
implantation Yes Elective surgery Yes
(BMS: 30 d and DES:365 d)
≤4–6 wk
(Class I)

No
No

Continue DAPT
Risk of surgival delay DES ≥30 d, unless risk of
is greater than risk of Yes but ≤365 d* bleeding is
DES thrombosis greater than risk
of stent
thrombosis
(class I)

Yes No
No

Proceed to Delay surgery until

surgery after after optimal period
180 d (BMS: 30 d and
(Class IIb) DES:365 d)
(Class I)

Does surgery
demand discontinuation
P2Y12 inhibitors*?

No Yes

Continue ASA
Continue current and restart P2Y12
DAPT regimen ASAP
(Class I)

Fig. 12.3 Algorithm for management of patients taking dual antiplatelet therapy following cardiac stent placement. ASA, Acetylsalicylic acid; BMS,
bare-metal stent; DES, drug-eluting stent; DAPT, dual antiplatelet therapy; P2Y12, inhibitor. (With permission from 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–e137.)

neurologic compromise or in the presence of unexplained MANAGEMENT OF INTRAOPERATIVE ISCHEMIA

hemodynamic instability.53 A recent review of 364 rescue
TEE scans performed for unexplained hemodynamic insta-
bility in general operating room patients found new regional
wall motion abnormalities to be the fourth most common
cause of perioperative decompensation (13.5%) after hypo-
volemia (24.5%) and global left ventricular (16.5%) or right
ventricular (16.2%) failure.54 In the case of suspected
intraoperative ischemia or persistent hemodynamic insta-
bility, TEE is an excellent monitor to guide therapy.
Once the presence of intraoperative ischemia is suspected or
confirmed, the anesthesiologist must take steps to attempt to
minimize myocardial damage and direct appropriate ther-
apy.52 The approach to intraoperative ischemia should be
directed by (1) the timing of onset, (2) the urgency of the
surgical procedure, (3) the type of ischemia or ECG changes
that are observed, and (4) the degree of hemodynamic insta-
bility. If evidence of myocardial ischemia is observed prior to
150 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
the beginning of the surgical procedure, the procedure
should be delayed to allow for further evaluation and possi-
ble intervention. If the surgical procedure is urgent or emer-
gent, or the ischemia occurs at a point at which the
procedure cannot be aborted, the anesthesiologist should
attempt to mitigate myocardial demand ischemia by opti-
mizing the patient’s myocardial oxygen supply and demand.
This is accomplished by increasing diastolic blood pressure
(augmenting coronary perfusion pressure), decreasing
heart rate, increasing the fraction of inspired oxygen, and
increasing oxygen delivery via blood transfusion, depending
on the degree of surgical blood loss and need for ongoing
resuscitation.52 Nitroglycerin and heparin may also be used
if the patient is hemodynamically stable and anticoagula-
tion is acceptable to the surgical team.
Patients with evidence of myocardial ischemia and hemo-
dynamic instability require aggressive resuscitation to
attempt to prevent further decompensation and cardiac
arrest. TEE can provide guidance as to the cause of hemody-
namic instability and the degree of myocardial dysfunc-
tion.54 These patients may require vasopressor support in
addition to inotropic support, though caution should be
exercised when using inotropes in patients with ongoing
ischemia because of the risk of exacerbating the myocardial
oxygen supply and demand mismatch as well as the risk of
malignant arrhythmias.55 In patients with refractory myo-
cardial ischemia and hemodynamic decompensation, the
use of intra-aortic balloon counterpulsation can be consid-
ered as a bridge to definitive therapy (Fig. 12.4).
The postoperative management of the patient with peri-
operative myocardial ischemia is challenging, as the anti-
platelet and anticoagulant agents that are commonly
used during the acute medical management of cardiac
ischemia may worsen surgical bleeding. With the exception
of patients with an absolute contraindication to anticoagu-
lation, patients with ongoing ST-elevation myocardial
infarction should be referred for emergent PCI. The manage-
ment of the patient with non ST-elevation myocardial
infarction is less clear but should proceed with consideration
of patient risk stratification and the degree of hemodynamic
instability. Hemodynamically unstable patients with sus-
pected ischemia typically require PCI. Patients who are
hemodynamically stable can often initially be managed
medically, with the administration of antiplatelet agents,
statins, titrated beta-adrenergic blockade, and ACE inhibi-
tors. If the patient exhibits other high-risk features for pro-
gression to worsening infarction or death, they may be
referred for PCI. Lower-risk patients can be managed more
conservatively, with close postoperative follow-up.56
The use of anticoagulant agents for the prevention of sub-
sequent adverse clinical events after perioperative myocar-
dial injury is an emerging strategy to minimize the clinical
sequelae of these events. In 2018, the MANAGE (Manage-
ment of Myocardial Injury After Noncardiac Surgery) trial
assessed the utility of dabigatran, a direct thrombin inhibi-
tor, to prevent a composite of vascular complications or
mortality, MI, nonhemorrhagic stroke, peripheral arterial
thrombosis, amputation, and symptomatic venous throm-
boembolism following noncardiac surgery complicated by
myocardial injury (as assessed by postoperative troponin).57
This trial showed an overall reduction in the incidence of
the composite outcome without an increase in bleeding
complications in patients who received twice-daily dabiga-
tran. On the basis of these data, the authors of the trial
recommended the measurement of troponin in at-risk
patients undergoing noncardiac surgery and treating
patients with myocardial injury using dabigatran postoper-
atively. To date, this process has not been widely
implemented.
ISCHEMIC PRECONDITIONING
The use of a brief period of ischemia to attempt to mitigate
subsequent ischemic damage is known as ischemic precondi-
tioning.58 The mechanisms underlying ischemic precondi-
tioning have been subject to extensive investigation
starting in the 1980s.59 Early research focused on direct
ischemic preconditioning, in which temporary occlusion
of the coronary arteries was used to attempt to reduce sub-
sequent ischemic damage.60 Direct myocardial ischemic
preconditioning was shown to be beneficial in reducing bio-
chemical evidence of ischemia, as well as in reducing infarct
size in a number of species.60 Interestingly, ischemic precon-
ditioning appears to be associated with a bimodal period of
protection. Following the initial ischemic insult, there is a 1-
to 2-hour period of temporary ischemic protection, which
resolves and then reappears between 24 and 72 hours fol-
lowing the ischemic event.60 The application of direct ische-
mic preconditioning in cardiac surgery was evaluated in a
meta-analysis that showed fewer ventricular arrhythmias,
lower inotropic requirements, and a shorter duration of
intensive care unit stay.61,62 The underlying mechanisms
of ischemic preconditioning are extraordinarily complex,
but they primarily involve activation of multiple signal
transduction pathways that regulate apoptosis and intracel-
lular energy metabolism.61
Early in the investigation of ischemic preconditioning, it
was discovered that these protective cellular effects can be
mediated by a temporary period of ischemia at a site remote
to the heart, either an extremity or another organ. This is
known as “remote ischemic preconditioning.”61 This
broadens the potential applicability to noncardiac surgical
cases, as direct manipulation of the aorta and heart are
no longer necessary. Preliminary data suggested that this
could potentially be equally protective in cardiac surgery
patients, but two large clinical trials in 2015 failed to show
any benefit.63,64 In light of the outcomes of these two trials,
the authors of this text do not recommend the use of routine
remote ischemic preconditioning in noncardiac surgical
patients.
Future Directions in Ischemia
Prevention/Management
To date, perioperative risk stratification has been primarily
been performed by assessing patient comorbidities in con-
junction with the perceived risk of their operation, broadly
categorized into low, intermediate, or high risk. Recent evi-
dence suggests that a more granular approach to risk strat-
ification may be possible.65 In the future, the development of
increasingly complex surgical risk calculators to allow for
more precise preoperative risk assessment will be feasible,
 12 • Prevention of Ischemic Injury in Noncardiac Surgery 151

NSTEMI

Hemodynamic instability/
Hemodynamic stable
cardiogenic shock

Aspirin
Vasopressors as needed
+/–IABP

Refractory
Immeduate cardiac catheterization ischemia
with planned revascularization Initial medical management*
+/–IABP

Aspirin +/–Clopidogrel
Beta blockers
HMG-CoA reductase inhibitors
(Statins).
+/–ACE inhibitor

Recurrent symptoms
High risk features**

Yes No

Caradiac catheterization once

Risk stratification in 4–6 weeks
bleeding risk acceptable

Fig. 12.4 Suggested algorithm for the management of perioperative non-ST elevation myocardial infarction. ACE, Angiotensin-converting enzyme;
IABP, intra-aortic balloon pump; NSTEMI, non-ST elevation myocardial infarction. (With permission from Adesanya AO, de Lemos JA, Greilich NB, et al.
Management of perioperative myocardial infarction in noncardiac surgical patients. Chest. 2006;130(2):584–596.)Pa

given the increasing availability of large perioperative data-
sets and outcome registries.65,66
The use of machine learning to personalize medical inter-
ventions has gained increasing traction in the medical com-
munity, though its utility in changing patient trajectory is
still under debate.67 Although the application of simple deci-
sion support tools to augment perioperative management
has been shown to be beneficial, the role of machine learn-
ing in improving perioperative outcomes remains less
clear.68–70 In the future, it is anticipated that the application
of complex data analysis techniques to develop a personal-
ized approach to perioperative management will likely
become a component of anesthetic care and may help to
mitigate major ischemic events and improve patient
outcome.
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12 • Prevention of Ischemic Injury in Noncardiac Surgery 153
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 13 Treatment of Perioperative
Ischemia, Infarction, and
Ventricular Failure in Cardiac
Surgery
MUATH BISHAWI and CARMELO A. MILANO
Perioperative Myocardial
Ischemia and Infarction
DEFINITION
Perioperative myocardial ischemia is difficult to define, as it
represents a continuum with clinically irrelevant events at
one end of the spectrum and myocardial infarction (MI)
leading to complete ventricular failure at the other end.
The diagnosis of perioperative myocardial ischemia and/or
infarction is challenging in the setting of cardiac surgery,
specifically because of the elevation of cardiac enzymes
that accompanies even uncomplicated procedures
(Fig. 13.1A,B).1 For instance, using high-sensitivity tropo-
nin release assays, Markman et al1 demonstrated a rise in
troponin even after transcutaneous aortic valve implanta-
tion. Similarly, the electrocardiographic (ECG) changes that
typify ischemia and infarction in the nonoperative setting
may instead reflect postoperative pericardial inflammation
or subclinical myocardial injury incurred during routine
surgical manipulation. Therefore, accurate determination
of ongoing ischemia often requires a systematic, multiface-
ted approach, including serial evaluation of ECG changes,
biochemical markers, echocardiography, and even angiog-
raphy. Importantly, early detection of perioperative ische-
mia may prompt therapies to relieve the ischemia and
minimize the incidence of subsequent infarction.
The interpretation of ECG changes remains valuable for
defining ischemia in the perioperative period. Table 13.1 sum-
marizes various clinical entities that may lead to ST-segment
changes in this setting, including myocardial ischemia and
infarction.2,3 After cardiac surgery, the initial ECG may be dif-
ficult to interpret because of lead placement changes related to
surgical dressings, because of cardiac pacing, and because of
the common presence of conduction abnormalities. For exam-
ple, right bundle branch block and first-degree atrioventricu-
lar (AV) block occur very frequently but typically resolve
within the first few postoperative hours.4
Other ECG abnormalities in cardiac surgery patients are
not uncommon findings, as noted in the Bypass Angioplasty
Revascularization Investigation (BARI) study (Table 13.2),
and often portend increased cardiac mortality, especially the
development of postprocedural Minnesota code Q-wave
abnormalities (Table 13.3).5 Therefore, most centers perform
154
preprocedural and serial postprocedural ECGs.6 ECG alone,
however, may lack sufficient sensitivity and specificity for
the detection of myocardial ischemia. Transesophageal
echocardiography (TEE), which has become a standard com-
ponent of perioperative monitoring at most centers, provides
a very effective adjunct to the diagnosis of myocardial ische-
mia and infarction. During surgical revascularization, normal
wall motion indicates effective revascularization, whereas
newly detected regional wall motion abnormalities usually
reflect underlying ischemia or infarction. These regional
wall motion abnormalities can consist of akinesia or dyskine-
sia in a ventricular segment that was normokinetic or
hypokinetic preoperatively. A study of 351 coronary artery
bypass graft (CABG) patients monitored with intraoperative
TEE and ECG demonstrated that wall motion abnormalities
detected by TEE were more common than ST-segment
changes, but there was only a 17% positive concordance
between the two modalities.7 In addition, TEE was found to
be twice as predictive as ECG in identifying patients who ulti-
mately met criteria for MI.7 These results indicate that TEE
may be a more sensitive method of detecting myocardial
ischemia in the perioperative setting and should probably
be routinely used in cardiac surgery monitoring. An impor-
tant observation with TEE is that new interventricular
septal wall abnormalities appear to be common postprocedu-
rally but do not appear to be associated with irreversible myo-
cardial damage.8 Importantly, technical development of
perioperative TEE has led to recent advances in 3D echocar-
diography, tissue Doppler imaging (TDI), and contrast echo-
cardiography, all of which are readily being investigated in
their utility to better detect perioperative ischemia in a
number of studies.9
Precise diagnostic criteria for defining perioperative myo-
cardial ischemia have not been uniformly adopted, and thus
the published incidence varies. A recent study found that
6.4% of patients undergoing CABG (n ¼ 2052) experienced
perioperative myocardial ischemia, using the following cri-
teria: (1) an increase in the creatine kinase-to-creatine
kinase-MB isoenzyme (CK/CK-MB) ratio of greater than
10%; (2) new onset of elevated ST-segment change of
greater than 1 minute’s duration and involving a shift from
baseline of at least 0.1 mV and a new associated postoper-
ative Q wave; (3) recurrent or sustained ventricular
tachyarrhythmia or fibrillation; and (4) hemodynamic dete-
rioration on inotropic support.10 In a meta-analysis of
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 155

Postoperative Troponin T profiles

1000
900

High-sensitivity Troponin T (ng/L)

800
700
600
500
400 MVR
300 AVR
200 CAPG
TAVI
100
OPCAB
0
0 12 24 36 48 60 72
A Time since first myocardial injury (hours)
CK-MB Troponin T
30 2.5
25 2
20
1.5
mg/L 15 mg/L
1
10
5 0.5

0 0
0 24 48 72 96 120 0 24 48 72 96 120
Hours after surgery Hours after surgery

Troponin I Myoglobin
12 500

10 400
8
300
mg/L 6 mg/L
200
4
2 100

0 0
0 24 48 72 96 120 0 24 48 72 96 120
B Hours after surgery Hours after surgery
Fig. 13.1 (A) Changes in troponin T values after common cardiac surgery operations. (B) Biochemical values measured in patients who received
uncomplicated cardiac surgery. AVR, Aortic valve replacement; CABG, coronary artery bypass grafting; CK-MB, creatine kinase-MB isoenzyme; MVR, mitral valve
repair/replacement; OPCAB, off-pump coronary artery bypass; TAVI, transfemoral aortic valve implantation. ([A] is adapted with permission from Markman PL,
Tantiongco JP, Bennetts JS, et al. High-sensitivity troponin release profile after cardiac surgery. Heart Lung Circ. 2017;26:833-839. [B] is redrawn with permission
from Holmvang L, Jurlander B, Rasmussen C, et al. Use of biochemical markers of infarction for diagnosing perioperative myocardial infarction and early graft
occlusion after coronary artery bypass surgery. Chest. 2002;121:103–111.)

randomized controlled trials in patients undergoing cardiac 22 trials of 1853 patients had a 5% overall incidence of
surgery, 20 trials (n ¼ 1522 patients) had a 17% overall PMI.12 Across the literature, the reported rate of PMI ranges
incidence of ischemic events.11 Ischemia was defined as from 5% to 15%. Despite advances in cardiac surgery, this
an ST-segment deviation on the ECG or new wall motion incidence does not appear to be declining.13 The diagnosis of
abnormalities on the TEE. PMI has classically relied heavily on the development of new
As with myocardial ischemia, there is considerable dis- and persistent pathologic Q waves on an ECG, which may
agreement on the diagnostic criteria used to define periop- not always be truly representative of transmural necro-
erative myocardial infarction (PMI), which again explains sis.14,15 Indeed, in an autopsy study performed on cardiac
discordant reports in the literature of its incidence and prog- surgery patients who died within 1 month after surgery,
nostic implications. In the same meta-analysis cited earlier, 23% of patients had significant transmural myocardial
156 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 13.1 Conditions that affect ST-segment changes. ventriculography demonstrated non–Q-wave PMI to be
three times more common than Q-wave PMI,
Condition Electrocardiographic features with equally deleterious effects on left ventricular (LV) func-
Left bundle branch Wide QRS complex tion.17 A study evaluating the clinical significance of a new
block Q wave after cardiac surgery suggested that patients with
ST-segment deviation
this pathologic ECG change, without any concomitant ele-
Acute pericarditis Diffuse ST-segment elevation vation in myocardial enzyme markers or other indicators of
Reciprocal ST-segment depression in lead PMI, had uneventful outcomes.18 These findings highlight
aVR, not in lead aVL the critical importance of combining various diagnostic
modalities to define PMI.
Elevation seldom >5 mm
Although Q waves do not necessarily reflect transmural
PR-segment depression necrosis, appreciation of these and other ECG changes and
Hyperkalemia Widened QRS and tall, peaked, tented T their linkage to adverse outcomes cannot be disregarded.
waves New perioperative ST-segment changes (>0.1 mV) have
Low-amplitude or absent P waves
been identified as an independent predictor of PMI, which
accounts for up to 40% of preoperative CABG deaths.19 In
ST-segment usually downsloping the Coronary Artery Surgery Study (CASS; n ¼ 1340
Pulmonary embolism Changes simulating myocardial patients), 62 patients with a new Q wave postoperatively
infarction, seen often in both inferior and experienced 9.7% in-hospital mortality, compared with
anteroseptal leads 1.0% in the remaining 1278 patients.20 In patients who
Classically, right bundle branch block survived to hospital discharge, the presence of new post-
and S1Q3T3 pattern, right-axis deviation operative Q waves did not adversely affect 3-year survival.
Cardioversion Striking ST-segment elevation, often Among the 1427 CABG patients in the BARI trial, 5-year
>10 mm, lasting only minutes cardiac mortality was increased with new Q-wave develop-
immediately after direct-current shock ment (8.2% versus 3.7% for no new ECG changes; adjusted
Myocardial ischemia Flattened, downsloping ST-segment relative risk, 2.6) (Fig. 13.2).5 Results from the GUARD dur-
ing Ischemia Against Necrosis (GUARDIAN) study of 2918
T-wave inversion high-risk CABG patients further emphasize the negative
Myocardial infarction ST-segment elevation with a plateau, impact of Q-wave development on survival (Table 13.3).21
shoulder, or upsloping Namay et al22 reported a 5-year survival rate of 76% in
Reciprocal behavior between aVL and III; CABG patients (n ¼ 77) with new Q waves compared with
progression to Q waves 90% in the unaffected CABG patients (n ¼1790).
Along with new postoperative Q-wave development,
Adapted with permission from Wang K, Asinger RW, Marriott HJL. ST-segment
elevation in conditions other than acute myocardial infarction. N Engl J Med.
enzymatic criteria are routinely used to define PMI and to
2003;349:2128–2135. enhance the overall sensitivity and specificity of PMI detec-
tion.23 In a study performed on 499 cardiac surgery patients
Table 13.2 Incidence of new electro- at the Brigham and Women’s Hospital, PMI occurred in 5%
cardiographic abnormalities among of patients and was designated by the following criteria:
1427 patients after coronary artery total peak CK greater than 7000 μg/L, CK-MB greater than
bypass graft. 30 ng/mL, and new Q waves on ECG.24 In the GUARDIAN
study of 2918 CABG patients, the 6-month mortality asso-
New ECG abnormality Incidence
ciated with a postoperative peak CK-MB of less than 5, of
n (%) between 5 and 10, of between 10 and 20, and of greater
Major Q wave 65 (4.6)
than 20 times the upper limit of normal (ULN) was 3.4%,
5.8%, 7.8%, and 20.2%, respectively (Fig. 13.3).21 This
ST elevation 216 (15.1) highly significant association was conserved even after
ST depression 220 (15.4) adjusting for other risk factors. The Cleveland Clinic experi-
ence with 3812 CABG patients revealed that a postopera-
T-wave abnormality 557 (39.0)
tive CK-MB level 10 times ULN was independently
No ECG abnormality 557 (39.0) predictive of increased mortality at 3 years (Table 13.4
and Fig. 13.4).25 The Arterial Revascularization Therapies
With permission from Yokoyama Y, Chaitman BR,
Hardison RM, et al. Association between new Study (ARTS) prospectively evaluated 496 CABG patients
electrocardiographic abnormalities after coronary and also demonstrated that increased levels of CK-MB (>5
revascularization and five-year cardiac mortality in times ULN) was highly predictive of cardiac death and
BARI randomized and registry patients. Am J recurrent MI after the postoperative period (Fig. 13.5).26
Cardiol. 2000;86:819–824.
The specificity of CK and CK-MB as markers of myocardial
injury is limited by the fact that these enzymes are also
necrosis but no pathologic Q waves, and 20% of patients present in and released from skeletal muscle. Significant
without transmural necrosis exhibited new postprocedural skeletal muscle injury and release of large quantities of
Q waves.16 Reliance on the presence of Q waves alone to CK-MB occurs during cardiac surgery.27 An abundance of
diagnose PMI can dangerously overlook infarctions. In a experimental evidence has emerged in the literature on
study of cardiac surgery patients, transthoracic quantitative the superior sensitivity and specificity of serum troponins
echocardiography analysis with ECG and radionuclide as biochemical markers of myocardial damage and
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 157

Table 13.3 Six-month mortality after coronary artery bypass graft surgery: effect of two-step Minnesota code worsening
electrocardiographic abnormalities.
ECG Frequency Dead Alive Total Disease Disease 95% CI Incidence Relative
Abnormality (%) (n) (n) (n) Odds Odds (per 100) Risk 95% CI Ratio
a a
None or one step 54.4 74 1194 1268 0.062 1.00 — 5.84 1.00 —
Two-step worsening 23.6 18 532 550 0.034 0.55b 0.31-0.95 3.27 0.56b 0.34-0.93
T wave
Two-step worsening 14.2 11 320 331 0.034 0.55 0.27-1.09 3.32 0.57 0.31-1.06
ST-segment
elevation
Two-step worsening 2.7 4 59 63 0.068 1.09 0.33-3.24 6.35 1.09 0.41-2.88
ST-segment
depression
Two-step worsening 0.4 0 10 10 0.000 0.00 — 0.00 0.00 —
ST-segment
elevation and
Two-step worsening
ST-segment
depression
Two-step worsening 4.7 12 98 110 0.122 1.98 0.98-3.90 10.91 1.87b 1.05-3.33
Q wave

CI, Confidence interval.

a
Reference category.
b
P < .05.
With permission from Klatte K, Chaitman BR, Theroux P, et al. Increased mortality after coronary artery bypass graft surgery is associated with increased levels of
postoperative creatine kinase-myocardial band isoenzyme release. J Am Coll Cardiol. 2001;38:1070–1077.

predictors of adverse outcomes.6,8,13,27–36 Cardiac troponin
isoforms I and T (cTnI, cTnT) are cardiac-specific proteins
involved in regulation of muscle contraction via the tropo-
myosin complex.6 No cross-reactivity with skeletal muscle
isoforms has been described, and the levels of cardiac
troponins do not increase in healthy subjects, even when
they are exposed to strenuous muscular activity or after
noncardiac operations.31 The levels of cTnI also appear to
be unaltered by renal dysfunction, and its plasma concen-
tration decreases very slowly, allowing for retrospective
detection of myocardial damage if necessary.8,28 Interest-
ingly, troponin levels drawn preoperatively may also enable
stratification of patients into subgroups with increased
risk for postoperative cardiac complications, notably PMI
(Fig. 13.6).30 Outcomes for these high-risk patients, who
presumably have undetected ongoing myocardial injury,
might be improved with a tailored perioperative approach
that would include pharmacologic support or an intra-
aortic balloon pump (IABP).
A study comparing the efficacies of cTnT and CK-MB in a
series of 224 cardiac surgery patients indicated that serum
cTnT concentrations greater than 1.58 ng/mL (which repre-
sented the upper quintile) were the most powerful indepen-
dent predictor of postoperative death or shock within the
first 24 hours after surgery.33 Greenson and colleagues dem-
onstrated that stratification of cardiac surgery patients by peak
cTnI levels of less than 40 and greater than 60 ng/mL was
exquisitely predictive of intensive care unit (ICU) length of
stay, prolonged mechanical ventilation, new arrhythmia
development, and especially cardiac events (Fig. 13.7).27
Similar results were obtained in a larger series of 502 patients
undergoing conventional heart surgery, where the cTnI level
proved to be an independent predictor of in-hospital mortality
and associated with other major postoperative complications
such as PMI, ventricular arrhythmias, low cardiac output,
prolonged mechanical ventilation, and acute renal failure
requiring dialysis (Table 13.5).35 The long-term prognostic
value of cTnI levels has also been validated, and it is clearly
associated with increased mortality, death from cardiac
causes, and nonfatal cardiac events within 2 years after CABG
(Fig. 13.8).32 The variable cutoffs of predictive troponin values
reported by different studies is concerning and may be attrib-
uted to lack of standardization of troponin detection kits by
different suppliers.28
ETIOLOGY
During the preprocedural phase of cardiac surgery, myo-
cardial ischemia usually represents extension of an acute
coronary presentation triggered by hypertension, hypo-
tension, hypoxia, tachycardia, bleeding, or surgical manip-
ulation. Causes for postprocedural myocardial ischemic
injury include inadequate myocardial protection during
surgery, coronary graft failure, native coronary or graft
spasm, extension of a preoperative infarction,37 inadequate
revascularization, coronary injury secondary to a valve
procedure,38,39 and distal coronary embolization.40 These
etiologic considerations are notorious predictors of myocar-
dial ischemia, PMI, and other adverse outcomes in cardiac
surgery. Predictors of PMI have been defined and include
158 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Post Procedure 5-Year Adjusted Relative Risk 5-Year Adjusted Relative Risk
ECG Changes Cardiac Mortality and Its 95% CI Cardiac Mortality and Its 95% CI
Major Q
Yes 8.0 18.1
2.6 4.6
No 3.2 5.6
ST Elevation
Yes 4.2 8.5
1.7 1.5
No 3.3 5.7
ST Depression
Yes 3.8 8.9
1.4 1.2
No 3.5 5.2
T Inversion
Yes 2.8 6.0
1.0 1.1
No 3.8 5.7

0.1 1.0 10.0 0.1 1.0 10.0

CABG PTCA
A
CABG PATIENTS PTCA PATIENTS
100 100
96.8%
94.4%
92.0%
90 90
P ⫽ 0.020
P ⫽ 0.039
81.9%
Percentage

80 80

70 70
CABG/No major Q (N ⫽ 1362) PTCA/No major Q (N ⫽ 1852)
CABG/Major Q (N ⫽ 65) PTCA/Major Q (N ⫽ 17)

60 60

50 50
0 1 2 3 4 5 0 1 2 3 4 5
Years after study entry Years after study entry
No. at Risk No. at Risk
Major Q 65 57 36 Major Q 17 14 10
No major Q 1362 1294 858 No major Q 1852 1734 1105
B
Fig. 13.2 (A) Bypass angioplasty revascularization investigation (BARI) randomized and registry patients’ cumulative survival from cardiac mortality.
Patients had undergone coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). The development of major
Q waves was associated with significantly increased long-term risk for cardiac mortality in the CABG patients (P ¼ .02). (B) Five-year Kaplan-Meier cardiac
mortality and adjusted relative risk for cardiac mortality for any postprocedural electrocardiographic (ECG) changes. Cardiac mortality was significantly
increased by the development of new postprocedural major Q waves, regardless of the type of coronary revascularization procedure performed. In this
analysis, the postprocedural ECG variables were adjusted for study group, treated diabetes, age, prior myocardial infarction, renal dysfunction, con-
gestive heart failure, ejection fraction, body mass index, presence of class C lesions, baseline ST elevation, and baseline ST depression. CI, Confidence
interval. (Redrawn with permission from Yokoyama Y, Chaitman BR, Hardison RM, et al. Association between new electrocardiographic abnormalities after
coronary revascularization and five-year cardiac mortality in BARI randomized and registry patients. Am J Cardiol. 2000;86:819–824.)

advanced age, emergent procedure, previous revasculariza-
tion, longer duration of cardiopulmonary bypass (CPB) or
aortic cross-clamp time, need for inotropic support, need
for coronary relocation (or reimplantation), prior MI, and
preoperative ventricular dysfunction.24,26,41,42 Awareness
of high-risk patients may increase monitoring and enable
earlier intervention.
Prior to the widespread implementation of cold potassium
cardioplegia and other advancements in myocardial preser-
vation, PMI often resulted from suboptimal myocardial
preservation.41 Consistent with this etiology was the
pathologic finding of contraction band necrosis, which indi-
cated intraoperative ischemia and subsequent reperfusion
injury.16,41 A high percentage of infarctions analyzed from
patients in these early studies were in areas supplied by
patent grafts, again suggestive of injury mediated by an
ischemia-reperfusion phenomenon. Improvements in tech-
niques of myocardial preservation have reduced the inci-
dence of perioperative myocardial ischemia and PMI.17,41
Myocardial preservation techniques have undergone
significant evolution during the past five decades. The
implementation of cold crystalloid cardioplegia was an
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 159

100 1.00
96.6%
94.2%
Cumulative survival (%)

0.95

Cumulative proportion surviving

92.2%
90
0.90

79.8% 0.85
80 P ⬍ 0.001
⬍5 ULN
ⱖ5 and ⬍10 ULN 0.80
ⱖ10 and ⬍20 ULN
ⱖ20 ULN ⬍1 ⫻ ULN
0.75 1–3 ⫻ ULN
70
3–5 ⫻ ULN
0 30 60 90 120 150 180 210
0.70 5–10 ⫻ ULN
Days after CABG ⬎10 ⫻ ULN
Fig. 13.3 Association between survival after coronary artery bypass
grafting (CABG) and level of postoperative creatine kinase-MB isoen- 0.65
0 500 1000 1500
zyme (CK-MB). All pairwise comparisons between the categories were
significant, except for the 5 and <10 upper limits of normal (ULN) Time (days)
group versus the 10 and <20 ULN group (P ¼ .26). (Redrawn with Fig. 13.4 Cumulative survival in patients with coronary artery bypass
permission from Klatte K, Chaitman BR, Theroux P, et al. Increased mortality grafting, stratified by postoperative degree of creatine kinase-MB iso-
after coronary artery bypass graft surgery is associated with increased form elevation. ULN, Upper limit of normal. (Redrawn with permission
levels of postoperative creatine kinase-myocardial band isoenzyme from Brener SJ, Lytle BW, Schneider JP, et al. Association between CK-MB
release. J Am Coll Cardiol. 2001;38:1070–1077.) elevation after percutaneous or surgical revascularization and three-year
mortality. J Am Coll Cardiol. 2002;40:1961–1967.)

Table 13.4 Three-year mortality rates associated with 100

elevation of creatine kinase isoenzyme MB after coronary artery 95
bypass graft surgery.
Patients without event (%)

90
CABG PATIENTS (N ¼ 3812) 85
CK-MB level At risk, no. (%) Death (%) 80
75
1  ULN 386 (10) 7.2
70
1–3  ULN 1922 (50) 7.7
65
3–5  ULN 853 (22) 6.3
60
5–10  ULN 427 (11) 7.5 55
Any MACCE P ⫽ 0.0001
>10  ULN 224 (6) 20.8 50
P (trend) — <.001 0 50 100 150 200 250 300 350 400
ULN, Upper limit of normal. Time (days)
With permission from Brener SJ, Lytle BW, Schneider JP, et al. Association Fig. 13.5 Relationship between creatine kinase-MB isoform (CK-MB)
between CK-MB elevation after percutaneous or surgical revascularization levels and major postoperative complications after cardiac surgery.
and three-year mortality. J Am Coll Cardiol. 2002;40:1961–1967. Kaplan-Meier curves illustrate the incidence of major adverse cardiac
complications at 1-year follow-up in patients with normal CK-MB levels
(dashed blue line), greater than one to three times normal (solid blue
line), three or more to five times normal (dashed red line), and greater
than five times normal (solid black lines). MACCE, Combined major
important early advancement that improved overall out- cardiac death, myocardial infarction, repeat revascularization, and
cerebrovascular events. (Redrawn with permission from Costa MA, Carere
comes. The introduction of blood cardioplegia led to further RG, Lichtenstein S V, et al. Incidence, predictors, and significance of
improvements in maintaining myocardial energy stores and abnormal cardiac enzyme rise in patients treated with bypass surgery in
reducing anaerobic lactate production.43 Clinically, the the arterial revascularization therapies study (ARTS). Circulation.
advantage of blood cardioplegia is supported in studies that 2001;104:2689–2693.)
show a reduction in PMI and other morbidity when directly
compared with crystalloid cardioplegia.44 The advent of ret-
rograde delivery of cardioplegia via the coronary sinus was
another important advance in myocardial protection, allow- crystalloid components of this solution include a 1-L
ing fewer cardioplegic interruptions, perfusion to regions Plasma-Lyte base solution with mannitol, magnesium sul-
supplied by stenosed arteries, and enhanced cardioplegic fate, sodium bicarbonate, potassium chloride, and lidocaine
delivery to the subendocardial region.45 added. Unlike other cardioplegia solutions, del Nido is given
An important, relatively recent advance in cardioplegia as a single dose, with less need for frequent redosing. Even in
has been the introduction and wide adoption of del Nido car- low-risk, first-time CABG patients, the use of del Nido cardi-
dioplegia in the adult cardiac surgery population.46,47 The oplegia was associated with less defibrillation and lower
160 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
22
MI (%)
20
CHF (%)
MI ⫹ CHF (%)
18
16
14
Mortality (%)
12
10
8
6
4
2 75
0 50
0–0.02 0.02–0.1 ⬎0.1
Preoperative troponin T serum level (mg/L)
Fig. 13.6 Predictive value of preoperative troponin T levels and cardiac
events after coronary artery bypass grafting. The positive correlation
between circulating troponin T levels before the operation and the rate
of postoperative myocardial infarction (MI) (P ¼ .03), congestive heart
failure (CHF) (P ¼ .0006), and combined cardiac events (MI + CHF) (P ¼
.0001) was significant. Group 2 was composed of patients with tro-
ponin T levels below the discriminator value of 0.02 μg/L. Group 1
patients had elevated troponin T values. They were divided into two
subgroups: those with troponin T values between 0.02 μ/L and 0.1 μg/L
and those with values >0.1 μg/L. (Redrawn with permission from Carrier
M, Pelletier LC, Martineau R, et al. In elective coronary artery bypass
grafting, preoperative troponin T level predicts the risk of myocardial
infarction. J Thorac Cardiovasc Surg. 1998;115:1328–1334.)
costs. Its use has significantly increased in minimally inva-
sive cardiac surgery, mainly due to decreased need for
additional dosing.48 In a recent study by Vistarini et al,
del Nido cardioplegia was found to be safe and easy in a
group of consecutive patients undergoing minimally inva-
sive aortic valve replacement.48 Most of the data related
to the use of del Nido in adult cardiac surgery patients
has been retrospective in nature, with the lack of large-scale
randomized controlled trials.
Ischemic injury in the current era may be more fre-
quently the result of technical issues, early graft occlusion,
anastomotic stenosis,49 graft, or native coronary spasm
(Figs. 13.9 to 13.11),50–58 poor distal runoff, incomplete
revascularization, steal phenomena,58 or embolization.
Graft compression by mediastinal chest drains has even
been described as a cause of ischemic injury (Fig. 13.12).
Atheromatous embolization in the coronary microcircula-
tion can also occur intraoperatively and lead to PMI.
Potential embolic sources include atherosclerotic plaque
present in the ascending aorta or major epicardial coronary
arteries.40 In the reoperative setting, mechanical
100 P of Difference ⬍0.0001
No cardiac events
Troponin level (ng/mL)
Cardiac events
50
0
0 1 2 3 4 5 6 7
Days after surgery
A
150
Peak concentration of Troponin I
125
100
60 ng/mL
40 ng/mL
25
0
Cardiac events No cardiac events
B
Fig. 13.7 Usefulness of cardiac troponin I (cTnI) in patients undergoing
cardiac surgery. (A) Troponin I levels after cardiac surgery. Levels of
troponin I were plotted over time in patients with and without cardiac
events. P <.0001 between groups by use of analysis of variance. (B)
Cardiac events by peak troponin level. Patients with and without car-
diac events are shown with their respective peak cTnI levels. An upper
level of 60 ng/mL and a lower level of 40 ng/mL are illustrated.
(Redrawn with permission from Greenson N, Macoviak J, Krishnaswamy P,
et al. Usefulness of cardiac troponin I in patients undergoing open heart
surgery. Am Heart J. 2001;141:447–455.)
disruption of atheroma in old vein grafts has also been
described.40 Retrograde cardioplegia may be protective in
cases of coronary or graft embolization.
PMI caused by coronary spasm occurs with an incidence
as high as 1% and involves both grafted and ungrafted
vessels.51–53 Coronary spasm can lead to sudden hemody-
namic collapse and is often heralded by acute hypotension.
Conventional treatment methods for perioperative hypo-
tension, such as pressor agents, may only exacerbate
the vasospastic reaction in this scenario.51 Similarly, in
patients experiencing PMI associated with a hyperdynamic
state, elevated circulating catecholamine levels create an
environment conducive to persistent coronary spasm.59
Mechanistically, abrupt withdrawal of preoperative calcium
channel blockers can lead to rebound vasoconstriction of
the native coronary arteries and is an important factor to
consider in preoperative planning.57 Additional factors that
may render cardiac surgical patients particularly susceptible
to coronary vasospasm include thromboxane release caused
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 161

Table 13.5 Cardiac troponin I concentrations and clinical RIMA

outcome among 502 patients.
CTNI CONCENTRATIONA ( NG/ML) RIMA
Complication With Without
complication complication
(No. of patients) (No. of patients) RC
b
Q-wave perioperative 56.5 [43; 175.5] 4.2 [2.4; 7.6]
myocardial (n ¼ 7) (n ¼ 495)
RC
infarction
Ventricular 8.4 [4.2; 28.2]b 4.3 [2.4; 8.0]
arrhythmias (n ¼ 17) (n ¼ 485)
Low cardiac output 9.5 [4.4; 26.78]b 4.3 [2.4; 7.7]
(n ¼ 81) (n ¼ 421)
b
Prolonged (48-h) 56.5 [5.2; 22.3] 4.5 [2.5; 8.1]
mechanical (n ¼ 46) (n ¼ 456)
ventilation
Acute renal failure 18.2 [9.1; 33.5]b 4.6 [2.5; 8.2] A B
requiring dialysis (n ¼ 18) (n ¼ 484) Fig. 13.9 Treatment of right coronary artery (RCA) spasm after coro-
nary artery bypass grafting (CABG). (A) Coronary artery angiogram
a
cTnI values are expressed as median [25th; 75th percentiles]. showing a diffuse spasm of the RCA beyond the level of the anasto-
b
P < .0001. mosis (arrow) with the right internal mammary artery (RIMA). (B) RCA
From Lasocki S, Provenchère S, Benessiano J, et al: Anesthesiology spasm resolution after intracoronary infusion of nitroglycerin. (With
2002;97:405–411. permission from Trimboli S, Oppido G, Santini F, et al. Coronary artery
spasm after off-pump coronary artery by-pass grafting. Eur J Cardiothorac
Surg. 2003;24:830–833.)
100

75
Survival (%)

50

25 Low cTnI, Group 1

High cTnI, Group 2 P ⫽ 0.006

0
0 6 12 18 24
Time (month)
Fig. 13.8 Cumulative percentage of surviving patients according
to elevation of cardiac troponin I (cTnI). Group 1 (n ¼ 174; cTnI,
<13 ng/mL; solid red line) and group 2 (n ¼ 28; cTnI, 13 ng/mL;
dashed red line). Only one patient (in group 1) was lost to follow-up
after 1 year. P value refers to between-group comparison (log-
rank test). (Redrawn with permission from Fellahi JL, Gu
e X, Richomme X,
et al. Short- and long-term prognostic value of postoperative cardiac
troponin I concentration in patients undergoing coronary artery bypass
grafting. Anesthesiology. 2003;99:270–274.)

Fig. 13.10 Postcoronary artery bypass grafting (CABG) angiography.

by heparin–protamine interactions, CPB, platelet activation,
anaphylactic reactions, calcium administration, and
increased alpha-adrenergic tone from vasoconstrictor
administration.60
Another well-described etiology related to perioperative
ischemic injury is the internal mammary artery (IMA)
malperfusion syndrome, caused by inadequate myocardial
perfusion through the IMA graft.61 In a series of 2326
Narrowing of a left internal mammary artery to left anterior descending
artery bypass graft (square). The segment above the anastomosis and
the toe of the anastomosis are stenotic. There was no response to
intraluminal nitroglycerin. This graft underwent surgical revision. At
revision, the upper stenosis was diagnosed to be a spasm, which had
been fixed by fibrin glue. The stenosis at the toe was the result of
surgical technique. After revision, an open anastomosis and perfect
flow were present. (With permission from Bonatti J, Danzmayr M,
Schachner T, et al. Intraoperative angiography for quality control in
MIDCAB and OPCAB. Eur J Cardiothoracic Surg. 2003;24:647–649.)
162 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

A B
Fig. 13.11 Coronary artery spasm after coronary artery bypass grafting (CABG). (A) Postoperative coronary angiogram showing the left anterior
descending artery (LAD) coronary artery spasm just distal to the left internal mammary artery (LIMA) to LAD anastomosis and the first diagonal
coronary artery spasm. (B) Postoperative angiographic control after intracoronary verapamil and nitroglycerin infusion produced relief of the
coronary spasm. (With permission from Caputo M, Nicolini F, Franciosi G, et al. Coronary artery spasm after coronary artery bypass grafting. Eur J
Cardiothorac Surg. 1999;15:545–548.)

A B
Fig. 13.12 Angiogram for perioperative myocardial infarction after coronary artery bypass grafting. (A) The saphenous vein graft to the posterior
descending artery was externally compressed by a mediastinal chest tube (arrow). (B) Obstruction was relieved by removal of tube.

CABG patients in which the IMA was used, 45 patients
(1.9%) with this syndrome were identified.61 Although
the IMA is the proven conduit of choice for myocardial
revascularization,62,63 immediate flow through this arte-
rial graft is generally less than through a saphenous vein
graft and may not adequately meet myocardial demand.61
Other factors that may precipitate this syndrome include
vasospasm, kinking, or overstretching of the IMA; steal
phenomena via flow diversion into major intercostal
side branches;64 and residual competitive flow from the
native coronary artery.61 As with radial artery grafts,
direct mechanical manipulation of the IMA during har-
vesting may produce transient endothelial dysfunction
and provoke a vasospastic response.57,60
A number of large angiographic studies have correlated
clinical suspicion of myocardial ischemia or PMI with
angiographic evidence of graft failure.10,65 In a series of
2003 CABG patients, 71 (3.5%) had suspected myocardial
ischemia and underwent acute reangiography (n ¼ 59) or
an immediate reoperation (n ¼ 12) if they were hemody-
namically unstable.65 Angiographic findings in the first
group included the following: occluded vein graft(s)
(32%), poor distal runoff to the grafted coronary vessel
(17%), IMA stenosis (7%), IMA occlusion (5%), vein graft
stenoses (5%), and IMA subclavian artery steal (3%).65 In
the immediately reoperated group, 92% of patients had graft
occlusions. A more recent study including 2052 CABG
patients had similar findings.10 These studies emphasize
that the majority of patients who experience myocardial
ischemia or PMI following revascularization have underly-
ing graft failure warranting angiography and either percu-
taneous or surgical reintervention.
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery
Valvular procedures may lead to technical complications
with a specific myocardial ischemia. The proximity of the
posterior mitral annulus and the left circumflex coronary
artery predisposes to circumflex injury and LV lateral wall
ischemia with mitral reconstruction.38,39 An analogous sit-
uation exists for tricuspid valve surgery and the right coro-
nary artery. Aortic valve procedures may compromise
either the left main coronary or the right coronary ostia,
and cases of coronary ostial thrombosis with severe ische-
mia have been reported. Finally, debrided valvular material
may also be involved in deleterious coronary embolization.
MANAGEMENT
Intraoperative Preprocedural Phase
The preprocedural phase is a critical period during which
appropriate clinical management can prevent myocardial
ischemia and PMI. Stabilization of blood pressure and main-
tenance of normal sinus rhythm should be the goal. A rate–
pressure product below 12,000 may minimize perioperative
myocardial ischemia.11 The importance of precise and con-
tinuous hemodynamic measurements cannot be overem-
phasized. It should at least include continuous monitoring
of the ECG, cuff blood pressure, direct arterial pressure, cen-
tral venous pressure (CVP), continuous pulse oximetry, and
end-tidal CO2.66 Placement of a pulmonary artery (PA)
catheter is warranted for high-risk patients, for example,
in cases of unstable angina, ventricular hypertrophy,
poor ventricular function, and combined valvular and cor-
onary artery disease pathology.67 The PA catheter enables
continuous assessment and maintenance of cardiac filling
pressures, cardiac output, and mixed venous oxygen satura-
tion (MVO2) to prevent myocardial ischemia.
Pharmacotherapy with vasodilators such as intravenous
nitroglycerin (NTG) may be required preoperatively for
patients with unstable angina. The reduction in total ische-
mic burden may improve prognosis with regard to infarct
progression and may prevent deterioration of LV function.
Intravenous NTG has also been shown to improve postinduc-
tion regional wall motion abnormalities in a prospective
study of CABG patients.68 On the basis of these results,
TEE-guided NTG use after induction may yield a more opti-
mal baseline echocardiogram.68 Other important phar-
macotherapies to reduce ischemia include intravenous
beta-blockers, with esmolol as the most titratable agent.
Beta-blockers reduce heart rate, contractility, and blood pres-
sure and thereby greatly reduce overall myocardial work.
Beta-blockers also reduce the incidence of ischemic ventric-
ular and atrial arrhythmias. Use of intravenous NTG
and beta-blockers requires careful monitoring and titration,
as both agents can induce hypotension; in patients with
fixed coronary stenosis, reduced perfusion pressure can
result in dangerous ischemia and subsequent myocardial
dysfunction.
In patients with cardiogenic shock or medically refractory
ischemia, preoperative stabilization with an IABP has been
shown to reduce overall surgical mortality and improve out-
comes in high-risk coronary patients.69,70 IABP counterpul-
sation enhances myocardial perfusion via augmentation of
diastolic blood pressure and redistribution of coronary blood
flow toward regions of myocardial ischemia.69 IABP
provides partial LV assistance. Proper timing consists of
163
Increased coronary
artery perfusion
120
C
D F
mm Hg
100
B
80 E
Reduced
A myocardial O2
demand
Fig. 13.13 Intra-aortic balloon pump (IABP) timing: synchronization
with the cardiac cycle. Arterial pressure waveform with correct IABP
timing. (A) One complete cardiac cycle. (B) Unassisted aortic
end-diastolic pressure. (C) Unassisted systolic pressure. (D) Diastolic
augmentation. (E) Reduced aortic end-diastolic pressure. (F) Reduced
assisted systolic pressure. (Redrawn with permission from Helman DN.
In Goldstein DJ, Oz MC, eds. Cardiac Assist Devices. Armonk, NY: Futura;
2000: 298.)
balloon inflation just after aortic valve closure and deflation
immediately prior to systole (Fig. 13.13). Balloon inflation
during diastole augments coronary perfusion, whereas
deflation during systole reduces afterload, decreases cardiac
work (myocardial oxygen consumption), and increases
stroke volume and cardiac output. Efficacy of IABP support
is determined by several factors, including balloon volume;
location in the aorta; rate of inflation and deflation; and,
most important, timing relative to the cardiac cycle. IABP
counterpulsation is less effective in the presence of moderate
or severe aortic regurgitation and should be avoided. Fur-
thermore, timing may be difficult because of tachycardia
or arrhythmias. Aortoiliac or femoral occlusive disease
may make placement more difficult and increases the risk
for limb ischemia.
Retrospective review of 4756 cases of IABP support at the
Massachusetts General Hospital suggests that a 24- to 48-
hour period of preoperative IABP support is preferable in
unstable or postinfarction angina and enables preoperative
recovery of ischemic myocardium.70 In this study, preoper-
ative IABP placement was associated with a lower mortality
(13.6%) than intraoperative (35.7%) or postoperative
(35.9%) use.70 A prospective, randomized study was per-
formed in 60 high-risk CABG patients to evaluate optimal
timing for preoperative IABP placement.69 In this and other
studies, preoperative IABP support led to reduced CPB time,
higher postoperative cardiac index, decreased incidence of
postoperative low cardiac output, and a diminished period
of mechanical ventilation and hospital stay.69,71 These stud-
ies suggest the beneficial impact of preoperative IABP sup-
port in high-risk coronary patients. Preoperative risk
factors that designated high-risk status in these studies
included preoperative left ventricular ejection fraction
(LVEF) less than 30%, unstable angina, left main coronary
artery stenosis greater than 70%, diffuse coronary artery
disease, and reoperative CABG.
A recent meta-analysis reviewed studies between 1977
and 2015 on the use of IABP in patients undergoing cardia
surgery.72 A total of 46,067 patients were included with
11 randomized controlled trials and 22 observational
164 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
studies. Analyses from the included randomized controlled
trials suggested that IABP prior to CABG was associated
with shorter ICU (weighted mean difference [WMD],
1.47 d; 95% confidence interval [CI], 1.82 to 1.12 d;
P < .00001) and hospital length of stay (WMD, 3.25 d;
95% CI, 5.18 to 1.33 d; P ¼ .0009). Importantly, IABP
use was also found to have a significant reduction in hospital
mortality (odds ratio [OR], 0.20; 95% CI, 0.09–0.44;
P < .0001) and 30-day mortality compared with no preop-
erative IABP (OR, 0.43; 95% CI, 0.25–0.76; P ¼ .003).72
Patients with profound preprocedural myocardial ische-
mia or evolving MI probably benefit from a strategy that
rapidly establishes CPB. Currently, many surgical revascu-
larizations are performed without CPB, and for others, the
initial period of conduit harvest is conducted off CPB. In
unstable patients, immediate institution of CPB may dra-
matically reduce myocardial workload and risk for ischemic
injury. Conduit harvest and further surgical preparation
can be performed with the heart protected on CPB. In the
setting of reoperative cardiac surgery and prior sternotomy,
groin dissection and cannulation of the femoral vessels may
be the safest and most rapid method to establish CPB.
Aggressive use of mechanical unloading may help avoid
ischemic ventricular arrhythmias and ventricular dysfunc-
tion, which may be difficult to reverse once established. Nota-
bly, CPB does not directly unload the left heart and further LV
unloading can be achieved with the addition of an LV vent.
Intraoperative Postprocedural Phase
During the intraoperative postprocedural phase, rigorous
attention to ECG pattern, hemodynamic parameters, and
TEE findings must be continued. As discussed previously,
the collective information obtainable with these modalities
can be sensitive and specific for intraoperative myocardial
ischemia and PMI. For cases of revascularization, intrao-
perative ischemic ECG patterns, new regional wall motion
abnormalities, or hemodynamic instability requires assess-
ment of the grafts to rule out graft failure as the cause.
Assessment of graft integrity and graft patency can be read-
ily accomplished using Doppler flow probes. These probes
provide a rapid and highly sensitive method of detecting
graft failure, as shown in a recent study of patients under-
going off-pump CABG.73 In this study, flow probe results
were correlated with intraoperative angiographic findings,
and Doppler analysis was 100% accurate for confirming
graft patency and detecting failed grafts.73 To qualify as a
normal Doppler study, the observed pattern of flow should
be predominantly diastolic, with a diastolic flow velocity
of greater than 15 cm/s.73 Additional flow parameters to
consider when evaluating graft integrity include total flow,
systolic flow, diastolic-to-total flow ratio, systolic peak flow,
diastolic peak flow, systolic-to-diastolic peak flow index, and
pulsatility index (PI; defined as difference between systolic
peak flow and diastolic flow divided by mean flow).74 The
PI value should be between 1 and 5, where higher values
are indicative of a graft problem.75 When an abnormal
Doppler flow study is encountered, consideration should
be given to revision of the offending graft. This decision is,
however, complex and ultimately relates to the surgeon’s
confidence in achieving a better technical result. Small
or diffusely diseased target coronary arteries predictably
result in grafts with limited flow. In a recent analysis for a
large multicenter CABG trial, 1-year graft patency and
intraoperative revision rates in patients undergoing CABG
based on intraoperative flow probe assessment were evalu-
ated. For the 1607 patient (2738 grafts) with available flow
probe data, 1-year FitzGibbon grade A patency and intrao-
perative revision were compared based on TTF measure-
ments (<20 [low flow] vs 20 mL/min [normal flow]) and
PI values (<3, 3–5, and >5). FitzGibbon grade A patency
was much less common in grafts with a low flow (71.3%)
vs (87.2%) for graft having a normal flow. An inverse rela-
tionship was seen between 1-year patency and intraoperative
PI values, with 85.6% of grafts having FitzGibbon A patency
when the PI <3, 74.7% with a PI of 3–5, and 67.9% with a PI
>5 (P  .01). As expected, intraoperative graft revision was
more frequent in grafts with low flow at 7.7% than in those
with normal flow (0.4%; P < .01). What remains unknown is
the percentage of grafts that had a meaningful improvement
after revision versus those that did not.76
Perhaps one of the most common causes of postproce-
dural myocardial ischemia is coronary air embolization.
This event is important to recognize; the right coronary
artery or right coronary graft is specifically affected. Air
may actually be seen within the graft, and needle aspiration
of the graft can help limit the problem. The left coronary sys-
tem is more dependent and infrequently involved. Profound
right ventricular (RV) dysfunction can follow. TEE may
show inferior LV wall myocardial air. Venting of the heart,
aorta, or graft is indicated. Often, transiently raising perfu-
sion pressure with an alpha-adrenergic receptor agonist
alleviates the problem, presumably by forcing the obstruct-
ing air out of the major coronary arterial branches. Perform-
ing procedures under CO2, which dissolves more readily in
blood, may reduce this complication. Importantly, in the
absence of continued air embolization, this ischemia should
resolve rapidly, and persistent evidence for ischemia war-
rants consideration of other causes.
Postoperative Phase
The early postoperative phase should include careful hemo-
dynamic and clinical monitoring. Adequate oxygen delivery
and systemic blood flow must be ensured: MVO2, cardiac
output, blood pressure, heart rate, urine output, acid–base
status, and pulse should all be carefully monitored. The
presence of myocardial ischemia may be indicated by
ST-segment changes (via ECG monitoring), ventricular
arrhythmia, or hemodynamic collapse. In other cases, more
subtle hemodynamic changes or increased inotropic
requirement may be the only clues. Many postcardiac sur-
gery units obtain routine postprocedural 12-lead ECGs and
serial serum cardiac enzyme results. Concerns for myocar-
dial ischemia warrant echocardiography to assess LV func-
tion and regional wall motion.
Administration of calcium antagonists in the postopera-
tive period may reduce rates of myocardial ischemia, PMI,
and long-term mortality.11,12 These agents enhance the
balance between myocardial oxygen supply and demand
by mediating negative chronotropy, negative inotropy,
afterload reduction, and coronary vasodilation.11 Recent
studies have advocated the use of this therapy to prevent
post-CABG graft vasospasm.57 Native coronary or graft
spasm should always be suspected in the setting of postop-
erative ischemia, and aggressive management with NTG
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 165

and a sublingual calcium channel blocker should be insti-

1.0
tuted.77 These agents are routinely recommended when
radial arterial grafts have been used. Unfortunately, postop- 0.9

Probability of hospital death

erative myocardial ischemia may be secondary to hypoten- 0.8
sion or low cardiac output, limiting the use of calcium 0.7
channel blockers and NTG. 0.6
Postoperative ischemia or PMI accompanied by hemody-
namic instability necessitates IABP placement and urgent 0.5
reoperation. In more stable patients with evidence of signifi- 0.4
cant myocardial ischemia, coronary angiography should be 0.3
strongly considered. Early angiography can identify technical 0.2
issues and guide further therapy before permanent myocar-
0.1
dial damage has occurred.8,58 Specifically, graft or native
artery occlusions or stenoses may be identified, and angio- 0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
plasty or stenting of the native vessels or new grafts can be
Cardiac index
safely achieved.42 Similarly, angiography can identify native
coronary or graft vasospasm and enables targeted intralum- Fig. 13.14 Hospital death versus cardiac index. Relationship between
inal infusion of NTG or calcium channel blocker (see postoperative cardiac index (L/min/m2) and probability of death for
adults after mitral valve replacement. A sharp rise in hospital mortality
Figs. 13.9 to 13.11).50–58 In cases of IMA steal phenomenon, is noted among patients with cardiac index less than 2.0. (Courtesy of
transarterial catheter embolization to obliterate undivided Nicholas T. Kouchoukos, MD. In Davila JC, ed. Henry Ford Hospital Inter-
vessels is another effective treatment that is feasible in the national Symposium on Cardiac Surgery, 2nd ed. New York: Appleton-
angiography suite.64 Furthermore, specific problems may Century-Crofts; 1977.)
be identified angiographically that require return to the oper-
ating room for surgical revision. Important examples include 7.0
incomplete revascularization and the IMA malperfusion syn-
drome, in which placement of an additional saphenous vein
graft is widely regarded as the optimal treatment option.61
Clinical studies have evaluated other alternative pharma- 6.0
cotherapies to prevent ischemia-reperfusion injury and PMI
in the setting of cardiac surgery. The Pexelizumab for
Reduction in Infarction and Mortality in Coronary Artery
Bypass Graft surgery (PRIMO-CABG) study was a random- 5.0
Cardiac output, L/min

ized, double-blind, placebo-controlled prospective trial eval-

uating whether pexelizumab, a C5 complement inhibitor,
would decrease PMI in CABG patients.78 Therapy with this
agent resulted in a significant reduction in the 30-day inci-
dence of death or MI in 3099 patients undergoing CABG
surgery with or without valve surgery.78 A follow-up trial
in higher-risk patients (PRIMO-CABG II) failed to meet
the primary endpoint of death or MI at 30 days or the devel-
opment of new or worsening congestive heart failure. How-
ever, in a combined analysis of both trials (PRIMO-CABG I
and II; N ¼ 7353), death at 30 days was significantly
reduced for the greatest risk subset (n ¼ 2156; pexelizumab
5.7% vs placebo 8.1%; P ¼ .024).79
Sodium–hydrogen exchange inhibition with the agent
cariporide has also demonstrated promising results.80 In a
study evaluating the CABG cohort of the GUARDIAN trial,
therapy with cariporide yielded a modest risk reduction in
all-cause mortality and MI that was evident on postopera-
tive day 1 and persisted at 6 months postoperatively.80
These therapies remain far from wider clinical adoption,
however.
Perioperative Ventricular
Dysfunction and Failure
Postoperative ventricular failure with low cardiac output
state after cardiac surgery is an important predictor of
perioperative mortality and sudden death (Figs. 13.14
4.0
3.0
2.0
Ventricular Atrial
pacing pacing
Fig. 13.15 Effect of atrioventricular (AV) synchrony on cardiac output
after cardiac surgery. Cardiac output with ventricular pacing (without
synchronous atrial systole) is compared with cardiac output with atrial
pacing. An overall increase in cardiac output of approximately 26% is
achieved with A-pacing and restoration of AV synchrony with left
ventricular end-diastolic preload augmentation. (Redrawn with per-
mission from Hartzler GO, Maloney JD, Curtis JJ, et al. Hemodynamic
benefits of atrioventricular sequential pacing after cardiac surgery. Am J
Cardiol. 1977;40:232–236.)
and 13.15).81,82 Even patients with normal preoperative
ventricular function exhibit transient dysfunction after
uneventful cardiac operations.82 When ventricular dys-
function is encountered in the perioperative period, treat-
ment should consist of restoring adequate oxygen delivery
166 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
to prevent end-organ damage and rapid recognition and
correction of the underlying cause. In addition, recognition
of well-described preoperative risk factors for the develop-
ment of low cardiac output syndrome may prevent its
occurrence via earlier intervention and more aggressive
preoperative optimization.67,82,83 A retrospective review
of 4558 CABG patients identified eight independent predic-
tors of postoperative ventricular dysfunction. These risk
factors included preoperative LVEF less than 20%, redo
operation, emergency operation, female sex, age greater
than 70, left main coronary artery stenosis, recent MI,
and extensive three-vessel coronary artery disease.73 The
observed incidence of low cardiac output was 9.1% in this
population, with an operative mortality of 16.9%, as
opposed to 0.9% in the remaining patients with normal
ventricular function.67 In another study of over 20,000
CABG patients, the incidence of low cardiac output syn-
drome varied from 6% with preoperative LVEF greater
than 40% to 23% in patients with LVEF less than
20%.84 Importantly, these studies highlight that advances
in therapeutic management strategies have led to a decline
in mortality rates and perioperative low cardiac output
states despite the increasing risk profile of cardiac surgery
patients.
FAILURE TO WEAN FROM CARDIOPULMONARY
BYPASS
Failure to wean from CPB represents a sentinel intrao-
perative event in cardiac surgery and warrants indepen-
dent discussion. An expeditious and properly performed
cardiac procedure is the best strategy to avoid this prob-
lem. However, the process of successful weaning from
CPB is complex and has many prerequisites, not just ven-
tricular function. Bradycardia and absence of AV syn-
chrony are very detrimental and must be corrected
with temporary pacing wires (Figs. 13.15 and 13.16).
Atrial fibrillation should be aggressively cardioverted
and treated pharmacologically. Frequent premature ven-
tricular contractions (PVCs) should be suppressed with
amiodarone or lidocaine. Appropriate preload must be
determined relative to preoperative filling pressures, dura-
tion of clamp time, and consideration of ventricular stiffness.
Appropriate afterload provides critical coronary perfusion
pressure and may be compromised by inflammatory
responses to prolonged CPB. In this setting, agents that pro-
mote vasodilation, such as NTG and milrinone, must be
stopped. Consideration should include vasopressin or
alpha-adrenergic receptor agonists.
To avoid failure to wean from CPB, a comprehensive
checklist of clinical variables should be systematically eval-
uated prior to initiating weaning efforts. First, intraoperative
TEE evaluation of prosthetic valve function and ventricular
wall motion, as well as Doppler flow probe analysis of bypass
grafts, should be instituted. Any abnormality in body tem-
perature, heart rate and rhythm, preload and perfusion
pressures, acid–base status, electrolytes, and hematocrit
must be addressed. Hyperkalemia, hypocalcemia, acidosis,
hypoxia, and anemia can all profoundly depress ventricular
performance and must be rapidly corrected. Surgical correc-
tion of mechanical deficiencies may be required to success-
fully separate from CPB. The status of RV function must also
be examined, given its important impact on CPB weaning
7.0
150
220 150
6.0
250
150
180
200
Cardiac output, L/min
5.0
250
4.0
240
3.0 280
2.0
Atrial AV
pacing Sequential
(PR) pacing
(AV)
Fig. 13.16 Cardiac output with atrioventricular (AV) sequential versus
with atrial pacing: Impact of PR interval duration. A comparison of AV
sequential pacing and atrial pacing in patients with a prolonged
postoperative PR interval. (Intrinsic and paced PR intervals are shown in
milliseconds to the left for atrial pacing and to the right for AV
sequential pacing.) Note the uniform increase in cardiac output despite
absolute differences in the shortening of the PR interval that is induced
by pacing and overlap between paced PR intervals and intrinsic PR
intervals between patients. (Redrawn with permission from Hartzler GO,
Maloney JD, Curtis JJ, et al. Hemodynamic benefits of atrioventricular
sequential pacing after cardiac surgery. Am J Cardiol. 1977;40:232–236.)
and overall outcome.75 Nitric oxide and inodilators such
as milrinone should be considered. Prophylactic initiation
of inotropic support in select, high-risk patients may be
advocated to enhance the likelihood of successful separation
from CPB.83
If weaning from CPB is still unsuccessful after these
optimizing measures, CPB may need to be reinitiated to
allow further recovery of myocardial stunning. Although
a period of ventricular rest has proved helpful in many
cases, prolonged CPB and repeated failures to wean
may result in worsening coagulopathy, emphasizing the
importance of a timely decision to institute mechanical
support. IABP placement is warranted during this rest
period.85 Refractory ventricular failure in this setting
necessitates more advanced mechanical support, includ-
ing extracorporeal membrane oxygenation (ECMO) or a
ventricular assist device (VAD);86 these mechanical
options should be instituted with even less hesitation if
preoperative ventricular dysfunction was present
(Fig. 13.17). Complete mechanical support may serve
as a bridge to recovery or to transplant or as a destination
left ventricular assist device (LVAD) therapy. A more
detailed discussion of device options for mechanical
support, various inotropic agents, and other therapeutic
strategies is presented later.
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 167

Revascularization
(PCI or surgical)58

Treatable problem with

coronary circulation

Rule out problem with coronary Recovery

Normal New Postprocedure circulation (cardiac catheterization
LV dysfunction or intraoperative flow probe)

Precardiac surgery Coronary circulation intact Optimize rhythm,

LV function Persistent LV dysfunction hemodynamics, inotropes,
place IABP76,80,105

Persistent
Severe Persistent or worse shock
dysfunction postprocedure
LV dysfunction

Recovery

Complete Extracorporeal
mechanical LVAD
support
Yes
Yes No
Withdraw
Significant Elderly support
ECMO pulmonary VAD Many comorbidities
edema? Biventricular failure

No
Cardiopulmonary End-organ recovery
Persistent cardiac Good transplant candidate
recovery
dysfunction isolated LV failure

Withdraw
support
Consider implantable
LVAD

Transplantation Destination
LVAD therapy

Fig. 13.17 Algorithm for management of patients with ventricular failure after cardiac surgery. ECMO, Extracorporeal membrane oxygenation; IABP,
intra-aortic balloon pump; LV, left ventricular; LVAD, left ventricular assist device; PCI, percutaneous coronary intervention; VAD, ventricular assist device.

POSTOPERATIVE LOW CARDIAC OUTPUT STATE
Assessment
General Assessment. Immediately on arrival to the ICU,
the cardiac surgery patient must be thoroughly evaluated
in a systematic fashion. Part of this evaluation should
encompass the airway and ventilation, body temperature,
serum electrolyte levels, acid–base status, hemodynamics,
and initial postoperative chest radiograph. Data on the
nature of the procedure performed, response of the cardio-
vascular system to the procedure, intraoperative complica-
tions, current and preoperative medications, and patient
comorbidities should be communicated to the ICU team.
Adequate oxygen delivery (a function of cardiac output,
hemoglobin concentration, and arterial oxygen saturation)
is the top priority. Therefore, a central feature of the initial
168 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Rate
Rhythm
Preload Hypoventilation
Afterload V/Q Mismatch
Contractility Anemia Intrapulmonary shunt

Oxygen Cardiac Hemoglobin Oxygen

transport output concentration saturation

Fig. 13.18 Components of oxygen transport. (Adapted with permission

from Levy JH, Michelsen L, Shanewise J, et al. In Kaplan JA, Reich DL,
Konstadt SN, eds. Cardiac Anesthesia, 4th ed. Philadelphia: Saunders; 1999:
1233–1257.) A

evaluation is examination of all physiologic and patho-

physiologic parameters that influence the determinants
of oxygen delivery and overall global cardiac function
(Fig. 13.18).87 Adequate oxygen delivery and CO2 elimina-
tion can be confirmed via measurements of pulse oximetry,
mixed venous oximetry, and arterial gas tensions.
Heart rate and rhythm are key determinants of cardiac
output, and every effort is made to establish and maintain
normal sinus rhythm and adequate rate in the early postop-
erative period. Arrhythmias may require immediate cardio-
version, especially if poorly tolerated from a hemodynamic
standpoint. Rhythm disturbances may also be caused by elec-
trolyte or acid–base imbalances, hypothermia, proarrhyth-
mic inotropic agents, or even a malpositioned PA catheter
irritating the RV outflow tract.88 As discussed previously,
unexpected ECG changes, such as ST-segment deviation or
Q-wave development, may very well reflect myocardial ische-
mia or PMI, which may also cause arrhythmias.
Despite intraoperative rewarming efforts, residual hypo-
thermia is frequently noted in postoperative cardiac surgery
patients, with core temperatures less than 35°C.54 The
characteristic decline in temperature after separation from
CPB may be attributed to redistribution of heat within the
body or to actual heat loss, particularly if the chest remains
open for an extended period after rewarming.54 Hypother-
mia impairs cardiac function, causes shivering (which
dramatically increases myocardial oxygen demand), aggra-
vates rhythm disturbances, and interferes with coagulation
and platelet function, which can contribute to postoperative
hemorrhage.87,88 To limit these deleterious effects, the use
of blankets and other auxiliary warming devices should
be aggressively implemented.
Recognition of electrolyte and acid–base disturbances is
another critical component of the assessment. Typical post-
operative electrolyte abnormalities that negatively impact
ventricular function include hypokalemia, hypomagnese-
mia, and hypocalcemia. These electrolyte deficiencies
should be aggressively corrected and monitored. Similarly,
arterial pH should be checked and often ranges widely in
postoperative cardiac surgery patients. Deviations in pH
from normal in either direction, regardless of etiology,
adversely affect myocardial function and the response to
inotropic agents.89,90
On arrival to the ICU, an immediate portable chest
radiograph should be obtained. The critical items include
the position of the endotracheal tube and exclusion of
pneumothorax, hemothorax, or lobar collapse (Fig. 13.19).
B
Fig. 13.19 Early respiratory distress in a postoperative patient
on mechanical ventilation is frequently difficult to assess without
emergency chest radiography. A pneumothorax, which can produce
intrathoracic tension and hemodynamic compromise, must be differ-
entiated from lobar collapse. A chest radiograph of a patient with
respiratory distress early after coronary surgery shows a large right
tension pneumothorax (A) that is readily reversed with chest tube
insertion (B).
Additional important features include width of the mediasti-
nal silhouette and correct location of invasive catheters,
radiopaque markers, sternal wires, and drainage tubes.88
Hemodynamic and Echocardiographic Assessment. A
flow-directed PA (Swan-Ganz) catheter enables measure-
ment of ventricular filling pressures, cardiac output, and
MVO2. These catheters are routinely employed for high-risk
cardiac surgery. There are, however, notable limitations
with hemodynamic measurements obtained via PA cathe-
ters.88 For example, cardiac output measurements acquired
through thermodilution may be inaccurate in the setting of
tricuspid regurgitation. Similarly, positive end-expiratory
pressure (PEEP), a common feature of ventilatory manage-
ment, may artificially elevate filling pressures. Significant
mitral valve insufficiency may confound accurate assess-
ment of capillary wedge pressure. Intracardiac shunting
may negate the utility of MVO2 measurements. Finally,
malposition or improper setup of the PA catheter can lead
to confusing data and inappropriate management. There-
fore, although the PA catheter provides critical patient
information, the clinical conditions should always be
assessed and the limitations of the PA catheters understood.
After cardiac surgery, a cardiac index of at least 2.2
L/min/m2 is generally deemed necessary for normal conva-
lescence.90 Therapeutic manipulation of heart rate and
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery
rhythm is critical to optimizing cardiac output and often
requires temporary, epicardial, atrial, and ventricular pac-
ing.91–93 Another fundamental aspect of postoperative
management is maintenance of adequate preload. Postoper-
ative cardiac surgery patients generally exhibit relative
hypovolemia and labile vascular tone as a result of sponta-
neous diuresis, ongoing hemorrhage, capillary leak, and
vasodilation with rewarming.94 The end result of these
physiologic changes is a diminished preload, as indicated
by low pulmonary capillary wedge pressure (PCWP) and
CVP measurements. Volume expansion can be accom-
plished with administration of crystalloid or colloid intrave-
nous fluids, or blood products. Optimal preload conditions
should be individualized, but a PCWP range of 14 to
18 mm Hg has been proposed.95 Patients with markedly
hypertrophic and noncompliant left ventricles resulting
from preoperative aortic stenosis may require significantly
higher filling pressures to achieve adequate cardiac output.
Afterload is commonly elevated after cardiac surgery, as
indicated by increased blood pressure and systemic vas-
cular resistance (SVR; >1200 dyn/s/cm5). The frequency
of elevation typically varies with cardiac pathology and
operative procedure. The reported incidence ranges
between 8% and 12% after valve replacement96 and
between 8% and 61% after CABG.96–98 Potential etiologies
include decreased baroreceptor sensitivity,94,99 elevated
renin-angiotensin activity,90,91 elevated catecholamine
levels,97,100,101 and postoperative pain.102 If cardiac output
remains suboptimal despite adequate preload conditions,
pharmacologic afterload reduction often improves stroke
volume and cardiac output. Importantly, afterload reduc-
tion in the setting of inadequate filling can have deleterious
consequences, such as compensatory tachycardia or
increased infarction size.103
Some patients exhibit a vasoplegic syndrome shortly after
CPB, with very low SVRs and decreased vascular reactiv-
ity.104 This syndrome, which is further characterized by
severe hypotension and increased volume and vasopressor
requirements, results from a systemic inflammatory
response incited by CPB and may occur even with normal
preoperative ventricular function. Given the defective
release of baroreflex-mediated arginine vasopressin (AVP)
that may underlie this syndrome, management requires
administration of vasoconstrictive agents to normalize after-
load.105 Methylene blue and hydroxocobalamin have both
been demonstrated to improve blood pressure in postcardiac
surgery vasoplegic syndrome.106
Assessment of hemodynamics should not occur at a single
time point. Early postoperative cardiac surgery patients dis-
play rapidly changing hemodynamics, and treatments sel-
dom effect abrupt improvements. Therefore, multiple
repeat assessments of hemodynamics are warranted. Trends
should be defined and are of greater importance in dictating
treatment interventions. Patience in assessing trends may
lead to a better understanding of overall physiology.
If postoperative low cardiac output state persists and fails
to respond to standard manipulation of heart rate, preload,
and afterload, echocardiography may provide supplemental
information, such as the status of ventricular filling, the
nature of ventricular dysfunction (global, segmental, right
or left), and whether there is any evidence of external
compression. When abnormal ECG readings or cardiac
enzyme levels suggest ischemia or PMI, echocardiography
169
can confirm wall motion abnormalities and guide further
therapy. For patients who have undergone valve surgery,
low cardiac output state or heart failure symptoms warrant
echocardiography to exclude perivalvular leak or disruption
of the repair. Specifically for cases of mitral valve repair, sys-
tolic anterior motion of the valve and dynamic LV outflow
obstruction can occur and are best diagnosed with echocar-
diography. Echocardiography is also valuable in assessing
adequacy of ventricular septal defect repair.
Echocardiography can provide valuable additional data to
help elucidate the diagnosis of cardiac tamponade.107
In patients with circumferential pericardial effusion,
echocardiography frequently reveals RV diastolic collapse,
right atrial collapse, and left atrial collapse, which are useful
signs of cardiac tamponade.99 Recent evidence suggests
that early diastolic invagination of the LV free wall and
LV diastolic collapse may be a particularly useful echocar-
diographic finding to aid in the diagnosis of tamponade.108
Compressive hematomas may selectively affect the superior
or inferior vena cava or pulmonary veins, leading to tampo-
nade, and this can often be identified with transthoracic
echocardiography or TEE.
Cardiac tamponade is caused by accumulation of fluid or
clotted blood in the mediastinum, thereby restricting dia-
stolic filling of the ventricles. Notably, in some instances,
chest wall and pericardial edema can cause significant com-
pression without any evidence of clot of effusion. Studies
indicate that it can occur acutely in 3% to 6% of postcardiac
surgery patients.109–111 The characteristic signs of acute
postoperative cardiac tamponade include (1) increased
variation in blood pressure with respiration (pulsus para-
doxus);88 (2) equalization and elevation of CVP, PA diastolic
pressure, and left atrial pressure or PCWP;112 (3) decreased
urine output; (4) excessive chest tube drainage or, con-
versely, sudden cessation of chest tube drainage, when
heavy clots obstruct the chest tubes; (5) mediastinal widen-
ing on chest radiograph; (6) low cardiac output (late); and
(7) hypotension (late). Tamponade is definitively diagnosed
and managed with urgent surgical exploration and hema-
toma evacuation. Temporizing measures include volume
loading, inotropic support, and reduction of airway pressure
(elimination of PEEP, anesthetic agents, and decreasing
tidal volume with increasing ventilatory rate).3 Although
many tests can suggest the diagnosis of cardiac tamponade,
there is no single definitive study, and the diagnosis remains
a clinical judgment. Because this condition is readily treat-
able, a strategy of aggressive re-exploration should be advo-
cated; re-exploration in the operating room is definitive,
and, when tamponade is not present, there is little risk to
the patient. Persistent treatment of tamponade with trans-
fusion or inotropes can lead to circulatory collapse, cardiac
arrest, and precarious wound reopening in an ICU setting.
Delayed re-exploration is a failure of clinical judgment
and can result in death of the patient.
Management Strategies for Postoperative Low
Cardiac Output
Optimization of Cardiac Rate and Rhythm. The first
hemodynamic parameters to be addressed in the manage-
ment of postoperative low cardiac output are heart rate
and rhythm. Maintenance of normal sinus rhythm cannot
be overemphasized. When sinus rhythm is achieved, the
170 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

optimal rate for most patients is between 80 and 100 beats/
min.113 AV synchrony provides end-diastolic preload aug-
mentation and can increase cardiac output by 25% (see
Fig. 13.15).114 Heart rate disturbances are common after
cardiac surgery and include sinus bradycardia, junctional
rhythm, and first-, second-, or third-degree heart block. These
disturbances are usually temporary and may be secondary to
perioperative beta-blockade or to metabolic derangements
from cardioplegic arrest.115,116 Ischemia of the conduction
system caused by inadequate myocardial protection, or per-
manent injury to the conduction system caused by direct
surgical trauma are other possible etiologies.116,117
Management of heart rate disturbances must be individual-
ized for each patient and commonly incorporates use of tem-
porary pacing wires placed intraoperatively. If temporary
epicardial pacing is not available, alternatives include
transvenous or transthoracic pacing, or pharmacologic treat-
ments for bradyarrhythmias (e.g., isoproterenol or atro-
pine).118 For sinus bradycardia or junctional arrhythmias,
simple atrial pacing (range, 90 to 110 beats/min) is appropri-
ate. Conversely, AV nodal blocks are treated with AV pac-
ing.119 With this strategy, the optimal AV interval depends
on the chosen heart rate (see Fig. 13.16). It is important to note
that AV pacing leads to a loss of normal ventricular activation
sequence and consequent depression of ventricular function
by 10% to 15% for a given preload and afterload. Therefore,
careful adjustments of heart rate selection must be correlated
with cardiac output measurements to determine the optimal
settings. Slower heart rate settings may be preferred in patients
with dynamic LV outflow obstruction. In these cases, rapid
heart rate prevents ventricular filling and accentuates outflow
tract obstruction.
Preload and Afterload. Therapeutic measures to optimize
preload conditions were discussed previously. Vasodilatory
shock, a state of severely depressed afterload, is often
effectively managed with AVP.97 However, elevated after-
load should be pharmacologically reduced if cardiac out-
put remains suboptimal despite adequate volume loading.
The extent to which afterload reduction improves stroke
volume is dependent on the end-systolic pressure–volume
relationship of each patient. In patients with mitral120,121
and aortic insufficiency,122 afterload reduction may
be more important to enhance forward ejection. NTG,
cardipine, and sodium nitroprusside (SNP) are the most fre-
quently used pharmacologic agents for afterload reduction.
SNP may exacerbate postoperative myocardial ischemia by
causing significant intracoronary shunting.123 Never-
theless, SNP remains the preferred agent for treatment of
postoperative hypertension.121,124,125 NTG is frequently
used after CABG surgery because of its favorable effects of
improving coronary collateral flow and prevention of coro-
nary spasm.123,126
Inotropic State. Postoperative myocardial dysfunction may
require inotropic support when measures to optimize heart
rate, rhythm, hemoglobin concentration, preload, and after-
load have been exhausted. Use of inotropic agents to improve
cardiac function must be carefully tempered because of
resultant increases in myocardial oxygen consumption.
Table 13.6 summarizes currently available inotropic agents
for pharmacologic support of cardiac function. Inotropic
agents are generally administered by continuous infusion
through a central venous catheter. The majority of inotropic
agents function as beta-adrenergic agonists, leading to
an increase in intracellular cAMP and calcium concentra-
tion.127 These beta-adrenergic agonist agents are also classi-
cally associated with proarrhythmic effects and should be used
cautiously. Moreover, many inotropes (e.g., dopamine,
epinephrine, and norepinephrine) also possess prominent
alpha-adrenergic agonism and at high doses can induce
dangerous vasoconstrictive effects, leading to limb, mesen-
teric, or renal ischemic injury. Nonadrenergic inotropes,
such as phosphodiesterase inhibitors (e.g., amrinone,
milrinone), can be particularly effective in the management
of right heart dysfunction. Combinations of milrinone and
beta-adrenergic receptor agonists may have synergistic effects
on improving myocardial function.

Table 13.6 Pharmacologic agents for ventricular failure after cardiac surgery.
AR Activation PHYSIOLOGIC RESPONSE
Drug Dose (mg/kg/min) α1 β1 β2 SVR MAP CO HR PAWP
Dopamine <5 ++ $ " " " $
>5 ++ ++ "" "" " " "
Dobutamine 2-20 ++ + # " " " #
Epinephrine <0.05 ++ + # " " " #
>0.05 ++ ++ + "" "" " " "
Norepinephrine 0.03-1.0 ++ + "" "" $ " "
Phenylephrine 0.6-2.0 ++ "" "" # $ "
Isoproterenol 0.03-0.15 ++ ++ # $ " "" #
Milrinone 0.3-1.5 PDEI # " " $ #
Amrinone 5-20 PDEI # " " $ #
a
Vasopressin 0.01-0.1 "" "" # $ "

α1, Peripheral vasculature; β1, myocardium; β2, peripheral vasculature and myocardium; AR, adrenergic receptor activation; CO, cardiac output; HR, heart rate; MAP,
mean arterial pressure; PAWP, pulmonary artery wedge pressure; PDEI, phosphodiesterase inhibitor; SVR, systemic vascular resistance.
a
Dosage in U/min.
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery
Levosimendan, a calcium sensitizer, has also been used in
this setting, with multiple smaller studies showing a possible
benefit. However, a large scale multicenter trial (Levosimen-
dan in High Risk Patients Undergoing Cardiac Surgery
[CHEETAH]) was prematurely stopped due to futility (after
506 patients) with failure to show a difference over placebo
in 30-day mortality.128
Intra-aortic Balloon Pump. When conventional mea-
sures fail to achieve acceptable hemodynamics, mechanical
circulatory assist devices should be considered.129–131 After
cardiac surgery, significant ventricular dysfunction requir-
ing mechanical assistance occurs in less than 5% of
patients.86 Most of these patients (60% to 90%) can be sta-
bilized with an IABP, and only a small percentage (0.2% to
1%) require more advanced circulatory assist devices.86 The
objective for mechanical circulatory assistance in postoper-
ative cardiac surgical patients is to provide adequate circu-
lation and to diminish myocardial work, thus allowing
recovery of stunned myocardium.
IABP represents the most frequently employed system for
LV mechanical support, with an estimated >100,000
patients being supported annually.132 The most common
design consists of a sheath that is percutaneously placed
into the common femoral artery employing a guidewire
and a series of dilators. Sheathless introduction has been
advocated to reduce vascular complications in smaller
patients.133 The balloon catheter has a central lumen for
arterial pressure monitoring and a side lumen for helium
gas shuttling; the typical balloon volume is 40 mL, and diam-
eters are 8 to 9.5 F. The balloon catheter is positioned in the
descending thoracic aorta, just distal to the left subclavian
artery. Appropriate positioning must be confirmed with
fluoroscopy or echocardiography.134 Severe aortoiliac ath-
erosclerotic disease may prevent safe placement by the percu-
taneous femoral approach. The presence of aneurysmal
disease of the aorta or the iliac vessels or the presence of
an aortofemoral prosthetic graft increases the risks of femoral
placement, but successful IABP placement is still feasible in
both of these settings. If femoral placement is not possible,
IABP can be placed via the ascending aorta, typically with
the balloon placed through a polytetrafluoroethylene or vein
graft that is sewn to the aorta. This technique prevents bleed-
ing and enables the device to be well secured. Removal of the
IABP from the ascending aorta usually requires that the
patient return to the operating room for open removal.
Finally, the presence of moderate or severe aortic insuffi-
ciency represents a relative contraindication, as aortic coun-
terpulsation is ineffective.135
Once IABP is properly positioned, the operator must make
several selections on the console. The balloon inflation may be
triggered in one of three ways: by the arterial pressure, the
R wave of the ECG, or the pacing spike from an artificial pace-
maker. Generally, the R-wave trigger is most efficient. How-
ever, if the patient has frequent arrhythmias, such as PVCs or
atrial fibrillation, the arterial pressure may provide a better
trigger. The operator also selects whether the balloon coun-
terpulsation will occur with each cardiac cycle (1:1) or with
every other or every third cycle (1:2 or 1:3). Generally, 1:1
support is used initially, and 1:2 or 1:3 is reserved for when
the device is weaned. With frequent arrhythmias or heart
rates greater than 120 beats/min, 1:2 support may be more
efficient. The most important setting, however, is the timing of
171
balloon inflation and deflation relative to the cardiac cycle.
Balloon inflation should begin during early diastole, just
beyond the dicrotic notch (closure of the aortic valve). Balloon
deflation should end just prior to systole and effect a reduc-
tion in diastolic pressure. Proper inflation serves to increase
coronary perfusion, and properly timed deflation reduces
LV afterload and oxygen consumption (see Fig. 13.13).
Typically, efforts to discontinue IABP support should pro-
ceed cautiously and only after patients are first weaned from
significant inotropic support. Patients are frequently treated
with significant volume to support hemodynamics and
should be aggressively diuresed prior to removal of the device.
During weaning of IABP support, MVO2 saturations, cardiac
output, and ventricular filling pressures should be carefully
monitored. A slight decline in hemodynamics may be antic-
ipated, but significant decreases in cardiac output or mixed
venous saturations or large rises in filling pressures indicate
that ventricular function is not sufficiently recovered. Devel-
opment of ventricular or atrial arrhythmias is another indi-
cator that IABP support should not be discontinued.
Postoperative IABP placement does not require immedi-
ate anticoagulation. Patients who require postoperative
IABP support for more than 48 to 72 hours are generally
anticoagulated with heparin, given as a continuous
infusion without a bolus dose. Bivalirudin has also been
used for anticoagulation during the early postoperative
period in patients who may have heparin-induced thrombo-
cytopenia. Failure to anticoagulate patients who have IABP
for an extended period may increase the risk for vascular
complications. Vascular complications represent the most
frequent morbidity associated with IABP; these problems
range from simple hematoma or false aneurysm to more
serious limb ischemia. With femoral IABP, pedal pulses or +.
Doppler signals should be monitored every 2 hours.136 If
pedal Doppler signals cannot be appreciated in the ipsilateral
limb, withdrawal of the introducer may occasionally result
in return of significant limb perfusion. However, if pedal
Doppler signals remain absent, the safest approach is to
remove the pump and place a new device in the contralat-
eral femoral artery. If removal of the IABP fails to restore
perfusion to the limb, surgical exploration of the femoral
artery is warranted with Fogarty catheter embolectomy
and arterial repair. If arterial inflow has been lost, femo-
ral–femoral bypass may be performed.
Another well-recognized complication is that of balloon
rupture, with a reported rate of 0.5% to 6%.135,137 It is her-
alded by blood in the balloon catheter, and important
sequelae include helium gas embolization, infection, and
loss of ventricular assistance. The IABP should be stopped
and removed immediately when this is diagnosed.
Venoarterial Extracorporeal Membrane Oxygenation.
The decision to proceed to more advanced mechanical cir-
culatory support (MCS) is of critical importance. For exam-
ple, a patient may be supported on very high doses of
epinephrine or norepinephrine (>0.1 mg/kg/min) for many
hours with inadequate hemodynamics. In these scenarios,
renal or mesenteric injury may occur, or the patient may
experience cardiac arrest. Therefore, a timely decision for
MCS remains an important determinant of positive out-
comes. In general, high-dose inotropes and IABP should
be attempted first. Most patients show hemodynamic stabi-
lization or gradual improvement. If the patient fails to
172 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
stabilize or improve within hours, the treatment team
should proceed rapidly to MCS. Waiting for more advanced
deterioration with oliguria, acidosis, or arrhythmias is a
common error, and it prevents successful outcomes. Greater
familiarity with MCS strategies generally leads to earlier
application and improved outcomes.
Venoarterial extracorporeal membrane oxygenation
(VA-ECMO) support has become the most common support
strategy for patients who are unable to wean from CPB.
Most centers would use IABP first followed by ECMO if IABP
support alone is inadequate. Notably, unlike IABP support,
VA-ECMO provides gas exchange as well and does not
require native LV ejection. Therefore, ECMO constitutes a
temporary method to provide complete cardiac and pulmo-
nary support. Initial experience with ECMO for postcardiot-
omy cardiogenic shock reported poor survival (25%),138 but
survival has gradually improved to 40% with technical
advances in circuit and oxygenator design.139
In one study of 517 patients receiving ECMO for postcar-
diotomy shock, average support was 3.28 days, and 63.3%
weaned successfully off ECMO. However, only 24.8% of all
patients made it to hospital discharge.140
A recent systematic review was conducted evaluating
the outcomes of ECMO across 20 observational studies
(2877 patients) in postcardiotomy cardiogenic shock.141
The pooled survival rate to hospital discharge was 34.0%
(30.0%–38.0%), with a 1-year survival rate of 24.0%
Paracorporeal
Mechanical circulatory support devices
Percutaneous
Intracorporeal
Fig. 13.20 Different options for mechanical circulatory support devices. Important differences exist, based on the preferred support strategy. As of
2019, fewer centers will be implanting the HeartMate II, because most centers would be transitioning to the HeartMate III, not shown on the figure. The
HeartMate III is a centrifugal continuous flow pump. (Adapted with permission from Sen A, Larson JS, Kashani KB, et al. Mechanical circulatory assist devices:
A primer for critical care and emergency physicians. Crit Care. 2016;20:153.)
(19.05%–30.0%). Risk factors for mortality after ECMO sup-
port in cardiogenic shock include age >65 years, higher
blood lactate, renal insufficiency, a longer duration of ECMO
support, and neurologic complications.129,141–144
A typical ECMO circuit consists of cannulae for drainage
and inflow, a centrifugal vortex pump, a membrane oxygen-
ator, and a heat exchanger. The unit is constructed with either
a venovenous configuration or a VA configuration; the former
provides solely pulmonary support (gas exchange), whereas
the latter provides both cardiac and pulmonary support. Can-
nulation for VA-ECMO may be performed centrally, using the
aorta and right atrium, or peripherally via the femoral artery
and vein. An important morbidity for patients supported on
peripheral ECMO is vascular complications leading to limb
ischemia. The rate of this complication varies between
10.0% and 20.0% and can be decreased by the use of a distal
antegrade perfusion cannula.145 This typically consists of a
5- to 7-French cannula inserted into the superficial femoral
artery and attached with blood tubing to the main arterial can-
nula. Additional limitations associated with ECMO include
inability to directly unload the left ventricle, which may result
in supraphysiologic pressures in the pulmonary circulation
and lung injury.113
Ventricular Assist Devices. Choosing the most appro-
priate type of VAD for the patient with postoperative
ventricular failure is complex. Fig. 13.20 provides a
Pulsatile VAD (PVAD)
RVAD/
LVAD
BiVAD
Continous flow-centrifugal
centriMag ECMO pump,
Rotaflow pump
TandenHeart
RVAD/
LVAD Impella LP 5.0/2.5
Impella RP
BiVAD
Thoratec IVAD,
Pulsatile
Abiomed BVS 5000
HeartMate II, Jarvik 2000,
LVAD Axial continuous
HeartAssist 5, Incor
HVAD, EvaHeart,
Centrifugal continuous
VentrAssist, DuraHeart5
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery 173

summary of available VADs.146 The advantages of
extracorporeal devices include (1) ease of implantation,
(2) capability for weaning, (3) ease of removal, and (4)
option for biventricular support (both right ventricular
assist device [RVAD] and LVAD). On the other hand, the
intracorporeal or implantable LVAD systems (HeartWare
and HeartMate III; Thoratec, Pleasanton, CA) (Fig. 13.21
and 13.22) have the following advantages: (1) they provide
greater mobility and enable discharge from ICU or hospital,
(2) they have greater durability and can support patients
for months or years, and (3) they are approved as bridges
to transplant or destination therapy. Therefore, the extra-
corporeal devices are more appropriate for patients who
are likely to require only short-term support and may expe-
rience ventricular recovery. They are also more appropriate
for patients who need biventricular support. The implant-
able device would be the better choice if ventricular
recovery is unlikely and the patient is an appropriate can-
didate for transplant. Severely depressed preoperative LV
function may lead to planned strategy for postoperative

Fig. 13.21 An illustration of the Impella system. The system is based on a catheter-mounted axial flow pump. On the left is the Impella 2.5/5 system and
on the right the Impella RP. From Desai, S. and Hwang, N., 2020. Strategies for Left Ventricular Decompression During Venoarterial Extracorporeal Membrane
Oxygenation – A Narrative Review. Journal of Cardiothoracic and Vascular Anesthesia, 34(1), pp. 208–218.

Fig. 13.22 The HeartWare Pump demonstrating the positioning of the pump and the outflow graft. (Adapted with permission from Rogers JG, Pagani FD,
Tatooles AJ, et al. Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med. 2017;376:451–460.)
174 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
intracorporeal LVAD support as a bailout strategy if heart
function is limiting after conventional cardiac surgery.
On the other hand, normal ventricular function pre-
operatively and unanticipated poor ventricular function
after cardiac surgery may leave greater hope for recovery,
and therefore support with extracorporeal VADs may be
more appropriate. Detailed descriptions of specific types
of extracorporeal and implantable VADs follow. (See
Fig. 13.23.)
Several commercially centrifugal pumps are available, all
of which display pump head velocity (in revolutions per
minute [RPM]) as well as flow. The operator typically is able
to increase the RPM to achieve progressively higher pump
flow. In general, the RPM are set as low as possible to
achieve a flow greater than 2.0 L/min/m2; this approach
limits the hemolysis that can occur at higher RPMs. Ulti-
mately, flow with this system depends on cannula size
and placement, preload, and the RPM setting. With this type
of support, ventricular filling pressures are monitored and
kept within normal physiologic range with infusions of col-
loid or blood products.
CentriMag. The CentriMag (Thoratec, now Abbott, Santa
Clara, CA) is a widely used extracorporeal centrifugal pump
approved by the U.S. Food and Drug Administration (FDA)
that can provide up to 10 L/min of blood flow. It has a mag-
netically suspended rotor to decrease friction and hemolysis.
The CentriMag system can be used for both LV or RV sup-
port, as well as the pump in an ECMO circuit.
Impella System. Over the last decade, percutaneous
options for ventricular support have been developed,
Fig. 13.23 The HeartMate III pump demonstrating the positioning of the pump and the outflow graft. (Adapted with permission from Mehra MR, Uriel N,
Naka Y, et al. A fully magnetically levitated left ventricular assist device - final report. N Engl J Med. 2019;380:1618–1627.)
clinically tested, and approved by the FDA. The most popu-
lar system is the Impella pump (Abiomed Inc, Danvers, MA)
(Fig. 13.23). The Impella 2.5 and 5.0 systems (Abiomed Inc)
are catheter-mounted, electrically driven, axial flow pumps
that can be placed across the aortic valve and used to unload
the LV and support systemic blood pressure. Blood enters the
device through an inlet positioned in the LV and is then
pumped out above the aortic valve. Insertion strategies have
included percutaneous and open femoral artery, axillary
artery, and direct ascending aorta. Important limitations
of this device include high rate of malposition or catheter
migration.149 Furthermore, when higher RPMs are used,
these devices are associated with significant hemolysis,
given the small catheter sizes and sheer stress on red blood
cells.150 Vascular complications at the insertion site are also
common.151 Finally, when compared with ECMO, the
Impella system provides less hemodynamic support and
no support for gas exchange.
Many of these pumps require early anticoagulation with
heparin to prevent thrombus formation in the pump head.
Antiplatelet therapy with aspirin should also be considered.
The goal of anticoagulation is typically an activated clotting
time of 180 to 200 seconds or a partial prothrombin time of
approximately 60 to 80 seconds. Anticoagulation must be
balanced against postoperative bleeding and coagulopathy,
which are typically a problem in these patients. Most sur-
geons delay anticoagulation until postoperative bleeding
has fallen below 100 mL of chest tube drainage per hour.
Periodic inspection of the pumps/oxygenator is required,
with exchange as needed. Furthermore, increased anticoa-
gulation may be warranted during periods of weaning when
flow rates are decreased.
 13 • Treatment of Perioperative Ischemia, Infarction, and Ventricular Failure in Cardiac Surgery
After the implantation of an extracorporeal VAD device,
there are several important patient management goals.
First, bleeding must be controlled so that patients may be
properly anticoagulated to prevent thromboembolism. The
cessation of postoperative bleeding and achieving appropri-
ate anticoagulation is critical to positive outcomes. Initially,
these devices should provide complete ventricular unload-
ing, and inotropes should be aggressively weaned off. End-
organ function must be monitored and supported; diuresis
should be stimulated to clear any pulmonary edema.
Patients may require periods of continuous hemodialysis if
renal function is severely impaired. Neurologic function is
assessed on a daily basis. Echocardiography and weaning
efforts may be initiated as early as 3 days after implantation,
but some patients may require weeks of support before ven-
tricular recovery occurs.
Implantable LVADs (see Table 13.7) have received FDA
approval as bridges to transplant for recovery or as destina-
tion therapy. The electrical drive line is tunneled out of the
upper abdomen and is the only component exiting the body.
These devices receive drainage from a cannula placed in
the LV apex; outflow is via a graft to the ascending aorta.
Recent advances in these devices led to significant impro-
vement in patient outcomes in both the short and long
terms.147,148,153 Implantable LVADs have the major advan-
tage of allowing complete physical recovery. Patients with
these devices may resume ambulation rapidly and are dis-
charged to home. Some patients even return to work with
these devices.
Historically, thromboembolic events affected up to 20%
of patients supported with implantable LVADs. However,
newer-generation devices with fully magnetically levi-
tated rotors and speed change algorithms that introduce
some pulsatility have significantly reduced the thrombo-
embolic event rate, including stroke. Other adverse events
continue to limit broader application of these implantable
Table 13.7 Examples of mechanical assistance for ventricular
failure.
Pump
Device design Indications
Temporary
extracorporeal
support
Extracorporeal Centrifugal Cardiopulmonary failure,
membrane bridge to recovery
oxygenation
BioMedicus Centrifugal Postcardiotomy ventricular
dysfunction, bridge to recovery
Levitronix
CentriMag
Common
implantable chronic
support
Thoratec HeartMate Centrifugal Bridge to transplantation,
III destination therapy
HeartWare Centrifugal Bridge to transplantation,
destination therapy
175
LVADs, including high rates of GI bleeding, device-related
infection, and right-sided heart failure. Future device
design changes such as completely implanted systems
with transcutaneous powering may reduce some of these
side effects.147,153,154
PERIOPERATIVE RIGHT VENTRICULAR
DYSFUNCTION
Etiology
Perioperative low cardiac output syndromes are usually
attributed to LV or biventricular impairment, but some
patients display isolated RV dysfunction. The incidence
of postcardiotomy acute refractory RV failure has a
reported range of 0.04% to 0.1%, but RV dysfunction also
occurs in 2% to 3% of postoperative heart transplant
patients and nearly 20% to 30% of LVAD recipients.155
Postoperative RV dysfunction may arise even when preop-
erative RV function was normal.142,156 However, preoper-
ative functional impairment of the RV could be predictive
of more severe RV dysfunction postoperatively. In the peri-
operative setting, abnormalities of RV performance can be
related to LV dysfunction, RV ischemia or infarction, inad-
equate myocardial protection, increased pulmonary vas-
cular resistance (PVR), and altered interventricular
balance.84 During LVAD support, leftward shift of the
interventricular septum occurs as the LV is unloaded. This
alteration in interventricular balance leads to significant
reductions in RV contractility and afterload that may man-
ifest as RV dysfunction, especially with preexistent or peri-
operative RV ischemia.157
Relative to the left ventricle, the thin-walled right ventri-
cle has significantly reduced muscular reserve, rendering
it more sensitive to increases in afterload (PVR).87 Revers-
ible increases in PVR during and after CPB have been
described158 and may be attributed to extravascular com-
pression by pulmonary congestion, vasoactive substances
released from activated platelets and leukocytes,159 or
obstruction of pulmonary vascular beds by leukocytes or
platelet aggregates.160 Once established, RV dysfunction
in the perioperative period has detrimental effects on global
cardiac performance and may be self-propagating unless
appropriately treated. Specifically, reduced RV stroke vol-
ume will decrease LV filling, and RV dilation can induce
a leftward shift of the interventricular septum and conse-
quent impaired LV distensibility. The resultant decrease
in LV output will exacerbate further the already dysfunc-
tional RV.87
Diagnosis
Accurate interpretation of RV function is complex. Hemody-
namic parameters suggestive of RV dysfunction include low
cardiac output caused by inadequate LV filling, markedly
elevated CVP (>18 mm Hg), and a normal or low PCWP
as a result of poor left atrial filling.155 In cases of severe
RV dysfunction, PA pressures are low due to reduced RV
work capability. Echocardiographic evaluation is a critical
diagnostic tool for determining the status of RV function
and identifying potential etiologies of RV impairment.
The classic echocardiographic appearance of isolated RV
176 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
failure is that of a dilated RV with a small, empty, and hyper-
contractile LV. Echocardiography can quantitate RV func-
tion by measurement of RV ejection fraction, provide
qualitative assessment of RV size and configuration of the
interventricular septum, and detect RV free wall akinesis
or dyskinesis, indicative of underlying ischemic injury or
infarction.
Management
Treatment of RV dysfunction should begin with optimization
of heart rate and rhythm to maximize the atrial contribution
to RV filling. As with the treatment of LV dysfunction, tem-
porary atrial or AV pacing may be required. Preload, as
reflected by the CVP, should be augmented by volume load-
ing, provided there are reciprocal increases in cardiac out-
put.87,155 Efforts to increase RV inotropy through
administration of classic agents (e.g., epinephrine, norepi-
nephrine, and dopamine) may paradoxically increase PA
vasoconstriction and PVR and thus worsen RV failure.
Instead, phosphodiesterase inhibitors (e.g., milrinone, amri-
none) are more appropriate pharmacologic treatments
because of their positive inotropic effects and capacity to
reduce PA pressure and PVR simultaneously. Selective
pulmonary vasodilation can be achieved with inhaled nitric
oxide to optimize RV function with targeted afterload
reduction. Additional effective therapies for pulmonary vaso-
dilation include oral sildenafil161,162 and inhaled prostaglan-
dins, such as iloprost.162 A number of treatable conditions
may increase PVR, including hypercapnia, hypoxia, pleural
effusion, and pneumonia. These should be identified and trea-
ted. Finally, refractory RV dysfunction may require place-
ment of an RVAD. Options for RVAD support include a
surgically placed system with open cannulation of the RA
and PA and use of an extracorporeal centrifugal pump.
One limitation of this support strategy is the need for reo-
peration through a major thoracic incision for RVAD
removal. Percutaneous systems have also been developed;
for example, the Impella RP (Abiomed) uses a catheter-
based axial flow pump that is placed into the femoral vein
and positioned through the right heart, drawing blood in
at the right atrium/inferior vena cava junction and pump-
ing out into the main PA (Fig. 13.21).152 Another system
that is inserted percutaneously is the Protek Duo system
(TandemHeart; TandemLife, Pittsburgh, PA). This consists
of a catheter with two separate lumens. Blood is drained into
the cannula at the RA and then driven with an extracorpo-
real centrifugal pump through a lumen that delivers into the
main PA.163 A recent study by our group of 43 patients that
required an extracorporeal RVAD; 67% (n ¼ 29) were
implanted concurrently, and 33% (n ¼ 14) were implanted
as staged after the LVAD.164 Morbidity and mortality rates
of this mode of biventricular support remain high. Two-
thirds of these patients could be weaned to an isolated
LVAD. The 30-day mortality rate for this cohort was
14%.164 The overall mortality rate in the study period for
the staged implants was 71% versus 45% for the concurrent
implants (P ¼ .101). In addition, staged RVAD implantation
carried a significantly higher rate of postoperative renal fail-
ure (64% versus 28%; P ¼ .044). These findings again
emphasize the importance of early application of the
right-sided MCS before end-organ damage.
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 14 Perioperative Management
of Valvular Heart Disease
NATHAN H. WALDRON, MARTIN I. SIGURDSSON, and JOSEPH P. MATHEW
Preoperative Assessment
Valvular heart disease (VHD) is frequently observed in
patients undergoing surgery. As the medical and minimally
invasive management of coronary artery disease increases,
the number of patients with untreated advanced valvular
disease is likely to supersede the number of patients with
advanced coronary disease. Similarly, the rapidly expanding
use of percutaneous transcatheter aortic valve replacement
for high- and intermediate-risk patients with aortic stenosis
(AS),1,2 as well as the emergence of devices such as the
Mitraclip for symptomatic management of high-risk pati-
ents with ischemic mitral regurgitation (MR),3 may increase
the pool of patients with significant valvular disease un-
dergoing noncardiac surgery. The association of VHD with
other clinical predictors of increased perioperative cardio-
vascular risk is of prime importance, particularly as it relates
to unstable coronary syndromes, decompensated heart fail-
ure with left ventricular (LV) dysfunction, and significant
arrhythmias.4 For example, VHD has been reported to be
a major predictor of increased perioperative cardiovascular
risk, including myocardial infarction, heart failure, and car-
diac death.4 In patients older than 65 years presenting for
noncardiac or coronary artery surgery without concomi-
tant valvular surgery, a history of VHD is predictive of lower
LV ejection fraction (LVEF),5 and patients with preoperative
symptomatic valvular disease have increased risk of conges-
tive heart failure (CHF) after elective general surgical pro-
cedures.6 Similarly, significant aortic and mitral valvular
dysfunction diagnosed by preoperative transthoracic echo-
cardiography is an independent risk factor for perioperative
myocardial infarction.7 Significant AS is one of the major
factors adversely affecting the clinical outcome after non-
cardiac surgery,7,8 where it is found to increase the risk of
both myocardial infarction and mortality.9 Thus, although
it is important to preoperatively evaluate the presence, type,
and severity of VHD, its natural history and relation to
other disease states are key factors in determining the cli-
nical management strategy for the perioperative period.
The physician must know the patient’s preoperative his-
tory and the results of the physical examination. If a cardiac
murmur10 is present on preoperative evaluation, the anes-
thesiologist needs to decide whether it represents significant
VHD (see later). Current American Heart Association/
American College of Cardiology guidelines suggest that val-
vular intervention before elective noncardiac surgery is
effective in reducing perioperative risks, so delaying elective
noncardiac surgery if additional diagnostic interventions
and treatment are needed is reasonable (Fig. 14.1).
Furthermore, while surgery not amenable to delays for
definitive treatment can be performed, mapping the valvu-
lar lesion and its severity at minimum can usually be per-
formed quickly. This can be helpful to facilitate discussion
with the patient about the perioperative risks and to guide
the anesthesiology team about anesthetic approaches,
increased hemodynamic perioperative monitoring (includ-
ing invasive hemodynamic catheters and echocardiogra-
phy), and postoperative disposition of the patient to an
appropriate setting (such as the intensive care unit).4
Patients with severe VHD may be more prone to hemody-
namic instability during the operation, coupled with longer
times for both anesthesia and surgery when compared with
patients without VHD.11 High-risk surgical procedures
(emergent major operations, aortic and peripheral vascular
surgery, and prolonged surgical procedures associated with
large fluid shifts or blood loss) pose a greater risk of hemo-
dynamic instability and increased perioperative morbidity
and mortality.4,8,12,13 Although no randomized trials have
been performed to ascertain the best timing of surgical inter-
vention, the indications for evaluation and treatment of val-
vular lesions prior to elective noncardiac surgery are the
same as in the nonoperative setting.4,14 Thus, symptomatic
stenotic lesions often require valve replacement or percuta-
neous valvotomy prior to noncardiac surgery to decrease
cardiac risk,15 while it may be reasonable to perform
elevated-risk elective noncardiac surgery in patients with
asymptomatic severe stenotic lesions4 or with regurgitant
lesions, as these may be more amenable to medical manage-
ment in the perioperative setting. However, all of these
patients have elevated risk for postoperative morbidity
and mortality compared with patients free of VHD.9,16,17
Transthoracic echocardiography usually provides the
most thorough assessment of the significance of a cardiac
murmur, although preoperative electrocardiography and
chest radiography can provide clues to the severity of
VHD and associated cardiac conditions. Echocardiography
is an important tool for assessing the significance of cardiac
murmurs by imaging cardiac structure, function, and the
direction and velocity of blood flow through cardiac valves
and chambers.14 Current guidelines recommend perform-
ing preoperative echocardiography for patients with clini-
cally suspected moderate or greater degrees of valvular
stenosis or regurgitation, provided there is no echocardiog-
raphy exam available in the year prior to the procedure.
Furthermore, a repeat examination is indicated for patients
with a significant change in either clinical status or physical
examination since last echocardiography.4 If the results
of transthoracic echocardiography are inconclusive in
181
182 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Symptomatic
1. Angina
2. Syncope
3. Heart failure
4. Dyspnea
Patient with known or
suspected valvular disease
undergoing elective non-
cardiac surgery
(AS, AI, MS, MR)
Asymptomatic
Consider echocardiography
• Disease severity unclear
• LV/RV function unclear
• More than 1 year since
last echo
Fig. 14.1 Approach for perioperative treatment of patient with valvular disease. AI, Aortic insufficiency; AS, aortic stenosis; CVC, central venous catheter;
MR, mitral regurgitation; MS, mitral stenosis; PA-catheter, pulmonary artery catheter; TAVR, transcatheter aortic valve replacement; TEE, transesophageal
echocardiography. (Based on Fleisher LA, Fleischmann KE, Auerbach AD, et al; American College of Cardiology; American Heart Association. 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:e77-e137.)
defining the diagnosis, other tests, including transesopha-
geal echocardiography (TEE) and cardiac catheterization,
should be considered. It is important to glean from the echo-
cardiography report not only the severity of the most signif-
icant valvular lesion but also other indices of cardiac
function, including presence of dilated atriae, the size and
thickness of the left and right ventricles, evidence of elevated
right ventricular pressures, and presence and severity of dia-
stolic dysfunction. Preoperative knowledge of those param-
eters is very helpful in the perioperative management of
patients with VHD. In determining whether symptoms are
present, exercise testing may be helpful, as many patients
tend to limit their daily activity.14,18–20
Finally, the specific type of surgery and urgency of the
operation are important factors in stratifying perioperative
risk for VHD surgical patients. High-risk surgical procedures,
including emergent major operations, aortic and peripheral
vascular surgery, and prolonged surgical procedures associ-
ated with large fluid shifts or blood loss, pose a greater threat
of hemodynamic instability and portend an increase in
perioperative morbidity and mortality.4,8,12,13
Preoperative Preparation
ANTIMICROBIAL PROPHYLAXIS
Surgical procedures may induce bacteremia and thus
expose patients to the risk of acquiring infective endocardi-
tis, a potentially lethal disease if not aggressively treated.21
Valvular abnormalities, particularly those that result in
high-velocity jets, can damage the endothelial lining, lead
• Delay elective surgery
• Repeat echocardiography
Assess:
• Valvular disease severity
• LV and RV function
• Medical optimization
Proceed with case
• Differs based on valvular
when optimized
lesion (See Figure 15-2)
• Consider valvular intervention
• Valve replacement/repair
• percutaneous replacement/
treatment (TAVR, balloon
valvuloplasty)
Reasonable to proceed with case
• Risk of mortality and morbidity
increased
Consider
• Invasive hemodynamic monitoring
Severe (A-line, TEE, PA-catheter)
• CVC for vasopressors/inotropes
• Postoperative ICU admission
• Strict adherence to hemodynamic
goals (See Figure 15-2)
Mild/Moderate Proceed with case
to platelet aggregation and fibrin deposition at those sites,
and create a higher risk for bacterial colonization.14 To date,
the efficacy of prophylactic antibiotics is based on laboratory
animal models and small-scale clinical studies using primar-
ily surrogate markers of infective endocarditis.14,21,22
Current clinical strategies in endocarditis prevention are
based on recommendations from the American Heart
Association in 200723 and are outlined in Box 14.1 and
Table 14.1. These recommendations are substantially differ-
ent from earlier guidelines from 1997. Current guidelines
suggest that antibiotic prophylaxis solely for prevention of
infective endocarditis is reasonable only for a small subset
of patients with valvular disease at a high risk of adverse
outcome from endocarditis. These patients include surgical
patients with prosthetic valves, patients with previous his-
tory of endocarditis, unrepaired cyanotic congenital heart
disease, or completely repaired congenital heart defect with
prosthetic material or device within 6 months of the proce-
dure. Furthermore, cardiac transplant patients with second-
ary valvulopathies are at a high risk of endocarditis.
Antibiotic prophylaxis for these high-risk patients (see Box
14.1) is considered reasonable for dental and oral proce-
dures involving manipulation of gingival tissue, the periapi-
cal region of teeth, or perforation of the oral mucosa. In
addition, prophylaxis is reasonable for surgical procedures
involving the respiratory tract or infected skin, skin struc-
tures, or musculoskeletal tissue.23 In contrast, prophylaxis
is not routinely recommended for infective endocarditis pre-
vention in patients undergoing genitourinary or gastroin-
testinal procedures. In terms of administration, the initial
dose of antimicrobials should begin within 1 hour prior to
surgical incision.23,24
 14 • Perioperative Management of Valvular Heart Disease 183

Box 14.1 Endocarditis prophylaxis for cardiac conditions.

Endocarditis prophylaxis recommended ▪ Completely repaired congenital heart defect with prosthetic
High-risk category material or device, whether placed by surgery or by catheter
▪ intervention, during the first 6 months after the procedure
▪ Prosthetic cardiac valve or prosthetic material used for cardiac ▪ Repaired CHD with residual defects at the site or adjacent to
valve repair
the site of a prosthetic patch or prosthetic device (which
▪ Previous infective endocarditis inhibit endothelialization)
▪ Congenital heart disease (CHD) ▪ Cardiac transplant recipients who develop cardiac
▪ Unrepaired cyanotic CHD, including palliative shunts and valvulopathies
conduits

Reproduced with permission from Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart
Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on
Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality
of Care and Outcomes Research Interdisciplinary Working Group. Reprinted with permission Circulation. 2007;116:1736–54. © 2007 American Heart
Association, Inc.

Table 14.1 Prophylactic regimens for individuals at high risk for endocarditis.
REGIMEN: SINGLE DOSE 30 TO 60 MIN
BEFORE PROCEDURE
Situation Agent Adults Children
Oral Amoxicillin 2g 50 mg/kg
Unable to take oral medication Ampicillin 2 g IM or IV 50 mg/kg IM or IV
Allergic to penicillins or ampicillin–oral OR
Allergic to penicillins or ampicillin and unable Cefazolin or ceftriaxone 1 g IM or IV 50 mg/kg 1M or IV
to take oral medication Cephalexina,b 2g 50 mg/kg
OR
Clindamycin 600 mg 20 mg/kg
OR
Azithromycin or clarithromycin 500 mg 15 mg/kg
Cefazolin or ceftriaxoneb 1 g IM or IV 50 mg/kg IM or IV
OR
Clindamycin 600 mg IM or IV 20 mg/kg 1M or IV
a
Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.
b
Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin.
IM, Intramuscular; IV, intravenous.
Reproduced with permission from Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a
guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the
Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research
Interdisciplinary Working Group. Reprinted with permission Circulation. 2007;116:1736–54. © 2007 American Heart Association, Inc.

ANTICOAGULATION
Some patients with VHD receive chronic anticoagulation
therapy. It is important to understand the indication for
anticoagulation to determine the risks associated with hold-
ing anticoagulation in the perioperative period as well as
options for anticoagulation bridging. In general, anticoagu-
lation should not be held for procedures that do not have ele-
vated bleeding risk. Patients with mechanical valves are
currently all chronically anticoagulated with warfarin, as
novel oral anticoagulation agents (NOACs) have not been
tested or found to have excess risk.25 Per current guidelines,
patients with mechanical mitral valves, mechanical caged-
ball or tilting-disc aortic valves, or patients with mechanical
valves and recent stroke/transient ischemic attack are con-
sidered at high risk for thrombotic complications, and peri-
procedural bridging is recommended for procedures with
elevated bleeding risk.26 Bridging can either be performed
by unfractionated heparin (UFH) infusion or subcutaneous
low-molecular-weight heparin.27 Patients with bileaflet
mechanical aortic valves but without atrial fibrillation and
other stroke risk factors are considered to be at low risk for
thrombotic complications, so no bridging is recommended.
Patients with bileaflet mechanical aortic valves and either
atrial fibrillation or risk factors for stroke (prior stroke or tran-
sient ischemic attack, hypertension, diabetes, CHF, or age
over 75 years) are considered at moderate risk for thrombotic
complications, so the risk of thrombosis must be weighed
carefully against the risk of increased bleeding during the
perioperative period.26 Patients with VHD who have not
undergone a surgical replacement but require anticoagula-
tion for atrial fibrillation are generally either considered to
be at low or moderate risk of thrombotic complication, with
the exception of patients with stroke or transient ischemic
attack less than 3 months ago, a high burden of stroke risk
factors (indicated by CHADS2 score of 5 or higher), or
rheumatic heart disease. Most of these patients will therefore
not require an anticoagulation bridge from warfarin.26 Fur-
thermore, many of these will be chronically anticoagulated
with NOACs that allow patients to relatively quickly reverse
anticoagulation by stopping the medication secondary to
their short half-life compared with warfarin.
184 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
With regard to pregnancy, the American College of Chest
Physicians concluded that it is reasonable to use one of the
following three regimens to manage anticoagulation during
pregnancy: (1) either LMWH or UFH between 6 and
12 weeks of gestation and close to term, with warfarin admi-
nistered at all other times; (2) aggressive dose-adjusted UFH
throughout pregnancy; or (3) aggressive dose-adjusted
LMWH throughout pregnancy.28,29 In general, anticoa-
gulation should be resumed postoperatively as quickly as
possible from a procedural bleeding standpoint.
CHRONIC MEDICATIONS
Patients with severe VHD are often treated with antiarrhyth-
mic, inotropic, or diuretic therapy (or more than one of
these), and it is extremely important that these drugs be con-
tinued during the perioperative period.30–32 An inability to
administer postoperative oral medications in a timely fashion
to heart failure patients could be one reason for the occur-
rence of postoperative CHF.32 Similarly, cessation of antiar-
rhythmic drugs may pose a serious risk for the patient with
severe AS in whom cardiac output and hemodynamic stabil-
ity critically depend on normal sinus rhythm.33 Finally, ther-
apy aimed at minimizing the perioperative cardiac risk has to
be considered. Perioperative beta-blockade has been shown
to reduce the risk of cardiac events in patients with a risk
of myocardial ischemia undergoing noncardiac sur-
gery.4,11,34–36 Withholding beta-blockers has shown to be
a strong risk factor for postoperative atrial fibrillation after
coronary bypass surgery,37 and continuation of beta-blockers
after noncardiac surgery is associated with lower operative
mortality and lower incidence of myocardial infarction.38
However, initiating beta-blockade in all-comers in the periop-
erative setting has been shown to increase mortality and ele-
vate risk of strokes.39 Thus, the safety and efficacy of beta-
blockers in heart failure patients undergoing noncardiac sur-
gery is uncertain and should be evaluated on a case-by-case
basis. The benefit has to be balanced against the risk of
compromising cardiac inotropic function in unstable VHD
patients or those with limited contractile reserve. Further-
more, recent data have cast some doubt on the efficacy of
perioperative beta-blocker therapy in patients with interme-
diate risk factors.40,41 There is also growing evidence that
alpha-2-agonists and statins reduce the risk of adverse car-
diac events in surgical patients11,42,43; however, additional
large-scale trials are still needed to further delineate the role
of these agents. Finally, although an active inflammatory
process contributing to calcific AS has been recognized,10,44
a prospective randomized clinical trial45 concluded that
intensive lipid-lowering therapy with statin drugs did not halt
the progression of stenosis or induce its regression.
Intraoperative Management
PATHOPHYSIOLOGY OF DISEASE AND
PHYSIOLOGIC PRINCIPLES OF MANAGEMENT
The current hemodynamic principles of perioperative man-
agement of patients with VHD (see Table 14.2) are based on
underlying pathophysiology and the natural history of the
disease.10,31,46–50 As such, perioperative management is
guided by basic physiologic and pathophysiologic principles.
In general, blood flow through a valve is governed by simple
hydraulic principles,51 where the valve area, the square root of
the pressure gradient across the valve, and the duration of
transvalvular flow during a specific phase of the cardiac cycle
are the principal determinants of this flow. Lowering or raising
these determinant factors will decrease or increase the trans-
valvular flow accordingly. In stenotic lesions, the anesthetic
goal is to support transvalvular flow, which is partially “fixed”
by an obstructive lesion. In regurgitant lesions, the primary
goal is to minimize the fraction of regurgitant flow through
the abnormal valve while simultaneously increasing the
degree of forward flow. Another consideration in regurgitant
lesions is that the regurgitant orifice area can change dynam-
ically because of changes in valvular annulus or ventricular
dimensions produced by varying loading conditions.52 Thus,
perioperative management of heart rate, preload, and sys-
temic and pulmonary vascular resistance (PVR) depend on
the specific type of valvular abnormality (see Table 14.2).
NONPHARMACOLOGIC MANAGEMENT
Nonpharmacologic factors53,54 may facilitate or interfere
with the provision of anesthesia for patients with VHD. For
example, the Trendelenburg position may help to support
preload in an emergency, but it may also promote pulmonary
vascular congestion and decompensation in patients with
elevated pulmonary artery pressures (such as in severe mitral
stenosis [MS]) or right-sided valvular lesions. Similarly,
changing to the upright position increases venous pooling,
decreasing preload, cardiac output, and potentially worsen-
ing dynamic LV outflow tract obstruction in patients with
hypertrophic cardiomyopathy. Positive pressure ventilation
and positive end-expiratory pressure may also decrease
venous return to the right heart and increase PVR.55 Other
important conditions that increase PVR include hypoxia,
hypercapnia, acidosis, and hypothermia. Hypothermia also
increases the sympathetic drive and represents an additional
risk factor for morbid cardiac events.56 Additionally, preser-
vation of normothermia57 has been shown to reduce the inci-
dence of surgical infection.
PREMEDICATION
Premedication may be helpful in preventing perioperative
anxiety and stress-induced tachycardia. However, in some
patients, acutely withdrawing the sympathetic tone may
be undesirable. In patients with severe VHD, premedication
should be tailored to preserve myocardial function and to
avoid significant reduction in preload and systemic vascular
resistance (SVR).48,58 In patients with pulmonary hyperten-
sion, right-sided valvular disease, or severe mitral disease,
hypoventilation leading to hypoxemia or hypercapnia
should also be avoided.
TYPE OF ANESTHESIA: GENERAL, REGIONAL, OR
LOCAL WITH MONITORED SEDATION
Many anesthetic regimens are used for patients with VHD
who are undergoing noncardiac surgery.48 Today, there
 14 • Perioperative Management of Valvular Heart Disease 185

Table 14.2 Hemodynamic principles for perioperative management of valvular heart disease: stenotic lesions.
VHD Rhythm HR Contractility Preload SVR PVR Other concerns
AS Maintain NSR Avoid Maintain Maintain Avoid Maintain Consider preinduction
tachycardia, normovolemia sudden arterial line and external
Treat AF severe decreases defibrillator
promptly bradycardia Consider augmenting Proceed carefully with
Maintain May not prior to anesthetic neuraxial anesthesia
HR 60–80 withstand induction
beta-
blockade
MS Often AF, rate Avoid Maintain Maintain normovolemia Avoid Avoid Avoid respiratory
control tachycardia within (left atrial pressure) sudden increases in depression (cautious
important Maintain normal limits Avoid rapid fluid infusion decreases PVR (avoid premedication) Be aware of
If baseline NSR HR 60–80 Caution with hypoxia, left atrial thrombi
and converts to Trendelenburg position hypercarbia, Gentle neuraxial dosing to
AF, prompt acidosis) avoid sudden drops in SVR
cardioversion Control sympathetic
warranted response with adequate
analgesia, maintenance of
normothermia
TS Often AF, rate Avoid Maintain Maintain without Avoid Maintain Hepatic dysfunction
control tachycardia producing venous sudden common
important Maintain congestion decreases PA catheter placement can
HR 60–80 be challenging
PS May be in AF Maintain Avoid Maintain normovolemia Maintain Avoid Consider hepatic
baseline myocardial Consider gentle increases in dysfunction
heart rate depression augmentation of PVR (avoid Be mindful of associated
intravascular volume hypoxia, congenital lesions or
hypercarbia, concomitant tricuspid
acidosis) disease

AF, Atrial fibrillation; AS, aortic stenosis; HR, heart rate; MS, mitral stenosis; NSR, normal sinus rhythm; PA, pulmonary artery; PS, pulmonic stenosis; PVR, pulmonary
vascular resistance; SVR, systemic vascular resistance; TS, tricuspid stenosis; VHD, valvular heart disease.

is no strong evidence to support a specific anesthetic tech-
nique in providing optimal perioperative outcomes. Moni-
tored anesthesia care with sedation alone may cause less
hemodynamic disturbance than general or neuraxial
approaches, but it is useful in only a limited number of sur-
gical procedures. The risk of deep venous thrombosis is gen-
erally lower with spinal or epidural anesthesia than with
general anesthesia.59 Neuraxial anesthesia may, however,
reduce sympathetic tone, SVR, and preload,60 potentially
promoting hemodynamic instability. Although decreases
in afterload may help to maintain forward flow in regurgi-
tant valvular lesions, sudden and profound drops in SVR can
be detrimental to patients with stenotic lesions.48 Unfortu-
nately, there is a paucity of high-quality data pertaining to
regional anesthesia in stenotic valvular lesions, but case
report data indicate that it may be a safe approach.61–64 Cer-
tain neuraxial techniques, such as continuous spinal and
epidural anesthesia, can be tailored to minimize the rapid
changes in sympathetic tone.61 In particular, avoiding the
blockade of the thoracic sympathetic nerve fibers by using
lower-level block may help to reduce these side effects.
Reduction of local anesthetic doses by using them in combi-
nation with epidural and intrathecal narcotics also helps to
minimize the sympatholytic effects of regional anesthesia.65
For patients with normal ventricular function, a balanced
general anesthesia with lower concentrations of volatile
anesthetics is usually a safe option that minimizes adverse
effects on contractility and loading conditions.31,48 Patients
with compromised ventricular function may be particularly
intolerant of the vasodilation accompanying volatile anes-
thetics. Nitrous oxide should be used carefully in patients
with mild or moderate pulmonary hypertension, and possi-
bly avoided when significant disease is present, because of
the potential of this gas to increase pulmonary artery pres-
sures.31,48,66,67 Light anesthesia and poor pain control are
other factors that may contribute to the increase in sympa-
thetic drive and PVR. The choice of muscle relaxant is
related to the specific hemodynamic effects it may cause.68
Regardless of the type of anesthesia, there must be prompt
response to sudden hemodynamic changes. Intraoperative
fluctuations in mean arterial pressure increase the probabil-
ity of postoperative heart failure in high-risk patients under-
going elective general surgery.6 Thus, for patients with
severe VHD, inotropic and vasoactive drips should be readily
available. Additionally, the preoperative placement of
defibrillator pads and provision of a defibrillator to facilitate
expeditious cardioversion is reasonable for patients with
severe valvular disease.
MONITORING OPTIONS
The use of invasive monitoring for patients with VHD is based
on the severity of disease, associated cardiac and noncardiac
problems, the nature of the surgical procedure, and the prac-
tice setting.31,69,70 Asymptomatic patients without concur-
rent disease going for minimal risk surgery require ASA
standard monitoring just as those without VHD do. On the
other hand, symptomatic patients undergoing major surgical
186 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
procedures require invasive monitoring that provides hemo-
dynamic data on an instantaneous basis. Such intensive
monitoring has been shown to attenuate risk during noncar-
diac surgery in some patient groups, such as those with
severe AS.71 Therefore, except for minor surgical procedures
(e.g., cataract extraction), direct arterial pressure monitoring
should be used for most patients with severe stenotic lesions
(i.e., AS, MS) and should be considered in patients with regur-
gitant lesions accompanied by concomitant ventricular dys-
function or hemodynamic instability.
Right heart catheterization with a pulmonary artery
catheter (PAC) is an important technique to assess the ade-
quacy of circulating blood volume (right ventricular [RV]
and LV preload), cardiac output, and mixed venous oxygen-
ation. However, the use of the PAC remains controversial
in perioperative medicine.33,70,72,73 In the practice guide-
lines of the American Society of Anesthesiologists,69 it is
emphasized that with some exceptions, routine pulmonary
artery catheterization is generally inappropriate for low-
or moderate-risk patients. PAC monitoring is, however,
appropriate or necessary in patients undergoing high-risk
procedures with large fluid changes or hemodynamic distur-
bances or with high risk of morbidity and mortality, or in
those with severe cardiac disease whose hemodynamic dis-
turbances have a great chance of causing organ dysfunction
or death.69 Additionally, practice settings, particularly cath-
eter use skills and technical support, play an important role
in decisions related to PAC use. For patients with VHD,
interpretation of PAC data involves understanding that cen-
tral venous waveforms are altered with significant tricuspid
valve lesions, and the pulmonary artery wedge pressures are
not reflective of LV end-diastolic pressures in patients with
severe mitral disease.70
TEE is widely used during cardiac and noncardiac surgery
and in the early postoperative period.74 Because global and
regional heart function, loading conditions, and valvular
dysfunction can be effectively monitored by this technique,
monitoring with TEE is particularly beneficial for patients
with severe VHD31 and those with a significant risk of
hemodynamic disturbances during surgery.75 There is
strong evidence supporting the perioperative use of TEE
for evaluating acute, persistent, and life-threatening hemo-
dynamic disturbances in which ventricular function and its
determinants are uncertain and have not responded to
treatment.75 In situations where invasive monitoring is
not required for postoperative care, intraoperative TEE alone
may be sufficient for monitoring during periods of changing
hemodynamics.
Postoperative Management
The principles of hemodynamic optimization based on the
pathophysiology of specific VHD apply also to the postoper-
ative management of these patients. Both preoperative sta-
tus and intraoperative course4,32 should be taken into
consideration as risk factors for postoperative complications.
Patients with severe VHD are prone to develop a number of
postoperative problems, including myocardial ischemia,
arrhythmias, and heart failure. Continuation of invasive
monitoring enables prompt and effective management
while the patient is stabilizing after surgery. Effective pain
management is of paramount importance so that uncon-
trolled surges in sympathetic activity are prevented. Allevi-
ation of postoperative pain may also help to decrease
perioperative morbidity and mortality.65,76 Patients who
were on beta-blockers preoperatively should have them
continued postoperatively to reduce the risk of myocardial
ischemia.77 Antimicrobial agents should be discontinued
within 24 hours of the end of surgery.23,24 Avoidance of
perioperative hyperglycemia reduces the rate of postopera-
tive infections and overall in-hospital mortality among crit-
ically ill patients in the surgical intensive care unit.78–80
Oral anticoagulants should be reinstituted as soon as possi-
ble, with initial administration of heparin if necessary.14,28
In patients with tenuous valvular lesions, including severe
AS or MS, admission to the intensive care unit for closer
monitoring may be warranted.81
Specific Valvular Lesions
The type of valvular lesion should be determined prior to the
surgical procedure, because the perioperative management
of stenotic lesions differs significantly from that of regurgitant
lesions.33 Each type of VHD imposes a unique set of stresses
on the LV and RV, leading to specific hemodynamic profiles
and recommendations for anesthetic and therapeutic priori-
ties for each lesion (see Tables 14.2 and 14.3).58 Aortic and
mitral lesions are the most common and are discussed in
greater detail. Tricuspid and pulmonary lesions are less fre-
quent and therefore less studied in the perioperative environ-
ment. Management of tricuspid lesions is generally thought
to be similar to the matching lesion in the left heart (i.e., a
mitral lesion), but high-quality evidence is lacking.
AORTIC STENOSIS
Calcific degenerative disease is the most common cause of AS
in adults with a normal trileaflet valve.10,82,83 In those with a
congenital bicuspid valve, stenosis usually develops earlier in
life. Patients with bicuspid aortic valve will also commonly
have aortopathy rendering them susceptible to aortic dila-
tion, affecting around 50% of these patients.84 Rheumatic
AS is less common in Western countries and is always
accompanied by some degree of mitral valve disease. The
hemodynamic goals for AS are shown in Table 14.2. In
patients with AS, a hypertrophic process allows the left ven-
tricle to adapt to the pressure overload.85 The increased wall
thickness with associated diminished LV compliance, how-
ever, produces an increase in LV end-diastolic pressure.
Therefore, atrial contraction plays an important role in ven-
tricular filling and explains the significant deterioration seen
in patients with AS who are tachycardic or who lose the atrial
contribution to filling (e.g., atrial fibrillation). Hypertrophy
may also reduce coronary blood flow per gram of muscle
while increasing the sensitivity to ischemic injury,86–89 fur-
ther explaining why this lesion substantially increases risk
of myocardial ischemia in patients undergoing noncardiac
surgery.4,8,90,91 Valvotomy or aortic valve replacement prior
to noncardiac surgery may be considered for eligible patients
with symptomatic severe AS in order to alleviate the fixed
cardiac output that is a hallmark of this lesion.4
 14 • Perioperative Management of Valvular Heart Disease 187

Table 14.3 Hemodynamic principles for perioperative management of valvular heart disease: regurgitant lesions.
VHD Rhythm HR Contractility Preload SVR PVR Other concerns
AR Maintain NSR Maintain high Inotropic Maintain Avoid increases in Maintain IABP contraindicated
normal heart augmentation SVR to reduce
rate can be helpful regurgitant fraction
Avoid
bradycardia
MR Often AF Maintain high Avoid Maintain Lowering SVR will Avoid Avoid respiratory
If baseline NSR, normal heart myocardial without increase forward increases in depression (cautious
conversion to AF rate (exception: depression producing flow and decrease PVR premedication)
may worsen ischemic MR, pulmonary regurgitant fraction Regional anesthesia may
hemodynamics where elevated edema be useful to prevent
heart rate may sympathetic discharges
precipitate and reduce SVR
myocardial
ischemia)
TR Often AF Avoid Avoid Increase Maintain Decrease Often hepatic
Rate control bradycardia myocardial while dysfunction
important depression avoiding CO measurements from
systemic PA-catheter inaccurate
congestion
PR Maintain NSR Maintain high Avoid Increase Maintain Decreasing Significant RV dilation
normal heart myocardial PVR increases may increase risk of
rate depression forward flow ventricular dysrhythmias
Consider etiology of PR,
i.e. long-standing
pulmonary HTN

AF, Atrial fibrillation; AR, aortic regurgitation; CO, cardiac output; HR, heart rate; HTN, hypertension; IABP, intra-aortic balloon pump; MR, mitral regurgitation; NSR,
normal sinus rhythm; PA-catheter, pulmonary artery-catheter; PR, pulmonic regurgitation; PVR, pulmonary vascular resistance; RV, right ventricular; SVR, systemic
vascular resistance; TR, tricuspid regurgitation; VHD, valvular heart disease.

MITRAL STENOSIS AORTIC REGURGITATION

MS is an obstruction to LV inflow that prevents proper
opening of the valve during diastolic filling of the left ven-
tricle. Rheumatic fever is the most common cause of MS,
and although MS is increasingly rare because of the
decreased incidence of rheumatic disease in the developed
world,92 it remains an important lesion because of the
associated perioperative risk.4 When valve area is reduced,
blood can flow into the left ventricle only if it is propelled by
a pressure gradient. This increased transmitral gradient is
the characteristic feature of MS and results in elevated left
atrial and pulmonary venous pressures significantly
increasing susceptibility to pulmonary edema. As the
severity of stenosis increases, cardiac output falls below
normal at rest and does not increase with exercise.93
In patients with chronic MS, pulmonary vascular perme-
ability may decrease significantly, thus diminishing the
likelihood of pulmonary edema, but this is often offset by
the onset of pulmonary hypertension. For any given orifice
size, the transmitral gradient is a function of the square of
the transvalvular flow rate and dependent on the diastolic
filling period.51 Thus, increased sympathetic tone, infec-
tion, and tachycardia may drastically worsen hemody-
namics in MS due to the reduction in the diastolic filling
period (Table 14.2).
Aortic regurgitant lesions are a very common finding on
pulsed Doppler echocardiography, but in the majority of
cases, these jets represent a trivial regurgitant volume
and are of no clinical significance.94 Aortic regurgitation
(AR) results from multiple abnormalities affecting aortic
leaflets or aortic root and annulus.94,95 The primary pathol-
ogy includes congenital bicuspid aortic valve, rheumatic
heart disease, infective endocarditis, and aortic root dis-
eases. Acute AR, most commonly caused by infective endo-
carditis, aortic dissection, or blunt chest trauma, results in
catastrophic elevation in LV filling pressures and often
requires emergent surgical replacement of the valve.95 In
chronic AR, compensatory mechanisms include eccentric
hypertrophy followed later by concentric hypertrophy and
increasing chamber compliance to accommodate a larger
diastolic volume.96 The hemodynamic goals for AR are
shown in Table 14.3. The greater diastolic volume main-
tains forward stroke volume by ejecting a larger stroke vol-
ume, and the hypertrophy helps to maintain normal
ejection performance despite an increased afterload.97,98
Vasodilator therapy reduces the hemodynamic burden in
these patients by improving forward stroke volume and
reducing the regurgitant volume. Similarly, an increase in
heart rate can be beneficial in maintaining cardiac output
188 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
by reducing diastolic (regurgitant) time. Therefore, these
patients usually tolerate the reduction in SVR and mild ta-
chycardia associated with induction of anesthesia very well.
MITRAL REGURGITATION
MR has many causes, the most common being papillary
muscle dysfunction, mitral valve prolapse, and dilation of
the mitral valve annulus and LV cavity.99,100 Chronic myo-
cardial ischemia can also result in MR secondary to
increased leaflet tethering and a reduced closing force of
the mitral valve.52,101 Acute MR secondary to chordae ten-
dineae rupture or papillary muscle infarction imposes a sud-
den volume overload on the left atrium and ventricle,
resulting in pulmonary edema. Chronic MR also produces
eccentric hypertrophy and an increase in LV end-diastolic
volume as compensatory mechanisms. The increase in
end-diastolic volume restores forward cardiac output, and
the increase in left atrial and ventricular size allows accom-
modation of the regurgitant volume at a lower filling pres-
sure. Afterload reduction is again beneficial in patients with
chronic MR associated with LV dilation and systolic dys-
function. However, there is no indication for vasodilator
therapy in asymptomatic, normotensive patients with MR
and preserved LV function.14,102 As with AR, an increase
in heart rate can be beneficial in maintaining cardiac output
(Table 14.3). Rapid progress in the area of transcatheter
mitral interventions may change the landscape of severe
mitral disease in the near term.100
TRICUSPID VALVE DISEASE
Tricuspid valve disease is most commonly seen as a congen-
ital abnormality, with Ebstein’s anomaly being the most
common, wherein failure of leaflet coaptation leads to
severe tricuspid regurgitation (TR). Acquired TR is most
often secondary to RV dilation and failure resulting from
pulmonary or RV hypertension.94 Tricuspid stenosis is most
commonly caused by rheumatic disease and is usually asso-
ciated with MS.58
PULMONIC VALVE DISEASE
The pulmonary valve is the least likely valve to be affected
by acquired heart disease, and almost all cases of pulmonary
valve stenosis are congenital in origin. Although pulmonary
regurgitation is rare as an isolated congenital lesion, it is an
almost unavoidable result of valvuloplasty of pulmonary
stenosis or surgical repair of tetralogy of Fallot.14,103
MIXED VALVULAR LESIONS
Multivalvular disease occurs in the context of rheumatic
heart disease, myxomatous valvular disease, and bacterial
endocarditis. The relative contribution of each of these
lesions is difficult to assess noninvasively, and cardiac cath-
eterization and angiocardiography may be required.10 Peri-
operative management of multivalvular heart disease is
based on the severity and hemodynamic significance of each
valvular lesion.58 In mixed single-valve disease (e.g., AR
with AS), one lesion usually predominates over the other,
and the pathophysiology resembles that of the dominant
lesion. Similarly, in patients with multiple valve regurgita-
tion (e.g., MR and AR), the best strategy is to determine
the dominant lesion and to treat it accordingly. However,
it is not always easy to establish which lesion is domi-
nant—the pathophysiology in patients with mixed valvular
lesions can be confusing.
Summary and Recommendations
The perioperative management of patients with
VHD14,31,47,49,58 requires interaction between the cardiol-
ogy, surgery, and anesthesiology teams to optimize manage-
ment and minimize risk to the patient. Fig. 14.1 illustrates
an evidence-based perioperative approach to the most com-
mon valvular lesions (AS, AR, MS, and MR). However,
when defining the perioperative management of patients
with VHD, strong trial-based evidence for most recommen-
dations is lacking—even more so for intraoperative care.
Although our knowledge is rapidly expanding, many of
the clinical advisories are still based on anecdotal reports
or extrapolations from the pathophysiologic principles rele-
vant to the chronic medical management of these patients.
Therefore, the clinician has a responsibility to recognize
unusual cases, account for specific practice settings, and
develop a comprehensive approach that satisfies the needs
of any given patient with VHD.
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 15 Prevention and Management
of Perioperative Dysrhythmias
STEPHEN A. ESPER and AMAN MAHAJAN

Introduction
Cardiac dysrhythmias are quite common in the general pop-
ulation. In fact, approximately 33 million people worldwide
experience atrial fibrillation, and the leading cause of sud-
den cardiac death is ventricular tachyarrhythmias.1 From
2003 to 2015, there were approximately 312.6 million sur-
geries performed in 66 countries,2 and the average patient
in the United States will have approximately nine surgeries
during their lifetime.3 Its significance is detailed in that
nearly 11% of patients undergoing general anesthesia expe-
rience an abnormal heart rhythm.4,5 This may potentially
increase the number of procedural events during a lifetime
because patients are increasingly opting for procedural over
medical therapies to treat their arrhythmias. While most
intraoperative arrhythmias are transient and clinically
insignificant, they may indicate underlying pathology
(i.e., electrolyte abnormalities, hypoxia, and myocardial
ischemia) that would require further treatment. Further-
more, these arrhythmias may cause hemodynamic instabil-
ity, which could lead to postoperative mortality and
morbidity. The goal of this chapter is to address the mech-
anisms of arrhythmia generation and to delineate different
types of arrhythmias that can occur under anesthesia, in
addition to their prevention and potential treatments and
therapies in the perioperative setting.
Mechanisms of Arrhythmia
Generation
Cardiac arrhythmias can manifest as abnormally slow (bra-
dyarrhythmias, bradycardia) heart rhythms or fast (tachy-
arrhythmias, tachycardias) heart rhythms, such as
ventricular tachycardia (VT) and supraventricular tachy-
cardia (SVT). There are generally two primary mechanisms
by which bradyarrhythmias may occur, which are a failure
of impulse propagation (i.e., heart block) or failure of impulse
generation (i.e., sick sinus syndrome). Bradyarrhythmias
may be secondary to intrinsic dysfunction of the conduction
system or extrinsic factors that cause a decrease in
heart rate.
The following are the three primary mechanisms gener-
ally responsible for clinically relevant tachyarrhythmias:
1. Triggered activity, which results from cardiac membrane
oscillations occurring before full repolarization, which, if
they exceed a certain threshold, may prematurely depo-
larize the myocardial cell, which leads to a tachycardia.
The best example for this class would be the prolonged
QT syndromes, where an early afterdepolarization can
trigger polymorphic VTs.
2. Abnormal automaticity, in which metabolic insults such
as ischemia, hypoxemia, electrolyte imbalance, acid–
base disorders, and increased sympathetic tone lead to
the development of automatic pacemaker activity in
atrial or ventricular cells that do not generally play a role
in cardiac intrinsic pacemaker function.
3. Reentrant pathways, which lead to the most common
mechanism of tachyarrhythmias. Rhythms such as
Wolff-Parkinson-White (WPW) syndrome, atrial flutter,
and sustained monomorphic VT are classified as reen-
trant tachyarrhythmias, which occur when a depolari-
zation spreads through the myocardium and returns
via an anatomical or a functional pathway to depolarize
the part of the heart from which it originated.
Management of tachycardic and bradycardic rhythms, as
well as cardiac arrest, should be done through logical pro-
gression of advanced cardiovascular life support (ACLS)
algorithms (Figs. 15.1–15.3).
Contributing Factors
Several factors may influence the generation of arrhythmias
under anesthesia. These include anesthetic medications,
electrolyte disturbances, hemodynamic or other physiologic
causes, and other causes.
ANESTHETIC MEDICATIONS
Of the amnestic and sedative medications, many anesthetic
medications can lengthen the QT interval to greater than
440 milliseconds (Fig. 15.4), including etomidate,6,7 keta-
mine,8 and volatile agents, though there does not appear
to be an increase in the likelihood of malignant arrhyth-
mias9–13 with the administration of these medications. In
contrast to the other intravenous (IV) amnestics, propofol
does not appear to prolong the QT interval.14 Midazolam
does not significantly prolong the QT interval.15 Dexmede-
tomidine can decrease sinus node and atrioventricular (AV)
nodal function, leading to bradycardia, and can also
increase the QT interval.16 None of the neuromuscular
blocking agents—succinylcholine or the nondepolarizing
agents—or sugammadex change the QT interval.17–20
Most opioids do not prolong the QT interval. In fact, some
have been shown to shorten the QT interval. Fentanyl at a
dose of 2 μg/kg has been shown to decrease QT prolongation
191
192 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Emergency treatment:
Attempt to identify cause Vagal maneuvers
but do not delay treatment Synchronized cardioversion
Medication

Maintain oxygen
saturation >94%

Unstable = hypotension
decreased LOC,
Stable?
shock,
chest pain

No Yes Establish IV or IO

Synchronized cardioversion
Consider adenosine
6 mg bolus; may
give second dose
Cardioversion rules: at 12 mg
QRS narrow and regular;
cardiovert at 50–100 joules

QRS narrow and irregular;

cardiovert at 120–200 joules If adenosine not effective;
consider procainamide
QRS wide and regular; OR amiodarone
cardiovert at 100 joules

QRS wide and irregular, turn

off the synchronized mode
and defibrillate immediately Consider an
antiarrhythmic infusion Fig. 15.1 Advanced Cardiac Life Support
algorithm for tachycardia.

associated with laryngoscopy21; however, this effect may be
mitigated at higher doses.7 While remifentanil has not been
shown to prolong the QT interval, it has been shown to
cause sinus nodal depression and bradycardia.22,23 Con-
trarily, sufentanil has been shown cause QT prolongation
in both animal models and human case reports by delaying
cardiac cell action potential.24,25 Within the opioid group,
methadone is the most highly associated with QT prolonga-
tion, having been linked with torsades de pointes (TDP) VT
(Fig. 15.5), and it appears to be a dose-dependent
response.26 In a large US Food and Drug Administration
(FDA) study of over 5000 hospitalized patients, 16
(0.78%) experienced TDP.27 Even though other drugs used
during the perioperative period are not associated with clin-
ically significant QT abnormalities, patients who are receiv-
ing chronic methadone therapy prior to and during an
anesthetic should have baseline preoperative ECGs as well
as close intraoperative and postoperative monitoring, with
a high index of suspicion for QT prolongation and TDP.
Droperidol, an antidopaminergic medication that acts as
an antiemetic, has experienced decreased use in recent
years due to the FDA’s “black box” warning of fatal arrhyth-
mias that have occurred with its administration. However,
its recent replacement, ondansetron, which acts on the 5-
HT3 receptor, have been shown to increase QT interval
length like its predecessor, droperidol.28,29 Thus, caution
should be used when both medications are administered
together.
Local anesthetics, many of which are used to combat pain
in the perioperative period, injected IV or peripherally, such
as lidocaine, bupivacaine, and ropivacaine, have not been
shown to prolong the QT interval. It is the case, however,
that bupivacaine has been shown to increase the QRS
width.30,31 Any local anesthetics, because of their
 15 • Prevention and Management of Perioperative Dysrhythmias 193

Bradycardia
identified
Possible Causes:
Hypoxia
Acidosis
Hyperkalemia
Hypothermia
Look for cause
Heart block
but do not delay
Toxins
treatment
Trauma

Establish airway;
assist breathing
if necessary

Monitor pulse
oximtry or
Monitor heart rate waveform
and rhythm and capnography
blood pressure if available

Establish an IV or IO access

Continue to monitor; Atropine 0.5 mg

call for consults repeat every 3–5
No Yes minutes to 3 mg;
Hypotension
or Shock?

If atropine not effective,

consider transcutaneous
pacing OR
dopamine infusion OR
epinephrine infusion

Fig. 15.2 Advanced Cardiac Life Support algorithm for bradycardia.

mechanism of action, will cause a dose-dependent arrhyth-
mia beyond a certain threshold.
ELECTROLYTE DISTURBANCES
Both hypokalemia and hyperkalemia can be associated with
a wide variety of tachyarrhythmias, including the “simple”
premature ectopic beat to nonsustained VT, sustained VT,
or ventricular fibrillation (VF).32 Hyperkalemia can lead to
a variety of conduction abnormalities (e.g., left bundle branch
block [LBBB], right bundle branch block [RBBB], bifascicular
block, advanced AV block), as well as sinus bradycardia,
sinus arrest, VT, VF, and asystole. It is associated with a pro-
gression of ECG findings, including peaked T waves, prolon-
gation of PR interval, widening of the QRS complex, loss of
P wave, a sine wave, and asystole. Any of these changes
can happen instantly, and a progression need not occur.
By widening the QRS complex, hypomagnesemia can lead
to a unique form of TDP. It has also been associated with
atrial fibrillation33 and other ventricular arrhythmias. Hyper-
magnesemia (generally considered any level >4 mEq/L)
may cause bradycardia with associated conduction defects
and hypotension. The final outcome for the cardiac muscle
with hypermagnesemia is conduction defect leading to no
conduction at all, or asystole. Hypocalcemia can prolong
the QT interval but has a decreased potential to trigger
TDP compared with hypokalemia or hypomagnesemia.
Since electrolytes can be severely altered due to surgical
stress, bleeding, and intraoperative medications, when car-
diac arrhythmias occur, electrolytes should be checked and
corrected as quickly as possible. Patients who take antihy-
pertensives such as diuretics or other rhythm-controlling
agents, such as flecainide, should have electrolytes checked
and treated preoperatively to reduce the risk of arrhythmia.
194 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Continue CPR;
Airway; Oxygen;
Connect monitors
Continue CPR;
Airway; Oxygen;
Connect monitors

Identify rhythm Evaluate Epinephrine

and go to No rhythm: 1 mg ASAP and every
appropriate VTach or VFib? 3–5 minutes
algorithm

Yes Evaluate
Go to cardiac arrest:
VTach or VFib Yes rhythm:
120–200 joules on a algorithm VTach or VFib
biphasic defibrillator
or Defibrillate
360 joules on a
monophasis defibrillator
No

Continue CPR for

2 minutes
Review listing Evaluate and treat
No
of Hs and Ts reversible causes

Epinephrine
1 mg every 3–5 minutes

Return of
No spontaneous
circulation?
Amidarone OR
Iidocaine

Yes

Go to post cardiac arrest case

Go to post Return of
cardiac arrest Yes spontaneous B
case circulation?

Fig. 15.3 (A) Advanced Cardiac Life Support algorithm for cardiac arrest. (B) Advanced Cardiac Life Support algorithm for pulseless electrical activity and
asystole.

HEMODYNAMIC AND PHYSIOLOGIC CAUSES
Since coronary perfusion pressure is dependent on both aor-
tic root pressure and left ventricular end-diastolic tissue
pressure, severe and prolonged intraoperative hypotension
can decrease myocardial perfusion, leading to cardiac ische-
mia and cardiac conduction defects. If a patient experiences
diastolic dysfunction or has an elevated left ventricular end-
diastolic pressure, sometimes commonly associated with left
ventricular hypertrophy (as found in aortic stenosis), the
hypotensive effect may be even more pronounced. Similarly,
severe hypertension can increase left ventricular wall
tension (or afterload), which would increase myocardial
oxygen demand, precipitating ischemia and arrhythmias
as well. Any patient with blood pressure issues prior to sur-
gery should be screened, in general, by at least an ECG, so as
to better guide the anesthetic approach during the
perioperative period.
OTHER CAUSES
The most common complications of central line placement
or pulmonary artery catheter (PAC) placement are transient
arrhythmias.34 Starting from the venae cavae, if the

Fig. 15.4 Prolonged QT interval. The QT interval in this
case is prolonged at a heart rate of 45 beats per minute.
The rate-corrected QT (QTc) is equal to the QT interval/sqrt
(RR interval).
Fig. 15.5 Single-lead electrocardiogram with torsades de pointes
ventricular tachycardia, characterized by continuously changing axis of
QRS morphologies that are polymorphic.
guidewire or catheter enters the right atrium, one may visu-
alize premature atrial contractions (SVT) on the monitor. If
the guidewire or catheter passes through the tricuspid valve
into the right ventricle, premature ventricular contractions
(PVCs) or even VT may develop. In addition, the PAC may
cause RBBB.35 Caution should be used when PACs are
inserted in the setting of LBBB, as a complete heart block
may ensue. Transcutaneous pacing pads should be placed
on the patient for backup pacing capabilities. Caution
should also be exercised when inserting PACs in patients
who have aortic stenosis, as any arrhythmia can result in
loss of diastolic filling time, reduction in cardiac output,
severe hypotension, and even death. In rare cases of ventric-
ular septal defect, the PAC may be in the left ventricle,
which could also precipitate a tachyarrhythmia.
Intracardiac surgical manipulation, either during cardiac
surgical cases (on or off cardiopulmonary bypass), cardiac
catheterization lab cases, intrathoracic cases, or lung trans-
plant, may also precipitate arrhythmias. Manipulation of
the right atrium, particularly during placement of venous
cannulae for cardiopulmonary bypass or coronary sinus
cannulae for retrograde cardioplegia, may precipitate atrial
15 • Prevention and Management of Perioperative Dysrhythmias 195
II aVL
III aVF
VI
fibrillation or SVT. Surgical manipulation of the right ven-
tricle or left ventricle may precipitate VT. Catheter manipu-
lation during electrophysiology cases may also cause atrial
or ventricular arrhythmias, though, in many cases, this
may be the intended outcome, as those procedures are gen-
erally meant to ablate malignant rhythms. During thoracic
surgical cases, inadvertent contact with cardiac structures
or pulmonary venous structures may precipitate arrhyth-
mias as well. Use of electrocautery directly applied to the
myocardium may also precipitate arrhythmias. Low-
frequency (50–60 Hz) monopolar cautery leakage is well
within the range of precipitating cardiac dysrhythmia
(30–110 Hz).36
Surgical manipulation of other organs may precipitate
reflexes that cause bradycardia. In eye surgery, the activation
of stretch receptors in the ciliary ganglion (from extraocular
muscle manipulation and traction) are carried by the ophthal-
mic branch of the trigeminal nerve to the central nervous sys-
tem, causing a vagal, parasympathetically mediated reflex of
either severe bradycardia or asystole. This is called the “oculo-
cardiac reflex” or “Aschner reflex.” Another parasympatheti-
cally mediated reflex occurs when the peritoneum is stretched
during open or laparoscopic surgery and can cause bradycardia.
In both cases, the surgeon should cease manipulation. While
the heart rate is expected to increase with cessation of traction,
if it does not, one should consider administration of anticholin-
ergics such as glycopyrrolate or atropine.
Finally, electroconvulsive therapy deserves its own
consideration. A parasympathetic discharge will follow
the initial electrical stimulus, which could cause brady-
cardia, hypotension, and possibly asystole. After a period
of 10–15 seconds, a sympathetic discharge ensues. This
discharge increases not only heart rate and blood pres-
sure but also myocardial oxygen consumption. Especially
in the vulnerable patient population with coronary artery
disease, all of these events may precipitate arrhythmia,
including VT. This will start a vicious cycle by which
the arrhythmias increase myocardial oxygen consumption
196 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fig. 15.6 Sinus tachycardia at a rate of approximately 150 beats per
minute.
and cause ischemia, which may exacerbate the arrhyth-
mias. Care must be taken to treat bradycardia or asystole
with anticholinergic agents if needed, and to lower the
heart rate and blood pressure if needed to decrease the risk
of ischemia, generally with the use of a short-acting beta-
receptor blocker.
Types of Tachyarrhythmias
Tachyarrhythmias are defined by a heart rate greater than
100 beats per minute (bpm) and are divided into two
types: narrow QRS complex tachycardias and wide complex
QRS tachycardias. Their diagnosis and treatment varies
(Fig. 15.1).
NARROW QRS COMPLEX TACHYCARDIA
Originating above (“supra-”) the AV node, narrow (QRS
duration <120 milliseconds) complex tachycardia activates
a rapid ventricular response (RVR) via an intact His-Purkinje
conduction system. These SVTs include sinus tachycardia,
AV nodal reentrant tachycardia (AVNRT), atrial flutter,
atrial fibrillation, and multifocal atrial tachycardia (MAT).
SINUS TACHYCARDIA
Sinus tachycardia (Fig. 15.6) is a regular heart rhythm
that is diagnosed on ECG by a normal P wave followed
by a QRS wave and T wave at a rate greater than 100
bpm. In the intraoperative setting, this is usually second-
ary to sympathetic stimulation because of the procedure
in spite of adequate anesthesia, inadequate anesthesia,
or blood loss. However, many other causes, minor and
Fig. 15.8 Atrial flutter, 2:1 pattern.
Fig. 15.7 Rhythm of atrioventricular nodal reentrant tachycardia.
serious, insipid and obvious, such as hypoxia, hypercarbia,
fever, sepsis, pneumothorax, pulmonary embolism, myo-
cardial ischemia or infarction, thyroid storm, or malignant
hyperthermia, should also be considered. Prompt diagnosis
with laboratory work and vital sign measurement is neces-
sary, and immediate treatment of the cause of the tachy-
cardia should be initiated. These treatments will vary
depending on the cause, and it is inappropriate to treat
all cases of sinus tachycardia indiscriminately. For exam-
ple, one would not administer a beta-receptor blocker to
a patient who is volume depleted.
AV NODAL REENTRANT TACHYCARDIA
AVNRT (Fig. 15.7) is a regular, paroxysmal SVT that occurs
due to formation of a reentry circuit around the AV
node. Patients present with heart rates between 150 and
250 bpm. In patients who have AVNRT and hemodynamic
compromise (“unstable SVT”) or are under general anes-
thesia, cardioversion should be attempted. For patients
who do not have hemodynamic compromise or altered
mental status, adenosine is the first line of treatment to
break the rhythm. Vagal maneuvers and calcium channel
blockers can also be used.
ATRIAL FLUTTER AND ATRIAL FIBRILLATION
Atrial flutter (Fig. 15.8) is caused by a reentrant circuit in
the atria and around the tricuspid valve and generally
presents as a regular rhythm with an atrial rate in excess
 15 • Prevention and Management of Perioperative Dysrhythmias
Fig. 15.9 Atrial fibrillation.
of 300 bpm but a ventricular rate of 130–150 bpm, second-
ary to the conduction block imposed by the AV node. Atrial
fibrillation (Fig. 15.9) is an irregular rhythm characterized
by a total absence of P waves on ECG. Foci of the impulses
proceed from pulmonary veins or other atrial regions,
spreading to the rest of the atria in waves.37 Ventricular
rates <120 bpm are often hemodynamically well tolerated,
whereas RVR rates above 150 bpm are often associated
with acute hypotension. Patients who are at high risk for
imminent hemodynamic compromise, including patients
with aortic or mitral stenosis, or other conditions with
increased left ventricular end-diastolic pressure that depend
on atrial systolic contribution to left ventricular end-
diastolic volume, should be immediately cardioverted with
synchrony. Patients who have new-onset atrial fibrillation
with RVR should be immediately cardioverted. In patients
with known atrial fibrillation and hemodynamically stable
RVR, calcium channel blockers or beta-blockers should be
attempted to control the rate, as a thrombus can occur in
the left atrial appendage (LAA) and an embolic event can
occur when sinus rhythm is reestablished. AV nodal block-
ing agents should be avoided in these patients, as blockade
of the AV node may potentiate the preexcitation accessory
pathway and degenerate the rhythm into VT or VF.
MULTIFOCAL ATRIAL TACHYCARDIA
In MAT (Fig. 15.10), heart rates exceed 100 bpm, and this
usually occurs in the setting of pulmonary disease, com-
monly chronic obstructive pulmonary disease. The defining
characteristic of this arrhythmia is an ECG showing P waves
of at least three differing morphologies. Rhythms that dis-
play morphologically differing P waves and heart rates less
than 100 bpm are considered to indicate a wandering atrial
pacemaker. Similar to those with atrial fibrillation, these
Fig. 15.10 Multifocal atrial tachycardia: a tachyarrhythmia that has at least three different nonsinus P waves in the same lead.
197
patients do not present with hemodynamic compromise,
though those with RVR did have hypotension. In addition,
patients with rapid rates may be at risk for myocardial ische-
mia and heart failure, and thus rate control should be
attempted with calcium channel blockers or beta-blockers.
The underlying disorder should be addressed, and any elec-
trolyte abnormalities should be readily corrected.
WIDE QRS COMPLEX TACHYCARDIA
Wide QRS complex (QRS >120 milliseconds) tachycardia
stems from abnormalities within the His-Purkinje system,
direct activation of the myocardium via accessory pathway
above the AV node, or electrical stimulus origination out-
side of the conduction system. Wide QRS complex tachycar-
dias include VT, SVT with aberrant conduction, or
ventricular paced rhythms.
PREMATURE VENTRICULAR CONTRACTIONS
PVCs (Fig. 15.11) have an estimated prevalence of 1%–4%
in the general population on standard ECG and between
40% and 70% of patients on 24-hour continuous ECG mon-
itoring.38,39 While isolated PVCs in healthy patients under
anesthesia may not hold any real clinical significance, in
patients with comorbid cardiac conditions, PVCs may be a
symptom of unmasked structural heart disease, subendo-
cardial ischemia, or electrolyte abnormalities. Electrolyte
repletion and correction of hypotension, if present, should
be a priority.
NONSUSTAINED VENTRICULAR TACHYCARDIA
Nonsustained ventricular tachycardia (NSVT) (Fig. 15.12)
occurs when there are three or more consecutive PVCs or
198 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fig. 15.11 Premature ventricular contraction (PVC). The third beat is a
PVC, with a wide and different morphologic QRS wave, duration
greater than 0.16 s.
aberrant ventricular beats conducted at a rate of greater
than 120 bpm for less than 30 seconds. Similar to the situa-
tion in patients who experience PVCs, this aberrant conduc-
tion may be a symptom of structural heart disease (unmasked
under anesthesia), subendocardial ischemia, or electrolyte
abnormalities. Electrolyte repletion and correction of hypo-
tension, if present, should be the immediate priority. NSVT
that occurs without hemodynamic compromise should still
be monitored with vigilance in the perioperative period, as
it can degenerate into a nonperfusing rhythm such as VT
or VF. Beta-blockers and calcium channel blockers may be
attempted in the patient with NSVT who is not hypotensive
or who does not have compromised cardiac function.
V2
V3
Fig. 15.12 Repetitive monomorphic ventricular tachycardia.
VENTRICULAR TACHYCARDIA
VT on ECG monitoring presents as a widened monomorphic
(Fig. 15.13) or polymorphic complex. Patients with VT may
present without a pulse or severe hypotension and hemody-
namic compromise. Defibrillation and the ACLS algorithm is
the first choice of treatment for pulseless VT. Those who
have VT with a pulse should be treated with immediate
and synchronized cardioversion. Without synchronization,
VT may progress to VF (Fig. 15.14) or even asystole. The
inciting cause should be investigated and treated, with par-
ticular attention to hypoxia, hypovolemia, acidosis (hydro-
gen ion), hypo- or hyperkalemia, hypothermia, tension
pneumothorax, cardiac tamponade, toxins, or pulmonary
or coronary thrombosis.40 If needed, myocardial perfusion
can be augmented with fluid and vasoconstrictors such as
phenylephrine, vasopressin, or norepinephrine. Epinephrine
or another beta-receptor agonist should be used with cau-
tion, as this can cause worsening tachycardia and increase
myocardial oxygen demand, which would worsen the
already high demand from the VT that is occurring. Lido-
caine and amiodarone can also be used for rate control.
SUPRAVENTRICULAR TACHYCARDIA WITH
ABERRANT CONDUCTION
SVT may present with a widened QRS complex if there is
aberrant conduction due to a bundle branch block or con-
duction over an accessory pathway. Management is similar
to narrow QRS complex SVT.
VENTRICULAR PACED RHYTHMS
Pacemakers activating the myocardium may cause a wide
QRS complex on ECG (Fig. 15.15). In the setting of SVT,
V5
V6
 15 • Prevention and Management of Perioperative Dysrhythmias
Fig. 15.13 Monomorphic sustained ventricular
tachycardia.
Fig. 15.14 Ventricular fibrillation.
Fig. 15.15 Biventricular pacing.
Fig. 15.16 Wolff-Parkinson-White syndrome.
the pacemaker may “track” the atrial rate and pace the ven-
tricle with the same rate, which may appear similar to VT on
the ECG. The pacemaker may also cause retrograde conduc-
tion (ventricle to atrium back to ventricle), resulting in a
pacemaker-mediated wide complex tachycardia or endless
loop tachycardia. Switching the pacemaker to an asynchro-
nous mode at a lower rate through a magnet (Medtronic or
St. Jude Medical devices) or reprogramming (Boston Scien-
tific) should allow return to a normal heart rate.
WOLFF-PARKINSON-WHITE SYNDROME
Patients who present with intraoperative preexcitation syn-
dromes with atrial fibrillation, such as WPW syndrome
(Fig. 15.16), present a diagnostic conundrum. Pharmaco-
logic treatment depends on whether conduction occurs in
199
an antidromic (antegrade down the accessory pathway, ret-
rograde down the accessory pathway) or orthodromic
(antegrade through the AV node, retrograde through the
accessory pathway). Patients with orthodromic conduction
can present with either narrow complex tachycardia or
wide complex tachycardia (if bundle branch block is pre-
sent). Patients with antidromic conduction present with a
wide QRS complex tachycardia.41 Hemodynamically unsta-
ble patients should receive immediate synchronized cardio-
version. Patients with orthodromic WPW syndrome, or AV
reentry tachycardia, can be given adenosine, calcium chan-
nel blockers, or vagal maneuvers. Caution should be exer-
cised in patients who have antidromic AVRT, as blocking
the AV node with pharmacologic agents may result in
increased conduction of atrial impulses to the ventricle via
the accessory pathway, which increases the ventricular rate.
This may result in hemodynamic instability due to RVR or
degeneration of the rhythm into VT or VF.42 Options for rate
and rhythm control include procainamide and ibutilide.
Bradyarrhythmias
Bradyarrhythmias, which may include sinus bradycardia,
junctional rhythms, and AV block, can present
intraoperatively.
SINUS BRADYCARDIA AND ASYSTOLE
Sinus bradycardia (Fig. 15.17) is defined as a rate less than
60 bpm with normal atrial and ventricular depolarization.
This can be a normal variant for patients, who may intrin-
sically have a bradycardic heart rate. Patients on beta-
receptor blockade agents often present for surgery and
have a reduced heart rate, though it is not generally nor-
mal that they have a heart rate less than 60 bpm. Brady-
cardia and asystole are most commonly the result of the
vagal reflex (i.e., oculocardiac reflex or peritoneal trac-
tion). Cessation of surgical manipulation should resolve
the pathology, and the patient should be treated with anti-
cholinergic agents. Other causes of bradycardia should also
be considered, including severe and prolonged hypoxia,
excessive opioid or phenylephrine administration, or cal-
cium channel blocker or beta-blocker overdose. With con-
tinued and potentially pathologic sinus bradycardia, the
patient may need to be treated with beta-adrenergic stim-
ulating agents such as epinephrine, dobutamine, or
isoproterenol to increase heart rate. External transcutane-
ous pacing may also be needed. Patients with asystole
should undergo immediate cardiopulmonary resuscitation
and ACLS.
200 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Fig. 15.17 Sinus bradycardia.

V5

II

V6

Fig. 15.18 Left bundle branch block.

III
VI

Fig. 15.19 Right bundle branch block.

BUNDLE BRANCH BLOCKS

Either RBBB or LBBB (Figs. 15.18 and 15.19) can occur
under anesthesia. RBBB, generally identified by a widened
QRS complex with R- and S-wave vector changes and
right-axis deviation on ECG, rarely occurs in the healthy
patient. It presents more as an objective finding in someone
with intrinsic cardiac disease, myocardial insult, lung failure
with right ventricular failure, or acute events such as pul-
monary embolus. New-onset LBBB, manifesting as a wid-
ened QRS complex with an absent Q wave and tall R
waves in the lateral leads (I, V5, V6) and deep S waves in
the right precordial leads (V1, V2, V3), can typically be a
sign of myocardial infarction or ischemia. The left bundle
is formed by the left anterior and posterior fascicles of the
Purkinje fibers. Any injury or ischemia to either fascicle
can cause a fascicular block (Figs. 15.20 and 15.21), which
manifests on the ECG as a QRS complex of normal duration
Fig. 15.20 Left anterior fascicular block.
but with abnormal directionality. If any of these bundle
branch blocks or fascicular blocks should occur at any time
during the perioperative period, the inciting cause—
typically ischemia—should be rapidly addressed before
end-organ damage or hemodynamic compromise occurs.
If a patient has LBBB and a PAC is being placed, this may
incite RBBB and cause complete heart block, which requires
immediate pacing.
CONDUCTION DEFECTS
AV block occurs with prolonged or even missed conduction
from the atria to the ventricles, generally at the site of the
AV node. This occurs in the setting of intrinsic structural or
functional cardiac disease, ischemia, electrolyte abnormalities,
 15 • Prevention and Management of Perioperative Dysrhythmias
III
III
Fig. 15.21 Left posterior fascicular block.
or excessive vagal tone. Other causes can be from medical/sur-
gical treatment, as may be the case during an open sternotomy
or transcatheter minimally invasive aortic valve replacement.
First-degree AV block (Fig. 15.22), identified by a PR interval
greater than 200 milliseconds by ECG, occurs when there is
delayed but intact conduction from the atria to the ventricles.
Two types of second-degree AV block can occur, both of which
are characterized by intermittent conduction from the atria to
the ventricles. Progressive prolongation until a dropped beat is
the characteristic that defines type I (Fig. 15.23). Type II
(Fig. 15.24), which is an increase in severity from type I, is
Fig. 15.23 Second-degree Mobitz
type I atrioventricular block
(Wenckebach).
201
Fig. 15.22 First-degree atrioventricular block.
identified with prolonged PR intervals and dropped beats with-
out progression. Third-degree AV (Fig. 15.25) block occurs
when atrial impulses do not conduct to the ventricles, leading
to discordant P and QRS waves. This can also be identified on
central venous pressure tracings by visualizing ‘Canon A’
waves, representing the contraction of the atrium against
the tricuspid valve. Patients with second-degree AV block
may require pacing in the event of severe bradycardia with
hemodynamic compromise. Patients with third-degree AV
block will almost always require pacing, as the intrinsic ven-
tricular rhythm is generally very slow (30–40 bpm). These
patients are pacemaker dependent.
Diagnosis and Medical Therapy
for Arrhythmias
STANDARD ELECTROCARDIOGRAPHY
The ECG is continuously monitored for any patient receiving
anesthetic agents. Both leads II and V5 are employed in
patients with risk factors for myocardial ischemia or
arrhythmias.43 If a tachyarrhythmia or bradyarrhythmia
develops, all available leads should be displayed on the mon-
itor, and a 12-lead ECG should be obtained as soon as feasi-
ble to make a more precise diagnosis.
RECOGNITION OF ARTIFACTS
Notably, artifact due to electrocautery or pacing spikes can
mimic VT or VF. Ventricular paced rhythms can also mimic
VT. Stable waveforms from the pulse oximeter, intra-arterial
catheter, and/or central venous catheter may be helpful to
distinguish artifact from a true arrhythmia.
aVF
202 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
I VR
II VL
III VF
Fig. 15.24 Second-degree Mobitz type II atrioventricular block.
Medical therapy varies by type of arrhythmia. A brief dis-
cussion of anesthetic considerations follows.
ATRIAL FIBRILLATION AND FLUTTER
Patients with atrial fibrillation may be placed on anticoagu-
lants such as warfarin, dabigatran, rivaroxaban, or apixaban
for prevention of intracardiac thrombosis.44 Prior to elective
or emergent surgery, one should consider both bridging (elec-
tive) and reversal (emergent) of anticoagulation for safety.
Multiple studies have compared rate control with rhythm
control in varied patient populations, with no consensus that
rhythm control is superior.45–51 It should be noted, however,
that the development of acute atrial fibrillation or other
arrhythmia in the setting of aortic or mitral stenosis, or in
patients with diastolic dysfunction, can result in hemody-
namic compromise, as the atrial systolic contribution to
left ventricular end diastolic volume will be significantly
hindered. The ventricular rates may be controlled with
V1 V4
V2 V5
V6
V3
Fig. 15.25 Third-degree complete
atrioventricular block.
beta-blockers or nonhydropyridine calcium channel blockers,
aiming for a heart rate of between 60 and 80 bpm.44 In
patients with preexcitation, beta-blockers, calcium channel
blockers, and amiodarone should be avoided, as previously
discussed. Flecainide, dofetilide, propafenone, ibutilide, amio-
darone, dronedarone, or sotalol can all be used to achieve
rhythm control and maintain sinus rhythm.44
VENTRICULAR TACHYCARDIA
No antiarrhythmic medications have been shown to
improve survival for patients with VT. On the contrary, class
I antiarrhythmics have been shown to increase mortality in
patients with ischemic heart disease.52 Amiodarone and
sotalol have been shown to decrease the frequency of recur-
rent VT,53–55 but there does not appear to be an improve-
ment in survival. For patients with VT, catheter ablation
or cardiac sympathetic denervation may provide longer
VT-free survival.
 15 • Prevention and Management of Perioperative Dysrhythmias
Interventions for Cardiac
Arrhythmias
While interventional or surgical approaches are infre-
quently used as primary approaches to manage postopera-
tive arrhythmias, it is important for perioperative medicine
physicians to be familiar with the therapeutic applications of
these increasingly commonly performed techniques. Fur-
ther, perioperative arrhythmias can also manifest in these
patients as a result of the primary disease or as a conse-
quence or complication of the interventions.
CATHETER ABLATION FOR ATRIAL FIBRILLATION
For patients with atrial fibrillation, the pulmonary veins and
posterior left atrium are common foci for reentry.56,57 Creat-
ing a scar by radiofrequency or cryoablation can destroy the
foci and cure the disease indefinitely. Radiofrequency abla-
tion (RFA) conducts alternating electrical current, dissipating
energy as heat and causing tissue necrosis and scar. Cryoa-
blation delivers liquid nitrous oxide near the endocardium.
Liquid nitrous oxide at room temperature vaporizes, becomes
a gas, and freezes the surrounding tissue and creates a scar.58
Studies comparing the two techniques potentially favor
cryoablation, known for its shorter procedure times and
lower complication rates.59 Unfortunately, cryoablation util-
ity is limited to pulmonary vein isolation, and arrhythmias
originating from other foci may still require RFA. Unfortu-
nately, repeat ablation is required in up to 25% of patients
because of late recurrence of AF.60,61
Other sites that have localized left atrial reentrant circuits,
called “rotors,” can disorganize into atrial fibrillation; tar-
geted ablation of these areas has been shown to increase suc-
cess rates of freedom from AF.62 Continuous, complex
electrical activity for reentry of fibrillation waves or overlap
of different wavelets is called a “complex fractionated atrial
electrogram” (CFAE) and can be detected by catheter map-
ping and ablated in conjunction with pulmonary venous iso-
lation. Targeting these CFAEs and ganglionated plexi, which
innervate the myocardium, can increase the success rate of
catheter ablation63 and can also be effective in treating AF.64
SURGICAL ABLATION FOR ATRIAL FIBRILLATION
Patients undergoing open cardiac surgery can have both
radiofrequency energy or cryoablation of arrhythmias at
the sites mentioned earlier. In follow-up studies, up to
85% of patients remained free from atrial fibrillation at
1 year.65 “Stand-alone” surgical ablation for atrial fibrilla-
tion occurs through a minimally invasive technique or
through a thoracotomy. Freedom from atrial fibrillation at
1 year was 93% in one systematic review.66
LEFT ATRIAL APPENDAGE OCCLUSION
Patients with atrial fibrillation who also have contraindica-
tions to anticoagulation for prevention of stroke may be eli-
gible for percutaneous LAA occlusion devices. The Lariat
suture delivery device (SentreHEART, Inc, Redwood City,
CA) uses a suture loop to close the LAA at the base, guided
by an epicardial wire and a transseptal wire positioned at
203
the LAA ostium. The Watchman LAA closure device (Bos-
ton Scientific, Marlborough, MA) is delivered percutane-
ously to the LAA and self-expands to anchor into the
myocardium at the ostium of the LAA. The Amplatzer Amu-
let LAA occluder (St. Jude Medical, St. Paul, MN), similarly is
delivered to the left atrium and self-expands to shape itself
into the wall of the LAA. The largest randomized clinical tri-
als to date have been done with the Watchman device; both
the PROTECT AF trial and the PREVAIL trial demonstrated
noninferiority of the device compared with conventional
anticoagulation for prevention of stroke.67,68
CATHETER ABLATION FOR VENTRICULAR
TACHYCARDIA
Catheter ablation for VT appears to be more successful than
using medical management. In randomized controlled trials,
compared with medical management alone, patients with
ischemic cardiomyopathy who underwent catheter ablation
had better VT-free survival at 2 years.69,70 RFA treatment is
typically used.71 An endocardial approach is typically used
for VT ablation. In some cases, an epicardial ablation via a
subxiphoid incision is used for foci located closer to the sub-
epicardium. Needle-based pericardial access under fluoro-
scopic guidance has become more popular of late.72 A
guidewire and catheter are advanced through a needle intro-
duced into the pericardial space. The rate of major acute and
delayed complications was low (5% and 2%, respectively).73
The use of ablation catheters in both the right and left ven-
tricles can increase the likelihood of achieving a transmural
ablation scar.74 Ethanol ablation, highly reliant on suitable
coronary vasculature, can also be used to generate a trans-
mural scar, but the scar size remains unpredictable.75
High-intensity focused ultrasound may be a future noninva-
sive technique for VT ablation, and research is ongoing.76
IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS
FOR VENTRICULAR TACHYCARDIA
Implantable cardioverter-defibrillators (ICDs) are placed for
primary and secondary prevention of VT.77 Devices include
those manufactured by Boston Scientific, Medtronic, and St.
Jude Medical. The subcutaneous ICD, or SICD, is being used
more often (product of Boston Scientific), especially in
patients with difficult vascular access or at high risk of infec-
tion. It is implanted at the midaxillary line between the fifth
and sixth intercostal spaces, with a lead and shocking coil
placed subcutaneously adjacent to the sternum.78
NEUROMODULATION THERAPIES FOR
VENTRICULAR TACHYCARDIA
Neuromodulation has emerged as a new therapy for
patients with VT because of the role the autonomic nervous
system in mediating ventricular arrhythmias.79 Cardiac
sympathetic denervation has been successful in reducing
the inducibility of VT/VF in animal studies.80 Fifty percent
of patients experienced freedom from ICD shocks, sustained
VT, death, and orthotopic heart transplantation (OHT) at
1 year in a large multicenter retrospective study of patients
with structural heart disease undergoing either left or
204 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
bilateral cardiac sympathetic denervation.81 In patients
with electrical storm who may be too unstable to undergo
surgery, thoracic epidural anesthesia may be an option; tho-
racic epidurals have been used in the short-term manage-
ment of patients with VT refractory to medical
management and have been associated with large decreases
in VT burden.82
PACEMAKERS FOR BRADYARRHYTHMIAS
Permanent pacemakers are recommended for patients with
symptomatic bradycardia and third-degree, advanced and
symptomatic second-degree AV block, and left ventricular
ejection fraction less than 35% for cardiac resynchroniza-
tion therapy.83 It may also be recommended for patients
who experience ventricular dyssynchrony. There is an
eclectic variety of device configurations, ranging from
single- versus dual-chamber to unipolar versus bipolar pac-
ing and sensing, and many of them have different types of
sensor responses. Discussion of each particular device is
beyond the scope of this chapter. Modern devices are smaller
and possess capabilities for wireless monitoring. Recently, a
leadless pacemaker has been introduced that is delivered
percutaneously through femoral catheters and implanted
into the right ventricle; the Micra Transcatheter Pacing Sys-
tem (Medtronic Inc, Minneapolis, MN) has been shown to
have a lower risk of major complications at 12 months than
traditional transvenous systems.84
Conclusion
Cardiac arrhythmias cause significant morbidity and mor-
tality. Mechanisms underlying abnormal heart rhythms
are complex, but continuing advances in both medical
and procedural therapy reduce the burden of complications.
Patients with cardiac arrhythmias will present for peri-
operative care; furthermore, arrhythmias may also occur
spontaneously under anesthesia. Anesthesiologists must
understand the mechanisms behind the generation of
cardiac arrhythmias, as well as potential treatments, to
optimize care.
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 16 Perioperative Fluid
Management
MICHAEL J. SCOTT

Overview Physiological Stressors of Venous

The approach to perioperative fluid therapy has changed
and Arterial Volume
markedly over the last 40 years. This has followed the
Enhanced Recovery Pathways have simplified the approach
change in approach by surgeons recognizing that by reduc- to modern fluid therapy because the time a patient stays on
ing primary injury and blood loss during surgery the phys-
an intravenous fluid infusion is reduced because patients
iological impact for the patient is reduced, resulting in
will have early return of enteral fluid intake and enteral food
reduction in complications and improved outcomes.1,2 according to the type of surgery. Even patients undergoing
The establishment of minimal invasive surgery as a repro- bowel resection will have an early diet of protein drinks
ducible way of performing complex colorectal resections
within 24 hours of surgery, which has a profound effect
developed at the same time as the introduction of enhanced
on the metabolic response to surgical injury.4 The principles
recovery pathways in parts of Europe. The synergism
of fluid therapy within Enhanced Recovery Pathways are
between both approaches has led to rapid uncomplicated
outlined in Fig. 16.2. Key principles are to avoid fluid shifts,
recovery in a field where only 20 years ago the length of
individualizing fluid, hematocrit, and MAP, then rapid nor-
stay was an average of 10–14 days and mortality
malization to enteral intake postoperatively. Patients should
approached 4%. These figures are now closer to 2–6 days
arrive hydrated prior to induction of anesthesia. Oral fluid
and less than 2% mortality. Ultrashort lengths of stay have
loading and avoidance of bowel preparation if not needed
also been reported.3 These guiding principles have now are key strategies. There are many stressors that modify
transcended all surgical specialties with published guide- perioperative fluid requirements outlined in Fig. 16.3. The
lines and national adoption of enhanced recovery pathways surgeon has a major role in minimizing injury and blood
in most surgical specialties in many countries. (See https:// loss, which directly affect fluid shifts and activate the inflam-
www.ahrq.gov/hai/tools/enhanced-recovery/index.html; matory response.1 Although blood loss and fluid shifts
https://www.gov.uk/government/publications/enhanced-
during surgery are well recognized factors contributing to
recovery-partnership-programme.)
blood volume, the effects of drugs, anesthetic agents, inter-
When open surgery and high blood loss were common,
mittent positive pressure ventilation, pneumoperitoneum,
a lot of work around fluid therapy concentrated on main-
and position of the patient all affect venous and arterial tone
taining central intravascular volume using normal saline
with a resulting effect on effective intravascular volume.1
or colloid solutions. This led to a lot of research and
When considering the dynamic interaction of all these
debate around the risk/benefit of which type of solution
factors, it becomes apparent that in order to maintain opti-
to use during the perioperative period. The medical com-
mal intravascular volume at all times there needs to be con-
munity has gone full circle using dextrose or normal stant clinical vigilance by the anesthesiologist to maintain
saline infusions, crystalloids versus colloids, the use of
optimal intravascular volume, venous and arterial tone to
albumin and early use of coagulation factors in blood loss
maintain MAP. Postoperatively the patient should return
resuscitation.
to a normal oral fluid intake as soon as possible, which
Modern fluid therapy is just a single piece of the strat-
avoids the iatrogenic intravenous fluid and sodium loading.
egy for hemodynamic optimization, which involves
Tolerance to oliguria is also key because it is a normal
manipulating stroke volume and cardiac output, hemato-
response to surgical injury with 0.3 mL/kg per hour aver-
crit, oxygen delivery, and maintenance of arterial tone
aged over 2–4 hours a good starting point to assess ade-
and venous capacitance and mean arterial pressure
quacy of renal function; however, extra diligence is
(MAP) (Fig. 16.1).
necessary in higher risk patients.
This new concept of Goal Directed Hemodynamic Ther- Enhanced Recovery Pathways also address many of the
apy (GDHT) is focused on maintaining body homeostasis
issues facing patients during the perioperative period.
for as much of the perioperative time as possible. Preopera-
In a traditional surgical pathway, patients arrive dehy-
tive hemoglobin optimization, avoiding preoperative dehy- drated because of prolonged NPO status (and in some cases
dration, optimizing intravascular volume, cardiac output
exacerbated by bowel preparation). Patients are thus likely
and MAP using balanced intravenous fluids and low dose
to have splanchnic hypoperfusion after induction of anes-
vasopressors during physiological derangement and then
thesia and commencement of intermittent positive pres-
rapidly restoring normal enteral intake is now a key strategy
sure ventilation. The prolonged use of intravenous fluids
of modern surgical care.

208
 16 • Perioperative Fluid Management 209

Fig. 16.1 Key components of goal directed hemodynamic therapy.

Fig. 16.2 Principles of fluid therapy in enhanced recovery pathways.

MAP, Mean arterial pressure; SIRS, systemic inflammatory response
syndrome.
postoperatively can lead to salt and fluid overload, pulmo-
nary edema, ileus, and other complications. An ERAS
pathway starts with the patient hydrated and a goal Liberal Versus Restrictive Fluid
directed hemodynamic approach keeps the patient intra-
vascularly normal. Intravenous fluids are reduced and
Therapy
stopped as soon as the patient can take oral intake avoid-
ing the fluid and salt overload leading to edema, ileus and DANGERS OF FLUID OVERLOAD
complications. These two pathways are illustrated in Although it is important to maintain intravascular volume,
Fig. 16.4. the indiscriminate use of intravenous fluids leads to positive

Fig. 16.3 Perioperative physiological stressors of intravascular volume and vascular tone. ECF, Extracellular fluid; Hb, hemoglobin; Hct, hematocrit.
210 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fig. 16.4 Fluid therapy overview: traditional versus Enhanced Recovery Pathways.
fluid balance, which is associated with a multitude of down-
stream complications as summarized in Fig. 16.5 by Mal-
brain et al.5 Brandstrup et al. first demonstrated this
relationship and the terms restrictive and liberal fluid ther-
apy have been used since then.6 However, there has been no
strict definition of what this actually means in practice7 and
in modern randomized controlled trials (RCTs) such as the
‘Relief Study’, the liberal fluid regime was similar to
Brandstrup’s restrictive arm. There are now recognized
‘zones of risk’ in postoperative fluid balance.8 The Relief
Study compared two arms with resultant fluid balance on
POD 1 of 3 mL/kg versus 18 mL/kg POD 1. There was min-
imal difference but increased risk of AKI in the 3 mL/kg
group. Therefore, it is now considered a positive fluid bal-
ance of 5–20 mL/kg (1–1.5 L on ideal body weight) is opti-
mal in elective major abdominal surgery whilst avoiding
excess of 30–40 mL/kg (2–3 L on ideal body weight).
PREOPERATIVE FLUID MANAGEMENT
One of the biggest dogmas in medicine is still nil by mouth
from midnight for patients undergoing surgery. The intro-
duction of carbohydrate fluid loading in patients undergoing
colorectal surgery within enhanced recovery pathways
showed the process of oral fluid loading up to 2 hours before
surgery to be safe. This has now been accepted as the new
standard in medical practice in all National Anesthesiology
Society’s recommendations for oral intake before surgery.
Six hours for solid food remains standard because of the risk
of aspiration of particulate matter.
Carbohydrate loading was introduced with the concept of
avoiding dehydration prior to major surgery as well as giv-
ing a carbohydrate load large enough and close enough to
surgery to improve insulin sensitivity as the first step of
improving the metabolic response to surgery.9 The effects
of carbohydrate loading in abdominal surgical patients
are reduction in postoperative insulin resistance,10,11
reduced catabolism,12 and improved muscle mass and
strength.13,14
The type of carbohydrates used in solution are maltodex-
trins, which do not cause a delay in gastric emptying. Car-
bohydrate loading is normally given the night before and
the morning of surgery; the night before dose is 800 mL
in volume containing 100 g of carbohydrates.15 The dose
of the night before ensures the patient is well hydrated
and the extracellular fluid volume is normalized. In our
modern society, patients are often dehydrated because of
their lifestyle, caffeine intake, and alcohol intake, therefore
the night before dose aims to make sure the patient is prop-
erly hydrated prior to surgery. The morning dose is 400 mL
in volume with 50 g of carbohydrate—enough to improve
insulin sensitivity. The benefits of carbohydrate loading
are less evidence-based in patients who have early return
of gut function such as elective orthopedic surgery. This is
probably because the patients do not have bowel manipula-
tion and have early predictable postoperative feeding.
Therefore in patients undergoing nonabdominal surgery,
the key goal is to ensure the patient is not dehydrated prior
to induction of anesthesia. Proprietary oral carbohydrate
drinks come as either cartons or powder to be mixed
with water.
Purposes of oral carbohydrate drinks:
▪ To avoid dehydration prior to surgery and improve
patient well-being
▪ To allow safe general anesthesia without the increased
risk of aspiration of gastric contents; the solution is com-
posed of maltodextrins, which empty readily and predict-
ably from the stomach.
▪ To give a large enough carbohydrate load (50 g) to allow
the patient to be in a metabolically fed state prior to

Fig. 16.5 The dangers of intravenous fluid overload. (From Malbrain MLNG, Manu LN, Van Regenmortel N, et al. Principles of fluid management and
stewardship in septic shock: it is time to consider the four Ds and the four phases of fluid therapy. Annals of Intensive Care. 2018;8(1). https://doi.org/10.1186/
s13613-018-0402-x)
surgery (800 mL; 100 g night before, 400 mL; 50 g
morning of surgery). The optimal metabolic effect occurs
when given 2–4 hours before surgery.
▪ Improved compliance with patients drinking a suitable
volume of liquid to have the desired physiological effect.
Although the majority of patients can take carbohydrate
drinks without any issues, there are certain patient groups
who have a high risk of aspiration or have had gastric sur-
gery where there is minimal evidence base. The safe admin-
istration of oral carbohydrate drinks according to patient
and surgery type is provided in Fig. 16.6.
Maintaining Normal Intravascular
Volume During Perioperative
Period
GOAL-DIRECTED FLUID THERAPY
Goal-Directed Fluid Therapy (GDFT) is a term used where
some form of monitoring is used to target fluid boluses in
the range of 250 mL to maximize stroke volume of the heart
and maximize oxygen delivery. Many different studies using
different monitors, endpoints, goals and in different surgery
types have been published. A meta-analysis by Grocott
16 • Perioperative Fluid Management 211
et al.16 has shown benefit but more recent RCTs have not
always shown the benefit in patients within an ERAS proto-
col.17 This is probably a result of the advancement of surgi-
cal technique to reduce blood loss and fluid shifts and ERAS
protocols to avoid preoperative dehydration and minimize
the time on intravenous fluids. The benefit is not manifest
unless the patient has significant comorbidities such as car-
diopulmonary disease.
In order to determine whether a patient is fluid respon-
sive, a fluid bolus should be given rapidly (i.e., 250 cc over
10 minutes). Rapid mini fluid boluses of 100 mL have also
been shown to predict fluid responsiveness. The choice of
colloid or crystalloid to be used for the boluses is still under
debate.18–20. Importantly, by targeting an optimal stroke
volume by giving small intermittent boluses, it reduces
the total volume given when compared with having set
maintenance rates of IV fluid. The more modern approach
to GDFT is to use monitoring to guide fluid boluses and avoid
giving too much, i.e., Goal Directed Fluid Restriction whilst
maintaining optimal intravascular volume and perfusion of
organs.
The aim of GDFT is to optimize flow using small fluid
boluses to increase stroke volume near the top of the
curve and maximize myocardial efficiency. Stroke volume
gain is less as the top of the Starling Curve is reached
(Fig. 16.7).
212 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fig. 16.6 An algorithm for preoperative administration of carbohydrate drinks (from VCU Health, USA).
Fig. 16.7 Optimizing stroke volume with fluid boluses: relationship
with the Frank-Starling Curve. The aim is to optimize flow using fluid
boluses to put the cardiac function at the top of the Starling Curve.
GDFT has consistently shown benefit in clinical studies
and meta-analysis with reduced renal and GI-related mor-
bidity, reduced AKI, reduced surgical site infection and
reduction in ileus. However, since ERAS pathways have
become standardized the signal of benefit is now mainly
in high-risk patients or surgery where there is large blood
loss or fluid shifts. The most recent meta-analysis studying
95 randomized trials (11,659 patients) showed lower risk
of mortality (OR 0.66; 95% CI, 0.50 to 0.87), AKI (OR
0.73; 95% CI, 0.58 to 0.92), pneumonia (OR 0.69; 95% CI,
0.51 to 0.92), and hospital LOS (–0.90; 95% CI, –1.32 to –
0.48;) compared with standard fluid management.21
Other prior reviews demonstrated similar results showing
reduced complications; however, large meta-analyses of
these studies have significant limitations given the heteroge-
neity of protocols, monitoring devices, resuscitation strate-
gies, and sample sizes.
HIGHER LEVELS OF CARDIOVASCULAR
MONITORING
Static parameters of CVS monitoring such as heart rate and
blood pressure do not reflect the intravascular volume or
physiological changes in ways that could guide fluid ther-
apy. Although urine output is a good reflection of renal per-
fusion, patients are often oliguric during surgery and the
initial postoperative phase because of hormonal and stress
effects. The term ‘dynamic parameters’ is used when phys-
iological measurements more accurately reflect acute
physiological changes in arterial volume and tone. There
are now many different types of cardiovascular monitors
approved for clinical use by the FDA. This means they are
within 30% of the measurements using a Swan Ganz
catheter and thermodilution as a means of measuring stroke
volume and cardiac output. Concern amongst anesthesiol-
ogists that derived figures may not be exact has led to under-
use of these monitors in clinical practice. In reality different
technologies have advantages and disadvantages but all
will track change in stroke volume and cardiac output.
The ability to track changes in stroke volume in response

to a fluid bolus is a key requisite for non-invasive cardiac
output monitors to be approved by the FDA.
In patients undergoing major surgery the use of an arte-
rial waveform can be used to calculate pulse pressure vari-
ations (PPV) or stroke volume variation (SVV). These are
well validated indices in ventilated patients with a tidal vol-
ume of 8 mL/kg to reflect the need for a fluid bolus.22–24
Other noninvasive devices such as bioimpedance can
be used.
The esophageal Doppler is a soft, thin Doppler device mea-
suring descending aortic blood flow. It can give values for
blood velocity, stroke volume, and SVR with a continuous
waveform. This device measures flow directly and has been
used in most of the GDFT studies where a positive effect has
been noted.25 Pulse contour wave analysis from the arterial
line is another way of getting more information from the arte-
rial line to interpret changes in flow from the waveform.
Recent advances using computer algorithms have also led
to an FDA approved Hypotensive Prediction Index (HPI)
(Edwards Lifescience, The Acumen Hypotension Prediction
Index (HPI) software) from the arterial waveform that can
advise which components of preload, contractility, or afterload
are contributing to an imminent drop in MAP <65 mmHg.26
The use of transesophageal echo (TEE) is still viewed by many
as the optimal intraoperative monitor despite lack of outcome
data and utilization remains limited because of resource
allocation and the need for training. TEE can assess LV and
RV volume status and contractility issues and is extremely
useful in patients with complex cardiac issues.
MAINTAINING ADEQUATE MEAN ARTERIAL
PRESSURE
Background
There is increasing recognition that a MAP of less than
65 mmHg can cause organ dysfunction, particularly AKI
and myocardial injury after noncardiac surgery (MINS).
The lower and longer the hypotension, the greater the
harm. A recent retrospective cohort analysis of 57,314
patients having noncardiac surgery between 2005 and
2015 demonstrated MAPs below absolute threshold of
65 mmHg were progressively related to both myocardial
and renal injury.27 Time spent below a MAP of 65 mmHg
for a total of 13 minutes was associated with increased risk
of AKI and MINS (OR 1.2 and 1.34 respectively). This risk
increased with longer duration and lower BP, for example
just 1 minute at a MAP of 50 also significantly increased risk
of AKI and MINS. This relationship also holds for a drop in
MAP compared with a patient’s baseline pressure and is
illustrated in Figs. 16.8 and 16.9.
These data are consistent with prior studies showing a
significant increase in myocardial injury, AKI, and mortality
following perioperative hypotension. Sun et al. reviewed
5127 noncardiac surgical patients and showed odds ratios
of 2.34 and 3.53 for AKI with 11–20 min and greater than
20-minute exposures to a MAP of <55 respectively.28 Monk
et al. studied over 18,000 patients in the VA system and
showed increased 30-day mortality risk with SBP <67 to
70 mmHg for >5 to 8 min, MAP <49 mmHg for 4 to 5
min, and DBP <30 to 33 mmHg for >4 to 5 min.29 Other
studies have shown similar trends emphasizing the impor-
tance of avoiding intraoperative hypotension.27,28
16 • Perioperative Fluid Management 213
FIXING FLOW, THEN MAINTAINING MEAN
ARTERIAL PRESSURE
Multiple randomized trials have shown the benefit of a peri-
operative hemodynamic management protocol that com-
bines GDFT with selective use of vasopressor or inotropic
support. These studies follow the principle of optimizing flow
followed by use of vasoactive drugs to achieve targeted hemo-
dynamic goals (i.e., MAP, cardiac index, indexed stroke vol-
ume, etc.). A review of selected studies is provided. The
OPTIMISE trial published in 2014 was a randomized, multi-
center trial in the UK of 734 patients older than 50 years of
age undergoing major gastrointestinal surgery.21 Patients
were randomized to a cardiac output-guided hemodynamic
algorithm versus standard therapy. The intervention group
protocol maximized stroke volume and maintained a contin-
uous infusion of inotrope with dopexamine at 0.5 μg/kg/min.
The patients were to maintain a MAP of >60 mmHg with
vasopressor support as needed (type or pressor was unspeci-
fied for the study). Despite the trial not being statistically sig-
nificant for the primary endpoint, results showed the
intervention group had a reduction in complications and
improvement in mortality at 180 days. The FEDORA trial
published by Calvo-Vecino et al., in 2018 was a prospective,
multicenter randomized control trial studying 420 patients
assigned to intra-op GDHT versus traditional therapy.30 Eligi-
ble patients underwent major abdominal, urologic, gyneco-
logic, or orthopedic surgery with both laparoscopic and
open surgical approaches. The primary outcome was moder-
ate or severe complications (AKI, SSI, pulmonary edema,
ARDS) occurring within 180 days of surgery. Patients in
the GDHT group had hemodynamic monitoring with an
esophageal Doppler monitor to guide fluid, vasopressor,
and inotrope administration. Fluid boluses of 250 cc were
given to achieve an optimal stroke volume, after which either
vasopressors or inotropes were started to maintain MAP of
>65 mmHg and cardiac index of >2.5 L/min/m2. Compared
with traditional therapy, the GDHT group had statistically
significant lower risk of AKI (1.44% vs. 8.53% p¼0.001)
ARDS (0.48% vs. 5.69% p¼0.003), cardiopulmonary edema
(0% vs. 6.16% p<0.001), pneumonia (1.91% vs. 8.53%
p¼0.003), superficial SSI (0.96% vs. 4.74% p¼0.036), and
deep SSI (1.91% vs. 8.06% p¼0.006). Secondary outcomes
also demonstrated shorter average hospital LOS (5 vs. 7 days)
and shorter average ICU LOS (16 h vs. 24 h) in the GDHT
group compared with traditional therapy. Similar reductions
in complications rates were demonstrated with the INPRESS
trial in 292 high-risk surgical adult patients with a preoper-
ative AKI risk index of class III or higher undergoing major
surgery for >2 hours.31 Patients were randomized to an indi-
vidualized or standard treatment strategy. Both groups
received maintenance LR at 4 mL/kg/h. Fluid boluses of
250 cc were given to patients in the arm to maintain a max-
imal stroke volume (i.e., when a peak SVI was reached) based
on cardiac output monitoring. These patients were then
started on continuous low-dose norepinephrine to achieve
SBP within 10% of the patient’s preoperative baseline. The
standard therapy group received intermittent 6 mg boluses
of ephedrine for any decrease in SBP below 80 mmHg or
lower than 40% from the patient’s baseline. Results showed
that 68 patients (46.3%) in the individualized treatment
group and 92 (63.4%) in the standard treatment group
had postoperative organ dysfunction by day 30 (adjusted
214 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

7 7
6 6
5 5
Estimated probability of MINS (%)

Estimated probability of MINS (%)

4 4

3 3

2 2

1 1
Cumulative 10-minute Cumulative 10-minute
Cumulative 5-minute Cumulative 5-minute
Cumulative 3-minute Cumulative 3-minute
Cumulative 1-minute Cumulative 1-minute
0.5 0.5
40 50 60 70 80 40 50 60 70 80
(A) Lowest MAP (mmHg) (B) Lowest MAP (mmHg)

7 7
6 6
5 5
Estimated probability of MINS (%)

Estimated probability of MINS (%)

4 4

3 3

2 2

1 1
Cumulative 10-minute Cumulative 10-minute
Cumulative 5-minute Cumulative 5-minute
Cumulative 3-minute Cumulative 3-minute
Cumulative 1-minute Cumulative 1-minute
0.5 0.5
–60 –50 –40 –30 –20 –10 –60 –50 –40 –30 –20 –10
Lowest percent decrease from baseline MAP (%) Lowest percent decrease from baseline MAP (%)
(C) (D)
Fig. 16.8 Lowest mean arterial pressure (MAP) thresholds for myocardial injury after noncardiac surgery (MINS). Univariable and multivariable rela-
tionship between MINS and absolute and relative lowest MAP thresholds. (A) and (C) Estimated probability of MINS were from the univariable moving
window with the width of 10% data; (B) and (D) were from multivariable logistic regression smoothed by restricted cubic spline with three degrees
and knots at 10th, 50th, and 90th percentiles of given exposure variable. Multivariable models adjusted for covariates in Table 1. (A) and (B) show
that there was a change point (i.e., decreases steeply up and then flattens) around 65 mmHg, but 20% was not a change point from (C) and (D). Salmasi,
V., Maheshwari, K., Yang, D., Mascha, E.J., Singh, A., Sessler, D.I., Kurz, A., 2017. 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 126,
47–65.

hazard ratio, 0.66; 95% CI, 0.52 to 0.84; P ¼ .001). Lower randomized to GDHT versus a standard fluid regimen.32
rates of renal dysfunction were observed in the individualized The protocol in GDHT gave patients fluid with a goal of max-
group compared with standard therapy (32.7% vs. 49%). imizing their stroke volume intraoperatively. This study
Delirium was also less common in the individualized group showed an increase in LOS and readiness for discharge time
(5.4% vs. 15.9%) as was sepsis (15.0% vs. 26.2%). in the GDHT group, contrasting with the studies mentioned.
Although many older studies show benefits from GDFT, One explanation may be that aerobically fit patients
some more recent studies using GDFT within Enhanced increase their stroke volumes as their normal response to
Recovery Pathways have not been so convincing. In a study fluid, leading to excessive fluid administration when target-
published in 2012, ‘fit’ or ‘unfit’ patients undergoing major ing maximizing stroke volume. In addition, a meta-analysis
open or laparoscopic colorectal surgery were each by Rollins et al. in 2016 reviewed 23 studies and showed no
 16 • Perioperative Fluid Management 215

11 11
10 10
9 9
8 8
Estimated probability of AKI (%)

Estimated probability of AKI (%)

7 7

6 6

5 5

4 4

3 3
Cumulative 10-minute Cumulative 10-minute
Cumulative 5-minute Cumulative 5-minute
Cumulative 3-minute Cumulative 3-minute
Cumulative 1-minute Cumulative 1-minute
2 2
40 50 60 70 80 40 50 60 70 80
Lowest MAP (mmHg) Lowest MAP (mmHg)
(A) (B)
11 11
10 10
9 9
8 8
Estimated probability of AKI (%)

Estimated probability of AKI (%)

7 7

6 6

5 5

4 4

3 3
Cumulative 10-minute Cumulative 10-minute
Cumulative 5-minute Cumulative 5-minute
Cumulative 3-minute Cumulative 3-minute
Cumulative 1-minute Cumulative 1-minute
2 2
–60 –50 –40 –30 –20 –10 –60 –50 –40 –30 –20 –10
Lowest percent decrease from baseline MAP (%) Lowest percent decrease from baseline MAP (%)
(C) (D)
Fig. 16.9 The lowest mean arterial pressure (MAP) thresholds for acute kidney injury (AKI). Univariable and multivariable relationship between AKI and
absolute and relative lowest MAP thresholds. (A) and (C) Estimated probability of AKI were from the univariable moving-window with the width of 10%
data; (B) and (D) were from multivariable logistic regression smoothed by restricted cubic spline with three degrees and knots at 10th, 50th, and
90th percentiles of given exposure variable. Multivariable models adjusted for covariates in Table 1. (A) and (B) show that there was a change point
(i.e., decreases steeply up and then flattens) around 65 mmHg, but 20% was not a change point from (C) and (D).

difference in mortality, return of flatus, or ileus in patients
treated with GDHT.33 In addition, clinical reviews of GDHT
have numerous limitations given the heterogeneity of
protocols, monitoring devices, and limited information
regarding peri- and postoperative care.
CHOICE OF INTRAVENOUS PERIOPERATIVE FLUID
AND POSTOPERATIVE IV FLUID MAINTENANCE RATE
The choice of intravenous (IV) fluid has been the focus of
much debate over the last 30 years. It is beyond the scope
of this chapter to go into detail but an overview is provided.
Crystalloids are a mixture of water and electrolytes and are
cheap and readily available. Sodium-containing crystalloid
fluid solutions should be used for intravascular resuscita-
tion and maintenance of intravascular volume because
using only dextrose solutions leads to hyponatremia. The
use of large quantities of normal 0.9% saline is associated
with an increased risk of hyperchloremic acidosis and pos-
sible harm.34–36 However, with the reduction in total IV
fluid use in ERAS pathways, the significance of this is less
clear. Balanced solutions such as Ringers lactate, Hart-
mann’s solution or Plasmalyte avoid this problem.36 Post-
operative fluids should be minimized to that needed to match
ongoing losses once intravascular volume is obtained. The
use of dextrose solutions leads to hyponatremia, therefore a
good alternative is 0.45% saline with or without dextrose.
This avoids the sodium load but reduces the risk of
216 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
hyponatremia. Maintenance fluids should be targeted
between 1 and 1.2 mL/kg/h ideal body weight with 3 mL/
kg fluid boluses of balanced crystalloid targeted to goals such
as urine output and passive leg raise (PLR) or cardiac output
monitoring should be used to assess fluid responsiveness.
Patients should be allowed to drink freely postoperatively
and given regular protein drinks unless there are specific
contraindications.15 By the morning of postoperative day1,
the IVI should be reduced and then discontinued provided
the patient is taking adequate oral intake.
Colloids can be derived from plasma (FFP, albumin) or are
semisynthetic (gelatins, HetaStarches). Colloids have a larger
molecular weight and properties that help them stay in the
intravascular volume for longer compared with crystalloids,
reducing total IV fluid administration. They are therefore
used in situations such as bleeding (before the need for blood
product administration) and to try and reduce the down-
stream risk of edema from too much crystalloid administra-
tion. Hetastarch can have different concentrations,
molecular weight, and molar substitutions represented by
the numbers after them. For example Hespan is HES 6%
(600/0.75) with a volume effect of 100% and a high molar
substitution of 0.75. HES solutions have been implicated in
causing renal injury and the impairment of platelet reactivity
and decreased circulating plasma coagulation factor VIII and
von Willebrand factor, which may result in weakening of clot
formation and bleeding. In one study of more than 800
patients low molar-substituted HES 130/0.4 solution versus
0.9% saline boluses to target a goal-directed fluid protocol did
not reduce the composite outcome of death or major postop-
erative complications and increased the relative risk of post-
operative AKI (relative risk 1.34, 95% CI, 1.00-1.80).37 HES
use is now restricted in some parts of the world because of
increased risk of renal toxicity and hemostasis effects. Like
all drugs, the negative effects appear to be dose-dependent
and some studies have not shown these negative results in
surgical patients compared with those who are critically ill.
Gelatins are cheap and have a volume effect of 70%–80%,
minimal effects of coagulation or renal effects. However,
there is a reportedly relative high risk of anaphylaxis.
Human albumin has been increasingly used since the
demise of hetastarches but remains expensive. There are
yet no convincing studies that demonstrate an advantage
over crystalloids.38
Blood administration using packed red blood cells (PRBC)
should be minimized and individualized to maintain nadir
hematocrit for the patient—the Hb level below which organ
dysfunction will occur. This is covered in Section 9.
The use of fresh frozen plasma (FFP) and cryoprecipitate
should be guided by clinical blood loss, coagulation tests,
and thromboelastogram (TEG) to maintain adequate
coagulation and fibrinogen levels appropriate for the
surgical case.
Maintaining Optimal Hemoglobin
Levels and Nadir Hematocrit
Preoperative anemia is an all cause risk factor for complica-
tions and mortality in patients undergoing major surgery.39–
41
Blood product transfusion also has associated risk factors
such as transfusion reactions, surgical site infection, and
Fig. 16.10 Graph showing risk of mortality and organ dysfunction with
different comorbidities in cardiac surgery. (Reprinted with permission
from Loor G, Koch CG, Sabik JF, Li L, Blackstone EH. Implications and
management of anemia in cardiac surgery: current state of knowledge.
J Thorac Cardiovasc Surg. 2012;144(3):538–46.)
decreased survival in certain cancers. Therefore, it is now best
practice to optimize preoperative hemoglobin as much as pos-
sible in the time frame available up to surgery.42 Newer intra-
venous iron infusions are safe and effective resulting in some
patients improving their Hb by 1 g/dL per week.43,44
Although often considered in isolation, hemoglobin man-
agement plays an important role in perioperative fluid man-
agement. Nadir hematocrit is the hemoglobin level below
which the patient will have some form of organ dysfunction
or increased risk of complications/mortality. The American
Society of Anesthesiologists (ASA) recommend maintaining
an intraoperative Hb of 6–10 g/dL individualized according
to potential/actual ongoing bleeding, intravascular volume
status, signs of organ ischemia, and the patient’s cardiopul-
monary reserve.45 Fig. 16.10 by Loor et al. shows the rela-
tionship of nadir hematocrit in patients undergoing cardiac
surgery.46 Blood transfusion should be given on a single unit
basis to maintain Hb above these nadir levels or in the situ-
ation of major blood loss otherwise crystalloid or colloid
solutions can be given to maintain intravascular volume.
Red cell salvage and tranexamic acid are proven intraopera-
tive interventions to reduce the need for blood transfusion.47
Laparoscopic Surgery
Laparoscopic and robotic-assisted surgery poses particular
challenges for the anesthesiologist. There are a series of
physiological changes during the induction of anesthesia,
establishment of positive pressure ventilation, and then
insufflation outlined in Fig. 16.3. Work by Levy et al. in fluid
optimized patients undergoing laparoscopic colorectal
surgery used an esophageal Doppler to measure aortic
velocity, stroke volume, cardiac output, and oxygen deliv-
ery. Systemic Vascular Resistance (SVR) could also be cal-
culated.48,49 Patients followed a consistent pattern of
hemodynamic response as shown in Fig. 16.11. The
increase in both systolic and diastolic pressures is a combi-
nation of increased SVR and catecholamines with resultant
increase in myocardial work.
 16 • Perioperative Fluid Management 217

6000
O18 O18

5000
O18

4000 O18
O14 O14 O13

3000 O13

2000

1000

0
N= 16 16 16 16 16 16 16 16 16 16 16
SV

SV

SV

SV

SV

SV

SV

SV

SV

SV

SV
R

R
Ip

Ir

IP

IP

I5

I1

I1

I2

I2

I3

I3
ev
os

5
ne

ne

m
er

m
t

in
um

un
25

in

in

in

in

in

in
se

o
op
0

he
er

ad
ito
ne

do
u

w
Fig. 16.11 The hemodynamic effects on systemic vascular resistance with the establishment of a pneumoperitoneum in laparoscopic surgery.

The positioning of the patient during surgery can exacer-
bate other physiological changes. Impact on venous return
is significantly different with head up producing a hypovo-
lemic model and head down resulting in high venous return
and cerebral venous congestion. The body habitus of the
patient (particularly obesity) adds further differences as a
result of reduced intra-abdominal space and increased chest
wall compliance.50 The cardiac pulmonary status of the
patient also compounds these, particularly if the cardiac
function is impaired such that increased afterload is poorly
tolerated.
The physiological effects of laparoscopy, compounded by
either head up or head down position make intraoperative
monitoring of stroke volume sometimes difficult to interpret.
The author’s suggestion is to optimize stroke volume using
whatever minimally invasive cardiac output device, SVV
and PPV, prior to start of surgery and insufflation of the
pneumoperitoneum. Then clinical acumen can be used to
interpret physiological changes with the need for fluid
boluses being used judiciously to maintain cardiac output.
At the end of surgery once the pneumoperitoneum has
ended, the patient’s stroke volume should be reoptimized
prior to extubation using the same indices.
Emergency General Surgery
Morbidity and mortality in emergency general surgical
patients is extremely high. Mortality across many different
health-care systems is consistently in the region of around
14% for all-comers presenting with a surgical condition
needing emergency laparotomy. This statistic is consistent
across different health-care systems around the world.
The elderly are at particular risk with those over 80 years
of age having a mortality of over 25% and those who are
over 90 years of age having a 1-year life expectancy of less
than 10%.
Another key concern for elderly patients is not just mor-
tality but a return to a functional level after surgery. Unfor-
tunately, a prolonged course in hospital leads to a poorer
functional outcome. Analysis by Ogola et al. shows that
patients presenting for emergency general surgery will be
a major burden on US health-care resources, costing over
40 billion dollars by 2060.51
There have been several projects on emergency general
surgery to try and reduce morbidity and mortality. All of these
projects have been challenged by the difficulties of quality
improvement in a complex population presenting through
the emergency department for major surgery and with
multi-system dysfunction, hypovolemia, and sepsis. In the
UK, there has been a centrally organized process to try and
optimize outcomes. Initial data were collected through the
Emergency Laparotomy Initiative. After initial studies showed
an improvement with a systematic approach to address mod-
ifiable risk factors, a step wedge cluster study was performed
called EPOCH.52 Disappointingly this study did not show any
improvement in mortality; however, this was felt to be a fail-
ure in the challenges of quality improvement implementation
rather than the approach to the pathophysiology with multi-
ple intervention points. The intervention points were all
evidence-based but the challenges of implementing 38 points
across the health-care system proved too challenging. A smal-
ler group called ELPQUIC had a bigger impact on mortality
and morbidity using a more simplified approach concentrat-
ing on immediate resuscitation with volume replacement and
antibiotics for the treatment of sepsis, urgent CT scan of the
abdomen for diagnosis, immediate surgery within 6 hours
and admission postoperatively for all patients to a critical care
facility.53 This quality improvement bundle, which was
focused on early detection, sepsis and fluid treatment, early
218 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

VCUHealth LapQuic TM

Laparotomy Quality Improvement Careset

ALL PATIENTS presenting with emergency abdominal conditions THAT
MAY REQUIRE EMERGENCY LAPAROTOMY or necrotizing soft tissue
infection REQUIRING EMERGENCY DEBRIDEMENT are to be started on the
Surgical Sepsis pathway and comply with the care-bundle goals below

Recognition and Resuscitation

• Sepsis alert + abdominal complaint or necrotizing soft tissue
infection
• Lactate
• Ultrasound and fluid resuscitation (up to 30 mL/kg)
• Rapid CT imaging
• Surgical assessment within 30 minutes

Rapid Delivery of Antibiotics

• Within 1 hour
• Standardize to Zosyn
• Ciprofloxacin + metronidazole if penicillin allergic
• Add Vancomycin and Clindamycin for soft tissue infections

Early Surgery
• Operative booking at attending surgeon discretion
• OR prioritization
• Early anesthesiology consult for surgical planning
• Incision no later than 8 hours

Goal Directed Fluid Therapy

• Protocolized resuscitation and volume assessment
• Non-invasive cardiac output monitoring
(FloTrac, esophageal doppler)
• Appropriate initiation of vasopressors and inotropes

Post-operative ICU Admission

• STICU bed for all patients
• Continue goal directed fluid therapy
• Appropriate use of vasopressors and inotropes
• Multimodal analgesia and early mobilization

Fig. 16.12 ELPQUIC Emergency Laparotomy Quality Improvement Bundle. (Rothstein WB, Navarrete S, Goldberg S, Peden C, Quiney N, Scott M. Adoption of
a proven quality improvement bundle for ERAS in emergency general surgery in a US health-care system. Clinical Nutrition ESPEN. 2019;31:114.)

surgery and protocolized admission to ICU with appropriate
de-escalation did have a significant impact on mortality of
42% in the population over 75 years of age with 2–8.9 lives
saved per 100 people treated using a linear regression model
depending on age.
The approach to fluid therapy using this five-step approach
has changed the focus of persistent fluid boluses to restore
intravascular volume to initial fluid resuscitation with the
early consideration of vasopressors and invasive hemody-
namic monitoring to reduce the incidence of downstream
fluid overload and its subsequent increase in pulmonary dys-
function, ileus, and all cause morbidity. The principles have
been introduced successfully into an academic US medical
center and an approach of using early hemodynamic moni-
toring and vasopressors prior to surgery if needed is used to
optimize the circulation (Figs. 16.12 and 16.13).54
Summary: Perioperative Fluid and
Hemodynamic Plan
Every patient undergoing elective surgery should have a
fluid and hemodynamic plan according to their type of sur-
gery and the surgical approach and adjusted according to
their comorbidities (Fig. 16.14). Intravascular fluid volume
should be optimized then low-dose vasopressors used to
 16 • Perioperative Fluid Management 219

Fig 16.13 Comprehensive pathway in emergency general surgery for fluid, hemodynamics, and vasopressors. CVC, Central venous catheter;
ED, emergency department; ICU, intensive care unit; IVC, interior vena cava; LTTE; MAP, mean arterial pressure.

Fig. 16.14 A perioperative fluid and hemodynamic plan.

220 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
maintain an individualized MAP, which should be at least
60–65 mmHg unless there are surgical indications not to
do so. Hemoglobin should be kept at a level above the nadir
hematocrit at which organ dysfunction is predicted to
occur. This should also be individualized according to the
patient’s comorbidities and type of surgery. High-risk
patients and patients undergoing high-risk surgery benefit
from a higher level of clinical monitoring, be it an arterial
line to use dynamic indices of fluid responsiveness, mini-
mally invasive cardiac output monitoring, or other inter-
ventions such as TEE or PA catheter. Fluid therapy for
patients undergoing specific surgical procedures within an
Enhanced Recovery protocol can be protocolized with con-
sistent outcomes. However, blood loss, an inflammatory
response, or the patient’s cardiopulmonary or renal physiol-
ogy may necessitate deviation from this.
Emergency surgery patients need a different approach
because of preexisting fluid shifts, intravascular hypovole-
mia, and the presence of sepsis and vasoplegia. Early intra-
vascular resuscitation and use of vasopressors such as
norepinephrine prior to going to the operating room are
key parts of reducing morbidity and mortality in this group.
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3. Levy BF, et al. 23-hour-stay laparoscopic colectomy. Diseases of the
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4. Scott MJ, et al. Enhanced Recovery After Surgery (ERAS) for gastroin-
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 17 Preservation of Renal Function
JAMIE R. PRIVRATSKY, ANNE CHERRY, BENJAMIN Y. ANDREW, and MARK STAFFORD-SMITH
Introduction
A rapid decline in glomerular filtration evidenced by the
accumulation of nitrogenous waste products (blood urea
nitrogen and creatinine) reflects acute kidney injury
(AKI), a common major medical problem that occurs in
7%–18% of hospitalized patients including 50%–60% of
those admitted to intensive care units.1 AKI manifesting
in the early postoperative phase is particularly common
after some surgeries, complicating up to 20%–70% of car-
diac, vascular, major trauma, and hepatobiliary proce-
dures.2 The importance of postoperative AKI lies in its
consistent association with worsened outcome, including
higher in-hospital mortality, delayed recovery in survivors,
and overall increased cost.3–5 Even evidence of minor renal
impairment carries with it a related risk of major postoper-
ative complications and mortality.6–8
Clinical practice modifications can eliminate or limit renal
insult in cohorts and reduce the burden of postoperative
AKI. In contrast, once AKI has occurred, beyond dialysis
the portfolio of evidence-based interventions that improve
outcome is sparse to nil. This unfortunate observation has
gained attention from research agencies such as the United
States National Institutes of Health9,10 and the Cochrane
Database of Systematic Reviews.11 In this context, the
aim of this chapter is to review evidence (or lack thereof)
for putative renal preservation strategies, including those
directed at the postoperative critically-ill patient.
The kidneys constitute less than 0.5% of body weight but
receive 25% of cardiac output, making them the most highly
perfused major organs. Among their many active roles are
regulation of body fluid composition and volume; the kidneys
filter equivalent to a 12-oz (355 mL) can of soda every
3 minutes, returning all but 1% (approximately 4 mL of urine)
to the circulation. The ability of the kidneys to control the con-
tents of urine precisely is the basis of whole body homeostasis.
As highlighted by the renal physiologist, Dr. Homer Smith: “It
is no exaggeration to say that the composition of the blood
is determined not by what the mouth ingests but by what
the kidneys keep; they are the master chemists of our internal
environment, which, so to speak, they synthesize in
reverse.”12 Hence, acute derangements that have systemic
effects are thought to underpin some of the risk for adverse out-
come related to AKI, a notably different state from compen-
sated chronic kidney disease (CKD) where homeostasis is
maintained in the context of limited renal reserve.
Although some elements of perioperative AKI pathophys-
iology are mechanistically well understood and available to
guide the clinician, much is still not known. Nonetheless,
identified factors can be divided generally into culprits sus-
pected of adding to a cumulative burden of renal insult and
those identifying kidney vulnerability. Pathophysiologic
222
contributors to renal insult are discussed in elsewhere in this
textbook, and mechanistic understanding of their role in
AKI (and potential avoidance) remains the most important
overarching renal preservation principle. Sometimes a sole
AKI insult is evident (e.g., renal artery atheroembolism), but
AKI is most commonly a multifactorial problem. For specific
procedures and even individual patients, renal insults may
be obvious, and sometimes their effects are avoidable or can
be attenuated through thoughtful clinical care. Vulnerabil-
ities such as comorbid disease (e.g., diabetes) are also exten-
sively discussed in elsewhere in this textbook. However,
beyond CKD these premorbid conditions only modestly
predict variability in postoperative creatinine rise.2,3,13–29
Renal Physiology
To understand the “renal paradox” (that such a highly per-
fused organ is so susceptible to injury) requires an appreci-
ation of normal kidney vasculature. The most highly studied
pathophysiologic model of AKI is cardiac surgery, which has
provided many insights about the kidney response to stress
that are generalizable.
MEDULLARY HYPOXIA
Normal blood flow is unevenly distributed within the kid-
ney, with the renal medulla disproportionately under-
perfused (5% total). Notably, such heterogeneous blood flow
facilitates “mission critical” urine concentrating ability of
the kidney, but also places the medulla at particular risk
of ischemia. To add to this “low-flow” threat, medullary per-
fusion is notably inefficient; with entering and exiting ves-
sels arranged in parallel, allowing “escape” of oxygen
prior to its arrival at tissues. Known as oxygen countercurrent
exchange, this oddity is a byproduct of sluggish perfusion that
also allows creation of the medullary urea gradient, an
essential ingredient for the urine concentrating process.
Finally, adequacy of perfusion is further challenged by high
oxygen demands of the outer medulla as a result of active
solute transport (thick ascending limb [mTAL] of the
loop of Henle). These challenges result in a very low medul-
lary pO2 even in healthy individuals (10–20 mmHg;
Fig. 17.1), with medullary oxygen needs met through extrac-
tion at the highest levels in the body (79%). Originally
reported in the 1960s, this important phenomenon is referred
to as medullary hypoxia.30 Local paracrine systems (e.g., nitric
oxide and the renin-angiotensin system) mediate the precar-
ious balance between medullary oxygen demand and delivery
to maintain local homeostasis.31 For clinicians, an additional
important consideration is that increased renal blood
flow does not provide a luxurious supply of oxygen to the
medulla, since equivalent increases in glomerular filtration
 17 • Preservation of Renal Function 223

25% Hemorrhage
Reinfusion

Blood pressure (mmHg)

180

90

PO2 80
pH
7.35
73
PCO2
61.7
55 PO2
39.
30 ⬚C 38.7
37⬚C HCO3 33.3
20 OC 06.1
13:30 14:00 14:30 15:00 O2Sat 69.8
Time (h)
Fig. 17.1 An example of renal medullary hypoxia and the adverse effects of hypovolemic shock on medullary perfusion. In a pig model, a renal
medullary oxygen sensor demonstrates medullary hypoxemia at baseline. Blood pressure changes are represented during experimental hemorrhage
(25% blood volume). Exaggerated medullary hypoxia develops during the period of hypoperfusion. Note the close correlation between perfusion
pressure and renal medullary oxygen levels. (With permission from Stafford-Smith M, Grocott HP. Renal medullary hypoxia during experimental cardio-
pulmonary bypass: A pilot study. Perfusion 2005;20:53-58.)

and tubular active transport reabsorption occur, negating
any potential gains.
Direct measurement demonstrates that medullary hypoxia
is exacerbated by common perioperative occurrences such as
dehydration, hemorrhage, low cardiac output, and cardiopul-
monary bypass. In addition to the direct effects of such condi-
tions, related homeostatic fluid retention responses may also
add to renal risk. Interestingly, urine pO2 measurement may
be useful as a sensitive monitor of medullary perfusion32;
one clinical study found that a drop in urine oxygen levels after
cardiac surgery predicted postoperative creatinine rise.33
UNIQUE PHYSIOLOGY/VULNERABLE POPULATIONS
The Immature Kidney
Neonates are born with their adult number of nephrons,
which mature and grow throughout infancy to reach full
function at around the age of 2 years. Glomerular filtration
is reduced because of relatively low systemic blood pressure
and high renal vascular resistance and in early infancy tubu-
lar transport mechanisms are incompletely developed, reduc-
ing the reserve for toxin elimination and increasing the risk of
(sodium and water) fluid retention.34 Finally, as a result of the
immaturity of the tubule in premature infants and newborns,
measures normally used to differentiate pre- from intrarenal
injury may be misleading (i.e., urine osmolality, urine
sodium, and fractional excretion of sodium).
The Kidney During Pregnancy
During pregnancy, hormonal effects contribute to a system-
ically vasodilated state. Renal changes also include dilation
of the urinary collecting system and increases in renal
plasma flow and glomerular filtration (hyperfiltration),
which can be complicated by urine protein wasting. In
the setting of CKD, the demands of pregnancy can over-
whelm renal reserve and increase the risk of accelerated
deterioration of renal function and associated adverse
maternal and fetal outcomes.35 Treatment of hypertension,
proteinuria, and nephrotic syndrome is particularly impor-
tant in the management of parturients.
Geriatrics and Renal Function
Beyond the age of 50 years, kidney parenchyma becomes
smaller mainly because of accelerated cortical loss and the
crowding effects of benign cysts.36 On a microscopic level,
there are fewer functional nephrons and nephrosclerosis
is more prevalent. Some functional compensation is
achieved through hypertrophy of remaining nephrons,
but averaged over cohorts, glomerular filtration falls accord-
ingly, declining by roughly 0.75 mL/min per year after the
age of 30 years. Therefore, even in the absence of renal dis-
ease geriatric patients commonly meet CKD criteria, and
because of limited reserve are at a higher risk of sustaining
AKI to levels requiring dialysis.37
CARDIAC SURGERY-ASSOCIATED AKI AS A
GENERALIZABLE MODEL FOR PERIOPERATIVE AKI
Cardiac surgery is the most common source of postoperative
AKI in the United States38, occurring following up to 30% of
such procedures.39 Observations in postcardiac surgery AKI
cohorts commonly generalize to other surgical settings.
Therefore, postcardiac surgery AKI (often referred to as
CS-AKI) is a prevalent perioperative AKI research model
224 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

and often the source of evidence to support or to refute
putative renal preservation strategies.
Notably, although the physiologic renal trespass of major
surgery is well represented by cardiac surgery, elements
such as aortic cross clamping and cardiopulmonary bypass
differentiate cardiovascular from most other major surgeries.
Although the immediate ischemic consequences of cross
clamping on the kidney require little explanation, the complex
effects on renal perfusion of cardiopulmonary bypass (and
other circulatory assist devices) are reviewed elsewhere.40–42
Diagnosis of Acute Kidney Stress/
Injury
Lack of consensus on a “gold standard” definition for AKI
previously hampered progress in its research.43 One review
from the mid-1990s identified 28 perioperative studies, with
no two using the same criteria.2 More recently, consensus
AKI criteria have allowed for more uniform reporting and
comparison of outcomes. Furthermore, the search for
reliable early biomarkers that enable prompt AKI detection
earlier than the measurement of serum creatinine accumu-
lation alone is a continuously evolving field.
CURRENT CONSENSUS DIAGNOSTIC CRITERIA FOR
AKI AND RELATED ADVERSE OUTCOMES
Consensus criteria have been developed to facilitate AKI diag-
nosis, four of which are worthy of mention (Table 17.1).
Limited to surgical populations, the Society of Thoracic
Surgeons postoperative AKI criteria include either new
need for dialysis or a serum creatinine rise of at least
a 50% from baseline to exceed 2 mg/dL (177 μmol/L).44
However, three more recently developed (related) definitions
are the most commonly used to contrast nonsurgical and
surgical studies. These include: (1) RIFLE (Risk, Injury, Fail-
ure, Loss, End-stage kidney disease), (2) AKIN (Acute Kidney
Injury Network), and (3) KDIGO (Kidney Disease: Improving
Global Outcomes) criteria.45–48 The most current of these
(KDIGO) defines AKI as either (1) a serum creatinine rise
0.3 mg/dL ( 26.5 μmol/L) within a 48-hour period; or
(2) a 50% serum creatinine rise within the prior 7 days;
or (3) urine volume <0.5 mL/kg/h for 6 hours.48 Each defi-
nition uses serum creatinine and urine output criteria to
define AKI. Although these consensus criteria have brought
stability to the definition of AKI, they are not without their
problems, as discussed later.
Notably, all of the above-mentioned consensus definitions
use changes in serum creatinine to reflect changes in glo-
merular filtration rate (GFR) and overall kidney function.
One inconvenience of this approach is the nonlinear rela-
tionship between changes in GFR and serum creatinine.
Additionally, serum creatinine does not generally reliably
reflect CKD until GFR rates fall below 50 mL/min, hence
serum creatinine may be “normal” in patients even with
important underlying chronic renal impairment. Following
surgery, creatinine accumulation requires up to 48 hours to
confirm AKI and a rise that reflects significant kidney injury
may occur while levels remain within the “normal” range
(e.g., 50% increase). These factors represent sources of sig-
nificant delay in the implementation of kidney protective
strategies that confound study of their effectiveness. Fur-
thermore, small changes in serum creatinine that never
meet the threshold for AKI criteria are still associated with
increased mortality and despite their subthreshold degree
probably also reflect important AKI episodes.7,49
Controversial (and often also difficult to measure perio-
peratively) is the significance of urine output as a diagnostic

Table 17.1 Consensus acute kidney injury definitions and classification systems.45–48
Serum Creatinine Urine Output

RIFLE CRITERIA
Risk Increase in SCr to 1.5 times baseline or decrease in GFR by >25% within 7 days < 0.5 mL/kg/h for >6 h
Injury Increase in SCr to >2 times baseline or decrease in GFR by >50% within 7 days < 0.5 mL/kg/h for >12 h
Increase in SCr to >3 times baseline or decrease in GFR by >75% within 7 days or increase in SCr to < 0.3 mL/kg/h for >24 h or anuria
Failure
4 mg/dL with an acute rise of 0.5 mg/dL for 12 h
Loss Complete loss of kidney function requiring dialysis for >4 weeks
ESRD Complete loss of kidney function requiring dialysis for >3 months

AKIN CRITERIA
Stage 1 Increase in SCr by 0.3 mg/dL or increase in SCr to 1.5 times baseline within 48 h < 0.5 mL/kg/h for 6 h
Stage 2 Increase in SCr to >2 times baseline within 48 h < 0.5 mL/kg/h for  12 h
Increase in SCr to >3 times baseline within 48 h or increase in SCr to 4 mg/dL with a rise of <0.3 mL/kg/h for 24 h or anuria
Stage 3
0.5 mg/dL within 24 h or initiation of dialysis for 12 h

KDIGO CRITERIA
Stage 1 Increase in SCr by 0.3 mg/dL within 48 h or increase in SCr to 1.5 times baseline within 7 days <0.5 mL/kg/h for  6 h
Stage 2 Increase in SCr to >2 times baseline within 7 days <0.5 mL/kg/h for 12 h
Increase in SCr to >3 times baseline within 7 days or increase in SCr to 4 mg/dL or initiation of <0.3 mL/kg/h for 24 h or anuria
Stage 3
dialysis for 12 h

AKIN, Acute kidney injury network; ESRD, end-stage renal disease; GFR, glomerular filtration rate; KDIGO, kidney disease improving global outcomes; RIFLE, risk,
injury, failure, loss, end-stage kidney disease; SCr, serum creatinine.

biomarker of postoperative AKI. This contrasts with ICU
patients where urine output measurements add explanatory
power to AKI predictive outcome models: inclusion of oli-
guria increases AKI incidence50 and isolated oliguria (i.e.,
exclusive of serum creatinine rise criteria) is associated with
higher ICU mortality50 and 1-year mortality or need for
renal replacement therapy (RRT).51 Furthermore, critically
ill patients meeting both oliguria and creatinine criteria are
at greatest risk.51 However, the value of immediate periop-
erative oliguria to define AKI in surgical populations is less
clear. Alpert and colleagues documented oliguria in 137
aortic surgery patients given either crystalloid solution,
mannitol, furosemide, or no intervention when urinary flow
dropped below 0.125mL/kg/h.52 These authors from the
1980s found no correlation between intraoperative mean
urinary output or lowest hourly urinary output and subse-
quent AKI development by change from pre to peak postop-
erative levels of serum creatinine. The findings of this study
are consistent with data from several other more recent
studies that suggest that oliguria in the immediate perioper-
ative period is not as useful as a marker of AKI. For example,
in a retrospective study of cardiac surgery patients, the addi-
tion of urine output to serum creatinine criteria (AKIN) con-
siderably increased AKI incidence but added no prognostic
value for either in-hospital mortality or new requirement for
RRT.53 In contrast, another prospective study of cardiac
surgical patients found meeting either creatinine-only or
oliguria-only (KDIGO) criteria was related to equally ele-
vated long-term mortality risk when compared with
patients without AKI. Furthermore, patients meeting both
creatinine and oliguria criteria in this study had additional
long-term mortality risk above that of the patients meeting
only one such criterion.54
Notably, perioperative oliguria is typical during unevent-
ful surgical procedures and simply represents an appropriate
homeostatic response to perioperative fasting and the nor-
mal response to anesthesia (i.e., acute renal “success”) as
opposed to a pathologic response reflecting renal injury.41
In the absence of consensus, it is recommended that urine
output criteria to diagnose AKI should be used cautiously
in the immediate postsurgical setting, in contrast to nonsur-
gical and/or chronic critically ill patient populations. In
addition, irrespective of surgical status, it appears that
patients meeting both urine output and serum creatinine
criteria are at highest risk of poor outcomes.
Loss of
function
Creatinine
cystatinC,
GFR
Stress
Normal TIMP-2*
IGFBP7
Damage
NGAL, KIM-1
Fig. 17.2 Schematic demonstrating how kidney biomarkers can be used to diagnose stages of kidney stress/injury/failure. Kidney protective strategies
can be used to decrease progression to next stage of kidney failure. (Biomarkers for each stage listed in small font.) GFR, Glomerular filtration rate; IGFBP7,
insulin like growth factor binding protein 7; KIM-1, kidney injury molecule 1; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of
metalloproteinase 2.
17 • Preservation of Renal Function 225
Long-term kidney outcomes are important and include
persistent CKD, temporary or chronic need for dialysis,
and death. Although consensus AKI criteria have improved
the ability of clinicians to report and to compare acute renal
events and their short-term consequences across popula-
tions, these do not reflect important long-term kidney out-
comes.55 As a long-term measure of renal outcome, Major
Adverse Kidney Events (MAKE) reflect chronic outcomes
that may demonstrate improvements with effective reno-
protective interventions (e.g., benefits seen in successful
phase III renoprotection clinical trials).55 The MAKE metric
is a composite of persistent renal dysfunction (25% or
greater decline in eGFR), new hemodialysis, and death to
identify poor outcomes following AKI.55 It is typically
reported at 30 (MAKE30), 60 (MAKE60), or 90 (MAKE90)
days after AKI diagnosis.55. MAKE90 is particularly rele-
vant because this MAKE version aligns with the 90-day cri-
teria typically used in other CKD diagnostic criteria. The
MAKE composite is important for clinicians to link AKI with
chronic morbidities and for the assessment of meaningful
outcomes in AKI intervention trials.55
FUTURE (EARLY) AKI BIOMARKERS
Several putative biomarkers are postulated to have better
sensitivity and specificity than serum creatinine for detect-
ing early kidney stress and AKI; however, these have yet to
be widely adopted in the clinical setting. Although still
requiring validation, these biomarkers have the advantage
of both detecting AKI at earlier time points and discriminat-
ing types and degrees of injury as outlined later. AKI
biomarkers may be useful to reflect progress along a contin-
uum towards renal injury. In this continuum, an acute pre-
injury kidney stress phase typically precedes renal structural
damage which proceeds overt functional loss.56 Thus, AKI
biomarkers can be divided into those that detect: (1) kidney
stress, (2) impaired function without structural damage, (3)
structural damage with intact function, and (4) structural
damage with loss of function.57 The framework for how
these biomarkers could be useful to detect the phase of renal
injury in hopes of guiding more specific interventions (e.g.,
preventing overt AKI, limiting kidney damage, etc.) is
shown in Fig. 17.2. Furthermore, studies have indicated
that such early AKI biomarkers could be useful for long-
term risk stratification following AKI. Nonetheless, to date
Loss of
function Kidney Chronic
and failure kidney
damage Dialysis/death
creatinine, disease
Creatinine * GFR GFR
NGAL/KIM-1
226 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
serum creatinine remains a reliable and readily available
gold standard test to diagnose AKI. In this context, some
newer biomarkers (e.g., TIMP-2 * IGFBP7) may have poten-
tial to predict AKI and allow clinicians to intervene earlier.
Further validation is needed for most of these potential clin-
ical tools, with the hope that in the future potential bio-
marker profiles may enable more precise risk stratification
and earlier intervention of patients with AKI.
Measures of Kidney Stress
Insulin-like growth factor-binding protein 7 (IGFBP7) and
tissue inhibitor of metalloproteinases-2 (TIMP-2) are kidney
stress biomarkers. Both substances arrest the G1 phase of the
cell cycle and levels of each can be measured in the urine.56
These kidney stress biomarkers were identified as the top
performing among a collection of related biomarkers for
detecting AKI in a variety of high-risk critically ill patients
including those with sepsis, shock, major surgery, and
trauma.58 Furthermore, a urinary TIMP-2 * IGFBP7 mea-
surement greater than 0.3 is a strong predictor of AKI in
critically ill patients.59 Several prospective analyses and a
recent meta-analysis of cardiac surgery studies also support
TIMP2 * IGFBP7 levels measured several hours after cardiac
surgery as predictive of subsequent postoperative AKI.60–64
Finally, relative to long-term outcomes, TIMP-2 * IGFBP7
levels >2.0 at ICU admission are associated with death or
dialysis at 9 months (HR, 2.16; CI 1.32–3.53).65
Measures of Kidney Function
Beyond serum creatinine, steady-state cystatin C level is an
alternative biomarker that reflects changes in kidney filtra-
tion function. Notably, the use of cystatin C does not appear
to add significantly more information regarding AKI com-
pared with serum creatinine. Cystatin C is a cysteine prote-
ase inhibitor protein produced by all nucleated cells,66 and is
freely filtered by the glomerulus and completely reabsorbed
in renal tubules. In a prospective observational study of sep-
tic ICU patients, urinary cystatin C levels were indepen-
dently associated with sepsis, AKI, and mortality within
30 days.67 However, in a large meta-analysis, postoperative
urinary Cystatin C poorly discriminated for cardiac surgery
(CS) of AKI of any stage (composite AUC 0.63 [0.37–0.89];
diagnosis by AKIN), but plasma cystatin C was modestly
more useful (composite AUC 0.69 [0.63–0.74]; diagnosis
by RIFLE, AKIN, KDIGO).68
Measures of Kidney Tubular Damage
The three most studied major biomarkers that indicate renal
damage are: (1) neutrophil gelatinase-associated lipocalin
(NGAL), (2) kidney injury molecule-1 (KIM-1), and (3)
interleukin-18 (IL-18).
NGAL is a small protein with notable upregulation follow-
ing acute kidney tubular injury,69 that can be measured
either in the urine or plasma. However, in numerous studies
both urine and plasma NGAL have modest predictive value
for subsequent traditionally diagnosed AKI in critically ill
patients. A meta-analysis by Ho et al. also demonstrated
modest discrimination for AKI after cardiac surgery for
urine NGAL (composite AUC 0.72 [0.66–0.79]) and plasma
NGAL (composite AUC 0.71 [0.64–0.77]).68 Both urine and
plasma NGAL have shown only a modest ability to predict
AKI severity, renal recovery, and long-term outcomes.70–72
Expression and release of KIM-1 is induced in the proxi-
mal tubule after renal injury.73 A meta-analysis revealed
a sensitivity of 74% and specificity of 86% for urinary
KIM-1 to diagnose AKI.74 Blood KIM-1 levels are elevated
in patients with AKI and CKD of various etiologies. Urine
levels of KIM-1 perform similarly to NGAL in discrimination
for CS-AKI (composite AUC 0.72 [0.59–0.84]). Measure-
ment of KIM-1 has not been widely adopted in practice.
IL-18 is a proinflammatory cytokine involved in the evo-
lution of tubular ischemia75. As a biomarker for detecting
CS-AKI, urine levels of IL-18 perform similarly to both
KIM-1 and NGAL.68,76,77 In ICU patients, urinary IL-18
levels may be useful for the early diagnosis of AKI and
may predict mortality risk in patients with acute respiratory
distress syndrome (ARDS).78 In a broader ICU population,
urinary IL-18 was not reliable in predicting subsequent
AKI but was associated with poor clinical outcomes such
as death and dialysis.79 Urinary IL-18 has not been widely
adopted in clinical practice.
Mechanisms of Surgery-Related
Acute Renal Injury
The sources of postoperative renal insult are extensively
reviewed elsewhere.6 Two primary mechanisms that con-
tribute to perioperative AKI are ischemia-reperfusion and
nephrotoxic effects, with three notable sources of insult
common to many surgical procedures where postoperative
renal dysfunction is prevalent: hypoperfusion, inflamma-
tion, and atheroembolism. Several less common sources of
renal insult may contribute in selected patients (e.g.,
rhabdomyolysis, specific drug-related, etc.).
ISCHEMIA/REPERFUSION
Abnormalities of renal perfusion that exceed the autoregula-
tory reserve of the renal circulation, such as cardiopulmonary
bypass,30 are believed to be a major source of perioperative
ischemia-reperfusion injury. Other conditions, including low
output states, hypovolemic shock (Fig. 17.1), vasoconstrictor
use, and circulatory arrest, may all contribute to the renal
ischemic burden of specific surgical procedures.15,20,24 As
described earlier, the normally low medullary pO2 (10–
20 mmHg) makes this tissue particularly vulnerable to hypo-
perfusion.80 Paracrine systems, such as the renin-angiotensin
system and nitric oxide synthase, are key to regulation of renal
blood flow and modulation of microvascular function and oxy-
gen delivery in the renal medulla.31 Autonomic influences are
also important, with the alpha-1 adrenergic receptor-mediated
vasoconstriction and alpha-2 adrenergic receptor-mediated
vasodilation contributing to modulation of renal perfusion.
Lastly, it is increasingly recognized that venous congestion
caused by elevated central venous pressure may contribute
to postsurgical AKI pathophysiology.81
INFLAMMATORY
Both systemically and locally in the kidney, surgery provides
a consistent trigger for the generation of proinflammatory
cytokines (e.g., tumor necrosis factor alpha [TNFα] and
 17 • Preservation of Renal Function 227

interleukin 6 [IL-6]) and an inflammatory response caused

by the disruption of tissues and the potential for periopera-
tive endotoxemia.82–85 Preexisting infection may further
predispose surgical patients to postoperative renal dysfunc-
tion.86 Other postoperative factors, such as infectious and
septic complications, transfusion, and interventions such
as cardiopulmonary bypass, contribute to the generation
of cytokines that have major effects on the renal microcircu-
lation and may lead to tubular dysfunction through a com-
mon path of apoptosis.87

EMBOLIC
Showers of emboli are common during certain surgical pro-
cedures. Although some types of emboli do not appear to
have an important role in postoperative AKI (e.g., air) others
are significant contributors to renal injury. Atheroembolism
is common during some surgical procedures, particularly
those involving operative aortic manipulation, and is highly
associated with AKI.88 The strong association of intra-aortic
balloon counterpulsation with AKI may also be related to
the dislodgement of aortic plaque.89 Thromboembolism
and infectious emboli from endocarditis may also contribute
to renal insult (Figs. 17.3 and 17.4). Atheroembolism can
produce all degrees of renal injury, ranging from the
obstruction of major renal vessels from large fragments of
plaque90 to the occlusion of multiple small renal vessels
by cholesterol microcrystals.91

PIGMENT (HEMOGLOBIN AND MYOGLOBIN)

Hemoglobinuria occurs when intravascular hemolysis releases
sufficient hemoglobin to exceed the adsorptive capacity of
circulating haptoglobin and renal tubular reuptake mecha-
nisms. Only approximately 25% of circulating free hemoglobin
is in a form readily filtered by the kidney. Myoglobinuria occurs
with muscle cell necrosis in conditions such as ischemic limb
reperfusion and major trauma (crush syndrome).93 The
mechanisms underlying myoglobin- and hemoglobin-related
AKI are similar. Deterioration in kidney function comes from
the combined effects of renal vasoconstriction, tubular obstruc-
tion by casts, and direct cytotoxicity.94 The nitric oxide scav-
enging potential of these pigments contributes to renal
vasoconstriction.
Fig. 17.3 A gross kidney specimen demonstrates the wedge-shaped
pattern typical of a renal infarct. The organization of the renal vascu-
lature means that embolic arterial obstruction is poorly compensated
for by collateral flow. (from Robbins and Cotran Atlas of Pathology, 2014.
3rd edition. 2014. Elsevier.)
Fig. 17.4 Angiography (30 ) demonstrates embolic occlusion of an
interlobular arterial in a patient with subacute bacterial endocarditis.
Note the total obstruction and complete absence of collateral flow.
(With permission from Bookstein JJ, Clark RL. Renal Microvascular Disease:
Angiographic-Microangiographic Correlates. Boston: Little, Brown; 1980.)
NEPHROTOXINS
Several well-known nephrotoxins are relevant to the periop-
erative period. Aminoglycoside antibiotics have potent neph-
rotoxic effects.95 Non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and indomethacin, are nephro-
toxic, and cause renal vasoconstriction through inhibition
of endogenous locally synthesized vasodilator prostaglan-
dins.96 Perioperative treatment with cyclosporin as part of
transplant surgery can have acute effects on renal function
in addition to the well-known long-term adverse effects.97
Although more controversial, intravenous contrast has
been associated with AKI. With the use of less toxic con-
trast agents and lower dosing strategies, evidence suggests
that use of intravenous contrast for diagnostic imaging
studies (i.e., computed tomography [CT] scans) is not asso-
ciated with AKI.98 However, it is still unclear whether
higher doses of intravenous contrast agents (i.e., cardiac
catheterization, interventional radiology procedures) cause
contrast-induced nephropathy. The judicious use of intra-
venous contrast agents in these settings, particularly in
those with preexisting renal dysfunction, is still
warranted.99
228 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Renal Preservation: Best Practices
There is good evidence to support the role of perioperative
clinical management decisions in affecting important renal
outcomes. A vast majority of these best practices involve
kidney insult reduction or avoidance at all stages through-
out the perioperative period. Notably, there is little evidence
to support significant value in therapeutic interventions
to accelerate recovery once AKI has occurred (short of tem-
porary RRT); rather management of patients with estab-
lished kidney injury involves mostly minimizing further
AKI to facilitate normal recovery. Potential interventions
and best practices are outlined later and discussed by time
period (preoperative, intraoperative and postoperative),
and topics are also organized for practical purposes into
three tables by their value (Table 17.2: recommended prac-
tices to avoid; Table 17.3: limited value probably no harm;
and Table 17.4: recommended practices).
Individualized for specific patient level concerns, the con-
text to apply this outlined “optimal renal practices”
approach to clinical management can be gained from con-
sideration of renal risk stratification, as outlined elsewhere
in this textbook3,13–18,20–29,100 However, AKI prediction
beyond knowledge of the risk associated with specific proce-
dures, and the greater likelihood of need for dialysis with
chronic kidney disease is notoriously poor, particularly
at pre-identifying the victim of severe AKI. This inability
to pre-identify at-risk patients with confidence further high-
lights the importance of developing a safe “renal best prac-
tices” approach to reduce the overall burden of AKI as part
of routine patient management.
PREOPERATIVE MANAGEMENT AND PLANNING
Renal preservation strategies with the goal of avoiding, pre-
venting, or attenuating renal insult before it occurs include
Table 17.2 Practices recommended to avoid.
CLASS III: RISK > BENEFIT
Preoperative/Procedural Planning
Level A
(consistent
evidence)
Level B (some • Sodium bicarbonate or oral
evidence) acetylcysteine prior to contrast
exposure
• Coronary angiography within one
day prior to CPB
Level C (limited
evidence)
AKI, Acute kidney injury; COX, cyclooxygenase; CPB, cardiopulmonary bypass.
the use of preoperative risk stratification to influence proce-
dure selection, procedure modification, and management of
chronic medication administration. Procedure modifica-
tions with lowered AKI risk have already been part of the
justification for transitions in routine care such as stent
grafting (versus open surgical procedures) to treat aortic
aneurysmal disease. Potential future tools also include pre-
operative genetic screening to identify subgroups at high
renal risk. The following section focuses on procedural
choice, nonpharmacologic interventions, and pharmaco-
logic agents.
Procedural Selection
Recent surgical innovations have embraced the philosophy
that fewer invasive procedures requiring smaller incisions
and less physiologic disturbance can safely achieve surgical
goals and may reduce postoperative organ dysfunction and
improve overall outcome. Examples include the use of stent-
graft technology, videoscopic-assisted procedures, avoid-
ance or modification of cardiopulmonary bypass, and
reduced aortic manipulation. Although some innovations
appear to confer renal benefit, this is not the case for all of
these minimally invasive procedure modifications.
Cardiac Surgery Modifications
Modifications of coronary artery bypass graft (CABG) sur-
gery have been studied extensively.101–111 Although the
use of extracorporeal circulation during cardiac surgery
has been speculated as a major pathophysiologic driver of
postoperative AKI, the value of off-pump procedures in stud-
ies has been inconsistent in mitigating renal risk. One rea-
son for this could be that comparisons of off-pump and
on-pump approaches may be limited by baseline imbalance
between groups. In particular, patients receiving off-pump
procedures are often healthier at baseline, with reduced
preoperative renal risk. Thus, stratification of patients
by preoperative renal risk in such studies may improve
Intraoperative Postoperative
• Aprotonin for cardiac surgery • Hydroxyethyl starch solutions for
volume expansion in critically ill patients
• Prolonged CPB duration • COX-2 inhibitor therapy
• Mannitol therapy for kidney • Loop diuretic therapy for treatment of AKI
protection except for kidney in cardiac surgery patients
transplant • Nesiritide in heart failure
• Sodium bicarbonate in cardiac • Intensive insulin control (<110 mg/dL)
surgery
• Restrictive (net zero balance) fluid
regimen
• Prolonged intraoperative
hypotension (non-CPB)
• Liberal erythrocyte transfusion
• Loop diuretics for AKI prevention
• Maintaining CPB perfusion pressure
>60 mmHg
• Hyperthermia on rewarming
 17 • Preservation of Renal Function 229

Table 17.3 Practices with limited or no benefit but minimal harm.

Preoperative/Procedural Planning Intraoperative Postoperative
Level A (consistent • Off-pump CABG for patients with normal renal • IGF-1 • Low-dose dopamine
evidence) function • Steroids infusion
• Remote ischemic preconditioning in all cardiac
surgery patients
• Statin therapy
• Beta blockers
Level B (some • Dopexamine infusion • Vasopressin as first-line
evidence) • Delaying elective surgery after contrast • N-acetylcysteine therapy vasopressor
exposure • Transfusion of RBC with low • Calcium channel blocker
storage age therapy
• ANP • ANP
• Nesiritide
• Aminocaproic acid for cardiac
surgery
Level C (limited • PortAccess mitral valve surgery • Vasopressin as preferred • RAS blockers during AKI
evidence) • Stent-graft AAA repair vasoconstrictor
• Withholding RAS blocker therapy • PGE1, PGI2 therapy
• Withholding preoperative chronic loop diuretic • Pulsatile flow on CPB
• TEVAR vs. open approach

AAA, Abdominal aortic aneurysm; AKI, acute kidney injury; ANP, atrial natriuretic peptide; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; IGF,
insulin-like growth factor; PGE1, prostaglandin E1; PGI2, prostaglandin I2/prostacyclin; RAS, renin-angiotensin system; RBC, red blood cell; TEVAR, thoracic
endovascular aortic aneurysm repair.

Table 17.4 Practices recommended to implement.

CLASS I: BENEFIT >> RISK
Preoperative/Procedural Planning Intraoperative Postoperative
Level A • TAVR by trans-femoral approach if • Balanced crystalloids for
(consistent technically feasible (vs. trans-apical) resuscitation (vs. 0.9% normal
evidence) saline)
• Norepinephrine as first-line
vasopressor
Level B (some • Remote ischemic preconditioning prior • Goal-directed perfusion therapies • KDIGO kidney protective
evidence) to cardiac surgery for high risk patients • Serum glucose target levels of 150-200 mg/ bundle
• Epidural analgesia combined with dL • Serum glucose target levels of
general anesthesia • Alpha-2 adrenergic agonist agents <180 mg/dL
• Balanced crystalloid for fluid choice (vs. • Alpha-2 adrenergic agonist
0.9% normal saline) agents
• Mannitol administration prior to cross- • Early RRT in post-surgical
clamp removal during kidney patients with stage II AKI
transplantation
• Nitric oxide during valve surgery
• Leukocyte-depletion of transfused
erythrocytes
Level C • Off pump CABG in CKD stage 4 • Atheroma avoidance during cardiac surgery • Angiotensin II for vasodilatory
(limited • Mini-thoracotomy valve surgery in using epiaortic scanning shock
evidence) patients with CKD • Fenoldopam • Restart aspirin within 48 h of
CABG surgery

AKI, Acute kidney injury; CABG, coronary artery bypass graft; CKD, chronic kidney disease; KDIGO, kidney disease improving global outcomes; RRT, renal replacement
therapy; TAVR, transcatheter aortic valve repair.

interpretability. Nonetheless, a meta-analysis of several ran-
domized trials comparing on-pump versus off-pump CABG
procedures did not demonstrate a protective effect with
regard to risk of postoperative RRT.112 However, some more
recent studies report a reduction in AKI rate with off-pump
procedures.113,114 In particular, studies involving the sub-
group of patients with preoperative CKD stage 4, but not
those with CKD stage 5 (i.e., end-stage renal disease),
may benefit from off-pump procedures with respect to both
mortality and need for postoperative RRT.115,116
Reduction of Tissue Trauma. Similar to the potential
value of avoiding extracorporeal circulation, avoidance of
tissue trauma from large incisions has been proposed as a
strategy to reduce postoperative renal dysfunction. Hence,
minimally invasive surgical approaches that use smaller
incisions and alternative catheter-based circulatory support
strategies that avoid major tissue disturbance (such as
median sternotomy) have been studied as methods to
reduce inflammatory renal insult and AKI.
230 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
SMALLER INCISIONS: MINI-THORACOTOMY/MINI-STERNOTOMY. Both
mitral and aortic valve procedures (i.e., valve repair or replace-
ment) can be performed using peripheral catheter-based
cardiopulmonary bypass (CPB) and a mini-thoracotomy or
mini-sternotomy approach in place of the traditional median
sternotomy. With respect to AKI, although initial data
suggested a benefit with mini-sternotomy in these proce-
dures,117,118 some subsequent retrospective studies have
not confirmed these findings.119,120 Similar to off-pump CABG
procedures, the use of minimally invasive valve procedures
may preferentially provide benefit to patients with CKD prior
to surgery.121
ENDOVASCULAR APPROACHES. For major aortic procedures,
endovascular stent graft rather than surgical approaches
to repair represent another minimally-invasive strategy to
reduce tissue trauma. Potential advantages for the kidney
of endovascular stenting of abdominal aortic aneurysm
(EVAR) have been well studied and yield conflicting results.
A number of well-designed retrospective studies support a
reduced incidence of postoperative AKI with EVAR com-
pared with an open surgical approach.122,123 However, this
does not appear to translate into any benefit with respect to
requirement for postoperative RRT.124 As with retrospec-
tive studies of off-pump cardiac surgical procedures, identi-
fying renal benefit with EVAR is complicated by baseline
patient characteristics. Thus, while the use of endovascular
approaches for aortic aneurysm repair may provide a benefit
with respect to AKI, selection of this approach in patients
with high-risk aortic lesions should not be based solely on
reducing renal risk.
Fewer studies have compared open surgical repair and
thoracic endovascular aortic aneurysm repair (TEVAR) rel-
ative to postoperative AKI. In the largest available retro-
spective study to date, there was no difference in the
renal complication rate between TEVAR and an open surgi-
cal approach.125 However, several smaller studies have
reported reduced rates of postoperative renal injury with
either endovascular repair126 or a hybrid approach (aortic
debranching and endovascular repair).127 In patients with
aortic arch aneurysmal disease, several studies have failed
to show a difference in AKI incidence or requirement for
new RRT among the various options.128,129
For patients with aortic valve stenosis, transcatheter aortic
valve replacement (TAVR) is increasingly used. While early
studies were limited to high surgical-risk patients, TAVR is
now an alternative to surgical aortic valve replacement
(SAVR) for intermediate surgical-risk patients.130 In a large
trial of randomized intermediate-risk patients, investigators
noted significantly lower AKI rates with TAVR compared
with SAVR procedures.131 Other reports suggest that differ-
ential renal risk among patients undergoing TAVR are
related to both the TAVR procedural characteristics and pre-
operative patient characteristics. In a meta-analysis among
TAVR approaches, transapical TAVR has been associated
with increased risk for postoperative AKI compared with
the more common transfemoral approach.132 This result
may be, at least partially, an artifact of selection bias: transa-
pical TAVR is often used in patients with worse peripheral
vascular disease and unfavorable femoral artery anatomy,
a factor known to be associated with elevated renal risk.
Notably, postoperative mortality following SAVR, but not
TAVR, are directly related to baseline renal function.133
In summary, when considering renal risk, the current lit-
erature supports TAVR as the favorable approach for aortic
valve replacement for aortic stenosis, particularly when a
transfemoral approach is used. With regard to aortocoron-
ary bypass procedures, off-pump procedures may provide
benefit for patients with CKD.
Neuraxial Analgesia
Relative to procedure-planning, combined neuraxial and
general anesthetics have been postulated to reduce the risk
of postoperative AKI. Beyond improved analgesia, a sup-
porting rationale comes from the potential for epidural
analgesia to block renal autonomic alpha adrenergic inner-
vation and the systemic adrenergic stress-response to sur-
gery. In a randomized study of cardiac surgery patients,
thoracic epidural analgesia (TEA), in combination with
general anesthesia (GA), reduced AKI risk (unadjusted odds
ratio [OR] for GA versus GA + TEA 3.69, 95% confidence
interval [CI] 1.34–10.2, P ¼ 0.016).134 Other retrospective
studies in cohorts of thoracotomy patients report similar kid-
ney protective benefits with epidural analgesia.
When considering the potential value of epidural anes-
thesia, renal benefits must be evaluated relative to other
concerns (e.g., risk of spinal hematoma, intraoperative
hypotension). Available studies support the potential
renal benefit of epidural analgesia in cardiac and thoracic
procedures, but further investigations are needed to
determine whether epidural analgesia is helpful in other
settings.
NONPHARMACOLOGIC INTERVENTIONS
Procedure Delay Versus Avoidance of Contrast
Agents. Historically, iodinated contrast exposure has been
a major source of in-hospital kidney injury; however, with
the advent of less toxic contrast agents and lower dosing
strategies, this concept has more recently come under scru-
tiny and is currently debated for its significance as an AKI
risk factor. In emergency room patients undergoing diag-
nostic computed tomography (CT) scans, a meta-analysis
and a large retrospective propensity-matched cohort analy-
sis found no association with contrast administration and
AKI incidence (Fig. 17.5).135,136 However, these findings
may not be transferable to patients receiving high contrast
loads for angiography procedures such as coronary artery
catheterization or endovascular procedures.
A meta-analysis of retrospective cardiac surgery studies
relating renal risk to pre contrast dye exposure including
more than 11,500 procedures with cardiopulmonary
bypass found lower AKI rates when the time between sur-
gery and coronary angiography was more than 1 day,
but little added “benefit” when surgery was more than
3 days after the contrast exposure.137 A more recent retro-
spective study suggests there is increased risk when surgery
is separated from coronary angiography by less than
7 days.138
In summary, administration of limited doses of newer
contrast agents for diagnostic CT scans appears to be rela-
tively AKI risk-free; however, evidence coming mostly from
retrospective study of cohorts of cardiac surgery patients
suggests caution should be exercised in giving large contrast
loads during angiography and ideally such exposures should
 17 • Preservation of Renal Function 231

Acute Kidney Injury

Studies Estimate (95% C.I) #AKI/Total CECT #AKI/Total non-CECT

Hinson 2017 1.052 (0.938, 1.180) 766/7201 559/5499

Ehrlich 2016 0.587 (0.182, 1.896) 5/157 7/132
Hellar 2016 0.889 (0.702, 1.126) 598/6954 87/132
Gao 2015 1.225 (0.918, 1.634) 70/474 235/1896
Hemment 2015 1.184 (0.695, 2.016) 36/326 26/274
Paliwal 2015 0.236 (0.077, 0.724) 5/203 9/93
Sonhaye 2015 1.928 (0.941, 3.953) 21/620 12/672
Alsafi 2014 2.787 (1.608, 4.830) 62/677 17/487
McDonald 2014 0.944 (0.834, 1.068) 515/10673 544/10673
Davenport 2013 0.960 (0.869, 1.060) 835/10121 867/10121
Kidoh 2013 1.111 (0.556, 2.222) 13/143 27/327
Cely 2012 0.642 (0.280, 1.472) 14/53 19/53
Murakami 2012 0.978 (0.680, 1.407) 57/938 68/1096
Silcock 2012 1.000 (0.445, 2.247) 13/132 13/132
Sinert 2012 0.613 (0.441, 0.852) 44/773 265/2956
Aulicky 2010 0.776 (0.181, 3.332) 5/164 3/77
McGillicuddy 2010 1.209 (0.476, 3.073) 18/822 6/330
Lima 2010 0.450 (0.269, 0.755) 28/575 35/343
Ng 2010 1.000 (0.443, 2.258) 14/81 14/81
Bansal 2009 1.343 (0.459, 3.932) 8/65 7/74
Bruce 2009 0.728 (0.622, 0.854) 252/5790 440/7484
Oleinik 2009 0.581 (0.304, 1.111) 21/348 19/191
Langner 2008 0.552 (0.208, 1.466) 7/100 12/100
Tremblay 2005 0.204 (0.039, 1.069) 2/56 6/39
Heller 1991 1.917 (1.045, 3.516) 35/479 16/405
Cramer 1985 1.623 (0.359, 7.340) 4/193 3/233

Overall (1^2=6513%, P<0.001) 0.938 (0.825,1.065) 3448/48118 3316/44677

0.04 0.08 0.19 0.39 0.78 1.94 3.58 7.34

Mortality
Odds Ratio (log scale)

Fig. 17.5 Forrest plot from meta-analysis demonstrating that contrast exposure for diagnostic imaging is not associated with acute kidney injury. AKI,
Acute kidney injury; CECT, contrast-enhanced computed tomography. (With permission from Aycock RD, Westafer LM, Boxen JL, et al. Acute kidney injury
after computed tomography: A meta-analysis. Ann Emerg Med 2018;71:44–53 e4.)

be separated from surgery by at least 24 hours. Of note, if mortality).143 Thus, although RIPC does not appear to
contrast exposure does occur, the literature suggests that improve early (less than 90 days) mortality and renal out-
sodium bicarbonate and oral acetylcysteine do not appear comes, this practice appears safe and is worthy of more
effective at preventing contrast nephropathy.139 study for high-risk patients.

Ischemic Preconditioning Reflex. A brief exposure to Pharmacologic Agents

ischemia attenuates injury resulting from subsequent ische-
mic episodes in many organs; this reflex phenomenon,
known as ischemic preconditioning, is present in the kidney.
In preclinical studies in rats, Cochrane and colleagues
observed that 2 minutes of renal ischemia, or three such epi-
sodes separated by 3 minutes of reperfusion, protects the
kidney from subsequent prolonged (45 minutes) renal ische-
mia.140 An example of remote ischemic preconditioning
(RIPC) involves occluding the blood supply to the arm for
short periods of time in an effort to protect the kidneys.
The mechanisms of RIPC for kidney protection are well
understood and have been extensively discussed else-
where.141 In humans, RIPC for the kidney has been most
studied in the setting of cardiac surgery, as summarized in
a meta-analysis of 12 cardiac surgery trials, which reported
no difference in AKI risk between patients randomized to
preincision RIPC or sham.142 Notably, in a subgroup anal-
ysis of three trials in which the anesthetic regimen did not
include propofol, RIPC was associated with significantly
reduced AKI risk, suggesting that propofol may attenuate
the potential renal benefit of RIPC. Furthermore, in high-
risk patients, RIPC significantly reduced 3-month risk for
major adverse kidney events (MAKE: a composite outcome
consisting of persistent renal dysfunction, new RRT, and
Preoperative management decisions regarding chronic
therapies may contribute to perioperative renal risk. How-
ever, the retrospective nature of most available studies
means that there is limited high-quality evidence to guide
decisions regarding which drugs to continue or to withhold
prior to surgery. Evidence comes mostly from retrospective
assessments of cardiac surgery populations and the majority
of these reports focus on the management of a limited num-
ber of agents, including renin-angiotensin system (RAS)
antagonists, diuretics, statins, and beta blockers.
Evidence to guide perioperative management of chronic
RAS blocker therapy is inconclusive and even confusing
regarding whether to continue or to withhold. Angioten-
sin-converting enzyme inhibitors (ACEIs) and angiotensin
I receptor blockers are prescribed for various reasons that
relate to kidney disease, including to delay progression of
chronic kidney disease;144 however, these agents notoriously
precipitate acute renal deterioration in situations where
angiotensin is critical to the regulation of renal filtration
(e.g., renal artery stenosis, volume depletion).145,146 In a
large meta-analysis of retrospective cardiac surgery studies;
the authors found an increased risk for both CS-AKI
(OR 1.17, 95% CI 1.01–1.36, P ¼ 0.04) and mortality (OR
1.20, 95% CI 1.06–1.35, P ¼ 0.005) for patients who
232 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
continued their chronic RAS-blocker therapy up to the day of
surgery.147 In contrast, a second meta-analysis involving both
cardiac and general surgical patients found no association.148
However, in the second study, an analysis limited to one ran-
domized control trial (RCT) and several propensity-matched
retrospective studies found RAS-blockers had a net-protective
effect (relative risk [RR] of 0.92, 95% CI 0.85–0.99).148
Although no firm conclusions are warranted, the authors
from the first meta-analysis suggest it may be wise to withhold
pre RAS blockers, at least in cardiac surgical patients.
Regarding preoperative diuretics, retrospective studies in
cardiac surgery patients have shown an increased risk of kid-
ney insult for patients taking preoperative diuretics.149 In
noncardiac surgery patients, preoperative diuretic use was
independently associated with postoperative AKI; loop
diuretics had the strongest association with AKI.150 Thus,
although the evidence is very limited, it would be prudent
to withhold these diuretics prior to surgery, especially loop
diuretics.
The preoperative use of statins and beta-blockers has been
extensively studied, again mainly in the cardiac surgery
population. A meta-analysis of nine RCTs examining the
use of preoperative statins found no net benefit with respect
to either CS-AKI or RRT.151 A large retrospective analysis
also found no association between preoperative beta-blocker
therapy and CS-AKI.152 Thus, these agents probably have
limited effects on perioperative kidney function or injury.
INTRAOPERATIVE MANAGEMENT
Intraoperative Fluid Choice
Fluid choice has been much better studied in the context of
critical illness and will be discussed at length in the postop-
erative section. However, there have been a number of stud-
ies to guide fluid choice specific to the intraoperative
environment. A meta-analysis of randomized trials in surgi-
cal patients showed that compared with normal saline, bal-
anced crystalloids were associated with fewer minor
metabolic derangements but were not associated with a
lower need for RRT.153 Colloid solutions include hydro-
xyethyl starch (HES) solutions and albumin preparations.
A trial using a closed-loop goal directed fluid therapy system
randomized patients to receive boluses of either intraopera-
tive colloid (HES) or balanced crystalloid in addition to a
background crystalloid infusion for maintenance fluid ther-
apy. Although these investigators reported fewer major
complications in patients receiving intraoperative HES
boluses, there was no difference in kidney injury.154 In clin-
ical trials, colloids have never shown any benefit over crys-
talloids for kidney protection. Thus, when considering
kidney protection, for the majority of patients a balanced
crystalloid should be used as the primary intraoperative
fluid.
The use of sodium bicarbonate has been studied for kid-
ney protection in the setting of cardiac surgery since a small
randomized trial reported promising findings.155 However, a
larger trial by the same study group,156 a second random-
ized trial,157 and a retrospective study158 all failed to dem-
onstrate sodium bicarbonate-mediated kidney protection. In
the context of cardiac surgery, sodium bicarbonate should
not be used for the purpose of kidney protection.
Intraoperative Volume Management
Goal-directed fluid therapy (GDFT) as a part of an enhanced
recovery after surgery (ERAS) protocol has become the stan-
dard of care at many institutions. Typically, GDFT involves
an algorithm where fluid administration is targeted to
achieve a continuously-measured hemodynamic variable
such as cardiac output, stroke volume, pulse pressure vari-
ation, or stroke volume variation. GDFT is meant to optimize
oxygen delivery to organs such as the kidney, limiting
injury. Unfortunately, although it has been demonstrated
to improve overall recovery and to reduce complications
after major surgery, a beneficial renoprotective role has
not been validated. In a prospective, randomized control
trial of 180 patients undergoing major abdominal surgery,
GDFT was not superior to standard care for reducing
AKI.159 The large, randomized OPTIMISE trial also did
not demonstrate a difference in postoperative AKI, although
it was not intended for this purpose.160 It can be debated
whether the widespread adoption of ERAS protocols has
raised the standard of care to where it will be difficult for
GDFT to show benefit. Nevertheless, one proposed beneficial
component of GDFT is to restrict fluid administration and
avoid fluid overload, which is also associated with kidney
injury.81 However, overly restrictive fluid regimens should
also be avoided, as the RELIEF trial showed higher rates of
RRT in restrictive fluid regimens compared with traditional
liberal fluid regimens (median fluid balance at 24 hours for
restrictive versus liberal: +1.38L versus +3.09L; RR 3.27,
95% CI 1.01–13.8, P ¼ 0.048).161 Further studies are
needed to determine whether this is because of restrictive
fluid management, as would be supported by the RELIEF
trial, or caused by other factors, such as increased NSAID
use as a component of multimodal analgesia. Nevertheless,
it seems prudent to avoid gross fluid overload, but also not
to be overly restrictive in fluid administration, particularly
in the context of renal protection and in patients at
high risk of renal injury. The old adage “everything in mod-
eration” appears to hold true for perioperative fluid
administration.
Blood Pressure Management
Intraoperative blood pressure management has received
considerable attention relative to perioperative outcomes
and AKI in both cardiac and noncardiac surgical patients.
A number of large retrospective analyses have shown no
association between hypotension (<50–55 mmHg) during
CPB and development of CS-AKI.13,162,163 This is addition-
ally supported by results from a randomized trial comparing
two CPB blood pressure strategies (target of 75–85 versus
50–60 mmHg), which found no difference in rate of CS-
AKI.164 Notably, CPB blood flow is typically maintained
regardless of blood pressure, unlike during noncardiac sur-
gery where blood pressure fluctuations often reflect parallel
changes in flow. Thus, in retrospective cohort studies of
noncardiac surgery procedures (where blood pressure
may be a useful surrogate for perfusion), both degree and
duration of intraoperative hypotension are independent pre-
dictors of AKI.165–167 In summary, maintenance of intrao-
perative blood pressure within 10%–20% of baseline may be
prudent during procedures when CPB cannot be relied upon
to maintain perfusion during episodes of low blood pressure.

Cardiopulmonary Bypass Management
Although CPB represents only a small portion of the total
perioperative period, research suggests that this period is
associated with significant renal risk. Animal studies indi-
cate that oxygen supply demand inequalities are exagger-
ated and medullary hypoxia is extreme during CPB; effects
that last well beyond separation from circulatory support.30
In humans, changes known to occur at the initiation of CPB
include: greater reduction in renal than systemic perfusion,
loss of renal blood flow autoregulation, and stress hormone
and inflammatory responses known to be harmful to the
kidney.168–170 These effects may explain why the duration
of CPB independently predicts CS-AKI.3,16,24,25,171
Modifiers of Renal Oxygen Delivery. Organ perfusion
and oxygen delivery are primary goals of CPB; however,
the relationship between standard CPB management guide-
lines and renal complications is only partly understood.
Renal blood flow during CPB is not autoregulated and varies
with pump flow rates and blood pressure.168 Fischer and
colleagues retrospectively compared CPB flow rates in a case
control analysis of three groups of patients with normal
baseline renal function that postoperatively either required
dialysis (n ¼ 44), sustained a renal injury without requiring
dialysis (n¼ 51), or had no renal impairment (n ¼ 48).172
These authors noted that, on average, greater renal injury
was associated with longer bypass durations and lower flow
rates. A serious limitation of this study is the potential for
confounding surgical or CPB variables and unknown or
undocumented renal risk factors.
Pulsatile blood flow has been postulated to mediate kid-
ney protection by improving renal microcirculation and
lowering vascular resistance. Unfortunately, studies exam-
ining pulsatile versus nonpulsatile blood flow on CBP have
been inconsistent on their effect on postoperative kidney
function: a propensity-matched study did not show benefit
from pulsatile flow,173 but a small, randomized trial noted
improvements in perioperative GFR.174 Thus, pulsatile flow
during CPB is not considered an effective renoprotective
strategy.
Renal perfusion is affected by renal artery stenosis. In a
retrospective study of 798 aortocoronary bypass patients
whose cardiac catheterization procedures routinely included
renal angiogram, Conlon and colleagues found that 18.7% of
patients had at least 50% stenosis of one renal artery (nine
patients had >95% renal artery stenosis bilaterally).175
However, the presence or severity of renal artery stenosis
was not associated with postoperative AKI. However,
another propensity-score adjusted retrospective study found
that the occurrence of postoperative AKI was higher in
patients with renal artery stenosis compared to those with-
out (OR 2.858, 95% CI 1.26-6.48, P¼ 0.011).176 Further
evidence is needed to determine whether renal angiograms
should be a universal preoperative study.
The relationship of anemia and hemodilution with CS-
AKI is an area of high clinical interest and highly-
investigated, although mostly through retrospective studies.
Hemodilution occurs during initiation of CPB because crys-
talloid or colloid solutions are typically the mainstay of
prime for the extracorporeal circuit. Thus, CPB initiation
is associated with an acute drop in oxygen-carrying
17 • Preservation of Renal Function 233
capacity. Animal studies indicate that moderate hemodilu-
tion reduces the risk of kidney injury during CPB through
improved regional blood flow and reduction of blood viscos-
ity.177,178 However, in the clinical setting, where extreme
levels of CPB anemia are sometimes tolerated (e.g., hemat-
ocrit <20%), hemodilution has been linked to adverse out-
comes.179–181 Several large retrospective studies have
linked low hematocrit levels during CPB with CS-AKI.182–
185
However, to complicate the matter, a first line alterna-
tive to tolerating extreme CPB anemia, transfusion, also
confers AKI risk.182,184
A large retrospective study by Kertai et al. found anemia
at times other than CPB to be independently relevant to
renal risk, with preoperative anemia (hazard ratio of
1.23) and a combination of preoperative and postoperative
anemia (hazard ratio 1.24) associated with CS-AKI.186 As
previously mentioned, red cell transfusion but also the need
for surgical reexploration for bleeding are also indepen-
dently associated with risk of CS-AKI.187,188 To date no tri-
als have been examined for any benefit from addressing
preoperative anemia (e.g., through iron supplementation).
Several studies have examined the relationship between
degrees of extreme anemia and likelihood of CS-AKI. An
“inflection point” where worsening AKI risk escalates is pre-
sent at a threshold lowest CPB hematocrit below 21%
(Fig. 17.6).183, 185,187,189,190 Notably, although extreme
anemia is linked to CS-AKI, the occurrence of anemia with
low blood pressure during CPB is not associated with ele-
vated risk beyond that of anemia alone.163,187,188 Although
there is consensus that avoiding anemia, transfusion and
the need for reexploration is ideal (i.e., meticulous hemosta-
sis, limiting hemodilution), evidence regarding transfusion
thresholds or “trigger” is just emerging. The TRICS III car-
diac surgery trial compared transfusion thresholds, demon-
strating that a threshold of 7.5 g/dL was noninferior to a
9.5 g/dL transfusion threshold in all endpoints studied,
35 All Pts (R2 = 0.86)
No Intra-OP XFN
30
% ∆CR
25
20
15
16 18 20 22 24 26 28 30
Lowest Hct (%)
Fig. 17.6 Graph displaying association of lowest hematocrit (Hct)
during cardiopulmonary bypass and degree of kidney injury, as mea-
sured by percentage change in creatinine (%ΔCr). Note the “inflection
point” where worsening acute kidney injury risk is present at a
threshold of lowest cardiopulmonary bypass hematocrit below 21%
(XFN: transfusion). (Used with permission from Habib RH, Zacharias A,
Schwann TA, et al. Role of hemodilutional anemia and transfusion during
cardiopulmonary bypass in renal injury after coronary revascularization:
Implications on operative outcome. Crit Care Med 2005;33:1749-1756.)
234 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
including renal failure.191 Thus, while extreme anemia
should be avoided, it appears that low transfusion thresh-
olds are an acceptable way to avoid transfusion risk. Similar
findings have been reported in ICU patients.192
The storage age of transfused red blood cells (RBCs) has
been interrogated as an AKI risk factor. With current preser-
vatives, the accepted storage life of RBCs is 42 days. Early
retrospective studies associated older RBCs transfused in
cardiac surgery patients with increased mortality and post-
operative AKI.193,194 However, multiple subsequent high-
profile cardiac surgery and randomized trials of critically
ill patients have not confirmed that RBC age affects mortal-
ity or other secondary outcomes such as kidney injury and
renal failure.195–198 Thus, the age of transfused RBC is not
thought to play a large role in postoperative AKI risk.
Utilization of cell saver technology may reduce red cell
transfusion, particularly intraoperatively. However, in a
large meta-analysis of randomized cardiac surgery trials,
despite reducing transfusion, cell saver use did not reduce
AKI or mortality risk.199 In contrast, a small meta-analysis
of randomized cardiac surgery trials, comparing transfusion
with leukocyte filtered and unfiltered blood there was a large
(five-fold) reduction in AKI risk.200 Because there is no sug-
gestion of harm with cell saver use, it should be routinely
used to minimize allogeneic transfusion, and the use of leu-
kocyte filtered red blood cells is also recommended.
In summary, optimal hematocrit management during
CPB is still being defined, but both extreme anemia and
transfusion may contribute to the development of CS-AKI
and transfusion should only be considered after all sources
of hemodilution have been minimized.201
Modifiers of Renal Oxygen Demand. Because of its well-
known association with organ transplant, hypothermia dur-
ing CPB has been proposed as a strategy to reduce CS-AKI.
However, in contrast to the protection conferred by extreme
cold (e.g., 0–4°C), several randomized trials involving
mild hypothermia (e.g., 32–34°C) have failed to show a pro-
tective effect.202–204 Regarding temperature, however,
multiple retrospective analyses suggest that cumulative
duration of hyperthermia during CPB (arterial outlet
temperature >37°C) and at the time of ICU arrival are inde-
pendent CS-AKI risk factors.205,206 Overall, these data dis-
courage clinicians both from the use of aggressive CPB
rewarming strategies and from targeting hypothermic
temperatures to reduce renal risk meaningfully in cardiac
surgical populations.
Hyperglycemia increases renal O2 demand through energy
consumption to achieve glucose reuptake in the proximal
tubule.207 Several retrospective studies linking elevated pre-
and/or intraoperative serum glucose levels with increased
postcardiac surgery mortality and AKI16,182,208,209 made
intensive intraoperative glucose management protocols seem
a logical approach to reducing renal risk. However, it is likely
this link was mainly the result of the corelationship of a
patient’s glucose intolerance with AKI risk, because in a well
conducted randomized trial, intensive intraoperative and post-
operative glucose control (i.e., target 80–100 mg/dL) was inef-
fective at reducing rates of CS-AKI.210,211 Furthermore, this
regimen was associated with episodes of significant hypoglyce-
mia, an increased risk of stroke, and mortality. Thus, current
recommendations advise the administration of insulin therapy
in the perioperative period targeting more modest glucose
levels of 150–200 mg/dL.
Avoidance of Ascending Aortic Atheroembolism.
Embolic arterial obstruction is poorly compensated for by
collateral flow in the kidney, partly because of the organiza-
tion of renal vasculature.92 Embolic vessel occlusions typi-
cally cause ischemic wedge-shaped infarcts in the cortex
and medulla. Cardiovascular surgical procedures involving
atherosclerotic vessels are known to have high particulate
emboli rates (57%–77%).212,213
Clamp occlusion and cannulation of the ascending aorta
are actions that can disrupt atheromatous plaque and cause
embolization. Measures of atherosclerosis of the ascending
aorta and intraoperative arterial emboli counts are strong
independent predictors of CS-AKI.88,214 Technologies have
been introduced to reduce embolization by limiting aortic
manipulation or trapping emboli. The Symmetry aortic con-
nector system (ACD) is a technology developed to implant
saphenous vein coronary bypass grafts onto the aortic wall
with less manipulation of the aorta, with the hope that this
might reduce embolization and organ dysfunction.215,216
In a large retrospective analysis comparing AKI after off-
pump coronary artery bypass (OPCAB) procedures using
Symmetry devices with standard OPCAB and standard CABG
procedures, there was no difference in AKI rates.104,217
Another emboli-reducing device is the Embol-X intra-aortic
filtration system, which catches emboli during aortic cross-
clamp release. In a randomized trial of the Embol-X, there
was no difference in a composite outcome of ischemic events;
however, in a post hoc assessment of high-risk patients,
Embol-X use was marginally associated with reduced
renal complications (17/124 ¼ 14% versus 28/117 ¼ 24%,
P ¼ 0.04).218 In summary, there is no strong evidence that
atheroembolism-reducing devices reduce AKI.
Selection of Antifibrinolytic Agent. The use of serine
protease inhibitors (e.g., aprotinin) or lysine analogue anti-
fibrinolytic agents (e.g., tranexamic acid, ε-aminocaproic
acid) is associated with reduced bleeding and transfusion
in cardiac, orthopedic, and trauma surgery patients,219–221
but questions have been raised regarding their effects on kid-
ney function.222 Both groups of drugs are filtered by the kid-
ney and saturate brush border binding sites of the low
molecular weight protein transport system in the proximal
renal tubule.223,224 Saturation by these agents prevents the
transport system from processing other small proteins,
which pass into the urine, causing “tubular proteinuria”
that is presumed benign. This phenomenon has confused
study of the safety of antifibrinolytic agents, because in other
settings impaired protein reuptake is used as evidence of
subtle renal injury.224
Several studies have looked for clinical effects of antifibri-
nolytic agents on postoperative kidney outcomes. The best
studied is aprotinin. As a result of earlier clinical trials that
associated aprotinin use with increased mortality, aprotinin
is not available in the United States. It has been approved for
use in Canada and Europe but only for CABG surgery.225 In
these countries aprotinin carries a warning to avoid use in
patients with preoperative kidney dysfunction because of its

known strong association with AKI.226–229 One retrospec-
tive study of ε-aminocaproic acid use reported no change
in the incidence of CS-AKI with its introduction at a single
institution.230 However, its use has been associated with
kidney failure both in a prospective randomized study231
and another retrospective study.232 In contrast, tranexamic
acid has not been associated with risk of kidney injury and
may be the antifibrinolytic agent of choice in high-risk
patients.
Selection of Vasoactive Agents
In addition to the indirect hemodynamic, humoral, and
autonomic effects that typically influence intraoperative
renal blood flow,233,234 use of vasoactive agents may have
important additional direct effects on kidney perfusion. This
section will cover vasopressor agents in both the intraopera-
tive and postoperative settings.
Adrenergic receptor-mediated drugs are a mainstay
among the agents available to the anesthesiologist and inten-
sivist. Catecholamine-mediated renal effects include vaso-
constriction through alpha-1 adrenergic receptors and
vasodilation through dopaminergic, beta-2, and alpha-2
adrenergic receptors. In early animal models, long-lasting
severe renal vasoconstriction and reductions in glomerular
filtration resulted from brief high-dose infusions of norepi-
nephrine.235,236 However, norepinephrine-induced kidney
injury was queried because of subsequent animal models of
sepsis, in which norepinephrine increased both global and
medullary renal blood flow.237,238 Some authors have sug-
gested that the idea that norepinephrine induces kidney
injury in shock is “flawed, not evidence-based, contradicted
by the available observations, and misleading.”239 This was
supported by a high-profile randomized control trial demon-
strating fewer adverse events overall and a trend toward
fewer days of renal support (P ¼ 0.07) in patients receiving
norepinephrine versus dopamine for circulatory shock.240
Overall evidence supports norepinephrine being a safe vaso-
pressor for patients at high risk of AKI.
Arginine vasopressin (also called antidiuretic hormone) is
a peptide secreted by the posterior pituitary that is used to
treat vasodilatory hypotension and has widespread effects
mediated by V1 and V2 receptors.241,242 Low-dose vasopres-
sin activates baroreceptor reflexes, which contributes to this
agent’s clinical usefulness when baroreceptor reflexes are
impaired, such as during septic shock. Higher doses activate
vascular smooth muscle V1a receptors that mediate direct
vasoconstrictor effects and increase systemic vascular resis-
tance. In animal models of septic shock, vasopressin
increases perfusion pressure while preserving renal blood
flow.243 In a small double-blind trial, 24 septic shock
patients were randomized to a 4-hour infusion of either nor-
epinephrine or low-dose vasopressin, and open-label norepi-
nephrine was available to both groups to maintain blood
pressure.244 Urine output increased substantially in the
vasopressin group but was unchanged in the norepineph-
rine group. Similarly, creatinine clearance was increased
by 75% in the vasopressin group but did not change in
the norepinephrine group (P< 0.05). As such, some have
speculated that vasopressin is a useful renoprotective agent
rather than conventional catecholamines for the treatment
of vasodilatory shock. However, a high-profile, large,
17 • Preservation of Renal Function 235
randomized control trial did not confirm this, although this
study did not aim to detect AKI rate changes.245 Regarding
intraoperative vasopressin use, a retrospective review found
that its administration was independently associated with
CS-AKI (OR 3.60, 95% CI 1.22–10.62, P ¼ 0.02). Thus,
although vasopressin may be the preferable vasopressor in
postoperative and critically ill patients, it remains unclear
whether intraoperative vasopressin use should be avoided
in patients at high renal risk.
The longstanding controversy surrounding dopamine
infusion and kidney preservation highlights the importance
of careful evaluation of a therapy before widespread
adoption occurs. Dopamine infusion at rates less than
5 μg/kg/min selectively stimulates mesenteric dopamine-1
(DA1) receptors, causing increased renal blood flow, reduced
renal vascular resistance, natriuresis, and diuresis. Although
animal studies promoted the kidney protective potential of
dopamine 40 years ago,246 numerous subsequent random-
ized studies in surgical and nonsurgical settings have not sub-
stantiated this claim.247 Meta-analyses of randomized trials
have also failed to support dopamine as a kidney protective
agent,248–250 without benefit regarding mortality, dialysis,
or adverse events.251 A number of strongly worded editorials
and reviews discourage the use of dopamine for kidney pro-
tection; with articles entitled “Bad Medicine: low-dose dopa-
mine in the ICU”252 and “Renal-dose dopamine: from
hypothesis to paradigm to dogma to myth and, finally, super-
stition?”253 These articles highlight the numerous negative
studies and catalogue undesirable consequences of low-dose
dopamine, including worsened splanchnic oxygenation,
impaired gastrointestinal function, impaired endocrine and
immunologic system function, blunting of ventilatory drive,
and increased risk of postcardiac surgery atrial fibrilla-
tion.252,254 A body of literature cumulatively strongly dis-
courages the routine use of dopamine infusion for kidney
protection, but this therapy remains common.
Other vasoconstrictor agents have been less well-studied
for their relationship to postoperative kidney impairment.
A small study of 20 patients taking preoperative ACE inhib-
itor agents randomized to receive either 24-hour perioper-
ative phenylephrine or angiotensin II for the control of
systemic vascular resistance255 found no CS-AKI and con-
cluded that angiotensin II is a safe alternative to phenyl-
ephrine. A high-profile randomized trial reported that
angiotensin II infusion effectively increased blood pressure
in critically ill patients with refractory vasodilatory
shock.256 Post hoc analysis of this study also found that
28-day survival and RRT discontinuation was improved
in patients receiving angiotensin II compared with pla-
cebo, among those with AKI requiring RRT at time of ran-
domization.257 Although further studies are needed to
support the routine use of angiotensin II, these findings
indicate that patients with both severe vasodilatory shock
and kidney injury might benefit from this agent.
Phosphodiesterase III inhibitors (milrinone, amrinone,
enoximone) have positive inotropic and vasodilatory effects.
The small number of studies addressing their effects on kid-
ney function draw conflicting conclusions. In an animal
model, milrinone exacerbates endotoxin-induced renal fail-
ure258 and anecdotal cases of renal dysfunction and failure
in humans have been associated with the use of milri-
none.259,260 In a randomized study of 40 CABG patients
236 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
receiving enoximone or placebo, there was a significant rise
in urinary α1-microglobulin in controls, compared with the
enoximone group.260 Currently, there is insufficient data to
characterize the kidney effects of phosphodiesterase III
inhibitors; however, as they are excreted mainly through
the kidney, their use is cautioned in patients with kidney
failure.
Pharmacologic Agents
Fenoldopam. Fenoldopam mesylate, the first clinically
available selective agonist of DA1 receptors, is an approved
therapy for the treatment of hypertension.261,262 Much like
dopamine, its less DA1-selective predecessor, fenoldopam
showed preclinical promise as a kidney protective
agent.263,264 A randomized prospective study involving
160 cardiac surgery patients with baseline renal dysfunc-
tion noted lower postoperative serum creatinine values
and higher creatinine clearance values compared with base-
line with fenoldopam, but not placebo.265 However, a study
involving 80 high-risk cardiac surgery patients found no
benefit.266 Similarly, a prospective randomized double-blind
study of 155 critically ill patients with established renal
injury (including postcardiac surgery patients) found no
benefit and even discussed possible increased adverse out-
comes in diabetic patients.267,268 In liver transplant sur-
gery, data from two studies identified improvements in
kidney function in the first 3–5 postoperative days with
fenoldopam (versus dopamine and placebo).269,270 Simi-
larly, in aortic surgery patients, Halpenny and colleagues
found a decline in creatinine clearance with aortic cross-
clamp application and higher postoperative day 1 serum
creatinine values in patients receiving placebo, but not in
the fenoldopam group.271
A subsequent meta-analysis of randomized control trials
evaluating fenoldopam for kidney protection after major
surgery noted that larger trials are needed because there
was heterogeneity in surgical type, AKI definitions, and a
high risk of bias in the majority of available studies,
although they did report a reduction in postoperative AKI
without changes in RRT or hospital mortality.272 Overall,
current studies provide insufficient data to draw definitive
conclusions on fenoldopam for kidney preservation.
Dopexamine. Dopexamine hydrochloride is a DA-1 recep-
tor and beta 2-adrenoceptor agonist with renal vasodila-
tory, natriuretic, and diuretic effects that has shown
promise in animal studies as a kidney protective
agent.273,274 In a study of 44 CABG surgery patients ran-
domized to three different infusion doses of dopexamine or
placebo, Berendes and colleagues noted improved systemic
oxygen delivery, increased postoperative creatinine clear-
ance, and reductions in markers of perioperative inflamma-
tory response with dopexamine.275 In contrast, in a study of
CABG surgery patients with normal (n¼ 24) or impaired
(n ¼ 24) baseline renal function randomized to dopexamine
or placebo, Dehne and colleagues found no evidence of kid-
ney protection.276 In a randomized comparison of dopexa-
mine with dopamine in 24 liver transplant patients, Gray
and colleagues found a trend toward better kidney function
with dopexamine, but no overall outcome difference
between the two therapies.277 A notable property of dopex-
amine is that its metabolism is significantly reduced in the
presence of impaired liver function.278 A systematic review
of 21 randomized-controlled trials involving dopexamine by
Renton and colleagues concluded that existing evidence is
inconsistent and insufficient to recommend dopexamine
for kidney protection for either high-risk surgical or criti-
cally ill patients.279
Mannitol. Mannitol is an osmotic diuretic with kidney pro-
tective potential in animal models280–283 and effects that
include augmentation of renal blood flow284,285 and
increased glomerular filtration rate.280,282 Because of these
properties and augmented urine output, mannitol has com-
monly been used as a part of CPB priming solutions.286–289
However, mannitol is no longer commonly used for this pur-
pose because randomized studies have failed to show a reno-
protective benefit.202,264 A meta-analysis of nine trials
relating mannitol use with AKI prevention found no benefit
following cardiac or major noncardiac surgery, and even
potentially added risk with radiocontrast agents.290 As an
exception, kidney transplant patients may have a reduction
in rates of kidney failure when mannitol is administered
prior to cross-clamp removal.290 More research is needed
in this area. Thus, although mannitol is useful for renopro-
tection during kidney transplant, it should not be used
routinely for AKI prevention in other surgeries.
N-Acetylcysteine. N-acetylcysteine has antioxidant prop-
erties, is a vasodilator, enhances the endogenous glutathi-
one scavenging system, and in animals counteracts renal
ischemia and hypoxia. Although early clinical studies com-
paring N-acetylcysteine with mannitol or placebo suggested
benefit,291 this was not supported in subsequent investiga-
tions.292,293 A meta-analysis of cardiac surgery studies
reported that N-acetylcysteine does not reduce the risk of
CS-AKI.294 There is no evidence to support its use to reduce
postoperative renal dysfunction.
POSTOPERATIVE MANAGEMENT
Many issues related to postoperative kidney protection mir-
ror those discussed in the intraoperative period (e.g., vaso-
active agents, pharmacologic agents). This section focuses
on fluid management, glucose management, and other
select pharmacologic agents.
Intravenous Fluid Choice
The best known link between intravenous fluid choice and
kidney injury is for HES preparations. In randomized trials of
septic critically ill patients, the use of HES was strongly asso-
ciated with kidney failure and the need for renal replace-
ment therapy.295–297 After these trials in 2012, HES
preparations were largely pulled from the market and una-
vailable in the United States.
The administration of normal saline (0.9% sodium chlo-
ride) or saline-based colloid solutions results in an acid-base
abnormality frequently observed in postoperative and criti-
cally ill patients: metabolic hyperchloremic acidosis. Hyper-
chloremic acidosis promotes AKI because of the adverse
effects of elevated chloride levels and acidosis on kidney
homeostasis, including reduced blood flow and glomerular
filtration rate, increased afferent arteriolar tone, and altered

renin release.298,299 The propensity of studies in this area
seem to support the notion that administration of
chloride-liberal fluids (i.e., normal saline) are associated
with AKI. In one study of critically ill patients, a chloride-
restrictive fluid policy (versus chloride-liberal) was associ-
ated with a reduced rate of AKI.300 Interestingly, the SPLIT
randomized trial comparing buffered crystalloid with nor-
mal saline did not confirm this finding;301 however, it was
argued that the fluid volume administered in this trial
(2 L) was insufficient. Two subsequent large pragmatic,
cluster-randomized, cross-over trials have since demon-
strated that balanced crystalloids are safer than normal
saline with regard to kidney injury. The SMART trial exam-
ined the effect of balanced crystalloids versus normal saline
in critically ill patients and demonstrated that balanced
crystalloids were associated with lower rates of MAKE30
(OR 0.90, 95% CI 0.82–0.99, P¼ 0.04) and a trend toward
lower mortality at 30 days (OR 0.90, 95% CI 0.80–1.01,
P¼ 0.06).302 Furthermore, in the SALT-ED study, the lower
rate of MAKE30 for balanced crystalloids compared with
normal saline extended to a heterogenous emergency
department population.303 These findings mirror those of
a very large, retrospective, propensity matched cohort study
on this topic.304 Thus, except where saline is specifically
clinically indicated (i.e., significant hyponatremia, cerebral
edema), balanced crystalloids are preferable over normal
saline for kidney protection.
Regarding GDFT, early studies demonstrated outcome
benefits related to septic shock, organ dysfunction, and mor-
tality.305 However, a high-profile, randomized trial subse-
quently did not confirm these benefits from GDFT
compared with usual care,306 although some argue that
the original Rivers trial had already improved baseline stan-
dard of care for patients with sepsis. Notably GDFT did not
decrease kidney injury in either trial. Nevertheless, the
debate continues whether GDFT should be used in patients
with septic shock; however, existing data appear to indicate
that it should not be used for the purpose of kidney
protection.
Fluid Removal/Diuretics
Fluid overload has been consistently linked to worse out-
comes in critically ill patients.81 Diuretic agents are fre-
quently used to promote fluid clearance after the initial
resuscitation period. Diuretic agents increase urine genera-
tion by reducing reuptake of tubular contents; this can be
achieved by numerous mechanisms, including blocking
tubular solute reuptake through active transport mecha-
nisms (e.g., loop diuretics), altering the tubular osmotic gra-
dient to favor solute remaining in the tubule (e.g.,
mannitol), or by affecting the hormonal signaling to the
tubule to increase urine generation (e.g., atrial natriuretic
peptide [ANP]). In general, the rationale underlying kidney
protection from diuretic agents relates to the decreased like-
lihood of tubular obstruction by casts with increased solute
flow through injured renal tubules, thus retaining tubular
patency and avoiding oligo/anuria and the need for dialysis
caused by fluid overload. Importantly, despite the clinician’s
satisfaction at seeing increased urine output in response to
diuretics, this increase does not insure improved renal func-
tion.52 The classes of diuretics are discussed in the following
sections.
17 • Preservation of Renal Function 237
Loop Diuretics. Loop diuretics, including furosemide,
ethacrynic acid, and bumetanide, are also called “loop
inhibitors” because they inhibit active solute reabsorption
in the mTAL of the loop of Henle, causing more solute to
remain in the kidney tubule and increasing urine genera-
tion. Furosemide also induces renal cortical vasodilation.
In animal models, furosemide raises oxygen levels in the
medulla,307 and in some settings even protects tubules
from damage after ischemia-reperfusion or nephrotoxic
insult.308–310
However, in surgical and critically ill patients, numer-
ous retrospective studies have shown no benefit and
have even suffered harm with loop diuretic use.311–316
A randomized study of patients undergoing major
thoraco-abdominal or vascular surgery procedures found
no kidney protective benefit of an extended postoperative
furosemide infusion compared with placebo.311 Another
double-blind, randomized-controlled trial comparing infu-
sions of low-dose dopamine, furosemide, and placebo in
cardiac surgery patients found a two-fold greater post-
operative rise in serum creatinine in the group receiving
furosemide relative to dopamine and placebo groups.317
In addition, multiple meta-analyses have been performed
on this topic.318–322 Some meta-analyses have demon-
strated improvements in urine output321,322 and possible
shorter duration of RRT,321 but no meta-analysis has shown
improvements in AKI. The sum of evidence does not
support the use of loop diuretics as perioperative kidney
protective agents and suggests they may even have nephro-
toxic effects, especially in cardiac surgery patients.320
The potential harm of loop diuretics to the kidney may be
explained by inhibition of loop of Henle solute transport,
which causes greater solute delivery and active transport
demands downstream in the distal renal tubule, where
higher oxygen expenditure is required per unit sodium reab-
sorbed.323 Restated, loop diuretics may spare injury to the
loop of Henle at the expense of insult to the metabolically
less-efficient distal renal tubule. Rats were chronically
administered loop diuretics and showed hypertrophied distal
tubular cells with increased numbers of mitochondria.324
Thus, loop diuretics may displace injury from the loop of
Henle to more distal tubular locations.
Natriuretic Peptides. The natriuretic peptides are hor-
mones that interact with a specific signal transmission sys-
tem involved in the regulation of volume homeostasis. In
response to volume expansion, the release of these hor-
mones (atrial natriuretic peptide [ANP], renal natriuretic
peptide [urodilatin], and brain natriuretic peptide [BNP])
is associated with receptor-mediated vasodilation and
natriuresis.
ANP is normally synthesized by the atria in response to
atrial wall tension; anaritide is the human recombinant
form of ANP. ANP increases glomerular filtration and uri-
nary output by constricting efferent while dilating afferent
arterioles and is associated with attenuation of renal cell
injury in animal models of AKI.325 Unfortunately, human
trials of ANP as a kidney protective agent have not been
conclusive. In a multi-center randomized double-blind,
placebo-controlled clinical trial of ANP as a 24-hour intra-
venous infusion (0.2 μg/kg/min) in critically ill patients
with established acute renal injury, the primary end point
238 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
of improved dialysis-free survival after 21 days was not
achieved.326 A secondary analysis revealed that dialysis-
free survival was higher in the ANP group for oliguric
patients. Conversely, in nonoliguric patients, dialysis-free
survival was higher in the placebo group. Some have spec-
ulated that the disparity of outcomes in this study is a result
of the vasodilating properties of ANP; hypotension was more
frequent in the nonoliguric patients and may have over-
whelmed any kidney protective benefit. However, a second
similar study was designed to reproduce the favorable find-
ings from the first study. In critically ill patients with estab-
lished oliguric renal dysfunction, there was no benefit.327
Two randomized trials in cardiac surgery patients have been
performed examining the effect of ANP on perioperative
kidney function. Both studies examined low-dose (0.02
μg/kg/min) starting on the initiation of CPB and continuing
until 12 hours after oral intake. The authors demonstrated
improvements in postoperative creatinine levels and serum
creatinine levels up to 1 year.328,329 However, both trials
had concerns regarding study methodology (randomization,
blinding, etc.), and it is therefore difficult to draw firm con-
clusions from these studies.11 Further trials are needed to
determine whether ANP can be used for AKI prevention
or treatment.
Urodilatin differs from ANP only by the addition of four
amino acids to the N terminus end of the peptide but has
more potent natriuretic properties. Three small randomized
trials indicate kidney protective benefit from this agent in
patients with established kidney dysfunction, including
reduced duration of hemofiltration and frequency of hemo-
dialysis following heart transplant (n ¼ 24) and reduced
incidence of dialysis after cardiac (n¼ 14) and liver trans-
plant (n ¼ 9) surgery.330–332 However, interpretation of
these data is complicated by very high (up to 86% in the
control group) dialysis rates. A larger randomized, double-
blind trial including 176 critically ill patients with oliguric
acute renal failure did not demonstrate a benefit from any
of four different urodilatin dose regimens compared with
placebo.333
BNP is normally synthesized by the left and right ventri-
cles in response to ventricular dilatation and BNP assay has
become a diagnostic tool for congestive heart failure. The
human recombinant form of BNP is nesiritide. Nesiritide
has potent vasodilating properties and has been approved
by the US Food and Drug Administration (FDA) as a treat-
ment for acutely decompensated heart failure, partly
because of its ability to reduce ventricular filling pressures
rapidly, to relieve dyspnea, and to induce sustained diuresis.
Studies have indicated that BNP treatment may worsen kid-
ney function in heart failure patients.334,335 Nesiritide has
been tested in cardiac surgery patients with reduced left
ventricular function; however, results have been inconsis-
tent, with nesiritide showing some benefit for AKI preven-
tion, but no benefit on death or dialysis.336–338 With the
current evidence, the routine use of nesiritide for AKI pre-
vention is not encouraged for cardiac surgery patients
and should be discouraged for those with nonsurgical heart
failure.
Glucose Management
Early clinical ICU studies suggested that improved glucose
management resulted in improved survival and better
kidney outcome (e.g., target in ICU: 80–110; post-ICU:
180–200 mg/dL).339 Unfortunately this has not been con-
firmed, with even increased mortality from over-aggressive
insulin therapy, in numerous subsequent studies including
cohorts of medical and surgical critically ill patients, includ-
ing multiple intraoperative randomized studies of cardiac
surgery patients.210,211,340–342 Consequently, although
intensive glucose control (target <110 mg/dL) may provide
some kidney protection, the risk of mortality outweighs the
benefit and a more modest glucose level of <180 mg/dL
should be targeted.
Pharmacologic Agents
Steroids. Corticosteroids attenuate the inflammatory
response and provide kidney protective effects in animal
models.343 Clinically, in a small, randomized, placebo-
controlled, double-blind trial of 20 patients undergoing car-
diac surgery with cardiopulmonary bypass, there was no
evidence of kidney protection in patients receiving dexa-
methasone 1 mg/kg before induction of anesthesia and
0.5 mg/kg 8 hours later.344 The DECS randomized control
trial also found no kidney protective effects of high-dose
dexamethasone (1 mg/kg) when compared with placebo
in cardiac surgery patients.345 In a post hoc analysis of
the DECS trial, Jacob et al. reported that high-dose dexa-
methasone did decrease the rate of severe AKI as defined
by need for RRT, with 0.4% of patients requiring RRT in
the dexamethasone group and 1.0% in the placebo group.
The greatest benefit was for those with CKD, especially those
with eGFR <15.346 However, another very large random-
ized control trial, the SIRS trial, also failed to show a kidney
protective effect for methylprednisolone in cardiac surgery
patients.347 Thus, although steroids were safe in these trials
apart from an increased rate of hyperglycemia, steroids
should not be used for kidney protection as they have shown
no convincing evidence of benefit.
Non-steroidal Anti-Inflammatory Drugs: Aspirin and
Cyclo-Oxygenase-2 Inhibitors. Although there is little
evidence or rationale for the use of many nonsteroidal
anti-inflammatory agents (NSAIDs) for kidney protection,
in a retrospective study of 5065 coronary artery bypass sur-
gery patients, Mangano and colleagues reported that early
re-institution (<48 hours) of aspirin therapy after surgery
was associated with a three-fold reduction in mortality
and a 74% reduction in the incidence of renal failure.348
In contrast, the POISE-2 trial examined the effects of periop-
erative aspirin in patients undergoing major noncardiac
surgery who were at high risk of vascular complications.
Although it was a tertiary outcome of the study, the authors
reported that patients receiving aspirin were at higher risk of
AKI with RRT.349 The kidney injury substudy of the POISE-
2 trial demonstrated that one dose of preoperative aspirin
and then aspirin for up to 30 days postoperatively did not
reduce the risk of kidney injury compared with placebo.350
Regarding other NSAIDs, a review by Lee et al. reported the
combined findings from randomized controlled postopera-
tive NSAID analgesia trials that recorded renal function,
including over 1200 patients receiving ketorolac, diclofe-
nac, indomethacin, or placebo. These authors noted a
16 mL/min decline in creatinine clearance and a reduction
in potassium clearance in NSAID patients at 24 hours after

surgery, but no episodes of acute renal failure requiring dial-
ysis.351 Lee and colleagues concluded that postoperative
NSAID analgesia has only small temporary negative effects
on kidney function in adults with normal kidneys at base-
line, stressing that these findings might not apply to children
or adults with already impaired kidney function. Although
similar analyses have not been performed for cyclo-
oxygenase (COX)-2 selective NSAIDs, a randomized,
double-blind, placebo-controlled postoperative analgesia
trial involving 462 CABG patients showed a greater
incidence of serious adverse events in patients receiving
valdecoxib/paracoxib, including a trend toward more post-
operative kidney dysfunction.352 The interim findings from
this trial prompted the investigators to terminate the study
for safety reasons. A second similar randomized trial includ-
ing 1671 CABG patients or placebo also noted increased
adverse outcomes, in particular an increase in cardiovascu-
lar events in patients receiving valdecoxib/paracoxib.353
The incidence of kidney failure or dysfunction in this study
was insignificantly higher in the valdecoxib/paracoxib
groups than in the placebo group. Taken together, NSAIDs
at best have negligible effects on perioperative kidney func-
tion but might be associated with increased risk of kidney
injury, therefore they should not be used for kidney protec-
tion. In the case of aspirin, however, the current recommen-
dation is to restart aspirin within 48 hours of cardiac
surgery to maintain graft patency.
Alpha 2 Adrenergic Agonist Agents. The normal phys-
iology of the kidney includes a role for adrenergic receptors
in modulating vasoconstrictor (alpha 1) and vasodilating
(alpha 2) effects, respectively. Vasoconstriction contributes
to the pathophysiology of acute renal injury, and several
preclinical studies confirm that clonidine (an alpha 2 ago-
nist) attenuates experimental acute renal injury.354–358 A
double-blind, randomized placebo-controlled trial in 48
CABG surgery patients evaluated preoperative clonidine
for kidney preservation and found a significant benefit on
kidney injury in the first postoperative day but no difference
3 days after surgery.359 However, the kidney injury sub-
study of the POISE-2 trial showed no benefit for periopera-
tive administration of clonidine to prevent AKI.350
Dexmedetomidine has shown some promise for kidney pro-
tection. A meta-analysis of 10 randomized control trials
reported improvement in AKI in cardiac surgery patients
receiving dexmedetomidine; however, the trials included
were small and did not have uniform definitions of
AKI.360 Taken together, insufficient data are available to
recommend these agents and currently they are not com-
monly used for kidney protection.
Calcium Channel Blockers. Three major classes of cal-
cium blockers exist with varying pharmacologic properties:
benzothiazepines (e.g., diltiazem), phenylalkylamines (e.g.,
verapamil), and dihydropyridines (e.g., nifedipine, nimodi-
pine). Calcium channel blockers decrease renal vascular
resistance and increase glomerular filtration361 and have
been reported to exert beneficial effects in experimental
models of toxic and ischemic acute renal failure.362,363 A
meta-analysis of randomized studies comparing periopera-
tive use of calcium channel antagonist agents with control
or other agents (e.g., nitroglycerin, dopamine) in cardiac
17 • Preservation of Renal Function 239
surgery demonstrated no overall effect, but post hoc analysis
identified some benefit if preoperative creatinine clearance
was less than 95 mL/min.364 The overall inconclusive
findings from trials of calcium channel blockers do not sup-
port the use of these agents for perioperative kidney
preservation.
Renin-angiotensin System (RAS) Blockers. The RAS
mediates vasoconstriction and contributes to the paracrine
regulation of the renal microcirculation. AT1 blockers and
ACE inhibitors act by decreasing activation of the RAS and
animal studies suggest that these agents may have protec-
tive properties in experimental AKI.365 While both drug
classes are recognized for their ability to slow the progres-
sion of chronic renal disease,366 their perioperative use is
controversial. Pertinent to the renal effects of these agents
is their potential to precipitate acute kidney deterioration
in clinical conditions in which RAS activation is critical to
the regulation of renal filtration, such as with renal artery
stenosis or volume depletion.145,146 These agents can also
lead to hemodynamic instability when initiated soon
after cardiac surgery.367 Two retrospective studies have
not found perioperative ACE inhibitor therapy to be an inde-
pendent predictor of kidney outcome after cardiac sur-
gery.104,368 However, in a prospective study of aortic
surgery patients, Cittanova and colleagues reported an
increased risk of postoperative kidney dysfunction in
patients receiving chronic ACE inhibitor therapy.369 In a
retrospective review of cardiac surgery patients, Chou
et al. reported an independent association of RAS blocker
therapy with a lowered risk of ensuing CKD.370 More studies
are needed to determine whether RAS antagonists provide
harm or benefit in the perioperative period and, if benefit,
the timing of their administration.
Endothelin Receptor Antagonists. Endothelin is a
potent vasoconstrictor that severely limits renal blood flow
and may contribute to the pathophysiology of acute renal
failure.371 Two types of endothelin receptors have been
identified: ETA receptors are located on vascular smooth
muscle cells and mediate endothelin-induced vasoconstric-
tion, and ETB receptors are on endothelial cells and mediate
release of nitric oxide and prostacyclin. The development of
endothelin receptor antagonists has provided the opportu-
nity to assess the kidney protective potential of this class
of drug. Most studies to date have been preclinical. However,
endothelin antagonists are being studied in the setting of
diabetic nephropathy and glomerular disease. It is possible
that these agents could be used to prevent the AKI to
CKD transition, but no studies would support their clinical
use for this at the present time.
Erythropoietin. Recombinant human erythropoietin is
typically prescribed for anemia associated with cancer che-
motherapy or end-stage renal failure; however, this agent
has also been shown to have kidney protective properties
in at least nine studies in animal models of acute ischemic,
hypovolemic, endotoxic, and nephrotoxic renal injury.372
Although it appears safe, a meta-analysis of 10 randomized
control trials did not show a benefit for erythropoietin to
prevent AKI.373
240 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Growth factors (IGF-I, EGF, HGF). When the kidney is
acutely injured, animal models indicate that growth factors
are involved in tubular recovery, such as insulin-like growth
factor-I (IGF-I), epidermal growth factor (EGF), and hepato-
cyte growth factor (HGF). Therefore, providing an exoge-
nous source of these substances has been identified as
potential kidney protective strategy. However, human stud-
ies do not support the effectiveness of this strategy. In a
multi-center, randomized-controlled double-blind study of
72 critically-ill dialysis patients receiving recombinant
human IGF-I or placebo, there was no difference in the rate
of recovery of kidney function or mortality.374 In a second
study involving 44 post-kidney transplant patients with
established kidney dysfunction, there was no difference in
the return of kidney function or subsequent requirement
for dialysis with IGF-1 compared with placebo.375
Pulmonary Vasodilators (PGE1, PGI2, NO).
Prostaglandins (PGs) are mediators of microvascular blood
flow distribution and there is rationale for the potential kid-
ney benefit of prostaglandins PGE1 and PGI2. Studies exam-
ining the kidney protective benefit of PGE1 (also known as
alprostadil) were not conclusive.376 A small study random-
ized CABG patients with poor ventricular function random-
ized to either low-dose PGI2 (2 ng/kg/min) or placebo and
found 24 hour postoperative creatinine clearance to have
dropped 32% in controls, but a rise of 13% in patients receiv-
ing PGI2.377 PGI2 therapy was also associated with signifi-
cantly higher 24 hour postoperative creatinine clearance
values (P< 0.01). These authors concluded that PGI2 (also
known as prostacyclin, epoprostanol, PGX, and Flolan) may
have kidney protective properties.
Nitric oxide (NO) has vasodilating properties that could be
beneficial in preventing AKI. Furthermore, hemolysis is com-
mon during CPB and results in release of oxyhemoglobin.
Oxyhemoglobin promotes oxidative stress in the kidney
and can deplete endogenous NO through formation of methe-
moglobin. Thus, it was postulated that supplemental NO dur-
ing cardiac surgery could prevent postoperative AKI. Lei et al.
randomized 244 patients undergoing multiple valve surgery
(mostly caused by rheumatic fever) to 80 ppm of inhaled
1. Avoidance of nephrotoxic agents
2. Discontinuation of ACE-I and ARB for 48 hours following surgery
3. Close monitoring of serum creatinine and urine output
4. Avoidance of hyperglycemia for 72 hours following surgery
5. Consideration of alternative to radiocontrast agents for imaging
6. Close hemodynamic monitoring with PICCO catheter and
implementation of a volume/hemodynamic optimization
algorithm
>11
SVV 500–1000 ml crystalloid
<11
<3L/min/m2
CI
2
>3L/min/m
<65 mmHg
MAP
>65 mmHg
Goal Met ?
NO or N2. They found that NO reduced postoperative AKI,
MAKE30, MAKE90, and MAKE at 1 year.378 These results
are very promising and warrant future trials to assess the effi-
cacy of NO to prevent AKI in other types of cardiac surgery,
cardiac surgery on patients with multiple comorbidities, and
other disease states with elevated hemolysis.
Kidney Protective Bundle
Because there are currently no pharmacologic agents
proven to attenuate ongoing AKI, the “KDIGO bundle”
was designed. The KDIGO bundle is a group of treatments
aimed at precise hemodynamic monitoring/support and
avoidance of nephrotoxic agents379 (Fig. 17.7). Meersch
et al. randomized cardiac surgical at high risk of postopera-
tive AKI (TIMP-2 * IGFBP7 >0.3 at 4 hours postoperatively)
to usual care or the KDIGO bundle. They demonstrated
improvements in hemodynamics, glycemic control, and
the frequency and severity of CS-AKI.379 It appears that
the most effective kidney protective strategy currently avail-
able for stressed kidneys is an astute clinician who provides
optimal, timely, and goal-directed care with particular
attention to minimizing renal related insults.
Kidney Failure Requiring RRT
One particularly relevant topic related to AKI and RRT is the
timing of dialysis initiation. A number of RCTs have com-
pared the utilization of early versus delayed initiation strat-
egies; however, in these trials, heterogeneity exists in
definitions and indications for early versus late RRT initia-
tion, making a true comparison difficult. The two largest
and most robust trials in critically ill patients presented con-
flicting results: the AKIKI trial found no mortality difference
in early versus late initiation;380 however, the ELAIN trial
showed a reduced risk of mortality at 90 days, an increased
rate of renal recovery, reduction in length of RRT, benefits
up to 1 year on MAKE and renal recovery, and decreased
hospital length of stay in the early RRT group.381,382 These
conflicting results are likely a result of differences in the two
study designs: ELAIN was a single-center study (as opposed
to multi-center), which enrolled mostly surgical (not medi-
cal) patients in KDIGO stage 2 (not stage 3), and initiated
Fig. 17.7 Schematic showing components of kidney-
protective KDIGO bundle. ACE-I, Angiotensin converting
enzyme inhibitor; ARB, angiotensin receptor blocker; CI,
D/Epi cardiac index; D, dopamine; Epi, epinephrine; KDIGO,
kidney disease improving global outcomes; MAP, mean
arterial pressure; NE, norepinephrine; PICCO, pulse con-
tour cardiac output; SVV, stroke volume variation. (With
NE permission from Meersch M, Schmidt C, Hoffmeier A, et al.
Prevention of cardiac surgery-associated AKI by imple-
menting the KDIGO guidelines in high risk patients identi-
fied by biomarkers: The PrevAKI randomized controlled trial.
Intensive Care Med 2017;43:1551-1561.)
 17 • Preservation of Renal Function 241

RRT based on KDIGO stage (as opposed to other clinical cri-
teria). Because it was mostly conducted in surgical patients,
the ELAIN trial results are more likely to be applicable peri-
operatively. Finally, in a meta-analysis of 10 RCTs con-
ducted in both surgical (cardiac and noncardiac) and
nonsurgical patients, there was no association between
early RRT implementation and mortality (30 day, 60 day,
90 day, in-hospital) or dialysis dependence at day 90.383
Thus, it is still unclear whether early initiation of dialysis
affords long-term kidney protection, although surgical
patients might benefit uniquely, especially in light of signif-
icant fluid shifts in the perioperative period.
In the postoperative setting, RRT is most commonly deliv-
ered through either intermittent hemodialysis (IHD) or con-
tinuous RRT (CRRT), which includes any option with
continuous activity. CRRT is associated with a number of
potentially benefits compared with IHD: increased hemody-
namic stability, increased net fluid removal, and improved
removal of some inflammatory mediators.384,385 However,
the clinical relevance of these factors is less clear. A number
of randomized trials and observational studies have exam-
ined the clinical efficacy of CRRT versus IHD. Some studies
suggest improved kidney recovery with CRRT;386 however,
in meta-analyses of several RCTs and prospective cohort
studies, there is no significant difference in recovery of kid-
ney function for CRRT versus IHD.387,388
Summary and Future Directions in
Renal Preservation
Although significant work remains to improve and expand
knowledge about perioperative kidney protection, as out-
lined in this chapter there is already much on which to
base sound clinical kidney-protective practice. The status
quo of the past 20–30 years has become unacceptable;
few experts now dispute the lack of benefit from “tradi-
tional” agents such as low-dose dopamine, mannitol,
and furosemide, and yet use of these agents remains prev-
alent. Continued use of these agents may in fact be delete-
rious and may distract the unaware from adopting other
effective therapies. While there are still no kidney protec-
tive or pro-kidney recovery pharmacologic agents, imple-
mentation of the kidney protective KDIGO bundle shows
promise in preventing further AKI in patients with kidney
stress. Also, appropriate procedure choice and excellent
clinical care can achieve significant reductions in kidney
injury. An algorithm for clinical application of evidence-
based perioperative kidney preservation is provided
(Fig. 17.8). The ideal randomized clinical kidney preserva-
tion trials of the future will avoid the pitfalls of evaluating a
substance through numerous small studies that neither
strongly support nor refute potential benefit and will be

Procedural
Patient risk
risk

Low High Low-risk Medium-risk High-risk

• Ortho/plastics • Cardiac patient patient patient
• Gastrointestinal • Major Vascular
• ENT • Hepatobiliary
• Thoracic • Trauma
• Sepsis
Consider Kidney-protective
Procedural Strategies:
• Transfemoral TAVR over other
approaces
CPB • Minimally invasive valve surgery in
Non-CPB
Procedures patients with CKD
Procedures
• Off-pump CABG in CKD4
• ?RIPC prior to cardiac surgery

Intraoperative Perioperative During CPB

• Optimize hydration
• Avoid overly restrictive fluid strategy
• Use balanced crystalloids (vs. 0.9%
normal saline)
• Serum glocose target 150−200
mg/dL
• Maintain BP within 10-20% of
normal range
• Mannitol prior to cross-clamp
removal in kidney transplantation
recipient
• Use balanced crystalloids (vs. 0.9%
normal saline)
• Target Hgb> 7.0g/dl
• >7.5 mg/dL in cardiac surgery pateints
• Target serum glucose < 180 mg/dL
• Norepinephrine as first-line vaspressor
• Avoid COX2 inhibitors
• Minimize loop diuretics
• Avoid volume overload
• KDIGO kidney-protective bundle,
especially in cardiac surgery pateints
• Epiaortic scanning for atheroma
avoidance
• Minimize hemodilution (e.g. cell
salvage)
• Transfusion: consider threshold Hcl
21%–24%, consider leukocyte-
depleted RBC
• Avoid hyperthermia on rewarming
• Avoid prolonged CPB time
• Avoid aprotinin
• Minimize loop diuretics

Fig. 17.8 An evidence-based perioperative kidney preservation algorithm. BP, Blood pressure; CABG, coronary artery bypass graft; CKD, chronic kidney
disease; COX2, cyclooxygenase 2; CPB, cardiopulmonary bypass; ENT, ear, nose, throat; Hct, hematocrit; Hgb, hemoglobin; KDIGO, kidney disease
improving global outcomes; RBC, red blood cell; RIPC, remote ischemic preconditioning; TAVR, transcatheter aortic valve repair.
242 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
sufficiently large to answer meaningful questions in a “yes
or no” fashion regarding kidney preservation.
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 18 Evaluation and Treatment
of Acute Oliguria
RAMESH VENKATARAMAN* and JOHN A. KELLUM
Oliguria is a one of the commonest clinical problems
encountered by critically ill patients. The prevalence of
the problem has been difficult to establish because of a wide
variety of definitions used in the literature. Some studies
have estimated that up to 18% of intensive care unit
(ICU) patients with intact renal function exhibit episodes
of oliguria.1 Furthermore, 69% of ICU patients who develop
acute kidney injury (AKI) are oliguric.2 With the introduc-
tion of modern definitions of AKI (Box 18.1),3 comparisons
of urine output and creatinine criteria have shown that
even isolated oliguria (no creatinine criteria) is associated
with significant short- and long-term adverse consequences
including death or permanent dialysis (Box 18.2).4 A similar
result has been reported in pediatric patients where use of
plasma creatinine alone failed to identify AKI in 67.2% of
patients with low urine output.5
Although numerous definitions for oliguria exist, most
use a urine output of less than 200 to 500 mL in 24 hours
to denote oliguria, whereas urine output of less than 50 to
100 mL/day is generally termed anuria. To standardize the
use of the term across different studies and populations, the
Acute Dialysis Quality Initiative (ADQI) proposed a defini-
tion of oliguria as urine output less than 0.5 mL/kg/h for
at least 6 hours and this definition has been adopted by
international guidelines3 (see Box 18.1). It has been con-
vincingly demonstrated that AKI is associated with excess
mortality even in the absence of the need for renal replace-
ment therapy (RRT)6,7 and early identification of the cause
of AKI and appropriate intervention may alter the progress
of AKI. Hence oliguria being an early marker of AKI should
be identified and evaluated with utmost urgency. Thus oli-
guria should warrant evaluation when the urine flow rate is
less than 0.5 mL/kg/h for two consecutive hours.
However, oliguria is also context-specific and the
0.5/mL/kg/h threshold may not be appropriate for all.
For example, it may be possible to excrete the daily solute
load at a lower rate of urine production particularly if
patients are not receiving nutrition and are at bed rest.
The 0.5 mL/kg/h threshold was proposed by ADQI for
patients in the ICU where average daily fluid administra-
tion often exceeds 3 L in an adult. In conditions where fluid
use is far less, the threshold may not be as predictive. For
example, Mizota and colleagues recently reported that
intraoperative oliguria only predicts outcome when urine
volume is less than 0.3 mL/kg/h.8 However, the approach
outlined in this chapter is recommended when urine out-
put is less than 0.5 mL/kg/h. Another issue is body compo-
sition. In comparison with adipose, muscle will generate
*Previous edition author.
more nitrogenous waste and therefore require a higher
mean urine output per gram of tissue. We recommend
using lean body mass (or similar approximations) to avoid
over diagnosis of oliguria in obese patients.
One of the most common reasons for a fluid bolus in the
ICU is oliguria. However, routine administration of a fluid
bolus for oliguria has been shown to not improve the urine
output in most cases9 and can potentially cause harm. A
more thorough systematic approach is warranted to under-
stand the pathophysiology of oliguria and implement the
appropriate intervention. The goal of this chapter is to pro-
vide both a physiologic background and a practical clinical
approach to evaluate and treat oliguria.
Pathophysiology
Urine output is a function of the glomerular filtration rate
(GFR) and of tubular secretion and reabsorption. GFR is
directly dependent on renal perfusion. Therefore oliguria
generally indicates either a dramatic reduction in GFR or
a mechanical obstruction to urine flow (Box 18.3).
PRERENAL OLIGURIA
When the cause of oliguria is impaired renal perfusion, it is
often termed “prerenal oliguria.” However, renal perfusion
is a function of circulating volume, cardiac output, mean
arterial pressure, renal vascular resistance, and venous
pressure (back pressure on the renal veins). Hence so-called
prerenal oliguria can occur as the result of an absolute or a
relative decrease in circulating volume, decreased cardiac
output, decreased mean arterial pressure, vascular disease,
or high pressures in the abdomen or right heart. In short,
the term has probably outlived its usefulness as a counter-
point to urinary tract obstruction (postrenal) and it would
be better to focus on the specific pathophysiology that is
occurring.
An absolute decrease in circulating volume can be caused
by hemorrhage or volume losses from a variety of sources.
A relative decrease in circulating volume can be caused
by fluid sequestration after surgery or an increase in the
capacitance of the vasculature that results from vasodila-
tation (e.g., as a result of sepsis). Perioperative cardiac
ischemia or underlying impaired left-ventricular function
can lead to decreased cardiac output and impaired renal
perfusion. A less frequent but serious cause of decreased
cardiac output after major abdominal surgeries is abdom-
inal compartment syndrome (ACS) in which an acute rise
in intra-abdominal pressure both decreases venous return
251
252 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Box 18.1 Criteria for acute kidney injury.
Stage Serum creatinine (SCr) Urine output
Increase to 1.5 to 1.9 times
baseline <0.5 mL/
1 OR kg/h for
Increase of 0.3 mg/dL 6 to 12 h
(26.5 μmol/L)
Increase to 2 to 2.9 times <0.5 mL/kg/h for
2 and anuria at a pressure of greater than 30 mmHg.
baseline 12 h
Increase greater than 3 times
baseline
OR
SCr 4 mg/dL (353.6 μmol/L) <0.3 mL/kg/h for
OR 24 h
3
Initiation of renal replacement OR
therapy Anuria for 12 h
OR
eGFR <35 mL/min/1.73 m2
(<18 years)
to the heart and increases renal venous congestion, dra-
matically impairing renal perfusion. Right-heart failure
and fluid overload also commonly lead to AKI by increas-
ing venous pressure and thus reducing renal perfusion
pressure. Massive postoperative pulmonary thromboembo-
lism and pneumothorax can cause obstructive shock and
decreased cardiac output. Systemic vasodilation leading
to decreased mean arterial pressure (MAP) and renal
hypoperfusion may occur as a result of the inflammatory
response triggered by the surgery itself, sepsis, or medica-
tions (sedative and analgesics).
Finally, other rare causes of decreased renal perfusion and
oliguria include aortic dissection and inflammation (vascu-
litis, especially scleroderma), affecting either the intrarenal
or extrarenal circulation. Renal atheroemboli (usually
caused by cholesterol emboli) generally affect older patients
with a diffuse erosive atherosclerotic disease. This condition
is most often seen after manipulation of the aorta or other
large arteries during arteriography, angioplasty, or sur-
gery.10 This condition may also occur spontaneously or
after treatment with heparin, warfarin, or thrombolytic
agents.
Rarely, decreased renal perfusion may occur as a result of
an outflow problem such as renal vein thrombosis or ACS.
ACS is defined as organ dysfunction that results from an
increase in intra-abdominal pressure. Normal intra-
abdominal pressure is 5–7 mmHg. Abdominal perfusion
pressure (APP) is the pressure difference between the
MAP and intra-abdominal pressure (IAP) (APP ¼ MAP–
IAP). Sustained intra-abdominal pressure >12 mmHg is
called intra-abdominal hypertension. When the IAP is sus-
tained >20 mmHg with or without APP >60 mmHg, it is
called ACS.11 ACS can be seen in a wide variety of medical
and surgical conditions, most often after major abdominal
operations requiring administration of a large volume of
fluid (e.g., ruptured abdominal aortic aneurysm repair),
emergent laparotomies with tight abdominal wall closures,
acute severe pancreatitis, and abdominal-wall burns with
edema. ACS leads to acute oliguria and AKI mainly via
increasing renal outflow pressure, and thereby reducing
renal perfusion. Other possible mechanisms in ACS include
direct renal parenchymal compression and renin-mediated
arterial vasoconstriction. However, evidence suggests that
the rise in renal venous pressure, rather than the direct effect
of parenchymal compression, is the primary mechanism of
kidney injury. Generally, these changes occur in direct
response to the increase in intra-abdominal pressure, with
oliguria developing at a pressure of greater than 15 mmHg
OLIGURIA AS A CONSEQUENCE OF RENAL
TUBULAR INJURY
The most common cause of oliguria in the ICU is AKI. For
many years the term acute tubular necrosis (ATN) was used
to describe AKI caused by an ischemic and/or nephrotoxic
insult. So-called ischemic ATN was thought to result from
untreated “prerenal factors,” while nephrotoxic ATN was
understood to occur as a consequence of the direct nephro-
toxicity of agents such as antibiotics, heavy metals, solvents,
contrast agents, and crystals (uric acid or oxalate). How-
ever, we now understand that most cases of AKI are caused
by a variety of insults affecting the renal tubules and the
microcirculation and that most AKI is in fact a “toxic
nephropathy” whether caused by endogenous mediators
(e.g., cytokines, hemoglobin), bacterial toxins (e.g., endo-
toxin), or medications. Uncommonly, drugs (e.g., nafcillin,
pantoprazole, sulfamethoxazole-trimethoprim, furosemide)
can also cause an acute interstitial nephritis leading to oli-
guria and AKI.
OBSTRUCTIVE OLIGURIA
Oliguria secondary to mechanical obstruction distal to the
kidneys is traditional termed “postrenal” oliguria. This prob-
lem can result from tubular-ureteral obstruction (caused by
stones, papillary sloughing, crystals, or pigment), urethral
or bladder neck obstruction (secondary to prostatic enlarge-
ment), or simply a malpositioned or obstructed urinary
catheter. Rarely, urine volume can be increased in cases
of partial obstruction because of pressure-mediated impair-
ment of urine concentration.
Evaluation of Patients With
Oliguria
Detection of oliguria requires measurement of urine volume.
In recent years, concern for catheter-associated urinary
tract infections has resulted in the reduced use of catheters.
However, in critically ill patients, close monitoring of urine
output has been shown to be associated with improved
detection of AKI, less fluid overload, and improved survival
in patients developing AKI.12 While these observational
results cannot establish a causal relationship, it seems pru-
dent to monitor urine volume closely in critically ill patients
and others at high risk of AKI.
Oliguria is an early manifestation of either reduced renal
perfusion or impaired renal function. If the underlying cause
 18 • Evaluation and Treatment of Acute Oliguria 253

Box 18.2 Panel A: AKI based on urine output and serum creatinine. Panel B: Clinical outcomes of AKI
based on urine output and serum creatinine.
Panel A

N = 32,045 ICU Pasients

UO Only
KDIGO Stage
No AKI Stage 1 Stage 2 Stage 3 Total
SC Only No AKI 8,179 3,158 5,421 440 17,198
Dead 4.3% 5.3% 7.9% 17.7% 5.9%
RRT 0.0% 0.0% 0.1% 1.1% 0.1%

Stage 1 1,889 1,262 3,485 842 7,478

Dead 8.0% 11.3% 13.0% 32.1% 13.6%
RRT 0.3% 0.7% 0.6% 10.9% 1.7%

Stage 2 618 476 1,533 831 3,458

Dead 11.3% 23.9% 21.5% 44.2% 25.5%
RRT 1.0% 1.3% 1.7% 21.7% 6.3%

Stage 3 371 321 1,019 2,200 3,911

Dead 11.6% 38.6% 28.0% 51.1% 40.3%
RRT 3.2% 17.8% 14.2% 55.3% 36.6%

Total 11,057 5,217 11,458 4,313 32,045

Dead 5.6% 10.5% 13.0% 42.6% 14.0%
RRT 0.3% 1.4% 1.7% 34.6% 5.6%

Panel B

1.0
Age adjusted survival function

Group 1
0.8 Group 2
Group 3
Group 4
0.6
Group 5
0.4
Group 6

0.2

0.0
0 50 100 150 200 250 300 365
Days from ICU admission to death

No. at risk
Group 1 8174 7680 7553 7447 7356 7278 7214 7111
Group 2 10465 9405 9101 8905 8744 8605 8473 8335
Group 3 5734 4813 4549 4382 4264 4155 4057 3972
Group 4 2449 1832 1722 1650 1583 1549 1519 1492
Group 5 3013 1910 1698 1592 1533 1489 1465 1436
Group 6 2200 1143 973 899 847 815 793 768

Age-adjusted 1-year survival rates by acute kidney injury (AKI) severity. Groups refer to combinations of urine output (UO) and creatinine
(SC) criteria. Group 1 (green), no AKI by either criterion; group 2 (blue), stages 1–2 by UO criteria but no AKI by SC or stage 1 by SC and no
AKI by UO; group 3 (yellow), stages 1–2 by UO plus stage 1 by SC or stages 2–3 by SC alone; group 4 (orange), stages 1–2 by UO plus stage
2 by SC or stage 3 by UO alone; group 5 (red), stage 3 by UO plus stages 1–2 by SC or stage 3 by SC plus stages 1–2 by UO; and group 6
(dark red), stage 3 by both criteria.

Figures reused from Kellum JA, Sileanu FE, Murugan R, et al. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol 2015;
26(9):2231-2238.
254 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Box 18.3 Causes of oliguria.
Prerenal oliguria
1. Decreased renal perfusion
a. Decreased intravascular volume:
i. Absolute hypovolemia: bleeding, gastrointestinal losses
ii. Relative hypovolemia: third-spacing, vasodilatation
b. Decreased cardiac output: cardiogenic shock, cardiac
tamponade
c. Decreased renal perfusion pressure: sepsis, drugs
2. Increased renal outflow pressure: abdominal compartment
syndrome
Intrarenal oliguria
1. Ischemic acute tubular necrosis: hypotension, untreated
prerenal oliguria
2. Nephrotoxic acute tubular necrosis: drugs (vancomycin,
aminoglycosides), contrast media, rhabdomyolysis
3. Acute interstitial nephritis: nafcillin, furosemide
Postrenal oliguria
1. Urinary obstruction: bilateral renal calculus, prostate enlarge-
ment, Foley catheter obstruction
of oliguria is not corrected, AKI usually results. However,
merely reacting to oliguria, with “shotgun” therapy of
either fluid and/or diuretics (which can be said to fix the
chart while neglecting the patient) is no substitute for mak-
ing a diagnosis and prescribing specific therapy. It is imper-
ative that underlying pathologic mechanism(s) of oliguria
are promptly identified and targeted therapy applied rapidly.
Evaluation of a patient with oliguria includes focused his-
tory taking, chart review, and clinical examination. Supple-
mentary urine testing, including examining the urinary
sediment and measuring urinary electrolytes, may assist
in the diagnosis. However, it is important to be alert to
the possibility that oliguria may be postrenal, because iden-
tification and correction of this cause can be rapidly reward-
ing and avoid wasting time with ineffectual testing and
interventions. Hence, it is worthwhile to rule out urinary
obstruction as a cause of oliguria prior to embarking on
any elaborate workup.
OBSTRUCTIVE OLIGURIA
In the non-ICU setting, a prior history of prostatic hypertro-
phy, recent spinal anesthesia, bladder discomfort, and renal
colic may provide some clues to the presence of distal
obstruction. History of trauma and blood at the urethral
meatus along with perineal ecchymoses and a “high-riding”
prostate can suggest the diagnosis of urethral disruption. A
rapid increase in serum blood urea nitrogen (BUN) concen-
tration and creatinine concentration (especially a doubling
every 24 hours) also suggests a diagnosis of urinary obstruc-
tion. The urine sediment in postrenal failure is often bland
without casts or sediments. Renal ultrasonography is usu-
ally the test of choice to exclude urinary tract obstruction.13
This test is noninvasive and can be performed at the bedside.
It carries the advantage of avoiding the potential allergic
and toxic complications of radiocontrast media. However,
under some circumstances, renal ultrasound may not yield
good results. For example, in early obstruction or in obstruc-
tion associated with severe dehydration, hydronephrosis
may not be seen on the initial ultrasound, although it
may appear on a subsequent study. Computed tomographic
scanning should be considered if the ultrasound results are
equivocal or if the kidneys are not well visualized, or if the
cause of the obstruction cannot be identified. In the ICU set-
ting, distal obstruction appearing as oliguria is commonly
caused by obstruction of the urinary catheter (especially
in male patients). Hence, in patients with new-onset unex-
plained oliguria, the urinary catheter must be flushed or
changed to rule out obstruction. Early diagnosis of urinary
tract obstruction is important because many cases can be
corrected and a delay in therapy can lead to renal injury.
FUNCTIONAL OLIGURIA VERSUS AKI
History
A careful, targeted chart review and clinical examination
can help identify the cause of oliguria. History suggestive
of intravascular volume depletion such as history of vomit-
ing and/or diarrhea, evidence of ongoing bleeding, perioper-
ative fluid losses or deficits (e.g., gastric/ileostomy losses or
vomiting), or extravascular fluid sequestration can point to
a functional cause of oliguria with or without changes in
serum creatinine or urea. Routine clinical examination for
volume status including skin turgor, dry mucosa, and pres-
ence of pedal or sacral edema can help in decision making
but are often insensitive and nonspecific. History of patient
comorbidities, prior myocardial infarction, left ventricular
systolic, or diastolic dysfunction can provide clues to
impaired cardiac output as a cause of oliguria. Fever,
increased white cell count, and a wide pulse pressure indi-
cate sepsis-induced vasodilatation, leading to impaired renal
perfusion and relative hypovolemia. A history of periopera-
tive contrast administration for imaging, of intraoperative
hypotension, or of administration of nephrotoxic agents
can suggest an intrarenal cause of oliguria in an adequately
volume-resuscitated patient.
Clinical Parameters
Although traditional indicators of hydration status and tis-
sue perfusion, such as heart rate, systemic blood pressure,
capillary refill, jugular-venous pulsation, and peripheral
edema can provide guidance for making appropriate inter-
ventions, they are neither sensitive nor specific. In the
ICU, hemodynamic monitoring (measurements of central
venous pressure [CVP], pulmonary artery occlusion pres-
sure [PAOP], or mixed/central venous oxygen saturation)
can provide some information about intravascular volume
status. However, many of these traditional measures may
be unreliable in the critically ill patient. The jugular-venous
pulsation does not provide any information about left heart
function and is not an accurate surrogate for right ventric-
ular filling pressures in the presence of positive-pressure
ventilation and positive end-expiratory pressure (PEEP).
Similarly, peripheral edema is often caused by hypoalbumi-
nemia and decreased oncotic pressure in critically ill
patients. Thus patients may exhibit total body water
overload and yet be intravascularly volume depleted. In

addition, blood pressure and heart rate are affected by
numerous physiologic and treatment variables in the ICU
and are unreliable measures of volume status. In the
ICU, increased CVP or PAOP does not ensure adequate pre-
load and low values are not specific for fluid responsive-
ness. These parameters assume a linear pressure–volume
relationship that is often not the case in sick patients with
comorbidities. Moreover, studies have shown very poor
correlation between these parameters and fluid responsive-
ness.14 Assessment for fluid responsiveness including the
newer dynamic measures such as inferior vena cava
(IVC) diameter and collapsibility, passive leg raise maneu-
ver or changes in stroke volume variation (SVV) or cardiac
output resulting from heart–lung interactions provide a
more accurate estimate of whether a patient will benefit
from a fluid bolus. These measures require continuous car-
diac output monitoring using one of the newer pulse con-
tour techniques. An arterial pulse pressure variation (PPV)
greater than 13% in a patient who is not breathing spon-
taneously and who is on positive-pressure ventilation (TV
8 mL/kg or higher) is highly predictive of fluid responsive-
ness (reflecting the likelihood that a fluid challenge will
increase cardiac output). In a spontaneously breathing
patient or in a patient with arrhythmia, an increase in car-
diac output by >10% with passive leg raise is a strong indi-
cator of fluid responsiveness. Although each of these
dynamic measures has their fallacies, when two or three
of them are combined at the bedside, they provide valuable
information on whether a fluid bolus will improve the car-
diac output.
Bedside hemodynamic assessment using ultrasound is
now standard care in the hemodynamic optimization of a
critically ill patient and hence should be incorporated with
other parameters in deciding the appropriate interven-
tion.15 Evaluation of IVC size and respiratory variation in
diameter provide insight into the intravascular volume.
Looking at the left and right ventricular size and contractil-
ity will help decide on the need of inotropes. Bedside ultra-
sound also enables the clinician to rule out quickly
obstructive shock caused by pericardial tamponade, pneu-
mothorax, and massive pulmonary embolism. In addition
to assessment of fluid responsiveness, it is imperative that
fluid tolerance be assessed. Although worsening hypoxemia
or lung crackles may provide some clues, they are insensi-
tive and nonspecific. B-lung profile on lung ultrasound sug-
gests increasing fluid overload16 and when available,
combining it with estimation of the extravascular lung
water17 by one of the new commercially available pulse
contour cardiac output monitors will help the clinician
decide whether the patient can tolerate more fluids. When
a patient is thought to be fluid responsive and fluid tolerant,
a fluid challenge with 250 to 500 mL of isotonic crystalloid
is necessary to assess the clinical response.
Finally, ACS should be suspected in any patient with a
tensely distended abdomen, progressive oliguria, or an
increased airway pressure (transmitted across the dia-
phragm). The mainstay of the diagnosis is measurement
of intra-abdominal pressure. The most common measure
of intra-abdominal pressure is by bladder pressure, which
is easily accessible. Bladder pressure has been shown to cor-
relate well with intra-abdominal pressure over a wide range
of pressures.
18 • Evaluation and Treatment of Acute Oliguria 255
Laboratory Parameters
Although the yield may be low, examining the urine sedi-
ment may provide some important insight into the cause
of oliguria. The presence of tubular epithelial casts increases
the likelihood of AKI. However, the discriminating ability of
this finding is very limited. The main usefulness of examin-
ing the urine sediment is for detecting red cell casts, which
indicate glomerular disease (rare in the ICU setting). Urine
eosinophilia is neither sensitive nor specific for acute inter-
stitial nephritis and should not be relied on.
Urine sodium and urea concentrations can be of value in
assessing oliguria. A fractional excretion of sodium (FENa) is
more accurate, and a value less than 1% has traditionally
been used as a marker for a prerenal cause of oliguria,
whereas a value greater than 1% generally suggests a loss
of tubular function and hence AKI. Importantly, conditions
such as rhabdomyolysis, contrast nephropathy, and sepsis
are all causes of AKI in which FENa can be low.18 Further-
more, these indices are unreliable once the patient has
received diuretic or natriuretic agents (including dopamine
and mannitol) and may also be confounded by endogenous
osmolar substances such as glucose or urea. In patients who
have received diuretics, fractional excretion of urea (FEurea)
may be useful. The FEurea is 50% to 65% in normal subjects
and usually below 35% in settings where oliguria is not
caused by tubular damage per se. A recent study concluded
that a low FEurea (35%) was a more sensitive and specific
index than FENa in identifying intact tubular function espe-
cially if diuretics were administered.19
Several biomarkers have been evaluated in AKI and their
utility in predicting progression of AKI in critically ill
patients explored.20 Biomarkers in AKI can be stratified into
those that primarily correspond to GFR (Cystatin C) and
those that reflect tubular damage (e.g., neutrophil
gelatinase-associated lipocalcin [NGAL], kidney injury
molecule-1 [KIM-1]) or stress (tissue inhibitor of
metalloproteinases-2 [TIMP-2] and insulin-like growth fac-
tor binding protein 7 [IGFBP 7]). NGAL is a 25 kDa protein
of the lipocalcin family that is produced at the thick ascend-
ing loop of Henle and the intercalated cells of the collecting
duct. NGAL has been detected as early as 3 hours after
injury and it remains elevated up to 5 days based on AKI
severity. Several studies have found NGAL to be a useful
marker in predicting AKI onset and progression in a varied
population.21
Few biomarkers have been tested against full AKI criteria
including urine output. One exception is the combination of
TIMP-2 and IGFBP 7, which has been validated to predict
moderate to severe (stages 2–3) AKI using serum creatinine
and urine output criteria.22 The test has been validated
using expert adjudication23 and has been approved by the
US Food and Drug Administration. Importantly, biomarkers
may have a role in evaluating oliguria. Koyner et al. found
that death or dialysis at 9 months after ICU admission was
lowest for patients without AKI but significantly increased
in biomarker-positive patients (using TIMP-2 and IGFBP
7) with AKI compared with those with AKI who were bio-
marker negative.24
In addition to biomarkers, there is an increasing number
of published studies on the use of furosemide in the evalua-
tion of oliguria. In a recent study, Koyner et al. used a
256 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
furosemide stress test (FST) to evaluate renal tubular func-
tional integrity and its ability to predict progression of AKI
and compared its performance with traditional bio-
markers.25 In this study, a standard intravenous dose of
furosemide (1 mg/kg for furosemide naive patients and
1.5 mg/kg for furosemide exposed patients) was adminis-
tered to patients with stage 1 or 2 AKI and the authors
found a cut-off 2-hour urine output of <200 mL to be highly
predictive of progression to stage 3 AKI (area under the
curve [AUC]: 0.87) and need for RRT (AUC: 0.86). In a
recent randomized control trial, FST nonresponse was used
as a strategy to identify patients who might need RRT and
these patients were randomized to early versus standard
RRT.26 Although this small study did not find any differ-
ences between treatment groups, it is one of the first studies
to utilize a clinically applicable functional marker of AKI to
select a population that may potentially need and benefit
from RRT. Importantly, authors have cautioned that FST
should not be attempted on hypovolemic patients and ample
care should be exercised when using it.
Treatment
Sometimes a good rule is “don’t just do something; stand
there.” Telephone orders from the on-call room for fluids
and then for diuretics, or for both at the same time, are
far too common an occurrence in modern ICUs, and such
practices are inherently dangerous. Oliguria is a clinical
sign, not a diagnosis. There is no single therapeutic strategy
for oliguria; there are only treatments for conditions that
cause it. Augmenting urine output with forced diuresis only
masks the problem and may actually worsen fluid depletion.
Conversely, the assumption that all oliguria is fluid respon-
sive until proven otherwise leads to fluid overload. Always
evaluate first and treat the underlying cause of oliguria,
not the urine output.
HYPOVOLEMIA AND SHOCK
Although hypovolemia is a common contributing factor in
the development of oliguria, it is important that careful
assessment of fluid status, preload responsiveness, and fluid
tolerance be performed and thoughtful decision taken
before a fluid bolus is given. Routine empiric fluid therapy
for every episode of oliguria should be strongly discour-
aged. Both the type of fluid and the volume of fluid given
have important therapeutic implications. When fluid ther-
apy is needed, 500 mL of crystalloid with physiologic
amounts of chloride such as Ringer lactate or one of the
newer balanced crystalloids should be administered.
Hyperoncotic colloids such as 20% albumin and several
starch preparations have been shown to cause AKI and
to increase the need for RRT and mortality and hence
should be avoided.27–29 Although 5% albumin has been
shown to be equivalent to normal saline,30 its relatively
short intravascular half-life (only slightly longer than crys-
talloids) and higher cost make it less preferred fluid com-
pared with crystalloids. Importantly, 0.9% saline should
be avoided except in select cases (e.g., acute hyponatremia
with hypochloremic alkalosis) because it can potentially
worsen AKI.31,32
Fluid overload caused by repeated overzealous fluid
boluses has been consistently shown to worsen AKI and
mortality.33,34 Fluid overload increases renal intracapsular
and renal venous pressures leading to renal hypoperfusion.
Hence fluid boluses for oliguria should be done only when
the patient is hypotensive, with a low cardiac output, and
there is clear evidence of preload responsiveness and fluid
tolerance. Renal hypoperfusion is quite common in critically
ill patients since the autoregulatory mechanisms that main-
tain GFR despite fluctuations in MAP are disrupted in
patients with sepsis or other causes of AKI. Hence, in these
patients, renal perfusion is directly related to systemic arte-
rial pressure. Therefore rapid correction of hypotension with
fluid resuscitation when indicated and often with vasoactive
drugs is paramount. Vasoactive drugs should be initiated
once adequate intravascular volume has been ensured. In
critically ill patients, vasoactive drugs may be initiated con-
currently with volume expansion when life-threatening
hypotension exists. Vasoactive drugs, once initiated, should
be titrated to maintain adequate mean arterial pressures.
The ideal blood pressure to aim for in patients with oliguria
must be individualized on the basis of factors such as pre-
morbid blood pressure or presence of vascular disease but
rarely below MAP of 65 mmHg. Similarly, in patients with
chronic hypertension and renal vascular disease, the auto-
regulation curves are shifted to the right and therefore a
higher MAP may be required to ensure adequate renal per-
fusion.35 Hemodynamic monitoring devices may provide
important information to guide assessment of intravascular
volume status and may enable a more streamlined, goal-
directed approach to therapy.
CARDIAC DYSFUNCTION AND ACS
Some patients may have impaired cardiac contractility (left-
or right-sided) despite adequate intravascular volume.
These patients may require treatment with an inotrope to
improve renal perfusion. Finally, if ACS is diagnosed, prompt
measures to decrease intra-abdominal pressure including
operative decompression of the abdominal cavity with
maintenance of an open abdomen through use of temporary
abdominal wall closure techniques should be considered to
improve renal perfusion.
Low-dose dopamine (<5 μg/kg/min) is not recommended
to augment renal perfusion in patients with oliguric AKI.
Dopamine increases urine output because it is a natriuretic
agent mediated by inhibition of Na+- K+ - ATPase at the
tubular epithelial cell level and not by increasing renal per-
fusion. There is abundant evidence that low-dose dopamine
does not afford any renal protection in oliguria. One multi-
center randomized controlled trial and two comprehensive
meta-analyses of dopamine in critically ill patients have
shown that dopamine does not prevent the onset of AKI,
decrease mortality, or reduce the need for RRT.36–38
The selective dopamine-1 agonist fenoldopam was evalu-
ated in a multicenter trial that randomized 315 patients
with baseline creatinine clearance less than 60 mL/min to
fenoldopam mesylate or placebo39 and found no difference
between the groups in the incidence of contrast nephropa-
thy. Furthermore, fenoldopam has been shown to cause
hypotension and therefore can predispose patients to AKI
by reducing renal perfusion pressure.40 On the basis of these

data, we strongly recommend against the use of dopamine
and fenoldopam to augment renal perfusion in patients with
oliguria.
OLIGURIA SECONDARY TO AKI
Continued maintenance of adequate intravascular volume,
maintenance of an adequate MAP, and avoidance of neph-
rotoxic agents are the only interventions shown to impact
outcome once AKI has occurred. The use of diuretic agents
in oliguric renal failure is widespread despite the convincing
lack of evidence supporting efficacy. Traditionally, diuretics
have been used in the early phases of oliguria in an attempt
to convert oliguric AKI to nonoliguric AKI. Presumably, the
absence of oliguria makes it easier to regulate volume status
and prevent fluid overload. Many small trials have evaluated
the efficacy of loop diuretics in preventing AKI and have pro-
vided inconsistent results. One systematic review compared
fluids alone with diuretics in people at risk of AKI from var-
ious causes. This study failed to show any benefit from
diuretics with regard to incidence of AKI, the need for dial-
ysis, or mortality.41 Two extensive observational studies
have been published on diuretic use in AKI and have pro-
vided conflicting results. The first was a cohort study
(PICARD study) of patients with AKI in the ICU, in which
patients were characterized by the use of diuretics on or
before the day of renal consultation.42 In this study, with
adjustments for relevant covariates and propensity scores,
diuretic use was associated with significantly increased risk
for death or nonrecovery of renal function (odds ratio [OR],
1.77; 95% confidence interval, 1.14–2.76). Although this
association does not establish a causal link between diuretic
use and harm in the setting of oliguric AKI, it does suggest
that this therapy does not afford any benefit to the kidney.
Subsequently, a recent multinational observational study of
1743 patients evaluated the effect of loop diuretics on clin-
ical outcomes.43 The study investigators created three mul-
tivariate models to assess the relationship between
diuretics and mortality and found that diuretic use was
not significantly associated with increased mortality in
any of the three models (OR for death was about 1.2 in
all three models). However, no benefit was seen. On the
basis of the current evidence, diuretics should never be
considered a treatment for oliguria but may be necessary
to prevent and manage volume overload in critically ill
patients.
Finally, oliguric patients with fluid overload not respond-
ing to a diuretic trial should be considered for early RRT.
Although there is little dispute about the necessity of renal
replacement therapy for the treatment of fluid overload
refractory to diuretic therapy, there is no consensus on
the degree of azotemia or duration of renal failure warrant-
ing initiation of therapy in the absence of this absolute indi-
cation. When oliguria persists and AKI progresses despite
optimization of volume, maintenance of adequate MAP,
improved hemodynamics or a diuretic trial, RRT should
be considered sooner rather than later. Current available
evidence does not allow recommendation of the optimal
timing of the initiation of renal replacement therapy. The
FST discussed previously may have a role in identifying
patients who are likely to recovery quickly and for whom
early RRT is not indicated.
18 • Evaluation and Treatment of Acute Oliguria 257
OLIGURIA SECONDARY TO OBSTRUCTION
The definitive treatment for obstructive oliguria is to relieve
the obstruction. This might be as simple as flushing or
changing the urinary catheter. Other patients require more
invasive procedures such as a percutaneous nephrostomy or
a suprapubic decompression of the bladder. Prompt man-
agement is the key to avoiding renal injury.
Conclusion
Oliguria is one of the most common clinical problems
encountered by physicians caring for perioperative patients
in the ICU. Any delay in its recognition and treatment can
lead to the progression to AKI, which in turn carries signif-
icant morbidity and mortality. Hence, the presence of oli-
guria should alert the clinician to undertake a diligent
search for any correctable underlying causes (Box 18.3).
Ensuring adequate renal perfusion through optimization
of volume status, cardiac output, and MAP together with
avoidance of nephrotoxins is key. Diuretic use may not alter
the need for RRT or outcomes. Diuretics may be required to
treat fluid overload, but they are not treatments for oliguria.
Early renal replacement therapy should be considered in
patients with oliguria secondary to AKI and fluid overload
especially if they fail to respond to diuretics.
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 19 Perioperative Management
of Renal Failure and Renal
Transplant
HOLDEN K. GROVES and H.T. LEE
Introduction
Safely guiding the patient with renal failure through the
perioperative period presents a challenging set of problems
such as the substantial comorbidity associated with chronic
kidney disease (CKD), the risk of acute kidney injury
(AKI), management of perioperative dialysis, and altered
pharmacology.
Patients presenting with renal failure fall into two distinct
classes: acute renal failure or chronic renal failure (CRF).
Although acute and chronic renal failure are clinically sep-
arate entities, recent advances in epidemiology suggest a
complex interplay between preexisting kidney disease, acute
kidney injury, and the progression of CKD.1
Acute Renal Failure
Patients might present with acute renal failure when arriv-
ing for surgery. This is often the case in an emergency sur-
gery or a critically ill patient coming to the operating room
from the intensive care unit. Traditionally, acute renal fail-
ure has been subdivided by etiology (prerenal azotemia,
postrenal urinary tract obstruction, and intrinsic renal dis-
ease). This subdivision is helpful because it suggests a treat-
ment approach such as percutaneous nephrostomy tube
placement to treat urinary tract obstruction.
Advances in epidemiology reframed the classification sys-
tem of acute renal failure by degree of injury and expected
outcome. This classification system has gone through sev-
eral versions in recent decades from RIFLE (risk, injury, fail-
ure, loss, end-stage renal disease [ESRD]) to AKIN (Acute
Kidney Injury Network) to KDIGO (Kidney Disease: Improv-
ing Global Outcomes). All three systems share a common
theme where increases in baseline creatinine or decreases
in urine output are associated with adverse outcomes.
The current internationally accepted grading system for
AKI is provided by KDIGO (Table 19.1). KDIGO stage 1 is
characterized by a high sensitivity for AKI and stage 3 iden-
tifies patients at highest risk of needing renal replacement
therapy. While the primary purpose of the KDIGO grading
system is for research, it is useful for the perioperative phy-
sician to standardize their understanding of the degree of
acute kidney injury.
Patients presenting for surgery with acute renal failure are
a particularly comorbid group and deserve special attention. A
recent large study of vascular surgery patients demonstrated
AKI is an important indicator of perioperative harm in patients
undergoing surgery.2,3 Managing patients with AKI is essen-
tially the same as managing patients with CKD in that the goal
is preservation of kidney function. Specific aspects of manage-
ment will be discussed later in the chapter.
Chronic Renal Failure
Chronic renal failure indicates the progressive spectrum of
CKD from a mild decrement in renal function to severe renal
failure (also called ESRD). The term end-stage renal failure
persists in the literature because it has important implica-
tions for dialysis coding in the United States. When a patient
has progressed to ESRD, they require renal replacement ther-
apy or transplantation to sustain life. Without these thera-
pies they will die from pulmonary edema or hyperkalemia.
Physiologically, renal failure is a reduction in the number
or function of nephrons in the kidney that leads to reduced
ability to filter the blood. The National Kidney Foundation
Disease Outcomes Quality Initiative (K/DOQI) provided a
consensus definition of renal failure in 2002.4 This definition
used a glomerular filtration rate of less than 60 mL/min/
1.73m2 lasting for more than 3 months to identify CKD. This
step was important because it changed the conceptual frame-
work for diagnosing CKD from a disease that only affected a
few patients with end-stage kidney disease to a progressive
disorder that affects a large percentage of the population.5
The K/DOQI definition further subdivided renal failure based
on glomerular filtration rate into five classes ranging from
CKD stage 1 (mild impairment of glomerular filtration) to
CKD stage 5, more commonly referred to as ESRD as shown
in Table 19.2. In 2012, a second collaborative, Kidney Dis-
ease Improving Global Outcomes (KDIGO) issued an updated
definition of chronic kidney disease that expanded on the pre-
vious definition to include albuminuria.6
The modern perioperative physician interested in optimiz-
ing outcomes approaches CKD as a progressive spectrum
rather than a dichotomous state (healthy versus renal fail-
ure) for four reasons discussed in following sections.
CHRONIC KIDNEY DISEASE IS COMMON
The global burden of CKD is substantial with a prevalence
estimated at 8%–16%.7 Over one million deaths have been
reported worldwide from CKD and the burden of CKD is
increasing. In 1990, CKD was the 27th leading cause of
death in the world, but by 2013 it had become the 13th
259
260 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 19.1 Kidney Disease: Improving Global Outcomes Table 19.3 Clinical abnormalities in patients with chronic
(KDIGO) acute kidney injury criteria. renal failure.
KDIGO Creatinine FLUID AND ELECTROLYTE DISTURBANCES
stage Concentration Urine Output
▪ Hypervolemia, hypovolemia
1 1.5–1.9  baseline <0.5 mL/kg/h for 6–12 h ▪ Hypernatremia, hyponatremia
0.3 mg/dL above ▪ Hyperkalemia, hypokalemia
baseline ▪ Hyperphosphatemia
▪ Hypocalcemia
2 2.0–2.9  baseline <0.5 mL/kg/h for >12 h ▪ Metabolic acidosis
3 3.0  baseline <0.3 mL/kg/h for 24 h or CARDIOVASCULAR DISTURBANCES
Initiation of renal anuria for 12 h
replacement therapy ▪ Hypertension
▪ Coronary artery disease
▪ Generalized atherosclerosis
▪ Vascular calcifications
Table 19.2 Chronic kidney disease (CKD) staging. ▪ Congestive heart failure
▪ Pericarditis
Chronic Kidney GFR mL/min/
Disease stage Definition 1.73 m2 HEMATOLOGIC AND IMMUNOLOGIC DISTURBANCES
▪ Anemia
1 Kidney damage with normal 90 ▪ Bleeding diathesis
GFR ▪ Increased susceptibility to infection
2 Kidney damage with mild 60–89 GASTROINTESTINAL DISTURBANCES
decrease in GFR
▪ Gastritis
3A Mild-moderate decrease in 45–59 ▪ Peptic ulcer
GFR ▪ Bleeding
▪ Nausea and vomiting
3B Moderate-to-severe 30–44 Delayed gastric emptying
decrease in GFR
▪
4 Severe decrease in GFR 15–29 NUTRITIONAL AND METABOLIC DISTURBANCES

5 End-stage renal disease <15

GFR, glomerular filtration rate.
leading cause of death in the world.8 CKD also significantly
detracts from patients’ quality of life and is associated with
cardiovascular mortality. The prevalence of earlier stages of
CKD is 100 times greater than the prevalence of patients
with ESRD requiring dialysis or transplantation, which is
0.1%.9 CKD is age-related: the median prevalence of CKD
was about 7% in people older than 30 years of age but about
30% among patients 64 years or older.10 As the population
of patients presenting for surgery increases there will be an
increase in the perioperative prevalence of CKD.
A diverse set of pathologies contribute to the development
of CKD (Table 19.3). In the developed world, the leading
causes of CKD are old age, diabetes, hypertension, obesity,
and cardiovascular disease.11 The underlying pathological
process is often difficult to discern exactly, but the two most
common processes are diabetic glomerulosclerosis and
hypertensive nephrosclerosis.
Because of its overall prevalence, many patients presenting
for surgery have CKD. Among those presenting for major sur-
gery, 8% have CKD and 4% have end-stage renal failure.12
Among patients presenting for vascular surgery, the rate
CKD is much higher, estimated at 30% in one study of patients
presenting for carotid endarterectomy,13 probably reflecting
the association between CKD and cardiovascular disease.
CHRONIC KIDNEY DISEASE INCREASES
CARDIOVASCULAR RISK
Cardiovascular mortality is 30 times higher in patients with
CKD and patients with CKD are more likely to die from
▪ Carbohydrate intolerance
▪ Hypertriglyceridemia
▪ Protein-energy malnutrition
▪ Hypoalbuminemia
NEUROLOGIC DISTURBANCES
▪ Encephalopathy
Peripheral neuropathy
▪
▪ Autonomic neuropathy
▪ Fatigue
▪ Lethargy
▪ Impaired mentation
▪ Neuromuscular irritability
▪ Hiccups
▪ Muscle cramps and fasciculations
cardiovascular causes than to progress to ESRD.14 Cardio-
vascular disease (CVD), in the form of hypertension, coro-
nary artery disease (CAD), and congestive heart failure
are the most common causes of morbidity and mortality
in patients with CKD and account for greater than 50% of
the mortality in this group.15
Large population studies demonstrate that even mild
CKD is associated with an increased risk of cardiovas-
cular events, death, and hospitalization. Moderate CKD
(GFR 15–29 mL/min/1.73 m2) and severe CKD (eGFR less
than 15 mL/min/1.73 m2 without dialysis were associ-
ated with very high rates of adverse events almost as high
as those with ESRD.14
For patients with ESRD who are treated with dialysis,
CVD mortality is 10 to 30 times higher than for patients
in the general population.16 The etiology of CVD in patients
with CKD is multifactorial, stemming from preexisting con-
ditions (diabetes and hypertension), uremia (toxins, hyper-
lipidemia, and hyperhomocysteinemia), and for those with
 19 • Perioperative Management of Renal Failure and Renal Transplant
ESRD, dialysis-related conditions such as dialysis membrane
reactions and hemodynamic instability episodes. Hyperten-
sion is the most common cardiovascular problem in patients
with chronic renal disease (CRD). It is associated with fur-
ther impairment of renal function and progression of CVD.
Patients with CKD often have co-occurring left ventricu-
lar hypertrophy that develops secondary to long-standing
pressure and volume overload.17 Several CKD-related fac-
tors may contribute to the development of left ventricular
hypertrophy, including chronic sodium and water retention
leading to volume overload, increased cardiac output from
an arteriovenous fistula, and chronic anemia. Pressure
overload may result from increased afterload secondary to
hypertension and arteriosclerosis that develops concomi-
tantly with progressive CKD. It is important to identify left
ventricular hypertrophy because it affects intraoperative
management. Important points include sensitivity to ade-
quate preload for a stiff ventricle and diastolic dysfunction,
which may lead to flash pulmonary edema.
Myocardial infarction is a risk for patients with CKD.
Patients with CKD often suffer from accelerated athero-
sclerosis because of the combination of hypertension, dys-
lipidemia, and often diabetes contributing to endothelial
dysfunction. CKD can also contribute to accelerated ath-
erosclerosis via the production of reactive oxygen species.
Finally, increased calcifications lead to vascular calcifica-
tions, which can precipitate vascular injury.18
The association between CVD and CKD has long been rec-
ognized in the perioperative arena. The most commonly used
risk stratification system, the revised cardiac risk index (RCRI)
for cardiac complications after noncardiac surgery,19 iden-
tifies preoperative serum creatinine >2.0 mg/dL as an inde-
pendent predictor of increased risk of cardiac complications.
Long-term hemodialysis through arteriovenous (AV) fis-
tulas is associated with a 40% incidence of development
of pulmonary hypertension. The reason for this is unclear
and a corresponding development in patients undergoing
peritoneal dialysis has not been demonstrated.20 Pulmonary
pressures normalize in the majority of patients after kidney
transplantation. The creation of AV fistulas may also lead to
increased cardiac output, which further increases the car-
diac workload. Pulmonary hypertension in a patient with
an AV fistula is particularly at high risk of mortality.21 Con-
gestive heart failure, which has a prevalence of 40% among
hemodialysis and peritoneal dialysis patients, is an indepen-
dent predictor of death.16
CHRONIC KIDNEY DISEASE IS A RISK FACTOR FOR
ACUTE KIDNEY INJURY
Patients with preoperatively reduced kidney function are at
risk of suffering acute or chronic kidney injury in the peri-
operative period. Preoperative renal failure is a risk factor
for postoperative renal failure.22 The link between CKD
and AKI risk is undergoing intense research.
ACUTE KIDNEY INJURY ACCELERATES THE
PROGRESSION OF CHRONIC KIDNEY DISEASE
There is an association between acute kidney injury, even
minor acute kidney injury, and the subsequent development
of chronic kidney disease in hospitalized patients.23–25
261
Hospitalized patients with preexisting CKD and AKI are
40 times more likely to progress to ESRD as those without
CKD or AKI.26 Several mechanisms explaining the progres-
sion of CKD after AKI have been proposed including
maladaptive repair, impaired regeneration, and ongoing
organ dysfunction.1
Pathophysiology of Chronic Renal
Failure
UREMIA
Uremia occurs with ESRD when the kidney can no longer
adequately filter blood and organic waste products accumu-
late.27 Uremia is a combination of symptoms that presents
insidiously with increasing anorexia and lethargy. The clas-
sic signs and symptoms of advanced uremia include uremic
pericarditis, uremic frost on the skin, headaches, nausea,
seizures, and sleep disturbances. Untreated uremia may lead
to coma and even death. However, the advanced complica-
tions of uremia are rarely seen because uremia can be
reversed with dialysis or renal transplantation. Although
temporarily reversible with dialysis, chronic exposure to
uremia is associated with insulin resistance,28 oxidative
stress,29 and systemic inflammation, which can accelerate
both cardiovascular disease and kidney disease.
Urea is only one of the organic waste products that accu-
mulate and is not closely linked to the signs and symptoms
of uremia. Some of the other organic waste products include
guanidines, which at appreciable levels in the cerebral spi-
nal fluid correlate with altered mental function.30 Other
nitrogen-containing solutes that accumulate include mono-
methylamine, dimethylamine, and trimethylamine, which
are produced by human cells and gut microbiota.31 They
represent the basic pathophysiologic disorder of uremia,
i.e., defective ion transport across cell membranes, resulting
in intracellular sodium and water accumulation. The only
cure is to replace renal function, i.e., dialysis or transplanta-
tion. Uremia is an indication for dialysis and a harbinger of
ESRD. A uremic patient in the perioperative period should
be closely evaluated.
FLUID AND ELECTROLYTE BALANCE
Sodium and Water Homeostasis
Patients with severe renal disease, especially those on dial-
ysis, are extremely sensitive to excess salt and water intake,
which can cause hypervolemia, hypertension, and pulmo-
nary edema. In patients with mild or stable CKD, the body’s
sodium and water content are modestly increased. This
chronic mild fluid overload can stimulate chronic low level
inflammation and accelerate the progression of renal dis-
ease.32 One proposed mechanism is that the chronic edema
alters gut permeability releasing inflammatory mediators.33
One of the essential functions of the kidney is to manage
sodium homeostasis. Patients with impaired renal function
are unable to tolerate sodium loading either through dietary
intake or iatrogenic from large volumes of saline solution.
Large volumes of saline solution will result in hyperchlore-
mic metabolic acidosis in patients with impaired renal
262 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
function. The hypercholeremia may reduce renal blood flow
and GFR.34
In contrast, patients with ESRD have impaired mecha-
nisms for conserving sodium, which can lead to volume
depletion. This makes patients with ESRD particularly prone
to the deleterious effects of extrarenal fluid losses such as
diarrhea, vomiting, and sweating. The resulting hypovole-
mia can worsen prerenal kidney disease and result in acute
renal failure. In some cases, gentle volume loading may be
considered in the perioperative period.35
Potassium Balance
Hyperkalemia is a frequent safety event for patients with
CKD.36 One reason that patient with CKD are at risk of
hyperkalemia is that many of the medications that treat
CKD increase the risk of hyperkalemia (potassium >5.5).
Acute hyperkalemia may suppress electrical conduction in
the heart leading to asystolic cardiac arrest. Hyperkalemic
asystolic cardiac arrest is often preceded by prolonged PR
interval, widened QRS, and tall peaked T waves, but be
aware that hyperkalemic asystole has been reported with-
out these electrocardiogram (ECG) changes.
Patients with stage 5 CKD are at risk of developing hyper-
kalemia for several reasons either from exogenous potas-
sium or transcellular potassium shifts caused by acidosis
or insulin deficiency. Beta blockers may increase the risk
of hyperkalemia. Other important causes of hyperkalemia
in a patient with CKD include: rhambomyolysis secondary
to trauma or major surgery, catabolic state such as
sepsis, non-steroidal anti-inflammatory drugs (NSAIDS),
angiotensin-converting enzyme inhibitors, potassium spar-
ing diuretics, nephrotoxic drugs such as cyclosporine or
aminoglycosides, or radiocontrast material (Table 19.4).
Hyperkalemia is an indication for perioperative dialysis.
Some patients with CRF tolerate stable potassium levels of
6 to 6.5 mmol/L without showing any conduction distur-
bances. However, if potassium levels increase to higher than
that, these patients may rapidly show signs of hyperkalemia.
A preoperative potassium level of 6 mmol/L or greater
should be corrected before the start of anesthesia unless
there is a dire emergency. Treatment alternatives for lower-
ing potassium level consist of normalizing pH if acidosis is
present, and intravenous administration of insulin or glu-
cose and/or a beta-2-adrenergic agonist, all of which work
by shifting potassium into the cells. Dialysis or administra-
tion of sodium polystyrene sulfonate, either orally or as
an enema, removes potassium ions.37
Hypokalemia in patients with CKD usually reflects diuretic
use. A study in cardiac surgery patients demonstrated that
Table 19.4 Causes of hyperkalemia in patients with chronic
renal failure.
▪ Acute acidosis
Rhabdomyolysis (trauma, major surgery)
▪
▪ Increased catabolism, sepsis
▪ Non-steroidal anti-inflammatory drugs
▪ Angiotensin-converting enzyme inhibitors
▪ Potassium-sparing diuretics
▪ Beta-blockers
▪ Nephrotoxic drugs (cyclosporine, aminoglycosides)
▪ Radiocontrast material
preoperative hypokalemia was associated with serious peri-
operative arrhythmias.38 More rarely, hypokalemia is asso-
ciated with primary renal potassium wasting, as seen in
Fanconi syndrome, Bartter syndrome, and renal tubular aci-
dosis. Acute hypokalemia increases excitability and lowers
the arrhythmia threshold. Both supraventricular and ven-
tricular arrhythmias may occur. These may be refractory
to normal antiarrhythmic treatment until the serum potas-
sium concentration is normalized.
Magnesium Balance
Magnesium dysregulation in CKD can result in complica-
tions and may result from inadequate dialysis. Hyper-
magnesemia may cause muscle weakness and potentiate
nondepolarizing muscle relaxants. Hypomagnesemia may
result in the development of both supraventricular and ven-
tricular arrhythmias.
Calcium Phosphate Balance
Secondary hyperparathyroidism is common in patients with
CKD. Dysregulated calcium and phosphate balance is a hall-
mark of CKD. Phosphate is regulated by renal extraction. A
decrement in glomerular filtration rate allows for the accu-
mulation of phosphate. Retained phosphate directly stimu-
lates parathyroid hormone (PTH) synthesis and indirectly
causes PTH release by lowering ionized calcium levels and
suppressing calcitriol production. Calcitriol is necessary for
calcium absorption from the gastrointestinal (GI) tract.
Without calcitriol, ionized calcium levels fall, stimulating
PTH secretion and proliferation of parathyroid cells. This
syndrome is called hyperparathyroidism.
Secondary hyperparathyroidism ultimately leads to high
bone resorption and turnover, abnormal osteoid production,
and weak bone strength. Consequently, these patients are at
high risk of fractures.
A rare but interesting complication of abnormal calcium-
phosphate production is calciphylaxis in which extraoss-
eous calcifications accumulate in soft tissues and blood ves-
sels. This can even cause a painful itchy rash when
deposited in the skin. Accelerated calcification of coronary
arteries may be one factor predisposing progressive coro-
nary artery disease in patients with CKD and similarly accel-
erate deposition in arteries and arterioles, causing stiff
arterioles and blood vessels. Phosphate binders such as seve-
lamer are typically given to these patients. Sometimes these
patients are also treated with bisphosphonates.
Metabolic Acidosis. Patients with mild CKD typically pre-
sent with a mild, chronic anion-gap metabolic acidosis.
These patients are unable to excrete acid adequately
because the failing kidney cannot synthesize ammonia.
Consequently, they develop a metabolic acidosis with
reduced plasma bicarbonate. This chronic metabolic acido-
sis is often treated in the outpatient setting with oral sodium
bicarbonate. A recent systemic review allayed concerns that
IV sodium bicarbonate caused hypotension and volume
overload. It may be necessary to treat patients with IV
sodium bicarbonate in the perioperative period.39
But be aware that the reduced bicarbonate leads to the
CKD patient’s reduced ability to buffer an acid load. There-
fore, postoperative respiratory or lactic acidosis can quickly
 19 • Perioperative Management of Renal Failure and Renal Transplant
become severe. A common consequence of this is severe
hyperkalemia.40
Vascular Access. Vascular access can be particularly vex-
ing for the perioperative physician taking care of the patient
with ESRD. Patients treated with dialysis or those soon to
need dialysis require preservation of vascular access. Vascu-
lar access can be maintained either through arteriovenous
fistula (AVF), arteriovenous graft (AVG), or long- or short-
term catheters. Long-term catheters are often tunneled. For
long-term dialysis, AVF is preferable to tunneled catheters
because it has demonstrated reduced mortality probably
because of a reduced risk of infection. However, creating
an arteriovenous fistula requires surgery and several
months to mature before it can be used. Importantly, in
patients who might need dialysis, the cephalic vein should
be preserved by limiting access.41
When AVF may take too long to develop, the K/DOQI
guidelines suggest using a tunneled dialysis catheter for dial-
ysis. These may be cuffed or uncuffed. It is recommended to
avoid using these for indications other than dialysis and the
patient will require that catheter for life-sustaining dialysis
treatment. The preferred placement for tunneled catheters
is the inferior jugular vein because subclavian vein place-
ment can lead to stenosis with nearly 50% of patients with
subclavian vein catheters demonstrating subclavian vein
stricture,42 which can make fistulas unusable. Femoral
placement should be avoided in patients who may receive
renal transplant because external iliac vein stenosis will
interfere with blood flow to the graft.43
HEMATOLOGIC ABNORMALITIES
Anemia. Anemia is common among patients with CKD and
particularly severe among those with ESRD. The main culprit
for anemia in this population is depressed erythropoietin-
stimulating agent (ESA) production by failing kidneys where
it is synthesized. The situation is exacerbated by vitamin defi-
ciencies such as B12, iron, and folate deficiency. Further-
more, chronic blood loss and hemolysis from dialysis
reduce red blood cells. Finally, chronic inflammation induces
a perpetual anemia of chronic disease. The typical anemia in
CKD/ESRD is normochromic, normocytic anemia. The intro-
duction of erythropoietin in 1989 and the analog darbopoe-
tin alpha, into the treatment of patients with ESRD has
improved quality of life and reduced the need for transfu-
sions.44 For patients who are chronically anemic, current
guidelines suggest maintaining blood levels at 9.5–11 g
per 100 mL.45 Lower hemoglobin levels constitute a periop-
erative risk.46
Uremic Bleeding Diathesis. Patients with CKD tend to
have a bleeding diathesis, which can be severe. The bleeding
tendency is primarily related to platelet dysfunction, specif-
ically decreased activity of platelet factor III, abnormal plate-
let aggregation, abnormal interaction between platelets and
vessel walls, and defective release of von Willebrand fac-
tor.47 Patients with CRF are therefore at risk of surgical
bleeding, GI tract bleeding, intracranial hemorrhage, and
hemorrhagic pericardial effusion. Despite the hemostatic
effect there is also a tendency toward hypercoagulability
263
and thrombosis.48 The bleeding tendency is improved by
dialysis, which is the principal treatment, but infusion of
desmopressin (DDAVP), cryoprecipitate, and conjugated
estrogens may be of value for temporary treatment.49
GASTROINTESTINAL ABNORMALITIES
Gastritis, peptic ulcer disease, and mucosal ulcerations,
which can occur at any level of the GI tract, are common
in uremic patients. Symptoms include abdominal pain, hic-
cups, nausea, vomiting, and bleeding. Bleeding may be
exacerbated by uremic hemostasis defects and use of hepa-
rin during hemodialysis. Central nervous system effects of
uremia contribute to worsening of hiccups, nausea, and
vomiting. Patients with ESRD are therefore at increased risk
of regurgitation and aspiration at induction of and emer-
gence from anesthesia.
NUTRITIONAL AND METABOLIC DISTURBANCES
Patients with CRD have impaired glucose and fat metabo-
lism and are prone to hyperglycemia and hypertriglyceride-
mia because of increased peripheral insulin resistance and
decreased lipoprotein lipase activity. This contributes to
the high incidence of CAD in patients with CRD. These
patients are often on a protein-restricted diet to reduce nau-
sea and vomiting, which, in combination with deficient
caloric intake or utilization, makes them susceptible to mal-
nutrition. Hypoalbuminemia and decreased colloid oncotic
pressure tend to promote interstitial fluid accumulation.
In the lungs, this leads to decreased functional residual
capacity and ventilatory reserve, increasing the risk for post-
operative pulmonary complications.
NEUROLOGIC DISTURBANCES
Central, peripheral, and autonomic nervous system neurop-
athies are common in patients with CRD. Retained nitrog-
enous metabolites and disturbed calcium homeostasis all
contribute to the various manifestations of central neurop-
athy. Early signs and symptoms include disturbances in
memory, concentration, and sleep. Later, neuromuscular
irritability with hiccups, cramps and muscle fasciculations
become evident. Full-blown encephalopathy with myoclo-
nus, seizures, and coma may develop, often precipitated
by major surgery or GI bleeding. Uremic encephalopathy
is associated with slow delta waves on the electroencepha-
logram, and magnetic resonance imaging may reveal
increased signal intensity in a characteristic pattern in the
occipital and parietal lobes.34 The treatment is dialysis.
Peripheral neuropathy is very common in patients with
ESRD. Manifestations include loss of vibration sense and
asymmetric and symmetric neural deficits. Another com-
mon deficit is the “glove and stocking” sensory distribution,
with pain or sensory loss affecting distal nerves.
The presence of peripheral neuropathy should always
trigger an awareness of the possible coexistence of auto-
nomic neuropathy. Important consequences of autonomic
dysfunction include silent myocardial ischemia, orthostatic
hypotension, impaired circulatory responses to anesthetic
and surgical stress, and impaired gastric emptying, which
increases the risk for aspiration.
264 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
IMMUNOLOGIC DYSFUNCTION
The combination of uremia, anemia, and poor nutritional sta-
tus induces a state of decreased resistance to infections in
patients with ESRD. It is based both on leukocyte dysfunction
(depressed chemotaxis, phagocytosis and bactericidal activity)
and on immunosuppression (e.g., reduced interleukin-2 pro-
duction and hypogammaglobulinemia) and is associated with
increased mortality. Infections are particularly common, both
localized at shunt and peritoneal catheter sites and dissemi-
nated in the form of sepsis. Additional infection risks stem from
the impaired wound healing seen in these patients, which
results in slow-healing or nonhealing wounds after surgery
and a tendency for bedsore development.
Pharmacology in Chronic Renal
Failure
The pharmacodynamics and pharmacokinetics of certain
drugs may be affected by CKD, which may alter excretion
and disposition of drugs, the latter through changes in
plasma protein binding and hepatic metabolism.
Elimination of water-soluble, highly ionized drugs is highly
dependent on renal excretion. Therefore, depending on the
severity of renal failure, excretion of such drugs may be mark-
edly impaired. Digoxin and certain antibiotics and muscle
relaxants belong to this group. Drugs that are partially depen-
dent on renal elimination (e.g., atropine, glycopyrrolate,
neostigmine, pancuronium, and vecuronium) may show
significant prolongation of action (Table 19.5).
Thiopental and benzodiazepines, frequently used in anes-
thesia practice, are highly protein bound and increase their
unbound free fraction in the presence of uremic conditions
(hypoalbuminemia and acidemia) and may demonstrate
exaggerated clinical effects. Depending on the timing and
effectiveness of dialysis, the volume of distribution for drugs
may be increased in addition to the plasma volume, which
tends to prolong elimination half-life and also counteracts
the effects of the increased free fraction of protein-bound drugs.
Many drugs are lipid soluble and depend on hepatic metab-
olism and/or glucuronization to generate water-soluble com-
pounds that can be excreted by the kidneys. If these
compounds maintain some or all of the parent drug’s pharma-
cologic activity, their clinical effects may be quite prolonged
(Table 19.2). Another risk is that such accumulated metabo-
lites may have toxic effects when their concentrations increase
(Table 19.2).
Table 19.5 Drugs dependent on renal excretion.
DRUGS CHIEFLY DEPENDENT ON RENAL EXCRETION
▪ Gallamine, metocurine
▪ Penicillins, cephalosporins, aminoglycosides, vancomycin
▪ Digoxin
DRUGS PARTIALLY DEPENDENT ON RENAL EXCRETION
▪ Atropine, glycopyrrolate
▪ Neostigmine, pyridostigmine, edrophonium
▪ Pancuronium, vecuronium
▪ Amrinone, milrinone
▪ Phenobarbital
CRF is often a debilitating condition. Many patients have
reduced muscle mass and other characteristics, with the result
that pharmacodynamic effects are altered. It is therefore pru-
dent, when the clinical situation allows, to titrate drugs to
effect rather than to administer “normal” doses of drug.
CHOICE OF ANESTHETIC TECHNIQUE
General Considerations
Patients with ESRD pose a significant challenge to the peri-
operative clinician. Dialysis increases not only the risk of
comorbidities but also the challenges of renal replacement
therapy before, after, and even during surgery.
At the preoperative visit, the history-taking should focus
on the cause of ESRD and manifestations of systemic disease,
keeping in mind that myocardial ischemia may be silent in
diabetic patients. The autonomic neuropathy in such
patients may also impair circulatory responses to anesthesia
and surgery. Bleeding, encephalopathy, and neuropathy are
other possible and important complications of ESRD that
should be ascertained. Whether or not the patient is anuric
has significant impact on the planning of fluid management.
Patients on dialysis are not in a homeostatic state. Infor-
mation on the type of dialysis, frequency, and most recent
treatment is important. In most nonurgent surgery patients,
the ideal timing of hemodialysis is the day before surgery.
This avoids immediate dialysis-related complications, such
as rebound heparinization, hypovolemia, hypokalemia,
and dysequilibrium syndrome. Ideally, patients should be
normovolemic and their potassium should be no higher
than 6 mmol/L on the day of surgery. A blood urea nitrogen
(BUN) value below 100 mg/L usually keeps coagulopathy
and encephalopathy under control. However, this BUN level
neither guarantees normal platelet function nor improves
immunity and the impaired wound healing that often occur
postoperatively.
Individuals with a prior history of perioperative uremic
bleeding should be treated before surgery. In addition to
dialysis, cryoprecipitate and/or intravenous or intranasal
administration of desmopressin, 0.3 μg/kg, should be
considered.50
General Anesthesia
General anesthesia is the most common choice for surgical
procedures, although regional anesthesia is successfully
used in many cases (see later). Before induction of anesthe-
sia, the patient’s volume status should be evaluated. If the
patient has had recent dialysis (within 12 hours), consider
fluid loading with 250 to 500 mL fluid prior to induction.
Gastric emptying is delayed in uremic patients and they
should always be treated as having risk of aspiration.
Induction Agents. Thiopental has an increased free frac-
tion in patients who have CRD and hypoalbuminemia, and
it is recommended that the induction dose be decreased in
these patients.51 Etomidate also has an increased free frac-
tion, which does not seem to be of clinical importance.51
Propofol’s pharmacokinetic and pharmacodynamic proper-
ties are unchanged in patients with CRD. Its safe use in
patients with renal failure has been documented.51 Keta-
mine is less extensively protein bound than thiopental
 19 • Perioperative Management of Renal Failure and Renal Transplant
and its free fraction is unaffected by renal failure. However,
ketamine has the potential of causing impressive increases
in blood pressure if it is used in hypertensive patients with
CKD52 and its use should be limited to emergency anesthetic
induction.
Muscle Relaxants. Patients with ESRD may have reduced
bowel motility secondary to uremic neuropathy and co-
occurring diabetes.53 Therefore, rapid sequence induction
should be considered to reduce the risk of aspiration. Succi-
nylcholine can be safely used in patients with ESRD. How-
ever, a serum potassium should be checked first and only
used if the potassium concentration is less than
5.5 mmol/L.54 The effect of increased potassium with succi-
nylcholine induction may be more pronounced in patients
with ESRD because of already depressed cardiac function.
Alternatively, rocuronium will not increase potassium
levels but its effect will be significantly prolonged in patients
with renal failure.55 Vecuronium effects will also be pro-
longed in patients with renal failure.56 Cisatracurium is
an ideal maintenance agent for neuromuscular blockage
because it undergoes Hoffman elimination in blood and tis-
sue, a process that is totally independent of renal function,
and unlike atracurium, does not cause histamine release.
Caution should be used when rapid sequence induction with
rocuronium is used and cisatracurium is used for mainte-
nance as it could have synergistic effect that delays recovery
from paralysis.57
In all cases, neuromuscular monitoring throughout the
case and full reversal is warranted. It should be noted that
the suggamadex–rocuronium complex is entirely renally
cleared and therefore suggamedex should not be used in
patients with ESRD who have received rocuronium until
further studies demonstrate safety in this regard.58,59
Opioids. The use of morphine and meperidine is of concern
in patients with CRF. Both have metabolites that are depen-
dent on renal elimination (Table 19.6). Normeperidine, the
active metabolite of meperidine, accumulates in patients
with renal failure after repeated doses or continuous infu-
sion and may cause seizures.60 About 10% of morphine is
metabolized to morphine-6-glucuronide, which is a very
potent sedative and dependent on excretion by the kidney.
This metabolite may accumulate to 10–15 times its normal
concentration in cerebrospinal fluid in patients with CRF.61
The pharmacokinetic and pharmacodynamic profiles of fen-
tanyl, remifentanil, and sufentanil are not significantly
Table 19.6 Drugs with active metabolites dependent on
renal excretion.
Drug Metabolite Effect
Morphine Morphine-6-glucuronide Analgesic
Meperidine Normeperidine Neuroexcitatory
Diazepam Oxazepam Sedative
Midazolam 1-Hydroxy-midazolam Sedative
Pancuronium 3-Hydroxy-pancuronium Muscle relaxant
Procainamide N-acetylprocainamide Neurotoxic
265
influenced by renal failure.62 They can therefore be used
with little or no modification of their dosage.
Inhaled Anesthetics. Elimination of inhaled anesthetics is
independent of renal function. Of the modern inhaled anes-
thetics, desflurane and isoflurane have no nephrotoxic prop-
erties, but there are some concerns with sevoflurane.
Sevoflurane is defluorinated during its metabolism to
approximately the same extent as enflurane. Initial studies
reported plasma levels of fluoride, in connection with sevo-
flurane anesthesia, comparable to those seen after enflurane
administration.63 Because of sevoflurane’s low blood–gas
solubility, only limited stores build up during anesthesia,
and as a result, fluoride levels fall very quickly after termi-
nation of anesthesia. No renal function impairment has
been reported in patients with normal renal function.
The safety of sevoflurane in patients with impaired renal
function has been widely studied. The consensus from these
studies is that sevoflurane has little potential to cause
fluoride-induced nephrotoxicity. Sevoflurane undergoes
degradation in carbon dioxide absorbers using soda or barium
hydroxide lime. The chief degradation product is fluoromethyl-
2,2-difluoro-1(trifluoromethyl) vinyl ether, also known as
compound A.64 Compound A concentrations in the anesthesia
circuit correlate directly with sevoflurane concentrations and
absorbent temperature, and inversely with fresh gas inflow
rate.56 Compound A is nephrotoxic in rats at thresholds esti-
mated at 180 ppm/h.65 Renal toxicity is characterized histolog-
ically by corticomedullary necrosis and biochemically by
proteinuria, glucosuria, and enzymuria (N-acetyl-D-
glucosamine [NAG] and alpha-glutathione-S-transferase
[alpha-GST]), with increased serum creatinine and BUN con-
centrations occurring with severe toxicity.66,67
In humans, there seems to be a dose-dependent associa-
tion between compound A exposure and the appearance of
urinary biomarkers such as albumin, glucose, and enzymes
(NAG and alpha-GST). These findings appear in studies
where the compound A exposure exceeds 160 ppm/h68,69
but they are absent in studies with lower compound A expo-
sure.64–66 In all studies associated with higher exposure of
compound A, the urinary markers have been transient, last-
ing 3 to 5 days, with total normalization within 1 week.
There was no correlation between serum creatinine and
the urinary markers. Since its introduction in the United
States in 1995, sevoflurane has been administered to tens
of millions of patients without a single report of nephrotox-
icity.70 The concerns around the degradation of sevoflurane
can be avoided by using a calcium hydroxide-based absor-
bent (Amsorb), which does not degrade sevoflurane.68
Total Intravenous Anesthesia. Total intravenous anes-
thesia (TIVA) based on propofol and remifentanil, and using
cisatracurium as the muscle relaxant, is a good alternative
to inhaled agents, because the pharmacologic properties of
these intravenous drugs are not affected by renal failure.
Regional Anesthesia
Regional anesthetic techniques are used successfully in
patients with ESRD. There are concerns about uremic bleed-
ing diathesis. Prolonged bleeding time (>15 minutes) is a
contraindication to central neuraxial anesthesia. In these
266 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
patients, it is also best to avoid using the axillary artery
puncture technique while administering an arm block.
However, a normal platelet count and coagulation param-
eters is no guarantee against bleeding and hematoma devel-
opment, because the platelets may be dysfunctional. There
are reports of both spinal and epidural hematoma develop-
ment after use of regional anesthesia in patients with
ESRD.70 Patients who have CRF and autonomic neuropathy
and who receive epidural or spinal anesthesia have
increased risk of developing significant hypotension caused
by exaggerated sympathetic blockade. Patients with CRF
have increased risk of catheter site infection, which should
be factored into the choice of anesthetic technique.
Brachial plexus and axillary blocks are used in many cen-
ters to provide anesthesia for insertion or revision of AV
shunts. This is often an excellent anesthetic choice in
patients with suitable psychological disposition.
Intraoperative Considerations
Monitoring. Standard monitoring of patients with CRF
should include five-lead ECG, noninvasive blood pressure,
pulse oximetry, end-tidal CO2 and other gases, peripheral
nerve stimulator, temperature, and, if applicable, urine out-
put. Preexisting renal function impairment is a major risk
factor for further perioperative deterioration of renal func-
tion. The maintenance of effective intravascular volume
and normal hemodynamics is very important for preventing
renal hypoperfusion.71 Central venous pressure monitoring
is therefore recommended in most patients with advanced
renal failure undergoing major surgical procedures and
invasive peripheral arterial pressure monitoring should be
considered. The benefits of direct arterial pressure monitor-
ing should be weighed against the risks of arterial damage,
making the site unsuitable if future AV shunt placements
should become necessary. In cases of unexplained refractory
hypotension, transesophageal echocardiography, or a PA
catheter, may help differentiate between hypovolemia and
decreased myocardial contractility.
Fluid Management
Recent research advocates for an integrated approach to
monitoring and fluid management to prevent perioperative
renal dysfunction. This integrated approach is called goal-
directed hemodynamic therapy. The concept of goal-
directed hemodynamic therapy is to optimize blood flow
using a vasopressors, inotropes, and fluid therapy. Tradi-
tionally pulmonary artery catheters have been used to
directly measure cardiac output, however placing a pulmo-
nary artery catheter is invasive, time consuming, and is not
without risk. Technological advances have introduced new,
less invasive modalities such as transpulmonary indicator
dilution, arterial waveform derived, esophageal doppler,
echocardiography, partial CO2 rebreathing, and bioreac-
tance.72 A recent meta-analysis of 95 randomized con-
trolled trials of various goal-directed therapy monitoring
techniques found modest reductions in perioperative mor-
tality and a consistent reduction in AKI.72 This evidence
suggests that a goal-directed approach is superior for pre-
serving renal function than a one size fits all fluid adminis-
tration approach. A recent trial—FEDORA—showed that
esophageal doppler guided goal-directed hemodynamic
therapy reduced the risk of moderate to severe postoperative
complications (including AKI) compared to usual care.73
Expert guidelines from the international fluid optimiza-
tion group (IFOG) advocate for a goal-directed hemody-
namic therapy approach and specifically emphasize the
utility of dynamic parameter monitoring (such as pulse
pressure variation), fluid challenges with measurement
of dynamic parameter change, and above all, developing
individualized fluid management plans for patients.74
Goal-directed hemodynamic therapy should be tailored
to the patient and the surgery. Different patients undergo-
ing different surgeries have different hemodynamic goals;
a patient presenting for emergency surgery with severe
volume overload, acute heart failure, and pulmonary
edema will have different hemodynamic targets than a
young healthy patient undergoing an elective laproscopic
appendectomy.75
What type of fluid is best?
Balanced Crystalloid Solution. The type of fluid admin-
istered affects kidneys. In a series of large randomized con-
trolled trials, involving ED (SALT-ED), medical ICU (SMART-
MED), and surgical ICU patients (SMART-SURG), resuscita-
tion with a balanced crystalloid solution such as lactated
ringers or plasmalyte was associated with reduced adverse
renal events such as persistent renal dysfunction and need
for renal-replacement therapy compared to resuscitation
with normal saline.76,77 A meta analysis of six trials in kid-
ney transplant surgery corroborated the increased acidosis
with normal saline but could not determine whether graft
outcomes differed between normal saline and balanced
crystalloid.78
Colloids vs crystalloids. Colloids offer another effective
volume expander. Colloids are not thought to harmful than
kidneys than crystalloids for resuscitation in critically ill
patients.81 However there is insufficient evidence to deter-
mine whether colloids protect renal function compared to
crystalloids. In the United States, hetastarch carries a black
box warning about adverse renal effects—although a recent
meta-analysis did locate sufficient data to determine if a
difference between crystalloids and hetastarch exists.79
Similarly, long term follow-up up of trials comparing hetas-
tarch and crystalloids did not find a difference. 80 A trial of
goal-directed hemodynamic therapy with hetastarch vs
crystalloid did not detect increased renal damage with
hetastarch. 82
Liberal vs restrictive. Trials of “liberal” vs “restrictive”
perioperative fluid administration demonstrate that restrict-
ing perioperative fluid may lead to increased renal dysfunc-
tion.84 on the other hand, liberal perioperative fluid
administration may delay time to recovery of gastrointesti-
nal function and to hospital discharge.83 However, as dis-
cussed in the beginning of the section, goal-directed
hemodynamic therapy tailored to the individual patient
may be more renal protective than a one size fits all
approach to fluid administration.
Positioning. Patients with CRD often present with both
neuropathies and poor nutritional status because of uremia.
As a consequence, they are very vulnerable to the develop-
ment of new nerve deficits or the worsening of existing
 19 • Perioperative Management of Renal Failure and Renal Transplant
nerve deficits during surgery, as they have very little endog-
enous padding for protection. In addition to the standard
positioning considerations, extreme diligence should be paid
to protecting pressure points with extra padding. If an AV
fistula is present in the arm, a rigid cushioned protector is
helpful.
Kidney Transplantation
The preferred treatment option for patients with ESRD is
renal transplantation. Renal transplantation provides better
survival and quality of life than hemodialysis.71,85 In one
study, the projected life expectancy for patients with renal
transplantation was 17 years compared with 5.8 years for
patients undergoing dialysis.86 Admittedly, only healthier
patients qualify for renal transplantation, which biases mor-
tality outcomes toward transplantation benefit.
Why does renal transplantation improve survival? As dis-
cussed at the beginning of the chapter, dialysis accelerates
cardiovascular disease, dramatically increasing ESRD
patients risk of major adverse cardiovascular events. Trans-
plantation has been demonstrated to reverse some of the
cardiovascular comorbidity accrued from ESRD and renal
replacement therapy exposure.87 Renal transplantation
may reduce left ventricular hypertrophy, possibly reduce
diastolic dysfunction,88 and in some cases pulmonary
hypertension may resolve.89 Persistence of an AVF graft
after transplantation, even if not used for dialysis, may affect
resolution of cardiac morbidity.90
In 2014 a new kidney allocation system (KAS) was imp-
lemented in the United States. The previous system allocated
kidneys with an emphasis on waiting time on the transplant
list. The United Network for Organ Sharing (UNOS) imple-
mented the new system to improve equity in access to
kidneys, to increase priority for highly sensitized patients,
and to incorporate dialysis time. UNOS is only beginning
to see the changes in how the allocation system affects
kidney transplantation at a population level. The most
recent UNOS data show that in 2014, 90,000 patients were
listed for kidney transplant. There were 13,000 deceased
donor transplants that year. The average age of patients
on the kidney transplant list continues to increase as more
people aged 50–73 years are listed. Of patients, 36% were
transplanted for renal disease secondary to diabetes. Other
etiologies by order of likelihood are hypertension, glo-
merular nephropathies, and CKD. In 2016, 20% of listed
patients had been on dialysis for at least 6 years. In 2016
one-fourth of patients were removed from the transplant list
because of death or worsening medical status, which indi-
cates a persistent shortage in available deceased donor
organs.91
Reliable early transplantation can avoid the deleterious
effects of renal replacement therapy. The 2014 KAS system
is in part designed to resolve this issue by better matching
patient longevity with donor organs. It is too early to tell
the effect of the KAS system in terms of survivorship for
transplant recipients.
KIDNEY DONOR CRITERIA
The perioperative physician may be familiar with the old
kidney allocation system and some of the terms listed.
267
SCD: Standard Criteria Donor. The best donor is a young
healthy individual who donates after brain death, for
example, a 30 year-old who suffers a head injury in a
motor vehicle accident.
DCD: Deceased Criteria Donor. Organ donation does not
require brain death. Donation after cardiac death is still
viable but delayed graft function should be anticipated.
Delayed graft function means that the patient will require
dialysis within the first week after transplantation. ECD:
Expanded criteria donor. In the old kidney allocation sys-
tem, ECD designated kidneys from older kidney donors
with any of these features: hypertension, elevated serum
creatinine, or death from cerebrovascular accident. Com-
pared with a Standard criteria donor (SCD) ECD kidneys
were 70% more likely to fail and benefited the recipient
only 5 versus 10 added-life-years.92
These terms grouped donated kidneys by the expectation
of graft function. However, the groupings were contentious
and complex. The new kidney allocation system supplants
the alphabet soup of the prior system with a continuous risk
index.
KDRI: Kidney Donor Risk Index. The KDRI compares
the expected rate of graft failure for an organ with that
of a healthy 40-year-old donor. Some of the fourteen fac-
tors incorporated into the KDRI calculation include donor
age, medical history of hypertension or diabetes, serum
creatinine, cause of death (cerebrovascular accident or
donation after cardiac death), immunologic matching,
cold ischemia time, and transplant type (double or en bloc
donor).93
The KDRI index is then mapped onto a cumulative per-
centage scale known as the KDPI. Essentially, an ECD kidney
is analogous to a KDPI >85% kidney in terms of expected rate
of graft failure. That is to say, a KDPI > 85% kidney is more
likely to fail than 85% of all kidney transplanted last year.94
LIVING-DONOR KIDNEY TRANSPLANTATION
Living-donor kidney transplantation is a preferred alterna-
tive to waiting for a deceased donor organ to become avail-
able. Living-donor kidney transplantation can now occur
beyond immediate relatives. Complex exchange systems
have emerged to allow donation between anonymous indi-
viduals when there is biological incompatibility with the
desired recipient.93 In the United States there are about
5000 living-donor kidney transplants a year. Unfortu-
nately, this number has been stable over the last decade.
Of living-donor kidney transplants 50% will survive for
12.5 years versus 11.4 years for 0%–20% KDPI, 8.9 years
for a 21%–85% KDPI, and 5.6% for a >86% KDPI kidney.91
RECIPIENT SELECTION
Listing a patient for renal transplantation is a complex pro-
cess that is managed by a transplant nephrology team
beginning long before the perioperative period. Typically,
when kidney function declines toward ESRD, transplanta-
tion is considered with the goal of transplanting before renal
replacement is required. Centers that perform transplants
typically have defined protocols for listing transplants.
These guidelines should be used in conjunction with the
268 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
transplant team’s preoperative protocol because there is sig-
nificant practice variation in the United States.
There are several absolute contraindications to renal
function such as active cancer, active drug use, uncon-
trolled psychiatric disease, short life expectancy, and major
organ comorbidity. There are also several relative contrain-
dications such as obesity, history of noncompliance, and
systemic autoimmune disease.95
CARDIAC DISEASE EVALUATION AND
MANAGEMENT
There are national American Heart Association/American
College Cardiology (AHA/ACC) guidelines for cardiac dis-
ease evaluation and management of the kidney transplant
candidate.96 In general, the goal of preoperative cardiac risk
assessment for kidney transplant is to minimize cardiovas-
cular risk in the perioperative period. Patients with ESRD
often have high cardiovascular morbidity that places them
at substantial perioperative risk. Kidney transplantation has
been demonstrated to reverse some cardiovascular disease.
On the other hand, allocating an organ to a patient who
would suffer a major adverse cardiovascular event during
the perioperative period would waste a scarce organ and
potentially cause more harm to the patient than avoiding
transplantation altogether. These carefully balanced deci-
sions are made during transplant workup by a multidisci-
plinary team including a transplant nephrologist and a
cardiologist. Compared with the cardiac evaluation for non-
cardiac surgery, cardiac evaluation for kidney transplant is
more diagnostically aggressive and recognizes that trans-
plantation may occur shortly after cardiac workup.
Below are some of the key recommendations from the
AHA/ACCF 2012 recommendations:96
▪ ECG in the immediate perioperative period.
▪ Noninvasive stress testing if the patient has cardiovas-
cular risk factors. Usually performed at the time of trans-
plant listing.
▪ Resting echocardiogram. May be repeated for change in
cardiac/functional status.
▪ Referral to a cardiologist should be made for kidney
transplant candidates with:
▪ LVEF less than 50% or evidence of ischemic left
ventricular dilation
▪ exercise-induced hypotension
▪ angina
▪ ischemia in the distribution of multiple coronary
arteries.
A cardiologist who works closely with the transplant
team should be consulted regarding medical management
and/or need for revascularization. Some patients may ben-
efit from a coronary artery bypass graft. Timing of percuta-
neous coronary intervention and stenting may affect
transplant list activation. In general, a strategy of bare-
metal stent or balloon angioplasty with dual antiplatelet
therapy for 4–12 weeks is recommended. Antiplatelet ther-
apy should be considered in consultation with the cardiolo-
gist because it is often a challenging decision.
▪ Transplant within 3 months of bare-metal stent is not
recommended.
▪ Transplant within 12 months of a drug-eluting stent
is not recommended.
▪ Transplant within 4 weeks of balloon angioplasty is
not recommended.
▪ Continue beta blockers for patients already taking beta-
blockers. Beta blockers should not be initiated the night
before surgery.
▪ Continue statins and reinitiate postoperatively.
POSTOPERATIVE MANAGEMENT
Post-transplant complications in the perioperative period
include surgical issues such as bleeding and infection and
vascular issues such as thrombosis or kinking of the artery
or vein; urine leaks can also occur.97 If kidney function is
inadequate, volume, metabolic, and electrolyte derange-
ment can occur as is typical of ESRD. Because it is a trans-
planted organ, there can also be hyperacute rejection.
Delayed graft function is always possible.95
TRANSPLANTATION IMMUNOLOGY
The essential goal of transplant immunosuppression is to
suppress allograft rejection.98 There are many different
protocols for managing immunosuppression and each
transplant center has developed their own protocol. Periop-
erative physicians should familiarize themselves with their
local protocol.
Immunosuppression with calcineurin inhibitors is the
mainstay of treatment and the rate of acute rejection has
decreased tremendously in recent decades. Rejection occurs
because the injured graft increases HLA antigen expression
and inflammatory mediators increasing the host immune
response.99 Recipients typically do not have antibodies
against HLA molecules before transplantation unless the
recipient was exposed via pregnancy, blood transfusions,
or prior transplant.100 Hyperacute rejection can result from
this process and may occur immediately with graft reperfu-
sion. Improved crossmatching strategies that detect donor
specific antibodies have reduced this problem.101 However,
acute antibody-mediated rejection may occur days after
transplantation, which results in graft dysfunction. This
type of rejection can be treated with plasmapheresis or
high-dose glucocorticoids, intravenous immune globulin.
Antiproliferative agents such as rituximab may also be used.
T-cell mediated rejection can also occur and is much more
common. The immune system responds to HLA mismatches
between the donor and recipient through a complex process
involving antigen-presenting cells and T cells.
Induction is the initial immunosuppression and occurs in
the operating room. Conventional treatment is with anti-
CD25 antibody or a polyclonal antithymocyte globulin.
Alternatively, induction can be done using alemtuzu-
mab.102 Many induction regimens exist. In the periopera-
tive period a maintenance therapy will be initiated.
Maintenance therapy conventionally involves calcineurin
inhibitors, mycophenolate mofetil, and prednisone.
Some of the complications associated with immunosuppres-
sion include nephrotoxicity, hypertension, hyperlipidemia,
diabetes, and anemia. Over time, calcineurin inhibitors con-
tribute to renal failure.
 19 • Perioperative Management of Renal Failure and Renal Transplant
ANESTHESIA MANAGEMENT
Anesthetic management for kidney transplantation is simi-
lar to caring for patients with CKD and ESRD. It is important
to recognize that it is vascular surgery with the potential for
serious blood loss. Renal transplant is characterized as an
intermediate risk procedure.103 Dialysis is not necessary
before kidney transplant unless there is significant hyperka-
lemia or volume overload. Dialysis will delay the operation.
Many patients will have a baseline metabolic acidosis,
which does not need to be aggressively corrected because
this would affect the kidney graft.104
General anesthesia is recommended for renal transplan-
tation. Although it is possible to perform a kidney trans-
plant under only neuraxial anesthesia,105 the approach
is rarely used in most centers. There has been recent inter-
est in using continuous transversus abdominis plane
block106 or single injection transversus abdominis plane
block107 as part of a balanced analgesia regimen for renal
recipients.
Adequate venous access either with large bore peripheral
access or a central line is necessary to respond to significant
blood loss. An arterial line may be used for frequent blood
gas assessment and hemodynamic monitoring. No single
induction agent is preferred. Succinylcholine should be used
with caution after checking the serum potassium and not-
ing the last dialysis session. Cisatracurium is the preferred
maintenance muscle relaxant and should be guided by
peripheral nerve stimulator. There should be close discus-
sion with the transplant surgeon to ensure correct immuno-
suppression induction therapy and appropriate antibiotics
are given at the right time. Diuretics may also be given once
the graft is in place depending on the specific transplant
protocol.
KIDNEY VIABILITY IN TRANSPLANT SURGERY
Living Kidney Donor
Living donors contribute more than 25% of renal allografts
in the United States. Donor nephrectomy is a unique surgery
because both donor and recipient outcomes are required to
assess the success of donor surgery. An ideal donor nephrec-
tomy should fulfill the criteria of minimal warm ischemia
time, adequate length of damage-free renal vessels, ade-
quate length of well-vascularized ureter, atraumatic organ
removal, and a low donor and recipient morbidity. Laparo-
scopic donor nephrectomy has gained widespread popular-
ity in recent years. The operation is performed under general
anesthesia. The renal vein, artery, and ureter are exposed
and dissected. An incision is made in the lower midline to
facilitate extraction. After systemic heparinization, the ure-
ter, renal artery, and vein are divided, and the kidney is
extracted with the help of a plastic specimen-retrieval
bag. The kidney is immediately immersed in ice slush and
taken out of the operating room for perfusion with preserva-
tive solution.
The advantages offered by the laparoscopic technique, as
opposed to open nephrectomy, include decreased hospital
stay, decreased postoperative pain, improved donor cos-
metic outcome, and earlier return to work. Disadvantages
include longer surgery time and longer warm ischemia
269
time, which result in longer time for the transplanted kidney
to achieve nadir serum creatinine postoperatively. How-
ever, the long-term outcome does not seem to be negatively
influenced by laparoscopic organ procurement.108
Deceased Donor Kidney (DDK)
Most kidney recipients lack a suitable or willing living
related donor and require a DDK. Factors affecting kidney
viability include the donor having primary renal disease,
a history of cardiac arrest or prolonged hypotension
before harvesting, advanced age (>60 years), the use of
vasopressor drugs, the presence of oliguria before harvest-
ing, and the duration of warm and cold ischemia time.
Ischemia time starts with the clamping of the renal
vessels in the donor and ends with completion of the vas-
cular anastomosis in the recipient. Minimizing ischemia
time, particularly the warm ischemia period, is very
important because acute tubular necrosis increases with
its duration.
Warm ischemia time starts when the donor vessels are
clamped and is interrupted when the kidney is perfused with
cold preservation solution. Warm ischemia resumes when
the kidney is placed in the recipient and ends when the kid-
ney is revascularized and perfusion starts. During cold ische-
mia, the kidney is usually stored at 4°C. Ideally, the duration
of cold ischemia should not exceed 24 hours.
Kidney Preservation
The procured kidney’s cellular energy requirements are sig-
nificantly reduced by hypothermia. This is achieved by sur-
face cooling, followed by hypothermic pulsatile perfusion
or flushing with an ice-cold solution.109 The kidney is then
put in cold storage. The flush solution is made slightly
hyperoncotic with impermanent solutes such as mannitol,
lactobionate, raffinose, or hydroxyethyl starch, to prevent
endothelial swelling and prevent the “no-reflow” phenome-
non. A review of 35,057 DDK transplants demonstrated
no significant difference in 3-year graft survival between
kidneys preserved by pulsatile machine perfusion and those
preserved by simple cold storage.110
The two Euro-Collins solutions developed in 1969 and the
newer University of Wisconsin (UW) solution developed in
the late 1980s111 are widely used to preserve kidneys.
The UW solution can also be used to preserve other solid
organs and it appears to offer some other advantages over
the Euro-Collins solution. A prospective randomized study
of 695 DDKs preserved with either UW or Euro-Collins solu-
tion and subjected to cold storage up to 24 hours showed
that the UW solution resulted in a significantly more rapid
reduction in the postoperative serum creatinine level, a sig-
nificantly lower postoperative dialysis rate, and a 6% higher
1-year graft survival than the Euro-Collins solution.112
However, the UW solution has limitations, evidenced by
the high failure rate for kidneys subjected to cold storage
for more than 24 hours regardless of which of the two pres-
ervation solutions is used.113
The unavoidable detrimental effects of events surround-
ing DDK retrieval and preservation, particularly those
resulting from cold storage ischemia, are shown by the
6% better 1-year graft survival in living unrelated donor kid-
ney transplants, compared with primary deceased donor
kidney transplants.114
270 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Experimental Techniques to Increase Viability.
Ischemic Preconditioning. The phenomenon of ischemic
preconditioning (IPC), in which short periods of ischemia
are followed by reperfusion temporarily increasing the
resistance to further ischemic damage, was first described
in the canine heart111 and has subsequently been docu-
mented in the kidney.115 The question of whether IPC
would be able to protect the transplanted kidney from
the injuries of cold storage and reperfusion, when the
renal circulation is restored in the recipient, has been
addressed in a couple of recent animal studies. Torras
and colleagues used a rodent model and found a positive
IPC effect on kidneys transplanted after 5 hours of cold
storage.116 Using a dog model, Kosieradzki and coworkers
were unable to document any effect of IPC on the preser-
vation injury observed after transplantation of kidneys
cold-stored for 24 hours.117 Their conclusion was that
IPC had no significantly measurable effect in hypothermic
ischemic-reperfusion injury in large animals. The clinical
usefulness of IPC under renal ischemia conditions in
humans has yet to be determined.
Cold Storage. Recent experimental studies have suggested
that two strategies—fortifying the cold storage solution
with deferoxamine and preconditioning the kidneys with
hemeoxygenase-1 (HO-1)—may prove to be clinically
viable to limit cold ischemic injury.
Deferoxamine is an antioxidant. Its renoprotective effect
was tested in a rat kidney transplant model, which used
18 hours of cold storage before transplantation and reperfu-
sion of the kidney. Deferoxamine-treated kidneys had 75%
better function compared with untreated kidneys, as judged
by serum creatinine levels. Deferoxamine treatment was
also associated with a significant reduction of renal necrotic
and apoptotic injuries.118
Stress protein HO-1 is a microsomal enzyme that degrades
heme proteins. Overexpression of HO-1 in renal tubular
cells, either through gene transfer or induction with hemin,
protects these cells against cold storage injury.119 The reno-
protective effects of HO-1 have been supported by in vivo
findings in kidney and liver transplantation models.120
The inducibility of the HO-1 isoenzyme is modulated by a
(GT)n dinucleotide polymorphism in the HO-1 gene pro-
moter.121 Short (class S) GT repeats were found to be asso-
ciated with highly significant upregulation of HO-1.122 In a
recent study of 101 DDK recipients, 50 patients received a
kidney from a donor with at least one class S allele. These
recipients had significantly lower 1-year serum creatinine
levels, compared with the 51 recipients of a non-class S
allele donor kidney.123
INTRAOPERATIVE MANAGEMENT OF KIDNEY
RECIPIENTS
Deceased donor renal allografts with excellent immediate
graft function (IGF), defined as a serum creatinine (Cr)
level of less than 3 mg/dL on postoperative day 5, have
good long-term outcomes. Recipients with slow graft func-
tion (SGF), defined as a Cr level of greater than 3 mg/dL on
postoperative day 5 but no need for dialysis, have an
increased risk for acute rejection (AR). In the absence of
AR, 5-year graft survival of SGF recipients does not differ
from that of IGF recipients.124 The impact of delayed graft
function (DGF), defined by the need for dialysis in the first
week after transplant, is controversial. DGF is associated
with a higher incidence of AR than either IGF or SGF recip-
ients.125 Reports on the outcome for DGF recipients, with
no AR, disagree on the impact of DGF. Some authors con-
clude that DGF is associated with decreased long-term sur-
vival when compared with IGF recipients,114 but others
have been unable to find any influence of DGF on long-
term outcome.126,127
We will now examine the supporting evidence for some
intraoperative interventions that have been suggested to
improve the likelihood of IGF.
Hemodynamics and Intravascular Volume
A recent article labelled perioperative fluid management in
kidney transplantation a “black box”.128 Optimizing periop-
erative hemodynamics effectively reduces the rate of
delayed graft function (generally defined as the need for dial-
ysis within one week of transplantation).129 However, the
precise hemodynamic targets have eluded researchers. This
may be because variation in graft physiology, host physiol-
ogy, and surgical approach create unique combinations.
Hypothetically, a kidney donated from a chronically hyper-
tensive patient may benefit from a higher intraoperative
mean arterial pressure (MAP). In the past, central lines were
placed to measure central venous pressure (CVP) for tar-
geted volume infusion.130 The approach has shifted to using
fluid responsiveness to guide volume infusion.131 However,
volume responsiveness may still lead to fluid overload and
delay graft function. There are conflicting data about
whether measuring cardiac output reduces mortality and
postoperative complications.132 A recent trial using esoph-
ageal Doppler guided goal-directed hemodynamic therapy
showed promising reductions in AKI and length of stay
but no mortality difference at 180 days. Interestingly both
the control and experimental arms received similar total
fluid volumes, which suggests that the timing of fluid
administration may play a key role.73
Although no single fluid management strategy is univer-
sally accepted for kidney transplant, there is some general
agreement that kidney transplants often require 2–3 L of vol-
ume during the operation.133 If a central line is placed, a CVP
of 8–12 mmHG is reasonable134 or if stroke volume variation
is used, a variation of 6% is acceptable.135 In general, ade-
quate MAP should be maintained. In some studies, a higher
MAP (MAP >70 mmHg136 to MAP >95 mmHg134) reduced
the incidence of delayed graft function.
Choice of Resuscitation Fluid
A double-blind comparison of lactated Ringer’s solution and
0.9% NaCl during renal transplant demonstrated that LR
was associated with less hyperkalemia and acidosis com-
pared with NS.137 Further studies have duplicated these
results.138 Each transplant center probably has its own pro-
tocol or type of fluid administered.
Albumin. Colloid plasma volume expansion in living
donor-related graft recipients is associated with immediate
onset of urine output in more than 90% of patients.139
Intraoperative plasma volume expansion with albumin also
improved outcome in DDK recipients.140,141
 19 • Perioperative Management of Renal Failure and Renal Transplant 271

Kidney transplant
patient

Need dialysis?
Yes

Dialysis

No
Postdialysis
problems?
Yes No

Correct intravascular Comorbidities

volume and
bleeding diathesis

Cardiovascular Diabetes mellitus Bleeding diathesis?

Yes

Consider perioperative Need insulin? Desmopressin

beta blocker35 cryoprecipitate32
Yes No No

Insulin to acceptable
blood sugar level

Anesthesia
induction

Surgery

IV fluids to keep Calcium

CVP 10–15 mm Hg IV albumin IV mannitol Furosemide channel
Systolic BP ⱖ 100 mm Hg97 0.5–1 g/kg126 0.25–0.5 g/kg132 0.5–1 mg/kg129 antagonist136

Fig. 19.1 Flow chart for preoperative and intraoperative treatment of the kidney transplant recipient.a BP, blood pressure; CVP, central venous pressure.
a
See references 32,35,97,126,129,132,135

Diuretics. vasodilating prostanoids, increased urinary output, facil-

Furosemide. Furosemide blocks the chloride pump in the
thick ascending loop of Henle. The decrease in tubular
oxygen consumption associated with the reduced work-
load may confer resistance against ischemic injury. On
the basis of such deliberations, furosemide is often
included in intraoperative pharmacologic treatment of
transplant recipients. Any certain improvement of kidney
transplant outcome has not been documented.142
Mannitol. Mannitol is an osmotic diuretic. Postulated ben-
eficial effects of mannitol therapy include increased intra-
vascular volume with improvements of preload and
cardiac output, increased renal blood flow secondary to
release of atrial natriuretic peptide and intrarenal
itating the flushing out of debris from the tubules and
decreased endothelial cell swelling, and promoting
increased intrarenal blood flow. Mannitol is a known free
radical scavenger, with a possible attenuating effect on
reperfusion injury.143 During deceased donor renal trans-
plant surgery, mannitol administration before clamp
release is associated with a significant reduction in
post-transplant acute renal failure.144
Calcium Channel Antagonists
Calcium channel blockers have been proposed to protect the
transplanted kidney from the ischemia reperfusion injury.145
272 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Some aspects of ischemia reperfusion injury are mediated by
calcium. Detrimental effects of increased intracellular cal-
cium levels include reduced ATP production by uncoupling
of mitochondrial oxidative phosphorylation, activation of
phospholipases (causing membrane enzyme dysfunction
and membrane damage), and free radical generation. A sys-
tematic review of perioperative use of calcium channel
blockers in kidney transplant recipients in the Cochrane
Database suggested that calcium channel blockers may
reduce delayed graft function, but the results of should be
interpreted with caution.146
Dopamine
Low-dose dopamine was once widely used to increase renal
blood flow and glomerular filtration rate. However, later
randomized studies in larger populations of patients under-
going cardiac, vascular, and liver transplant or biliary sur-
gery have failed to demonstrate any efficacy of dopamine in
preventing acute renal failure or improving outcome.147
The use of dopamine in the transplant setting can take
place both in the DDK setting before procurement or in
the recipient in the peritransplant period. The use of dopa-
mine in the donor is, as already discussed, associated with
significantly lower 1-day serum creatinine values than
untreated kidneys and also with superior long-term graft
survival.148 Studies using dopamine in the range of 2 to 3
μg/kg/min perioperatively during DDK transplantation
failed to demonstrate any renal protection.149,150
Summary
Organ viability associated with renal transplantation is a
very complex issue. The successful kidney transplantation
involves the management of the donor, the allograft, and
the recipient. Both short- and long-term patient outcomes
are influenced by management of perioperative fluid,
hemodynamics, and drugs. The anesthesiologist plays an
important role in the perioperative setting by vigilantly
monitoring hemodynamics and optimizing intravascular
volume to maximize kidney perfusion, thereby contributing
to the overall success of renal transplantation (Fig. 19.1).
The meaning of renal failure has evolved in the last
20 years to encompass not just patients with ESRD but
the spectrum of progressive CKD. The expanded definition
is important for perioperative physicians to understand.
It is well known that patients with ESRD are at much
higher risk than the general population for a variety of peri-
operative complications. What is newly recognized is that
even moderate chronic kidney disease confers some of the
same heightened risk. Recent research has established a
strong link between CKD, especially ESRD, and cardiovascu-
lar pathology as the major driver of perioperative complica-
tions. Understanding renal failure as a spectrum yields an
intricate relationship between CKD and AKI. CKD potenti-
ates the risk of AKI, which in turn potentiates the risk of
worsening CKD. The astute clinician will notice that the
combination of CKD, cardiovascular risk, and AKI makes
perioperative management of the patient with even early
signs of renal failure a key opportunity to improve health
outcomes.
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blind comparison of lactated Ringer’s solution and 0.9% NaCl during
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138. Khajavi MR, Etezadi F, Moharari RS, et al. Effects of normal saline vs.
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 20 Prevention and Treatment
of Postoperative Pulmonary
Complications
BENEDICT CHARLES CREAGH-BROWN
Introduction
WHAT ARE POSTOPERATIVE PULMONARY
COMPLICATIONS (PPC)?
PPC have been defined in a variety of ways, reflecting the
lack of consensus.1 At its broadest, PPC may refer to almost
any pulmonary (respiratory) complication that follows sur-
gery. Complications related to the airway that occur during
or directly after surgery and anesthesia (such as laryngos-
pasm) tend not to be included. Combining a diverse range
of events into a single composite description or outcome
(PPC) has many limitations.
Pneumonia, invasive mechanical ventilation, and severe
hypoxemic respiratory failure could all be considered PPC
yet they describe different things: in this case diagnosis,
treatment, and severity, respectively. Equally unsatisfactory
is combining diseases with totally different pathophysiol-
ogies into one composite outcome (e.g., pneumothorax
and bronchospasm). This is particularly true if you want
to evaluate the efficacy of an intervention at reducing
PPC; for example, interventions that improve broncho-
spasm are unlikely to affect pneumothorax. Following car-
diac surgery, the occurrence of an asymptomatic pleural
effusion requiring no treatment is a PPC, but very different
from an episode of acute respiratory distress syndrome
(ARDS) requiring days of invasive mechanical ventilation.
Considering both events equally does not seem sensible.
Recognizing that clinical outcome measures for clinical
trials must be robust, clearly defined, and patient-relevant,
the European Society for Anaesthesiology and the Euro-
pean Society of Intensive Care Medicine (ESA-ESICM) joint
taskforce on perioperative outcome measures published
some standardized lists of clearly defined clinical outcome
measures, including PPC.2 This work was refined as part of
the Core Outcomes Measures in Perioperative and Anaes-
thetic Care (COMPAC) initiative. Standardized Endpoints
for Perioperative Medicine groups were convened with
the aim of identifying a core outcome set for perioperative
studies.3 One outcome of this endeavor was the recogni-
tion that none of the available definitions of PPC were suit-
able for use in clinical practice or as an endpoint in clinical
trials. A novel definition was proposed (Box 20.1) that
combines four diagnoses potentially sharing common
mechanisms and a separation of disease from severity of ill-
ness. It is not easy to separate severity of illness from receipt
of therapy because these necessarily go hand-in-hand.
These proposed definitions will require validation in future
studies.
HOW COMMON ARE POSTOPERATIVE PULMONARY
COMPLICATIONS?
In common with all questions about incidence, estimates
depend upon the definition used, the population under con-
sideration, and the method of data collection. In the decade
since the last version of this book the availability of analyses
of “big data” from electronic patient records (EPR) has
grown substantially, providing us far greater ability to esti-
mate outcomes, such as PPC.
The limitations of retrospective database analyses are well
recognized and summarized succinctly in a recent editorial.4
One major limitation is that they rely on coding data, which
does not always agree with the strict clinical definitions that
might be used with prospective data collection as would be
used in an interventional trial or prospective observational
study. For example, a diagnosis of pneumonia according to
the Centers for Disease Control and Prevention (CDC) clas-
sification (as you might use in a trial) has several specific
requirements that exceed those that might be used in rou-
tine clinical practice. A postoperative patient with a cough,
fever, and mildly impaired oxygenation might be given a
diagnosis of pneumonia and treated as such by a clinician
(and coded as such), but without the characteristic changes
on a chest x-ray, they would not meet the CDC criteria.
An analysis of cardiac and pulmonary complications from
45,969 patients following bowel surgery5 in over 600 hos-
pitals in the United States used a composite PPC that
included pneumonia, tracheobronchitis, pulmonary failure,
and mechanical ventilation more than 48 hours after sur-
gery. Using this definition gave an incidence of 19% of
PPC, with the commonest qualifying code being for pulmo-
nary failure (60% of PPC). These results should be taken in
the context of the coding for pulmonary failure being well
recognized as being poorly defined, with variable reporting.6
Nonetheless, an interesting finding of this study was that
PPC are considerably more common than postoperative car-
diac complications.
Another analysis based on coding data from an EPR
included over 109,000 heterogeneous patients who had
undergone a diverse range of types of surgery in three hos-
pitals in Massachusetts.7 Their primary question concerned
the potential role of type of intraoperative ventilation (dis-
cussed later) but they also reported the incidence of PPC;
277
278 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Box 20.1 Recommended definition of
postoperative pulmonary complications.
Postoperative pulmonary complications
Mechanism
Composite of respiratory diagnoses that share common path-
ophysiological mechanisms including pulmonary collapse and
airway contamination:
(i) atelectasis detected on computed tomography or chest
radiograph,
(ii) pneumonia using US Centers for Disease Control criteria,
(iii) Acute Respiratory Distress Syndrome using Berlin consensus
definition,
(iv) pulmonary aspiration (clear clinical history AND radiological
evidence).
Severity
None: planned use of supplemental oxygen or mechanical
respiratory support as part of routine care, but not in response to a
complication or deteriorating physiology.
Therapies that are purely preventive or prophylactic, for
example high-flow nasal oxygen or continuous positive airways
pressure (CPAP), should be recorded as none.
Mild: therapeutic supplemental oxygen <0.6 FiO2.
Moderate: therapeutic supplemental oxygen 0.6 FiO2,
requirement for high-flow nasal oxygen, or both.
Severe: unplanned noninvasive mechanical ventilation, CPAP, or
invasive mechanical ventilation requiring tracheal intubation.
Exclusions: Other diagnoses that do not share a common
biological mechanism are best evaluated separately and only
when clearly relevant to the treatment under investigation:
(i) pulmonary embolism,
(ii) pleural effusion,
(iii) cardiogenic pulmonary edema,
(iv) pneumothorax,
(v) bronchospasm.
From Abbott T, Fowler A, Gama de Abreu M. A systematic review and
consensus definitions for standardised end-points in perioperative
medicine: pulmonary complication. Br J Anaesth. 2018;120
(5):1066–1079.
using a different definition only 9.4% of patients were coded
in the first 7 days postoperatively for a PPC (a composite of
reintubation, pulmonary edema, pulmonary failure, or
pneumonia).
A prospective multicenter observational study conducted
at seven US academic institutions explored predictors of PPC
and the association between incidence of PPC and clinical
outcomes, specifically in 1202 high-risk patients with
American Society of Anesthesiologists (ASA) physical status
of 3 (indicates that these patients have preexisting severe
systemic disease) undergoing noncardiac surgery. This
study was able to avoid the problems of relying on coding
data and formulated a precise and detailed (yet novel) com-
posite PPC definition that explicitly included diagnoses (clin-
ical and radiologic) and receipt of therapies, including
supplemental oxygen administration. With such an inclu-
sive definition and a high-risk group, it is not surprising that
the incidence of PPC was 33.4%.8 A smaller prospective
multicenter study from the UK looked for PPC (using a stan-
dard definition derived from a trial) in 286 patients having
major elective abdominal surgery and reported a PPC inci-
dence of 11.9%.9
Table 20.1 Key parameters and definitions.
Key parameters
Vt Tidal volume is the volume of milliliters of gas per
each delivered breath. kilogram of ideal body
weight (mL/kg IBW)
Pplat Plateau pressure refers to the cmH2O
highest pressure during
inspiration when flow is
briefly paused to allow
equilibration.
PEEP Positive end-expiratory cmH2O
pressure is the pressure that
opposes lung emptying
during expiration. Use of no
opposing pressure, zero
PEEP, is also known as ZEEP.
OTHER TERMS
RM Recruitment maneuvers are interventions that aim to limit
atelectasis through the transient use of high airway
pressures. After a recruitment maneuver, there may follow
acute hemodynamic compromise.
delta Driving pressure, a term that relates to difference between
P (or ΔP) the plateau pressure and the PEEP. This relates to
pulmonary compliance.
A decremental PEEP trial is a relatively time-consuming series of
modifications of ventilatory parameters that aims to determine the
level of PEEP associated with either the best oxygenation or lung
compliance (change in lung volume per unit change in pressure).
A highly influential prospective study (Assess Respiratory
Risk in Surgical Patients in Catalonia: ARISCAT10) was con-
ducted in 59 Spanish hospitals and led to the ARISCAT
score (discussed more later), which was then validated in
a second study (PERISCOPE11) conducted across 63 hospi-
tals from across Europe. ARISCAT recruited a wide range of
patients (including cardiac) and, using a composite defini-
tion later adopted by ESICM-ESA, found that 5% of the
2464 patients developed a PPC. PERISCOPE recruited
5099 patients and 7.9% developed a PPC.
What conclusions can be drawn from these various
reports? The incidence of PPC (however defined) is highly
related to the population under consideration—the type of
surgery and associated anesthetic technique, and the risk
characteristics of the patients. Considerable work has gone
into predicting risk of PPC (described later in this chapter).
HOW IMPORTANT?
Developing a PPC is associated with increased length of stay
in hospital and associated health-care costs. Furthermore,
the greater the number of PPC, the greater the effect on
duration of stay and early mortality.8,11 PPC vary in their
severity and consequent impact.8 Patients developing pneu-
monia that causes respiratory failure requiring invasive
mechanical ventilation will have a far greater impact on
recovery from surgery than if they had just developed
uncomplicated pneumonia.
Longer-term outcomes are also worse in those who
develop PPC. This was convincingly demonstrated by a
landmark paper by Khuri et al. in 2005.12 The analysis
 20 • Prevention and Treatment of Postoperative Pulmonary Complications 279

combined data from the National Surgical Quality Improve- All can be determined preoperatively apart from duration
ment Program (NSQIP) and a database of vital outcomes in of surgery that is either estimated preoperatively or the score
more than 100,000 patients who underwent eight major is calculated postoperatively when the duration is known.
operations. Occurrence of a complication in the first 30 days Each of the seven variables are scored, the score summed
after surgery was independently associated with a reduction and then the patient under consideration falls into one of
in median survival, an effect that was present even having three groups: low, medium, and high risk of PPC (Box
corrected for all known confounding variables. Considering 20.2). In the PERISCOPE validation study11 the observed
PPC specifically (defined as pneumonia, reintubation, and rates of PPC were similar to the predicted rates, with better
failure to wean) this was associated with the greatest reduc- calibration in the higher risk patients.
tion in survival (apart from cardiac arrest) with median sur-
vival in those with a PPC being 2.2 years versus 17.3 years
without PPC. These patients’ surgeries took place between PATHOPHYSIOLOGY
1991 and 1999 and the health-care landscape has changed
very significantly since then. The authors concluded that The relationship between recent anesthesia and surgery
events in the postoperative period are more important than with the development of a new pulmonary condition reflects
preoperative patient risk factors in determining the survival the adverse effects of anesthesia and surgery on the respira-
after major surgery. tory system. These adverse effects are well described1 and
can only be directly pathophysiologically related to a pro-
portion of all possible pulmonary pathologies. Patients with
PREDICTION OF POSTOPERATIVE PULMONARY comorbidities are at increased risk of PPC and the severity of
COMPLICATIONS illness resultant from the PPC is heavily influenced by their
premorbid state.
A range of tools exist to assist in risk stratification of individ-
ual patients. It is always important to appreciate that a risk
prediction tool cannot accurately determine an individual’s
risk but provides an indication of the risk for a population of
similar patients. Box 20.2 ARISCAT score.
β Regression
ACS NSQIP
Coefficients Scorea
A popular tool is the American College of Surgeons National
AGE (YEARS)
Surgical Quality Improvement Program (ACS NSQIP) 50 0 0
Surgical Risk Calculator, which is an online tool (https:// 51–80 0.331 3
riskcalculator.facs.org/RiskCalculator/) that takes pre- >80 1.619 16
operative information about an individual patient and then PREOPERATIVE SPO2
provides an estimate regarding that patient’s risk of postop- 96% 0 24
erative complications. It is intended to function as a decision 9%–95% 0.802 0
aid and to assist in shared decision making and has been 90% 2.375 8
shown to have good calibration and discrimination in RESPIRATORY INFECTION IN THE LAST MONTH
large-scale investigations.13 Twenty patient characteristics No 0 0
(e.g., type of surgery, age, sex, health information) are Yes 1.698 17
entered online. These factors are then put into a statistical PREOPERATIVE ANEMIA (HB ≤ 10 G/DL)
model in order to predict outcomes for that specific patient. No 0 0
This model is built using data from over 4.3 million opera- Yes 1.105 11
tions in the ACS NSQIP database. The result of this model SURGICAL INCISION
shows a patient’s risk of having any of 18 different compli- Peripheral 0 0
cations within the first 30 days following surgery. It only Upper abdominal 1.480 15
provides two metrics relating to PPC: an estimated risk of Intrathoracic 2.431 24
pneumonia (defining according to CDC guidelines) and of DURATION OF SURGERY (HOURS)
venous thromboembolism. <2 0 0
There are a myriad of other tools specific to types of 2–3 1.593 16
surgery (e.g., cardiac) and for particular outcomes (e.g., >3 2.268 23
reintubation), some derived from administrative/coding/ EMERGENCY PROCEDURE
insurance databases (NSQIP, Gupta,14 Arozullah15) and No 0 0
some from prospective cohort studies. Few are in routine Yes 0.768 8
clinical use, but it is worth describing those that have been ARISCAT, Assess Respiratory Risk in Surgical Patients in Catalonia; Hb,
widely used to help target higher-risk groups for interven- hemoglobin; SpO2, arterial oxyhemoglobin saturation by pulse
tional clinical trials that aim to reduce PPC. oximetry.
a
Three levels of risk were indicated by the following cutoffs: <26 points,
ARISCAT low risk; 26–44 points, moderate risk; and 45 points, high risk.
From Mazo V, Sabate S, Canet J, et al. Prospective external validation of a
Initially derived from 2464 patients having surgery in predictive score for postoperative pulmonary complications.
Spain10 then validated in 5099 patients across Europe,11 Anesthesiology. 2014;121(2):219-231.
the ARISCAT score has seven independent variables.
280 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Pulmonary Aspiration
This refers to contamination of the airways with fluids from
the upper aerodigestive tract. This could be the passage of
vomitus from the stomach into the upper airway into the
trachea and distally, which is usually obvious but may be
subtle. For example, upon removing the supraglottic airway
at the end of a case, soiling of the airway is noted. Unless the
volume of fluid that enter the lungs is large, it may be diffi-
cult to detect with chest radiography.16,17
In patients on the intensive care unit, ventilator associ-
ated pneumonia is often caused by organisms that source
from the patient’s own mouth.18,19 Despite cuffed endotra-
cheal tubes being designed to isolate the lung from the upper
aerodigestive tract, they are imperfect in this regard.20
Repetitive microaspiration of secretions pass the endotra-
cheal tube’s cuff21 and the risk might be expected to be pro-
portionate to the duration of tube placement. This seems
highly likely to be relevant to patients having surgery under
anesthesia with endotracheal tubes in place, although the
duration of exposure will be less.
After the conclusion of anesthesia and once any airway
management devices have been removed, the patient relies
upon their intrinsic defenses against pulmonary aspiration.
Further predisposing to aspiration, both the cough and gag
reflex are impaired by anesthetic and analgesic drugs. Pulmo-
nary aspiration in this setting may be clinically silent. Residual
effects of neuromuscular blocking agents (NMBA) that persist
after surgery are well recognized to occur and are likely to be
major contributors to impairment of the intrinsic defenses. Use
of NMBA is associated with increased risk of PPC,22 and in one
analysis the association was dose-dependent.23
Atelectasis, Sputum Retention, and Loss of Airway
Patency
Atelectasis is a term used to describe loss of aeration of an
area of lung and it is likely that, to some extent, this is ubiq-
uitous following surgery under general anaesthesia.24,25 It
is usually clinically silent and in healthy people only mar-
ginally affects pulmonary function. If more extensive, or in
patients with abnormal lung, then it can contribute
toward respiratory failure. Areas of lung that are perfused
but not ventilated lead to a V/Q mismatch that will man-
ifest as impaired oxygenation. Areas of collapsed lung are
less compliant than aerated lung and reduced compliance
causes increased work of breathing, which may manifest
as subjective breathlessness or objective tachypnea. Mild
atelectasis may be detected on cross-sectional imaging of
the thorax (CT scans) or ultrasound of the lung26 and
may be difficult to detect with plain film radiography (chest
x-rays). Atelectasis results from a range of causes of hypo-
ventilation resulting from anesthesia and surgery, particu-
larly if pain from surgical wounds limits chest wall
excursion. Sputum retention refers to the end result of a
limitation in the physiologic process of expectoration,
whereby airway secretions (sputum) are expelled from
the respiratory tract through coughing. If coughing is
painful because of surgical wounds, there is less effective
coughing. Residual effects of anesthetic and continued
effects of analgesic drugs further contributes. Sputum
retention can gradually lead to loss of airway patency.
If atelectasis progresses and there is impaired sputum
clearance, it can lead to whole lobes of the lung losing aer-
ation.27 This is often termed lobar “collapse” but because
pneumothorax is often colloquially known as a collapsed
lung, it may lead to confusion and is best avoided. Physical
factors that predispose to the development of atelectasis
include the habitus of the patient and their intraoperative
positioning, with centripetal obesity and supine posture
being a disadvantageous combination.
A common unchallenged dogma is that atelectasis is the
prequel to pneumonia. More recent studies using lung ultra-
sound have demonstrated that the atelectasis can both
develop and resolve quickly.28 Perhaps adding to the confu-
sion is the historical teaching that postoperative atelectas
causes fever (a major feature of pneumonia), an assertion
that does not stand up to scrutiny.29
Pneumonia
Microbiologic etiology of postoperative pneumonia is very
different to community-acquired pneumonia and overlaps
substantially with aspiration pneumonia (for all the reasons
mentioned) and nosocomial pneumonia in general.30 In
patients undergoing gastrointestinal cancer surgery, pres-
ence of periodontal disease was found to be an independent
risk factor for postoperative infections,31 and patients who
have received dental care prior to major cancer surgery
had reduced risk of pneumonia.32
In addition to airway contamination, atelectasis, and lack of
effective sputum clearance, there is the possibility of hematog-
enous spread from bacteremia potentially caused by distant
infections or from enteric translocation.33,34 Patients who
develop postoperative pneumonia tend to already have multi-
ple comorbidities and functional impairment.35–37
Pulmonary Inflammation
In response to direct injury to the lung or severe systemic
illness, the lung can become inflamed, which can lead to loss
of the integrity of alveolocapillary membrane and passage of
protein-rich fluid into the alveolar space. This is part of the
pathophysiology of ARDS, the definition of which was
refined in 2012.38 In patients without ARDS who are
receiving invasive mechanical ventilation on the ICU, it is
widely believed that the ventilatory parameters can influ-
ence the development of ARDS39 through ventilator-
induced lung injury (VILI). Similarly, this has been the focus
of a large number of studies designed to explore the effect of
different parameters of intraoperative ventilation on inci-
dence of PPC (discussed later in this chapter). Indirect
causes of ARDS are when the primary disease is nonpul-
monary (i.e., pancreatitis) and they are thought to contrib-
ute to the development of ARDS through the actions of
systemic inflammatory mediators acting on the lung.40 In
perioperative patients, activation of the innate immune sys-
tem through the release of damage associated molecular
patterns could equally be contributing toward pulmonary
inflammation and “leakiness.”
Other Perioperative PPC
▪ Manipulation of the airways can cause laryngospasm or
bronchospasm but, if managed appropriately, these
rarely lead to complications.
 20 • Prevention and Treatment of Postoperative Pulmonary Complications 281

▪ Pneumothorax can occur in the intraoperative or post- length of stay. A seminal systematic review was published
operative setting but is rare and its association with in 200648 and another very recently (the paper is available
longer-term adverse outcome is uncertain. Injury to at https://www.bmj.com/content/368/bmj.m540.full or
the pleura causing a pneumothorax as a result of inser- https://doi.org/10.1136/bmj.m540) provide a good over-
tion of a central venous cannula under ultrasound guid- view of the literature.
ance is rare (<1%41) and as a result of invasive
mechanical ventilation (IMV) is rarer still. Intraoperative
IMV does not generally require high airway pressures PREOPERATIVE
(mean peak airway pressure in the “nonprotective”
Respiratory Muscles. There are several interventions that
arm of the IMPROVE trial was 20 cmH2O42) and the risk
can improve the strength and/or endurance of the respira-
of barotrauma is low, unless the patients has diseased
tory muscles. These can be used preoperatively in the hope
lungs (e.g., bullous emphysema).
that the patient will have increased resistance to developing
▪ Pulmonary edema is most commonly cardiogenic and
respiratory muscle weakness than might contribute
results from high pulmonary venous pressures and
towards atelectasis, sputum retention, pneumonia, and ulti-
patients with preexisting left heart disease (such as mitral
mately respiratory failure.
regurgitation, or impaired left ventricular systolic func-
Inspiratory muscle training (IMT) involves breathing in and
tion) are at increased risk. This may be precipitated
out through a handheld device that imposes a resistance, mak-
by excessively rapid or voluminous intravenous fluid
administration. ing breathing more strenuous than normal. It is safe and
applies the well-established principles of muscle resistance
▪ Venous thromboembolism (VTE) in the forms of deep
training and can therefore be likened to lifting a weight. It
venous thrombosis (DVT), and pulmonary embolism
needs to be done for about 15 minutes twice per day and
(PE) are exceedingly well recognized risks of surgery
can be performed at home whilst seated. It may preserve inspi-
and patients routinely receive multimodal prophylaxis
ratory muscle strength and reduce PPC but the overall quality
to prevent their occurrence.43 Surgery is commonly
of studies is moderate for the outcome of pneumonia and low
associated with factors that predispose to the formation
(or very low) for all other outcomes.49–52 A large study
of a VTE, including blood stasis, hypercoagulability,
designed to assess definitively the effectiveness of preoperative
and vascular trauma causing endothelial damage.
IMT is underway in the UK.53
Surgical duration is an independent risk factor for
VTE44,45 and there is a dose–response relationship Incentive spirometry (IS) is a deep breathing exercise per-
formed through a device offering visual feedback, both in
between the number of units of transfused blood and
terms of inspired flow and/or volume, which is thought to
risk of VTE.46
improve technique and motivation. It may be delivered by
physiotherapists and is believed to reexpand areas of col-
lapsed lung and to mobilize secretions. It can be performed
Prevention preoperatively and/or postoperatively. A Cochrane review54
included 12 studies in abdominal surgery patients and
Is Surgery the Best Option? The only guaranteed way to
found no evidence of effectiveness at preventing PPC.
prevent a PPC is to avoid surgery. In many patients who
Another review55 that included cardiac and thoracic surgi-
develop PPCs with serious consequences, it was predictable.
cal patients came to the same conclusions.
Gathering information (perhaps including cardiopulmonary
Supervised respiratory physiotherapy aims to achieve
exercise test results) to estimate risk of adverse events is nec-
many of the same outcomes and has been evaluated in a
essary prior to shared decision making (SDM). During SDM
range of trials. A major limitation is the difficulty of trying
discussions the risks and benefits of surgery, and alterative
to describe the intervention in order to replicate the results,
options are explored. On rare occasions, even if the surgery
to introduce into clinical practice, or to see whether it is rea-
is necessary (usually for oncologic reasons), patients should
sonable to pool data from several studies for meta-analysis.
be counseled in the risks and benefits of surgery prior to con-
Some studies, or meta-analyses of studies, include IS and
sent.47 SDM is necessarily a multidisciplinary endeavor and
even modes of ventilatory support such as continuous pos-
requires close cooperation between many specialties—for
itive airway pressure (CPAP) within respiratory physiother-
example a patient with a significant squamous carcinoma
apy.56 An interventional randomized control trial (RCT)
of the tongue and severe chronic obstructive pulmonary dis-
that produced spectacular results compared provision of
ease (COPD) will need careful discussions that include not
an information booklet (control) with an additional 30-
only surgeons, oncologists, and anesthetists, but also pul-
minute physiotherapy education and breathing exercise
monologists and critical care physicians. A prolonged period
training session (intervention) in patients undergoing upper
of ventilation in the critical care environment following
abdominal surgery.57 The incidence of PPCs within 14 post-
surgery may result in death or severe functional depen-
operative days, was halved in the intervention group com-
dency. A fully informed decision might even involve a visit
pared with the control group.
to a patient receiving tracheostomy ventilation following
similar surgery.
Evidence from Trials. Clinical trials designed to reduce
Smoking Cessation Therapy
PPC will commonly aim to reduce the incidence of a composite Patients who smoke are more likely to experience a range of
definition of PPC, the incidence of a specific disease process, complications, including PPC.58 Smoking cessation has
the incidence of specific interventions that may be required been extensively studied and two systematic reviews and
to treat a PPC, or to reduce a surrogate of PPC such as meta-analyses have both concluded that preoperative
282 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
cessation reduces overall complications, one specifically
found reduced PPC.59,60 In response to ill-founded concerns
that stopping smoking shortly before surgery might para-
doxically increase risk of PPC, a systematic review was con-
ducted that found no evidence to support this conjecture.61
Oral Decontamination
On the basis that postoperative pneumonia can be avoided
by decontamination of the mouth (including teeth, tongue,
and oropharynx) through the application of antiseptics
(chlorhexidine or povidone–iodine) there have been four
RCTs in cardiac surgical patients and a recent systematic
review and meta-analysis.62 The meta-analysis shows a
reduction in PPC, but no effect on mortality. A subsequent
RCT in thoracic surgical patients did not demonstrate any
reduction in PPC.31 As an inexpensive and low-risk inter-
vention with biological plausibility, a definitive RCT in non-
cardiac surgical patients who are at increased risk of PPC is
warranted.
Specific Therapies to Reduce Pulmonary Inflammation
Several drugs have been evaluated in RCTs that have aimed
to reduce the uncommon PPC of ARDS. Types of surgery
that have appreciable rates of ARDS include esophageal,
thoracic, and cardiac surgery. A pilot study of beta-ago-
nists63 suggested potential for benefit, but the definitive
phase III RCT (Prevention BALTI64) did not confirm this.
A phase II RCT exploring the effect of vitamin D on lung per-
meability in patients at high risk of developing ARDS65 sug-
gested that if vitamin D deficient patients could be targeted it
may be beneficial. A proof of concept study66 using simva-
statin has been followed by a definitive phase III RCT (Pre-
vention HARP2) that is recruiting67 thoracic surgical
patients across the UK at the time of writing. There are
no drugs used to modify postoperative pulmonary inflam-
mation in routine clinical use.
INTRAOPERATIVE
Ventilation
Inspired by one of the most influential papers in critical care,
the (K)ARMA study,68 there have been many trials conducted
to ascertain the optimal parameters for intraoperative ventila-
tion. The biologic rationale is that by reducing VILI this will
reduce PPC. However, patients receiving IMV during surgery
are different from those receiving IMV in the critical care unit
in the context of ARDS, both because they usually have unin-
jured lungs and because the duration of ventilation is far less
(hours vs days).
Lung protective ventilation (LPV) is not uniformly defined
but broadly refers to efforts to limit Vt (aiming for 6–8 mL/kg
IBW), keeping Pplat less than 30 cmH2O, and the use of
PEEP. A consequence of bundling different measures into
a single intervention package is that it makes interpretation
challenging: if an effect is seen, it is not clear which of the
measures is responsible. (See Table 20.1.)
The landmark study of LPV in abdominal surgical patients
(IMPROVE42) was published in 2013 and demonstrated
superior outcomes, including PPC, in those who received
LPV. To understand the extent to which the PEEP
contributed to the improved outcomes, the PROVHILO69 trial
compared high (12 cmH2O) versus low (2 cmH2O) PEEP in a
similar cohort of patients. All patients received 8 mL/kg IBW
tidal volume. Those in the high PEEP group also received
recruitment maneuvers (RMs). The high PEEP patients did
not have improved clinical outcomes but showed an
increased risk of harm related to the adverse effects of PEEP
on the cardiovascular system. A very similar study from
the same group (PROBESE70) looked at the effects of high ver-
sus low PEEP on PPC in obese patients and also found no
advantage to high PEEP.
Partly in response to critics who believed that comparing
a PEEP level that is too low with one that is too high does not
help us understand the role of intraoperative PEEP, a hugely
ambitious multicenter RCT of individualized ventilation was
conducted in Spain (iPROVE71). For proponents of optimiz-
ing intraoperative ventilation, it was disappointing that no
clinical benefits were demonstrated.
An individual patient meta-analysis of 15 RCTs found a
dose–response relationship between the appearance of
PPC and Vt size but not between the appearance of PPC
and PEEP level72 (see Fig. 20.1).
A systematic review and meta-analysis found eight RCTs
that looked at clinical outcomes in relation of intraoperative
ventilation in a range of types of surgery,73 the authors rec-
ommend a low tidal volume strategy and the cautious use of
low PEEP. Most recently, expert consensus recommenda-
tions concerning intraoperative ventilation to reduce PPC
were produced.74 They recommend low tidal volume venti-
lation (6–8 mL/kg IBW) and PEEP to be initially set at
5 cmH2O. Despite the evidence to suggest that aspects of
LPV are safe, effective, and without cost, there is evidence
to suggest that many anesthetists tend to use a one-size-
fits-all recipe: in the LAS VEGAS international observational
study of intraoperative ventilation, most patients received
500 mL tidal volume, 12 times per minute with either ZEEP
or a PEEP of 5 cmH2O.75
Residual Effects of Neuromuscular Blocking
Agents (NMBA)
NMBA are commonly used during surgery under general
anesthesia but a growing body of evidence suggests that
their use contributes toward the development of
PPC.22,23 To mitigate these risks, various interventions
have been proposed: use of improved monitoring of neu-
romuscular function, optimized use of drugs that reverse
NMBA actions, or the complete avoidance of use of
NMBA. These measures have had success in decreasing
incidence of adverse events in the immediate postopera-
tive period but no evidence that their introduction can
reduce PPC. A large international observational study
(POPULAR22) did not show use of neuromuscular moni-
toring, or the administration of reversal agents were asso-
ciated with decreased PPC. Neither the choice of drug for
NMBA reversal (sugammadex vs neostigmine), nor extu-
bation at a train-of-four ratio of 0.9 or more was associ-
ated with reduced PPC. It did confirm that use of NMBA
was associated with a 1.86 (1.53–2.26) increased risk of
PPC, but that in high-risk surgical patients avoiding
their use was very uncommon (2.3% of cases). Other
analyses have confirmed that use of neostigmine and
 20 • Prevention and Treatment of Postoperative Pulmonary Complications
Fig. 20.1 Relative risk of postoperative pulmonary complications
according to different tidal volumes and using at least 12 mL/kg
predicted body weight (PBW) of tidal volume as reference. (From
Serpa Neto A, Hemmes SN, Barbas CS, et al. Protective versus con-
ventional ventilation for surgery: a systematic review and individual
patient data meta-analysis. Anesthesiology. 2015;123:66–78.)
neuromuscular transmission monitoring has little effect
on PPC, and neostigmine administration may even
increase the risk of postoperative deoxygenation.76
POSTOPERATIVE
Ventilatory Support
Standard postoperative care usually involves administration
of unhumidified oxygen delivered via a face mask. This may
be given selectively to patients who are considered at risk of
hypoxemia (perhaps patients receiving an opiate patient-
controlled analgesia [PCA]), or those who have demon-
strated the need for additional oxygen to maintain accept-
able saturations, or occasionally less discriminately.
Support of this nature will tend to improve oxygenation,
but it will not support ventilation (see Table 20.2).
CPAP and NIV
Patients’ breathing can be augmented through the use of a
tight-fitting face mask connected to a ventilator. The venti-
lator produces a constant pressure of gas, which is termed
continuous positive airway pressure (CPAP). When the ven-
tilator is set to detect the patient’s inspiratory effort and pro-
duce an additional assistance during inspiration, producing
a (higher) inspiratory pressure and an expiratory pressure,
this is bilevel positive pressure ventilation, commonly
known as noninvasive ventilation (NIV). Unfortunately,
the terminology is used variably with some considering
CPAP to be a form of NIV. The interface between the airway
circuit and the patient is usually a tight-fitting face mask
that covers the nose and mouth (oronasal mask). Some
investigators used nasal-CPAP where the interface only
covers the nose, but it is now uncommon.
Use of either CPAP or NIV soon after extubation at the
end of surgery, with an aim of reducing the risk of PPC,
is significantly different to its common uses in health-care.
However, in common with its other uses there are some
disadvantages,77 mainly the risk of poor tolerance by
patients as it can be uncomfortable or claustrophobic.
The theoretical advantages of postoperative prophylactic
use are that, if applied correctly, it should reduce atelecta-
sis and improve pulmonary compliance, work of breathing,
and oxygenation. Additionally, in patients with partial
upper airway obstruction (i.e., obstructive sleep apnea)
or expiratory dynamic airway collapse (tracheomalacia
283
or bronchomalacia), the application of airway pressure
may improve airflow through preventing airway collapse.
Prophylactic postoperative CPAP has been subject to
many small RCTs and three meta-analyses provide coherent
evidence supporting a role in reducing PPC.78–80 A large,
pragmatic, international RCT is currently recruiting abdom-
inal surgical patients and half will receive 4 hours of CPAP
to determine whether this is effective at reducing a compos-
ite of PPC and death in 30 days.81
Prophylactic use of NIV (as opposed to CPAP) is not com-
monly undertaken unless the patient already has a degree of
respiratory failure (in which case it is not prophylactic) or if
they are at very significantly increased risk of respiratory
failure. A meta-analysis conducted in 201282 identified five
potentially relevant studies that used NIV postoperatively,
but on closer inspection two studies were treating postoper-
ative respiratory failure. The remaining three were all RCTs
comparing nasal-CPAP with standard care in very high-risk
patients: one trial showed only improved oxygenation83 and
two fewer PPC.84,85 Another review identified several other
small and heterogenous studies.86
High-Flow Nasal Oxygen (HFNO2)
These devices have become increasingly popular in adult
perioperative, emergency, and critical care. Air and oxygen
are combined in a blender unit, passed through a combined
active heater and humidifier, and administered to the
patient via a wide-bore inspiratory circuit and nasal cannu-
lae. The flow can be up to 60 L/min and the fraction of
inspired oxygen (FiO2) can be between 0.21 and 1.0. The
theoretical advantages include: (1) generation of degree of
CPAP, which is flow dependent and also dependent on
whether the person is breathing with mouth open or
closed87; (2) delivery of high-flow constant FiO2; (3) a
decrease in anatomic dead space resulting from the high
flow washing out expired CO2 from the upper airways; (4)
maintenance of normal mucociliary clearance as inhaled
gases may avoid mucociliary desiccation (as they are
warmed and humidified); and (5) reduction in work of
breathing.88,89 HFNO2 is considered comfortable (it is much
better tolerated than CPAP or NIV) and the main disadvan-
tage is the risk of delayed recognition of a complication that
requires more definitive management, such as IMV.
RCTs assessing the effectiveness of HFNO2 have been
mostly therapeutic as opposed to prophylactic, but the
potential for HFNO2 to reduce the development of PPC
 Table 20.2 Summary of characteristics of ventilatory support options.a, b
Simple face maska High Flow Nasal Oxygenb CPAPc NIVc
Interface

Pressure No pressure support Continuous flow into upper airways provides a small Continuous Noninvasive ventilation
amount of pressure support. positive airway typically provides an
Flow is up to 40–60 L/min pressure, inspiratory pressure of
typically 14–20 cmH2O and an
between 5 and expiratory pressure of
12 cmH2O 5–10 cmH2O
Supports + + ++
ventilation
Humidification No Yes Optional Optional
and warming
Delivered Up to approximately 80% when at full flow Can deliver 100% but if the patient breathes Up to 100% Up to 100%
oxygen (15 L/min) and with reservoir bag through their mouth then this will
concentration be reduced
Cost minimal $ $$ $$
Expertise minimal + ++ +++
required
a
From Silvestri LA, Silvestri AE, eds. Saunders Comprehensive Review for the NCLEX-RN Examination. 8th ed. Elsevier; 2020 [Fig. 69.22].
b
From Allardet-Servent J, Chiche L, Metz V, et al. Benefits and risks of oxygen therapy during acute medical illness: just a matter of dose! Rev Med Interne. 2019;40(10):670–676 [Fig.1].
c
From Rand S, Main E, Shannon H, et al. Physiotherapy Interventions. In: Deheny L, Main E (eds). Cardiorespiratory Physiotherapy: Adults and Paediatrics, 5th ed. Elsevier; 2016 [Fig. 7.43].
 20 • Prevention and Treatment of Postoperative Pulmonary Complications
Table 20.3 Elements of ERAS that potentially relate to reducing PPC.
Preadmission
Medical/anesthetic ▪ Optimization of pre-existing
conditions
Surgical/technical
Nursing/physiotherapist/health ▪ Smoking cessation
professional ▪ Alcohol reduction
▪ Prehabilitation
▪ Nutritional support
has been reported recently by several studies and others are
being compiled.
The OPERA study90 enrolled 220 abdominal surgical
patients and gave them either HFNO2 or standard therapy
from extubation at the end of surgery, until the following
morning. The primary endpoint was avoidance of hypox-
emia and secondary outcomes included PPC. Quite surpris-
ingly, none of the endpoints showed anything to suggest
that HFNO2 was beneficial. Several small studies in cardio-
thoracic patients91–96showed mixed results but when meta-
analyzed there was a strong suggestion that there may be
improved clinical outcomes, including reduced PPC.97
CARE BUNDLES AND ENHANCED RECOVERY AFTER
SURGERY
Enhanced Recovery After Surgery (ERAS) is a multimodal,
multidisciplinary approach to the care of surgical patients
that incorporates evidence-based interventions (often repla-
cing traditional practices) that span the whole perioperative
journey.98 The ERAS Society is an international nonprofit
professional society that promotes, develops, and imple-
ments ERAS programs (https://erassociety.org) for a diverse
range of surgical specialties.
ERAS pathways usually include >20 different elements
and the effectiveness of these elements in relation to reduc-
ing PPC has usually not been specifically established, none-
theless aspects common to most ERAS pathway are likely to
be beneficial and are summarized in Table 20.3.
Care bundles are collections (typically three to five) of
evidence-based interventions that, when performed collec-
tively and reliably, have been proven to improve patient out-
comes. They are often introduced as a quality improvement
program. A good example from critical care is ventilator-
associated pneumonia (VAP) prevention bundles, with
large-scale implementation reducing VAP.99
When multiple interventions are introduced together,
particularly when part of an overall investment into qual-
ity improvement, or when some of the evidence in support
of some components is uncertain, the extent to which
improvements in outcomes relate to the bundle or aspects
of the bundle is uncertain. Using the VAP bundle again, a
retrospective cohort study revealed that the potential
risks and benefits of different bundle components vary
considerably—four of six components were associated
with improved outcomes, by contrast two were associated
with inferior outcomes—and possibly even increased the
risk of VAP.100
285
Preoperative Intraoperative Postoperative
▪ Prophylaxis to ▪ Intraoperative fluid ▪ Multimodal opioid-
reduce optimization (goal- sparing analgesia
nausea and directed) ▪ VTE prophylaxis
vomiting ▪ Neuraxial blockade ▪ Early extubation
▪ Minimally invasive ▪ Early removal of drains
techniques and lines
▪ Early mobilization
A PPC-specific care bundle named “I COUGH” incorporat-
ing incentive spirometry, coughing and deep breathing,
oral hygiene, understanding (patient education), get up
(mobilization), and head of bed elevation has been evaluated
in several settings. In two before-after studies, a version of
this care bundle was applied to all patients (not just those
at high risk of POPC), prior to adoption of ERAS, it demon-
strated a reductions in PPC,101,102 and these reductions
were sustained.103 A quality improvement program incor-
porating I COUGH into ERAS pathways reduced PPC over
time.104
Treatment of PPC
SPECIFIC TO THE DIAGNOSIS
Treatment for PPC is generally identical to the diagnosis
outside the context of it developing following surgery. The
main exception to this is PE. Postoperative PE requires treat-
ment with anticoagulation but quite reasonably there will
be concerns regarding the risk of bleeding from the surgical
site. This is particularly the case when the PE is sufficiently
significant that thrombolysis is considered. If the PE is caus-
ing critical hemodynamic instability, the risks of bleeding
from systemic thrombolysis are likely to be outweighed by
the risk of death from the hemodynamic effects of the PE.
An important option to consider is catheter-directed throm-
bolysis because this may offer similar efficacy but with lower
risk of complications. There is very sparse evidence to guide
decision-making.
VENTILATORY SUPPORT IN RESPIRATORY FAILURE
The same options of supporting ventilation and improving
oxygenation that were presented earlier are available to
treat postoperative respiratory failure. There is a separate
Chapter 39 (Acute Respiratory Failure) that will cover this
in detail.
Reinstitution of IMV (reintubation) is often undertaken if
the respiratory failure is significant and immediately follows
tracheal extubation. If the onset of respiratory failure is later,
avoidance of IMV is often desirable and if the respiratory fail-
ure is significant, or there is risk of further deterioration, then
CPAP or NIV is commonly applied.105 Delaying IMV when it
is needed will substantially increase the risk of sedation and
tracheal intubation and therefore early involvement of expe-
rienced decision makers is desirable.
286 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Conclusions
PPCs are common, serious, and often potentially prevent-
able. Functional assessments and increased awareness of
the risk factors for PPC will inform shared decision making,
which should improve patient satisfaction and outcomes.
Prevention of PPC is acknowledged as a priority for periop-
erative research,106 and although there is good evidence for
some interventions there remains much to be done.
Although it may seem desirable to combine interventions
into perioperative care bundles and apply these to all
patients, perhaps in combination with ERAS, the risk-to-
benefit ratio will differ between patients, and therefore it
is preferable to restrict the use of such a care bundle to those
at higher risk of PPC.
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 21 Carotid and Intracranial
Surgery
VIJAY K. RAMAIAH, MICHAEL L. JAMES, and DHANESH K. GUPTA
Anesthesia for Carotid Surgery
In the United States, each year approximately 795,000 peo-
ple experience a new or recurrent stroke. Approximately
610,000 of these were first attacks and 185,000 were
recurrent attacks. In 2016 the age-adjusted death rate for
stroke as an underlying cause of death was 37.3 per
100,000.
The risk of stroke in the hyperacute period after the index
TIA in patients with 50%–99% carotid stenoses is: 5%–8% at
48 hours, 17% at 72 hours, 8%–22% at 7 days, and 11%–
25% at 14 days.1 Clinical predictors of increased late stroke
in patients with 50%–99% stenoses are: male gender, age
>75 years, hemispheric symptoms, increasing comorbidity.1
Clinical/imaging parameters associated with a lower risk of
stroke are: female gender especially those with 50%–99% ste-
noses, ocular symptoms/lacunar strokes, smooth stenoses,
chronic subocclusion.1 Imaging features associated with
increased late stroke in patients with 50%–99% stenoses
are: irregular stenoses, contralateral occlusion, increasing
stenosis severity but not subocclusion, tandem intracranial
disease, failure to recruit intracranial collaterals, low gray-
scale median (GSM) measurement on carotid ultrasound,
magnetic resonance imaging (MR) diagnosis of intraplaque
hemorrhage, spontaneous embolization on transcranial
doppler (TCD), increased fluorodeoxyglucose (FDG) uptake
in the carotid plaque on positron emission tomography
(PET).1
A number of interventions exist potentially to prevent
recurrent stroke. Carotid surgery is one such intervention.
Carotid surgeries performed for prevention of strokes are
carotid endarterectomy (CEA), carotid angioplasty/stenting,
and transcarotid artery revascularization. CEA is the most
frequently performed surgical procedure to prevent stroke
in the United States. In 2014, an estimated 86,000 inpa-
tient CEA procedures were performed in the United States.2
CAROTID ENDARTERECTOMY
CEA is recommended for symptomatic patients (e.g., with
ipsilateral transient ischemic attacks [TIAs] or nonprogres-
sing, nondisabling stroke within the previous 6 months)
who have 70% to 99% angiographic stenosis of the internal
carotid artery.3,4
CEA can be considered for men with 50% to 69% symp-
tomatic stenosis, especially men older than 75 years, but
additional clinical and angiographic variables that might
alter the risk-to-benefit ratio should be considered. For
290
symptomatic patients, life expectancy should be at least
5 years and perioperative stroke or death rate should be
less than 6%. CEA should not be considered for symptom-
atic patients when stenosis is less than 50%. Symptomatic
patients with near occlusion angiographically also do not
derive any long-term benefit from CEA. CEA can be consid-
ered for asymptomatic patients between the ages of 40 and
75 years with stenosis of 60% to 99%. Life expectancy
should be at least 5 years and the perioperative stroke or
death rate should be less than 3%. Notably, women with
symptomatic stenosis of 50% to 69% did not show clear
benefit in any of the large trials.5 Patients presenting with
retinal ischemia (amaurosis fugax or retinal infarction)
have a lower risk of subsequent stroke compared with
patients with hemispheric events. However, CEA may be
beneficial when other risk factors for stroke are also
present.6
PREOPERATIVE ASSESSMENT
Cardiovascular System
Up to 28% of patients presenting for CEA have severe angio-
graphic coronary artery disease7 and myocardial infarction
is a leading cause of death after CEA. However, the overall
incidence of perioperative myocardial infarction is low
(0.3% from North American Symptomatic Carotid Endarter-
ectomy Trial [NASCET] data).8
Medical complications occur in 8.1% of patients within
30 days after CEA with symptomatic stenosis (30% to
99%): 1% myocardial infarctions, 7.1% other cardiovascu-
lar disorders (arrhythmia, congestive heart failure, angina
pectoris, hypertension, hypotension, sudden death), 0.8%
respiratory complications, 0.4% transient confusions,
0.7% other complications. CEA was approximately 1.5
times more likely to trigger medical complications in
patients with a history of myocardial infarction, angina,
or hypertension.9 In patients with 50%–99% stenosis,
11%–25% will suffer stroke within 14 days of index symp-
toms. Based on this, delaying CEA for those who fit the cri-
teria is not recommended.5 Identification and optimization
of modifiable risk factors such as hypertension, coronary
artery disease, diabetes mellitus, and renal insufficiency
should occur in accordance with the guidelines for periop-
erative evaluation for noncardiac surgery.10 Patients with
major clinical predictors, such as suspected unstable coro-
nary syndrome, may require cardiac catheterization inde-
pendent of the need for CEA. In the unusual cases of
patients requiring coronary revascularization, staged or
combined operations may be necessary, depending on
the severity of the coronary and carotid disease.

Box 21.1 Preoperative risk factors for perioperative stroke.
Medical risk factors
Female sex5,12,13
▪ patients with stroke
▪ Chronic renal insufficiency (creatinine >1.5 mg/dL)14,15
▪ Active coronary artery disease (unstable angina or angina with
minimal activity in the past 12 months)16
▪ Diabetes mellitus, on insulin15
▪ Congested cardiac failure
▪ Severe, poorly controlled hypertension
▪ Advanced age (>70 years) with comorbidities
▪ Obesity
Chronic obstructive airways disease
▪ artery
Neurologic risk factors1
▪ Crescendo transient ischemic attacks (TIAs) (i.e., more than one
TIA per day)
▪ TIA while anticoagulated with heparin
▪ Multiple completed strokes
▪ Ischemic symptoms less than 24 hours before the surgical
procedure
Preoperative Risk Factors for Perioperative Stroke
Risk factors for stroke resulting from CEA can be divided into
preoperative medical, neurologic, and radiographic risk fac-
tors. Based on these factors, a risk stratification system was
proposed and has been validated as a valuable tool in pre-
dicting adverse neurologic outcome after CEA.11 An adap-
tation of this risk stratification is presented in Box 21.1.
ANESTHETIC MANAGEMENT
Physiologic Management
As part of the preoperative assessment, a series of blood pres-
sure and heart rate measurements should be obtained to
define patient-specific acceptable ranges for perioperative
management. Blood pressure should be maintained in the
high–normal range throughout the procedure, particularly
during the period of carotid clamping, in an attempt to
increase collateral blood flow to prevent cerebral ischemia.
Hemodynamic fluctuations are common during CEA.
Hypotension is more common under general anesthesia
and often occurs immediately after the induction of anesthe-
sia or after carotid unclamping and cerebral reperfusion.18
In patients with contralateral internal carotid artery occlu-
sion or severe stenosis, induced hypertension to approxi-
mately 10% to 20% above baseline may be helpful during
carotid clamping when neurophysiologic monitoring is
not used. Blood pressure preservation or augmentation
can be accomplished by appropriate intravascular hydra-
tion, avoiding unnecessarily deep levels of general anes-
thesia, and vasopressor therapy, such as phenylephrine
and ephedrine. In the absence of severe left ventricular sys-
tolic dysfunction, phenylephrine may be preferred over
ephedrine because increased contractility and heart rate
associated with ephedrine increases myocardial oxygen
21 • Carotid and Intracranial Surgery 291
▪ Symptom status of the patient: asymptomatic patients and
patients with only ocular ischemic events < patients with TIA <
Radiographic risk factors1
▪ Occlusion of the contralateral internal carotid artery
▪ Near occlusion on the operative side
▪ Lack of angiographic collateral blood flow
▪ Ipsilateral intracranial stenosis
▪ Plaque extension more than 3 cm distal to the origin of the
internal carotid artery or 5 cm proximal to the common carotid
▪ High bifurcation of the carotid artery
▪ Thrombus extending from the operative lesion
Perioperative stroke risk stratification17
▪ Group 1: no preoperative risks
▪ Group 2: angiographic risks only
▪ Group 3: medical risks with or without angiographic risks
▪ Group 4: neurologic risks with or without medical or angiographic
risks
consumption to a greater extent than the increase in wall
stress caused by phenylephrine.
Because intraoperative hypertension and tachycardia
can increase myocardial oxygen consumption, blood pres-
sure elevations above 20% of the baseline and tachycardia
should be avoided. Furthermore, such increases in blood
pressure might put the patient with a recent stroke at risk
of hemorrhagic conversion of the infarcted brain tissue.
Hypertension should be treated appropriately, taking into
account the stage of the operation, the level of anesthesia,
and the patient’s heart rate. Deepening the anesthetic,
beta-blocker therapy, nicardipine, and clevidipine are com-
monly used. Agents with a short half-life are preferred.
Bradycardia might occur during surgical manipulation of
the carotid sinus or direct stimulation of the vagus nerve
during dissection. Prophylactic injection of local anesthetic
between the internal and external carotid arteries before
manipulation of these vessels can attenuate bradycardia.
However, local anesthetic infiltration may increase intrao-
perative and postoperative hypertension. Administration
of anticholinergic drugs can result in tachycardia, excessive
hypertension, and increased myocardial oxygen require-
ments, and their use should therefore be avoided.
Severe carotid stenosis, in particular during cross-
clamping, represents a state of gross regional flow inequality
and collateral dependence. The vessels supplying ischemic
areas are usually maximally vasodilated and blood flow
could be diverted from these vascular beds to those already
adequately perfused by cerebral vasodilators such as carbon
dioxide, volatile anesthetic agents, and nitrates (i.e., cere-
bral steal). The reverse may occur in hypocapnia or as a
result of intravenous anesthetic agents such as thiopental
and propofol (i.e., inverse steal). On balance, normocarbia
is recommended and low levels of volatile anesthetic agents
are acceptable.
292 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
There is sufficient evidence that hyperglycemia in nondia-
betic patient is associated with poor outcome. Persistent
hyperglycemia, defined as hyperglycemia within 6 hours
of stroke and at 24 hours, is inversely associated with neu-
rological improvement, 30-day favorable functional out-
come, and 90-day negligible dependence.19
General Anesthesia
There is no difference in outcome between general and
regional anesthesia for carotid surgery. The choice of
anesthesia should be determined by patient and surgical
team preference and a specific patient’s comorbidities and
risk factors.20 General anesthesia can offer ideal operating
conditions. Provided that close attention is paid to the phys-
iologic variables and a rapid, controlled emergence from
anesthesia is ensured, no outcome-based evidence favors
one anesthetic over another. Although it would seem logical
that isoflurane or even barbiturate pretreatment would offer
cerebral protection during carotid cross-clamping, no out-
come data suggest reduction in either the incidence or
severity of intraoperative stroke during CEA.
Remifentanil infusion (0.05 to 0.2 μg/kg/min) ablates the
sympathetic response to surgery, although phenylephrine
infusion may be needed to maintain perfusion pressure.
For amnesia, a low dose of volatile anesthetic (isoflurane
or sevoflurane, usually between 0.3 and 0.5 of the mini-
mum alveolar concentration [MAC]), or less commonly a
propofol infusion, is titrated using electroencephalogram
(EEG) based hypnotic monitors such as bispectral index
(BIS). Muscle relaxation can be maintained with a nondepo-
larizing agent. This approach provides hemodynamic stabil-
ity and stable conditions for EEG monitoring. Nitrous oxide
can be safely used during CEA. Nitrous oxide decreases the
MAC of volatile agents and may decrease vasopressor
requirement. In a secondary analysis of the general anesthe-
sia versus local anesthesia for carotid surgery (GALA) trial,
patients who received nitrous oxide were more likely to have
coronary artery disease, peripheral vascular disease, and
atrial fibrillation, but intraoperative nitrous oxide exposure
was not associated with an increased risk of perioperative
stroke, myocardial infarction, or death.
After closure of the deep fascial layers, volatile anesthetic
can be discontinued and neuromuscular reversal agents
administered. On skin closure, the remifentanil infusion rate
is reduced to 0.02 to 0.05 μg/kg/min, allowing the patient
to emerge gently from anesthesia. This approach can allow
a neurologic assessment while the patient is still intubated.
Hypertension on emergence usually responds well to labeta-
lol, and in some instances infusion of nicardipine, clevidi-
pine, or nitroprusside may be required.
Regional Anesthesia
Superficial cervical plexus block, in combination with addi-
tional local anesthetic infiltration by the surgeon, can
achieve required sensory blockade of C2 to C4 dermatomes.
Deep cervical plexus blockade can also be performed safely
but adds risks, such as inadvertent intravascular or intrathe-
cal injections, paralysis of the ipsilateral diaphragm, and local
anesthetic toxicity, without reducing the need for intrao-
perative local anesthetic supplementation.21 Sedation
should be kept to a minimum to allow continuous neurologic
assessment, in particular during carotid cross-clamping.
Levels of consciousness, speech, and contralateral handgrip
are assessed throughout the procedure. Patient refusal, lan-
guage barriers, and difficult surgical anatomy, such as a high
carotid bifurcation, may be contraindications to regional
techniques.
CEREBRAL MONITORING TO DETECT ISCHEMIA
DURING CEA
Clamping of the carotid artery during CEA and balloon
insufflation during carotid angioplasty/stenting can lead
to cessation of blood flow in an already stenosed artery. Per-
fusion of the brain ipsilateral to the side of occlusion depends
on perfusion from collateral circulation. Brain ipsilateral to
the side of procedure is at risk of ischemia from poor collat-
eral circulation and thromboembolic stroke from ruptured
atherosclerotic plaque and/or surgical debris. The incidence
of periprocedural stroke in the stenting group is 4.1% and in
the endarterectomy group 2.3%.22 Therefore it is important
to monitor for signs of ischemia during carotid surgery.
Commonly used monitors are listed in Box 21.2.
Monitoring of neurological and cognitive functions in
awake patients is very reliable in detecting cerebral ische-
mia during CEA performed under regional or local anesthe-
sia. In a study of 314 awake patients undergoing CEA under
regional anesthesia, neurological monitoring in awake
patients was found to be more sensitive and specific in iden-
tifying patients requiring shunt placement compared with
EEG and measurement of carotid artery stump pressure.24
Awake monitoring under regional anesthesia requires the
patient to be cooperative, which might not be possible in
all cases. The GALA trial did not show any definite difference
in outcomes between general and local anesthesia for
carotid surgery.25
In patients undergoing CEA, intraoperative EEG and
somatosensory evoked potential (SSEP) monitoring with
selective carotid artery shunting had a stroke rate lower
than that of the routine shunting group.26 Stump pressure
of 25 mmHg and either transcranial Doppler (TCD) or EEG
was found to have best results in detecting brain ischemia
during carotid artery cross-clamping.27 EEG has a sensitivity
Box 21.2 Cerebral monitoring to detect
ischemia during carotid endarterectomy.23
Cerebral functions
▪ Clinical neurological monitoring of the awake patient
▪ Electroencephalography (EEG)
▪ Somatosensory evoked potentials (SSEP)
▪ Motor evoked potentials (MEP)
Cerebral blood flow
▪ Transcranial Doppler ultrasound
▪ Stump pressure
▪ Xenon 133 washout
Cerebral metabolism
▪ Near infra-red spectroscopy (NIRS)
▪ Jugular venous oxygen saturation
▪ Conjunctival oxygen tension

of 70% and a specificity of 96% and diagnostic odds ratio
increase with a high number of channels. Sensitivity and
specificity for SSEP (amplitude reduction greater than 50%)
in detecting postoperative neurologic deficits were 100%
and 94% when compared with EEG of 50% and 92% respec-
tively in 64 patients undergoing CEA under anesthesia with
isoflurane or halothane-nitrous oxide.28 SSEP is a highly spe-
cific test and patients with perioperative neurological deficits
are 14 times more likely to have had changes in SSEPs during
the procedure.28 Transcranial motor evoked potentials (MEP)
can be an adjunct to SSEP to avoid a false-negative of 1.5%
from SSEP.29
During CEA, TCD changes of middle cerebral artery veloc-
ity (MCAV) or cerebral microembolic signals showed speci-
ficity of 72.7% and sensitivity of 56.1% in predicting
perioperative strokes. Intraoperative MCAV showed strong
specificity of 84.1% and sensitivity of 49.7% for predicting
perioperative strokes.29
Carotid stump pressure is the measurement of internal
carotid artery back pressure at distal end after cross-
clamping. Stump pressure reflects adequacy of collateral cir-
culation and is used to determine selective shunt placement
during CEA. Carotid stump pressure of <50 mmHg and
abnormal EEG changes is indicated for selective shunting
in patients undergoing CEA under general anesthesia. In
a series of 474 CEA under cervical plexus block, shunting
was required because of neurologic changes in 7.2% of all
CEA; 0.9% had stump pressure 50 mmHg systolic versus
1.0% with stump pressure  40 mmHg systolic. Stump
pressure threshold of 40 mmHg systolic would have resulted
in shunting in 15% with the false-negative rate of 1.0% if
CEA had been performed under general anesthesia
(GA).30 These results were similar to CEA performed under
GA with EEG monitoring.
Near infrared spectroscopy (NIRS) is a noninvasive con-
tinuous cerebral oximetry measuring hemoglobin oxygen
saturation of the frontal region of the brain from the mea-
surements of near infrared light backscattered from the
brain. Cerebral oximetry has shown an ipsilateral decrease
in regional cerebral tissue oxygenation (rSCO2) during
carotid cross-clamp or balloon occlusion as a result of a
decrease in cerebral perfusion and oxygen delivery. In
patients undergoing CEA under regional anesthesia, a
20% decrease in rSCO2 from the preclamp baseline as a pre-
dictor of neurologic compromise has shown sensitivity of
80% and specificity of 82.2%. The false-positive rate was
66.7%, the false-negative rate was 2.6%, positive predictive
value was 33.3%, and a negative predictive value of 97.4%.
In patients undergoing CEA under GA, greater than 25%
reduction rSCO2 from baseline resulted in sensitivity of
100%, specificity of 90.6%, positive predictive value of
9%, and negative predictive value of 100%. A 20% reduc-
tion in rSCO2 persistent for more than 4 minutes resulted
in sensitivity of 100%, specificity of 82.83%, positive predic-
tive value of 2.26%, and a negative predictive value of 100%
respectively.31
Postoperative Management
Blood pressure may continue to be labile for several days
postoperatively, sometimes requiring continued use of
vasoactive drugs. Untreated hypertension in the post-
operative period may lead to cerebral hyperperfusion
21 • Carotid and Intracranial Surgery 293
syndrome, myocardial ischemia, and neck hematoma.
Hypertension unresponsive to labetalol may require a nicar-
dipine infusion.
In patients with severe carotid stenosis, regional intracra-
nial circulation may be unable to autoregulate blood flow
and remain maximally vasodilated in the postoperative
period. Sudden increase in cerebral perfusion pressure
(CPP) and blood flow may lead to edema formation, termed
“perfusion breakthrough.” This typically occurs within the
first few hours after surgery and may manifest as a severe
headache, seizure, or even intracranial hemorrhage. Intra-
cranial hemorrhage after CEA has high mortality and blood
pressure should therefore be carefully controlled in these
patients.
Wound hematoma is one of the more common early
postoperative complications, occurring in about 4% of
patients.32 Because of increased risk of airway obstruction,
these patients have to be intubated for emergent surgical
exploration. Tracheal deviation caused by the hematoma
and pharyngeal edema caused by venous and lymphatic
obstruction may complicate mask ventilation and intuba-
tion. Furthermore, pharyngeal edema may not resolve
immediately after hematoma evacuation and patients
should be extubated with great care if this was present at
the time of intubation.
ENDOVASCULAR CAROTID ARTERY ANGIOPLASTY
AND STENTING FOR CAROTID STENOSIS
Endovascular carotid artery angioplasty and stenting (CAS)
is gaining popularity. Advantages of CAS are minimal inva-
siveness, relatively short operative time, performance under
MAC, and accommodation of patient’s comorbid conditions
that increase risk with CEA. CAS may also be performed
when CEA is technically or anatomically difficult, including
challenging neck anatomy, carotid stenosis located too high
or too low in the neck, restenosis after CEA, or radiation in
the cervical area.33
Endovascular treatment for carotid stenosis is associated
with an increased risk of periprocedural stroke or death
compared with endarterectomy in patients >70 years of
age, despite lower risks of myocardial infarction, cranial
nerve palsy, and access site hematomas when compared
with CEA.32
Anesthesia for Intracranial
Surgery
Anesthesia for intracranial surgery requires detailed discus-
sion between anesthesiologist, surgeon, and attendants
regarding patient positioning, intraoperative use of steroids,
diuretics and anticonvulsants, anticipated blood loss, appro-
priate intraoperative management of blood pressure, PaCO2
and temperature. Special considerations should be given for
intracranial pressure and volume management, control of
hemodynamic response to endotracheal intubation and
Mayfield pin placement, and smooth emergence from anes-
thesia. The brain is enclosed in a rigid skull and may be intol-
erant of volume increases, but it is a highly vascular organ
and has the potential for massive hemorrhage. Tolerance to
294 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
interruption of substrate delivery is minimal and the brain is
therefore equipped with a highly developed and responsive
ability to autoregulate regional blood flow. Anesthetics and
physiologic factors controlled by the anesthesiologist have
profound effects on the brain and it is reasonable to expect
an anesthesiologist who is providing care for patients under-
going craniotomy to understand these interactions.
There is increase use of intraoperative neurophysiological
monitoring such as MEP, SSEP, brain stein auditory evoked
potentials (BAEP), cranial nerve monitoring, and electromyo-
gram (EMG) during intracranial surgery. Detailed discussion
with surgeons regarding intraoperative neurophysiological
monitoring dictates anesthetic selection during intracranial
surgery.
PREOPERATIVE EVALUATION
Preoperative considerations for neurosurgical patients are
similar to those for all surgical patients, with some signifi-
cant adjuncts. Of primary importance is the baseline neuro-
logic evaluation. At emergence from anesthesia, failure to
recover baseline neurologic function can be attributed to
a number of surgical or anesthetic-related factors of varying
degrees of urgency. First, the anesthesiologist must recog-
nize changes from baseline and participate in the
decision-making process. Second, the anesthesiologist must
recognize the magnitude of preoperative intracranial pres-
sure (ICP) and intracranial compliance, and the potential
for intraoperative intracranial hypertension. Third, the
anesthesiologist should be familiar with the location and size
of the lesion because this has a bearing on the surgical
approach and patient positioning, the potential for intrao-
perative hemorrhage, the effects of cerebral edema, and pos-
sible postoperative neurologic deficits, including airway
protection and arousal difficulties. Finally, the list of preop-
erative medications is important for a variety of reasons.
During the course of surgery, scheduled doses of antiepilep-
tics, steroids, and antibiotics may be missed, which could
result in postoperative complications. High-dose steroid
requirements may require intensive insulin regimens to
maintain normal serum glucose and patients receiving anti-
hypertensive therapy may exhibit exaggerated hemody-
namic responses to anesthetic agents.34 A focused history
and brief physical examination should incorporate all these
issues and adequately prepare the anesthesiologist for the
neurosurgical procedure.
In addition to preoperative evaluation, the anesthesiolo-
gist should consider any necessary premedication. As a gen-
eral rule, long-acting preoperative medications that might
result in an alteration of the postoperative neurologic status
should be minimized or avoided. Premedications for prophy-
laxis against postoperative nausea and vomiting is reason-
able, given its frequency.
ANESTHESIA INDUCTION
Concerns unique to induction of anesthesia for craniotomy
are principally related to maintaining cerebral perfusion
pressure and preventing intracranial hypertension. To
maintain cerebral perfusion in the presence of impaired
autoregulation, hypotension or intracranial hypertension
must be avoided. Early studies recognized that induction
of anesthesia for craniotomies is associated with major
increases in ICP35 and techniques evolved to minimize this.
Sympathetic responses and associated increases in ICP
caused by noxious stimuli such as endotracheal intubation,
line placement, and surgical stimulation can be effectively
blunted with an adequate depth of anesthesia. Complete
muscle relaxation should be achieved and maintained to
avoid coughing and straining and use of opioids and intra-
venous lidocaine prior to intubation is common. In addition
to blunting responses to intubation, intravenous anesthetic
agents decrease cerebral metabolic rate, cerebral blood flow
(CBF), intracranial volume, and ICP. Volatile anesthetic
agents are potent cerebrovascular vasodilators that over-
come blood flow reduction caused by metabolic suppression
and result in dose-dependent increase in CBF, blood volume,
and ICP. Increase in ICP can be blunted by simultaneous
moderate hyperventilation.36 Use of specific anesthetics
for ICP control has unclear effects on outcome after craniot-
omy and advocating any specific anesthetic or technique for
ICP control during induction is difficult.
ANESTHESIA MAINTENANCE
Maintenance of neurosurgical anesthesia, like that of other
surgeries, is usually uncomplicated. However, two special
considerations exist: attendance to intracranial volume
and necessity for rapid emergence. ICP and intracranial vol-
ume are usually managed by careful head positioning to
avoid neck vein compression, maintaining normocapnia
and normotension, avoiding high dosages of volatile anes-
thetic (greater than 1 MAC), and administering routine
osmotic diuretics, such as mannitol. Occasionally, problems
arise, particularly when the dura mater is opened or during
the posterior fossa procedures. A “swollen” brain can herni-
ate through dural defects, prohibiting further dural incision
or adequate surgical field visualization. Management of
acute intracranial hypertension is discussed later.
Rapid emergence is required for quickly and fully asses-
sing patients for any postoperative neurologic deficit related
to treatable causes (e.g., hematoma or cerebral edema). If
the patient does not return to preoperative neurologic func-
tion, brain imaging and possible empiric treatment may be
required. Therefore, it is imperative that residual anesthetics
play no role in altered levels of consciousness or postopera-
tive neurologic deficit. Methods that result in a fully awake,
cooperative patient after anesthesia include lower doses of
volatile agent (0.5 to 0.7 MAC) supplemented by remifenta-
nil infusion.36 This technique allows excellent hemody-
namic control through titration of remifentanil doses
during the stimulating portions of the surgery, with rapid
awakening at its end. All volatile anesthetic agents except
nitrous oxide suppress cerebral metabolic rate for oxygen
(CMRO2) in a dose-dependent manner. All volatile anes-
thetic agents are also intrinsic cerebral vasodilators. The
order of vasodilating potency is approximately halothane
>> enflurane > desflurane > isoflurane > sevoflur-
ane.37–40 Volatile agents (except nitrous oxide) at a dose
of 0.5 MAC cause predominant reduction in CMRO2 with
net reduction in CBF. At 1.0 MAC, CBF is unchanged, and
decrease in CBF due to CMRO2 suppression is balanced by
vasodilatory effects of volatile agents (increase in CBF).

Above 1.0 MAC, flow-metabolism uncoupling occurs with
vasodilatory activity of volatile agents and subsequent
CBF increase.
For surgical procedures where neurophysiological moni-
toring is used, volatile anesthetic agents can be replaced by
propofol infusion. Neuromuscular blockage can be avoided
with the use of remifentanil infusion when monitoring MEP
and EMG.
MANAGEMENT OF ARTERIAL BLOOD PRESSURE
In general, normotension is maintained in craniotomy
patients. However, at times either low or high blood pres-
sure may be more suitable. Blood pressure management
can usually be accomplished by adjusting the anesthetic
level. However, anesthetic techniques based largely on
high-dose remifentanil infusion may induce more pro-
nounced vasodilation and hypotension, and alpha agonism
via phenylephrine may be used to offset hypotension caused
by the anesthetic. When increased arterial blood pressure
may be of benefit (e.g., in a patient with a high ischemic
risk), phenylephrine is, again, in common use. However,
patients who might be in a low cardiac output state may
derive more benefit from appropriate intravascular volume
therapy and inotropic support in the form of mixed alpha–
beta agonism (i.e., norepinephrine). When strict blood pres-
sure maintenance is essential to avoid even minimal
amounts of hypertension (e.g., at induction during aneu-
rysm clipping and at emergence from anesthesia), infusion
of a calcium channel blocker, nicardipine41 or clevidipine
generally provides adequate control. Either agent rapidly
and effectively treats increased systemic blood pressure
and allows blood pressure to be maintained within a very
strict range. The choice of agent depends primarily on pro-
vider preference, although clevidipine pharmacokinetics
may be more favorable as a result of rapid onset of action
and ease of titration. The use of nitroprusside may interfere
with brain autoregulation of blood flow and cause increased
intracranial pressure via increased blood volume in the arte-
rial vasculature; this concern is not present with the use of
nicardipine.42 When less precise control is acceptable,
longer-acting agents, such as labetalol or clonidine, may
be used.
MANAGEMENT OF VENTILATION
Alteration of PaCO2, within the range of approximately 20
to 80 mmHg causes a parallel change in CBF, which is a sur-
rogate for cerebral blood volume (CBV). Because of the rigid
structure of the skull and the relatively unchangeable vol-
ume outside the intravascular space, CBV is a direct deter-
minant of ICP. Although CBF is easy to measure, CBV is not
(particularly in humans). Given constant mean arterial
pressure (MAP), PaCO2-induced changes in CBF correlate
with reproducible changes in CBV. Indeed, abundant clini-
cal evidence in patients with ICP monitors shows that
reduction of PaCO2 results in transient reduction in ICP
and vice versa.22 Historically, large reductions in PaCO2
were common practice. However, use of techniques to mea-
sure retrograde jugular venous hemoglobin O2 saturation in
patients with traumatic head injury has repeatedly shown
that reduction in PaCO2 can exacerbate cerebral
21 • Carotid and Intracranial Surgery 295
hypoperfusion, presumably as a result of vasoconstriction.43
As a result, it is no longer advocated that major reductions
in PaCO2 be made in patients undergoing craniotomy
for space-occupying lesions. Modest reductions in PaCO2
remain valuable, however, to counteract vasodilatory
effects of volatile anesthetics.43 Finally, it is important to
measure arterial to end-tidal CO2 gradients in all neurosur-
gical patients, because physiologic dead space variability
can be unpredictable.
INTRAOPERATIVE FLUID MANAGEMENT
The goals of intraoperative fluid management for patients
undergoing craniotomy includes maintenance of euvolemia
and avoidance of reduction in serum osmolarity. The induc-
tion of hyperosmotic therapy for the treatment of brain
edema results in a predictable diuresis. Despite this, euvole-
mia should be maintained because both hypervolemia and
hypovolemia are detrimental in some forms of brain
injury.44 Euvolemia promotes improved osmotic diuresis
and hypovolemia results in hypoperfusion, especially with
sudden large surgical blood loss. Therefore, preoperative
fluid deficit should be replaced and once hyperosmotic ther-
apy has been instituted, euvolemia should be maintained by
replacing urine volume. Because urine output should be
replaced with the solution that most closely approximates
the goal osmolality of 310 mM/dL, normal saline (with an
osmolality of 308 mM/dL) should be considered over
hypo-osmolar lactated Ringer’s solution, although no out-
come data exist to support any particular fluid choice. In
the setting of major blood loss, fluid management becomes
more challenging. Because of osmotic diuresis, urine output
cannot be used as a gauge for intravascular volume and
surgical loss should be carefully estimated while observing
the patient closely for signs of hypovolemia. Coagulopathy
should be anticipated and treated early with appropriate
products, as indicated by coagulation studies. Controversy
exists over the use of colloid to replace surgical blood loss
because of concern over potential bleeding diathesis
with the use of synthetic colloids.44 There is increasing evi-
dence that synthetic colloids starches are associated with
increased bleeding diathesis, requirement of blood transfusion,
and renal replacement therapy (RRT) in critically ill patients.
Human albumin and fresh frozen plasma when compared
with crystalloids were not associated with increased require-
ment for RRT.44 Although albumin has little effect on coagu-
lation and RRT, fluid resuscitation with albumin in critically ill
patients with traumatic brain injury (TBI) was associated with
higher mortality than resuscitation with normal saline.44
Human albumin use for resuscitation in patients with severe
TBI is associated with increased ICP and most likely mecha-
nism of increased mortality in these patients.44
MUSCLE RELAXANTS
Succinylcholine has received special consideration in the
context of craniotomy. In both experimental animals and
humans, succinylcholine can increase ICP when intracra-
nial compliance is poor, although the increase is typically
small and transient. Animal evidence supports the idea that
fasciculation plays a role in the ICP effects of succinylcholine
and there are data in humans that ICP changes caused by
296 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
this drug can be prevented by preadministration of a defas-
ciculating dose of nondepolarizing relaxants.45 A probable
mechanism is that the massive fasciculation-induced affer-
ent barrage from muscle spindles to the brain causes tran-
sient increases in metabolic rate and coupled increases in
CBF.46 As with any decision, the risk-to-benefit ratio must
be weighed when deciding whether succinylcholine is the
appropriate agent. In controlled settings for nonemergent
craniotomy, the ICP effects of succinylcholine can easily
be offset by pretreatment with a nondepolarizing agent.
At the same time, emergency airway management and
the need to minimize hypercapnia and hypoxemia in
patients with low intracranial compliance dictate that suc-
cinylcholine can be an appropriate adjunct for tracheal
intubation.
The majority of patients undergoing craniotomy have
been recently exposed to anticonvulsant agents. There is
clear evidence that the duration of action of nondepolarizing
muscle relaxants is reduced by anticonvulsant medica-
tions46 and even limited exposure can elicit this change.
The mechanism for this remains unclear, but nondepolariz-
ing agents that are metabolized by Hoffman elimination
(e.g., atracurium and cisatracurium) are largely resistant
to the effects of anticonvulsants.
MANAGEMENT OF EMERGENCE
With neurosurgical procedures involving craniotomy,
planning for emergence from anesthesia begins with induc-
tion. The goals of emergence are a predictable recovery to
allow testing of neurologic function in the context of stable
hemodynamics and airway. A unique concern is that failure
to emerge may be attributable to either anesthesia or sur-
gery, which drastically alters subsequent treatment. If fail-
ure to emerge is attributable to surgery, a computerized
tomographic (CT) scan is usually obtained to rule out hema-
toma formation or malignant cerebral edema. In contrast, if
residual anesthesia is the issue, the use of opioid antagonists
or additional reversal of neuromuscular blockade may be
necessary. Therefore, when planning the anesthetic, it is
helpful to restrict the use of agents to those that can be mon-
itored for concentration or to those for which sufficient
knowledge of pharmacodynamics allows highly probable
and predictable clearance or reversal for emergence. It is
best to keep the anesthetic simple so that each compound
can be independently ruled out as an etiology for failure
to emerge.
Although the magnitude of surgical stimulation after
dural opening is minimal, patients undergoing craniotomy
experience significant postoperative pain. Fear about
delayed emergence and sedating effects of opioids analgesics
frequently leads to emergence hypertension, tachycardia,
coughing, straining, and inadequate post-craniotomy pain
control.47 Ultra-short-acting opioid remifentanil as a sole
analgesic agent may provide stable hemodynamics and
rapid and smooth emergence48 but lacks postoperative
analgesic effect. Compared with fentanyl infusion, patients
receiving remifentanil infusion during craniotomy often
have higher postoperative systolic blood pressure and earlier
analgesic requirement.49 When used as a useful adjuvant,
dexmedetomidine has been shown to reduce anesthetic
requirement and to delay postoperative analgesic use.50
A practical approach is to assume that the anesthesiolo-
gist needs 5 to 10 minutes after completion of the head
dressing to allow a controlled emergence. Thus, neuromus-
cular blockade may be maintained until completion of the
head dressing, elimination of volatile anesthetics should
be complete by the time of head dressing, and anesthesia
is maintained by either residual concentration of opioid
(e.g., fentanyl or sufentanil) or continued infusion of remi-
fentanil. Additionally, nitrous oxide can be used to supple-
ment other volatile anesthetics. Compared with using
intravenous anesthetic agents, nitrous oxide concentration
can be defined by end-tidal gas analysis, which aids in defin-
ing failure to emerge. However, although nitrous oxide is
usually well tolerated, the anesthesiologist should be vigi-
lant in monitoring for a clinically apparent expanding pneu-
mocephalus. Furthermore, rapidly cleared intravenous
agents such as lidocaine can be of value in sustaining anes-
thesia for a few additional minutes. Finally, if remifentanil is
used, the rate of infusion can remain unchanged until the
dressing is complete.51 It is important, however, to provide
transitional analgesia (typically 50–100 μg/kg morphine or
1–2 μg/kg fentanyl in adults) before discontinuation of
remifentanil.
After the need for a predictable emergence, the second con-
cern is hypertension. For reasons not yet understood, patients
undergoing craniotomy often exhibit extreme hypertension
during emergence that is sustained through the early phases
of recovery. Because of possible intracranial hemorrhage, a
plan for treatment of hypertension before it manifests is
imperative. Aside from ensuring adequate analgesia, prophy-
lactic doses of labetalol may be helpful (typically, 40 to
60 mg). Additionally, nicardipine or clevidipine infusion is
rapidly and easily titratable and does not contribute to
increases in ICP (see earlier section “Management of Arterial
Blood Pressure”). While patients who develop postoperative
hematomas have episodes of hypertension during emergence
or early recovery, the source of hemorrhage is almost always
within the surgical field, and thus the quality of hemostasis is
undoubtedly important. However, because the mortality
associated with postoperative hematoma formation requiring
emergent evacuation is high, mitigating hypertension during
emergence is suggested.
Finally, postoperative nausea and vomiting (PONV) is a fre-
quent problem after craniotomy. In addition to being uncom-
fortable, it can contribute to postoperative hypertension.
Several studies have shown that more than 50% of patients
suffer this complication. Its incidence appears to be indepen-
dent of anesthetic technique (awake or general) or opioid
dose, suggesting that surgery itself is contributory. Women,
younger patients, and those undergoing infratentorial crani-
otomy are at greater risk,52 but prophylactic antiemetic ther-
apy markedly reduces the magnitude of this problem.
Droperidol (0.625 mg) appears to be at least as effective as
4 mg ondansetron without causing detectable sedation.53
Many patients require multiple agents to control nausea
and emesis. Combination of aprepitant 40 mg and dexameth-
asone 10 mg is found to be more effective than was the com-
bination of ondansetron 4 mg and dexamethasone 10 mg for
prophylaxis against postoperative vomiting but did not affect
the incidence or severity of nausea or the need for rescue
antiemetic.54 Regardless, some form of prophylaxis is gener-
ally warranted in patients undergoing craniotomy.

Procedure-Specific Issues
AWAKE CRANIOTOMY
Although brain scanning modalities (magnetic resonance
imaging [MRI] and PET) can identify the speech-dominant
cerebral hemisphere noninvasively, intraoperative mapping
of the eloquent cortex is still the most reliable method to
ensure preservation of speech function when the speech
center is close to the surgical field.55 Mapping the speech
cortex, originally developed to allow maximal resection of
epileptic foci in the dominant hemisphere, is equally useful
for safely maximizing the extent of other cortical resections
near language cortex, especially resections for low-grade gli-
omas and vascular malformations.56 Neuroleptanalgesia
with intermittent periods of general analgesia has been
the technique most often utilized in the past. The develop-
ment of short-acting titratable anesthetics and narcotics
has led to an “asleep-awake-asleep” technique (e.g., sponta-
neously ventilating general anesthesia with intraoperative
wakeup) for use during craniotomy when the eloquent cor-
tex is at risk. The combined use of narcotics and intravenous
anesthetics can result in decreased respiratory drive, hyper-
carbia, and elevated intracranial pressure. Patients with
reflux risk, morbid obesity, chronic obstructive airways dis-
ease, or a tendency to airway obstruction pose a particular
challenge, and these risk factors might even prohibit the use
of this technique.
The Wada Test: Determining Whether Speech
Mapping Is Required
Because the speech cortex is a unilateral structure, preoper-
ative identification by a Wada test of the hemisphere contain-
ing it may be required.57 The Wada test is advocated as a
preliminary to operations in the vicinity of the Sylvan area
in left-handed and ambidextrous patients, and also in the
right-handed patient if any doubt exists as to which cerebral
hemisphere is dominant for speech. The test is performed by
intracarotid amytal injection. This results in immediate
speech disruption, contralateral hemiparesis, and mainte-
nance of consciousness when the injected carotid supplies
the speech-dominant hemisphere. The nondominant hemi-
sphere is identified by speech preservation and contralateral
hemiparesis after carotid amytal injection.57
Intraoperative Electrophysiologic and Anatomic
Components of Speech Mapping
Electrical stimulation of the cortex allows mapping for
speech.56 Language function is measured by showing the
patient pictures of objects with common names. While
the patient names the pictures, cortical sites are stimulated.
Three sets of sites have been identified. At one set of sites,
repeated errors are evoked; a second set shows only single
errors on multiple samples, and the third group shows no
effect of stimulation at all. Regions in which repeated errors
are evoked seem to be essential for a particular language
function because when the cortical resection encroaches
on these sites, aphasia commonly occurs. However, regions
in which stimulation produces only occasional errors do not
seem to be essential for that particular language function,
21 • Carotid and Intracranial Surgery 297
and at least some of these sites can be included in a resection
without producing aphasia. Too low a current may not ade-
quately block local cortical function, whereas too large a
current is likely to evoke seizures.
Thus, it is essential to determine the after-discharge
threshold on electrocorticography and to use a current just
below that threshold to identify language cortex with stim-
ulation mapping while decreasing the chance of inducing a
generalized seizure. Alteration of the seizure threshold by
pharmacologic agents should be minimal and ideally the sei-
zure threshold should be constant during the period of test-
ing. Intraoperative seizures may be aborted by irrigating the
stimulated cortex with iced solution. Alternatively, a small
dose of a short-acting sedative (e.g., barbiturate, benzodiaz-
epine, or propofol) may be required.
Comparing Neurolept and General Anesthesia for
Awake Cortical Mapping
The technique of neuroleptanalgesia, also called conscious-
sedation analgesia, relies on the titration of fentanyl and dro-
peridol to a specific endpoint rather than administration of a
dose based on bodyweight.58 The goals of neuroleptanalgesia
technique are to enable the patient to tolerate surgical
discomfort during prolonged immobility while maintaining
verbal responsiveness. Short periods of unconsciousness were
induced to complete painful portions of the procedure by
increasing doses of fentanyl. The neurolept craniotomy tech-
nique is therefore more accurately described as neuroleptanal-
gesia with intermittent periods of general anesthesia. Loss
of consciousness could be accompanied by hypoventilation
or airway obstruction, leading to hypoxia, hypercarbia, and
elevation of the intracranial pressure. These complications
would occasionally necessitate the conversion to general
anesthesia with endotracheal intubation and controlled
ventilation.
Although the majority of patients undergoing awake cor-
tical testing can be managed successfully with a conscious
sedation technique, a small percentage of patients (2% to
16%) are unable to tolerate the conditions of the surgery
and require conversion to general anesthesia. In these
patients, gaining control of the airway can be a challenge.
Intubation by direct laryngoscopy necessitates rapid unco-
vering of the drapes and, if applicable, removing the fixation
holder from the patient’s head. Emergency blind nasal intu-
bation may be an option, although it is not always fast or
successful. Alternative options include the use of a fiberoptic
bronchoscope or an intubating laryngeal mask airway
(LMA), or the combined use of these two devices.
In a series of 140 patients, LMA (classic, Proseal or Igel)
were used. All patients were placed in lateral position and
ventilation was controlled with pressure-controlled ventila-
tion. The anesthetic maintenance included target-
controlled infusion of propofol and remifentanil. All patients
received a lidocaine scalp block before placing the Mayfield
head holder and making the incision. All patients awoke
smoothly for awake mapping and neurological testing. Dur-
ing the second asleep phase, LMA was inserted in 54
patients with no failure or technical difficulty in 46 patients
and difficult placement in eight patients. Orotracheal intu-
bation was attempted in 91 patients using video laryngos-
copy or a Fastrach LMA, with five failures with intubation
298 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
and no failure of airway control with LMA. One patient had
a severe pulmonary complication related to aspiration of
gastric contents.59
To minimize coughing and Valsalva associated with air-
way instrumentation or at the time of emergence, tech-
niques relying on spontaneous ventilation through a
natural or splinted airway continue to evolve. Careful titra-
tion of remifentanil and propofol infusions in an asleep-
awake-asleep technique produced good results, with only
2% of cases requiring conversion to general anesthesia dur-
ing cortical mapping.60 Airway support was dictated by the
patient’s ability to maintain airway patency and sufficient
respiratory drive and, when required, established with
positive-pressure ventilation through nasal trumpets or
LMA. Adverse side effects were equivalent to previously
reported rates using a neurolept technique. Some degree
of hypercarbia (median PaCO2, 50; range, 47 to 55 mmHg)
was seen and the incidence of apnea was high, underscoring
the importance of an available method to offer positive-
pressure ventilation.
Table 21.1 summarizes anesthesia techniques for craniot-
omy with awake intraoperative language testing and illus-
trates that no single method for the anesthetic management
of awake testing during craniotomy is perfect. The choice of
technique and the management of intraoperative complica-
tions are directed by patient and surgical requirements
(patient position, duration of surgery, duration of wakeful-
ness, and multiple periods of wakefulness). Close communi-
cation (both preoperative and intraoperative) between
surgeon, patient, anesthesiologist, and the electrophysiolo-
gists is critical. Focus on details of patient comfort, details
of patient monitoring, and requirements for patient wake-
fulness are necessary to increase the rate of successful
procedures.
CEREBRAL ANEURYSM CLIPPING AND COILING
PROCEDURES
Rupture of an intracranial aneurysm, the most common
cause of subarachnoid hemorrhage (SAH), occurs with a
frequency of between six and eight per 100,000 in most
populations.69 SAH is associated with a 32% to 67% case
fatality, and with long-term dependence in 10% to 20% of
survivors because of brain damage.70 To ablate the aneu-
rysm and prevent rebleeding, aneurysm clipping or endo-
vascular coiling are commonly performed on patients who
survive to reach the hospital after aneurysmal SAH. In addi-
tion, unique pathophysiologic changes occur after rupture
of an intracranial aneurysm that require special anesthetic
and intensive care management.
Hypertension, frequently seen with acute SAH, may
represent autonomic hyperactivity induced by cerebral
ischemia or direct trauma to cerebral autonomic control
mechanisms. Sudden or sustained elevations of MAP or
reductions of ICP tend to distend the aneurysmal sac and
may cause rupture and rebleeding of the aneurysm, the
most significant early complication after SAH. On the other
hand, prolonged reductions of CPP (MAP-ICP) may produce
neurologic ischemia in poorly perfused areas with impaired
autoregulation and may globally increase ICP through
ischemic disruption of the blood–brain barrier.71
Preoperative Management
Not only does SAH injure the brain at the time of the hem-
orrhage, but it is frequently followed by further neurologic
insults that may occur over a period of weeks. In addition,
the complications are by no means limited to the central
nervous system and there is frequent impairment of cardiac
and pulmonary function. Finally, there is a complex interac-
tion between neurologic and medical complications.
Neurologic. Headache, the most common clinical symp-
tom of SAH, occurs in 85% to 95% of patients.72 Many
patients present with a brief loss of consciousness followed
by various degrees of decreased mental acuity. Other symp-
toms of SAH include nausea, vomiting, and photophobia.
Other signs of neurologic involvement include motor or sen-
sory deficits, visual field deficits, abnormal motor posturing,
or loss of various brainstem reflexes.
Two grading scales are commonly used to assess neuro-
logic status after SAH: the modified Hunt and Hess grade73
(Table 21.2) and the grading scale of the World Federation
of Neurological Surgeons74 (Table 21.3). The scales are use-
ful for identifying a baseline neurologic status from which
any acute changes should be assessed. In addition, the scales
may correlate with physiologic status. Patients who are
Hunt and Hess grades I and II have near normal cerebral
autoregulation and ICP. Serious systemic disease or vaso-
spasm, if present, raises the Hunt and Hess grade one level
to the next worse grade.
Cardiopulmonary
ELECTROCARDIOGRAPHIC ABNORMALITIES AND CARDIAC INJURY.
Stratification of cardiac dysfunction after SAH ranges from
isolated electrocardiographic (ECG) abnormalities and myo-
cardial enzyme elevation to pulmonary edema and cardio-
genic shock. Injury to the posterior hypothalamus may
stimulate release of norepinephrine from the adrenal
medulla and sympathetic cardiac efferents.75 Norepineph-
rine, either through direct toxicity or via significant eleva-
tion of myocardial afterload, produces ischemic changes
in the subendocardium.76 Pathologic examination of the
myocardium after SAH may reveal microscopic subendocar-
dial hemorrhages and myocytolysis.77 By performing ECG
spectral analysis and measuring cardiac enzymes and
plasma catecholamines measurements, sympathetic and
vagal activity are enhanced during the acute phase of
SAH, thus contributing to the ECG abnormalities and the
onset of cardiac injury.78
ECG changes accompany 50% to 80% of SAH episodes,
occur during the first 48 hours, and normalize over a 6-
week period. Most ECG abnormalities appear to be neuro-
genic rather than cardiogenic.79,80 Also, the risk of death
from cardiac causes is low in patients with SAH and ECG
readings consistent with ischemia or myocardial infarction.
ECG abnormalities are associated with more severe neuro-
logic injury but are not independently predictive of
mortality.
Correlation between the ECG abnormalities and cardiac
ischemia is not high after SAH. However, it appears that
cardiac troponin I (cTnI) is a highly sensitive and specific
indicator of myocardial dysfunction and injury after aneu-
rysmal SAH.80 Cardiac dysfunction is usually reversible
Table 21.1 Summary of awake craniotomy studies.
Authors Date Patients Monitors Drugs Study technique Side effects and outcome
Trop 1986 2000 Noninvasive Droperidol 0.15 mg/kg Neurolept technique 70% managed neuroleptic technique
et al.58 (descriptive No Foley Fentanyl 0.5–0.75 μg/kg Repeat fentanyl and droperidol to maintain
review) analgesia and adequate ventilation 25% required methohexital in addition
Methohexital
Methohexital used for brief loss of 5% required conversion to GA
Local anesthetic: consciousness in painful portions
Infiltration used, but type, of procedure Nausea and vomiting, 12%
quantity, and location not
specified Seizure, frequency not stated
Archer 1988 354 Noninvasive Fentanyl 6 (1–24) μg/kg Neurolept technique Seizures, 16%
et al.61 No Foley Supplemental fentanyl kept to a minimum
Arterial catheter for Droperidol 10 (0–40) mg to maintain normal respiration, conserve Nausea/vomiting, 8%
those converting to airway reflexes, and provide alertness for Excessive sedation, 3%
GA Methohexital 150 (0–890) mg testing
Change to GAa, 2%
Local anesthetic: dibucaine, Methohexitone given to majority to
50 : 50 mix of 0.67% and 0.25% stimulate cortical activity “Tight” brain, 1.4%
with epinephrine Also given for sedation or control of seizures
Local anesthetic toxicity, 2%
Scalp infiltrated
initially, and along
middle meningeal artery and
dura if needed during
opening of the bone flap
Sartorius 1997 Not stated Arterial catheter _ Neurolept technique _
et al.62 Foley catheter The goal is patient responsiveness to verbal
commands with sufficient analgesia to
tolerate both local anesthetic infiltration
and prolonged relative immobility
Silbergeld 1992 9 Not stated Droperidol, 1.25–2.5 mg Sedative technique with intermittent GA Recall of portions of procedure during propofol
et al.63 Premedicate with droperidol, 1.25–2.5 mg administration, 33%
Fentanyl, 50–150 μg Fentanyl, 50–150 μg
Propofol titrated for sedation without apnea Duration of recovery and
Propofol bolus, 1–2 mg/kg nature of recovery not altered by propofol dosage or
“Adequate level of anesthesia is obtained duration
prior to beginning any potentially painful
part of the procedure” ECoG not altered by propofol

Continued
Table 21.1 Summary of awake craniotomy studies—cont’d
Authors Date Patients Monitors Drugs Study technique Side effects and outcome
Herrick 1997 37 Noninvasive Propofol PCS: propofol Sedative technique vs. neurolept technique Sedation scores significantly higher (i.e., patients
et al.64 Monitors 0.5 mg/kg bolus with a 3-min Prospective trial of PCS with propofol versus more alert) in the propofol group
lockout and basal infusion of neurolept technique
0.5 mg/kg/h Recall of intraoperative events not depressed in either
group
Neurolept: initial bolus
droperidol (0.04 mg/kg), All patients easily aroused throughout procedure
fentanyl, 0.7 μg/kg bolus, and
fentanyl infusion, 0.7 μg/kg/h Respiratory rate <8 more common in the fentanyl/
propofol group
All patients received scalp and
meningeal local anesthetic, Pain associated with tachycardia more common in the
bolus fentanyl (25 μg), and neurolept group
dramamine as needed
Intraoperative seizures more common in the
neurolept group
Welling 1989 4 Arterial catheter in 1 Droperidol, 2.5 mg Neurolept technique Etomidate used to elicit seizure in one patient
and case Patient sedated, breathing spontaneously
Donegan65 Alfentanil bolus, 5–7.5 μg/kg, and comfortable “Tight” brain in one patient unresponsive to
repeated Alfentanil infusion maintained at low level decreasing alfentanil infusion and auto-
Infusion, 0.25–2.0 μg/kg/min during testing hyperventilation

Mannitol achieved good result

Gignac 1993 30 Noninvasive BP Droperidol, 0.014 mg/kg Neurolept technique Nasal prong CO2 > 45 mmHg in 33%
et al.66 Nasal prong CO2 Dimenhydrinate, 0.25 mg/kg
Nausea in 50%
Opioid bolus and infusion:
Fentanyl 0.75 μg/kg and 0.01 Conversion to GA, 2/30
μg/kg/min
Oversedation, 2/30
Sufentanil 0.075 μg/kg and
0.0015 μg/kg/min Desaturation, 3/30

Alfentanil 7.5 μg/kg Seizure, 5/30

and 0.5 μg/kg/min
Huncke67 1998 10 Arterial catheters Induction: pentothal or GA with intraoperative wakeup, “asleep- Nosebleed, 2 patients
Foley catheter propofol awake-asleep”
Both inserted after Patient self-positioned Reintubation >50% patients
GA induction Maintenance: N2O and Awake nasal or oral intubation
desflurane, isoflurane, or Hyperventilation
sevoflurane Topical lidocaine to
Propofol trachea prior to intraoperative extubation
Reintubation after
Bupivacaine 0.5% for pin sites cortical mapping with bronchoscope or
and scalp incision with tube
changer
 Taylor68 1999 200 Infrequent use of Local anesthetic to pin sites _ Exclusion criteria explicitly stated (inability to
arterial catheters, cooperate because of dysphasia, severe language
central venous Short-acting sedatives barrier, mental retardation, emotional instability,
pressure, or Foley propofol, midazolam, and decreased level of consciousness) eliminated 105/305
catheters fentanyl (dosage not patients.
specified) to keep patient
comfortable Five mapping-negative patients developed new
permanent deficits.

Two mapping-positive patients developed new

permanent deficits.

Patients with intact preoperative mental status

had lower a complication rate than those with
preoperative deficits.
67% did not stay in ICU
Keifer 2005 98 Arterial catheters Remifentanil, 0.05 μg/kg/min Asleep-awake-asleep Successful testing, 98%
et al.60 Foley catheter
Propofol, 115 μg/kg/min Spontaneous ventilation with natural or Disoriented on emergence, 5%
“stented” airway
Positive-pressure ventilation when Required conversion to GA, 2%
indicated by apnea
Episodic apnea, 66%

Hypercarbia, hypertension at placement of Mayfield

head frame and at emergence

Headache, 16%

Nausea, 8%
Deras59 2012 140 Noninvasive monitors TIVA Asleep-awake-asleep Ventilation with facial mask during induction for
Foley catheter second asleep phase was possible in all patients (95%
Propofol and remifentanil TCI First asleep phase: TIVA with LMA in all easy, 5% difficult)
patients
Scalp infiltration with 20 mL Three different LMA: LMA classic, LMA Fastrach LMA for intubation: No failures.
lidocaine 2% with Proseal and I-gel. 85.2 % easy intubation and 14.2% difficult intubation
epinephrine Pressure controlled ventilation with
Dura mater infiltration with pressure at <15 cm H2O in lateral position Video laryngoscopy for intubation: 5.6% failures
lidocaine Failed intubation: airway control was achieved
Awake Phase: TIVA stopped and LMA with Fastrach LMA and no oxygen desaturation
removed in lateral position
Coughing during tracheal
Second asleep phase: LMA or an orotracheal intubation (10 patients), resulting in subpial
intubation in lateral position hemorrhage, 2%
Intubation with Fastrach LMA or video Pulmonary aspiration, 0.7%
laryngoscopy

BP, Blood pressure; ECoG, electrocorticography; GA, general anesthesia; LMA, laryngeal mask airway; PCS, patient-controlled sedation; TCI, target-controlled infusion; TIVA, total intravenous anesthesia.
a
Tracheal intubation, lateral position.
302 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Table 21.2 Hunt and Hess’ modified clinical grades.
Gradea Criteria
Grade 0 Unruptured aneurysm (0%–2%)
Grade I Asymptomatic or minimal headache and slight nuchal
rigidity (0%–2%)
Grade II Moderate to severe headache, nuchal rigidity, but no
neurologic deficit other than cranial nerve (2%–10%)
Grade III Drowsiness, confusion, or mild deficit (10%–15%)
Grade IV Stupor, mild to severe hemiparesis, possible early
decerebrate rigidity, and vegetative disturbance (60%–
70%)
Grade V Deep coma, decerebrate rigidity, moribund appearance
(70%–100%)
a
Serious systemic conditions such as hypertension, diabetes, severe
atherosclerosis, chronic pulmonary disease, and severe vasospasm seen on
arteriography, results in placement of the patient in the next less favorable
category.
From Hunt WE, Hess RM. Surgical risk as related to time of intervention in the
repair of intracranial aneurysms. J Neurosurg 1968;28:14–20.
Table 21.3 World Federation of Neurological Surgeons
(WFNS) grading scale for patients with subarachnoid
hemorrhage.
Glasgow coma WFNS grade
score (sum score) Motor deficit
I 15 Absent
II 14–13, without focal Absent
deficita
III 14-13, with focal deficit Present
IV 12–7 Present or absent
V 6–3 Present or absent
a Premedication. In patients presenting for aneurysm sur-
Cranial nerve palsies are not considered a focal deficit.
From Report of World Federation of Neurological Surgeons Committee on a
Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg
1988;68:985–986.
and should not necessarily preclude these patients from
undergoing operative interventions.81 Nevertheless, serial
cardiac enzymes, assessment of ventricular function, or car-
diac catheterization may be necessary to establish func-
tional and therapeutic implications associated with the
severity of the cardiac injury.
Life-threatening dysrhythmias may occur in patients dur-
ing the first 48 hours after SAH.82 Cardiac dysrhythmias
include sinus tachycardia, sinus bradycardia, premature
supraventricular complexes, supraventricular tachycardia,
atrial fibrillation, premature ventricular complexes, ventric-
ular tachycardia, ventricular fibrillation, torsades de
pointes, and QT prolongation. Development of ventricular
fibrillation is frequently preceded by torsades de pointes.
QT interval was significantly prolonged in those cases where
torsades de pointes was followed by life-threatening ventric-
ular dysrhythmias. Female sex and hypokalemia are inde-
pendent risk factors for QT interval prolongation after
SAH.83 An inverse correlation between the serum catechol-
amines and potassium levels suggests that a catecholamine
surge after SAH plays an important role in the pathogenesis
of hypokalemia during the acute phase of SAH, which may
instigate cardiac dysrhythmias.
HYPERTENSION. Management of hypertension may be difficult,
especially if the blood pressure rises above 200/110 mmHg.
The primary reason for treating hypertension is to reduce
transmural pressure in the aneurysm to prevent rupture.
However, after SAH, upper and lower limits of CBF autoregu-
lation curve becomes narrower, which makes brain perfusion
more dependent on MAP.84 In fact, intraoperative hypoten-
sion could have significantly adverse effects on SAH out-
come.85 Moreover, hypotension is also related to more
frequent and severe manifestations of vasospasm. Thus,
antihypertensive drugs might be best reserved for patients
with extreme elevations of blood pressure and evidence of
rapidly progressive end-organ deterioration, diagnosed from
either clinical signs (e.g., new retinopathy, heart failure) or
laboratory evidence (e.g., signs of left ventricular failure on
chest radiograph, proteinuria, or oliguria with a rapid rise
of creatinine level).
Calcium channel blockers have been effective in treating
acute hypertension and may have an additional beneficial
effect on cerebral vasospasm. (We suggest administration
of nicardipine, 1 to 15 mg/h. A bolus of labetalol [50 to
100 mg] is useful as an adjunct.) Adrenergic blockers have
the advantage of not directly affecting CBF86 and have the
theoretical advantage of shifting the autoregulatory curve
to the left.87
Anesthetic Management for Aneurysm Clipping
The goals of intraoperative management for cerebral aneu-
rysm surgery include preventing intraoperative aneurysm
rupture, minimizing potential neurologic injury, facilitating
surgical exposure, and providing optimal conditions for
smooth emergence and stable recovery.
gery with decreased levels of consciousness (World Federa-
tion of Neurological Surgery Scores [WFNS] 4 and 5),
significant anxiety is unlikely. Sedative premedication is
usually not required in these patients. Patients with WFNS
grades 1–3 may require only a reassuring preoperative visit.
Heavy sedation hinders preoperative neurologic assessment
and depresses ventilation. Depression of ventilation may
produce hypercarbia and corresponding increases in CBF
and ICP. If preoperative sedation is required to prevent
potential hemodynamic perturbations associated with anx-
iety, a small dose of a benzodiazepine is usually sufficient. If
the patient is at increased risk of aspiration because of a
decreased level of consciousness, prophylactic administra-
tion of agents that reduce gastric acidity and volume should
be given before induction.
Monitoring. Adequate monitoring should be established
prior to maneuvers that are likely to alter CBF, ICP, and
transmural aneurysmal pressure. Induction of anesthesia
and laryngoscopy are critical events that directly influence
intracranial physiology. Intra-arterial blood pressure moni-
toring is particularly useful as an early detector of hemody-
namic alterations. Many clinicians prefer to place an intra-
arterial catheter with local anesthesia to monitor blood
pressure responses continuously prior to and through
induction. Central venous access is helpful in assessing vol-
ume replacement needs prior to aneurysm clipping and in
managing volume and hyperosmotic therapy in patients
at risk of vasospasm. Rapid titration of vasoactive medica-
tions can be best achieved with the use of a central venous

catheter. There is a poor correlation between central venous
and left ventricular end-diastolic pressure in SAH. There-
fore, placement of a pulmonary artery catheter may be more
helpful in assessing perioperative volume status and cardiac
dysfunction than a central venous catheter. Alternatively,
volume status may be assessed through a variety of nonin-
vasive means, including ultrasound.
Intraoperative neurologic monitoring may be helpful in
patients undergoing aneurysm surgery. Monitoring of SSEP
for cerebral ischemia during temporary vessel occlusion is
limited by its inability to detect ischemia in the motor cortex,
subcortical structures, and sensory regions not topographi-
cally represented by the stimulated peripheral nerve. How-
ever, SSEPs detect reversible ischemia during temporary
vessel occlusion.87 Studies demonstrate relatively high
false-positive (38% to 60%) and false-negative (5% to
34%) detection rates.88,89 Posterior circulation aneurysms
appear best suited to brainstem auditory evoked potential
monitoring,89 but they may also benefit from SSEP monitor-
ing. Intraoperative EEG monitoring may also be helpful for
detecting cerebral ischemia during aneurysm surgery.90
In WFNS grades 3–5, probability of increased ICP during
the first 24 to 48 hours after SAH is high. Some groups mon-
itor ICP intraoperatively with intraventricular catheters.
This allows intraoperative drainage of cerebrospinal fluid
(CSF) to improve operating conditions and management
of elevated ICP.
Angiography is a useful diagnostic test when focal neuro-
logic deficits evolve in the intraoperative or perioperative
period. Intraoperative cerebral angiography ensures com-
plete obliteration of the aneurysmal neck and helps the sur-
geon recognize clip occlusion of the parent arterial trunk or
perforating arterial branches.90 Repositioning the clip
before emergence may decrease the incidence of ischemic
complications and reduce the need for reoperation.
Induction. Rupture of an aneurysm during induction is
associated with a mortality approaching 75%.91 Although
it seems appropriate to maintain lower blood pressure dur-
ing induction to prevent abrupt elevations in transmural
pressure, significant reductions in cerebral perfusion pres-
sure cause focal and global neurologic deficits in animal
models.92 This is particularly relevant to the patient with
SAH who may have impaired autoregulation and vaso-
spasm. Decreases in cerebral perfusion pressure for brief
periods during induction are probably less detrimental than
sudden elevations in transmural pressure.
To avoid increases in transmural pressure, the sympa-
thetic response to laryngoscopy and intubation must be
attenuated, while preventing coughing and straining.
Anesthesia may be induced in the usual fashion. Barbitu-
rates and propofol are similar in their ability to reduce
transmural pressure and cerebral metabolism. Narcotics
are usually added to the induction sequence to blunt
the hemodynamic response to laryngoscopy and intuba-
tion. Fentanyl 5–8 μg/kg is required to blunt hemody-
namic response to intubation, which is administered
3 minutes prior to laryngoscopy.93,94 Remifentanil
infusion (0.3 to 0.5 μg/kg/min) administered over 3 to
5 minutes before laryngoscopy to deepen anesthesia is
extremely effective in attenuating sympathetic responses.
Additional propofol (20 to 50 mg), intravenous lidocaine
21 • Carotid and Intracranial Surgery 303
(1.5 to 2.0 mg/kg), esmolol (0.5 mg/kg), or labetalol (10
to 20 mg) administered 90 seconds before laryngoscopy
can further attenuate rises in transmural pressure during
intubation.
The indication for rapid sequence induction in the
patient with an unclipped cerebral aneurysm is controver-
sial. The incidence of clinically significant aspiration is
0.05% during general anesthesia.95 The incidence of
aneurysm rupture during induction is in the range of 1%
to 2%.91 Careful consideration should therefore be given
to the risks and benefits before choosing a classic rapid
sequence technique.
Maintenance. The hemodynamic goals during mainte-
nance are similar to those during induction. Ideally, a main-
tenance agent allows rapid and reversible titration of blood
pressure, protects against cerebral ischemia, minimizes for-
mation of cerebral edema, allows control of intracranial
pressure, and provides for rapid emergence. Commonly,
anesthesia is maintained with combinations of oxygen, opi-
oids, isoflurane or sevoflurane, and nondepolarizing muscle
relaxant. When neurophysiological monitoring is used,
total intravenous anesthesia with propofol and remifentanil
is recommended. As with induction, choosing a particular
agent is less important than matching anesthetic depth to
the level of surgical stimulation. Maintaining stable hemo-
dynamic responses to the varying level of stimulation may
be particularly important in preventing aneurysm rupture.
Painful stimuli (e.g., pin insertion) should be anticipated and
adverse hemodynamic responses prevented by additional
anesthesia and/or sympathetic blockers. Local anesthetic
infiltration at the Mayfield pin sites prior to application
can reduce the hemodynamic response.
Intraoperative fluid administration is governed by the
patient’s maintenance requirements, urine volume, blood
loss, and measured cardiac filling pressures if central venous
access has been established. Hypovolemia should be avoided
in patients with subarachnoid hemorrhage, because it can
be associated with cerebral ischemia and perioperative neu-
rologic deficits, especially if there is also vasospasm.92
Dextrose-containing solutions should be avoided, as an
increased incidence of neurologic deficits is associated with
hyperglycemia and focal cerebral ischemia in experimental
models.96
Intraoperative maintenance of adequate CPP is impera-
tive. Although elevations of CPP increase transmural pres-
sure and may predispose to aneurysm rupture, this
concern is much less important after the aneurysm has
been secured. The acceptable and safe upper limit of blood
pressure after aneurysm clipping has not been systemati-
cally evaluated. Arterial pressure tends to rise spontane-
ously when anesthetic levels are decreased after clip
placement in volume-replete patients. This rise in pressure
may benefit patients, especially those with potential vaso-
spasm, by increasing CPP and CBF. Increased SBP at induc-
tion of anesthesia and the use of intentional intraoperative
hypotension with MAP <60 mmHg for 15 consecutive
minutes or more were independent factors associated with
increased rate of postoperative neurological deficits after
surgery for ruptured intracranial aneurysm.96 For practi-
cal purpose we recommend maintaining CPP at least
60–70 mmHg before securing to clipping. Once aneurysm
304 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
is secured, MAP can be increased 20% of baseline if vaso-
spasm is suspected.
Emergence. The primary goals during emergence are to
avoid coughing, straining, hypercarbia, and wide fluctua-
tions in blood pressure. All anesthetic drugs should be dis-
continued, the patient should be well oxygenated, and
residual neuromuscular blockade should be reversed. Intra-
venous administration of 1.5 mg/kg of lidocaine a few
minutes prior to extubation may minimize coughing. Blood
pressure should be reduced pharmacologically if there is evi-
dence of cardiac ischemia, pulmonary edema, or excessive
prolonged blood pressure elevation. In patients with multi-
ple or unclippable aneurysms, blood pressure should be kept
within 20% of normal (120 to 160 mmHg).
Low grade (WFNS 1–2) patients usually do not require
postoperative ventilation or airway support. Mid- to high-
grade (WFNS 3) patients may not be extubated after sur-
gery, depending on their level of consciousness at emer-
gence and their preoperative ventilatory status. Patients
with surgical clipping of vertebral-basilar aneurysms may
require postoperative airway support because of injury to
swallowing or airway protective brainstem reflexes.
If the patient does not return to preoperative neurologic
status, any residual effects of anesthetic agents should be
reversed, including neuromuscular blocking agents, opioids,
and sedatives. After elimination of anesthetic agents as a
cause for poor emergence, a thorough diagnostic evaluation
should be undertaken. Metabolic causes include hypoxia,
hypercarbia, hypoglycemia, and hyponatremia. Although
epileptic seizure activity is usually evident from clinical
examination, subclinical seizures are a possible cause of
delayed emergence and should be evaluated by diagnostic
EEG. Emergent brain imaging may be necessary to rule
out subdural hematoma, hydrocephalus, pneumocephalus,
and intracranial hemorrhage. A cerebral angiogram may be
helpful in ruling out the possibility of vascular occlusion.
Special Situations
Temporary Vessel Occlusion. Local decreases in trans-
mural pressure can be achieved by occlusion of the aneu-
rysm’s feeding vessels with temporary clips. The
advantages include effective reduction of transmural pres-
sure, reduced intraoperative rupture, technically easier
clipping, and reduced requirement for controlled hypoten-
sion.97 Considerable controversy exists concerning the
techniques and duration of temporary arterial occlusion.
The critical threshold for conversion of temporary cerebral
ischemia to permanent focal cerebral infarction is
unknown and may be patient- and scenario-specific. For
example, Samson et al. concluded that 15 to 20 minutes
of temporary occlusion is the critical threshold for the
development of postoperative cerebral infarctions.98 In
contrast, other series have reported safe time limits of up
to 120 minutes.99 If temporary occlusion involves ische-
mia to major deep nuclei or the brainstem, temporary clip
application times of less than 10 minutes may be more
appropriate.100
Several risk factors predispose patients to new neurologic
deficits after temporary vessel occlusion. These factors
include age greater than 61 years, poor neurologic condi-
tion before surgery (Hunt and Hess grades III to IV), and
distributions of the perforating arteries of the distal basilar
and horizontal segment of the middle cerebral artery.98
The duration of temporary clip application of at least
20 minutes is an independent factor associated with an
increased rate of postoperative neurological decline after
surgery for ruptured intracranial aneurysm.101
Adenosine-Induced Circulatory Flow Arrest.
Adenosine-induced transient circulatory flow arrest has
been successfully used to facilitate clip ligation of complex
intracranial aneurysms when clip application for temporary
occlusion is not feasible because of technical or anatomical
issues.102–104 The common indications for intravenous
adenosine flow arrest includes aneurysm softening and
paraclinoid location of aneurysm, followed by broad neck
and intraoperative rupture of aneurysm. A high dose of
IV adenosine provides transient asystole and a brief period
of hypotension, thereby softening complex aneurysms,
and facilitates clipping or trapping. Adenosine dose of 0.3
to 0.4 mg/kg ideal body weight provided approximately
45 seconds of profound systemic hypotension during a remi-
fentanil and low-dose volatile anesthesia with propofol-
induced burst suppression.102 In another study, the median
dose of adenosine resulting in bradycardia greater than
30 seconds was 30 mg, hypotension greater than 30 sec-
onds was 15 mg, and greater than 60 seconds was
30 mg.104 There was no increased incidence of poor neuro-
logical outcome or cardiac morbidity in the perioperative
period.102
Intraoperative Cerebral Protection. The International
Hypothermia Aneurysm Trial (IHAST) is the only random-
ized prospective trial to address cerebral protection during
aneurysm clipping.105 IHAST did not demonstrate any ben-
efit to mild (33°C) intraoperative hypothermia. No other
putative protective strategies have been submitted to pro-
spective randomized trials.
Despite this, some centers use a variety of anesthetic-
based techniques. The most common are barbiturates or
propofol given to achieve burst suppression.106 Barbiturates
decrease CBF, intracranial pressure, and metabolic rate.
Although animal investigations have shown that barbitu-
rates can protect against focal ischemia, the few uncon-
trolled human series in aneurysm surgery have not
demonstrated improvement in morbidity or mortality.107
In addition, the large dosages required to suppress EEG
activity and significantly reduce the cerebral metabolic rate
can produce profound cardiovascular depression.108 Propo-
fol’s cerebral hemodynamic profile is similar to that of bar-
biturates and, similarly, can cause burst suppression.
Animal studies have been equivocal in demonstrating cere-
broprotective effects.109
Intraoperative Rupture. Aneurysmal rupture may occur
during induction of anesthesia or during the operative pro-
cedure. The incidence of intraoperative rupture is 2% to
19%. In a retrospective review of 1269 patients with saccu-
lar aneurysms, incidence of intraoperative rupture was
7.9% per surgery or 6.7% per aneurysm or 8.9% per
patient.93,110 The stage in the operative procedure at which
the rupture occurs influences the severity of the outcome.
Sudden sustained elevations of blood pressure with or

without bradycardia suggest the possibility of aneurysm
rupture. Alterations in hemodynamic parameters may be
subtle when the patient is anesthetized. One report used
transcranial Doppler ultrasound to detect aneurysm rupture
immediately after induction;111 this information was used
clinically to manage intracranial hypertension. If rupture
occurs, therapy should be instituted to control ICP and
maintain cerebral perfusion. Some centers have demon-
strated good results with “rescue clipping” of an aneurysm
that ruptures at the time of induction.91
Rupture occurring during aneurysm dissection usually
has a lower mortality than when it occurs during induction.
The immediate anesthetic goals after rupture are to main-
tain adequate systemic perfusion and to facilitate prompt
surgical control of bleeding. Bleeding during repair of the
aneurysm does not change morbidity if quickly con-
trolled.112 However, if significant amounts of blood enter
the subarachnoid space, intraoperative rupture has resulted
in marked brain swelling refractory to steroids and diuretics.
Rapid induction of hypotension to achieve a MAP of 40 to
50 mmHg may reduce bleeding enough to clip the aneu-
rysm. If this method does not adequately reduce bleeding,
brief periods of manual compression of the ipsilateral carotid
may be considered for an anterior-circulation aneurysm.
The induction of hypotension to control bleeding may be
associated with worsened neurologic outcome compared
with maintaining cerebral perfusion pressure or controlling
bleeding with the placement of temporary clips.113
Anesthetic Management for Aneurysm Embolization
Endovascular treatment of intracranial aneurysms was
first described in the early 1970s by Fedor Serbinenko.114
In 1990, Guido Guglielmi was the first to describe the
technique of occluding aneurysms from an endovascular
approach with electrolytic detachable platinum coils,
termed Guglielmi detachable coils (GDCs).115 As a result
of increased clinical experience with this technique and
improved coil design, coil embolization has been used with
increasing frequency even in patients who could be treated
by conventional surgical clipping for some ruptured intra-
cranial aneurysms.116,117
Risk assessment of anesthesia and surgery is derived from
experience with cerebral aneurysm surgery, not endovascu-
lar coiling. Endovascular aneurysmal coiling may have less
cardiovascular impact than craniotomy and aneurysm clip-
ping. The timing of endovascular aneurysm coiling must be
determined in the context of the disease course, especially
with respect to the risk of rebleeding and vasospasm. Signif-
icant cardiopulmonary edema, malignant dysrhythmias, or
severe heart failure may warrant postponement of surgery
until adequate medical management can be achieved.
In a randomized trial of 2143 patients with acutely rup-
tured intracranial aneurysms, the International Subarach-
noid Aneurysm Trial (ISAT) showed that endovascular
treatment reduced relative and absolute risks of dependency
or death, compared with neurosurgical clipping, at the 1-
year follow-up.118
Anesthesiologists have several important concerns when
providing care to patients undergoing interventional neuro-
radiology (INR) procedures: (1) maintenance of patient
immobility and physiologic stability, (2) manipulating sys-
temic or regional blood flow, (3) managing anticoagulation,
21 • Carotid and Intracranial Surgery 305
(4) treating and managing sudden unexpected complica-
tions during the procedure, (5) guiding the medical man-
agement of critical care patients during transport to and
from the radiology suites, and (6) ensuring rapid recovery
from anesthesia and sedation during and immediately after
the procedure to facilitate neurologic examination and
monitoring.
Induction and Maintenance of Anesthesia. The goals
of anesthetic management specific to endovascular aneu-
rysm ablation are immobility, cardiorespiratory stability,
and rapid emergence from anesthesia. Two coincident
radiologic techniques, contrast angiography and real-time
fluoroscopy, enable the precise localization of aneurysm
and placement of intravascular coils and stents. The images
derived from these two methods are superimposed on a sin-
gle monitoring screen, producing an “interactive road map”
of the cerebral vasculature. If there is any movement of the
patient’s head after obtaining the road map, the position of
the intravascular catheter noted on fluoroscopy is inaccu-
rate and may be dangerously misleading. Immobility is
therefore essential throughout the procedure to ensure that
the angiogram and fluoroscopic image are precisely aligned.
To promote adequate CPP, normotension and normo-
carbia are maintained. The current methods to determine
the adequacy of cerebral perfusion include angiography,
transcranial Doppler, electroencephalography, and clinical
testing of neurologic function. Many of these modalities
require access to the patient’s head and are not practical
to perform during the coiling procedure. Clinical neuro-
logic testing of an awake patient is the standard for asses-
sing cerebral perfusion. However, the value of this testing
may be decreased in the sedated patient. Therefore, if a
general anesthetic technique is used, rapid emergence
enabling timely and accurate neurologic testing is impor-
tant to assess outcome.119
General Anesthesia Versus Sedation. In choosing an
anesthetic for intravenous sedation, the primary goals are
to alleviate pain, anxiety, and discomfort, and to provide
patient immobility. With adequate local anesthetic infiltra-
tion, the procedure itself is generally not painful. However, a
long period of recumbence can cause significant pain and
discomfort. A variety of sedation regimens are available,
and the decision is based not only on the primary goals
but also on the experience of the practitioner. The potential
for upper airway obstruction is common to all intravenous
sedation techniques. Placement of a nasopharyngeal airway
may cause troublesome bleeding in anticoagulated patients
and is generally avoided. An LMA may be helpful in the rare
emergency when a patient with a difficult airway has a neu-
rologic crisis.
The primary reasons to use general anesthesia are to
reduce motion artifacts and to improve the quality of images,
especially in small children and uncooperative adult patients.
Total intravenous anesthesia with remifentanil and propofol
is suitable and preferred when no scavenging is available.
Another technique is nitrous oxide combined with a low dose
of inhaled agent. Both of these techniques provide rapid
wakeup for neurologic assessment. There are some concerns
that N2O should be avoided because of the possibility of
306 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
introducing air emboli into the cerebral circulation, although
no evidence is available to support this opinion.
No data exist to show whether sedation is better than
general anesthesia. In large part, the choice of the anes-
thetic technique depends on institutional preference.
Management of Procedural Complications
Although the complications of aneurysm embolization were
lower than those of surgery in the ISAT trial,118 complica-
tions during INR treatment of cerebral aneurysms can be
rapid and life-threatening and require multidisciplinary col-
laboration. During these procedures, anesthesiologists must
be aware of the potential for two very serious complications
of aneurysm rupture and thromboembolism.117
Aneurysm Rupture. Aneurysm rupture may occur by per-
foration with the microcatheter or microwire, or during
delivery of the GDC coils. Sudden sustained increases in
MAP, with or without bradycardia, suggest the possibility
of aneurysm rupture. Hemodynamic stability (normoten-
sion or mild hypertension), adequate preload and filling,
and hemodilution are essential. In patients with signs of per-
sistent intracranial hypertension (Cushing response), a
remifentanil infusion and continuous infusion of nicardipine
with or without beta blocker is preferred. Meanwhile, deep-
ening the anesthetic level with a high-dose barbiturate or
propofol bolus followed by infusion therapy may also be indi-
cated. If intracranial bleeding is suspected, the patient can
be given intravenous protamine to reverse the systemic
heparinization. Emergent placement of a continuous intra-
cranial pressure monitor via ventriculostomy may be neces-
sary.120 However, with small hemorrhages, management
with mannitol and hyperventilation may be all that is
needed. The determination must be made whether to con-
tinue coiling the aneurysm to seal the bleed or to bring
the patient emergently to the operating room for microsur-
gical clipping of the aneurysm.
Thrombotic Complications. Thromboembolic and ische-
mic complications occur at a rate of 1% to 5% depending on
the complexity of the aneurysm during and after endovas-
cular procedures. The thrombogenic characteristics of
arterial catheters, contrast agents, and implanted devices
such as coils and stents are thought to be related to arterial
injury.
The anesthesiologist is integrally involved in the careful
management of coagulation parameters to prevent and to
treat thromboembolic complications during and after the
procedures. Activated clotting times are typically used in
the interventional suite to monitor heparin therapy. In
patients undergoing complex aneurysm embolizations
(e.g., stent-assisted procedures), potent antiplatelet therapy,
such as clopidogrel treatment, should be considered prior to
the procedure. Abnormal thrombus formation can usually
be seen on the angiogram during the procedure; however,
occasionally patients emerge from anesthesia with new
neurologic deficits. Intra-arterial thrombolytic therapy with
tissue plasminogen activator and urokinase has been
described.121 However, if there is abnormal thrombus for-
mation despite heparin therapy, the platelet glycoprotein
IIb/IIIa receptor antagonist abciximab can be used, because
it appears to be particularly effective in dissolving thrombus.
Nevertheless, the use of abciximab in conjunction with
aspirin, clopidogrel, and heparin as an adjunct to INR pro-
cedures can result in rapidly progressive intracerebral hem-
orrhages.122 Further research is required to develop both
prophylactic and treatment strategies to reduce the rate of
thromboembolic complications associated with INR proce-
dures and thus improve their overall success.
Management of Intracranial
Hypertension
The management of ICP (target, <20 mmHg) is a necessary
skill for the anesthesiologist. Perioperative ICP management
is frequently needed when there is cranial trauma. In this
setting, ICP control may have to be attempted empirically
on the basis of the clinical neurologic examination, without
an actual ICP measurement. Alternatively, therapy may be
titrated to a specific ICP if the patient has an intracranial
monitor in place. Perioperative ICP control is often an issue
in other settings as well. Patients with spontaneous intra-
cranial hemorrhage, aneurysmal subarachnoid hemor-
rhage, ischemic stroke, or mass lesions may require ICP
control when coming to the operating room for neurosurgi-
cal or non-neurosurgical intervention. Finally, the need to
prevent cerebral herniation through an open craniotomy
is a concern in any brain surgery. Interventions to control
ICP can also be used to control brain volume, shift, and
herniation.
Interventions to control ICP fall into two general catego-
ries. First are the interventions primarily aimed at the reduc-
tion of intracranial contents, with secondary improvements
in ICP. Second are the interventions aimed at the reduction
of cerebral metabolic rate (CMRO2), with secondary reduc-
tions in CBF, CBV, and ICP.
REDUCING INTRACRANIAL CONTENTS
REMOVAL OF MASS LESIONS. All efforts in the preoperative care
of the neurologically deteriorating patient with intracranial
hypertension are focused on the safe, expedient delivery of
the neurosurgical intervention.123,124 Removal of intracra-
nial mass lesions provides the most definitive control of ICP.
HEAD POSITIONING. The patient’s head should be positioned
to avoid jugular venous compression and to facilitate
venous drainage from the skull. Similarly, the head should
be kept in a nondependent position (usually elevated about
20 degrees) to avoid cerebral venous congestion.
VENTRICULAR CSF DRAINAGE. Drainage of CSF by means of a
ventriculostomy is a definitive treatment for intracranial
hypertension caused by hydrocephalus and it is an effective
method of reducing ICP in many nonhydrocephalic
patients. In the perioperative setting, care must be taken
to maintain the drain at an appropriate height, with close
attention to opening and closing. These measures are nec-
essary to avoid both over-drainage and unintended ICP
spikes caused by unintended clamping. Lumbar cisternal
CSF drainage must be used with extreme caution and is gen-
erally contraindicated in any patient with an intracranial
mass lesion.
HYPERVENTILATION. Hyperventilation provides a progressive
reduction in CBV and ICP as PaCO2 declines.125,126

Hyperventilation can be quickly implemented once the
anesthesiologist has control of the airway (target PaCO2,
25 to 30 mmHg).127 Critical reductions in CBF can result,
necessitating caution in the administration of this ther-
apy.128 It is best used as a temporizing measure to control
ICP or to reduce brain size. Efforts to restore normocapnia
should follow as soon as prudently possible.
CEREBRAL PERFUSION PRESSURE. Maintenance of cerebral
perfusion pressure (CPP ¼ MAP - ICP) is critical for the
patient with elevated ICP. Brain injury guidelines
(https://braintrauma.org/guidelines/guidelines-for-the-
management-of-severe-tbi-4th-ed#/:guideline/17-cerebral-
perfusion-pressure-thresholds) recommend a CPP of
greater than 60 to 70 mmHg. Routine use of vasopressors
and volume expansion to maintain CPP greater than
70 mmHg is not recommended because of respiratory
complications and poor outcome. In a patient with intra-
cranial hypertension, a drop in CPP causes a compensa-
tory cerebral vasodilation to maintain CBF, with a
subsequent elevation in ICP. The cerebral hypoperfusion
is also clearly injurious. In general, systemic (arterial)
hypertension is much safer than hypotension.129 Hyper-
tension can become injurious beyond the range of cerebral
autoregulation, and there is concern about promoting
continued intracranial bleeding with hemorrhagic lesions.
Current recommendations are to maintain a SBP less than
180 mmHg (SBP <180 mmHg postoperatively).130 Intra-
arterial blood pressure monitoring is highly advantageous
when managing ICP.
HYPEROSMOTIC THERAPY. Hyperosmotic therapy reduces
intracranial contents primarily by removing extravascular
water from the brain. Mannitol and hypertonic saline are
the hyperosmotic agents in current use. Older methods
using other solutes such as urea or glycerol have fallen
out of favor. The goal of hyperosmotic therapy is hyperos-
molar euvolemia with maintenance of CPP and CBF. Man-
nitol (20% solution; 1160 mOsm/L) is typically given in
bolus doses of 0.25 to 1 g/kg until the ICP target is reached.
Addition of low dose of furosemide 0.1 to 0.3 mg/kg to man-
nitol 1 mg/kg does not produce significant electrolyte
derangements or hypovolemia or hypoperfusion compared
with the administration of mannitol alone.131 Dosing
beyond a serum osmolality of 320 mOsm/L is generally con-
traindicated because of concerns about renal toxicity.132
Clinical trial data comparing mannitol with hypertonic
saline shows hypertonic saline is similar to mannitol with
respect to reduction of ICP and duration of action,133 and
there is no good evidence to support the use of one over
the other.134 Different formulations of hypertonic saline
(2% to 30%) have been used in various clinical studies
and there is no consensus for a specific tonicity. Our prefer-
ence is for 23.4% NaCl (23% solution; 8008 mOsm/L).135
This is administered in 30-mL doses via central venous cath-
eter and is often used for ICP refractory to mannitol in our
practice. The generally accepted limit on this therapy is a
serum osmolality of 320 mOsm/L.
REDUCING CEREBRAL METABOLISM
ANESTHETIC DEPTH. Adequate anesthetic depth, usually
coupled with neuromuscular blockade in the operative
setting, is essential to avoid increases in ICP in response
to laryngoscopy, bladder catheterization, line placement,
21 • Carotid and Intracranial Surgery 307
or surgical stimulation. Furthermore, anesthetic depth
can be increased to achieve a reduction in ICP through a
reduction in CMRO2. Burst suppression, as determined by
EEG monitoring, is associated with a 50% reduction
in CMRO2.136 Therefore, increasing anesthetic depth
decreases both noxious stimulation and ICP (the latter
through a reduction in CMRO2). The anesthesiologist must
choose the anesthetic agent carefully, as potent inhaled
anesthetics, such as isoflurane and sevoflurane, progres-
sively increase the CBF as alveolar concentration (MAC)
increases.136 This may offset the reduction in ICP brought
about by the decrease in CMRO2. 0.5 MAC of volatile anes-
thetic agents (VIAs) decreases CMRO2 thereby decreasing
CBF. VIAs at greater than 1 MAC greater are predominant
vasodilators and cause uncoupling of flow-metabolism. Pro-
pofol and barbiturates decrease ICP without causing cere-
bral vasodilation, but, like the inhaled anesthetics, they
still decrease the MAP and CMRO2.137–139 Attention to
CPP is critical when reducing ICP with anesthetic agents.
The issue of neuroprotection is discussed separately.
HYPOTHERMIA. Hypothermia causes approximately a 5%
reduction in CMRO2 per degree Celsius140 and can be used
to control ICP in the perioperative setting. The fastest prac-
tical way to induce hypothermia is with intravenous boluses
of refrigerated saline (4°C, 0.9% NaCl).141 However, this is
an extrapolation from the cardiac arrest literature and has
not been studied in a perioperative setting. Neuromuscular
blockade is necessary to prevent shivering. Maintenance
cooling can be accomplished with surface (liquid or air blan-
kets) or, if available, intravascular methods.141
Summary
The anesthesiologist usually chooses a multimodal approach
to control intracranial hypertension in the perioperative
arena. Ideally, therapy is guided by an ICP monitor, but it often
has to be administered empirically in a rapidly decompensat-
ing patient. Jugular venous compression should be avoided
and the head of the bed should be elevated to promote venous
drainage from the skull. Hyperventilation can be quickly
implemented while hyperosmotic therapy is being infused.
Anesthetic depth is increased, along with neuromuscular
blockade, while maintaining an uncompromised CPP
(>60 mmHg). If needed, systemic hypothermia can be initi-
ated with cold intravenous fluids and maintained with surface
cooling. Attention must be paid to restoring normocapnia
when other methods of ICP control have been successfully
implemented.
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 22 Protecting the Central Nervous
System During Cardiac Surgery
JOHN G. AUGOUSTIDES
Introduction
Multiple advances in perioperative techniques, especially
the maturation of cardiopulmonary bypass, have allowed
the practice of cardiac surgery to develop rapidly.1–4 Despite
these advances that have enabled contemporary cardiac
surgery to address a diverse range of cardiac pathologies,
neurological injury, ranging from delirium to stroke, has
persisted as a relatively common and important complica-
tion after cardiac surgery.1–4 As a result, extensive research
has explored the etiologies of neurologic injury after cardiac
surgery to identify interventions that may reduce its inci-
dence.1–6 Although the strategies for neuroprotection have
some similarities across the types of cardiac surgery, many
differences remain as a result of varied etiologies for neuro-
logical injury. For the sake of clarity, this chapter will
approach neurologic injury and neuroprotective strategies
by the type of cardiac procedure in the following four
sections: cardiac surgery with cardiopulmonary bypass;
off-pump coronary artery bypass grafting; transcatheter
aortic valve replacement; and thoracic aortic surgery.
Neurological Injury After Cardiac
Surgery with Cardiopulmonary
Bypass
INCIDENCE AND SIGNIFICANCE
Multiple clinical trials have demonstrated that the incidence
of new infarcts on diffusion-weighted magnetic resonance
imaging following cardiac surgery with cardiopulmonary
bypass (CPB) ranges from 25% to 40%.1–3 Although the vast
majority of these lesions are not clinically significant, the inci-
dence of clinical stroke after cardiac surgery with CPB has
persisted in the 5%–10% range, depending on the diagnostic
approach.4–11 Stroke in this setting remains an important
complication because it significantly increases perioperative
mortality and morbidity.1–12 Postoperative cognitive dys-
function including delirium is even more common than
stroke after cardiac surgery with CPB.7,8,12,13 This neurolog-
ical complication has also been associated with significant
reductions in independence and quality of life.7,8,12–14
RISK FACTORS
Multiple clinical trials have reported patient and procedure-
specific risk factors for the development of neurologic injury
after cardiac surgery with CPB.7,8 These risk factors include
advanced age, diabetes, preexisting cerebrovascular disease,
severe atherosclerotic vascular disease, previous cardiac
surgery, prolonged CPB time, and perioperative hypoten-
sion.1–8 The stroke risk is also typically significantly
increased in the setting of combined cardiac procedures
on CPB as follows: coronary artery bypass grafting (CABG)
< valve repair/replacement < CABG and valve repair/
replacement < multiple valve interventions.1–12 The risk
factors for neurologic injury in this setting are listed in
Table 22.1.
ETIOLOGIC FACTORS
Embolic Events
Cerebral embolization is a common etiology for neurological
injury after cardiac surgery with CPB.7,8,15–18 In a clinical
evaluation of an intra-aortic filter device deployed during
cardiac surgery with CPB (N ¼ 2297), detailed histopatho-
logical analysis confirmed filter-trapped debris in 98% of
study patients.19 The debris consisted of fibrous atheroma
in 79%, platelets and fibrin in 44%, red blood cell thrombus
in 8%, adventitial tissue in 3%, and miscellaneous debris in
2% of cases.19 Patients with neurological injury after cardiac
surgery with CPB will often have evidence of multiple cere-
bral lesions, consistent with cerebral embolization.11,12,16–19
Embolic material can be further classified into three cate-
gories: macroemboli, microemboli, and gaseous emboli
(Table 22.2).7,8,11,12 Macroemboli are frequently derived
from atheromatous plaque, valvular calcium, or thrombus
that become dislodged during surgical manipulation to
result in a focal stroke when they are clinically signifi-
cant.7,8,19 Microemboli are typically derived from small lipid
particles and platelet-fibrin aggregates and may be responsible
in part for delirium after cardiac surgery with CPB.7,8,13,14
Gaseous emboli can enter the CPB circuit during vascular can-
nulation and anastomosis, vacuum-assisted venous drainage,
as well as during open cardiac chamber procedures.6,7,12 The
amount of embolized gaseous microemboli very pro-
bably correlates with the degree of subsequent neurological
injury, including both delirium and stroke. Larger gaseous
emboli may result in discrete stroke.7,8,15
Hypotension, Hypoperfusion, and Cerebral
Autoregulation
Periods of hypotension are relatively common in cardiac
surgery compared with other surgical procedures. Most
patients with intact cerebral autoregulation can tolerate
moderate swings in mean arterial pressure and still
maintain adequate cerebral blood flow.20,21 Despite this
compensation, however, cerebral autoregulation may be
311
312 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Table 22.1 Risk factors for neurological injury after cardiac
surgery with cardiopulmonary bypass.
Advanced age
Diabetes
Prior cerebrovascular disease
Prior pulmonary disease
Atrial fibrillation
History of hypertension
Atherosclerotic vascular disease
Degree of ascending aortic manipulation
Prolonged cardiopulmonary bypass time
Perioperative low cardiac output syndrome/hypotension
Open chamber procedures, e.g., valve repair/replacement
Multiple cardiac procedures
Major air emboli during cardiopulmonary bypass
Major calcific debris during left-sided valve replacement
Major bleeding/major transfusion
Table 22.2 Etiologies of neurologic injury after cardiac
surgery with cardiopulmonary bypass.
Cerebral embolization
▪ Macroemboli, e.g., atheromatous plaque, large thrombi, calcium
debris
▪ Microemboli, e.g., platelet-fibrin aggregates, red blood cell thrombi
▪ Gas emboli
Hypotension with cerebral hypoperfusion
▪ Ischemic neurological injury
▪ Impaired cerebral blood flow autoregulation
Inflammation
▪ Systemic inflammatory response
▪ Blood–brain barrier dysfunction
▪ Cerebral edema
Genetic factors
▪ Predisposition to neurologic injury
▪ Search for therapeutic targets
Temperature regulation
▪ Protective hypothermia
▪ Dangerous hyperthermia
impaired in the setting of multiple factors including
advanced age, cerebrovascular disease, cardiopulmonary
bypass, sepsis, and temperature.20–24 As a consequence,
patients with impaired cerebral autoregulation may be at
greater risk of cerebral hypoperfusion and ischemia during
periods of hypotension.21,22 Hypoperfusion injuries are rel-
atively common in patients who develop strokes after car-
diac surgery with CPB, with a reported incidence of 20%–
40% in computed tomographic imaging and 40%–60% in
magnetic resonance imaging.25 Recent trials have demon-
strated that the duration and degree of hypotension during
cardiac surgery with CPB significantly predicted the risks of
stroke (P < 0.05) as well as major morbidity and mortality
(P< 0.05).25–27 A recent trial (N ¼ 197) randomized adult
cardiac surgical patients to one of two mean arterial pres-
sure groups during CPB: higher blood pressure defined as
a mean of 70–80 mmHg and lower blood pressure defined
as a mean of 40–50 mmHg.28 The defined primary outcome
was the total volume of new cerebral lesions detected on
diffusion-weighted magnetic resonance imaging in the first
postoperative week. The primary outcome was similar
between groups (median difference estimate 0; 95% confi-
dence interval -25 to 0.028; P¼ 0.99).28 There were new
cerebral lesions evident in over 50% of patients in each
group, a finding that is consistent with the existing litera-
ture.11,12,28 Taken together, these clinical trials suggest
that, in addition to optimal blood pressure management
and in consideration of the individual cerebral autoregula-
tion reserve, further multimodal trials are indicated to iden-
tify best practice measures for neuroprotection in cardiac
surgical procedures with CPB.29
The Inflammatory Response
The conduct of CPB triggers a profound systemic inflamma-
tory response because blood interacts with the hardware
components of the CPB circuit.30 This inflammatory
response includes activation of the coagulation system, fibri-
nolytic system, complement system, leukocytes, endothelial
cells, and platelets.30 This acute phase reaction may lead to
tissue injury, depending on factors such age, genotype, and
functional reserve.31–34 This systemic inflammatory
response may also have neurological effects by causing glial
cell injury, cerebral edema, and altering the integrity of the
blood–brain barrier.30–34 Clinical trials have suggested a
role for the systemic inflammatory response in neurologic
injury after cardiac surgery with CPB.8,12,30,35 Future trials
will probably investigate the modulation of this systemic
inflammatory response in a multimodal approach to neuro-
protection in this clinical setting.34
Genomic Factors
Neuronal necrosis can result from cellular injury, including
apoptosis.34 Neuronal apoptosis is mediated by gene activa-
tion that results in a protein cascade as the mechanism for
cell death. These neuronal pathways depend on individual
genomic predisposition for cerebral injury.34–38 Multiple
genes have been implicated in influencing the risk of neuro-
logic injury after cardiac surgery, including the apolipopro-
teins, interleukin polymorphisms, and platelet glycoprotein
alleles.12,34–38 Future trials will undoubtedly further explore
neurologic risk in cardiac surgery with CPB as a function of
genotype with the goal of identifying therapeutic targets
for neuronal protection in the perioperative period and
beyond.34
Temperature
Patients undergoing cardiac surgery with CPB are typically
cooled to a level of hypothermia depending on the procedure,
surgeon preference, institutional norms, and patient risk fac-
tors.12 As cerebral temperature is lowered, cerebral metabolic
rate decreases as does an ischemic tolerance with hypo-
thermia.39 Hypothermia alters gene regulation of multiple
inflammatory pathways to inhibit apoptosis and inflammation,
as well as suppress free radical formation.12,40,41
In contrast, perioperative hyperthermia has been clearly
shown to be detrimental to neurological outcomes after
adult cardiac surgery with CPB.40–43 This variable will be
discussed in further detail in the next section.
NEUROPROTECTIVE STRATEGIES
Modifications to the Cardiopulmonary Circuit
Contemporary cardiopulmonary circuit designs have been
gradually optimized to reduce the risks of the embolic gen-
eration and subsequent cerebral vasculature, given that the
circuit hardware is a major source of microbubble formation
 22 • Protecting the Central Nervous System During Cardiac Surgery 313

and embolization.40,44 Risk factors for microbubble forma-

tion include vacuum-assisted venous drainage, roller versus Suction tube
centrifugal pump exposure, bubble versus membrane oxy- Main tube
genator application, hard-shell versus soft-shell venous res-
ervoir, and low venous reservoir levels.44–47 Furthermore,
in-line arterial filters and venous reservoir filters have also
been integrated in contemporary perfusion practice for
removal of microbubbles and other embolic particles from
the CPB circuit.47–50 Although effective, these filters do
not remove all emboli, despite reduced pore size.47–50 The
benefits of reduced pore size must be balanced with the
increased risk of hemolysis and damage to other blood com-
ponents.47–50 In addition to air filters, the presence of a
dynamic bubble trap in between the arterial filter and aortic
Suction
cannula has been shown to reduce the incidence of micro- lumen inlet
bubbles passing into the arterial circulation.47,51
In addition to microbubbles and macroemboli, blood suc- Cannula
tioned directly from the surgical field via cardiotomy suction outlet
is known to contain high levels of lipid particles.52–53 These Fig. 22.1 CardioGard backward suction cannula. (Reprinted from:
lipid emboli have been associated with capillary occlusion Bolotin G, Huber CH, Shani L, et al. Ann Thorac Surg 2014;98:1627-1634.)
and cerebral ischemia.52–53 In an effort to reduce the effects
of lipid embolization due to blood returned from the cardiot-
omy suction, expert consensus has considered processing
the blood through a cell-saver device before returning it This returned blood is then filtered by the venous reservoir
to the CPB circuit.54–56 Two randomized controlled trials filter and the arterial filter.69,70 In vitro and animal studies
have explored this approach, with conflicting results, demonstrated a reduction in cerebral embolic load when
although both trials demonstrated increased transfusion compared with standard aortic cannulae.69 A multicenter,
in the cell-saver group.54–55 In a recent randomized trial randomized controlled trial of 66 patients demonstrated a
(N ¼ 30) testing the benefits of a lipid microemboli filter inte- significant decrease in the new lesion volume in the Cardi-
grated into the CPB circuit, the intervention group had a sig- oGard group as measured by diffusion-weighted magnetic
nificant reduction in lipid microemboli and serum markers resonance imaging.70
for neurological injury.56 Future trials will target ongoing The Embol-X intraaortic filtration device (Fig. 22.2) is a
improvement of clinical outcomes from a multimodal filter 24-French aortic cannula with a built-in side port through
strategy to minimize embolic load and protect against neu- which the filtration device can be deployed and recap-
rological injury.56,57 tured.73,74 In early studies, the device was deployed before
the removal of the aortic cross-clamp and left in place until
Aortic Cannulation Strategy the patient was weaned from CPB.71,72 Early results demon-
In addition to CPB components, investigators have also strated safety and facility of the procedure, as well as the
investigated the approach to aortic cannulation for CPB effectiveness of the device in capturing embolic debris.71,72
to reduce further the risk of cerebral embolization.58,59 Mul- Several trials have examined the Embol-X device in standard
tiple clinical trials have examined the effects of aortic can- cannulation in open heart surgery with somewhat
nula design with respect to features such as length and
tip design to reduce aortic wall sheer stress and minimize
cerebral atheroembolism.58–64 The goals in this design pro-
cess have been to reduce aortic jet velocity, to control direc-
tion of the jet, and to decrease turbulence with features such
as a funnel and curved tip, including side apertures for dis-
persal of flow. 58–66 Furthermore, cannulation of the distal
aortic arch has also been established as a cannulation strat-
egy to reduce the burden of cerebral emboli.67,68
Another area of innovation in embolic reduction has been
the addition of embolic protection to the design of the arte-
rial cannula itself.69–74 There are currently two aortic can-
nulae that have embolic protection devices incorporated
into their design, namely the CardioGard backward suction
cannula (CardioGard Medical, Israel) and the Embol-X
intra-aortic filtration device (Edwards Lifesciences, Irvine,
California).69–74 The CardioGard cannula (Fig. 22.1) is a
curved-tip, 24-French dual-lumen aortic cannula.69,70
The first lumen is a standard forward-flow lumen for CPB Fig. 22.2 Embol-X intra-aortic filtration device. (Reprinted from:
arterial outflow and the second lumen is placed to suction, Banbury MK, Kouchoukos NT, Allen KB, et al. Ann Thorac Surg
venting back into the venous reservoir of the CPB circuit. 2003;76:508-515.)
314 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
conflicting results.73–75 One trial has suggested that deploy-
ment of this device prior to aortic clamping, as opposed to
only after removal, may improve embolic capture.76
A recent multicenter, randomized controlled trial
assigned 383 patients to the Embol-X device (133 patients),
the CardioGard backward suction cannula (118 patients),
or standard aortic cannula (132 patients) during surgical
aortic valve replacement. In this landmark trial, significant
embolic debris was found in 99% of the Embol-X filters after
retrieval and 75% of the CardioGard suction cannulae.77
The investigators found no significant difference between
groups with regards to clinical endpoints such as clinically
apparent stroke and stroke volume as quantified by
diffusion-weighted magnetic resonance imaging.77 There
was no difference in mortality, length of hospital stay, and
hospital readmission rate.77 In secondary outcome analysis,
embolic protection was significantly associated with reduced
risks of perioperative delirium and acute kidney injury.77
Overall, this important trial did not find major significant
neuroprotective benefit from embolic protection.77 Future
adequately powered trials will probably focus on high-risk
patients in the search of further neuroprotective benefit from
refinements in aortic cannula design.
Reducing Gaseous Emboli with Carbon Dioxide
Cardiac surgical patients during CPB are exposed to a high
risk of gaseous emboli because of factors such as open cham-
ber procedures, vascular cannulation, and assisted vacuum
venous drainage.7,12 Once gas emboli reach the cerebral
vasculature, they may occlude small vessels causing ische-
mia, or activate an inflammatory cascade further exacerbat-
ing injury.7,12,78 It has been hypothesized that by flooding
the surgical field with highly blood-soluble carbon dioxide,
most of the gas introduced into the patient will dissolve,
reducing the risk of embolization.79,80 Although multiple
trials have tested his hypothesis by demonstrating reduced
intracardiac gas, they have collectively not proven that
there is clinical neuroprotection from this intervention.79–
81
A recent high-quality meta-analysis demonstrated no sig-
nificant difference in the incidence of clinical stroke (1.0%
versus 1.2%, P¼ 0.62) or neurocognitive decline (12% ver-
sus 21%, P¼ 0.35) with carbon dioxide exposure, despite a
reduction in gaseous microemboli as detected by transeso-
phageal echocardiography.81 Although there is evidence
of reduced gaseous embolic load from flooding the surgical
field with carbon dioxide, this has not translated to a reduc-
tion in stroke or neurocognitive impairment.81 A large ran-
domized control trial is currently in progress to examine the
effects of carbon dioxide application during coronary artery
bypass grafting.82 The results of this trial may determine the
future niche for this intervention in cardiac surgery with
and without CPB.
Assessment of Aortic Atheroma
The presence of atheroma in the ascending aorta is a signifi-
cant risk factor of neurological injury in cardiac surgery as it is
a major source of cerebral emboli.15–18 Aortic events such as
cannulation, clamping, graft anastomosis, and manipulation
may dislodge atheromatous debris and precipitate significant
cerebral atheroembolism.7,8 Furthermore, the “sandblasting”
effects of blood flow through the aortic cannula can embolize
atheromatous plaques, as outlined earlier.58–66
Traditionally, direct digital palpation of the aorta by the
surgeon guided final selection of the aortic cannulation
site.83,84 In contemporary practice, aortic imaging has
proven superior to digital palpation for assessment of
ascending aortic atheroma. The two imaging techniques
to assess aortic atheroma are transesophageal echocardiog-
raphy and epiaortic ultrasound.83–85 The major limitation
of transesophageal imaging is that it cannot reliably image
the distal ascending aorta and proximal arch because of the
interposition of the tracheobronchial tree at this mediastinal
level.84–86 This “blind spot” of transesophageal imaging has
been overcome with the A-view technique.86,87 This mod-
ified technique involves the introduction of a balloon cath-
eter into the left main bronchus, which is then filled with
sterile saline, allowing visualization of the distal ascending
aorta from the esophagus (Fig. 22.3).86,87
When epiaortic imaging has been applied to identify
atheroma, it is more likely to prompt a change in aortic can-
nulation site or strategy compared with palpation alone.88,89
Large trials have demonstrated that epiaortic imaging
was significantly associated with a reduction in stroke risk
after adult cardiac surgery with CPB.89,90 The cumulative
evidence suggests that epiaortic scanning provides the best
method overall for grading ascending aortic atheroma-
tous disease to guide aortic cannulation and to reduce
consequent stroke risk.85
Blood Gas Management During Cardiopulmonary
Bypass
There has been significant debate regarding the optimal pH
management strategy during cardiopulmonary bypass.91 In
the adult population, alpha-stat management is most often
utilized. In alpha-stat management, the hypocarbia and
alkalosis created by hypothermia is not corrected and the
1
7
2
4
6
3
5
Fig. 22.3 A-View balloon catheter. 1, endotracheal tube; 2, A-View
catheter; 3, balloon of A-View catheter; 4, transesophageal probe; 5, left
main bronchus; 6, ascending aorta; 7, innominate artery. (Reprinted
from: B. van Zaane B, Nierich AP, Buhre WF, et al. Resolving the blind spot
of transesophageal echocardiography: a new diagnostic device for
visualizing the ascending aorta in cardiac surgery. Br J Anaesth 2007;98:
434–441.)
 22 • Protecting the Central Nervous System During Cardiac Surgery
pH and carbon dioxide in the blood is measured at a temper-
ature of 37°C.91,92 Alpha-stat maintains electrochemical
neutrality and preserves the coupling between cerebral
metabolic rate and cerebral blood flow (both decrease with
cooling).91,92 In pH-stat management, carbon dioxide is
added to the CPB circuit to account for the increase in sol-
ubility as cooling occurs, in an effort to maintain a normal
pH and PaCO2. The increased levels of CO2 lead to increased
cerebral blood flow and oxygen delivery, but also increase
the risk of cerebral embolization.91–93 A landmark random-
ized controlled trial (N ¼ 316) demonstrated a significant
cognitive benefit to alpha-stat management in adult
patients undergoing CPB for more than 90 min.91 The cur-
rent evidence suggests that in cardiac surgery with deep
hypothermic circulatory arrest alpha-stat management
may be advantageous in adult cardiac surgery.92 In pediat-
ric cardiac surgery with CPB, pH-stat management may be
preferred for more efficient cooling of the brain and better
neuroprotection.92
Temperature Management: Hypothermia and
Hyperthermia
In cardiac surgery with cardiopulmonary bypass, patients
are often cooled to a certain hypothermia level, as outlined
earlier.39–41 The benefits of hypothermic CPB have not been
consistently demonstrated across multiple studies.12,94
Despite large meta-analyses (cumulative N > 10,000: nor-
mothermic versus hypothermic CPB), there was no signifi-
cant difference in neurological outcomes in both adult and
pediatric practice.95,96 It remains challenging with the
current evidence to rule out hypothermic CPB as being ben-
eficial because of the excessive heterogeneity across clinical
studies.
In contrast, perioperative hyperthermia has been clearly
shown to be detrimental to neurological outcome in cardiac
surgery with CPB.40–43 In a clinical trial evaluating the clin-
ical effects of temperature management during CPB and car-
dioplegia, the investigators found an increased stroke risk in
the setting of warm CPB with warm cardioplegia.97 Periop-
erative hyperthermia has also been significantly associated
with a higher risk of cognitive dysfunction after cardiac sur-
gery with CPB.43 Multiple clinical trials have shown a
reduction in neurological injury after CPB with a slower
rewarming strategy during CPB.98–100 A comprehensive
temperature management strategy during and after cardiac
surgery with CPB is an important neuroprotective strategy
in perioperative practice.41,47,101
Blood Pressure Management During Cardiopulmonary
Bypass
Cerebral ischemia can result not only from the obstruction
of blood flow caused by embolic events, but also from inad-
equate perfusion pressure despite cerebral autoregula-
tion.20–22 Higher blood pressure goals may be required in
the settings of chronic hypertension and cerebrovascular
disease to ensure adequate cerebral perfusion pressure dur-
ing CPB.24–26 In a single-center randomized trial (N ¼ 248),
a high mean arterial pressure (80–100 mmHg) compared
with low mean arterial pressure (50–60 mmHg) during
CPB significantly decreased the incidence of combined car-
diac and neurological complications (4.8% versus 12.9%:
P¼ 0.026).102 A second single-center randomized trial
315
(N ¼ 92) demonstrated that a lower mean arterial pressure
(60–70 mmHg) compared with a higher mean arterial
pressure (80–90 mmHg) during normothermic CPB was
significantly associated with increased risks of delirium
(P¼ 0.017) and cognitive dysfunction (P¼ 0.012).103 How-
ever, a recent large, multicenter trial (N ¼197) found no
significant difference in neurological injury with respect to
clinical or radiographic stroke whether the mean arterial
pressure was higher (70–80 mmHg) or lower (40–
50 mmHg) during CPB.28 These conflicting trials suggest
that it may not be appropriate to standardize a target mean
arterial pressure during CPB but rather to consider the
determination of an individual patient’s cerebral autoregu-
lation thresholds.29 This determination would then facili-
tate individualized maintenance of perfusion pressure
above the lower limit of cerebral autoregulation during
CPB to ensure adequate cerebral perfusion and optimal
neuroporotection.104,105
Cerebral oximetry with near-infrared spectroscopy has
displayed significant promise for estimating cerebral autore-
gulation and perfusion.20,104,107 Clinical trials have identi-
fied that low cerebral oximetry values significantly predict
the risk of delirium after CPB.108,109 A recent meta-analysis
(N¼ 2057: 15 randomized controlled trials) found that cere-
bral oximetry-guided blood pressure management was asso-
ciated with a significant reduction in cognitive dysfunction
(risk ratio 0.54; 95% confidence interval 0.33–0.90;
P¼ 0.02).110 Although this meta-analysis has suggested a
neuroprotective benefit with cerebral oximetry, this result
should be regarded as mostly hypothesis-generating, given
the high levels of heterogeneity across the included trials.
Future large, randomized trials with standardized monitor-
ing and management protocols will probably evaluate the
value of cerebral oximetry in the management of cerebral
autoregulation and perfusion during adult cardiac surgery
with CPB.
Pulsatile Perfusion During Cardiopulmonary Bypass
Recent clinical trials have suggested that pulsatile as com-
pared with the typical non-pulsatile perfusion during CPB
is more physiologic with enhanced preservation of the
microcirculation and attenuation the systemic inflamma-
tory response.111,112 Clinical trials thus far have not consis-
tently demonstrated neuroprotection because of pulsatile
perfusion during CPB.113,114 With such conflicting data,
there is no clear neuroprotective benefit of pulsatile flow
during CPB, suggesting that future trials should address
this gap.115,116
Pharmacologic Therapies
Because of the systemic inflammatory response to CPB and its
possible role in cerebral injury, the administration of cortico-
steroids has been examined for neuroprotective benefit.30
Multiple clinical trials presented results with conflicting
evidence.117 In high-quality meta-analysis, there was no
discernible neuroprotective benefit from steroid expo-
sure.117,118 Two recent, large, multicenter randomized con-
trolled, double-blinded trials, the Dexamethasone for Cardiac
Surgery (DECS) and Steroids in Cardiac Surgery (SIRS) trials,
examined the neuroprotective effects of steroids in cardiac
surgery with CPB.119,120 The DECS trial randomized 4494
patients to receive 1 mg/kg of dexamethasone or placebo.
316 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
The investigators found no difference in the composite pri-
mary study endpoint that included stroke: the risk of stroke
was also equivalent between groups.119 The SIRS trial ran-
domized 7507 patients to receive 250 mg methylpredniso-
lone at induction and another 250 mg at initiation of
CPB.120 The investigators found no significant difference in
stroke rates between study groups.120 A substudy of the
DECS trial also demonstrated no difference in neurocognitive
dysfunction in the first year after adult cardiac surgery with
CPB both at 1 month (relative risk 1.87; 95% confidence
interval 0.90–3.88; P ¼ 0.09) and at 12 months (relative risk
1.98; 95% confidence interval 0.61–6.40; P ¼ 0.24).121 A
recent, large, meta-analysis (N > 7000: 56 randomized clin-
ical trials) also did not demonstrate any neuroprotective ben-
efits from steroid exposure during cardiac surgery with
CPB.122
In addition to steroids, lidocaine has also been examined
for neuroprotection because of its sodium-channel blocking
and potential anti-inflammatory properties.122–125 Initial
clinical trials demonstrated inconsistent neuroprotective
effects of lidocaine.122–125 Subsequent meta-analyses have
suggested a dose-dependent protection from cognitive dys-
function after cardiac surgery with CPB, although there
was significant heterogeneity across the included
trials.126,127
Magnesium has also been studied for its neuroprotec-
tive effects, including its antiexcitotoxic agent and anti-
inflammatory properties.128,129 Although it is safe, magne-
sium does not appear to be neuroprotective in recent clinical
trials.128,129 Although ketamine may reduce delirium after
cardiac surgery, this result has not been consistently evident
in clinical trials.130,131
Multiple agents have been tested for neuroprotection,
including propofol, calcium channel blockers, beta blockers,
antioxidants, erythropoietin, piracetam, the complement
inhibitor pexelizumab, the serine protease inhibitor aproti-
nin, and dexmedetomidine.112 Despite all this research,
significant neuroprotective benefits have yet to be
demonstrated.112
Neurologic Injury After Off-pump
Coronary Artery Bypass Grafting
INCIDENCE AND SIGNIFICANCE
The incidence of clinical stroke after off-pump CABG is typ-
ically 1%–2%.7 Because many causes of neurologic injury
during cardiac surgery are related to CPB, off-pump CABG
provides a cardiac surgical option that obviates the require-
ments for CPB, including aortic cannulation, aortic clamp-
ing, and further aortic manipulation.5–7 Despite this, off-
pump CABG is still a major surgical procedure with concom-
itant tissue damage, hemodynamic swings, inflammation,
and manipulation of the ascending aorta to the extent
required for proximal graft anastomoses, and therefore the
risk of neurologic injury is still present.5–7
Multiple high-quality multicenter randomized trials have
compared the risks of neurologic injury between off-pump
and on-pump CABG.132–137 Despite these excellent trials,
they have collectively failed to demonstrate a clear neuro-
protective benefit of off-pump CABG.132–137 A recent
meta-analysis (N > 16,900) reported an increased incidence
of stroke in the on-pump CABG group, however a subgroup
analysis of only high-quality randomized control trials
showed no significant difference.138 A recent meta-analysis
looking at studies with 5-year follow-up did not find a signif-
icant difference in the incidence of stroke in on-pump or off-
pump CABG.139 In contrast, a separate large meta-analysis
(N ¼ 123,137) revealed a statistically significant reduction
in stroke associated with off-pump CABG.140 There may
be certain high-risk subpopulations that have a greater ben-
efit from off-pump CABG. Recent meta-analyses have
shown a reduction in the stroke risk in high-risk patients
because of a high-risk off-pump CABG.141,142
ETIOLOGIC FACTORS
Neurologic injury during off-pump CABG is most likely
caused by the systemic inflammatory response, cerebral
emboli, and/or cardiac manipulation, which can lead to
hemodynamic instability.7,15,116
Inflammation. Although off-pump CABG avoids CPB, mul-
tiple trials have demonstrated that it nevertheless elicits a
significant systemic inflammatory response.143–147 This
marked inflammatory response can play a role in organ dys-
function during the postoperative period, including delirium
and stroke. The neuroprotective effects of off-pump CABG
dissolve with conversion to on-pump CABG, regardless of
etiology for conversion.148 The increased risk of neurologi-
cal dysfunction in this setting may be because of the step-up
in the systemic inflammatory response. Because the conver-
sion rate is about 5%, the role of neuroprotective pharma-
cology has not been adequately studied in this setting.
Manipulation of the Heart and Aorta
Manipulation of the aorta and heart, especially lifting of the
heart, leads to acute and severe decreases in preload and
stroke volume, resulting in compromised cerebral perfusion
that can precipitate emergency conversion to on-pump
CABG.148 Multiple trials have reported significant drops in
jugular bulb saturation during manipulation of the heart,
which may be tied to the neurologic injury seen during
off-pump CABG.149,150 There may be an expanded role for
cerebral oximetry in this setting, given its ability to diagnose
cerebral hypoperfusion, as outlined earlier.
Cerebral Emboli
By avoiding aortic cannulation and clamping, it is likely that
there is a reduction in the risk of cerebral emboli during off-
pump CABG.151,152 However, clinical trials clearly demon-
strate that cerebral emboli still occur during off-pump CABG
with a consequent risk of stroke.5,7,151,152 Techniques to
minimize aortic manipulation are discussed in the next sec-
tion as a way to reduce stroke risk.
STRATEGIES FOR NEUROPROTECTION
Although the systemic inflammatory response of CPB may
be avoided by off-pump techniques, a certain level of inflam-
mation still ensues. Furthermore, manipulation of the heart
to perform distal anastomoses is unavoidable. However, sur-
gical techniques exist to reduce the manipulation of the
 22 • Protecting the Central Nervous System During Cardiac Surgery
Table 22.3 Neuroprotective strategies in cardiac surgery
with cardiopulmonary bypass.
Modified cardiopulmonary bypass circuit
▪ Thoughtful circuit design can enhance neuroprotection
▪ Titrate vacuum-assisted drainage
▪ Soft-shell venous reservoir
▪ Centrifugal pump
▪ Membrane oxygenator
▪ Dynamic bubble trap
▪ Embolic filters
Aortic cannulation strategy
▪ Customized cannula design preferred
▪ Embolic protection has clinical potential
▪ Cannulation of the distal aortic arch may reduce stroke risk
Carbon dioxide
▪ Reduces gaseous emboli
▪ Safe, may be neuroprotective
Assessment of aortic atheroma
▪ Epiaortic imaging is preferred
▪ Transesophageal echocardiography has blind spot
▪ Modified A-view imaging decreases the size of this blind spot
Blood gas management
▪ Alpha-stat management is preferred for adult cardiac
surgery with CPB
▪ pH-stat management may be preferred in pediatric cardiac
surgery with CPB
▪ Requires further evaluation in high-quality clinical trials
Pulsatile perfusion
▪ Probably more physiologic
▪ Requires further evaluation in high-quality clinical trials
Temperature management
▪ Hypothermia compared with normothermia does not offer a clear
neuroprotective advantage
▪ Hyperthermia should be avoided
Blood pressure management
▪ Cerebral autoregulation curve should be considered
▪ Ideal range for systemic mean arterial pressure remains to be
determined
▪ Individualized approaches require further evaluation in high-quality
clinical trials
▪ Cerebral oximetry has potential application in this setting
Pulsatile perfusion
▪ Probably more physiologic
▪ Requires further evaluation in high-quality clinical trials
Pharmacologic therapy
▪ Extensive candidate list with detailed evidence base
▪ No agent can be recommended for routine application
CPB, Cardiopulmonary bypass.
ascending aorta, consequently reducing hemodynamic
swings and cerebral embolization.
Surgical techniques to perform proximal anastomoses
during off-pump CABG include using a partial side-biting
clamp, clampless technique using a stabilizing device, or a
complete aortic “no-touch” technique utilizing only the
internal mammary artery with Y-grafts off the mammary
artery.151–154 A large meta-analysis (N ¼ 25,163) com-
pared a complete aortic “no-touch” technique with a prox-
imal anastomotic device with or without a partial side clamp
and found a significantly lower risk of cerebrovascular acci-
dent in the “no-touch” group.154 This was demonstrated
again in a recently published, large meta-analysis of
37,720 patients comparing anaortic off-pump CABG (no
touch) and off-pump CABG with the remainder of the CABG
techniques.5 This high-quality analysis found that the ana-
ortic approach was most effective in reducing the risk of
postoperative stroke at 30 days.5
317
Neurological Injury After
Transcatheter Aortic Valve
Replacement
INCIDENCE AND SIGNIFICANCE
Since the first transcatheter aortic valve replacement
(TAVR) was performed in 2002, this procedure has evolved
into a mainstream therapeutic option to manage severe
aortic stenosis.155 The indications for TAVR have gradually
expanded from patients with excessive operative risk to
high-risk and now to intermediate-risk patients with severe
aortic stenosis.155,156 As the indications for TAVR are pres-
ently expanding to low-risk patients with severe aortic ste-
nosis, it remains a priority to evaluate the clinical outcomes
of TAVR against surgical AVR, which is the current gold
standard for this population.155
Despite the clinical progress, neurologic injury after
TAVR remains a serious complication of TAVR.157 In the
landmark trials for balloon-expandable TAVR, the reported
stroke incidences at 30 days in the inoperable, high-risk,
and intermediate-risk cohorts were 6.7%, 5.5%, and 6.4%
respectively.157,158 The stroke risk, however, has steadily
fallen to below 5% in recent years.157–159 This steady reduc-
tion in stroke risk is probably attributable to multiple factors,
including technological advances in the newer generation
devices, increased operator experience, and inclusion of
lower-risk patients.155–157
ETIOLOGIES OF NEUROLOGICAL INJURY
AFTER TAVR
In studying cerebrovascular events after TAVR, a temporal
pattern has been established, with approximately one-half
of events occurring within 48 hours of TAVR (early phase),
an increased incidence within 30 days (delayed phase), and
another increase at 1 year (late phase).157,160 This temporal
distribution suggests varied causes of stroke, including pro-
cedural factors in the early phase and patient-related and
postoperative treatment-related factors in the late phase.
The etiologies of stroke after TAVR include procedural
and nonprocedural factors (Table 22.4).
Embolic Injury
Because of the calcific nature of the stenotic aortic valve and
coexisting atherosclerotic disease of the proximal thoracic
aorta, hardware manipulation during TAVR of guidewires,
delivery catheters, and balloon valvuloplasty results in cere-
bral embolization in almost all cases with a risk of ischemic
stroke.161,162 The embolic material has been identified as
including thrombus, calcium, tissue fragments, and foreign
material.161,162 Multiple clinical trials have also demon-
strated with intraprocedural transcranial Doppler ultrasound
that microembolization occurs throughout the procedure,
most frequently during valve positioning, deployment, repo-
sitioning, and balloon valvuloplasty.163,164 These data sug-
gest that limiting embolization events may reduce the risk
of stroke after TAVR.
Atrial fibrillation, especially new-onset atrial fibrillation,
also increases the risk of stroke associated with TAVR.157
318 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Table 22.4 Etiologies of stroke after transcatheter aortic
valve replacement.
Procedural factors: Catheter manipulation within an
1.1.1.1 atheromatous atheromatous thoracic aorta
and calcific Hardware manipulation across
emboli a calcific aortic valve
Balloon inflation events
Valve deployment
Procedural factors: Air embolism
1.1.1.2 alternative Thromboembolism
emboli
Procedural factors: Watershed ischemia caused by
1.1.1.3 variations in hypoperfusion
perfusion Acute hypertension after valve
deployment
Nonprocedural factors Female gender
Atrial fibrillation
Prior stroke
Diabetes
Chronic kidney disease
Atheromatous arterial disease
Chronic hypertension
Adapted from Patel PA, Patel S, Feinman JW, et al: Stroke after transcatheter
aortic valve replacement: Incidence, definitions, etiologies and
management options. J Cardiothorac Vasc Anesth 2018;32:968-981.
A meta-analysis (N ¼ 14078: 26 clinical trials) reported
from the TAVR population the incidences of chronic and
new-onset atrial fibrillation to be 33.4% and 17.5% res-
pectively.165 Furthermore, multiple trials have also de-
monstrated that atrial fibrillation significantly increased
the risk of stroke after TAVR because of cerebral
embolization.165,166
Nonembolic Etiologies
Nonembolic sources of cerebral injury during TAVR are pri-
marily caused by hypotension with falls in cerebral perfu-
sion.157,167 Severe hypotension can occur as a result of
induction of general anesthesia, bleeding, valve positioning,
and rapid ventricular pacing during valve intervention.157
Cardiovascular collapse may also accompany rare but seri-
ous complications in TAVR such as acute aortic regurgita-
tion after valve deployment, coronary occlusion, aortic
rupture, and acute aortic dissection.168 Fluctuations in
cerebral perfusion pressure can severely decrease blood flow
in the vulnerable cerebral watershed areas causing ischemic
insult, but also decrease washout of embolized material,
exacerbating their effects.169 In a study of 214 strokes after
TAVR, computed tomography demonstrated both embolic
and perfusion-related injury patterns.170 In contrast to cere-
bral hypoperfusion, acute hypertension following acute
relief of aortic stenosis with valve deployment in TAVR
can lead to cerebral hyperemia and hemorrhagic stroke.171
Preexisting factors such as chronic hypertension, history
of stroke, carotid vascular disease, diabetes, chronic atrial
fibrillation, and smoking may exacerbate the risk of stroke
after TAVR.157,158 Furthermore, a large systematic review
(N ¼ 72,318) identified the following significant predictors
for stroke after TAVR: female gender, chronic kidney dis-
ease, new-onset atrial fibrillation, and enrollment within
the first half of a center’s experience with TAVR.172 Another
clinical trial highlighted the following significant procedural
predictors for stroke after TAVR: total procedural time, total
time the delivery catheter was in vivo, rapid ventricular
Table 22.5 Strategies for neuroprotection in transcatheter
aortic valve replacement.
Preoperative strategies
▪ Optimize modifiable risk factors: hypertension, hyperlipidemia,
smoking, diabetes, and atrial fibrillation
▪ Detailed imaging studies: atheroma severity, aortic valve calcium
▪ Appropriate patient selection by the heart team
Intraoperative strategies
▪ Experienced heart team: procedural skill and efficiency
▪ Optimal anesthetic management
▪ Embolic protection devices
▪ Adequate perioperative anticoagulation
▪ Maintain cerebral perfusion
Postoperative strategies
▪ Aggressive management of atrial fibrillation
▪ Optimize antithrombotic and/or anticoagulation
▪ Rapid diagnosis of stroke
▪ Prompt referral for medical and/or interventional stroke treatment
pacing, and valve repositioning.173 This evidence under-
lines the importance of patient- and procedure-specific fac-
tors in the pathogenesis of stroke after TAVR (Table 22.4).
These collective risk factors for stroke after TAVR can be
managed in a systematic perioperative fashion to mini-
mize the stroke risk, as outlined in the following section
(Table 22.5).
NEUROPROTECTIVE STRATEGIES
Preoperative Neuroprotection
Preoperative neuroprotection strategies center around the
optimization of baseline comorbidities, including hyperten-
sion, hyperlipidemia, diabetes, smoking, and atrial fibrilla-
tion, given their roles in stroke risk.170–173 Furthermore,
detailed preoperative evaluation typically includes high-
quality imaging that can facilitate the assessment of stroke
risk factors such as aortic atheroma, aortic valve calcifica-
tion severity, left atrial size (risk of atrial fibrillation),
carotid vascular disease, and baseline cerebrovascular
disease.157,158
Intraoperative Neuroprotection
Heart team experience. A major factor in reducing
intraoperative stroke risk during TAVR is the experience
of the heart team performing the procedure. Multiple clini-
cal trials have demonstrated that stroke risk is reduced as
centers gain experience because of factors such as reduced
manipulation of hardware within the aorta and shorter pro-
cedural times.171–173 The maturation of alternative access
routes for TAVR has offered the heart team viable options
to avoid severely diseased aortic segments to minimize cere-
bral atheroembolism and subsequent stroke.174,175
In the first decade of TAVR, general anesthesia was the
anesthetic of choice.176 As the TAVR procedure has
matured and heart teams have gained considerable experi-
ence, monitored anesthesia care has become a common
anesthetic approach.176–178 The advantages of general
anesthesia include a secure airway, immobile patient, quick
conversion to open surgery, and the ready suitability for
transesophageal echocardiography.178 The advantages of
monitored anesthetic care include shorter procedural times,
 22 • Protecting the Central Nervous System During Cardiac Surgery 319

reduced intraoperative inotrope and vasopressor require-
ments, lower hospital costs, as well as shorter lengths of stay
both in the intensive care unit and hospital.176–178 Further-
more, this technique enables an earlier, more accurate neu-
rological examination and perioperative surveillance.176–
178
It is likely that monitored anesthetic care will evolve into
the preferred anesthetic approach for transfemoral TAVR,
given the steady advancements in valve design and heart
team experience.178,179
Embolic protection. The convincing evidence for cerebral
embolization during TAVR has prompted the development
of devices to capture this debris before it reaches the cerebral
circulation.157 To date, three such devices have reached
clinical trials (Fig. 22.4). The Embrella Embolic Deflector
(Edwards Lifesciences, Irvine, California) consists of two
porous polyurethane petals within a nitinol frame that
cover the right brachiocephalic trunk and left common
carotid artery during TAVR deployment (Fig. 22.4).180
The device is deployed through the right radial artery.
The filters allow blood to flow through while particles larger
than 100 μm are deflected away from the protected ves-
sels.180 Two pilot clinical trials have demonstrated reduc-
tions in both embolic events on transcranial Doppler and
new embolic lesion volume on magnetic resonance imag-
ing.180,181 Despite this embolic protection with the Embrella
device, there was no reduction in clinical stroke rate in these
initial clinical trials.180,181
The Sentinel Cerebral Protection System (Claret Medical,
Santa Rosa, California) is the second generation of a device
previously known as the Claret Montage Dual Filter Sys-
tem.157 The refined design included an improved delivery
system and two independent filters that cover the right bra-
chiocephalic trunk and left common carotid artery

A B C

D E F

G H I
Fig. 22.4 Embolic protection devices. (A) The Embrella device in the deployed position. (B, C) The procedural position of the Embrella device in the
aortic arch. (D) The TriGuard device in the deployed position. (E, F) The correct position of the TriGuard in the aortic arch. (G) The Sentinel device in the
deployed position. (H, I) The Sentinel’s position within the brachiocephalic and left common carotid arteries. (Reprinted from: Patel PA, Patel S, Feinman
JW, et al. Stroke after transcatheter aortic valve replacement: incidence, definitions, etiologies and management options. J Cardiothorac Vasc Anesth 2018;32:
968–981.)
320 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
(Fig. 22.4).157 A pilot randomized clinical trial (N ¼ 63)
demonstrated the safety and feasibility of this device, with
a significant reduction in both new cerebral lesions and
new neurocognitive deficits.182 A recent, larger randomized
controlled trial (N ¼ 363) demonstrated a favorable trend
both in clinical stroke and neurocognitive function when
using this device.183
A recent prospective propensity-matched clinical trial
(N ¼ 802;280 received the Sentinel device) demonstrated
a significant reduction in clinical stroke associated with
embolic protection from the Sentinel device (odds ratio
0.29; 95% confidence interval 0.1–0.93; P¼ 0.03).184
The composite endpoint of all-cause stroke and mortality
was also significantly reduced in the embolic protection
group (odds ratio 0.30; 95% confidence interval 0.12–
0.77; P ¼ 0.01).184 The main limitation of this clinical trial
was that lack of randomization, although propensity score
matching accounted in part for possible confounders.184
The TriGuard Embolic Deflection System (Keystone
Heart, Caesarea, Israel), deployed from the femoral artery,
consists of a mesh filter that covers all three major arch ves-
sels (Fig. 22.4).157,185 Like the Embrella deflection system,
this TriGuard deflects debris into the descending aorta
and away from the cerebral circulation. Unlike the previous
two embolic protection devices, the TriGuard protects all
regions of the brain.157 A pilot randomized clinical trial
demonstrated the safety of the device and showed a non-
significant decrease in new cerebral lesions and neurologic
deficits compared to the control arm.185 Although nonsig-
nificant, this favorable trend has laid the groundwork for
a larger clinical trial that is currently underway.185
Several meta-analyses have been undertaken with the
goal of increasing the power of these smaller device studies
to discover whether a clear benefit exists for embolic protec-
tion. A recent meta-analysis (N ¼ 1225) demonstrated a sig-
nificant reduction in stroke risk in the first week after TAVR
(relative risk ratio 0.56; 95% confidence interval 0.33–
0.96; P< 0.05).186 A second meta-analysis demonstrated
a significant reduction in new ischemic cerebral lesion bur-
den.187 A third meta-analysis also demonstrated a signifi-
cant reduction in clinical stroke at 30 days as a result of
embolic protection during TAVR (odds ratio 0.55; 95% con-
fidence interval 0.31–0.98; P ¼ 0.04).188 Because these
meta-analyses have combined data from smaller studies of
different embolic protection devices, there is considerable
heterogeneity in the data. Large, adequately powered ran-
domized controlled trials are still required to explore in detail
the neuroprotective effects of these devices in TAVR.
Although embolic protection devices have yet to demon-
strate a definite neuroprotective advantage, they are being
adopted in clinical practice, given the favorable safety and
efficacy.189 Thus, although the application of these devices
is not yet a standard of care in TAVR, their deployment is
safe and reasonable.189
Postoperative Neuroprotection
Because new-onset atrial fibrillation increases the risk for
stroke after TAVR, its early detection and protocol-driven
management are essential. As a result of the thrombogenic
nature of the TAVR procedure and prosthetic valve,
optimal perioperative anticoagulation is necessary to pre-
vent thromboembolism (Table 22.5). Although intrave-
nous heparin is preferred for adequate intraoperative
anticoagulation, such levels of anticoagulation are unac-
ceptable postoperatively because of the high risk of major
bleeding. Dual antiplatelet therapy with aspirin and clopido-
grel has been recommended to minimize the risks of valve
thrombosis after TAVR.190,191 Recent meta-analysis has
challenged this practice because of the excessive bleeding
risk (relative risk 2.52; 95% confidence interval 1.62–
3.92; P < 0.0001) with no difference in stroke risk, suggest-
ing that monotherapy may be adequate.192 In TAVR
patients who take coumadin for atrial fibrillation, dual anti-
platelet therapy is also not recommended because of the
excessive risk of bleeding.193 Future trials will identify the
next antithrombotic strategy after TAVR, examining the
options both for platelet blockade and the novel oral
anticoagulants.194,195
Neurologic Injury During Thoracic
Aortic Surgery
INTRODUCTION
Thoracic aortic disease is a major cause of mortality and
morbidity, with aortic aneurysm and dissection as the most
common pathologies.196–198 The aorta has five segments
from its origin at the aortic valve to its termination at the
iliac bifurcation in the abdomen (Fig. 22.5).196–198 An aor-
tic aneurysm is defined as having an aortic diameter greater
than 150% of normal with all three layers of the aortic wall
still intact. Aortic aneurysms are classified according to their
III
IIb IVa
IIa IVb
I
Va
Vb
Fig. 22.5 The segments of the aorta. (I) Segment I is the aortic root
that contains the aortic valve and the sinuses of Valsalva. This segment
joins the ascending aorta at the sinotubular junction. (II) Segment II is
the tubular ascending aorta and is subdivided into two subsegments:
IIa, sinotubular junction to the pulmonary artery level; and IIb, from the
pulmonary artery level to the brachicephalic artery. (III) Segment III is
the aortic arch. (IV) Segment IV is the descending thoracic aorta that is
subdivided into two subsegments: IVa, from the left subclavian artery
to the pulmonary artery level; and IVb, from the pulmonary artery level
to the diaphragm. (V) Segment V is the abdominal aorta that is sub-
divided into two subsegments as follows: Va, from the diaphragm to
the renal arteries; and Vb, from the renal arteries to the iliac bifurcation.
(Reprinted from: Goldstein SA, Evangelista A, Abbara S, et al. Multimodality
imaging of diseases of the thoracic aorta in adults: from the American
Society of Echocardiography and the European Association of Cardio-
vascular Imaging. J Am Soc Echocardiogr 2015;28:119-182.)
 22 • Protecting the Central Nervous System During Cardiac Surgery
size, shape, and extent. In the proximal thoracic aorta, an
aneurysm may involve the aortic root, the ascending aorta,
and/or the aortic arch (Fig. 22.5).197,198 An aortic aneu-
rysm distal to the arch may involve the descending thoracic
aorta and/or the abdominal aorta (Fig. 22.6).196–198 The
timing of intervention for a given aneurysm depends on fac-
tors such as clinical presentation, location, size, and comor-
bidities.196–198 Aortic dissection is caused by an intimal tear
that can extend to involve a variable extent of the aorta with
both a true and a false lumen.196–198 This challenging dis-
ease process is classified according to the dissection extent in
the DeBakey or Stanford systems (Fig. 22.7).196–199 The
timing of intervention for a given aortic dissection depends
on factors such as clinical presentation, location, and
extent.196–200 Thoracic aortic disease can present with cere-
bral and/or spinal stroke as a result of hypotension from aor-
tic rupture, emboli from an aneurysm, and/or malperfusion
from dissection.196–200
The open surgical management of thoracic aortic disease
entails resection of the diseased aortic segment with subse-
quent replacement with vascular tubular graft.196,197 If the
disease is isolated to the ascending aorta, then this repair is
achieved using traditional CPB with similar risks of neurologic
injury outlined in the earlier section “Neurological Injury after
Cardiac Surgery with Cardiopulmonary Bypass”.196,197 If,
however, the aortic pathology involves the aortic arch and/
or descending thoracic aorta, then surgical repair poses
unique threats to the central nervous system.196,197
When an aortic aneurysm or dissection affects the aortic
arch, from which the cerebral arterial vasculature arises,
the repair of this lesion requires the temporary cessation of
Descending Thoracoabdominal
A B C I II III IV
6th rib
Diaphragm
Celiac artery
Renal artery
Fig. 22.6 The classification of descending aortic aneurysms. The des-
cending thoracic aorta: Extent A: Aneurysm involving the proximal third of
the descending thoracic aorta; Extent B: Aneurysm involving the middle
third of the descending thoracic aorta; Extent C: Aneurysm involving
the distal third of the descending thoracic aorta. The thoracoabdominal
aorta (Crawford Classification): Type I: Aneurysm extending from above the
6th rib to the renal arteries; Type II: Aneurysm extending from above the
6th rib to below the renal arteries; Type III: Aneurysm extending from
below the 6th rib in the chest to the abdominal aorta; Type IV: Aneurysm
extending from below the diaphragm to involve the entire visceral
aortic segment and most of the abdominal aorta. (Reprinted from:
Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/
SCA/SCA/SIR/STS/SVM guidelines for the diagnosis and management of
patients with thoracic aortic disease. J Am Coll Card 2010;55: e27-e129)
321
True Entry
Entry lumen tear
tear
False
lumen False
lumen
True
lumen
Type I or Type A Type III or Type B
or Proximal or Distal
Fig. 22.7 The classification of aortic dissection. The Stanford System: Type
A Dissection: Dissection of the ascending aorta with variable distal
extent; Type B Dissection: Dissection of the descending thoracic aorta
with variable distal extent. The DeBakey System: Type I Dissection: Dis-
section of the ascending aorta with extent beyond the aortic arch into
the descending thoracic aorta and beyond; Type II Dissection: Dis-
section limited to the ascending aorta (not shown as it is the least
common dissection type); Type III Dissection: Dissection of the des-
cending thoracic aorta. Extent A: limited to descending thoracic aorta.
Extent B: involving the abdominal aorta as well. (Reprinted from: Hir-
atzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/
SCA/SCA/SIR/STS/SVM guidelines for the diagnosis and management of
patients with thoracic aortic disease. J Am Coll Card 2010;55:e27-e129)
blood flow to the brain.196,197,201 This circulatory arrest
allows surgical exposure to facilitate reconstruction of the aor-
tic arch. To mitigate its cerebral ischemic effects the period of
circulatory arrest is typically performed with a degree of hypo-
thermia with or without selective cerebral perfusion.201
Despite these advances, the stroke rate during aortic arch sur-
gery remains between 4% and 10%, with higher risk during
emergency settings such as acute type A dissection.196–203
Just as aortic arch surgery requires specialized maneuvers
to protect the brain, surgical repair of the thoracoabdominal
aorta requires tailored management to protect the spinal
cord because the spinal cord arterial network receives signif-
icant input from the thoracic aorta at multiple levels
(Fig. 22.8).196,197,204 In this surgical setting, spinal cord
ischemia manifesting as paraparesis or paraplegia remains
a serious complication that significantly increases mortality
and morbidity after thoracoabdominal aortic interven-
tions.196,197,205,206 Although the risks of spinal cord ische-
mia has decreased steadily with the multimodal advances in
open and endovascular thoracic aortic repair, the incidence
of spinal cord ischemia remains in the 2%–8% range,
depending on the level of operative risk.205,206
ETIOLOGIC MECHANISMS FOR NEUROLOGICAL
INJURY
Aortic Arch Repair
Hypothermic circulatory arrest (HCA) was pioneered as a
technique for aortic arch repair in the 1970s.196,197 The
concept in HCA is to cool the patient systemically to a hypo-
thermic level where cerebral metabolic rate and oxygen
322 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
1
2 Level of hypothermia
3
4
5
6
7
8 ing distal aortic reconstruction, it is essential to appreciate
9 network that is an arterial plexus along the surface of the
10
11
14
12
13
Fig. 22.8 The segmental blood supply of the spinal cord. The spinal
cord collateral network is an arterial plexus that supplies the entire
spinal cord. This arterial network has an extensive segmental supply
from the vertebral arteries, the intercostal arteries, the lumbar arteries,
and the iliolumbar arteries. 1, spinal cord; 2, vertebral artery; 3, anterior
spinal artery; 4, left subclavian artery; 5, aneurysmal descending tho-
racic aorta; 6, Adamkiewicz artery; 7, intersegmental collateral artery; 8,
segmental artery (includes intercostal and lumbar arteries); 9, anasto-
motic loop to posterior spinal artery; 10, filum terminal artery; 11,
common iliac artery; 12, external iliac artery; 13, internal iliac artery
(hypogastric artery); 14, iliolumbar artery. (Reprinted from: Backes WH,
Nijenhuis RJ, Mess WH, et al. Magnetic resonance angiography of collateral
blood supply to spinal cord in thoracic and thoracoabdominal aortic
aneurysm patients. J Vasc Surg 2008;48:261-271.)
consumption are significantly reduced to minimize cerebral
ischemia during arch repair with circulatory arrest.39 This
technique takes into account that cerebral metabolic rate
decreases about 5%–7% for every 1°C drop in tempera-
ture.39,207 Recent expert consensus has defined four levels
of hypothermia for aortic arch repair (Table 22.6).39
Although hypothermia induces a cerebral ischemic toler-
ance that correlates with the hypothermic level, the stroke
risk remains because of this global ischemia and embolic
material.196,197 Further risk factors for neurologic injury
after aortic arch repair include advanced age, previous cere-
brovascular disease, duration of CPB, and the duration of
HCA.207–209 Clinical trials have demonstrated that HCA
with deep hypothermia can be safely tolerated for
Table 22.6 Classification consensus for levels of hypothermia
in aortic arch surgery.
Patient temperature
Mild hypothermia 28.1–34.0°C
Moderate hypothermia 20.1–28.0°C
Deep hypothermia 14.1–20.0°C
Profound hypothermia 14.0°C or less
From Gutsche JT, Ghadimi K, Patel PA, et al. New frontiers in aortic therapy:
focus on deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth
2014;28:1159-1163.
30–40 minutes, with a significant increase in stroke risk
thereafter.203,207–209
THORACOABDOMINAL AORTIC REPAIR
When considering the etiology of spinal cord ischemia dur-
the spinal blood supply, known as the spinal cord arterial
entire spinal cord (Fig. 22–8).196,197,205,206 This arterial
network receives significant cephalad input from the ante-
rior and posterior spinal arteries, which arise cranially from
the vertebral arteries (Fig. 22.8).205,206 Thereafter, the spi-
nal cord arterial network receives thoracic input from the
intercostal arteries, abdominal input from the lumbar arter-
ies, and finally pelvic input from the internal iliac arteries
(Fig. 22.8).205,206 The artery of Adamkiewicz provides a
large thoracolumbar arterial input for the spinal cord, as
illustrated in Fig. 22.8.205,206
Spinal cord ischemia during thoracoabdominal interven-
tions results from interruption of spinal cord perfusion via
the extensive arterial network as a result of multiple periop-
erative factors (Table 22.7).196,197,205,206 These factors dis-
turb the net spinal cord perfusion pressure that is equal to
the difference between systemic mean arterial pressure
and cerebrospinal fluid pressure and result in ische-
mia.205,206 The extent of aortic disease is a major risk factor
for spinal cord ischemia as it defines the length of aortic
intervention and therefore the extent of segmental spinal
artery sacrifice and subsequent compromise of the spinal
cord arterial network (Figs. 22.6 and 22.8).205,206,209,210
As an example, type II thoracoabdominal aneurysms typi-
cally have the highest risk of spinal cord ischemia because
they have the longest extent of diseased aorta with severe
consequences for the spinal cord arterial network in the
perioperative period (Figs. 22.6 and 22.8).196,197,205,206
NEUROPROTECTIVE STRATEGIES: AORTIC
ARCH REPAIR
Neuroprotection during aortic arch repair consists of a mul-
timodal strategy that includes the entire heart team
(Table 22.8). The experience and quality of the heart team
in these complex procedures play a significant role in
achieving excellent neuroprotection.209 Furthermore, a
multidisciplinary heart team protocol can also enhance
the overall quality of patients undergoing aortic arch repair
with incremental gains in important clinical outcomes,
 22 • Protecting the Central Nervous System During Cardiac Surgery 323

Table 22.7 Risk factors for spinal cord ischemia in aortic Table 22.9 Advantages of axillary artery cannulation in aortic
surgery and stenting. arch repair for either aneurysm or dissection.
Risk factor Effect Clinical advantage Comment
Aortic dissection Branch vessel malperfusion Reduces risk of cerebral Axillary artery is typically
Previous aortic surgery Compromise of the SCAN with loss atheroembolism free from atherosclerotic
Severe PVD aortic of vascular reserve disease; avoids
Clamping systemic Chronic reduction of distal inflow to cannulation of
Hypotension the SCAN atheromatous
Increases in CSF pressure Acute loss of spinal cord perfusion ascending aorta
Acute decrease in spinal cord Reduces risk of retrograde aortic Blood flow is antegrade
perfusion pressure dissection: femoral arterial with axillary artery
Decreases spinal cord perfusion cannulation for type A dissection cannulation
pressure (compartment syndrome) repair not required
Sacrifice of SSA Acute loss of SCAN (surgical occlusion) Eliminates risk of retrograde cerebral Blood flow is antegrade
Poor coverage of SSA Acute loss of SCAN (stent coverage) embolization: femoral arterial with axillary artery
Distal perfusion Insufficient inflow into distal part of cannulation for type A dissection cannulation
SCAN (on pump/no pulsatile repair not required
perfusion) Often allows antegrade blood flow in Caution in innominate
Arterial steal Loss of spinal cord perfusion pressure true lumen to decompress false artery dissection
due to bleeding from patent SSA lumen
after surgical incision of the aortic May reduce risk of malperfusion and Caution in innominate
segment for replacement e.g. subsequent regional hypoperfusion artery dissection
aneurysm sac Provides access for subsequent Monitor adequacy of
Reperfusion injury Spinal cord edema from ischemia and unilateral antegrade cerebral contralateral
Thrombosis of SSA reperfusion perfusion cerebral perfusion
Postoperative loss of SCAN
Erbel R, Aboyans V, Boileau C, et al: 2014 ESC guidelines on the diagnosis and
CSF, Cerebrospinal fluid; PVD, peripheral vascular disease; SCAN, spinal cord treatment of aortic diseases. Eur Heart J 2014;35:2873-2926. Hiratzka LF,
arterial network; SSA, spinal segmental arteries such as intercostal and Bakris GL, Beckman JA, et al: 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCA/SIR/
lumbar arteries. STS/SVM guidelines for the diagnosis and management of patients with
From Etz CD, Weigang E, Hartert M, et al: Contemporary spinal cord protection thoracic aortic disease. J Am Coll Card 2010;55:e27-e129.
during thoracic and thoracoabdominal aortic surgery and endovascular
aortic repair: A position paper of the vascular domain of the European
Association for Cardio-Thoracic Surgery. Eur. J. Cardiothorac Surg
2015;47:943-957.

Axillary Artery Cannulation

Table 22.8 Multimodal neuroprotective strategies in aortic Cannulation of the axillary artery provides excellent arterial
arch repair.
access for CPB for planned aortic arch repair (Table 22.9).39
Neuroprotective strategy Comment It avoids the manipulation and cannulation of a diseased
Heart team experience Team training; perioperative protocol
ascending aorta that decreases the risks of cerebral ather-
Axillary artery cannulation Multiple advantages (see Table 22.9) oembolism in the presence of an atherosclerotic aneurysm
Hypothermia during CPB Standard of care as well as the risks of aortic rupture and cerebral malper-
Antegrade cerebral Less reliance on deep hypothermia fusion in the presence of acute dissection.39,196,197 Further-
perfusion during HCA Monitor arterial pressure in right more, in the presence of acute ascending aortic dissection, it
upper extremity
Retrograde cerebral Embolic washout avoids the requirement for femoral arterial cannulation to
perfusion during HCA Monitor central venous pressure in obviate the risks of retrograde cerebral atheroembolism
right internal jugular vein and malperfusion that accompany this cannulation strat-
Monitoring with Guiding of hypothermia egy.39,209 During HCA, antegrade cerebral perfusion can
electroencephalography Detection of ischemia
Monitoring with cerebral Detection of ischemia
be delivered via the acillary route. This modality will be dis-
oximetry cussed in more detail later in this chapter.
Monitoring with carotid Detection of cerebral malperfusion The innominate artery provides an alternative cannula-
imaging tion site to the axillary artery in the setting of aortic arch
Blood gas management Limited evidence repair.211,212 It not only offers all of the advantages already
Maintain physiologic milieu
Alpha-stat management discussed for axillary cannulation but also does not require
Temperature management Avoid hyperthermia an additional incision since the innominate artery can be
during CPB Avoid excessive thermal gradient readily accessed through a median sternotomy.
Follow guidelines (see Table 22.10)
Pharmacologic agents Limited evidence Hypothermia and Selective Cerebral Perfusion
CPB, Cardiopulmonary bypass; HCA, hypothermic circulatory arrest. As outlined earlier, a selected degree of hypothermia is
a major neuroprotective strategy for aortic arch repair
during circulatory arrest.209 Traditional HCA entails cool-
including neuroprotection.203,209 The neuroprotective strat- ing the patient during CPB to deep hypothermia (14–20°
egies for adult cardiac surgery with CPB outlined in the C) to allow safe aortic arch repair within 30–
section “Neurological Injury after Cardiac Surgery with 40 minutes.39,209 This safe duration of HCA may not allow
Cardiopulmonary Bypass” also apply here. adequate time for particularly complicated total arch
324 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
repairs. A search for techniques to reduce the neurologic
injury associated with HCA and prolong the safe period
of circulatory arrest led to the development of selective
cerebral perfusion techniques.196,197
Selective cerebral perfusion is now a common adjunct to
HCA in aortic arch repair cases, with recent European sur-
veys showing that over 90% of arch repairs included these
perfusion adjuncts.201,213 There are two types of selective
cerebral perfusion, retrograde and antegrade, the latter of
which can be delivered unilaterally or bilaterally. Retro-
grade cerebral perfusion consists of cold blood delivery ret-
rograde up the right internal jugular vein via the superior
vena cava cannula of the CPB circuit to a pressure of
15–20 mmHg.203 This retrograde perfusion contributes lit-
tle usable oxygen to the brain but does help maintain hypo-
thermia and assists with embolic washout from the
brain.214 Although this technique may confer protection
against stroke as a result of embolic washout and modest
extension of the safe duration for HCA, it has gradually
been replaced by a preference for antegrade cerebral
perfusion.196,196,201,213
The advantages of antegrade cerebral perfusion are that it
maintains the natural direction of blood flow and provides
metabolically adequate perfusion to the brain.217 It may
be delivered unilaterally via the axillary artery or innomi-
nate artery, as outlined earlier (Table 22.9). It can also be
delivered bilaterally via the left carotid artery along with
right-sided delivery.217 Flow targets during antegrade cere-
bral perfusion are typically in the range of 8–10 mL/kg/min
(800–1000 mL/min) with a goal pressure of 50–60 mmHg
measured at the right radial artery.196,197,218,219 Although
both unilateral and bilateral antegrade cerebral perfusion is
possible, no significant differences in neurological outcomes
have been identified in multiple clinical trials.196,197,202
The excellent neuroprotection afforded by antegrade cere-
bral perfusion during HCA has facilitated less reliance on
deep hypothermia for neuroprotection during HCA.220,221
Multiple clinical trials have demonstrated the clinical safety
and efficacy of HCA with mild-to-moderate hypothermia
(Table 22.6), including a possibly reduced risk of stroke
when compared with HCA with deep hypothermia
HCA.220,221 Furthermore, the conduct of HCA at warmer
temperatures reduces the risks of coagulopathy, inflamma-
tory response, and end-organ dysfunction seen with deep
hypothermia.221,222
Monitoring for Neurological Injury
Electroencephalography for aortic arch repair.
Intraoperative electroencephalographic monitoring can be
an adjunct to help individualize hypothermia for HCA, tar-
geting a level and duration of cooling that leads to an iso-
electric EEG.223,224 This approach leads to maximal
suppression of cerebral metabolic rate due to hypothermia.
Anesthetic management must be tailored not to confound
the effects of temperature in this setting.
Although continuous intraoperative electroencephalog-
raphy is not a standard of care for aortic arch repair requir-
ing HCA, it can not only guide the conduct of hypothermia,
but also monitor for neurologic injury and assess the ade-
quacy of selected cerebral perfusion adjuncts, especially at
mild-to-moderate hypothermia.207 Changes in the electro-
encephalographic signal pattern and amplitude may
indicate ischemia and guide efforts to restore cerebral perfu-
sion with respect to flow and pressure.223–226
During cooling, the neurotracings remain similar to base-
line initially, until around 30°C (+/- 3°C) when periodic com-
plexes appear in over 60% of cases.225 These periodic
complexes are probably related to gray and white matter dys-
function in the brain.225 As the brain continues to cool, these
periodic complexes disappear and burst suppression is reached
at a nasopharyngeal temperature of approximately 24°C (+/-
4°C).223–226 If cooling continues, an isoelectric tracing is
achieved at an average nasopharyngeal temperature of
17.8°C (+/- 4°C).225,226 There is significant variability, how-
ever, in the temperature at which an isoelectric pattern
occurs, and cooling to the physiologic endpoint of an isoelec-
tric EEG (as opposed to a fixed temperature) may therefore
have some benefit.223–225 On average, burst suppression reap-
pears 19 minutes (+/- 9 minutes) after the restoration of anter-
ograde blood flow to the brain and continuous activity returns
after 47 minutes (+/- 27 minutes).224,225 A delayed return to
continuous activity during rewarming on CPB may signal
neurologic injury.224,225
Cerebral oximetry. As outlined earlier, cerebral oximetry
with near-infrared spectroscopy is noninvasive because it
monitors the oxygen content of cerebral tissue via adhesive
pads applied to the forehead of the patient.20 The role of this
technology for cerebral monitoring during HCA with ante-
grade cerebral perfusion has proven feasible, safe, and effec-
tive. In this setting, it can detect cerebral ischemia and
prompt intraoperative interventions to restore adequacy of
cerebral perfusion whether unilateral or bilateral.20,221,227
Carotid Ultrasound
An alternative monitor to detect cerebral malperfusion in
these settings is carotid ultrasound. Scanning of the carotid
arteries bilaterally during operative repair for type A aortic
dissection can monitor the adequacy of cerebral perfusion
during critical phases of the procedure when the kinetics
of the intimal flap may precipitate cerebral malperfusion,
including initiation of CPB, clamping of the ascending aorta,
and during antegrade cerebral perfusion.228,229 Detailed
imaging of the carotid arteries can be achieved by with-
drawal of a transesophageal probe into the pharynx or by
transcutaneous scanning with a handheld probe.228–230
Detection of cerebral malperfusion in these phases may be
corrected by maneuvers such as adjusting the site of arterial
cannulation (e.g., axillary artery instead of femoral artery),
surgical fenestration of the intimal flap to restore perfusion
to both the true and false lumina, adjustment of the arterial
cannula, external carotid compression and/or initiation of
bilateral antegrade cerebral perfusion.228–232 Team dynam-
ics during these critical phases of the operative procedure
are of major importance to detect and correct these compli-
cations.228–232
Blood Gas Management
As outlined earlier, alpha-stat blood gas management is pre-
ferred during adult aortic arch repair with CPB and HCA.91–93
In pediatric CPB and HCA, pH-stat management may be
preferred as the relative hypercarbia leads to rapid symmet-
ric brain cooling as a result of cerebral vasodilation.93 In
adult patients, there are concerns that this management
 22 • Protecting the Central Nervous System During Cardiac Surgery
approach might increase stroke risk because of the increased
burden of cerebral emboli. The evidence supporting these
practice preferences are limited.
Temperature Management During Cardiopulmonary
Bypass
Rapid rewarming with overshoot hyperthermia during CPB
induces neurological injury.99–101 Recent high-quality mul-
tisociety guidelines have addressed temperature manage-
ment during CPB.233 The guidelines serve as a template
for the safe evidence-based conduct of cooling and rewarm-
ing during CPB: they are reviewed in detail in
Table 22.10.233 While these guidelines are important dur-
ing general adult cardiac surgery with CPB for optimal neu-
roprotection, they are even more important in the practice
of aortic arch repair with CPB and HCA, given the higher
stroke risk.233 Further trials should explore the evidence
gaps that are apparent in this area of CPB management.
Pharmacologic Agents
Many pharmacologic adjuncts have been tested in HCA to
see whether neurologic outcomes can be improved.234 Thio-
pental and propofol are commonly considered, because they
further suppress cerebral metabolic rate during HCA.213,234
Unfortunately, the data have not shown any clinical benefit
with these agents.234,235 Corticosteroids are also commonly
considered for aortic arch repair with HCA. A recent clinical
registry suggested that in acute type A dissection, steroid
administration may be associated with a decreased stroke
Table 22.10 Guidelines for temperature management
during cardiac surgery with cardiopulmonary bypass.
Class I recommendations
▪ The oxygenator arterial outlet blood temperature reflects cerebral
blood temperature during CPB (Level C evidence).
▪ It should be assumed that this temperature surrogate underestimates
cerebral perfusate temperature (Level C evidence).
▪ The heart team should run the arterial outlet blood temperature below
37°C to minimize the risk of cerebral hyperthermia (Level C
evidence).
▪ The temperature gradient across the oxygenator in the CPB circuit
should be below 10°Cto minimize the formation of gaseous
emboli during cooling (Level C evidence).
▪ The temperature gradient across the oxygenator in the CPB circuit
should be below 10°C to minimize outgassing during rewarming
(Level C evidence).
Class IIa recommendations
▪ The pulmonary artery and/or the nasopharyngeal temperature is a
reasonable guide for weaning of CPB (Level C evidence).
▪ When the arterial blood outlet temperature is below 30°C, the
maximal temperature gradient across the oxygenator should not
exceed 10°C (Level C evidence).
▪ When the arterial blood outlet temperature is above 30°C, the
temperature gradient across the oxygenator should not exceed
4°C (Level C evidence) and the rewarming rate should not exceed
0.5 degrees/min (Level B evidence).
No recommendation
▪ There is insufficient evidence to recommend a standard optimal
temperature for weaning of CPB.
CPB, cardiopulmonary bypass.
Engelman R, Baker RA, Likosky DS, et al: The Society of Thoracic Surgeons, the
Society of Cardiovascular Anesthesiologists, and the American Society of
Extracorporeal Technology: Clinical practice guidelines for cardiopulmonary
bypass - temperature management during cardiopulmonary bypass.
J Cardiothorac Vasc Anesth 2015;29:1104-1113.
325
risk (adjusted odds ratio 0.5; 95% confidence interval
0.24–0.96; P¼ 0.049).236 Further trials are required to con-
firm this neuroprotective benefit resulting from steroid expo-
sure in adult aortic arch repair with CPB and HCA.
NEUROPROTECTIVE STRATEGIES:
THORACOABDOMINAL AORTIC REPAIR
The protection of the spinal cord from ischemia during thor-
acoabdominal interventions is based on a multimodal neu-
roprotective strategy (Table 22.11).205,206 The main four
strategies are early clinical recognition, maximizing spinal
cord perfusion pressure, minimizing spinal cord ischemic
time, and extending spinal cord tolerance of ische-
mia.196,197 Each of these major strategies will now be
explored in more detail.
Early Recognition of Spinal Cord Ischemia
Intraoperative neuromonitoring. Given the high risk
and outcome importance of spinal cord ischemia during dis-
tal aortic interventions, intraoperative neurophysiologic
monitoring of spinal cord function is important to facilitate
early recognition and allow prompt intervention. There are
two types of widely used monitoring techniques: somatosen-
sory evoked potentials and motor evoked potentials.205,206
The former involves electrically stimulating a peripheral
nerve and measuring the resultant activity within the
somatosensory cortex via scalp electrodes, and the latter
consists of measuring muscle activity after transcranial
stimulation of the motor cortex.225 The anesthetic tech-
nique must be adapted to minimize anesthetic interference
with this neuromonitoring modality.205,206,225 Although
spinal cord ischemia reduces the electrical amplitudes in
both modalities, their sensitivities and specificities of these
modalities may or may not be complementary.237,238 The
decision of which type(s) of neuromonitoring to use varies
amongst high-volume institutions.205,206 Although motor
evoked potentials are more sensitive to spinal cord gray
matter injury, their application has not clearly improved
neurological outcomes after thoracoabdominal aortic
interventions.196,197,205,206,237,238
Table 22.11 Multimodal neuroprotective strategies in
thoracoabdominal aortic repair.
Early recognition of spinal cord ischemia
▪ Intraoperative neuromonitoring
▪ Fast-track emergence concept
▪ Serial neurological assessment by protocol
Maximizing spinal cord perfusion pressure
▪ Permissive systemic hypertension
▪ Cerebrospinal fluid drainage
▪ Segmental spinal artery preservation
Minimizing spinal cord ischemic time
▪ Sequential aortic clamping
▪ Staged aortic reconstruction
▪ Preservation of proximal/distal aortic flow with left heart bypass
Extending ischemic tolerance
▪ Deliberate mild hypothermia
▪ Optional deep hypothermic circulatory arrest
▪ Epidural cooling
▪ Pharmacologic agents
326 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Postoperative neuromonitoring. While the intraopera-
tive detection of spinal cord ischemia relies on high-quality
monitoring of evoked potentials under general anesthesia,
postoperative detection relies on serial assessment of the awake
patient after emergence from general anesthesia.196,197 There-
fore, the fast-track concept has also been advocated in thora-
coabdominal interventions to facilitate prompt emergence
from general anesthesia for detailed neurological assessment
in a serial and standardized fashion.205,206 Furthermore,
this postoperative neurosurveillance has also been incorpo-
rated into protocolized care to link high-quality recognition
of spinal cord ischemia with prompt spinal cord intervention
and rescue outlined later in this section.205,206,239
Maximizing Spinal Cord Perfusion Pressure
In addition to detailed neuromonitoring for early recognition
of spinal cord ischemia, there are several perioperative inter-
ventions that can help to reduce its incidence during thora-
coabdominal aortic interventions by maximizing the spinal
cord perfusion pressure.205,206 Given that spinal cord perfu-
sion pressure equals the difference between the mean sys-
temic arterial pressure and the cerebrospinal fluid pressure,
these interventions can target either raising the systemic
blood pressure or reducing cerebrospinal fluid pressure.
Permissive systemic hypertension. As outlined by for-
mula for spinal cord perfusion pressure, a prompt interven-
tion to improve spinal blood supply is to increase the
systemic mean arterial pressure to the 80–100 mmHg with
titrated volume expansion and vasopressor infusion. This
perioperative target can be prompted by early recognition
of spinal cord ischemia as outlined earlier as part of multi-
modal intervention to rescue the spinal cord.205,206,239
Cerebrospinal fluid drainage. In addition to increasing
the mean arterial pressure, spinal cord perfusion pressure
can be augmented by decreasing cerebrospinal fluid pres-
sure via titrated drainage. This drainage is typically accom-
plished through the placement of a specialized catheter into
the low lumbar (often L4–L5) intrathecal space to remove
CSF actively and to target a perioperative cerebrospinal fluid
pressure of 10–15 mmHg.205,206,239 The significant reduc-
tion in spinal cord ischemia with this intervention has been
validated in multiple trials.240,241 As a result of this, CSF
drainage is a class I recommendation for patients receiving
open thoracoabdominal repair.196,197,205,206
The complications of this procedure have an incidence of
approximately 1% and include intracranial hypotension,
subdural or intracerebral hematoma, spinal headache, per-
sistent CSF leak, intraspinal hematoma, meningitis, and
catheter fracture.205,206 These risks can be minimized with
a perioperative protocol that includes monitoring CSF pres-
sure, intermittent rather than continuous CSF drainage,
limiting drainage volume to 25 mL/h, and routine monitor-
ing of coagulation function at the times of drain insertion
and removal.205,206,239
Segmental spinal artery preservation. A surgical tech-
nique for maximizing perfusion pressure of the spinal cord
arterial network is the reimplantation of intercostal
and/or lumbar spinal arteries during open repairs.196,197
The final decision of the extent of intraoperative preservation
of segmental spinal arterial supply depends on multiple fac-
tors, including extent of bleeding, vessel quality, and surgical
experience.205,206 In nearly 25% of patients, the majority of
the segmental spinal arteries are occluded as a result of pre-
existing vascular disease.196,197,205,206 A recent large clinical
trial (N¼ 1096: 2001–2014) demonstrated that in open
thoracoabdominal interventions ligation of the 8th to 12th
intercostal arteries was independently associated with spinal
cord ischemia (odds ratio 1.3/artery; 95% confidence interval
P< 0.41).242 The critical importance of these segmental
arteries is probably explained by the fact they commonly give
rise to the artery of Adamkiewicz, the largest thoracolumbar
segmental arterial supply to the spinal cord arterial network
(Fig. 22.8).196,197,205,206
Minimizing Spinal Cord Ischemic Time
A segmental approach to distal aortic reconstruction offers
multiple advantages, including graded exposure of the spi-
nal cord to the total ischemic insult.205,206 This can be
accomplished during a given open thoracoabdominal repair
by sequential aortic clamping to facilitate segmental resec-
tion with subsequent reconstruction and reperfusion at that
aortic level.205,206 Furthermore, intermittent delay between
distal aortic reconstruction procedures also appears to
pose no additional risk to the spinal cord, despite the con-
cern about greater sacrifice of the spinal cord arterial
network.196,197,243 This suggests that this dynamic arterial
network can recover and develop perfusion reserve
over time.
Another major surgical method to minimize the ische-
mic time for the spinal cord has been the maturation of left
heart bypass in open thoracoabdominal reconstruc-
tion.205,206 This perfusion technique allows adequate pres-
surized arterial perfusion both proximal and distal to the
clamped aortic segment to preserve cephalad and caudad
arterial supply to the spinal cord arterial network during
distal aortic reconstruction (Fig. 22.8).196,197,205,206
These advantages have established this perfusion approach
at high-volume centers around the world as part of a mul-
timodal approach to protect the spinal cord perioperatively
(Table 22.11).205,206,244
Extending Spinal Tolerance of Ischemia
The major mechanism for inducing ischemic tolerance in
the spinal cord is deliberate hypothermia to some extent
during aortic repair.205,206 Although mild hypothermia is
commonly utilized, HCA with deep hypothermia has also
been established as a surgical technique for safe distal aortic
reconstruction in experienced centers.245,246
Epidural cooling has also been proposed to reduce spinal
cord ischemia during open thoracoabdominal intervention
by reducing spinal cord oxygen demand and thus increasing
spinal cord tolerance of ischemia.247 This can be accom-
plished by the insertion of a low thoracic epidural catheter
through which iced saline is infused to achieve an intrao-
perative spinal temperature of 25–28°C.247 While this tech-
nique has been associated with reduced SCI compared with
historical controls, its application has raised concerns about
contamination and spinal cord edema.247 Although this
technique has undergone further investigation, it has not
been widely adopted at high-volume thoracic aortic
centers.197,198,205,206,247
 22 • Protecting the Central Nervous System During Cardiac Surgery
Over the years, many pharmacologic interventions have
been evaluated in efforts to reduce spinal cord ischemia dur-
ing thoracoabdominal aortic intervention.205,206 While
there is weak evidence for many agents, steroids are com-
monly considered in this complex operative setting.205,206
A recent observational trial has also suggested a neuropro-
tective role for intrathecal papaverine.248
Thoracic Endovascular Aortic Repair
Thoracic endovascular aortic repair (TEVAR) with a stent
graft has become an established technique for aneurysms
and dissections of the descending thoracic and thoracoab-
dominal aorta.196,197 While TEVAR still sacrifices the seg-
mental spinal arteries in the covered aortic segment, it
avoids the temporary reduction in flow that occurs with
aortic clamping, as well as the significant hypotension,
blood loss, and fluid shifts that accompany open
repair.197,198,205,206 As a result, the risk of spinal cord ische-
mia after TEVAR is typically significantly lower than for an
equivalent open repair.205,206,249 Furthermore, while cere-
brospinal drainage is a mainstay of open repairs, its applica-
tion in the conduct of TEVAR is typically reserved for high-
risk patients, including the onset of delayed paraplegia in the
postoperative period.250, 251
An important risk factor of spinal cord ischemia after
TEVAR is coverage of the left subclavian artery with the stent
graft resulting in loss of cephalad input to the spinal cord arte-
rial network.205,206,252,253 Left carotid to subclavian bypass
grafting before TEVAR can reduce this risk significantly and
has therefore become a preferred management strategy to
preserve this flow from the left subclavian artery.252,253
Conclusions
Neurological injury after adult cardiac surgery with CPB
remains an important complication. The risk factors and eti-
ologies are extensively understood, as summarized in
Tables 22.1 and 22.2. The neuroprotective strategy in this
setting is multimodal, as summarized in Table 22.3. Future
trials will probably advance the protection of the central
nervous system in this setting through ongoing evaluation
of medical and mechanical interventions.
During off-pump CABG it is clear that emboli still migrate
to the cerebral circulation and a systemic inflammatory
response still occurs. Technological advances in cardiac sta-
bilization and proximal anastomosis devices can enable a
clampless technique with some neurologic benefit. Further-
more, the development of complete aortic no-touch tech-
niques have shown promising results in reducing
perioperative neurologic injury. In the end, the skill of the
heart team in performing off-pump CABG, specifically the
better outcomes at high-volume centers, must be taken into
account in the decision-making process. The risk of neuro-
logical injury after off-pump CABG is markedly increased
after intraoperative conversion to on-pump CABG for mul-
tiple reasons, including hemodynamic instability and the
addition of CPB.
Because TAVR will probably include low-risk patients in
the near future, the importance of neuroprotection is even
greater. With the advent of the newer generations of trans-
catheter aortic valves and increased operator experience,
the risks of neurological injury have steadily decreased.
327
The multifactorial etiologies for stroke after TAVR can be
related to the patient and/or the procedure. Neuroprotective
strategies should be integrated into the protocol-driven peri-
operative conduct of the procedure in the preoperative,
intraoperative, and postoperative phases of care. Embolic
protection devices will undoubtedly further enhance the
neuroprotective approach in TAVR, especially as the devices
mature in the years ahead.
As highlighted previously, a significant risk factor for neu-
rologic injury during surgery on the ascending aorta is cere-
bral atheroembolism. Epiaortic scanning is safe, effective, and
reliable for intraoperative assessment of atheroma severity to
guide aortic manipulation. It is reasonable to perform epiaor-
tic ultrasound in this setting, especially in high-risk patients
with a significant atheroma burden suggested by clinical
assessment. Although embolic protection with specially
designed aortic cannulae appears effective, larger clinical
trials are required to assess the outcome benefits further.
Surgical intervention for aortic arch and thoracoabdom-
inal repair has unique mechanisms of neurologic injury that
must be addressed in the anesthetic and surgical plan. Aor-
tic arch repair is typically performed with HCA with/with-
out selective cerebral perfusion to anchor a multimodal
neuroprotective strategy in this setting. An axillary arterial
cannulation strategy for complex aortic surgery confers sig-
nificant neuroprotection, including aortic arch repair
with HCA.
The conduct of aortic arch repair with HCA, including the
choice of cerebral perfusion adjuncts, has ongoing varia-
tions because of persistent gaps in the evidence. The emerg-
ing new paradigm in this setting is HCA with moderate
hypothermia and antegrade cerebral perfusion. This para-
digm has also been embedded in a multimodal team-based
strategy to maximize neuroprotection.
The development of spinal cord ischemia is an important
complication of aortic repair distal to the aortic arch. As
such, the surgical procedure should be planned carefully
to minimize this risk with a focus on the current concepts
of the spinal cord arterial network and spinal cord perfusion
pressure. The perioperative practice of spinal cord protection
in this setting is multimodal, including the strategies of early
recognition, maximizing perfusion pressure, minimizing
ischemic time, and inducing ischemic tolerance. The para-
digm shift towards TEVAR for thoracoabdominal aortic dis-
ease has steadily reduced the risk for spinal cord ischemia in
the setting of a multimodal neuroprotective strategy for all
these procedures. Although cerebrospinal fluid drainage is a
standard of care for open distal aortic repair, it is reserved for
high-risk patients in the conduct of TEVAR. Given the
advantages associated with TEVAR, it is likely that this sur-
gical intervention will continue to influence perioperative
aortic practice, especially with advances in stent design that
have targeted the aortic arch and ascending aorta.
Although continuous innovation will continue to advance
the practice of aortic surgery and stenting, protection of the
brain and spinal cord will remain a clinical priority that
requires further high-quality randomized trials to inform
neuroprotective strategies in the future. The Neurological
Academic Research Consortium has proposed a set of clinical
endpoints for these future trials (Fig. 22.9). This neurological
matrix will undoubtedly facilitate clarity in the journey
toward optimal protection of the central nervous system in
cardiac surgery.
328 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Safety trials Effectiveness trials

Symptom-driven Protocol required
imaging imaging

Serial neurologic + Serial neurologic +

delirium assessments delirium assessment

DWI +
DWI+
Serial cognitive Serial detailed
mic screening cognitive screening
he
Isc troke
s
/
ral d
1

reb noi
Type

Ce rach age
ba rh
Overt injury su mor
he ry
inju
oxic
p
Hy

DWI –

DWI –
T/A

Symptoms um
liri
De
3

without injury
Type

DWI+
Evaluate for subclinical
dysfunction,
n
ctio long-term cognitive changes,
ra and quality
inf
S
CN
e
ag
rh
or

Covert injury
2

em
Type

H
S
N
C

Fig. 22.9 Neurological events in cardiovascular clinical trials. (Reprinted from: Lansky AI, Messe SR, Brickman AM, et al. Proposed standardized neurological
endpoints for cardiovascular clinical trials: an academic research consortium initiative. J Am Coll Cardiol 2017;69:679-691.)

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 23 Preservation of Spinal Cord
Function
KIRSTEN R. STEFFNER and ALBERT T. CHEUNG
Introduction
Acute spinal cord injury (SCI) is a devastating medical con-
dition because of the impact of permanent disability pro-
duced by paraplegia or quadriplegia. Treatment of the
initial injury and reintegration of the injured patient into
society place a large burden on health-care systems and
society as a whole. Furthermore, acute SCI is particularly
taxing from an emotional standpoint, because the patient
often remains fully aware of the disability and the health-
care team recognizes that most injuries are permanent
and refractory to medical treatment. For these reasons,
efforts aimed at the preservation of spinal cord function
are primarily focused on the prevention of injury. Once
injury has occurred, treatment is largely supportive.
SCI can be classified according to etiology as ischemic,
toxic, or mechanical. The underlying mechanisms of spinal
cord injury can be further categorized into primary versus
secondary mechanisms. Primary mechanisms of injury
include immediate neuronal cell death from infarction,
exposure to toxic substances, or direct mechanical forces
(e.g., contusion, shear, laceration, distraction, or compres-
sion). Primary mechanisms of injury may also be a conse-
quence of direct injury to blood vessels, glial cells, or the
vertebral column necessary for spinal cord function. Sec-
ondary mechanisms of injury are more complex and are
the consequence of biochemical, cellular, and pathophysio-
logic responses to the primary injury. Secondary mecha-
nisms exacerbate the initial injury by way of
inflammation, apoptosis, intracellular protein synthesis
inhibition, glutaminergic dysfunction, electrolyte shifts,
neurotransmitter derangements, vascular changes, edema,
and loss of energy metabolism.1 Secondary mechanisms
result in the eventual death (over the course of days to
weeks) of an additional population of neuronal or glial cells
that had initially survived the primary injury. Finally, spinal
cord injuries can be further characterized as complete or
incomplete based on the total absence or partial presence
of neurologic function below the level of the injury.
Classifying spinal cord injuries according to underlying
etiology and mechanism is important because it highlights
potential targets for medical intervention. Ischemic injuries
may be prevented, limited, or treated by strategies directed
at improving spinal cord perfusion. The severity of mechan-
ical injuries may be abated by surgical stabilization or
decompression. Medical therapies aimed at limiting second-
ary mechanisms of injury, often referred to as neuroprotec-
tion strategies, can be instituted after the primary injury has
occurred with the aim of preventing further cell death and
functional disability. In theory, preserving even a small
quantity of functioning neuronal structures can result in
marked differences in rehabilitation potential. However,
the available evidence supporting the effectiveness of neuro-
protection strategies remains controversial.
Traumatic Spinal Cord Injury
The global incidence of traumatic SCI was approximately 23
cases per million persons (179,312 cases per year) in 2007.2
The reported incidence of traumatic SCI in the United States
alone ranged from 25 to 59 cases per million persons
(12,400 cases per year) in 2010.3 The average age at the
time of injury is 37.1 years. The large majority of new trau-
matic SCI cases are a result of falls, motor vehicle accidents,
and injury secondary to firearms.4 The rate of acute in-
patient mortality after traumatic SCI was 7.5% between
2010 and 2012. Survival is predicted by the patient’s age,
level of spinal cord injury, and severity or grade of cord syn-
drome. Compared with patients with T1–S5 spinal cord
injuries, patients with C1–C4 injuries had a 3.27 times
greater odds of first-year mortality, and patients with C5–
C8 injuries had a 2.30 times greater odds of first-year mor-
tality.5 The large majority of deaths occurring within the
first year post-injury are the result of cardiovascular or
respiratory complications.5 The cumulative expense of
direct medical care over the lifetime of one SCI patient
ranges from 500,000 to 2 million US dollars.1
The primary injury in SCI accounts for the majority of
subsequent neurologic dysfunction. However, the amount
of dysfunction occurring from secondary injury may also
be clinically significant, and the prevention of secondary
injury may be critical for long-term outcome.6 The
approach to the prevention of secondary injury after trau-
matic SCI includes stabilization of cardiovascular and pul-
monary function, immobilization of the spine,
determination of the level and extent of injury, initiation
of pharmacologic neuroprotection strategies, and surgical
stabilization of the spine.
The highest management priority in traumatic SCI is car-
diopulmonary resuscitation and medical stabilization of the
patient because the maintenance of adequate perfusion
pressure and oxygen delivery to the injured spinal cord
may be critical in preventing secondary ischemic injury.
Management goals in the immediate post-injury period
are to ensure an adequate airway, ventilation, oxygenation,
and blood pressure without worsening the spinal cord
injury. Supplemental oxygen should be administered and
335
336 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
an airway established with the head and neck immobilized
in a neutral position. The treatment of airway compromise
in a patient with suspected traumatic SCI is challenging
because it is difficult to prevent movement of the cervical
spine during emergency maneuvers to establish a patent
airway.7,8 All airway maneuvers cause some amount of cer-
vical spine movement. However, the degrees of movement
are often small and the contribution of these movements
to secondary injury is not clearly established. In a patient
with evidence of airway obstruction and hypoventilation,
the jaw-thrust maneuver should be tried initially. This
maneuver is performed by placing the palms of both hands
on either side of the patient’s head to provide in-line stabi-
lization of the neck and using the first two or three fingers
of each hand to lift the mandible forward and outward,
without extending the cervical spine. The jaw-thrust
maneuver can be combined with the use of an oral or naso-
pharyngeal airway or used to facilitate mask ventilation
(Fig. 23.1).
If ventilation is inadequate, tracheal intubation should be
performed with the two-person orotracheal or nasotracheal
technique. The two-person technique requires one rescuer
to provide manual in-line immobilization of the head and
neck while the other rescuer performs tracheal intubation.9
Manual in-line immobilization is performed by cradling the
occiput in the palms of the hands and gently applying forces
that are equal and opposite to those being applied during
laryngoscopy and tracheal intubation, with the goal of keep-
ing the head and neck in a neutral position. It is important to
avoid traction of the neck during manual in-line immobili-
zation because it could cause distraction of the spine at the
site of injury. If time permits and equipment is available, tra-
cheal intubation can be performed using fiberoptic broncho-
scopic techniques instead of direct laryngoscopy to decrease
the risk of spinal movement. However, if the airway is not
adequately topicalized during fiberoptic bronchoscopy, sub-
sequent coughing may lead to increased motion of the spine.
Moreover, visualization by fiberoptic bronchoscopy can be
challenging in the presence of secretions, blood, or emesis.
Ultimately, outcome data are lacking that demonstrate
the advantage of any specific technique for tracheal intuba-
tion.9 If an airway cannot be established by oral or nasotra-
cheal intubation, emergency cricothyroidotomy should be
considered.
Blood pressure should be measured and treatment
directed to maintain a mean arterial pressure (MAP) in
the range of 85 to 90 mmHg during the first week after trau-
matic injury.10,11 Hypotension associated with traumatic
SCI may be caused by hypovolemic or neurogenic shock
with sympathetic denervation. The etiology of hypotension
should be determined and treated with intravascular vol-
ume expansion, vasopressor therapy, or inotropic medica-
tions. Expert opinion, observational studies, and published
clinical guidelines support the treatment of hypoxia and
hypotension to lessen secondary ischemic injury and to
improve outcomes after acute traumatic SCI.6,12,13
After initial resuscitation of the patient with suspected
acute traumatic SCI, the next priority is immobilization of
the head, neck, and body until radiographic assessment
for spinal fracture can be performed. Optimally, immobiliza-
tion should be performed concurrently with resuscitation,
but there may need to be a compromise if it interferes with
efforts to reestablish cardiopulmonary function or treatment
of other immediately life-threatening injuries. The entire
spine, including the cervical spine, should be immobilized
if the site of injury is not known. Clinical indications for
immobilization of the spine include trauma from motor vehi-
cle accidents, diving accidents, or acceleration–deceleration
injuries that have a high risk of associated spinal cord injury.
Indications for immobilization also include physical signs of
tenderness along the posterior spine, decreased cervical
range of motion, pain with motion, neurologic deficits,
deformities, or decreased level of consciousness prohibiting
neurologic examination.9
The first step in immobilization is manual stabilization of
the head without applying traction until the application of
an appropriate-sized rigid or semi-rigid cervical collar. The
patient can then be log-rolled with the spine in a neutral
position onto a rigid spine board. The body is positioned
on the board with the arms straightened with the palms
Fig. 23.1 The jaw thrust maneuver using the first
two or three fingers of each hand to lift the mandible
forward and outward (arrow) to establish an airway.
The head and neck are immobilized in a neutral
position to prevent injury to the spinal cord in
patients with suspected cervical spine injuries.
 23 • Preservation of Spinal Cord Function 337

against the body and the legs straightened with the ankles 1. Any high-risk factor that
secured to each other with padding between them. Straps mandates radiography?
are applied to the lower extremities, the pelvis, and then the
trunk, in that order, to secure the body snugly against Age 65 years
the board. Tape is then applied across the forehead and the or
Dangerous mechanism1
cervical collar to prevent head and neck movement. Wedges or
or a lightweight head block provide additional stability to pre- Paresthesia in extremities
vent lateral movement of the head and neck. If there is obvious
deformity of the spine, immobilization should be modified to No
maintain a neutral position of the deformity. Yes
The objective of immobilization is to maintain the spine in 2. Any low-risk factor that
a neutral position. Neutral position can be defined as the allows safe assessment of
normal anatomic position of the head and torso when stand- range of motion?
ing and looking straight ahead.14 Achieving a neutral cer-
vical spine position in adults requires elevating the occiput Simple rear-end MVC2
or
approximately 2 cm above the spine board.15 The occipital Sitting position in ED
No
Radiography
elevation distance may need to be greater than 2 cm in or
patients with truncal obesity. In contrast, achieving a neu- Ambulatory at any time
tral cervical spine position in children on a spine board may or
require elevating the back and shoulders to accommodate a Delayed onset of neck pain3
relatively larger head.16 or
The proper radiographic evaluation of a patient with sus- Absensce of midline C-spine
tenderness
pected SCI varies based on the availability of imaging modal-
ities, level of consciousness, and the presence of systemic or Unable
neurologic deficit. The most conservative approach would Yes
be to require immobilization until radiologic evaluation of
the patient is obtained. However, two sets of criteria have 3. Able to actively rotate
neck?
been developed to identify low-risk patients who do not
require radiographic clearance. The National Emergency 45 degrees left or right
X-Radiography Utilization Study (NEXUS) identified five cri-
teria that must be met in order to exclude patients from Able
radiologic evaluation: lack of midline cervical tenderness,
lack of neurologic deficits, normal consciousness, no intox- No radiography
ication, and lack of significant systemic injuries that affect
the ability to examine the patient adequately
(Table 23.1). This decision tool demonstrated a 99.8% neg- 1Dangerous mechanism includes: 1) fall from ≥1M or 5 stairs, 2) axial load to
ative predictive value for cervical spine injury (99% sensitiv- head (e.g. driving), 3) MVC at high speed (>100 km/h), rollover, or ejection,
ity, 12.9% specificity).17 The Canadian C-Spine Rule for or motorized recreational vehicles, 4) bicycle collision.
Radiography (CCSRR) after trauma examined only alert 2Simple rear-end MVC excludes: 1) pushed into on-coming traffic, 2) Hit by
and medically stable patients. The decision to image the cer- large bus or truck, 3) rollover, 4) hit by high speed vehicle.
3Delayed:
vical spine was based on whether the patient had any high- onset of neck pain is not immediate
risk factors (age greater than 65 years, paresthesia, mecha- Abbreviations: ED = Emergency Department, MVC = Motor Vehicle Collision.
nism of injury) or low-risk factors (simple rear-end motor
vehicle collision, sitting position in emergency department, Fig. 23.2 The Canadian C-Spine Rule for Radiography (CCSRR) is a
clinical protocol that had a 100% sensitivity and 42.5% specificity for
ambulatory at any time since injury, delayed onset of neck identifying clinically significant cervical spine injuries in alert and
pain, or absence of midline cervical spine tenderness) for medically stable trauma patients. (Hoffman JR, Mower WR, Wolfson AB,
injury, followed by the ability to rotate the head actively et al: Validity of a set of clinical criteria to rule out injury to the cervical spine
45 degrees to the right and to the left (Fig. 23.2). This study in patients with blunt trauma. National Emergency X-Radiography Utili-
zation Study Group. N Engl J Med 2000;343(2):94-99.)

Table 23.1 The National Emergency X-Radiography Utiliza-

tion Study (NEXUS) low risk criteria for cervical spine injury in demonstrated 100% sensitivity and 42.5% specificity for
trauma patients. identifying clinically significant cervical spine injuries in
Cervical-spine radiography is clinically indicated for patients with
8924 patients.18 Patients with potential cervical spine
trauma unless all of the following criteria are met: injury who meet both the NEXUS and CCSRR criteria can
have spinal precautions relaxed and their cervical spines
1. No posterior midline cervical tenderness cleared without radiologic evaluation.
2. No evidence of intoxication In patients with suspected cervical spinal injury based on
3. A normal level of alertness
4. No focal neurologic deficit NEXUS and CCSRR criteria, radiographic evaluation begins
5. No painful distracting injuries with a three-view cervical series (lateral, anteroposterior,
and odontoid). When done with adequate technique,
338 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
three-view cervical spine plain films have a sensitivity for
detecting injury approaching 90%.9 A large percentage of
cervical spine films are inadequate because of lack of visual-
ization of the craniocervical and cervical-thoracic junction.
The combination of cervical spine radiographs and supple-
mental computed tomography (CT) through the areas that
are poorly visualized increases negative predictive values to
99% (Fig. 23.3). Clearance in the awake and neurologically
normal patient is then completed by moving the neck
actively and evaluating for pain. In a patient who cannot
be evaluated clinically but is at high risk of a cervical frac-
ture, the three-view cervical series, supplemented by high
resolution CT imaging, reduces the risk of missing a fracture
to less than 1%.9 In patients who have normal plain films
and cervical CT imaging, but who are suspected of having
spinal cord injury (e.g., presence of neurologic deficits or cer-
vical pain), magnetic resonance imaging (MRI) should be
considered for clearance.19,20 The benefit of MRI in the eval-
uation of traumatic SCI is not well defined, but it may help to
identify occult ligamentous injury, disc herniation, or epidu-
ral hematoma.
Guidelines for performing a detailed neurologic assess-
ment for spinal cord injury have been developed by the
American Spinal Injury Association (ASIA).21 Testing for
sensation is performed in response to pinprick and light
touch over each of the 28 dermatomes (C2 to S4–5) on both
the right and left sides of the body. Sensation to light touch
and pin prick is scored as 2 (normal), 1 (altered), or 0
(absent), compared with sensation on the patient’s cheek
Fig. 23.3 Traumatic C4 vertebral body fracture demonstrating the fracture through the vertebral body (arrows). (A) Lateral plain film, (B) axial computed
tomography (CT) scan, and (C) sagittal CT scan.
as the normal frame of reference. The sensory level is defined
by the most caudal dermatome with normal sensation.
Motor function is examined by testing key muscle functions
corresponding to 10 paired myotomes (C5–T1 and L2–S1).
Strength is rated on a six-point scale ranging from 0 to 5,
with 0 indicating total paralysis and 5 indicating full
strength against resistance. The motor level is defined by
the lowest key muscle function with a grade of at least 3
(anti-gravity function). This standardized neurologic exam-
ination and the ASIA scale has been shown to correlate with
clinical outcomes and therefore can be used to stratify
patients according to the severity of neurologic injury
(Fig. 23.4).22 Deep anal pressure awareness (innervated
by the somatosensory components of the pudendal nerve
from S4–5) is evaluated by applying gentle pressure to the
anorectal wall. The external anal sphincter (innervated by
the somatic motor components of the pudendal nerve from
S2–4) is evaluated by the absence or presence of reproduc-
ible voluntary contractions around the examiner’s finger.
Pharmacologic therapies for the treatment of acute SCI
have shown little benefit.23 The corticosteroid methylpred-
nisolone has been the most extensively studied pharmaco-
logic agent for SCI. Its mechanism of action is thought to
involve reduction of cord edema, support of energy metab-
olism, anti-inflammatory properties, membrane stabiliza-
tion, antioxidant effects, and free-radical scavenging.24,25
There is controversial class I clinical evidence to support
its use in SCI.6 This controversy has arisen over several large
clinical trials. The first National Acute Spinal Cord Injury
 INTERNATIONAL STANDARDS FOR NEUROLOGICAL Patient Name Date/Time of Exam
CLASSIFICATION OF SPINAL CORD INJURY
Examiner Name Signature
(ISNCSCI)

MOTOR SENSORY SENSORY MOTOR

RIGHT KEY MUSCLES KEY SENSORY POINTS
Light Touch (LTR) Pin Prick (PPR)
KEY SENSORY POINTS
Light Touch (LTL) Pin Prick (PPL)
KEY MUSCLES LEFT
C2
C2 C2
C3 C3
C4 C2
C4
C3
C3
C5 C5
UER Wrist extensors C6 C4 C4

T2
C6 Wrist extensors UEL
(Upper Extremity Right) C7 Elbow extensors (Upper Extremity Left)
Elbow extensors C7 T3
C5
T4
C8 T5
C8
T1 T6 T1
T7
T2 T2

C8
Comments (Non-key Muscle? Reason for NT? Pain? T8 MOTOR

C6

C7
Non-SCI condition?): T3 T9 T1 T3 (SCORING ON REVERSE SIDE)
Dorsum
T4 T10 C6
T4 0 = Total paralysis
T11 1 = Palpable or visible contraction
T5 T5 2 = Active movement, gravity eliminated
T12
T6 L1 T6 3 = Active movement, against gravity
4 = Active movement, against some resistance
T7 Palm T7 5 = Active movement, against full resistance
T8 S3
T8 NT = Not testable
0*, 1*, 2*, 3*, 4*, NT* = Non-SCI condition present
T9 Key Sensory T9
L2
Points
T10 S4-5
T10 SENSORY
(SCORING ON REVERSE SIDE)
T11 L T11 0 = Absent NT = Not testable
2
T12 L L3 T12 1 = Altered 0*, 1*, NT* = Non-SCI
S2 3 2 = Normal condition present
L1 L1
L2 L2
LER Knee extensorsL3 L3 Knee extensors LEL
L4
(Lower Extremity Right) L4 L4 (Lower Extremity Left)
L5
Long toe extensors L5 L
4 L5 Long toe extensors
S1 S1 S1
L5
S2 S2
S3 S3
(VAC) Voluntary Anal Contraction (DAP) Deep Anal Pressure
(Yes/No) S4-5 S4-5 (Yes/No)
RIGHT TOTALS LEFT TOTALS
(MAXIMUM) (50) (56) (56) (56) (56) (50) (MAXIMUM)
MOTOR SUBSCORES SENSORY SUBSCORES
UER +UEL = UEMS TOTAL LER + LEL = LEMS TOTAL LTR + LTL = LT TOTAL PPR + PPL = PP TOTAL
MAX (25) (25) (50) MAX (25) (25) (50) MAX (56) (56) (112) MAX (56) (56) (112)

NEUROLOGICAL R L 4. COMPLETE OR INCOMPLETE? (In injuries with absent motor OR sensory function in S4-5 only) R L
3. NEUROLOGICAL 6. ZONE OF PARTIAL SENSORY
LEVELS 1. SENSORY Incomplete = Any sensory or motor function in S4-5
LEVEL OF INJURY
2. MOTOR (NLI) 5. ASIA IMPAIRMENT SCALE (AIS) PRESERVATION MOTOR
as on reverse Most caudal levels with any innervation

REV 04/19
This form may be copied freely but should not be altered without permission from the American Spinal Injury Association.
Fig. 23.4 Guidelines from the American Spinal Injury Association illustrating their comprehensive system for scoring the severity and extent of motor and sensory dysfunction after spinal cord injury. (Reproduced with
permission from American Spinal Injury Association, 2011, with permission. Available at www.asia-spinalinjury.org/home/index.html. # 2020 American Spinal Injury Association. Reprinted with permission).
Continued
Fig. 23.4—cont’d

Studies (NASCIS) trial in 1984 randomized 330 patients to
either high or low dose methylprednisolone every 6 hours
for 10 days. There was no placebo arm in NASCIS I. The trial
demonstrated a statistically significant increase in wound
infections, but no difference in motor or sensory clinical out-
comes between the two treatment groups.26
The landmark NASCIS II study in 1990 was a double-
blind, controlled, multicenter trial in which 487 patients
were randomized into one of three treatment arms: (1)
methylprednisolone 30 mg/kg bolus followed by 5.4 mg/
kg/h for 23 hours; (2) naloxone 5.4 mg/kg bolus followed
by 0.5 mg/kg/h for 23 hours; or (3) placebo. The NASCIS
II trial showed no difference in clinical outcomes at 1 year,
although a secondary analysis demonstrated that patients
given methylprednisolone within 8 hours of injury had a
statistically significant improvement in their motor scores
compared with study patients who received methylprednis-
olone after 8 hours.27
The NASCIS III trial in 1997 was a multicenter study in
which patients who presented within 8 hours of acute trau-
matic SCI received a bolus dose of methylprednisolone (30
mg/kg) and were then randomized into one of three treat-
ment arms: (1) methylprednisolone 5.4 mg/kg/h for
24 hours; (2) methylprednisolone 5.4 mg/kg/h for 48 hours;
or (3) tirilazad mesylate (an inhibitor of lipid peroxidation)
2.5 mg/kg every 6 hours for 48 hours. The trial showed
no significant improvement in any of the primary outcome
measures at 1 year. However, secondary analysis demon-
strated that in patients who started treatment more than
3 hours after injury, 48 hours of methylprednisolone was
associated with an improvement in motor function at both
6 weeks and 6 months compared with 24 hours of methyl-
prednisolone treatment.28
Methylprednisolone was associated with a higher compli-
cation rate in all the NASCIS trials, although mortality was
similar in all treatment groups. Complications included
wound infection, pneumonia, and sepsis. Even though the
NASCIS trials were well-designed, randomized controlled
trials, the validity of the data showing benefit has been
called into question. Primary analyses in all three trials
failed to show significant improvement with methylprednis-
olone therapy in acute SCI. Improved outcomes were only
seen in secondary (and possibly post hoc) analyses. Some
experts argue that such findings, while interesting, are
not sufficient to support a standard of care in the treatment
of patients with acute SCI.29,30 The Consortium for Spinal
Cord Medicine concluded that because of insufficient evi-
dence of clinical benefit, the routine use of methylpredniso-
lone in acute SCI is not recommended.30 If it is used in this
context, methylprednisolone should not be started more
than 8 hours after injury. Methylprednisolone is contraindi-
cated in patients with acute SCI and concurrent traumatic
brain injury (TBI) because corticosteroid therapy has been
shown to be associated with increased mortality in patients
with moderate to severe TBI.31
Other pharmaceuticals studied in randomized clinical tri-
als for SCI (e.g. GM-1 ganglioside, tirilazad mesylate, nalox-
one) have not shown any benefit. Emerging treatments for
acute SCI include therapeutic hypothermia, transplantation
of progenitor or stem cells into the injured spinal cord, neu-
roprotective agents (e.g., riluzole, minocycline, basic fibro-
blast growth factor), and neuroregenerative agents (e.g.,
Cethrin, anti-Nogo).32
23 • Preservation of Spinal Cord Function 341
Surgery for patients who have suffered traumatic SCI can
be considered for stabilization of an unstable spine, to reduce
a deformity, or to decompress neural tissues.12 Surgical sta-
bilization of unstable spine lesions may prevent primary
neurologic injury. Incomplete injuries or progressive neuro-
logic injuries are more likely to benefit from decompressive
surgery for lesions impinging on the spinal cord. Surgery to
relieve a complete neurologic injury is not indicated because
primary cell death has already occurred and reversal of this
deficit will not occur. Most unstable injuries require anterior
and posterior fixation, although some cervical injuries
require anterior discectomy and fusion or posterior fixation
alone. The treatment of vertebral fractures is controversial
and may benefit from conservative treatment with an ortho-
sis. Although they do not result in an unstable spine, verte-
bral burst fractures may require surgery because the lesion
may result in collapse of the vertebral body with time, caus-
ing the loss of anterior height or kyphosis.12 There are no
definitive guidelines regarding the timing (early versus late)
of decompressive surgery. The available evidence supports
early surgery in patients with cervical spine injuries. How-
ever, evidence regarding patients with injury at other spinal
cord levels is limited.33
Paraplegia After Thoracic or
Thoracoabdominal Aortic
Aneurysm Repair
Despite improvements in surgical, anesthetic, and perioper-
ative care, spinal cord ischemia leading to postoperative
paraplegia or paraparesis remains a major cause of morbid-
ity and mortality after open and endovascular repair of des-
cending thoracic and thoracoabdominal aortic aneurysms
(TAAA) (Fig. 23.5). Spinal cord ischemia occurs as a conse-
quence of the temporary or permanent interruption of blood
flow from intercostal and segmental arteries originating
within the diseased segments of the descending thoracic
or thoracoabdominal aorta. Open surgical repair involves
replacement of the diseased segment of the aorta with an
interposition graft that requires the temporary interruption
of blood flow through the aorta and the sacrifice of intercos-
tal and segmental arteries that are not reimplanted within
the replaced segment of the aorta. Endovascular repair does
not require the interruption of blood flow through the aorta,
but instead excludes the intercostal and segmental arteries
that fall within the covered segments of the aorta. After
open surgical or endovascular repair of the thoracic or thor-
acoabdominal aorta, spinal cord perfusion becomes more
dependent on collateral supply from remaining perfused
intercostal and segmental arteries, the vertebral arteries,
and the hypogastric vascular network.
An understanding of the vascular anatomy of the spinal
cord is critical for the prevention, detection, and treatment
of spinal cord ischemia. The blood supply to the spinal cord is
composed of a complex collateral network (Fig. 23.6). The
anterior spinal cord is primarily supplied by the anterior spi-
nal artery, which is formed from the vertebral arteries after
they branch off the subclavian arteries.34,35 The posterior
spinal cord is primarily supplied by the posterior spinal arter-
ies, which are formed from either the vertebral or posterior
inferior cerebellar arteries. As the spinal arteries travel
342 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fig. 23.5 Magnetic resonance images of the thoracolumbar spine demonstrating spinal cord infarction in a patient with paraplegia after thora-
coabdominal aneurysm repair. T2-weighted sagittal imaging through the center of the spinal cord (left) showed central infarction extending from the
high thoracic level into the lumbar segments. T2-weighted axial images of the spinal cord at the thoracic level demonstrated central infarction (right).
Fig. 23.6 The spinal cord has a complex blood supply that comes from
the vertebral arteries, intercostal and segmental arteries, and the
hypogastric vascular network. The spinal cord blood supply varies
among individual patients and is often described as a vascular collat-
eral network.
caudally toward the thoracic and lumbar regions, their con-
tribution to spinal cord perfusion decreases while blood flow
from collateral vessels become increasingly important.36
Collateral flow is derived from arteries originating in the tho-
racic aorta. More specifically, dorsal branches of the poste-
rior intercostal arteries give rise to segmental medullary
arteries that, in turn, give rise to anterior and posterior
radicular arteries. These radicular arteries subsequently
form a network of anastomoses with the anterior and pos-
terior spinal arteries. Anterior radicular arteries and sacral
segmental arteries also provide collateral contributions to
the anterior spinal artery. One large segmental artery in par-
ticular, the arteria radicularis magna that is also known as
the artery of Adamkiewicz, is believed to be a major contrib-
utor of blood supply to the lower two-thirds of the thoraco-
lumbar spinal cord.37,38
The incidence of spinal cord ischemia after thoracic and
thoracoabdominal aortic aneurysm repair ranges between
2.1% and 37.5%.39–46 The most significant risk factors for
spinal cord ischemia are the extent of diseased aorta or
the length of the interposition or endovascular stent graft
(Fig. 23.7).39–44,47,48 Endovascular repair was initially
thought to be associated with a decreased risk of spinal cord
ischemia.47,49 However, subsequent analyses demonstrated
that the lower incidence of spinal cord ischemia was
observed among patients undergoing endovascular repair
of isolated descending thoracic aortic aneurysms. When
patients undergoing endovascular repair were stratified by
extent of their aneurysms, the incidence of spinal cord ische-
mia was comparable to that associated with open surgical
repair.41 Additional risk factors associated with spinal cord
ischemia include proximity of the aneurysm to the artery of
Adamkiewicz, cross-clamp time during open surgical repair,
the number of segmental or intercostal arteries sacrificed
during open surgical repair, perioperative hypotension, or
emergency operations.39,50 Risk factors associated with spi-
nal cord ischemia after endovascular repair include the
length of the endovascular stent graft, left subclavian artery
coverage, coexisting renal dysfunction, iliac artery injury, or
prior distal abdominal aortic operation.44,47,51–53
Intraoperative strategies to prevent, detect, and treat spi-
nal cord ischemia consist of surgical techniques to preserve
vascular collaterals and maintain spinal cord perfusion dur-
ing surgery, anesthetic techniques to decrease the metabolic
demand of the spinal cord, pharmacologic agents to increase
the spinal cord’s tolerance of temporary ischemia, augmen-
tation of spinal cord perfusion, and monitoring of spinal cord
function to permit early intervention (Table 23.2).37 The
original open surgical approach for TAAA repair involved
the “clamp and sew” technique whereby blood flow to the
 23 • Preservation of Spinal Cord Function 343

I II III IV
Fig. 23.7 Crawford classification of thoracoabdominal aortic aneurysms. The risk of paraplegia after surgery correlates with the extent of disease.
(Modified with permission from Coselli JS. Descending thoracoabdominal aortic aneurysms. In: Edmunds LH ed. Cardiac Surgery in the Adult. New York: McGraw
Hill; 1997: 1232.)

cord ischemia was 8% for cross-clamp times less than

Table 23.2 Management strategies to prevent and treat
spinal cord ischemia after thoracoabdominal aortic
30 minutes and up to 27% for cross-clamp times greater
aneurysm repair. than 60 minutes.39,54,55
Partial left heart bypass is a technique that can be used to
DECREASE THE SUSCEPTIBILITY TO SPINAL CORD ISCHEMIA
reduce the duration of spinal cord ischemia in open surgical
▪ Mild to moderate systemic hypothermia repairs. Partial left heart bypass involves redirecting blood
▪ Deep hypothermic circulatory arrest from the left atrium to the distal descending aorta or femoral
▪ Selective epidural hypothermia
▪ Avoid hyperthermia artery using an extracorporeal circuit while both the prox-
▪ Pharmacologic neuroprotection imal and distal segments of the aneurysm are clamped. Per-
MINIMIZE THE DURATION OF SPINAL CORD ISCHEMIA fusion is therefore maintained, at least to the areas proximal
and distal to the aneurysmal segment. The distal aortic
▪ Partial left heart bypass
▪ Sequential aortic clamping and repair cross-clamp can be incrementally advanced toward the dis-
▪ Staged repair tal anastomosis as more proximal segments of the aneurysm
AUGMENT SPINAL CORD PERFUSION AND BLOOD FLOW
are repaired. This sequential advancement of the distal aor-
tic cross-clamp minimizes the length of descending aorta
▪ Lumbar cerebrospinal fluid drainage that is excluded from circulation and thereby minimizes
▪ Arterial blood pressure augmentation
▪ Oversewing back-bleeding segmental arteries the duration of end-organ ischemia. Occlusion or over-
▪ Left subclavian artery revascularization sewing of segmental arteries that back-bleeding into the
▪ Avoid arterial hypotension open aorta may help to prevent vascular steal, because
▪ Avoid venous hypertension back-bleeding indicates the presence of collateral flow to
▪ Avoid anemia
the segmental artery.50
EARLY DETECTION OF SPINAL CORD ISCHEMIA Selective perfusion of mesenteric branch vessels can be
▪ Intraoperative somatosensory evoked potential (SEP) monitoring accomplished via a perfusion circuit with individual
▪ Intraoperative motor evoked potential (MEP) monitoring balloon-tipped catheters. Additionally, reattachment of
▪ Early postoperative serial neurologic examinations intercostal or segmental arteries into the interposition graft
▪ Avoid neuraxial anesthesia
during repair may decrease the risk of spinal cord ischemia.
However, the time required to reattach these vessels may
ultimately prolong the duration of spinal cord ischemia.
descending aorta is temporarily interrupted when a clamp is Moreover, additional vascular anastomoses to the prosthetic
placed across the proximal neck of the aneurysm while the graft may compromise the integrity of the final repair. Sur-
interposition graft is sewn into place. With the “clamp and gical reimplantation of intercostal or segmental arteries is
sew” technique, the risk of spinal cord ischemia is associated not possible during endovascular TAAA repairs. In thoracic
with the duration of aortic cross-clamping. The risk of spinal endovascular aortic repairs (TEVAR) that require exclusion
344 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
of the left subclavian artery by the endovascular stent graft,
preservation of flow to the left subclavian artery may be
achieved by surgical transposition of the subclavian artery
onto the carotid artery or construction of a left subclavian
to carotid artery bypass graft.56 Preservation of the left sub-
clavian artery is thought to be important for spinal cord per-
fusion because its branches that include the vertebral artery
supply the anterior spinal artery.
Clinical evidence to support the efficacy of pharmacologic
neuroprotection strategies for the prevention and treatment
of spinal cord ischemia is limited and cannot be relied upon
alone for spinal cord protection. Despite the absence of defin-
itive evidence, methylprednisolone 1 g intravenously (IV),
mannitol 12.5 to 25 g IV, magnesium 1 to 2 g IV, lidocaine
100 to 200 mg IV, thiopental 0.5 to 1.5 g IV, and propofol
25–75 μg/kg of body weight per minute IV, alone or in com-
bination, have been described and commonly used in clini-
cal protocol as adjuncts for spinal cord protection. The use of
IV naloxone 1 μg/kg of body weight per hour and intrathe-
cal papaverine 30 mg have also been reported as part of an
overall spinal cord protection strategy in several clinical
studies.57,58
Spinal cord perfusion pressure can be estimated as the dif-
ference between systemic MAP and lumbar cerebrospinal
fluid (CSF) pressure. If the CSF pressure cannot be measured,
spinal cord perfusion pressure can be estimated as the differ-
ence between the MAP and central venous pressure (CVP).
Spinal cord perfusion pressure can be increased by decreas-
ing the lumbar CSF pressure with CSF drainage or increas-
ing the MAP with vasoactive drugs. At the same time,
cardiac output should be maintained or augmented to
increase the MAP and to maintain the CVP within a low
or normal range. Drainage of CSF can be achieved by percu-
taneous placement of a silastic catheter into the subarach-
noid space between lumbar spinal processes. The CSF
pressure within the subarachnoid space is transduced via
the lumbar cerebrospinal fluid catheter, and CSF is drained
into a sealed reservoir for a lumbar CSF pressure exceeding
10 mmHg. 59,60 The lumbar CSF drain can be placed pro-
phylactically before open surgical or endovascular repair
or after repair in the setting of delayed onset postoperative
spinal cord ischemia.
Two meta-analyses have been published to assess the effi-
cacy of lumbar CSF drainage. These meta-analyses are
based on 372 published studies, including three randomized
controlled trials involving 289 patients.61,62 The meta-
analysis performed by Cina et al. found an odds ratio (OR)
of 0.35 (P¼ 0.05), indicating that lumbar CSF drainage
was effective for decreasing the risk of paraplegia.61 The
meta-analysis performed by the Cochrane Collaborative
found a pooled OR of 0.48 (95% CI, 0.25–0.92) favoring
the efficacy of lumbar CSF drainage in decreasing the risk
of paraplegia when three randomized controlled trials were
included in the meta-analysis. However, the pooled OR did
not reach significance at a value of 0.57 (95% CI 0.28 to
1.17) when one of the three randomized trials was elimi-
nated for the administration of intrathecal papaverine in
combination with lumbar CSF drainage (using data from
lumbar CSF drainage-only trials). The Cochrane Collabora-
tive ultimately concluded that there was insufficient evi-
dence to support the efficacy of lumbar CSF drainage
alone, but recommended the clinical use of lumbar CSF
drainage as a component of a multimodality approach for
prevention of neurologic injury.62
Since the publication of these two meta-analyses, evi-
dence in favor of lumbar CSF drainage for the prevention
and treatment of spinal cord ischemia has continued to
accumulate for patients undergoing both open surgical
and endovascular repairs. A class I recommendation for
lumbar CSF drainage, as a component of a multimodal
approach in the prevention of spinal cord ischemia and neu-
rologic injury, has been made in the American College of
Cardiology Foundation and American Heart Association
2010 guidelines for the management of patients with tho-
racic aortic disease, the 2014 European Society of Cardiol-
ogy guidelines on the diagnosis and treatment of aortic
diseases, and the European Association for Cardio-Thoracic
Surgery position paper on spinal cord protection during tho-
racic and thoracoabdominal aortic surgery and endovascu-
lar aortic repair.50,63 The safety of lumbar CSF drainage
appears to be acceptable, even in patients exposed to full
anticoagulation for extracorporeal circulation.64 Complica-
tions associated with the technique include subdural hema-
toma,65 intraspinal hematoma,66 remote cerebellar
hemorrhage,67 infection, and catheter fracture.64 The most
serious complications appear to be associated with intracra-
nial hypotension from excessive or rapid drainage of CSF.65
Arterial pressure augmentation by increasing MAP,
alone or in combination with lumbar CSF drainage, to
increase spinal cord perfusion pressure for the prevention
and treatment of spinal cord ischemia has not been tested
by randomized controlled trials, but has received a class
IIa recommendation (benefit >>risk: it is reasonable to per-
form) based on clinical experience from case series, expert
opinion, and physiologic rational.51,59,68 In general, vaso-
pressor agents such as norepinephrine, phenylephrine,
and vasopressin are administered as IV infusions are titrated
to achieve and to maintain a MAP of at least 80 mmHg to
ensure a spinal cord perfusion pressure of 70 mmHg.51,59,69
At the same time arterial pressure is being augmented,
intravascular volume expansion, transfusion, or inotropic
support may be necessary to ensure that the cardiac output
is adequate for perfusion and that the CVP is not elevated. In
clinical practice, the MAP is increased by increments of
5 mmHg based on neurophysiologic evidence or neurologic
findings on the physical examination suggesting the pres-
ence of spinal cord ischemia. Perioperative hypotension
from surgical bleeding or other causes can trigger the onset
of spinal cord ischemia after TAAA repair, but clinical obser-
vations suggest that unexplained hypotension may also be
an early clinical sign of spinal cord ischemia.45,51,59,69,70 In
this situation, hypotension is a consequence of spinal cord
ischemia causing autonomic dysfunction from neurogenic
shock. In either situation, early and immediate treatment
of hypotension associated with spinal cord ischemia is nec-
essary to prevent infarction (Figs. 23.8 and 23.9). In
the course of treatment, it is important to reassess continu-
ally the benefits of arterial pressure augmentation
against the risk of bleeding when implementing this tech-
nique in patients with major vascular disease in the
perioperative period.
Another important spinal cord protection strategy
involves intraoperative monitoring of spinal cord function
with motor evoked potentials (MEPs) and somatosensory
 23 • Preservation of Spinal Cord Function 345

Arterial pressure (mmHg)

200
180 Spinal cord at risk
160
140
120 Hypoperfusion
100
80
60
Spinal cord ischemia
40 (paraplegia or paraparesis)
20
A B
0

Phenylephrine (mg/min IV) Neurogenic shock

300 (autonomic dysfunction)

200

100
Hypotension
0

Norepinephrine (mg/min IV)

4
3
2
1 Spinal cord infarction
0 (permanent paraplegia)
10 20 30 40 50 60
Time after operation (hours)
Fig. 23.8 Two episodes (A and B) of delayed onset spinal cord ischemia associated with paraplegia after endovascular stent graft repair of a descending
thoracic aortic aneurysm were preceded by hypotension (left). Neurogenic shock causing autonomic dysfunction may explain the reason for hypo-
tension associated with spinal cord ischemia. Immediate treatment of hypotension with vasopressor therapy in patients with spinal cord ischemia is
necessary to prevent spinal cord infarction (right). (Adapted from Cheung AT, Pochettino A, McGarvey ML, et al: Strategies to manage paraplegia risk after
endovascular stent repair of descending thoracic aortic aneurysms. Ann Thorac Surg 2005;80:1280-1288.)

evoked potentials (SSEPs), whereby adequate conduction of
evoked potentials serves as a proxy for adequate spinal cord
perfusion (Fig. 23.10).51,59,68 During surgery on the des-
cending thoracic aorta, spinal cord ischemia may be caused
by hypoperfusion or loss of collateral blood flow through
critical radicular, intercostal, or lumbar arteries as a conse-
quence of aortic cross-clamping, vascular dissection, throm-
bosis, embolization, or surgical ligation. The aim of
intraoperative neuromonitoring is to detect spinal cord
ischemia while the patient is still under general anesthesia
in order to direct interventions aimed at treating spinal cord
ischemia and to identify critical vessels for reimplantation to
prevent spinal cord infarction. Intraoperative monitoring of
MEPs and SSEPs, in conjunction with a multimodal
approach to ischemia prevention and treatment, has been
shown to reduce rates of immediate paraplegia in the
postoperative period,71–73 although the risk of delayed
onset postoperative spinal cord ischemia has not been
eliminated.59
Intraoperative MEP monitoring is performed by deliver-
ing multipulse electrical stimulation to the scalp in areas
overlying the motor cortex. The evoked potentials elicited
from this stimulation travel from the motor cortex through
the cortical spinal tracts, anterior horn cells, peripheral
nerves, and finally to the innervated muscle groups. An
interruption in this pathway will result in loss of the
MEP. Therefore changes in MEP signals can detect anterior
spinal cord ischemia (Fig. 23.11). Intraoperative SSEP
monitoring is performed by placing stimulating electrodes
on the skin adjacent to peripheral nerves in the arms or
legs. Electrical stimulation of the peripheral nerves in the
limbs generates action potentials that are subsequently
detected by recording electrodes over the lumbar plexus,
brachial plexus, spine, brainstem, thalamus, and cerebral
cortex. Changes in SSEP signals can detect posterior spinal
cord ischemia.
Based on the available evidence, monitoring MEPs is more
sensitive and specific than SSEPs for the detection of spinal
cord ischemia among patients undergoing thoracic and
thoracoabdominal aortic repair. A small study of 56 patients
using both MEPs and SSEPs demonstrated that MEP moni-
toring was able to detect more transient and persistent
changes consistent with spinal cord ischemia than SSEP
monitoring.71 Furthermore, MEP monitoring has been used
to identify critical intercostal arteries for reattachment after
the acute loss of lower extremity MEP signals during TAAA
repair.72 Although the absence of SSEP changes has a neg-
ative predictive value of > 99%, the positive predictive value
of SSEPs may be as low as 60%.74 SSEP monitoring alone
may also fail to detect spinal cord ischemia confined to
the anterior spinal cord that causes a selective motor deficit
with intact sensation. However, clinical experience suggests
that isolated motor dysfunction is uncommon. In one clin-
ical series, 90% of patients with spinal cord ischemia after
TAAA repair had sensory deficits.59 The advantage of SSEP
monitoring is that it is relatively reliable and easy to
346 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

PATIENT NO. 1 PATIENT NO. 9 PATIENT NO. 10

200 200 200
Arterial pressure (mmHg)

150 150 150

100 100 100

50 50 50
R R R

E
E E
0 0 0

300 300 300

Phenylephrine
200 200 200
Drug dosage (␮g/min)

100 100 100

0 0 0
15 15 15
Norepinephrine
10 10 10
5 5 5
0 0 0
0 1000 2000 3000 0 1000 2000 0 1000 2000 3000
Time (min) Time (min) Time (min)
Fig. 23.9 Changes in arterial pressure over time in three patients with delayed-onset paraplegia caused by spinal cord ischemia after open thora-
coabdominal aortic aneurysm repair. In each case, the onset of paraplegia (E) was preceded by hypotension. Each patient recovered in response to
vasopressor therapy combined with lumbar cerebrospinal fluid drainage (R). Recovery of motor function coincided with recovery of arterial pressure,
indicating the return of autonomic function. (Reproduced from Cheung AT, Weiss SJ, McGarvey ML, et al: Interventions for reversing delayed-onset
postoperative paraplegia after thoracic aortic reconstruction. Ann Thorac Surg 2002;74:413-419; discussion 420-421.)

interpret. A specific classification system has been developed
to describe the findings of SSEP monitoring during thoracic
aneurysm repairs (Table 23.3).75
Both MEP and SSEP monitoring require adjustments in
anesthetic management. Volatile anesthetics cause a
dose-dependent attenuation of MEP and SSEP signals.
Although MEPs tend to be more sensitive to the effects of
volatile anesthetics in comparison with SSEPs, adequate
MEP and SSEP signals can usually be achieved with the
use of inhalational anesthetic agents at 0.5 minimum alve-
olar concentration (MAC) or less. In general, inhalational
anesthetic agents have a greater effect on neuromonitoring
signals than do IV anesthetic agents. Therefore low-dose
inhalational anesthesia can be supplemented by IV anes-
thetic infusions such a propofol, remifentanil, or ketamine.
MEPs also require neuromuscular blocking agents to be lim-
ited or avoided altogether. Hypothermia will also increase
the latency of SSEPs. A common technique to distinguish
spinal cord ischemia from anesthetic-induced changes in
the evoked potentials is to compare signals obtained from
the upper extremities to those of the lower extremities.
It should be noted that intraoperative changes in or loss of
MEP or SSEP signals are not always caused by spinal cord
ischemia. A functioning peripheral nerve is required to con-
duct evoked potentials and peripheral nerve injury from any
cause will affect the associated MEP and SSEP signals. Vas-
cular malperfusion of a lower extremity can cause loss of
peripheral MEP and SSEP signals in the absence of spinal
cord ischemia if blood flow to the limb is significantly com-
promised. Lower extremity malperfusion may be caused by
aortic dissection, atheroembolism, or most commonly by
arterial cannulation of the femoral artery for extracorporeal
circulation. Similarly, operations performed by cross-
clamping the aorta without distal aortic perfusion will cause
SSEP and MEP signals from the lower extremities to decay
over time after application of the aortic cross-clamp. This
decrease or loss of neuromonitoring signals after aortic
cross-clamping is not specific for spinal cord ischemia
and may also represent peripheral nerve ischemia. Acute
intraoperative stroke also alters MEPs or SSEPs, and such
changes can only be distinguished from changes caused
by spinal cord ischemia by comparing signals recorded at
different sites along the neural conduction pathway. Stroke
is associated with selective loss of cortical signals and typi-
cally affects evoked potentials for both upper and lower
extremities.
 23 • Preservation of Spinal Cord Function 347

1 2 5 6

3 4

Fig. 23.10 Example of multimodality intraoperative neurophysiologic monitoring (IONM). Panels 1 and 2 show somatosensory evoked potentials
(SSEPs) after left and right median nerve stimulation, respectively. The first three traces from top to bottom are cortical generated SSEPs; the fourth trace
is from the cervical spinal cord; and the fifth trace is generated from the brachial plexus. Panels 3 and 4 show left and right lower limb posterior tibial
nerve SSEPs, respectively. The first four traces from the top to the bottom are cortical generated SSEPs; the fifth trace is from the cervical spinal cord; and
the sixth trace is generated from the peripheral tibial nerve at the popliteal fossa. Panels 5 and 6 show transcranial motor evoked potentials (TcMEPs)
recorded from left and right sides, respectively. Recordings from top to bottom traces are from the following muscles: intrinsic hand muscles, psoas,
vastus lateralis, tibialis anterior, abductor halluces, and anal sphincter. Panel 7 shows a six-channel EEG waveform. The top three traces are generated
from the left cerebral hemisphere and the bottom three traces from the right hemisphere. The recording montage is as follows: F3, C3, P3, F4, C4, P4, all
referenced to Fz.

Deliberate hypothermia is the only intervention that has
been proven to protect consistently the central nervous sys-
tem in conditions of ischemia.76 Hypothermia is thought to
exert its protective effect by decreasing the metabolic
demand of the spinal cord, stabilizing cell membranes,
and attenuating the inflammatory and excitotoxic
responses to ischemia upon reperfusion. Mild systemic hypo-
thermia (32°C to 34°C) can usually be achieved by passive
cooling after induction of general anesthesia. Adding a heat
exchanger to the perfusion circuit also facilitates deliberate
hypothermia and rewarming. Importantly, consensus opin-
ion recommends the avoidance of hyperthermia during
rewarming because hyperthermia may potentiate reperfu-
sion injury.63
At present, the prevention and treatment of spinal cord
ischemia during and after TAAA repair requires a multi-
modal approach, with an emphasis on preserving collateral
blood flow to the spinal cord, optimizing spinal cord perfu-
sion with lumbar CSF drainage, augmenting MAP, avoiding
hypotension in the perioperative period, and early detection
and treatment of spinal cord ischemia (Fig. 23.12).51,59
Spinal Cord Injury From Central
Neuraxial Anesthesia and
Analgesia
SCI after central neuraxial anesthesia is a rare but devastat-
ing complication. Purported mechanisms of injury as a con-
sequence of epidural or spinal anesthesia include spinal
hematoma causing compressive myelopathy, mechanical
injury to the spinal cord or nerve roots from instrumenta-
tion, direct injection of medications into the spinal cord or
blood vessels causing toxic neurolysis, and infection.77
The most frequent neurologic injury associated with
neuraxial anesthesia is spinal hematoma, caused by intra-
spinal or epidural bleeding after instrumentation of the
spinal neuraxis.78 The true incidence of spinal cord dysfunc-
tion resulting from symptomatic bleeding within the spinal
neuraxis after epidural and spinal blockade is unknown,
although it has been estimated to be in the range of less than
1 in 150,000 epidural anesthetics and less than 1 in
220,000 spinal anesthetics.79 It should be noted that these
348 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Fig. 23.11 Intraoperative spinal cord ischemia demonstrated in serial transcranial motor evoked potential (TcMEP) recordings over time (top to bottom)
from the left (L) and right (R) hands, tibialis anterior (TA), and abductor halluces (AH). Spinal cord ischemia was manifested by the bilateral loss of lower
extremity TcMEPs from the TA and AH after aortic cross-clamping. The lower extremity TcMEPs recovered gradually over time within 30 minutes after
increasing the mean arterial pressure in response to the treatment of intraoperative spinal cord ischemia (arrows). TcMEPs from the right hand (RHand)
and left hand (LHand) were unaffected during the episode of spinal cord ischemia.

Table 23.3 Classification of intraoperative somatosensory
evoked potential (SSEP) alterations during thoracoabdominal
aortic aneurysm repair.
Type Etiology
Type 1 Distal spinal cord ischemia from aortic cross-clamping
Type 2 Peripheral nerve ischemia from femoral artery occlusion
Type 3 Segmental spinal ischemia from vascular insufficiency
Type 4 Left hemispheric ischemia from left carotid occlusion
Type 5 Global cortical ischemia from hypotension or stroke
Modified with permission from Guerit JM, Witdoeckt C, Verhelst R, et al. Ann
Thorac Surg 1999;67:1943-1946; discussion 1953-1958.
estimates are based on patient series including patients who
were not receiving venous thromboembolism prophylaxis.
However, it is known that neuraxial hematomas associated
with coagulopathy remain a significant source of high-
severity injury.80 Based on a number of case series of spinal
hematomas associated with epidural or spinal anesthesia,
the risk of clinically significant bleeding is associated with
hemostatic abnormalities, increasing age, spinal cord or ver-
tebral column abnormalities, difficult needle placement, and
the presence of an indwelling neuraxial catheter during
anticoagulant therapy.81,82 The increasing use of anticoa-
gulation and antiplatelet therapy in the perioperative period
has probably led to an increased risk and incidence of hem-
orrhagic complications associated with neuraxial anesthetic
techniques. Moreover, without a mandatory reporting sys-
tem or centralized registry, the frequency of spinal hemato-
mas is likely to be greater than estimates based on the cases
reported in the medical literature.81
The presenting symptoms of spinal hematoma include
progressive loss of sensory, and motor, or bowel and bladder
function (Fig. 23.13).82 The presence of back pain only
occurs in the minority of cases. MRI scans demonstrating
an epidural or paraspinal heme-containing collection caus-
ing cord compression or displacement is diagnostic for spinal
epidural hematoma. Spontaneous resolution of spinal epidu-
ral hematoma without treatment has been reported,83 but
two case series demonstrated that neurologic recovery
was more likely if patients undergo surgical decompression
within 8 to 12 hours after the onset of symptoms.82,84
Unfortunately, numbness or weakness in the postoperative
period can be mistakenly attributed to local anesthetic
action rather than spinal cord ischemia, which may delay
diagnosis.80 Recovery of neurologic function after surgical

decompression is also correlated to the severity of symptoms
before surgery.
The American Society of Regional Anesthesia (ASRA) has
recently published an updated consensus statement that
provides recommendations on the safe practice of neuraxial
anesthetic techniques in patients receiving anticoagulation
NEUROLOGIC ASSESSMENT
Neurophysiologic (SEP or MEP)
physical examination
Clinical diagnosis of spinal cord ischemia
1. MAPⱖ90 mmHg (Vasopressors)
2. CSF 10–12 mmHg (Lumbar CSF catheter)
3. Serial neurologic assessment
Improvement No improvement
Continue 1. MAP⬎95 mmHg
management 2. MAP⬎100 mmHg
3. MRI
Fig. 23.12 Algorithm for the detection and treatment of spinal cord
ischemia after surgery on the thoracic and thoracoabdominal aorta.
Neurologic deficits detected by intraoperative somatosensory evoked
or motor evoked potential monitoring or postoperative deficits
detected by neurologic examination are treated by augmenting the
arterial pressure with vasopressor therapy and decreasing the cere-
brospinal fluid (CSF) pressure by lumbar CSF drainage. MAP, mean
arterial pressure; MEP, motor evoked potential; MRI, magnetic reso-
nance imaging; SSEP, somatosensory evoked potential.
Fig. 23.13 Magnetic resonance imaging of the thoracolumbar spine, demonstrating an epidural hematoma in a patient after spinal anesthesia.
T2-weighted sagittal imaging showed extension of the epidural hematoma from T12 to L3 (arrows, left). T2-weighted axial imaging at the level
of L2 showed anterior compression of the spinal cord from the epidural hematoma (arrow, right). (Adapted with permission from Litz RJ, Gottschlich B,
Stehr SN: Spinal epidural hematoma after spinal anesthesia in a patient treated with clopidogrel and enoxaparin. Anesthesiology 2004;101:1467-1470.)
23 • Preservation of Spinal Cord Function 349
and antiplatelet therapy.81 According to the ASRA guide-
lines, non-steroidal anti-inflammatory drugs (NSAIDs),
including aspirin, do not significantly increase the risk of
developing spinal hematoma in patients receiving epidural
or spinal anesthesia. Therefore ASRA does not identify
any specific concerns with regard to the timing of single-
injection or catheter techniques relative to the dosing of
NSAIDs, postoperative monitoring, or the timing of neurax-
ial catheter removal. However, caution is advised if NSAIDs
are used concurrently with other medications that affect
normal clotting (e.g., non-NSAID antiplatelet agents, oral
anticoagulants, unfractionated heparin, low molecular
weight heparin [LMWH]). The recommended time interval
between the discontinuation of thienopyridine therapy and
neuraxial blockade is 10 days for ticlopidine, 5 to 7 days for
clopidogrel, and 7 to 10 days for prasugrel.81
In patients receiving low-dose, subcutaneous unfractio-
nated heparin (UFH) for thromboprophylaxis with dosing
regimens of 5000 units twice a day (BID) or three times a
day (TID), neuraxial block should not be performed within
4 to 6 hours after heparin administration. There is no con-
traindication to maintaining neuraxial catheters in the pres-
ence of low-dose UFH. In patients receiving prophylactic
LMWH, neuraxial instrumentation should be delayed by
at least 12 hours after LMWH administration. In patients
receiving higher (therapeutic) doses of LMWH (e.g., enoxa-
parin 1 mg/kg every 12 hours, enoxaparin 1.5 mg/kg daily,
dalteparin 120 units/kg every 12 hours, dalteparin 200
units/kg daily, or tinzaparin 175 units/kg daily), ASRA
recommends a delay of at least 24 hours prior to needle
or catheter placement. It may be worthwhile to check
anti–factor Xa activity levels on LMWH therapy, especially
in elderly patients and patients with renal insufficiency, but
an acceptable level of residual anti–factor Xa activity to
proceed safely with neuraxial block has not yet been
determined. Indwelling neuraxial catheters may be
350 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
maintained in patients receiving single daily prophylactic
dosing of LMWH. However, no additional medications that
may alter normal clotting should be administered. Indwell-
ing neuraxial catheters are contraindicated if a patient is
receiving twice-daily prophylactic dosing of LMWH or ther-
apeutic dosing of LMWH.81
In patients on chronic warfarin anticoagulation, antico-
agulant therapy should be discontinued for 5 days and
the INR normalized prior to neuraxial block. The ASRA con-
sensus statement also addressed safe neuraxial techniques
in the presence of novel oral anticoagulants and newer
antiplatelet agents, as well as specific guidelines for the tim-
ing of indwelling catheter removal and subsequent redosing
of various anticoagulant and antiplatelet agents.81
The ASRA guidelines on the safe practice of neuraxial
anesthetic techniques in patients receiving anticoagulation
and antiplatelet therapy must be interpreted with caution in
patients on combination therapy, with renal insufficiency,
with hepatic dysfunction, or with underlying coagulation
disorders that may increase the risk of hemorrhagic compli-
cations. Patients at risk of hemorrhagic or spinal cord injury
associated with neuraxial anesthesia or analgesia should be
managed with local anesthetic or narcotic analgesics that
do not completely block sensory and motor function in order
to permit serial neurologic examination.
Infection complicating neuraxial blockade and causing
meningitis, arachnoiditis, or spinal epidural abscess has
always been a concern, particularly in patients with sepsis,
localized infections, bacterial colonization, or immunosup-
pression. However, clinical experience suggests that infec-
tions related to neuraxial anesthesia are rare, with an
incidence ranging from 1 per 1000 to 1 per 10,000 cases.85
In reported cases, infectious complications have been attrib-
uted to performing procedures in patients with sepsis, infec-
tions close to the site of instrumentation, traumatic catheter
insertion, or indwelling catheters left in for prolonged
periods.64,85 Signs and symptoms of spinal or CNS infection
as a consequence of neuraxial techniques include back pain,
radiculopathy, paresthesia, paraplegia, bowel or bladder
dysfunction, fever, and altered mentation. On the basis of
clinical experience, it has been recommended that neuraxial
anesthesia can be performed safely in patients with systemic
infections or at risk of bacteremia when appropriate antibi-
otic therapy has been initiated prior to the procedure.85
Neuraxial anesthesia should be avoided when needle inser-
tion or catheter placement is in a region with a high risk of
bacterial contamination.
Cauda equina syndrome with permanent neurologic
injury is a recognized complication of continuous spinal
anesthesia and has been attributed to the neurotoxic poten-
tial of local anesthetic agents.86 Reports of this complication
suggest a mechanism of injury related to high concentra-
tions of local anesthetic administered into a restricted region
within the subarachnoid space. This condition can be
achieved by continuous spinal anesthesia with local anes-
thetic administered through a small-bore (<24-gauge) spi-
nal catheter, repeated injections of local anesthetic into the
subarachnoid space, or inadvertent injection of a large dose
of local anesthetic into the subarachnoid space originally
intended for epidural administration. Cauda equina syn-
drome is most commonly associated with lidocaine, but it
also been reported with chloroprocaine. This association is
consistent with the finding that lidocaine is more neurotoxic
than other local anesthetic agents when tested in a labora-
tory setting.87,88 For this reason, it has been recommended
that lidocaine should not be administered at a dosage of
greater than 60 mg or at a concentration greater than
2.5% when used for subarachnoid injection. The safety of
combining vasoconstrictor agents such as epinephrine to
prolong the duration of lidocaine subarachnoid blocks has
also been questioned because vasoconstrictor agents have
the potential to increase local anesthetic toxicity by promot-
ing ischemia or by limiting the distribution and uptake of the
local anesthetic agent.86
Spinal Cord Injury and Spine
Surgery
The surgical management of spinal deformities has evolved
dramatically over the last two decades. The increasing uti-
lization of pedicle screw fixation, in combination with
advancements in posterior and three-column osteotomy
techniques, has allowed more aggressive deformity correc-
tions.89 However, iatrogenic neurologic complications that
include complete or incomplete paraplegia are associated
with more complex corrections, staged procedures, and sig-
nificant perioperative blood loss. Although the precise inci-
dence of postoperative paraplegia after surgery for spinal
deformity is unknown, a retrospective analysis indicated
that the operative management of scoliosis with a high
degree of correction is associated with a 0.5% risk of neuro-
logic complication.90
Proposed mechanisms of spinal cord injury include ische-
mia, mechanical injury, or more likely a combination of
both. Ischemic injury can occur as a consequence of oper-
ative injury or ligation of radicular arteries providing collat-
eral circulation to the anterior spinal artery. Hypotension,
low cardiac output states, increased central venous pres-
sure, or “kinking” of arteries supplying the spinal cord as
a consequence of realigning the spine all may contribute
to ischemic injury. Mechanical injury to the spinal cord
may occur as a consequence of traction or transverse forces
to the cord during realignment, misplaced implants, or
direct injury to the spinal cord during surgical exposure.
Compression of the spinal cord from epidural hematoma,
bone chips, scar formation, or bone may cause both vascu-
lar insufficiency and mechanical injury. Risk factors for spi-
nal cord injury after spine surgery include operations for
short-curved kyphosis (as opposed to long-curved scoliosis),
congenital deformities with spinal cord malformation, pre-
operative neurologic deficits, and coagulopathy.90 The inci-
dence of postoperative epidural hematoma after spine
surgery has been estimated to be 0.2% in one series.91 Risk
factors for postoperative epidural hematoma complicating
spine surgery include age greater than 60 years, preopera-
tive use of NSAIDs, Rh-positive blood type, surgery involv-
ing more than five vertebral levels, hemoglobin
concentration less than 10 g/dL, estimated blood loss
greater than 1 L, or INR greater than 2.0 within the first
48 hours after surgery.91
Clinical strategies to prevent and to detect spinal cord
injury during spine operations include intraoperative
wakeup testing, SSEP monitoring, MEP monitoring, or a

combination of techniques. Prior to the use of intraoperative
evoked potential monitoring, the Stagnara Wakeup test was
the only available technique for evaluating spinal cord func-
tion.89 While the wakeup test remains the gold standard, it
comes with significant limitations. It is usually performed
after the surgical correction has already been performed,
and thus the precise moment of neurologic injury remains
unknown. Additionally, waking up patients intraopera-
tively may be dangerous, and some patients are unable to
cooperate with the examination because of age or impaired
mental status.92 Although a solitary neuromonitoring
modality such as SSEP alone can lead to false negatives
and unexpected neurologic deficits in the postoperative
period, an abundance of research demonstrates that a multi-
modal approach to intraoperative neurologic assessment that
combines SSEP with transcranial motor evoked potentials
(TcMEPs) and descending neurogenic-evoked potentials
(DNEPs) allows prompt detection and reversal of potential spi-
nal cord injury.93 In 2009, the Scoliosis Research Society
(SRS) released a statement recommending the use of multi-
modal intraoperative neuromonitoring for the detection
and prevention of neurologic complications. A consensus-
based best practice guideline was then published in 2014 that
defined warning criteria indicative of significant deterioration
in neurologic status as a 50% degradation in SSEP signal
amplitude from baseline, a sustained decrease in TcMEP sig-
nal amplitude, or a decrease in DNEP signal of >60%. This
best practice guideline also provided an intraoperative check-
list of recommendations in response to changes in neuromo-
nitoring signals.94 First, the surgical maneuvers performed
just prior to the occurrence of warning criteria should be
reversed. If the signals do not return to baseline despite
reversing the recent surgical steps, intraoperative imaging
can be used to assess for complications related to implant
placement. Simultaneously, MAP and hematocrit should be
augmented to optimize oxygen delivery to the spinal cord;
blood pH and PaCO2 should be normalized, normothermia
should be maintained; and the patient should be evaluated
for proper positioning. All anesthesia-related and technical
causes of neuromonitoring signal changes should also be
ruled out.89,94 Ultimately, communication and collaboration
among the surgeon, the anesthesiologist, and the neurologist
performing the neurophysiologic monitoring are absolutely
necessary to ensure early detection and rapid intervention
to prevent permanent injury.
Anesthetic and Medical
Management of the Patient With
Existing or Prior Spinal Cord Injury
It is not uncommon that a patient with an acute or estab-
lished spinal cord injury requires anesthetic and surgical
care. Even though the neurologic injury may be established
and nothing can be done to decrease the severity of injury,
spinal cord injuries can subsequently cause profound phys-
iologic alterations that require medical attention. Auto-
nomic nervous system dysfunction may cause neurogenic
shock, bradycardia, orthostatic hypotension, or autonomic
dysreflexia. Altered autonomic nervous system function
23 • Preservation of Spinal Cord Function 351
impairs vascular autoregulation in response to external
temperature changes and to intravascular volume shifts,
making the patient more susceptible to hypothermia from
exposure and to hypovolemia from blood and fluid losses
associated with surgery. Moreover, in the setting of altered
autonomic function, the renin-angiotensin-aldosterone sys-
tem may exert a more prominent role in blood pressure reg-
ulation, making the patient with a spinal cord injury more
susceptible to the antihypertensive actions of angiotensin-
converting enzyme (ACE) inhibitors or angiotensin receptor
blocking (ARB) drugs. Urinary retention and neurogenic
bladder dysfunction as a consequence of spinal cord injury
predispose the patient to urinary tract infections and renal
insufficiency. Constipation associated with spinal cord inju-
ries may lead to bowel obstruction, malnutrition, or an
increased risk of aspiration pneumonia. Motor paralysis
affecting the respiratory accessory muscles and abdominal
muscles is associated with reduced pulmonary reserve
and impaired cough, predisposing the patient to respiratory
failure or respiratory infections. Finally, spinal cord injury
causing quadriplegia, paraplegia, or paraparesis is a chronic
disease state associated with anemia, poor nutritional sta-
tus, skin breakdown, decubitus ulcers, risk of deep venous
thrombosis, and risk of infection.
Neurogenic shock is a complication of acute complete spi-
nal cord injury above the thoracic T6 level. Hypotension
attributed to neurogenic shock has also been observed as
a consequence of spinal cord ischemia and infarction after
TAAA surgery.59 Neurogenic shock is caused by dysfunc-
tion of the sympathetic paravertebral ganglia innervated
by the thoracic lumbar segments of the spinal cord that play
an important role in the maintenance of peripheral vascular
tone. In the classic description, neurogenic shock is charac-
terized as a state of hypotension with low systemic vascular
resistance and normal or increased cardiac output. Episodes
of hypotension from neurogenic shock typically occur in
about half of spinal cord injury patients within the first
24 hours after injury.95 Neurogenic shock generally persists
for 1 to 3 weeks after injury. The incidence and severity of
neurogenic shock appear to correlate with the level of the
injury and the extent of the injury.96 Patients with paraple-
gia may have compensatory tachycardia, whereas quadri-
plegic patients may suffer from bradycardia caused by
unopposed vagal tone.
The treatment of neurogenic shock is directed at pharma-
cologic support of blood pressure and circulatory function
until autonomic nervous system function is restored or com-
pensatory physiologic mechanisms are able to maintain
blood pressure within a physiologic range. Intravenous
vasopressor therapy with norepinephrine, phenylephrine,
dopamine, epinephrine, or vasopressin, often in high doses,
is necessary to treat hypotension and support the arterial
pressure. During treatment with vasopressor therapy, it is
important to assess intravascular fluid status and treat
hypovolemia with volume expansion.
Neurogenic shock should be distinguished from the term
spinal shock, which is a neurologic phenomenon describing
the transient inexcitability of the spinal cord below the level
of injury in the acute phase of injury. Spinal shock is char-
acterized by the loss of deep tendon reflexes, whereas motor
and sensory function below the level of the lesion may or
may not be affected in neurogenic shock.
352 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Autonomic dysreflexia or hyperreflexia is a complication
that occurs in patients with spinal cord injuries and is con-
sidered a medical emergency. 97 Autonomic dysreflexia
manifests as exaggerated sympathetic activity triggered in
response to a stimulus (often a surgical stimulus) below
the level of the spinal cord lesion. The “mass reflex” and dis-
charge of adrenergic transmitters occurs because the spinal
cord lesion prevents brainstem and higher cortical regula-
tion of autonomic tone. It is also possible that the peripheral
vasculature has developed increased sensitivity to adrener-
gic agonists over time. The incidence of autonomic dysre-
flexia ranges from 19% to 70% in patients with spinal
cord injuries.98 It is more common in patients with complete
lesions above the thoracic T6 level and a viable spinal cord
below the level of the lesion. Autonomic dysreflexia may
occur soon after spinal cord injury or may not manifest
for many years post-injury.
The primary clinical sign of autonomic dysreflexia is
severe hypertension with systolic blood pressures as high
as 200 mmHg to 300 mmHg. Severe vasoconstriction
may even render the noninvasive blood pressure monitor
and pulse oximeter nonfunctional. The adrenergic dis-
charge may produce signs and symptoms as mild as head-
ache, tinnitus, nausea, nasal congestion, cutaneous
flushing, anxiety, blurred vision, piloerection, fever, or ven-
tricular ectopic activity. Severe reactions may cause respira-
tory distress, loss of consciousness, pulmonary edema, heart
failure, cardiac arrhythmias, stroke, encephalopathy, intra-
cranial hemorrhage, or retinal hemorrhages. A hyperten-
sive episode may also be associated with reflex
bradycardia followed by hypotension. Known triggers for
autonomic dysreflexia include painful stimuli, trauma,
instrumentation of the genitourinary tract, bladder disten-
tion, vesicoureteral reflux, constipation, bowel obstruction,
biliary colic, or exposure to heat or cold.
Autonomic dysreflexia can be prevented by providing top-
ical, local, regional, or general anesthesia prior to stimula-
tion. Pretreatment with nifedipine or the alpha-adrenergic
antagonist terazosin or prazosin has also been
described.99,100 The emergency treatment is to remove the
offending stimulus and administer antihypertensive agents
to control the blood pressure. No single therapeutic agent
has been systematically evaluated for the treatment of hyper-
tension caused by autonomic dysreflexia, but commonly used
agents include sodium nitroprusside, nitroglycerin, trimetha-
phan, hydralazine, nifedipine, nicardipine, and labetalol.
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 24 Perioperative Management of
Acute Central Nervous System
Injury
JOVANY CRUZ NAVARRO and W. ANDREW KOFKE
Introduction
Neural function is essential to human existence. Thus, loss
of any neural element in the course of a critical illness
represents a major loss to a given individual. Neurons
or supporting elements may be lost in a small, virtually
unnoticeable manner, perhaps manifest as cognitive or
behavioral deficit, or there may be widespread selective
neuronal loss or tissue infarction with more apparent and
disabling deficits. Based on the notion that neural function
is the essence of acceptable survival from critical illness, it is
crucial for perioperative management to include consider-
ations of neural viability and the impact and interactions
of the primary diseases and therapeutics on the nervous
system.
There are numerous perioperative scenarios where a
patient may present with neurologic dysfunction. In a gen-
eral sense, these scenarios often involve ischemia, trauma,
or neuroexcitation. Each of these, as they progressively
worsen, at some point typically involve a period of decreased
cerebral perfusion pressure (CPP), usually resulting from
elevated intracranial pressure, eventually compromising
cerebral blood flow sufficiently to produce permanent neu-
ronal loss, infarction, and possibly brain death. A variety of
biochemical pathways play a major role. In this chapter we
review the important physiologic factors, and intracranial
pressure (ICP) considerations and therapeutic options criti-
cal to contemporary perioperative care of the patient with
injury to the central nervous system (CNS).
Monitoring Neurologic
Examination
The neurologic examination of the patient with an acute
neurologic condition is a process that requires the physi-
cian to have a specialized anatomic and physiologic knowl-
edge of the nervous system and the anesthesiologist should
be familiar with the most basic components of the neuro-
logic examination to identify promptly life-threatening
conditions that may require urgent action. The majority
of the information necessary to localize a lesion in the
patient with neurologic disease can be obtained through
a careful history and physical examination. Although a
detailed description of neurologic examination is beyond
the scope of this chapter, a rapid 5-min neurologic
assessment may be sufficient to establish baseline condi-
tions and to detect subsequent changes in neurologic sta-
tus. Therefore, for the nonneurologist it is important to
focus on the components of the neurologic examination
described in the following sections.
Mental Status, Cranial Nerves,
Motor and Sensorial Function,
and Reflexes
MENTAL STATUS
Certain findings of the mental status examination can only
be interpreted by knowing the patient’s ability to perform
fundamental daily living tasks. Mental status should be
reported starting with the level of alertness, followed by lan-
guage function and memory. The rest of the mental status
examination can be reported in any order and includes
attention and concentration, memory, visual spatial recog-
nition, praxis, calculations, etc.
Mental status is assessed by orientation to person, place,
and time. General mental status is determined by assessing
general information (i.e., the name of the president, obtain-
ing a description of some current events, assessing spelling
ability for simple words, and asking the patient to add or
subtract serial threes or sevens). In addition, the patient
can be asked to recall three objects several minutes after
the examiner mentions them. Attention is tested by asking
the patient to recall a series of numbers or to spell “world”
backward.
Cranial nerves can be assessed as follows:
CN I (olfactory): Test each nose nare with a mild agent such
as soap or tobacco.
CN II (optic): Near and far visual acuity and gross visual
fields are assessed. Ophthalmoscopic examination is
performed.
CN III, IV, VI (oculomotor, trochlear, abducens): Pupillary
light response. Lateral and vertical gaze are assessed.
CN V (trigeminal): Assessment of touch sensation in both
sides of the face is performed in all three trigeminal divi-
sions. In addition, corneal blink reflex can also be
assessed.
CN VII (facial): Symmetrical smile assessment is performed.
In addition, brow wrinkling can be assessed to determine
central versus peripheral seventh nerve function.
355
356 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
CN VIII (auditory): Ability to hear fingertips moving is
assessed. Lateralizing the sound of a tuning fork placed
over the mid-forehead can localize a hearing deficit.
CN IX, X (glossopharyngeal, vagus): Gag reflex is assessed
with a tongue blade or tonsil tip suction device.
CN XI (accessory): Bilateral shoulder elevation (trapezius)
and head-turning (sternocleidomastoid) strength is
assessed.
CN XII (hypoglossal): The patient is asked to extrude his/her
tongue. If there is weakness on one side of the tongue, the
tongue will deviate to that side.
Motor examination is performed by assessing pronator
drift of the upper extremity. A unilateral pronator drift in
one arm suggests an upper motor neuron lesion affecting
that arm. Hand grasps, toe and foot dorsiflexion, and the
major flexors and extensors of the upper and lower extrem-
ities are assessed. In addition, individual muscles can also be
assessed and graded (Table 24.1).
Sensory examination involves testing the primary
afferent sensory pathways with modalities such as light
touch, pain and temperature, vibration and joint position,
and then areas that test the ability of sensory and associ-
ation cortices to interpret sensory input. These areas test
sensory functions such as stereognosis, graphesthesia,
point localization, etc. A brief sensory examination can
be performed by stimulation with a pin on hands and feet
to determine the patient’s ability to distinguish between
sharp or dull sensation. The examination should be done
in a repetitive manner because patients can report both
stimuli as sharp bilaterally and then some 10 seconds
later report to only one side as sharp, indicating a subtle
deficit on the dull side. A similar maneuver is performed
on the cheeks for cranial nerve V and the dorsum of
the feet. It is important to note that this examination
technique has been associated with the spread of infec-
tious diseases1 and thus, a new pin or other sharp device
should be used for each assessment with every effort made
not to cause bleeding. Light touch sensation is tested in a
similar manner using the touch of a finger in the place
of a pin.
Coordination is assessed by finger-to-nose and heel-to-
shin testing and assessment of rapid alternating movements
of the hand and or foot. This aspect of the examination
Table 24.1 Muscle strength and reflex grading scale.
Muscle strength Reflexes
0 ¼ no contraction 0 ¼ absent
1 ¼ visible muscle twitch but no movement of 1 ¼ reduced
the joint (hypoactive)
2 ¼ weak contraction insufficient to overcome 2 ¼ normal
gravity
3 ¼ weak contraction able to overcome gravity 3 ¼ increased
but no additional resistance (hyperactive)
4 ¼ weak contraction able to overcome some 4 ¼ clonus
resistance but no full resistance
5 ¼ normal
tests cerebellar and basal ganglia function because these
structures play an important role in coordination. Deep ten-
don reflexes are assessed in the biceps, triceps, patella, and
Achilles tendon (see Table 24.1). The Babinski reflexes are
assessed by stroking the lateral foot. In addition to the test
for meningeal irritation, the Kernig (elevation of straight-
ened lower extremity) and Brudzinski (head flexion by
examiner) tests are performed.
The neurologic examination in a comatose patient rep-
resents a different challenge. Procedures performed in eval-
uation of the comatose patient include determination of
viable vital signs and assessment of hand drop over the
head when nonphysiologic coma is suspected. Pupil size
and response to light is assessed. Pinpoint pupils imply a
pontine lesion or drug effect whereas large pupils can
suggest a structural lesion, hypoxia, or a drug effect. Uncal
herniation will produce a unilateral pupillary enlargement
with ptosis and inferior–lateral position resulting from
third cranial nerve lesion. Eye movements are assessed
by first evaluating eye position. In destructive cerebral
lesions, the eyes deviate toward the side of the lesion.
Assessment of the oculocephalic (doll’s eye) reflex is per-
formed by turning the head suddenly to one side. Eyes
tend to lag behind when the patient has lethargy or is
semi-comatose, but they move with the head in the awake
state and when brainstem centers are impaired. Further
indication of brainstem impairment is present when the
corneal and gag responses are absent and when there is
extensor or flexor posturing. Response to noxious stimulus
is assessed peripherally by stimulating the sternum or nail
beds or centrally by supraorbital pressure. The Babinski
reflex is assessed.
Hourly evaluation of neurologic and mental status is
recommended as part of the neuromonitoring protocol.
Function of pyramidal and extrapyramidal systems, cranial
nerves, cerebellum, and spinal cord whenever possible, and
any trend in change of neurologic status should be recorded
for every patient. In critically ill patients, however, such a
complete neurologic evaluation can sometimes be unreli-
able or impossible owing to the use of sedatives and the need
for intubation and ventilatory support as part of the medical
treatment of the neurologic problem. Along with the neuro-
logic examination, information about vital sign trends and
key laboratory values should be available at all times. The
Glasgow Coma Scale (GCS) (Table 24.2) is used as a stan-
dardized scale for recording neurologic status in the ICU.
GCS has been the standard outcome tool for neurocritical
care for many years. Newer assessment tools such as the
Neurological Outcome Scale for TBI (NOS-TBI) have demon-
strated adequate concurrent and predictive validity as well
as sensitivity to change, compared with the gold-standard
outcome measure. The NOS-TBI may enhance prediction
of outcome in clinical practice and measurement of outcome
in TBI research.2
Pupillary assessment is vital to determine critical neu-
rologic conditions that may require urgent intervention.
However, observer variability exists and it is subject to
human error. A handheld pupilometer is a new technol-
ogy that may reduce observer variability in the neurologic
examination. Infrared quantitative pupillometry can pro-
duce accurate, reproducible pupillary measurements that
are clearly superior to those obtained manually at the
 24 • Perioperative Management of Acute Central Nervous System Injury 357

Table 24.2 Glasgow Coma Scale (GCS).

Type of response Score
MOTOR RESPONSE
▪ Obeys commands 6
▪ Localizes to pain 5
▪ Withdrawal response to pain 4
▪ Flexion to pain 3
▪ Extension to pain 2
▪ None 1

VERBAL RESPONSE
▪ Oriented 5
▪ Confused 4
▪ Inappropriate words 3
▪ Incomprehensible words 2
▪ None 1

EYE OPENING
▪ Spontaneously 4
▪ To verbal commands 3
▪ To stimulation 2
▪ None 1

patient’s bedside by even an experienced nurse or physi-

cian.3 A recent study using this device reported good
reliability when correlating the pupillary constriction
velocity as a predictor of ICP elevation in neurosurgical Fig. 24.1 The brain, spinal cord, and blood are encased in the skull and
vertebral canal, thus constituting a nearly incompressible system.
patients.4 Neuro-ICUs are quickly adopting this type of System capacitance is thought to be provided via intervertebral spaces.
monitoring, because evidence has shown that there is a (Reprinted with permission of Kofke, WA. Neurologic Intensive Care. In:
high inter-device reliability of automated pupillometers.5 Albin MS, ed. Textbook of Neuroanesthesia with Neurosurgical and Neuro-
An important limitation of this device is that assessment science Perspectives. 1247–1347.)
is quite challenging in patients with altered mental
status, in patients with periorbital or scleral edema, and
in uncooperative patients. Ambient light and physiologic
factors may also affect the measured pupillary
characteristics.6
Intracranial pressure (mmHg)

Intracranial Hypertension
PHYSIOLOGY
The brain, spinal cord, cerebrospinal fluid (CSF), and blood
are encased in the skull and vertebral canal, thus constitut-
ing a nearly incompressible system (Fig. 24.1). In a totally
incompressible system pressure would vary linearly with
increased volume. However, there is capacitance in the sys-
tem, thought to be provided by the intervertebral spaces and
the vasculature. Once this capacitance is exhausted, the ICP Chnege in intracranial volume (cc3)
increases dramatically with increased intracranial volume Fig. 24.2 Nonlinear relationship between intracranial pressure (ICP)
(Fig. 24.2). and intracranial volume. At normal ICP, small changes in intracranial
Based on the relation: volume produce small changes in the ICP. However, as ICP progres-
sively increases, the ICP increases per unit change in volume become
CBF ¼ ðMAP ICPÞ=CVR progressively larger and more dramatic.

where CBF is cerebral blood flow, MAP is mean arterial pres-

sure, and CVR is cerebrovascular resistance.
The concern arises that increasing ICP is necessarily
associated with decrements in CBF. However, the effect of
increasing ICP on CBF is not straightforward as MAP may
increase with ICP elevations,7 and CVR adjusts with
decreasing CPP (increasing cerebral blood volume) to
maintain CBF until maximal vasodilatation occurs.8–11 This
is thought to occur at CPP < 50 mmHg although consider-
able interindividual heterogeneity in this value exists12 and
the lower limit has been nicely critiqued by Drummond.13
358 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Thus, increasing ICP is often associated with cerebral vaso-
dilatation and/or reflexly increased MAP to maintain CBF.
Normal ICP is <10 mmHg. ICP > 20 mmHg is generally
associated with escalation of ICP-reducing therapy.14,15
However, this is an epidemiologically derived number.
Head trauma studies have indicated that patients with
ICP > 20 mmHg generally do not do well.15 However,
physiologically, simply elevating ICP to >20 mmHg is
not necessarily associated with decrements in CBF, pro-
vided the above-noted compensatory mechanisms occur.6
Recent guidelines recommend treatment of intracranial
pressure when it is >22 mmHg because values above this
level are associated with increased mortality.17
Nonetheless, increasing ICP because of mass lesions or
obstruction of CSF outflow can exhaust compensatory
mechanisms. When this occurs, compromise of CBF does
eventually occur. Initially, abnormality arises in distal run-
off of the cerebral circulation. As the process continues,
compromise of diastolic perfusion arises. With this the nor-
mally continuous (through systole and diastole) cerebral
perfusion becomes discontinuous18 (Fig. 24.3). Further
compromise of cerebral perfusion pressure results in anaer-
obic metabolism, exacerbation of edema, and ultimately
intracranial circulatory arrest.18,19 Thus, when ICP
increases it is important to detect it and ascertain whether
this lethal sequence of events may be occurring.
Factors That Exacerbate
Intracranial Hypertension
Under normal conditions, the intracranial volume is occu-
pied by the brain parenchyma (80%), CSF (10%) and blood
(10%). Pathologic structures, including masses caused by
blood (hematoma), neoplasia, or abscesses, may also
occupy space. Since the volume of the intracranial vault
is somehow fixed, when the volume of one or more of these
compartments enlarges sufficiently to exhaust normal
capacitive compensatory mechanisms, ICP begins to rise.
Further increases in volume of one or more of these com-
partments then leads to the sequence of events associated
with increasing ICP described previously.21
Two Types of Intracranial
Hypertension
In a general sense, there are two types of intracranial
hypertension, categorized according to CBF as hyperemic
or oligemic (Fig. 24.4). Although conceptualized here as a
dichotomous process, undoubtedly the real physiology is
more of a continuum between the two.
In the normal state, increases in CBF are not associated
with increased ICP, as the normal capacitive mechanisms
absorb the increased intracranial blood volume. However,
in the situation of disordered intracranial compliance, small
increases in intracranial volume resulting from increased
CBF produce increases in ICP. When cerebral blood volume
(CBV) increases, intracranial contents increase hence
increasing ICP in a noncompliant system.10,22
This, however, raises questions about an important issue.
Elevated ICP has traditionally been considered to be a con-
cern because it indicates that cerebral perfusion might be
jeopardized. It is, however, unclear whether it is appropriate
to be concerned about high ICP inducing intracranial olige-
mia when the cause of the high ICP is intracranial hyper-
emia. There have been no detailed examinations of this
question although there have been some studies that allow
reasonable inferences about the significance of hyperemic
intracranial hypertension.
For many years, it has been known that brief noxious
stimuli briefly increase ICP in the setting of decreased intra-
cranial compliance. Studies have reported that such situa-
tions are associated with hyperemia, strongly suggesting
that hyperemic intracranial hypertension is not a danger-
ous situation.23 However, it is reasonable to be concerned,
at least theoretically, about such hyperemia for three rea-
sons. First, elevated ICP caused by hyperemia in one portion

Normal “Spiky” High ICP Brain dead

200
150
TCD cm/s

100
50
0
–50

1s

Cerebral
perfusion CPP
pressure

Fig. 24.3 Progression of transcranial Doppler (TCD) waveforms after head injury from intact cerebral blood flow (CBF) and normal appearing TCD
waveform to intracranial hypertension sufficient to induce intracerebral circulatory arrest. Schematic of decreasing cerebral perfusion pressure (CPP)
indicated in the lower panel. ICP, intracranial pressure. (Reproduced by permission from Hassler W, Steinmetz H, Gawlowski J. Transcranial Doppler
ultrasonography in raised intracranial pressure and in intracranial circulatory arrest. J Neurosurg 1988;68:745–751.)
 24 • Perioperative Management of Acute Central Nervous System Injury 359

ICP Hyperemic ICP

0 20 40 0 20 40

A B
Oligemic, edematous ICP
0 20 40

C
Fig. 24.4 Two types of intracranial hypertension. From a baseline condition, intracranial pressure (ICP) can increase in two ways. One is via an increase in
cerebral blood volume associated with reflex vasodilation as a result of moderate blood pressure decreases or hyperemia. The second mechanism of
intracranial hypertension is via malignant brain edema or other expanding masses encroaching on the vascular bed to produce intracranial ischemia.
(Reprinted with permission of Kofke, WA. Neurologic Intensive Care. In: Albin MS, ed. Textbook of Neuroanesthesia with Neurosurgical and Neuroscience Per-
spectives. 1247–1347.)

of the brain may increase ICP to compromise CBF in other
areas of the brain in which rCBF is marginal. Second,
increased pressure in one area of the brain may produce gra-
dients that might lead to a herniation syndrome. Third,
there is theoretical concern that inappropriate hyperemia
may predispose the brain to worsened edema or hemor-
rhage as occurs with other hyperperfusion syndromes.22,24
Thus, hyperemic intracranial hypertension has a theoretical
potential to be deleterious but this has yet to be conclusively
demonstrated. For brief periods, as may occur during intu-
bation or other limited noxious stimuli, it is suggested that it
might not be problematic.25
In contrast, oligemic intracranial hypertension is associ-
ated with compromised cerebral perfusion.26 This is sup-
ported by the high mortality observed in head trauma
patients in whom ICP rises as a result of brain edema after
head injury with decrements in CBF.15,27 Transcranial
Doppler (TCD) and CBF studies on these patients have dem-
onstrated that CBF is low and perfusion is discontinuous
during the cardiac cycle18,27 (see Fig. 24.3). Moreover, jug-
ular venous bulb data indicates that O2 extraction is mark-
edly increased,28 suggesting anaerobic metabolism.27 In
this setting, noxious stimuli can further increase the ICP,
thus producing the situation of hyperemic or oligemic intra-
cranial hypertension. Presumably in this setting the hyper-
emic rise in ICP acts to compromise rCBF further in areas of
brain edema.
Presentation
Although frequently linked, intracranial hypertension is not
a synonym of brain herniation. These events can occur both
independently or in association. Intracranial hypertension
is currently defined as a sustained elevation for more than
5 minutes of ICP >22 mmHg,17 and its accurate
identification requires placement of an invasive intracra-
nial monitoring. However, intracranial monitors are usu-
ally absent during the acute phase of the traumatized brain
management, therefore, anesthesiologists should be famil-
iar with clinical signs and symptoms suggestive of ele-
vated ICP. These signs and symptoms include headache,
nausea, or vomiting, altered mental status, and the Cush-
ing triad (bradycardia, hypertension, and irregular respira-
tions or apnea).
On the other hand, herniation syndromes are the result of
differences in pressure gradients across the intracranial
compartments ultimately leading to the shifting or compres-
sion of vital neural and vascular structures. Common sites of
brain herniation are the medial temporal lobe (uncal), cin-
gulum (subfalcine), and inferior cerebellum (tonsillar herni-
ation). The classic signs of uncal herniation include loss of
consciousness associated with ipsilateral pupillary dilatation
and contralateral hemiparesis resultant from compression of
the ascending arousal pathways, oculomotor nerve (CN III),
and corticospinal tract (Table 24.3).
ICP Monitoring
The purpose of monitoring ICP is to improve reliably the cli-
nician’s ability to maintain adequate CPP and cerebral oxy-
genation. The only way to determine CPP reliably is to
monitor both ICP and MAP continuously. This combined
approach has been associated with the potential to improve
patients’ outcomes after closed head injury.29
Despite its widespread application, supporting evidence
from randomized clinical trials (RCTs) is lacking or
insufficient and indications outside TBI management are
somewhat ill-defined. In 2012, Chestnut et al. conducted
a multicenter, controlled trial in 324 patients who suffered
360 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 24.3 Common herniation syndromes. The current gold standard for ICP monitoring is the ven-
triculostomy catheter or external ventricular drain (EVD),
Clinical signs and where a catheter is inserted in either lateral ventricle, usu-
Syndrome Pathophysiology
symptoms
ally via a small right frontal burr hole. This ventricular cath-
Uncal ▪ Loss of ▪ Medial temporal lobe eter is connected to a standard pressure transducer via fluid-
consciousness (uncus) displacement filled tubing (Fig. 24.5). The external transducer must be
▪ Altered mental into the midbrain area maintained at a specific level to ensure adequate CPP.
status
▪ Anisocoria The reference point for ICP is the foramen of Monro,
▪ Unilateral although in practical terms, the external auditory meatus
dilated pupil is often used as a landmark (Fig. 24.6). EVDs allow the cli-
▪ Contralateral nician to measure global ICP and have some useful advan-
hemiparesis
tages over other ICP monitors, including the ability to
Central, ▪ Forced ▪ Downward perform periodic in vivo external calibration and therapeu-
transtentorial downward gaze displacement of the tic CSF drainage and sampling. The primary disadvantage of
(sunsetting diencephalon and
eyes) medial temporal lobes
intraventricular catheters is the associated increased rate of
▪ Dilated, into and/or through the infection and accidental overdrainage. This infectious risk
unreactive tentorium increases the longer the EVD is in place, and prophylactic
pupils catheter changes do not appear to reduce the risk of infec-
▪ Altered mental tion.31 Another potential disadvantage of intraventricular
status
▪ Abnormal systems includes a small risk of hemorrhage during place-
respiration ment; this risk is greater in patients taking anticoagulants
▪ Posturing or antiplatelets and misplacement (Fig. 24.7). In addition,
Tonsillar ▪ Respiratory ▪ Downward when intracranial mass lesions or ventricular effacement
arrest displacement of the caused by swelling are present, EVD placement may be dif-
▪ Cushing triad cerebellar tonsils ficult even for the most experienced neurosurgeon.
▪ Coma through the foramen In addition to intraventricular catheters, there is intra-
▪ Upper magnum causing
extremities brainstem compression
parenchymal, subarachnoid, and epidural ICP monitoring
dysesthesia catheters. Intraparenchymal catheters consist of a thin wire
with a fiberoptic transducer at the tip (fiberoptic Camino
Subfalcine ▪ Altered mental ▪ Brain tissue extending
status under the falx in the
system, Natus Medical Inc., Middleton, WI), inserted into
▪ Lethargy supratentorial tissue the brain parenchyma via a small skull burr hole. They have
▪ Headache a lower risk of infection and hemorrhage than EVDs.32 Dis-
▪ Contralateral advantages include the inability to drain CSF for therapeutic
leg paralysis or diagnostic purposes and the potential to lose accuracy or
▪ Small reactive
pupils development of “zero drift” (degree of difference relative to
zero atmosphere) over the course of days.33
Transtentorial ▪ Nausea/ ▪ Upward displacement
ascending vomiting of the midbrain
Noninvasive ICP monitoring devices have been developed
▪ Progressive resultant from to reduce the complications associated with invasive
loss of infratentorial mass
consciousness effect

from severe TBI. Patients were randomly assigned to one of

two specific protocols: guidelines-based management of ICP
in which a parenchymal monitor was used or a treatment
CSF collecting
protocol based on clinical and imaging findings. The pri-
chamber
mary outcome was survival time, impaired consciousness, Flushless
and functional status at 3 and 6 months after initial injury. transducer
Intracranial ICP monitoring failed to show superiority to
care based on imaging and clinical findings.30 A large body
of level II evidence exist with regard to ICP monitoring in
TBI. Management of severe TBI patients using information
from ICP monitoring is recommended to reduce in-hospital
and 2-week postinjury mortality.17 Thus, the current rec-
ommendations are to monitor ICP in all salvageable patients
with a TBI (GCS 3–8 after resuscitation) and an abnormal
CT scan that reveals hematomas, contusions, swelling, her- To EVD catheter
niation, or compressed basal cisterns. Also, ICP monitoring
is indicated in patients with severe TBI with a normal CT Fig. 24.5 Standard intracranial pressure (ICP) transducer composed of
scan if more than two of the following features are noted (1) a flushless transducer next to a three-way stopcock thats allows
at admission: age >40 years, unilateral or bilateral motor intermittent or continuous ICP monitoring and CSF drainage, and
posturing, or SBP <90 mmHg.17 (2) a collecting chamber to accurately quantify CSF drained.
 24 • Perioperative Management of Acute Central Nervous System Injury 361

Drip chamber (hanging from top of

IV pole and taped to the pole)

Tape measure to assess

height above brain

CSF drains
against set
level above Ventriculostomy
brain
Monitor tube

Monitor

25
Collection bag
50

75

Fig. 24.6 External ventricular drainage system. (Reprinted with permission from Kofke WA et al. Neurologic Intensive Care. In: Albin MS, ed. Textbook of
Neuroanesthesia with Neurosurgical and Neuroscience Perspectives. New York: McGraw-Hill; 1997.)

devices. Tympanic membrane displacement, TCD pulsatility

index,34 intraocular pressure,35 optic nerve sheath diame-
ter,36,37 and magnetic resonance imaging (MRI) of the optic
nerve sheath have been used to provide a noninvasive esti-
mate of ICP. So far, none of these methods has provided
accuracy sufficient to replace invasive ICP monitors.

Fig. 24.7 Development of subdural hematoma (SDH) after external
ventricular drain (EVD) placement in a patient taking oral anticoagu-
lation. (A) Initial head CT after EVD placement demonstrates a small
SDH. (B) Follow-up head CT at 6 hours after EVD placement with sig-
nificant expansion requiring decompressive surgery.
Waveform Analysis
Normal ICP waveform consists of three arterial components
superimposed on the respiratory rhythm. The first arterial
wave is the percussion wave (P1), which reflects the ejec-
tion of blood from the heart transmitted through the choroid
plexus in the ventricles. The second wave is the tidal wave
(P2), which reflects brain compliance; and finally, the third
wave is the dicrotic wave (P3), which reflects aortic valve
closure. Under physiologic conditions, the percussion
wave is the tallest, with the tidal and dicrotic waves having
progressively smaller amplitudes. When intracranial hyper-
tension is present, cerebral compliance is diminished. This is
reflected by an increase in the peak of the tidal and dicrotic
waves exceeding that of the percussion wave (Fig. 24.8).
362 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Pathologic waveforms include A, B, and C described by
Lundberg in the 1960s. Pathologic A or plateau waves
are abrupt, marked elevations in ICP of 50 to 100 mmHg,
which usually last for 5–20 minutes and represent the loss
of intracranial compliance and autoregulatory mecha-
nisms. Moreover, they can lead to development of a positive
feedback cycle that eventually leads to continuous reduc-
tion in CPP with subsequent cerebral ischemia.38,39 Thus,
the presence of A waves should suggest the need for urgent
intervention to help control ICP. Type B waves occur at a
frequency of 0.5 to 2 waves/min with elevations of ICP of
20–30 mmHg, reflecting change in vascular tone that
occurs when the CPP is at the lower limit of normal autore-
gulation. C waves occur at a frequency of 4–8/min; they
reflect changes in systemic vasomotor tone and have little
pathologic significance.
Treatment of Intracranial
Hypertension
The main goal in treating intracranial hypertension is to
prevent the development of secondary injuries by maintain-
ing adequate CPP, oxygenation, and glucose supply (with-
out hyperglycemia) to promote adequate oxygen and
nutrient supplies. The best clinical strategy is to diagnose
and to treat the underlying cause(s), avoid exacerbating fac-
tors, and reduce ICP (Table 24.4). Current management of
acute brain injury is aimed to maintain ICP < 22 mmHg,
CPP between 60 and 70 mmHg, and SBP at 100 mmHg
for patients 50 to 69 years old or at 110 mmHg for
patients 15 to 49 or >70 years.17 CPP augmentation to
higher perfusing pressures may elevate the risk of systemic
complications, including the development of acute respira-
tory distress syndrome (ARDS).40,41 More recent evidence
has failed to show such association.42,43 This can be
explained in part to the development of better lung-
protective strategies to treat ARDS. In addition, as the Lund
group has suggested in the past, hypertension-induced
exacerbation of brain edema can further increase ICP.
P1
P2
P3
P1
P2
P3
Fig. 24.8 Intracranial pressure (ICP) waveform. Upper tracing: Com-
ponents of a normal ICP waveform: P1, percussion wave; P2, tidal wave;
P3, dicrotic wave. Lower tracing: Typical noncompliant ICP waveform
seen in intracranial hypertension. As ICP increases, a distinctive
elevation of the P2 wave above P1 occurs.
Table 24.4 Possible causes of elevated intracranial pressure.
FOCAL LESIONS
▪ Brain tumors
▪ Abscesses
▪ Ischemic or hemorrhagic strokes
▪ Hydrocephalus
EXTRA-AXIAL FLUID COLLECTIONS
▪ Epidural hematoma
▪ Subdural hematoma
▪ Subdural hygromas
▪ Empyema
▪ Pneumocephalus
DIFFUSE LESIONS
Cerebral edema from toxic-metabolic encephalopathies
▪
▪ Traumatic brain injury
▪ Subarachnoid hemorrhage
▪ Meningoencephalitis
▪ Hepatic encephalopathy (hyperammonemia)
This increase in ICP leads to reduced venous outflow and
increased venous pressure, which in turn act to worsen
the brain edema, constituting a positive feedback cycle ini-
tially started by arterial hypertension.44
Therapy of intracranial hypertension is primarily directed
at removing the cause as far as possible. This is not always
possible. In such cases, therapy is aimed at controlling ICP,
hoping that the primary cause of the intracranial hyperten-
sion will resolve. Controlling ICP is thus a supportive maneu-
ver, intended to preserve viable neuronal tissue until the high
ICP situation resolves. In general, therapeutic maneuvers to
reduce ICP involve one of six classes of therapy: (1) decrease
cerebral blood volume, (2) decrease CSF volume, (3) induce
serum hyperosmolarity, (4) resect dead or injured brain tissue
or resect viable but less important brain tissue (e.g., anterior
temporal lobe), (5) resect non-neural masses or hematomas,
and (6) remove the calvarium to permit unopposed outward
brain swelling (decompressive craniectomy). For purposes of
this chapter, we will categorize interventions based on cur-
rent tiered therapy algorithms (Fig. 24.9).45 Recent advances
in the use of brain tissue oxygen monitors occasionally affect
the manner in which these maneuvers are used to ensure
continued optimal PbrO2. However, their use is somewhat
limited in the operating room given the invasive nature
and obstruction of the surgical field.
Intracranial Hypertension/
Cerebral Herniation Treatment
Algorithm
Level Tier zero: L0.
▪ ABCs
▪ Head of bed elevation
▪ Steroids
▪ Antipyretics and antishivering drugs
▪ CT scan
Airway, Breathing, and Circulation (ABCs)
The urgent assessment of airway patency, oxygenation,
ventilation, and adequate circulation are particularly
 24 • Perioperative Management of Acute Central Nervous System Injury
Intracranial hypertension or
cerebral herniation
Tier 0-L0
Standard measures
Tier 1-L1 Consider additional
• Transient ↓PaCO2 neuromonitoring
• Hyperosmolar
therapy
• CSF drainage
Revise ICP/MAP
goals
Tier 2-L2
Head CT* • HTS infusion
• Propofol
Tier 3-L3
Decompression • Penotobarbital
induced coma
• Hypothermia
• Laparotomy*
* If the brain has not yet been imaged, a non-contrast head CT scan should
be performed when the pateint can be safely transported.
Fig. 24.9 Tiered algorithm for management of elevated intracranial
pressure.
important in TBI to minimize development of secondary
insults such as hypotension and hypoxia. If emergent intu-
bation is required, care should be taken to minimize further
elevations in ICP during intubation through careful posi-
tioning, appropriate choice of paralytic agents (if required),
and adequate sedation (but not drug-induced coma). Pre-
treatment with lidocaine has been recommended as a useful
intervention to decrease the acute elevation in ICP associ-
ated with laryngoscopy; however, good clinical evidence
supporting this approach is limited.46
Head of Bed Elevation
Although the beneficial effect of head of bed elevation (HBE)
is unclear given the lack of consistency among existent tri-
als,47 HBE should be 30 degrees when possible and kept in a
neutral position to promote adequate cerebral blood venous
drainage.48,49 Reverse Trendelenburg position can be uti-
lized in the operating room if head elevation is not possi-
ble.50 Venous return improvement and CSF redistribution
are some of the proposed benefits of HBE. The main routes
for cerebral venous drainage include the deep and superfi-
cial sinus system and the internal and external jugular
veins.51 If a cervical collar is present, ensure it is not too
tight thereby limiting blood venous drainage. Providers
should minimize ICP raising maneuvers (suctioning, cough-
ing, pain). HBE should be considered when calculating
CPP.52,53
Antipyretics and Antishivering Drugs
Fever increases cerebral metabolism, thereby increasing
metabolic demand and CBF, which ultimately leads to ICP
elevation. Experimental studies have associated fever with
363
increased brain injury.54 A recent study of 355 TBI patients
evaluated the fever burden as an independent predictor for
prognosis of TBI. They found that early fever might be an
independent risk factor for poor prognosis in TBI.55
Steroids
In patients with TBI, the use of steroids is not recommended
for improving outcome or reducing ICP. High-dose methyl-
prednisolone was associated with increased mortality and is
contraindicated.56,57 Moreover, glucocorticoids are not
considered to be useful in the management of cerebral
infarction or cerebral edema secondary to intracranial
hemorrhage.
High-dose corticosteroids (dexamethasone) should be ini-
tiated if there is concern for vasogenic edema derived from
brain tumors, meningoencephalitis, or abscesses. Reduction
of intracranial pressure and improvement of symptoms usu-
ally occur within hours of steroid administration, and MRI
changes indicating edema improvement are usually seen
within 48–72 hours.58 Dexamethasone increases the clear-
ance of peritumoral edema, upregulates angiopoietin-1,
which is a strong stabilizing factor in the blood–brain barrier
(BBB), and downregulates vascular endothelial growth fac-
tor in astrocytes.59 The usual initial dose of dexamethasone
is 10 mg as a loading dose, followed by 4 mg every 6 hours.
Patients with steroid-refractory intracranial hypertension
may benefit from a carbonic anhydrase inhibitor.60
Imaging
In the setting of a neurologic emergency, a head CT scan
should be obtained without delay to identify a process that
may require immediate medical or surgical treatment.
Resuscitation measures and stabilization of the patient must
take place before transporting the patient to the CT scanner.
Because of its rapid availability and ease to perform, CT scan
is preferred over MRI in the initial setting, although MRI
may be required later in the course of treatment.
Level Tier 1: L1 Cerebral Blood Volume Reduction.
▪ Hyperosmolar therapy including mannitol and hyper-
tonic saline
▪ Transient hyperventilation
▪ External ventricular drain placement
▪ NOTE: If L1 interventions do not successfully achieve
adequate ICP control and/or there are impending signs of
herniation, emergency decompressive surgery should be
considered.
Hyperventilation
Hyperventilation is a quick and efficient method to lower
ICP transiently in acute emergencies. In normal adults,
CBV is 3–4 mL per 100 g of cerebral tissue and 70% of
the total volume corresponds to venous blood. Veins and
capillaries do not react to fluctuations in PaCO2; therefore,
hyperventilation-related changes in CBV are a result of arte-
rial reactivity to changes in PaCO2. Hyperventilation has
been utilized for almost a century61 and the earliest docu-
mented use was reported by Lundberg in 1959.62 Because
CBF is largely dependent on PaCO2, as PaCO2 decreases with
hyperventilation, there is an associated cerebral vasocon-
striction leading to a subsequent reduction in cerebral blood
364 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

volume and ICP. CBF decreases by 3% for every 1 mmHg
reduction in PaCO2 and this effect is mediated by extracel-
lular fluid (ECF) pH changes.63–68 Thus, PaCO2 levels
between 20 and 25 mmHg are associated with a reduction
of CBF up to 40%–50%.69 However, CBF returns to its orig-
inal state over 6–24 hours as the brain adapts by adjusting
the bicarbonate levels in the ECF to normalize the pH.65,66
At the level of the proximal renal tubule, bicarbonate reab-
sorption is inhibited and excretion of H+ is stimulated. These
responses initiate minutes after the onset of alkalosis and
persist for hours or days allowing normalization of CSF
and perivascular pH.70,71 It is important to recognize that
acute discontinuation of hyperventilation can cause a
rebound increase in CBF leading to an ICP crisis and hyper-
ventilation should therefore be discontinued gradually.
Hyperventilation is performed in the intubated patient by
increasing tidal volume or rate, and it is commonly used to
facilitate neurosurgical exposure as it provides “brain relax-
ation” in the surgical field. A prior multicenter randomized
trial showed that hyperventilation to PaCO2 ¼ 25 
2 mmHg) was effective at reducing ICP and improving the
surgical exposure during craniotomy.72 However, current
consensus is to maintain normocapnia during intracranial
surgery and to consider transient hyperventilation as a tem-
porary measure when the “tight brain” is resistant to other
means of treatment.73
CEREBRAL AND SYSTEMIC EFFECTS
OF HYPERVENTILATION
Multiple cerebral and systemic effects have been identified
that can affect all organ systems, not only the cerebral
vasculature. It decreases perfusion to kidneys, gastro-
intestinal tissue, skin, and muscle.28,70 Respiratory effects
include hypocapnia-induced bronchoconstriction, reduced
hypoxic pulmonary vasoconstriction, and increased
permeability of the alveolo-arterial membrane.70,74 More-
over, respiratory alkalosis complicates tissue hypoxia by
shifting the oxygen-dissociation curve to the left and com-
promises coronary blood flow, thus increasing the risk of
coronary spasm.28,70 Hyperventilation has also been found
to increase extracellular lactate and glutamate levels,
which may contribute to secondary brain injury.75
Hyperventilation introduces a risk of decreasing CBF to a
dangerous level76 (Fig. 24.10). A study in trauma patients
showed that routine hyperventilation was associated with
worse neurologic outcome at 3 and 6 months after the
injury77 (Fig. 24.11). The reason for this is uncertain as
no-one has demonstrated that anaerobic metabolism occurs
with hyperventilation in this setting. Possible causes are: (a)
HV produces alkalemia and increased affinity of oxygen for
hemoglobin, (b) it decreases seizure threshold,78 (c) the
potential exists for hyperventilation to produce only a tran-
sient effect or to produce a paradoxical increase in ICP
(Fig. 24.12), and (d) upon discontinuation of hyperventila-
tion, a paradoxical CSF acidosis can occur.65,66
Multiple clinical studies in TBI have confirmed that
hyperventilation can cause significant reductions in CBF.
Jugular bulb venous oxygen saturation (SjvO2) and partial
brain tissue oxygen pressure (PbtO2) values can be dramat-
ically reduced by continuous hyperventilation.79 Hypocap-
nia increases the likelihood of detecting brain tissue hypoxia
when using PbtO2 monitors.80 This effect is more pro-
nounced during the first few days post-TBI and it is associ-
ated with poor outcomes.81 Using a modified PET scan,
Coles et al. evaluated CBF, CBV and oxygen extraction factor
(OEF) in patients within 10 days of trauma. Hypocapnia was
found to cause a decrease in CBF, and an increase in volume
of ischemic areas and OEF.82
The presence of hyperemia can be determined by the use
of direct brain CBF determination or via jugular bulb oxim-
etry.83 Brain tissue PbrO2 may be helpful in this determi-
nation but this remains to be definitively demonstrated.

PaCO2 31 41
PaCO2 31 41

A B
Fig. 24.10 Effects of hyperventilation on cerebral blood flow (CBF). Two examples of disparate effects of hyperventilation on CBF. Both figures are stable
xenon CBFs in head trauma patients with and without hyperventilation. CBF scale is indicated on the right in mL/100 g/min and is indicated above each
study. CT images are indicated in the lower figures and CBF maps in the upper figures. (A) PaCO2 was decreased from 39 to 29 mmHg. The baseline scan
(right) shows hyperemia and the hyperventilated scan (left) shows CBFs of approximately 30 mL/100 g per minute, which are probably acceptable flows.
(B) PaCO2 was decreased from 46 to 30 mmHg. The baseline CBF (right) had only marginally acceptable CBF. The effect of hyperventilation (left) was to
produce widespread areas of CBF less than 20 mL/100 g per minute, which are probably unacceptable flows. (Reprinted with permission from Kofke WA
et al. Neurologic intensive care. In Albin MS, ed. Textbook of Neuroanesthesia with Neurosurgical and Neuroscience Perspectives. New York: McGraw-Hill; 1997.)
 24 • Perioperative Management of Acute Central Nervous System Injury 365

15
Hyperventilation
Control
12

(GCS motor score ≥ 4)

Number of patients
9

0
G/MD SD/V D G/MD SD/V D
3 Months 6 Months
Fig. 24.11 Head trauma patients were randomized to receive hyperventilation or normoventilation. Outcome was worse in hyperventilated patients.
D, Death; G/MD, good recovery/moderate disability; GCS, Glasgow Coma Scale; SD/V, severe disability/vegetative state.

35 to cerebral contusions or hematomas.85,86 Loss of pressure

PCO2
autoregulation and CO2 reactivity is usually associated with
poor TBI outcomes.87 For these reasons, it is vital to main-
Vent
30 tain CPP while avoiding hypotension and hypocapnia-
Bolt induced vasoconstriction.17,84,88
PCO2
ICP + PCO2 (mmHg)

No recent studies have established the direct association

25
20
15
10
0 2 4 6 8 10 12
Minutes
Fig. 24.12 Paradoxical rise in intracranial pressure (ICP) induced by
mechanical hyperventilation, presumably a result of mechanical
pressure effects predominating over hypocarbic cerebral vasocon-
striction. It is likely that hyperventilation induced a decrease in blood
pressure, which resulted in an opposing reflex increase in cerebral
blood volume. “Bolt” refers to subarachnoid screw, “vent” to ventricular
catheter. (Reproduced with permission from Ropper A, Kennedy S:
Postoperative neurosurgical care. In: Ropper A, ed. Neurological and
Neurosurgical Intensive Care. New York: Raven Press; 1993: 185–191.)
High ICP associated with a low A-VDO2 across the brain
(3–4 vol%) is thought to indicate that hyperventilation
can be safely used. In an emergency situation, even if
the nature of the high ICP (oligemic vs hyperemic) is not
known, acutely administered hyperventilation should be
used to keep ICP down or to reverse a herniation syndrome
or plateau wave until more definitive diagnosis or therapy
can be performed.
HYPERVENTILATION IN TBI
A post-traumatic brain is extremely sensitive to ischemic
damage.28,84 The autoregulatory pressure and the CO2
reactivity mechanisms are usually exacerbated during the
acute phase of TBI, especially in penumbral areas adjacent
of hyperventilation and clinical outcome after TBI. In 1971,
Gordon described a large retrospective series of 251 patients
treated with prolonged hyperventilation, 51 of whom were
hyperventilated to a PaCO2 between 25 and 30 mmHg for a
Vent
time period that varied between 6 hours and 41 days (mean
10 days). The hyperventilation group had a lower mortality
Bolt (9.8% vs 32.8%); however, survivors had increased severe
neurological sequelae. Among patients who experienced a
complete recovery, there was no difference between
groups.89 Another prior prospective, randomized study eval-
14 16 18 20 uated TBI outcome in patients who were treated with and
without hyperventilation for 5 days. Favorable outcomes
toward the hyperventilation group were seen at 3 and
6 months; however, after a year the differences were no lon-
ger significant.77
TARGET PACO2 RECOMMENDATIONS IN TBI
▪ Despite the fact that there is insufficient evidence to
establish clearly whether hyperventilation is beneficial or
deleterious after TBI, current guidelines recommend
against its prophylactic use.17
▪ In emergency situations, a short period of 10–15
minutes of hyperventilation to a PaCO2 of 30–35
mmHg is recommended to treat acute intracranial
hypertension.
▪ Targeted PaCO2 during normoventilation is 35–
40 mmHg with a pulse oxygen saturation of 95%
and/or PaO2 of 80 mmHg.
▪ Hyperventilation should be avoided during the first
24 hours after injury when CBF often is reduced critically
and the risk of ischemia is higher.
▪ If hyperventilation is used, SjvO2 or PbtO2 measurements
are recommended to monitor oxygen delivery.
▪ Do not stop hyperventilation suddenly because it may
cause rebound ICP elevation.
366 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
▪ If CBF is known and observed to be hyperemic, contrib-
uting to intracranial hypertension, there is a theoretical
basis for hyperventilation used in this personalized man-
ner, but with continued CBF monitoring. Such monitor-
ing is not currently widely available but may be an
element of future routine care.
Hyperventilation is recommended as a temporary measure
to reduce high levels of ICP in the following situations17,73:
▪ Herniation syndromes as described previously
▪ Life-threatening elevations of ICP. For example, type A
plateau waves, while investigating triggers and expect-
ing the effect of osmotherapy.
▪ Refractory intracerebral hemorrhage (ICH). Hyperven-
tilation is used in conjunction with other tier-3 level
measures, such as decompressive craniectomy, hypo-
thermia, or high doses of barbiturates.
▪ To facilitate brain relaxation during neurosurgical
interventions only when other measures have failed.
Hyperosmolar Therapy
The intravascular administration of hyperosmolar agents
such as mannitol and/or hypertonic saline (HTS) creates
an osmolar gradient that facilitates water transport across
the BBB into the circulation, where it is excreted by the kid-
neys. The net effect is a reduction of the interstitial fluid and
a decrease in ICP. For acute elevation in ICP, therapy with
either mannitol or HTS have shown similar efficacy in
decreasing ICP.90–92
Mannitol remains a commonly used hyperosmolar
agent. It is an osmotic diuretic freely filtered by the renal
glomerulus and does not undergo tubular reabsorption.
It lowers ICP through two main effects; first, through
hypoviscosity-mediated autoregulatory vasoconstriction,
also called the “rheological effect,”93 and second, it
may induce a further decrease in ICP through brain dehy-
dration in areas with intact blood brain barrier.94–96
However, this may be limited through generation of intra-
cellular idiogenic osmoles97,98 equalizing transmembrane
osmolar gradients.
Mannitol is administered as 0.5–1 g/kg as intravenous
(IV) bolus through either peripheral or central line and
can be repeated every 4–6 hours.90 Reduction in ICP is usu-
ally achieved within minutes, peaks at about 1 hour, and
last 4 to 6 hours.99 Fluid balance, renal function, and
plasma osmolality must be monitored because no therapeu-
tic effect is seen with osmolality >320 mOsm/kg. If plasma
osmolality is >320 mOsm/kg, osmolar gap (measured
osm – calculated osm) should be calculated and if
<20 mOsm/kg, mannitol should be administered. If
>20 mOsm/kg, HTS should be considered, because the risk
of renal dysfunction is higher.100 Patients with known renal
disease may be poor candidates for osmotic diuresis.
Another frequent complication related to mannitol is hypo-
tension because of its diuretic effect. Acute hypotension is
most commonly seen after rapid infusions and can be min-
imized by prolonged infusions (15–30 minutes).101
Unfortunately, mannitol can have delayed effects to
increase ICP. This can occur by four mechanisms. First, as
a potent osmotic diuretic, mannitol can have a secondary
effect to decrease systemic blood volume, thus decreasing
cardiac output and blood pressure. This can result in normal
reflex autoregulatory increases in CBV, which can increase
ICP.10 Second, the increased urine output, if not replaced
with commensurate IV fluid therapy, can elevate hemato-
crit, thus opposing the initial mannitol-induced decrease
in viscosity.102 Third, mannitol can cross the BBB in an
unpredictable manner with the possibility introduced of
rebound increase in ICP, similar to that observed with
urea.102,103 This is partly related to the reflection coefficient
of 0.9 indicating that it can even slowly diffuse into the nor-
mal brain.104 Fourth, there is a theoretical possibility of gen-
eration of increased intracellular osmolarity, via so-called
idiogenic osmoles, which may predispose to rebound
increase in brain volume with discontinuation of manni-
tol.97,98 These complications of mannitol are probably less-
ened if urine output is replaced with balanced crystalloid
infusion and if, once blood osmolarity is increased, it is
not allowed to decrease rapidly to the prior level unless clin-
ical improvement indicates that weaning of ICP-reducing
therapy is appropriate. This certainly should be considered
in any patient demonstrating periodic abrupt increases
in ICP.
HTS has increasingly been used for treatment of acute
elevated ICP, replacing mannitol as a first-line agent in mul-
tiple institutions. With a reflection coefficient of 1.0104 and
no potential to produce deleterious diuresis and undesired
hypovolemia, it has properties that made it the most attrac-
tive hyperosmolar agent.
The ability of HTS to lower ICP was initially described in
1919 by McKesson105 and it is available in different con-
centrations ranging from 2% to 23.4%.106 HTS can be given
as a bolus alone or in addition to mannitol. HTS 2% and
3% boluses can be given via a peripheral line and con-
centrations >5% should be given via a central venous
catheter because of elevated osmolarity (Table 24.5). How-
ever, in acute emergencies 3%–7.5% HTS should be admin-
istered regardless of the presence of central venous access.
Two prior prehospital trials using HTS 3% and 7.5% via
peripheral lines did not show any negative effects.107,108
Table 24.5 Commonly used hyperosmolar therapy.
Fluid Na Cl Osmolarity Dose
concentration concentration (mOsm/L)
Mannitol N/A 1098 0.5–1 g/kg
20%
Mannitol N/A 1375 0.5–1 g/kg
25%
HTS 3% 513 513 1027 150 mL
HTS 5% 856 856 1711 150 mL
HTS 4004 8008 30 mL
23.4%
Normal 154 154 308 N/A
saline
0.9%
Cl, Chloride; HTS, hypertonic saline; Na, sodium.
From Hinson HE, Stein D, Sheth KN. Hypertonic saline and mannitol therapy in
critical care neurology. J Intensive Care Med. 2013;28(1):3-11. doi:10.1177/
0885066611400688.
 24 • Perioperative Management of Acute Central Nervous System Injury 367

Administration of HTS through intraosseous access should
be done carefully and with concentrations of <7% because
of the potential risk of myonecrosis.109
The mechanism of action behind HTS involves many
theories, with the most common involving the creation of
an osmotic shift of fluid from the intracellular space to the
intravascular and interstitial space. In addition, HTS shrinks
red blood cells, making them more deformable and en-
hancing their passage across capillaries.110 A recent study
shows that HTS can reverse brain oxygenation and metab-
olism dysfunction through vasodilatory, mitochondrial, and
anti-edema effects.111 The combination of these effects
result in a biphasic reduction in ICP by improving rheologic
properties and then by osmotic activity through aquaporins
across the BBB.112 Aquaporins are water channels present
in the brain responsible for CSF production and water distri-
bution; its downregulation after TBI is associated with
development of cerebral edema. In addition, prior evidence
suggests that HTS modulates the innate immune response
by diminishing the neutrophil and endothelial cell activa-
tion leading to a reduction in microvascular injury and
permeability.113
HTS has been studied in animal models of ICH, subarach-
noid hemorrhage (SAH), and TBI. In a notable prior related
canine ICH study, HTS was associated with decreased intra-
parenchymal pressure throughout the brain, including the
perihematomal region.114 More recently, Schreibman et al.
described an experimental ICH model in which hyperosmo-
lar therapy shows reduction of neuroinflammation by caus-
ing a reduced activation of microglia/macrophages in
perihematomal tissues.115 Yin et al. suggest that HTS ame-
liorates TBI-induced cerebral edema by suppressing brain
edema, proinflammatory cytokine expression and apoptosis
via downregulation of aquaporin 4 in a rat TBI model.116 In
dogs with ICH treated with either mannitol or HTS, both
drugs effectively decreased ICP although HTS duration of
action was longer.114
In humans, the effect of HTS has been reported in ische-
mic stroke, ICH, SAH, TBI, and hepatic encephalopathy. All
studies show that HTS effectively and reproducibly reduces
ICP with concomitant improvement in CPP. Indeed, Suarez
et al.117 showed one important effect of 23.4% HTS in eight
patients as a therapy that effectively decreases ICP when
all other medical therapies do not work (Fig. 24.13).

70

60

50
Mean ICP (mm Hg)

40

30

20

10

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Cases of RIH
Fig. 24.13 This stacked-bar chart shows the mean pretreatment intracranial pressure (ICP) and the mean ICP 1 hour after treatment with 23.4% saline for
every episode of refractory intracranial hypertension (RIH). Patient distribution is as follows: 1, spontaneous basal ganglia hemorrhage; 2, subarachnoid
hemorrhage; 3, subarachnoid hemorrhage; 4–6, traumatic head injury; 7–8, subarachnoid hemorrhage; ^, subarachnoid hemorrhage; 10–12, sub-
arachnoid hemorrhage; 13–20, brain tumor. (Reproduced with permission of Suarez JI, Qureshi AI, Bhardwaj A, et al: Crit Care Med 1998;26:1118–1122.)
368 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Tseng et al. reported that in 10 patients with poor grade
SAH, ICP was found to decrease by around 75% and CBF
was enhanced in the face of decreased cerebrovascular resis-
tance, indicating potential rheologic and cerebral vaso-
dilatory of HTS 23.5%.118 Al-Rawi et al. demonstrated
that an increase in CBF is followed by improvement in
tissue oxygenation and metabolism when poor-grade SAH
patients are treated with 23.5%.119 More importantly, this
increment in tissue oxygenation was found to correlate with
improved neurologic outcomes.120
Ware et al. assessed the effects of 23.4% HTS in TBI
patients with elevated ICP refractory to mannitol. They
found HTS to have a longer effect on ICP reduction than
mannitol and to be effective in patients with Na
>150 mEq/L.121 Paredes-Andrade et al. studied HTS
23.4% on ICP in the setting of different serum and CSF
osmolarities. HTS was found to decrease ICP irrespective
of serum or CSF osmolarity, possibly indicating a nonosmo-
tic mechanism of action.122 More recently, a 30% HTS
concentration was tested in TBI and no associated harmful
or hematologic abnormalities were observed.123 In 2013,
Eskandari et al. tested HTS 14.6% after TBI and showed
that patients who exhibited refractory intracranial hyper-
tension can be treated effectively and safely with repeated
boluses of 14.6% with no significant change in renal func-
tion or hemodynamics.124 Oxidative stress processes play
an important role in secondary brain injury. In a study
of 33 adults with TBI, HTS showed antioxidant effects by
decreasing the amount of serum total antioxidant power,
reactive oxygen species and nitric oxide.125 Diringer
et al. studied the effects of HTS 23.4% and mannitol
20% on CBF, CBV, OEF, and cerebral metabolic rate
(CMR) O2 in nine patients who developed cerebral edema
with midline shift from acute ischemic stroke. They found
that increased CBF on the contralateral unaffected hemi-
sphere was dependent on mean arterial pressure. No effect
on CBV was observed, arguing against the compensatory
cerebral vasoconstriction previously proposed as a mecha-
nism for ICP reduction.126
Efficacy of HTS for Reduction of ICP
Several small studies in humans have assessed the ability of
HTS to reduce ICP. A retrospective study by Qureshi et al.127
showed that HTS decreases ICP in head trauma in postop-
erative brain edema but not nontraumatic ICH or ischemic
stroke. Schatzman et al. performed a prospective nonrando-
mized evaluation of HTS in severe head injury and found
that it effectively reduced ICP.128 A subsequent prospective
randomized study by Vialet et al.129 in TBI patients found
better ICP control compared with mannitol. Another pro-
spective randomized study did not show better ICP control
with HTS compared with standard therapy. However, in
this study the sample size was relatively small and the
HTS patients were sicker on entry into the study.130 Three
studies report that HTS can be safely and effectively used in
children to decrease ICP after TBI.131–133 Suarez et al.117
studying severe SAH patients reported that HTS therapy
effectively decreased ICP while concomitantly increasing
CBF (see Fig. 24.13). Schwartz et al.128 evaluated HTS/
hetastarch therapy in ischemic stroke patients with high
ICP, compared with mannitol. Both therapies decreased
ICP, but the HTS group had better control.
Patients with intracranial hypertension associated with
hepatic encephalopathy have also been demonstrated by
Murphy et al.134 to sustain ICP decrements after HTS. More-
over, HTS and mannitol have been reported as a useful
bridge therapy while awaiting liver transplant in patients
who suffer from cerebral edema.135
Although many studies show the efficacy of HTS in
improving ICP and other parameters, the effect of this inter-
vention on long-term clinical outcomes remains unclear. In
1991, Vassar et al.136 evaluated this hypothesis showing a
trend for better outcomes in HTS-treated patients. One con-
trolled trial randomly assigned 226 patients with TBI to pre-
hospital resuscitation with 250 mL HTS 7.5% or the same
volume of Ringer lactate. Survival until hospital discharge,
6-month survival, and neurologic function 6 months after
injury were not different.137 This study did not assess the
impact of systematic use of HTS throughout the hospital
course. Koenig et al. evaluated the effect of 23.4% HTS on
reversal of transtentorial herniation in 68 patients who suf-
fered from various intracranial pathologies. HTS reversed
transtentorial herniation quickly and reduced ICP, but clin-
ical outcomes remained poor.138
Overall, mannitol and HTS have been compared in some
randomized trials of patients with intracranial hypertension
derived from a variety of causes (traumatic brain injury,
stroke, tumors).90,91,129,139,140 Meta-analyses of these trials
have found that HTS appears to have greater efficacy in
managing elevated ICP, but clinical outcomes have not been
systematically examined.141,142 Further clinical trials are
required to clarify the appropriate role of hypertonic saline
infusion versus mannitol in the acute management of intra-
cranial hypertension.
HTS clearly has the potential to exert a positive impact in
the management of intracranial hypertension. However,
there are concerns expressed about possible deleterious
effects. Perhaps one of the most worrisome concerns is renal
failure. This was mentioned in a report by Peterson131
wherein 2 of 10 children developed reversible renal fail-
ure, also, however, related to multiorgan failure and sepsis.
Nonetheless, the issues were further underscored in
editorials by Valadka et al.143 and Dominquez et al.144
but with disagreement about this as a significant risk
expressed by Bratton et al.145 Other potential adverse effects
were reviewed by Suarez146 and include:
INTRACRANIAL COMPLICATIONS
▪ Rebound edema.
▪ Disruption of the BBB (“osmotic opening”).
▪ Excess neuronal death. Postulated after continuous
infusion of 7.5% saline in a rat model worsened outcome
after transient ischemia.147 This has not been found to be
clinically relevant.
▪ Alterations in the level of consciousness associated with
hypernatremia.148
▪ Central pontine myelinolysis. This is typically associated
with too-rapid correction of (chronic usually) hyponatre-
mia.149 It has not been associated with the use of HTS in
humans from a normal sodium concentration.
 24 • Perioperative Management of Acute Central Nervous System Injury
SYSTEMIC COMPLICATIONS
146
▪ Congestive heart failure.
▪ Transient hypotension. This has been reported inanimals
after rapid intravenous hypertonic fluid infusions.150,151
▪ Decreased platelet aggregation and coagulation factor
abnormalities of HTS.152 However more recent evidence
failed to show this effect in coagulation using rotational
thromboelastometry (ROTEM) to assess coagulation and
platelet function. Patients receiving HTS or mannitol
for ICP control did not exhibit impaired coagulation
function.153
▪ Hypokalemia and hyperchloremic metabolic acidosis
with large quantities of HTS.154
▪ Phlebitis. Infusion should be done via a central venous
catheter.146
▪ Renal failure.132,143–145 As discussed previously, the
relationship to HTS was not clear in the report in which this
was described. There are no reports of renal failure in ani-
mals or humans in the absence of more common ICU
etiologies of renal failure, such as sepsis and organ failure.
CSF Drainage
CSF volume is reduced by removal via ventricular drain
(see Figs. 24.5 and 24.6). This can be affected by setting
the drainage at a prescribed level above the midbrain or pre-
scribing that the drain be opened anytime ICP exceeds 20–
25 mmHg. Leaving a drain open risks excessive CSF drainage
when the patient coughs or with drain manipulation in the
course of routine nursing procedures and can contribute to
collapse of the ventricles or subdural hemorrhage. Excessive
and abrupt decrease in local pressure around the drain can
produce intracranial gradients, leading to a herniation syn-
drome. Leaving the drain clamped and monitored, however,
risks the development of untreated intracranial hypertension.
Level Tier 2: L2.
▪ Hypertonic saline infusion: If HTS has been initiated,
sodium goal should be established. In general, a sodium
level >160 mEq/L is unlikely to provide any extra bene-
fit. In order for HTS to be an effective ICP control mea-
sure, an intact BBB and a sodium gradient (Naserum -
Nabrain) must be present to promote the escape of water
from the brain tissue. If adequate ICP control is achieved
with HTS infusion, the serum sodium concentration at
which ICP was controlled should be maintained until
cerebral edema has subsided. (See Tier 1 section on
hyperosmolar therapy for detailed information.)
▪ Cerebral blood volume reducing drugs: propofol, etomi-
date, lidocaine.
CBV Decreasing Drugs
CBF decreasing (and therefore CBV decreasing) drugs that can
decrease ICP include barbiturates,155,156,157 benzodia-
zepines,158 etomidate,159,160 and propofol.155,161 Notably,
all are CNS depressants and become ineffective once the EEG
become isoelectric. Thus, their use indicates acceptance on
the part of the clinician to lose any reliable neurologic
369
examination. Unlike hyperventilation, these agents decrease
CBF coupled to CMR. Thus, the CBF decreases should not
provide a milieu for anaerobic metabolism. Lidocaine also
decreases CBF and CMR to decrease ICP although with a less
pronounced decrement in neurologic function.162,163 Manni-
tol’s immediate effects are also thought to be mediated by
reduction in cerebral blood volume, although this is undoubt-
edly minor and temporary as a mechanism. Barbiturates
are discussed as a tier-3 therapy in the next section.
PROPOFOL
Propofol has been shown to reduce ICP by decreasing
CMRO2 and CBF volume.164 In acute situations, it can be
given as a bolus of 1–3 mg/kg and continued as an infusion
in mechanically ventilated patients. Although propofol has
some ICP-reducing properties it also decreases blood pres-
sure significantly, especially when given as a bolus, which
should be corrected with fluids or vasopressors aimed at
maintaining CPP.165 Its use should be guided by bispectral
index (BIS) monitoring or other forms of EEG assessment.
Recent evidence shows that BIS is more reliable than Rich-
mond Agitation and Sedation Scale (RASS) for maintaining
a stable sedation status and ICP. Deeper sedation levels (BIS
40–50) are associated with a faster decrease in ICP.166 A
small subset of patients treated with propofol may develop
a propofol infusion syndrome (PRIS). PRIS is a collection
of clinical and laboratory findings that develop after propofol
infusion and are characterized by metabolic acidosis, ele-
vated CK, hyperkalemia, elevated liver enzymes, rhabdomy-
olysis, triglyceride elevation, and acute renal failure.167
PRIS is more frequently seen after long-term (>48 hours)
or high-dose infusion >4 mg/kg/h or 67 μg/kg/min. Man-
agement includes immediate discontinuation of propofol.
Its use should be limited to no more than 48 hours. Cardiac
dysfunction and arrhythmias are a major cause of mortality.
Cardiogenic shock should be managed with inotropic sup-
port and mechanical devices and extracorporeal support
in severe cases.168,169 If propofol is infused at these extreme
rates (200 μg/kg/min) it should only be done temporarily
while other corrective measures are executed. Children suf-
fering severe TBI appear to be particularly sensitive to PRIS.
Thus, this ICP lowering strategy is frequently avoided.
ETOMIDATE
Etomidate decreases ICP by decreasing CBF and CMR.159,160
Its hemodynamic effects are not as potent as those of barbi-
turates with the result that it can decrease ICP without
decreasing CPP as much as with thiopental. It is not suitable
for prolonged infusion to control ICP because of inhibition of
adrenal corticosteroid synthesis170 unless steroids are con-
comitantly administered and because of the possibility of
renal compromise resulting from propylene glycol toxicity.171
Nonetheless it can be used for brief periods as an adjunct in
ICP control during anesthesia induction, especially if there is
hemodynamic concern.172 The dose is 0.1–0.3 mg/kg IV.
LIDOCAINE
Lidocaine decreases ICP by decreasing CBF and CMR but with-
out as much CNS depression as barbiturates.162,163 It is not as
370 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
potent or reliable as barbiturates in decreasing ICP but it can
be useful to decrease ICP when there is hemodynamic insta-
bility or when barbiturates are thought to be not tolerated
hemodynamically. It can be useful prior to airway manipula-
tions163 but is not typically used in prolonged therapy of intra-
cranial hypertension. It is most useful when given 0.5–
1.5 mg/kg IV or intratracheally for acute treatment of high
ICP, particularly if associated with airway manipulation.
Level Tier 3: L3. Tier 3 measures account for the most
aggressive level of treatment in acute intracranial hyperten-
sion and as such carry the most serious side effects. Inter-
ventions include:
▪ barbiturates
▪ hypothermia
▪ transient hyperventilation to PaCO2 25–35 mmHg.
BARBITURATES
The use of barbiturates to decrease ICP is based on their abil-
ity to reduce CBF, CBV, CMR, and seizure activity.155–157
Pentobarbital infusion is generally used with a loading dose
of 5 to 20 mg/kg as a bolus, followed by maintenance infu-
sion of 1 to 4 mg/kg/h titrated to ICP/CPP goal or burst sup-
pression of 5–20 seconds on continuous
electroencephalogram (EEG). EEG burst suppression is an
indication of maximal dosing. Increasing the barbiturate
dose beyond that needed to produce burst suppression is
unlikely to provide further decreases in ICP because further
decrements in CMR are not thought to occur at doses
beyond that needed for significant burst suppression.173
Alternatively, serum pentobarbital levels can be monitored
aiming for 30–50 μg/mL. The pentobarbital infusion is con-
tinued for 24–96 hours while the processes driving elevated
ICP are treated.174 Discontinuation of barbiturate therapy
can be considered when (a) there is no decrease in ICP with
barbiturate loading, (b) despite an initial favorable response,
intracranial hypertension recurs despite maximal barbitu-
rate therapy, or (c) ICP has remained below 15 mmHg for
longer than 24–48 hours. In the latter case barbiturates
should be weaned with continued ICP monitoring.
The therapeutic value of this “barbiturate coma” is some-
what unclear. In a prior randomized trial of 73 patients with
intracranial hypertension refractory to standard therapy,
patients treated with pentobarbital were 50% more likely
to have their ICP controlled. However, there was no differ-
ence in clinical outcomes between groups.175 Two other
RCTs reported that barbiturates did not significantly affect
mortality outcome in TBI.176,177 Ward et al. assigned 53
patients to either prophylactic pentobarbital treatment versus
no pentobarbital treatment; there was no survival difference.
Moreover, higher incidence of hypotension was observed in
the pentobarbital group.177 Schwartz et al. studied the effect
of mannitol and pentobarbital on ICP control on patients with
and without hematoma after TBI. In both cohorts ICP control
was worse with pentobarbital.176 In general, the use of bar-
biturates is a "last-ditch" effort, because several studies show
that their ability to lower ICP does not appear to affect out-
comes. The most recent Brain Trauma Foundation Guidelines
recommend against administration of barbiturates to induce
burst suppression measured by EEG as prophylaxis against
the development of intracranial hypertension. Additionally,
high-dose barbiturate administration is recommended to con-
trol elevated ICP refractory to maximum medical and surgical
treatment. Hemodynamic stability is essential before initia-
tion of therapy.17
There are several adverse effects of prolonged barbiturate
therapy for high ICP. Barbiturates blunt the neurologic
examination. Thus, a growing intracranial mass lesion or
other neurologic exacerbation may not be obvious until it
causes an increase in ICP or increasing barbiturate require-
ment to maintain normal ICP. Hypotension and respiratory
depression may occur. Blood pressure may need to be phar-
macologically supported and intubation and mechanical
ventilation are mandatory. Dysfunction of the alimentary
tract may occur making it difficult to use enteral nutrition.
Thermoregulation is disturbed. Hypothermia may occur
inadvertently and infection may be masked because there
is no fever. Finally, physical addiction and tolerance may
occur with prolonged use making it difficult to discontinue
barbiturate treatment without seizure.
Thiopental 1–4 mg/kg can be given, repeated as needed,
to control ICP. It is subsequently infused as needed to con-
trol ICP. In this setting, thiopental has been reported to pro-
duce hypokalemia with induction and rebound
hyperkalemia on drug cessation
HYPOTHERMIA
See section on temperature control.
Surgical Decompression
Selected patients with evidence of rapid neurological deteri-
oration from focal-space occupying lesions and those who
failed medical management may benefit from surgical
decompression, even if medical therapy has not been
attempted. The following are procedures considered for dif-
ferent emergent scenarios.
▪ Evacuation of extra-axial collection (i.e., subdural or
epidural hematoma).
▪ Resection of intracerebral lesions caused by abscesses or
lobar hemorrhages.178 Occasionally, lobectomies can be
performed as life-saving procedures.
▪ Posterior fossa decompression in the event of obstructive
hydrocephalus resultant from vasogenic edema caused
by tumors and ischemic or hemorrhagic strokes.
▪ Uni- or bilateral decompressive hemicraniectomy after
traumatic brain injury or malignant ischemic stroke.
▪ Note: Surgical decompression can be performed at any point
in the tiered algorithm at the discretion of the neurointensi-
vist and neurosurgeon, if conventional therapy fails to
improve ICP or evidence of impending herniation exists.
Decompressive Craniectomy
First described by Thomas Kocher in 1901 and subse-
quently by Cushing in 1908,179 decompressive craniectomy
(DC) is a surgical procedure in which part of the skull uni- or
bilaterally is removed and the underlying dura opened. DC
removes the rigid confines of the cranial vault, allowing fur-
ther expansion of the intracranial contents with subsequent
reduction of intracranial hypertension and brain herniation
risk.180 Although intravascular arterial blood accounts for
the majority of the intracranial blood volume, venous
 24 • Perioperative Management of Acute Central Nervous System Injury
contribution to ICP is commonly overlooked. Diffuse brain
edema can lead to generalized venous compression and a
cycle of venous hypertension. In a recent study after TBI,
alleviation of venous sinus compression might have contrib-
uted to the ICP-reducing effect of DC.
Although DC has been investigated in a number of neuro-
logical conditions, RCTs have only been evaluated in TBI and
stroke. DC can be a primary or secondary procedure. A cohort
study of patients with traumatic subdural hematoma (SDH),
demonstrated lower mortality in patients undergoing pri-
mary DC compared with conventional craniotomy where
the bone flap is replaced. However, there is no high-quality
evidence to support this approach. The Randomized Evalua-
tion of Surgery with Craniectomy for patients Undergoing
Evacuation of Acute Subdural Haematoma (RESCUE-ASDH)
trial is a multicenter, randomized trial comparing the effec-
tiveness of primary DC versus craniotomy and bone-flap
replacement after evacuation of an ASDH in adult head-
injured patients (http://www.rescueasdh.org/); subjects
recruitment was completed in 2019. Results of trial are still
pending. Secondary DC is most commonly undertaken as a
last-tier (life-saving) intervention in a patient with severe
intracranial hypertension refractory to tiered escalation of
interventions to control ICP.180 There are three main
approaches to DC (bifrontal, uni- or bilateral hemicraniect-
omy, suboccipital). The craniectomy must be of sufficient size
to allow effective ICP control.
DECOMPRESSIVE CRANIECTOMY AND TBI
Nonrandomized trials have shown that DC is an effective
therapy to control intracranial hypertension and to improve
survival after severe TBI. However, it seems to be at the
expense of long-term functional outcome with variable
degrees of severe disability.181–183 Two recent randomized
clinical studies—the Decompressive Craniectomy (DECRA)
study184 and the Randomized Evaluation of Surgery with
Craniectomy for Uncontrollable Elevation of Intracranial
Pressure (RESCUEicp) study185—investigated DC to control
elevated ICP after severe TBI. The DECRA study randomized
155 adults to either bifrontal craniectomy or standard
care for elevated ICP. DC was associated with lower ICP
than medical treatment, but the long-term outcome was
unfavorable (vegetative state or severe disability). The
RESCUEicp study investigated the effect of bifrontal craniect-
omy or unilateral hemicraniectomy as a last-tier therapy for
refractory intracranial hypertension. A study was made of
408 subjects randomized to either continuing medical
treatment or DC if ICP > 25 mmHg for at least 1hour refrac-
tory to medical treatment. Compared with medical manage-
ment, DC resulted in lower mortality at 6 months (48.9%
vs 26.9%, respectively; P< 0.01), but higher rates of vege-
tative state and severe disability.
DECOMPRESSIVE CRANIECTOMY AND STROKE
Several trials have investigated the effect of DC on malignant
MCA stroke. The Decompressive Craniectomy in Malignant
MCA infarction (DECIMAL),186 the Decompressive Surgery
for the Treatment of Malignant Infarction of the Middle Cere-
bral Artery (DESTINY) trial,187 and Hemicraniectomy After
Middle Cerebral Artery infarction with Life-threatening
Edema Trial (HAMLET).188 The three trials confirmed the
371
mortality benefit of DC in patients with malignant MCA
stroke <60 years old, but with no individual improvement
in functional outcome. Hemicraniectomy in patients
>60 years old was investigated in the DESTINY II trial.189
Compared with medical treatment, hemicraniectomy within
48 hours of malignant hemispheric infarction resulted in
lower mortality (33% vs 70%; P< 0.001) but a higher pro-
portion of severely disabled survivors (mRS 4–5) in patients
between 61 and 82 years of age. Two systematic reviews
have summarized clinical findings after DC in stroke; irrespec-
tive of age, DC significantly reduces mortality and improves
functional outcome in adults with malignant MCA infarction
but with a nonsignificant increase in the risk of survival with
major significant disability.190,191
DC is a major surgery and it comes with associated poten-
tial complications including subdural hygromas, infection,
hydrocephalus, cerebral herniation through skull defect,
CSF leak, and ipsi- or contralateral EDH/SDH.192,193 The
“syndrome of the trephined” initially described by Grant
and Norcross in 1939 has become more frequently associated
with the resurgence of DC for intracranial hypertension. It
often occurs after a period of recovery and consists of seizures,
weakness or paralysis, sensory changes, altered mental sta-
tus, and headache.194,195 The treatment is cranioplasty.
A much less common but potentially lethal complication is
paradoxical transtentorial herniation after hemicraniect-
omy with a large skull defect. This may occur at any time after
DC, even after several months.196 DC renders the supraten-
torial space vulnerable to atmospheric pressure, which must
be buffered across potential herniation sites by CSF pressure
(i.e., foramen magnum or skull defect). When this buffer is
compromised by CSF leaks, lumbar puncture, or ventricu-
lostomy drains, herniation can occur. Usual symptoms
include those of acute ICP elevation such as decreased level
of consciousness, anisocoria, bilateral pupillary dilatation or
loss of reactivity, autonomic instability. However, treatment
aimed toward ICP control will not be effective and may aggra-
vate the situation. Instead, the patient should be placed
supine or in the Trendelenburg position, CSF drains should
be clamped, crystalloid fluid should be administered intrave-
nously, and an epidural blood patch should be placed for
patients with dural CSF leak.
Decompressive craniectomy has a major role in treating
intractable intracranial hypertension in severe TBI and
malignant stroke, but its meaningful benefits remain
unclear. Although DC is considered an option for ICP con-
trol, it should not be routine for management of intracranial
hypertension. Decision to perform DC should encompass not
only the acute scenario, but also the most likely long-term
outcome. The patient’s family should be informed exten-
sively about this procedure before a decision is taken.
PHYSIOLOGIC ISSUES
The essence of satisfactory perioperative neurologic care is
to provide a physiologic and biochemical milieu that will
promote a good recovery.
Cerebrovascular Reserve
Central to physiologic considerations in management of the
acutely injured brain are issues related to cerebrovascular
reserve. Simply stated, this refers to the capacity for the
372 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
brain to compensate successfully for physiologic stresses
such as hypoglycemia, hypoxemia, hypotension, and ane-
mia. In all of these situations, vasodilation arises to provide
a compensatory increase in CBF.
Animal experiments indicate that it is possible to produce
a condition in which cerebrovascular reserve is compro-
mised with increased tendency to cerebral infarction.197
For example, occlusion of one carotid artery or production
of moderate hypoxemia do not produce symptoms on the
own because cerebral vasodilatation occurs to compensate.
Indeed, some contend that arterial hypoxemia, occurring
with normal cerebral vascular compensatory mechanisms,
does not cause brain damage. Of course, one contributing
factor to this notion is that hypoxic myocardial dysfunction
produces organismic death such that isolated neuronal
injury cannot occur. However, add hypoxemia to carotid
occlusion, or vice versa, and a stroke occurs because com-
pensatory mechanisms, already fully utilized, cannot
accommodate the further decrease in O2 supply.197 Exam-
ples of variants of this situation abound clinically.198–201
Such examples of attenuated cerebrovascular reserve
include cerebral edema, hypoxemia, anemia, carotid steno-
sis, peri-infarct penumbra, and so on. In each of these situ-
ations, although not easy to quantitate, it is clear that added
compromise of O2 supply to the brain risks neuronal
injury.201
Airway Evaluation and
Management
CONCERNS
In patients with a damaged central nervous system, there
are several concerns with respect to airway management.
First, if there is intracranial pathophysiology, the associated
hemodynamic or respiratory changes associated with air-
way manipulation can lead to elevated ICP, exacerbated
brain edema, or worsened intracranial hemorrhage.
Although many patients arrive in the operating room
already intubated, some, particularly those with extradural
hematoma, may be conscious and breathing spontaneously.
Airway management in TBI can be complicated by several
factors, including urgency of situation, uncertainty of cervi-
cal spine status, uncertainty of airway obstruction (caused
by presence of blood, vomitus, debris in the oral cavity, lar-
yngopharyngeal injury, or skull base fracture), full stomach,
intracranial hypertension, and uncertain volume status. All
patients with TBI requiring urgent surgery must be assumed
to have a full stomach. If there is spinal cord injury, which
may not be initially clinically apparent, then cervical spine
manipulation risks producing or worsening any acute plegic
deficits. Most head-injured patients are assumed to have an
unstable cervical spine until definitive clearance can be
obtained.
EVALUATION
Evaluation of the airway is performed as for most preanes-
thetic evaluations. However, specific items need to be
sought in the history and physical examination:
1. NPO status. This is helpful history but impacts little on
plans as most acutely injured patients are assumed to
have a full stomach.
2. Evidence of elevated intracranial pressure. This may
affect choice of drugs used to support intubation. (See
previously for clinical signs and symptoms of intracranial
hypertension.)
3. History of the incident. This can lead to approaches based
on the cause of the injury being direct trauma or perhaps
a medical problem that led to trauma.
4. Other medical history if available.
5. Presence of neurologic deficits, especially paraplegia or
quadriplegia. This may impact on the choice of drugs to
support intubation and the methods by which intubation
is performed, or it may suggest possible autonomic dys-
function. Quadriplegic patients have a significant atten-
uation of the catecholamine response to intubation.202
6. Evidence of airway injury.
7. Evidence of aspiration or other impediments to adequate
gas exchange. Associated lung injuries or aspiration
related to altered mental status will lead to faster desa-
turation during intubation and probably worsen the
neurologic outcome.
THERAPEUTIC OPTIONS
The main options to consider in airway management have
to do with whether and how deeply to produce CNS depres-
sion and which tool will be used to effect intubation of the
trachea. There are pros and cons to each approach and con-
siderable clinical judgment is needed to match the spectrum
of benefits and risks to the underlying disease processes.
Awake Versus Asleep
There is a continuum of anesthetic states that may be used,
varying from awake and unsedated to fully anesthetized
with neuromuscular blockade. In the context of possible
intracranial hypertension or hemorrhage, the side effects
of anesthetic drugs can be usefully used to control systemic
and intracranial hypertension. The full spectrum of effects of
anesthetic drugs is beyond the scope of this chapter. But,
briefly, thiopental, propofol, and etomidate have direct
ICP-reducing qualities that can be of use during intubation,
a procedure well-known to produce intracranial hyperten-
sion.203,204 Attenuation of systemic hypertension can be
augmented with judicious use of an opioid such as fentanyl
in addition to a blood pressure–reducing drug such as thio-
pental or propofol. Neuromuscular blockade can be
achieved with vecuronium or rocuronium, neither of which
has any reported cerebrovascular effects.205 Succinylcho-
line can also be used although concerns remain about it
causing increased ICP, probably related to increased cere-
bral blood flow inducing afferent spindle stimulation.206
However, after a large bolus of one of the usual aforemen-
tioned induction drugs, succinylcholine seems to be associ-
ated with no significant problems. Moreover, its use is
theoretically safe with hyperacute onset paraplegia or quad-
riplegia (i.e., before nicotinic receptor upregulation) but
Dr. Cruz and Dr. Kofke refrain from its use at any time with
spinal cord injury patients because of concern about the
 24 • Perioperative Management of Acute Central Nervous System Injury
speed of receptor upregulation or inaccurate history leading
to fatal hyperkalemia.207
Awake endotracheal intubation is an option for coopera-
tive patients with acute spinal cord injury (SCI). However,
its use has advantages and disadvantages (Table 24.6). Ret-
rospective studies have not shown differences in neurologic
outcome with awake versus asleep fiberoptic intubation in
acute SCI. Thus, the choice of technique should be based
on clinical situation, patient cooperation, and clinical
expertise.208
Cricoid or No Cricoid Pressure? It has been hypothesized
that any unidirectional force applied to the cervical verte-
brae during cricoid pressure may cause excessive neck
movement and exacerbate preexisting lesions.209 Studies
have demonstrated that cricoid pressure causes cervical
spine displacement of different degrees when the posterior
aspect of the neck is not supported.210–212 The clinical impli-
cation of these movements was assessed retrospectively in
patients who had C-spine injuries and they were found to
be free of neurologic impairment.213 However, it would be
sensible to avoid movements of the potentially fractured cer-
vical spine, if at all possible. The double-handed maneuver,
which is popular in trauma patients to provide support to
the posterior cervical spine and to provide stabilization to
the posterior aspect of the neck, seems to be a safer alterna-
tive to the single-handed maneuver.214 The assistant per-
forming bimanual CP should not be assigned to other
duties until intubation has been completed. If the bimanual
technique is obstructing the glottic view, it may need to be
switched back to a single-handed maneuver to improve lar-
yngoscopic visualization.215 Cricoid pressure utilization is
controversial in SCI because forceful pressure over the site
of the C-spine fracture can cause displacement. Moreover,
the efficacy of cricoid pressure to prevent regurgitation
has been questioned. These authors do not routinely use cri-
coid pressure during rapid sequence induction for patients
with acute cervical SCI; a gentle BURP maneuver could
be utilized to improve glottic view.
Cervical Spine Distraction During Airway
Instrumentation. Although neurologic impairment dur-
ing airway manipulation is very uncommon, all airway
maneuvers are associated with some degree of C-spine
Table 24.6 Awake fiberoptic intubation.
Advantages Disadvantages
▪ Neurologic evaluation can be ▪ Time consuming.
performed after airway ▪ Even with adequate air
management. topicalization, coughing and
▪ Spontaneous ventilation is gagging may still occur with
maintained throughout the potential for C-spine motion.
procedure. ▪ Visualization may be difficult
▪ Head and neck are with excessive secretions,
maintained in neutral presence of blood and vomitus.
position while airway is ▪ Sedation is commonly required
secured. and might obscure clinical
assessment.
▪ Requires technical expertise.
▪ Risk of local anesthesia
systemic toxicity.
373
mobilization. However, this is based only on retrospective
evidence and expert opinion.208,216,217 In patients with cer-
vical cord injuries, it is generally better to use little or no
anesthetic drugs, except as needed for safe conscious seda-
tion and then to use fiberoptic bronchoscopy with good topi-
calization. This does require cooperation of the patient and if
that is not possible or the intubation needs to be done in an
emergency, direct laryngoscopy with in-line immobiliza-
tion218 has not been associated with apparent neurologic
complications, although its anatomic efficacy has been
questioned. Notably, Lennarsen et al.219 reported in fresh
cadavers that neither traction nor in-line immobilization
prevented distraction nor angulation of the C4–5 injured
cervical spine with laryngoscopy by Macintosh blade.
Because concern persists about this approach producing
or exacerbating cervical spine injury, it remains reserved
for emergencies or for the uncooperative patient in whom
general anesthesia with rapid intubation by laryngoscopy
is the only viable option. In fact, direct laryngoscopy with
manual in-line stabilization is the most commonly used
technique for emergency endotracheal intubation in
patients with acute cervical SCI, and it is recommended
according to Advanced Trauma Life Support guidelines.
In a survey of 122 physician anesthesiologists, indirect tech-
niques were preferred for elective intubation of patients with
cervical spine injury (CSI) and direct laryngoscopy was pre-
ferred for emergency intubation.220
There have been many reports of various approaches to
endotracheal intubation with various endpoints. Some are
simply case reports indicating that a given technique
worked in a given patient with cervical vertebral instability.
However, a prospective randomized study that provides con-
clusive outcome data favoring a given approach remains
unpublished. Nonetheless, there are some studies that used
other reasonable surrogate endpoints that can provide an
element of evidentiary support for some approaches.
Basic airway maneuvers such as mask ventilation, chin
lift, and jaw thrust have the potential for displacement
of the cervical spine even when a cervical collar is in
place.221,222 The sniffing position entails flexion of the lower
neck and extension of the head on the upper neck. In anes-
thetized normal patients, the majority of cervical movement
during classic Macintosh laryngoscopy occurs at the occipi-
toatlantal and atlantoaxial articulations (C1–C2). Lower
cervical segments are displaced only minimally with direct
laryngoscopy.223,224 In cadaver studies with cervical insta-
bility, chin lift and jaw thrust were found to result in
more C-spine displacement and increase in disc space than
either oral or nasal intubation, but jaw thrust without
chin lift or neck extension resulted in significantly reduced
displacement.225
Turkstra et al.226 in normal anesthetized patients carried
out a fluoroscopic evaluation of neck extension produced by
bag-valve-mask ventilation (BVM), Macintosh blade laryn-
goscopy, light wand, and GlideScope. They found minimal
movement during BVM, with the most extension noted by
Macintosh blade laryngoscopy. Both light wand and Glide-
Scope produced much less neck extension than Macintosh
blade laryngoscopy with the light wand taking an equiva-
lent time and the GlideScope taking longer.
Rudolph et al.227 compared Macintosh laryngoscopy
with a rigid Bonvil fiberoptic scope reporting less cervical
374 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

spine motion with the rigid fiberoptic scope but it was not with the Macintosh laryngoscope in humans with C-spine
zero. Hastings et al.224 evaluating external extension with- immobilization, Suppan et al. reported that the Airtraq
out fluoroscopy reported very little neck extension with the was associated with a significant reduction of intubation
Bullard laryngoscope compared with Miller and Macintosh failure at the first attempt, a higher rate of Cormack-Lehane
blades. grade 1, reduction of operational time, and oropharyngeal
Robitaille et al.228 reported that during intubation under complications.235 Br€ uck et al. compared C-MAC and Glide-
general anesthesia with neuromuscular blockade and man- Scope in patients with C-spine disorders and reported that
ual in-line stabilization, the use of GlideScope produced bet- both devices provide an excellent glottic view, but tracheal
ter glottic visualization but did not significantly decrease intubation was more successful on the first attempt with the
movement of the nonpathologic C-spine when compared GlideScope.236 Yumul et al.237 compared the C-MAC video
with direct laryngoscopy. laryngoscope with the standard fiberoptic scope with an eye
Brimacombe et al.229 in cadavers with C3 instability com- piece for intubation in patients with C-spine immobilization.
pared the effects of facemask application, esophageal/tra- The glottic view at the time of intubation did not differ sig-
cheal Combitube, laryngoscopy guided intubation, flexible nificantly with the two devices; however, the C-MAC facil-
fiberoptic-guided intubation, intubating laryngeal mask air- itated more rapid tracheal intubation compared with the
way (LMA), and maximal head/neck flexion and extension. fiberoptic scope. The peak heart rate response following
Displacement was negligible with the fiberscope, moderate insertion of the tracheal tube was also lesser in the C-
with LMA and with facemask/chin lift, worse with laryngos- MAC group. Holmes et al.238 reported that among patients
copy, and worst with Combitube. Extension of the neck data with acute CSI at a high-volume academic trauma center,
as a percentage of the maximum seen with purposeful neck video laryngoscopy was the most commonly used initial
extension are presented in Fig. 24.14. intubation technique. Awake fiberoptic bronchoscopy
In another fluoroscopic study of C-spine injured cadavers, (FOB) and direct laryngoscopy were performed infrequently
Gerling et al.230 compared laryngoscope blades combined and no cases of neurological deterioration secondary to air-
with in-line immobilization, reporting that the Miller blade way management occurred with any method.
produced less cervical vertebral displacement than the Mac- Fiberoptic intubation, either asleep or awake, causes little
intosh blade and that manual immobilization is superior to motion of the cervical spine.239 However, coughing and/or
cervical collar during intubation. gagging can occur during awake intubation if not ade-
The use of video laryngoscopes such as GlideScope, quately topically anesthetized, resulting in motion of the
C-MAC, McGrath, Airtraq, etc., has been associated with injured spine. In fact, fiberoptic scope in an emergency sit-
improvement in glottis visualization when manual in-line uation with providers who are inexperienced with this
stabilization is used and probably less C-spine displace- device has a high failure rate and can be very challenging
ment.228,231–233 However, procedural time may be longer if the patient is uncooperative or with excessive blood or
for inexperienced clinicians. Ruetzler et al. reported that secretions in the airway.240
in a simulated setting of difficult intubation, GlideScope In summary, airway management in the presence of
and C-MAC were superior compared with conventional acute CSI is probably the most challenging scenario for
direct laryngoscopy.234 In a recent systematic review and the anesthesiologist. Traditionally, awake fiberoptic has
meta-analysis of RCTs comparing any intubation device been recommended because it limits cervical spine motion
during tracheal intubation and allows neurological exami-
nation after the procedure. However, in the real world the
100 brain-injured patient typically is not cooperative such that
90 the agitation that might ensue with fiberoptic attempts
% maximal displacement

80 can produce unacceptable patient-induced neck movement.

70 This then results in the need for increasing amounts of seda-
60 tion, in the context of a full stomach. This may or may not
50 produce sufficient sedation while putting the patient in an
40 unacceptable in-between state of pharmacologically
30 depressed sensorium with persisting agitation and an
20
unprotected airway. The situation may be enough of an
10
emergency that the use of a fiberoptic technique, in a setting
of developing hypoxemia, full stomach, possible airway
0
injury with associated secretions, means the planned non-
Facemask and chin
lift/jaw thrust

Laryngoscopy

Fiberscope nasal
intubation

Esophageal/tracheal
Combitube

Intubating LMA

expeditious intubation has an unacceptable risk of hypox-

emia and/or aspiration. For these reasons, in such
situations many clinicians advocate direct laryngoscopy
with appropriate doses of CNS depressants and neuromus-
cular blockade with immobilization or in-line traction. If a
difficult airway problem arises in this situation, there should
Maneuver be no extreme laryngoscopy attempts that will clearly risk
quadriplegia. Rather the algorithm should move quickly
Fig. 24.14 Summary of effects of various airway maneuvers on fresh
cadavers with experimentally induced cervical instability. LMA, laryn-
to LMA to at least establish oxygenation followed by secur-
geal mask airway. (From data of Brimacombe J, Keller C, Kunzel K, et al: ing the airway via LMA and then by intubation, or by
Anesth Analg 2000;91:1274–1278.) tracheostomy.
 24 • Perioperative Management of Acute Central Nervous System Injury
Currently, with the widespread availability of video laryn-
goscopy, fiberoptic use is declining dramatically. Assuming
care is taken to limit neck movement, providers should use
the intubation technique with which they have the most
experience and skill. In applying these data to an individual
patient, considerable judgement may be needed. Often the
best evidence-based method may not fit your individual
patient situation. Nonetheless, video laryngoscopy of the
airway with intubation of the trachea seems to be the
new gold standard and certainly should be associated with
near zero risk of exacerbation of spinal cord injury.
OXYGENATION
PaO2 Physiology
The conceptual relationship of CBF to PaO2 is depicted in
Fig. 24.15. Hypoxemia, usually below a PaO2 of approxi-
mately 50–60 mmHg, is associated with vasodilation.241
At the opposite extreme, Floyd et al.242 in a group of healthy
volunteers demonstrated the vasoconstrictive effect of
hyperoxemia and its accompanying hypocapnea
(Fig. 24.16). Nakajima et al.243 evaluated this phenomenon
in patients with cerebrovascular disease, finding that areas
of the brain with impaired cerebrovascular reserve were not
adversely affected by hyperoxia.
Outcome Data
The optimal PaO2 to seek in a brain injured patient is pres-
ently unclear. There are data that support hyperoxic ther-
apy along with data that suggest such an approach is
deleterious. In addition, the bedside decision about PaO2
management is further coupled to cerebrovascular reserve
issues previously discussed. Thus, a low PaO2 that would
normally be tolerated through vasodilation may not be so
well tolerated if vasodilatory reserve is compromised with,
for example, carotid occlusion, brain edema, or anemia.
Fiskum et al. among others have reported in laboratory
studies that hyperoxic therapy promotes generation of free
radicals and that such oxidative stress causes mitochondrial
injury, which will act to impair neurologic recovery.244 This
notion from in vitro considerations is supported by in vivo
studies in rodents and dogs, which demonstrated worse
neurologic outcomes when hyperoxia is used before or after
an ischemic insult.245–247
CBF
0 25 50 200 400
PaO2 (mmHg)
Fig. 24.15 Hyperoxia vasoconstricts the brain and hypoxemia pro-
duces significant vasodilation. CBF, Cerebral blood flow.
375
Conversely, with the advent of reports supporting the fea-
sibility and reliability of brain tissue PO2 monitoring,248
data regarding increased brain tissue oxygen monitoring
show that normoxemic therapy, in the context of cerebral
hypoxia, may promote ischemic injury. Indeed, many
recent reports have described in nonrandomized retrospec-
tive and prospective series of both traumatic and SAH
patients that brain tissue PO2 less than 20–30 mmHg is
associated with worsened neurologic outcome248–253
(Fig. 24.17). Notably, however, these studies did not exam-
ine effects of hyperoxia, which is the negative situation iden-
tified by Fiskum et al. These studies point out the value of
avoiding tissue hypoxia, perhaps at the cost of systemic
hyperoxia but not intracranial hyperoxia. However, one
side observation made by these studies is the impact of
avoiding hyperoxia because brain tissue oxygen monitoring
allows the provision of minimal FiO2 that permits the opti-
mal (not too high not too low) brain tissue oxygen level.
Given these potentially conflicting therapeutic priorities,
it seems that the most sensible approach at this time is as
follows: In the presence of a brain tissue PO2 monitor, adjust
physiologic parameters to keep PbrO2 > 20 mmHg. This
may entail use of FiO2 > 60% with concomitant risk of pul-
monary oxygen toxicity.254 It seems that this risk can be
incurred for 1 to 2 days but that continued dependence
on pulmonary toxic oxygen concentrations should produce
a time-dependent increase in pressure on the caregivers to
decrease FiO2, even if this means use of higher airway pres-
sure or allowing PbrO2 to decrease after a few days.
In the absence of a PbrO2 monitor, the clinician is left bas-
ing therapy on assumptions about brain oxygenation. If it is
felt that many brain areas are well perfused and at risk for
hyperoxia, pulmonary management should aim for PaO2
just sufficient to produce SaO2 > 95%. Conversely, if there
is elevated ICP and/or areas of brain hypoperfusion then a
reasonable empiric approach would be to utilize an FiO2
of 0.60. This will maximize PaO2 and PbrO2 but without sig-
nificant risk of acute pulmonary injury.
PEEP and Intracranial Hypertension
Positive end expiratory pressure (PEEP) can increase ICP255
(Fig. 24.18), and this relationship has been the subject of
clinical research for decades. Two mechanisms can be pos-
ited. The first is through impedance of cerebral venous
return to increase cerebral venous pressure and ICP. The
second is through decreased blood pressure and reflex
increase in cerebral blood volume to increase ICP. Huseby’s
data256 suggest that cerebral venous effects only occur with
very high PEEP.
Frost demonstrated that applying PEEP between 5 and
12 cm H2O (and even transiently up to 40 cm H2O
improved arterial oxygenation without increasing ICP.257
Shapiro et al.255 demonstrated increases in ICP in head-
injured humans with intracranial hypertension with appli-
cation of PEEP (see Fig. 24.18). Examination of their data
indicates that the most profound decreases in CPP occurred
in patients with PEEP-induced decrements in mean arterial
pressure consistent with the notion put forth by Rosner10
that decreases in blood pressure increase CBV to increase
ICP Aidinis et al.258 Studies in cats confirmed these observa-
tions in a more controlled setting. In addition, they assessed
the role of pulmonary compliance, finding that decreased
376 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

CBF (mL/100g/min) CBF (mL/100g/min)

Air 100% O2
0 150 0 150

CBF (mL/100g/min) CBF (mL/100g/min)

Air/ 96% O2/
0 150 0 150
4% CO2 4% CO2

CBF (mL/100g/min) CBF (mL/100g/min)

Air/ 94% O2/
0 150 0 150
6%CO2 6% CO2

Fig. 24.16 Colorized continuous arterial spin labeled (CASL)-perfusion MRI images with scale depicting cerebral blood flow (CBF) changes in
response to air: air 4% CO2, air 6% CO2, 100% O2, 96% O2/4% CO2, and 94% O2/6% CO2. (Reproduced from Floyd T, Clark J, Gelfand R, et al: J App
Physiol 2003;95:2453–2461 with permission.)

1.0

0.9

0.8

0.7

0.6
Risk of death

0.5

0.4

0.3

0.2
PbrO2<5 mmHg
PbrO2<10 mmHg
0.1
PbrO2<15 mmHg

0 1 2 3 4 5 6
Time (hour)
Fig. 24.17 Restricted cubic spline functions of the relative risk of death as related to initial low values categorized into <5, <10, and <15 mmHg. The
ordinal characterization follows from the layering of the curves, <5 being worse than <10, which is worse than <15. Note that the curves stabilize at
long durations of hypoxia. (Redrawn from van den Brink W, van Santbrink H, Steyerberg E, et al: Neurosurgery 2000;46:876–878.)
 24 • Perioperative Management of Acute Central Nervous System Injury
ICP
60 <10 mmHg
≥10 mmHg 7
ICP (mmHg)
40 11
8 12
1
3 9
2
20 4 10
6
5
0
130
1
12
110
6 8
BP (mmHg)
2 7
5 0
90
4 Change in PEEP (cmH2O)
10
3 11
9 expiratory pressure (PEEP) in dogs. Values are mean  standard error of
70
50
Pre-PEEP PEEP Pre-PEEP PEEP
Fig. 24.18 Intracranial pressure (ICP) and arterial blood pressure (BP)
before and with the application of positive end-expiratory pressure
(PEEP) (4 to 8 cmH2O) in severely head-injured patients. The
patients are arbitrarily divided into two groups: those with an ICP
increase equal to or above 10 mmHg and those with ICP gains below
10 mmHg. Note that PEEP-induced blood pressure decreased appear
to be more marked in patients sustaining larger ICP increases.
(Reproduced by permission from Battison C, Andrews PJ, Graham C,
et al: Randomized, controlled trial on the effect of a 20% mannitol
solution and a 7.5% saline/6% dextran solution on increased
intracranial pressure after brain injury. (Redrawn from Shapiro H,
Marshall L: J Trauma 1978;18:254–256.)
pulmonary compliance with oleic acid injections results in
less of an effect of PEEP to increase ICP. Such observations
indicate in situations where PEEP is likely to be needed,
often accompanied by decrements in pulmonary compli-
ance, that any adverse effects on ICP are less likely to man-
ifest. This may be related to observations that hemodynamic
effects of PEEP are less apparent with noncompliant
lungs259 such that hypotensive-mediated increases in
CBV do not occur.
Historically, use of high PEEP has been associated with
potential for ICP elevation; however, the intuitive notion
that PEEP increases cerebral venous pressure to increase
ICP is not as straightforward as some may indicate. For PEEP
to increase cerebral venous pressure to levels that will
increase ICP, the cerebral venous pressure must at least
equal the ICP. Thus, the higher the ICP, the higher PEEP
must be in order to have such a direct hydraulic effect on
377
10 Group 1 (initial ICP<20 cm H2O) n = 12
Group 2 (initial ICP 21–31 cm H2O) n = 7
Group 3 (initial ICP>40 cm H2O) n= 9
8
* P<0.05 when compared with
control group 1
Increase in ICP (cmH2O)
6
4
2
*
*
*
* *
0
5 0 10 0 15 0 20
Fig. 24.19 Increases in intracranial pressure (ICP) with positive end-
the mean. Group 1 included 12 animals with initial ICP less than
20 cmH2O; group 2 included 7 animals with initial ICP of 21 to
39 cmH2O; group 3 included 9 animals with initial ICP greater than
40 cmH2O. Blood pressure was maintained constant in all animals. Note
that with blood pressure maintained constant that the most
significant increases in PEP occur in the animals with the lowest starting
PEEP level. (Reproduced by permission from Huseby J, Luce J, Cary J, et al:
J Neurosurg 1981;55:704–707.)
ICP. This concept was proven by Huseby et al.256 in dog
studies in which PEEP was increased progressively with dif-
ferent starting levels of ICP (Fig. 24.19). It is important to
note that they prevented PEEP-induced decrements in blood
pressure, thus avoiding any reflex increases in cerebral
blood volume. They suggested a hydraulic model to concep-
tualize this better (Fig. 24.20). Thus, for example, if all of a
10 cm H2O PEEP application was transmitted to the cere-
bral vasculature, which is unlikely given the decreased pul-
monary compliance associated with the need for such PEEP,
then ICP will only be affected if it is < 10 cm H2O
(7.7 mmHg) with it increasing to a level no higher than
the applied PEEP. Such observations are consistent with
the notion that there is a Starling resister regulating cere-
bral venous outflow.260
More recent studies have found minimal to zero associa-
tion of PEEP with elevated ICP. Georgiadis et al. reported
that PEEP had no effect on ICP in patients with AIS.261 Sim-
ilar findings were reported for patients with SAH and
TBI.262,263 In a retrospective study, Boone et al. recently
reported that in patients with severe TBI without ARDS,
the application of PEEP had no effect on either ICP or
CPP. However, a mildly statistically significant relationship
was found between PEEP and both ICP and CPP in patients
with severe ARDS. They reported that a 5 cm H2O increase
in PEEP would potentially increase ICP by 1.6 mmHg with a
related 4.3 mmHg decrease in CPP. These findings suggest
378 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
MAP Superior
Pcv ICP
sagittal
sinus
Brain Cortical
vein SSP
Carotid
artery
To right
atrium
CSF
MAP>ICP>SSP
Fig. 24.20 Schematic illustration of the intracranial space during raised
intracranial pressure (ICP). The arrows indicate the position of the
hypothesized Starling resistor. Here, the mean arterial pressure (MAP) is
greater than ICP, which is greater than sagittal sinus pressure (SSP).
Cortical vein pressure (Pcv) cannot fall below ICP, and thus flow is
dependent on MAP-ICP and independent of small changes in SSP.
(Reproduced by permission from Huseby J, Luce J, Cary J, et al: J Neurosurg
1981;55:704–707.)
that PEEP can be safely utilized in the majority of mechan-
ically ventilated patients with severe brain injury.264
Although it is difficult to draw conclusions from these
studies given the small sample size commonly utilized, when
taken together, the complex association between mechani-
cal ventilation and cerebral hemodynamics appear to be
influenced by multiple patient-specific factors.
ARDS is a special area of great interest given the potential
benefits associated with lung-protective therapy based on
high PEEP and low tidal volume.265 ARDS is frequent in
patients with acute brain injury,266 and despite its high inci-
dence, the optimal ventilation strategy remains unclear.
Current evidence suggests that the application of PEEP for
patients with varying degrees of acute lung injury and con-
comitant severe acute brain injury does not appear to have a
clinically significant effect on ICP or CPP.264
VENTILATION
PaCO2 Physiology
PaCO2 is determined by the balance between CO2 produc-
tion and elimination. CO2 production is determined by met-
abolic rate and respiratory quotient (CO2 production divided
by O2 consumption) and is ordinarily 0.8. Factors that may
affect CO2 production to increase it are hyperthyroidism,
fever, elevated catecholamines, exercise, sepsis, and some
pharmacological stimulants. Respiratory quotient is affected
by energy metabolism such that intake of calories in excess
of needs results in lipogenesis, which is a CO2-producing
process that leads to more CO2 produced than oxygen
consumed.267
CO2 elimination is determined by minute ventilation and
dead space. There is a linear relationship between minute
ventilation and PaCO2 such that a simple proportion can
be used to predict the PaCO2 that will result with a given
change in minute ventilation. Dead space effects are more
complex. There are two types of dead space: anatomic
and physiologic. Anatomic dead space is that portion of
the airways that do not participate in gas exchange because
it has no proximity to pulmonary capillaries. Such struc-
tures include the mouth, trachea, bronchi, and other large
airways. Notably, anatomic dead space is roughly halved via
endotracheal intubation and halved again by conversion
from translaryngeal intubation to tracheostomy. Physio-
logic dead space is that portion of non–gas-exchanging ven-
tilation that occurs in alveoli that are suboptimally perfused.
Thus, physiologic dead space will be increased by anything
that increases the amount of gas in alveoli without com-
mensurate increase in alveolar perfusion or it will be
increased by anything that may decrease perfusion to alve-
oli without commensurate decrease in ventilation. Physio-
logic situations associated with elevated physiologic dead
space include use of PEEP in compliant lungs, pulmonary
emboli, or shock. A more detailed overview of this physiol-
ogy can be found in the study by West.267
In healthy brain, CBF varies linearly with PaCO2 between
about 20 mmHg and 60 mmHg.268 The mechanism of
effect is thought to be related to the effects of PaCO2 on
CSF pH.269 Thus, patients who are chronically hypercap-
neic and sustain pH adjustment in the CSF may not be
hyperemic. These patients, of course, may be expected to
sustain even more profound decreases in CBF with decre-
ments in PaCO2 to equivalent levels.
HYPERVENTILATION
The PaCO2-mediated changes in CBF are generally without
any neurologic effect on health. However, in the context of
head injury or other cause of ICP elevation, the effects can
be profound as the changes in CBF induce changes in intra-
cranial blood volume. In the brain with little capacitance for
such a change in intracranial contents, the change in
PaCO2 can have a significant impact on the intracranial
pressure.
Thus, hyperventilation for many years was embraced as a
mainstay of the treatment of intracranial hypertension.270
However, such therapy was observed to produce a signifi-
cant cerebral oligemia with the lowered ICP,271 often devel-
oped from a low CBF baseline. Conversely, at times, elevated
PaCO2 in patients with brain injury was noted to produce
both high ICP and high CBF, producing a therapeutic quan-
dary. Moreover, adding to the dilemma were observations
from the basic science literature of some neuroprotective
side effects associated with hypercapnic cerebral acidosis.272
(See section on hyperventilation for ICP management for
detailed information.)
Optimal PaCO2
Multiple studies debunked the previously accepted verity
that hyperventilation is an automatic element of treatment
of head injury. Muizelaar et al.77 did a prospective random-
ized study of the efficacy of hyperventilation in traumatic
brain injury (see Fig. 24.11). Their outcome data showed
a persuasively negative impact of hyperventilation, such
that it has been abandoned as a routine therapy in trau-
matic brain injury. However, there are some situations
where it is still accepted. Some authors suggest that brain
oxygen monitoring by either/or jugular oximetry or tissue
 24 • Perioperative Management of Acute Central Nervous System Injury
PbrO2, can be used to guide the use of hyperventilation.81
Direct CBF-measuring techniques could also be used.
Notably, such information can allow the clinician to iden-
tify whether the patient has an element of hyperemia con-
tributing to the elevated ICP, a situation that logically
seems appropriate for hyperventilation therapy, although
this notion has not undergone rigorous scrutiny. None-
theless, Coles et al.271demonstrated the potential for
hypocapnia to produce ischemic areas throughout an
injured brain (Figs. 24.21 and 24.22).
TEMPERATURE
Temperature has a profound effect on the brain. Fever is
convincingly associated with worsened outcomes with
greater release and toxicity of neurotoxic amino acids, mis-
match between flow and metabolism, oxidative stress, and
many other likely unknown processes.273,274 In normal
brains, hypothermia produces a 7% reduction in cerebral
metabolic rate for oxygen with every 1°C reduction in brain
temperature,275 thus decreasing consumption of energy
metabolites and increasing the time until an hypoxic stress
leads to high energy phosphate depletion and thus increas-
ing the time that the hypoxia can be tolerated.276 This
reduction in cerebral metabolic rate for oxygen cannot
entirely explain the potential neuroprotective effect of mild
hypothermia, which must be a result of synergism of many
physicochemical mechanisms. A comparison between the
neuroprotective efficacy of hypothermia and that produced
by an anesthetic producing an equivalent decrement in
cerebral metabolic rate always shows greater protection
by hypothermia. This is thought to be somehow related
to the differential effects of hypothermia and anesthetics
on the compartments of brain energy metabolism.277
Fig. 24.21 Effect of hyperventilation on the burden of hypoperfusion.
Radiographic computed tomography (left) and grayscale positron
emission tomographic imaging of cerebral blood flow obtained from a
31-year-old man 7 days after injury at relative normocapnia (middle),
PaCO2 35 torr (4.7 kPa), and hypocapnia (right), 26 torr (3.5 kPa). Voxels
with a cerebral blood flow of <10 mL
100g
min are shaded in black.
Note the right frontal contusion and small parietal subdural hematoma.
Baseline intracranial pressure (ICP) was 21 mmHg and baseline CPP was
74 mmHg. Baseline Sjvo2 values of 70% and AVDO2 of 3.7 mL/dL are
consistent with hyperemia and support the use of hyperventilation for
ICP control. Hyperventilation resulted in a reduction in ICP to 17 mmHg
and an increase in CPP to 76 mmHg, with maintenance of Sjvo2 and
AVDO2 within desirable ranges (58% and 5.5 mL/mL respectively).
However, despite these Sjvo2 and AVDO2 figures, baseline HypoBV was
141 mL and increased to 428 mL with hyperventilation. These increases
were observed in both perilesional and normal regions of brain tissue.
(From: Coles JP, Minhas PS, Fryer TD, et al: Effect of hyperventilation on
cerebral blood flow in traumatic head injury: Clinical relevance and
monitoring correlates. Crit Care Clin 2002;30(9):1950–1959.)
379
450
A
350
250
150
50
HypoBV (mL)
–50
450
B
350
250
150
50
–50
23 26 30 34 38 41 45 49
PaCO2 (torr)
Fig. 24.22 PaCO2 thresholds for cerebral hypoperfusion. (A) Plot of
hypoperfused brain volume (HypoBV) versus PaCO2 in healthy volun-
teers (blue squares) and post hyperventilation (black diamonds). (B)
Relationship of HypoBV to PaCO2 in patients imaged at baseline (blue
squares) and after hyperventilation (blue diamonds). (From: Coles JP,
Minhas PS, Fryer TD, et al: Effect of hyperventilation on cerebral blood flow
in traumatic head injury: Clinical relevance and monitoring correlates. Crit
Care Clin 2002;30(9):1950–1959
Anesthetics decrease metabolic processes related to the
work of the neuron (i.e., neurotransmitter synthesis and
metabolism), whereas hypothermia also affects the com-
partment responsible for constitutive activities of the cell
(membrane integrity, ionic concentration homeostasis,
etc.). In addition, there are other biochemical processes that
contribute to hypothermic protection. For example, with
mild hypothermia there is a substantial blunting of the
release of neurotoxic dicarboxylic amino acids such as glu-
tamate and aspartate.278 In normal physiologic conditions,
different areas of the brain are maintained at slightly differ-
ent temperatures, and such thermodynamic discrepancies
may be exacerbated during injury.279 Other processes
responsible for ongoing secondary brain injury include
mitochondrial dysfunction, production of free radicals,
BBB disruptions, release of proinflammatory cytokines,
among others. Hypothermia is also thought to be protective
by reducing hyperexcitability and minimizing thermody-
namic disparities, as well as altering the inflammatory
response.279
Why Hypothermia for Neuroprotection?
This arose from anecdotes describing miraculous recovery
from drowning and other brain ischemia situations in
cold environments. Hypothermia has been studied and
clinically used for much of the 20th century. Reports of
hypothermia as a means of treatment for brain injury date
as early as 1940s when Fay et al. cooled TBI patients for
up to 7 days.280 By the 1980s, interest in therapeutic
380 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
hypothermia grew exponentially because many experi-
mental studies demonstrated favorable outcomes when
cooled down to 32–34°C after induced brain injury.281
Deep hypothermic conditions have been used for many
years for neuroprotection during cardiac surgery and dur-
ing therapeutically induced deep hypothermic cardiac
arrest for a variety of procedures.282,283
Hypothermia and TBI
Induced hypothermia has been proposed as a therapy after
severe TBI given its potential role in ICP control and neuro-
protection.284–287 In traumatic brain injury, there have
been many reports and RCTs of neuroprotection with hypo-
thermia with conflicting results. Previous trials of early
induction of prophylactic hypothermia that have shown
benefit, however, were judged to be high on bias because
of randomization issues, outcome endpoints, and data com-
pletion.285 Higher quality recent trials have shown trends
toward unfavorable outcomes of hypothermia288,289 or
have been stopped because they are deemed futile.284,290
One of the most recent multicenter trials enrolled 387
patients to assess the benefit of hypothermia to control ele-
vated ICP. They found that in patients with ICP >20 mmHg
secondary to severe TBI, the combination of hypothermia
plus standard of care failed to improve outcomes than stan-
dard therapy alone. The trial was stopped because of con-
cerns over patient safety.291 A systematic review of 22
RCTs of mild to moderate hypothermia (32–35°C) following
TBI noted a small but significant decrease in the risk of death
(relative risk [RR] 0.76, 95% confidence interval [CI] 0.60–
0.97) or poor neurologic outcome (RR 0.69, 95% CI 0.55–
0.86) among more than 1300 patients; however, this pos-
itive effect was seen only in low-quality trials.287 A 2016
meta-analysis was unable to demonstrate improved survival
and suggested that therapeutic hypothermia may increase
the risk of new pneumonia and even cardiovascular compli-
cations.292 Other trials have also found no benefit of induced
hypothermia when specific subgroups of TBI were studied.
Clifton et al. showed that hypothermia was not beneficial
when initiated within 2–5 hours of TBI in younger patients
(aged 16–45 years).288 More recently, the Prophylactic
Hypothermia Trial to Lessen Traumatic Brain Injury-Ran-
domized Clinical Trial (POLAR-RCT) assessed the effect of
early hypothermia versus normothermia after severe TBI.
Early hypothermia failed to improve neurologic outcomes
at 6 months293
In conclusion, wide variability exists among studies in the
depth and duration of hypothermia, as well as the rate of
rewarming, limiting the ability to draw conclusions from
these studies. Given the uncertainties surrounding its
appropriate use and indications, therapeutic hypothermia
should be limited to clinical trials or to patients with ele-
vated ICP refractory to other therapies. The current Brain
Trauma Foundation guidelines recommend against early
(2.5 hours) and short-term (48 hours postinjury) pro-
phylactic hypothermia because of insufficient evidence.17
Hypothermia for Rescue ICP Therapy
Historically, elevated ICP has been treated with a tiered
approach, moving from less invasive to more invasive ther-
apy. Some studies have found hypothermia to be effective
in controlling elevated ICP, even during the late stages of
acute TBI. A meta-analysis of eight RCTs examining ther-
apeutic hypothermia for severe TBI found that hypother-
mia can lower ICP even in patients refractory to first-line
therapies.294 However, functional outcome benefit is
unclear.
The Eurotherm3235 RCT randomized patients with
severe TBI and refractory raised ICP (>20 mmHg for
>5 minutes) to receive second-tier interventions or
second-tier interventions with therapeutic hypothermia
(32–35°C). In the hypothermia group, the core temperature
was reduced to the highest temperature necessary to main-
tain an ICP of 20 mmHg. Hypothermia was maintained for
at least 48 hours and continued for as long as necessary to
keep ICP within goal. The primary outcome was the GOS-
extended score at 6 months. Although the trial was termi-
nated early because of safety concerns in the hypothermia
group, compared with controls, fewer hypothermia patients
required escalation of care to control ICP (i.e., decompres-
sive craniectomy or pentobarbital-induced coma).291
If the decision is to induce hypothermia as a means to
control an otherwise refractory intracranial hyperten-
sion, moderate hypothermia can be achieved using whole
body cooling, including lavage and cooling blankets, to
a goal core temperature of 32°C to 34°C.295,296 The best
method of cooling (local versus systemic), the optimal tar-
get core temperature, and the appropriate duration of
treatment are not completely clear, but it appears that
rewarming should be accomplished over a period of less
than 24 hours.286 Treatment may be associated with shiv-
ering, sepsis, arrhythmias, coagulopathy, and electrolyte
disturbances.
Hypothermia and Hypoxic-Ischemic Encephalopathy
After Cardiac Arrest
Neurologic injury is the most common cause of mortality in
patients with out-of-hospital cardiac arrest.297 The overall
benefit of therapeutic hypothermia (TH) in patients who
are successfully resuscitated following cardiac arrest was
summarized in a systematic review and meta-analysis that
included 1381 patients. It found lower mortality and
improved rate of good neurologic outcome in cardiac arrest
patients treated with targeted temperature.298 Patients
treated with TH were more likely to survive than patients
whose temperature was not managed with TH; however,
no difference in outcome was found based on the level of tar-
get temperature. Another study found that when combined
with standard postcardiac arrest care, cooling down to the
range of 32°C to 34°C during the first hours after cardiac
arrest improves neurologic outcome.299 A large RCT failed
to show any additional mortality benefit when using tar-
geted temperature to 33°C rather than 36°C.300 Conclu-
sions about the absence of any difference in outcome
based on the target temperature for TH are based primarily
on the findings of this well-performed, multinational ran-
domized trial of 939 unconscious survivors of out-of-
hospital cardiac arrest. In this RCT, 54% of patients in the
33°C group either died or demonstrated poor neurologic
function compared with 52% in the 36°C group. Similar
findings were reported when outcome was reported using
the modified Rankin scale, and a follow-up study of
 24 • Perioperative Management of Acute Central Nervous System Injury
survivors at 6 months reported no significant difference in
cognitive function between the two treatment groups.301
Whether 33°C or 36°C is used as target therapy, evidence
shows that hyperthermia must be avoided following cardiac
arrest, because failure to control core temperature is associ-
ated with the development of fever and worse neurologic
outcome.302–304 An observational study reported that the
risk of death increases for each degree over 37°C during
the first 48 hours after cardiac arrest.305 In a review of
336 patients, earlier onset of fever was associated with
worse outcomes, while delayed fever onset did not show
the same deleterious effects.303
This evidence suggests that TH between 32°C and 36°C
postcardiac arrest followed by active prevention of fever is
the optimal strategy for patient survival.
Timing and Duration of Targeted Temperature
Active control of a patient’s core temperature should be
achieved as soon as possible after cardiac arrest and main-
tained for at least 48 hours postcardiac arrest. Fever should
be avoided within the first 48 hours postcardiac arrest.
Active control should be undertaken and maintained even
if the patient is already at target temperature upon arrival.
In a trial of 355 out-of-hospital cardiac arrest patients ran-
domized to either 24 or 48 hours of TH at 33°C, the rate of
good functional outcome at 6 months was 4.9% higher in
the 48-hour group. However, the rate of adverse events
was higher in the 48-hour treatment group as well as the
ICU length of stay (151 vs 117 hours).306 Several studies
that assessed the use of prehospital induction of TH using
intravenous cold fluids failed to show outcome improve-
ment. In fact, it resulted in increased diuretic administration
and pulmonary edema during the first 24 hours postcardiac
arrest.307–310 Therefore, based on these data, there is no
benefit of prehospital initiation of hypothermia using cold
intravenous fluids.
Target Temperature. Clinical trials have used regimens of
TH with target temperatures of 32°C to 34°C for 12 or
24 hours, followed by gradual rewarming of 0.25°C/h,299
or regimens of 36°C for 24 hours, followed by rewarming
of 0.25°C/h.300 Although lower temperatures may reduce
cerebral edema, seizure activity, and metabolic demand,
current evidence does not support the superiority of either
regimen. Cerebral edema is a frequent complication follow-
ing cardiac arrest in up to 50% of patients311 that can lead
to intracranial hypertension. Lowering core body tempera-
ture to 33–34°C has been shown to decrease ICP in a variety
of conditions such as SAH,312 traumatic brain injury,313
cerebral edema from hepatic encephalopathy,314 and ische-
mic stroke. Thus, it seems reasonable to use lower target
temperatures when concern for elevated ICP exists.
Methods to maintain temperature and implement TH are
out of the scope of this chapter, but briefly there is intravas-
cular or surface methods to control temperature that clini-
cians can use. Intravenous administration of 30 mL/kg of
cold isotonic saline, reduces the core temperature by >2°
C per hour.307 The rate of temperature reduction is compa-
rable or faster than that achieved with endovascular cath-
eters but may result in volume overload, pulmonary edema,
and increased diuretic use.310 This approach should not be
used in patients with prior history of heart failure, renal
381
failure, or evidence of acute pulmonary edema. Surface cool-
ing measures such as ice packs and cooling blankets or an
intravenous cooling device should be used instead. Surface
cooling methods can reduce the core body temperature by
0.5°C to 1°C per hour.
Shivering is a common and expected side effect of TH. It
raises body temperature and must be suppressed during the
active cooling of the patient.310,315 This can be achieved
with sedation and potentially neuromuscular blockade.
Sedation can be achieved with different agents such as pro-
pofol, benzodiazepines, and opioids for pain control, and
must be tailored according to the patient’s hemodynamic
profile. Benzodiazepines may be an option in hemodynami-
cally unstable patients who do not tolerate propofol; how-
ever, accumulation of midazolam can obscure the
neurologic examination after rewarming.316 Dexmedetomi-
dine is an alternative to suppress shivering, but its use
maybe limited because of its side effects of hypotension
and bradycardia.317 An effective treatment for shivering is
the use of meperidine; however, its use has been in decline
because of the proconvulsant effect of its metabolite norme-
peridine, which is renally cleared. If neuromuscular block-
ade is needed to treat shivering, continuous EEG
monitoring is required to detect the presence of epileptiform
activity, because postcardiac arrest patients can present
with seizure activity in up 40% of the cases.318
Temperature Monitoring and Rewarming. Core body
temperature should be monitored continuously during TH
and targeted temperature management (TTM). If a central
venous temperature is not available, esophageal, bladder or
rectal temperature can be utilized as surrogate. Esophageal
temperature measurement is possibly the most accurate
surrogate method used to follow core temperature during
the induction of TH. During rewarming, the temperature
should be raised gradually (0.2–0.25°C per hour), being
careful not to exceed more than 0.5°C per hour.319 Rapid
rewarming can cause electrolyte abnormalities, rebound
cerebral edema, and seizures. Fast rewarming can be
avoided with the use of automated devices using surface
or intravascular methods to control temperatures during
the induction, maintenance, and rewarming phases of
TH.320
The rate of rewarming can also be increased by raising
the room temperature, applying a convective heating
device, using heating lamps, or warming the inspired air
via the ventilator heating circuit on the humidifier.
Complications Associated With TH. The most signifi-
cant side effects of TH are impaired coagulation and
increased risk of infection. With temperatures below 35°
C, clotting enzymes operate more slowly and platelets func-
tion less effectively.321 Hypothermia impairs leukocyte func-
tion, thereby increasing the risk of infection if TH is
maintained longer than 24 hours.322,323 In addition, TH
may slow cardiac conduction and can cause arrhythmias,
including bradycardia and QT segment prolongation.324
Some studies have noted development of hyperglycemia
resulting from insulin resistance during TH,324 requiring
continuous insulin infusion for adequate glucose control.
Hypothermia can lead to “cold diuresis,” which can cause
hypovolemia and electrolyte abnormalities including
382 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
hypokalemia, hypomagnesemia, and hypophosphate-
mia.325 On the other hand, during the rewarming process,
temperature fluctuations cause potassium to move between
the extracellular and intracellular compartments. There-
fore, careful monitoring of volume status and electrolytes
during TH/rewarming is advised. Nielsen et al. reported
that hypokalemia is more frequently seen in patients cooled
to 33°C.300 Finally, TH slows the metabolism and excretion
of many drugs including neuromuscular blockers and thus
the duration of effect may be prolonged.326 This effect
should be in the mind of the clinicians when performing
neurologic examinations.
FEVER
Fever is the opposite situation that has been convincingly
associated with exacerbation of neurologic outcome in the
injured brain, in both animal and clinical studies.327,328
Many neurologic ICU patients have recurrent problems
with significant fever in excess of 39°C in the absence of
identifiable sepsis. Indeed, in a prospective quantification
of 428 consecutive patients admitted to the neurovascular
or neurotrauma ICU, 46.7% of patients had at least one
febrile episode.329 This is most likely a sequela of the neu-
rological process thought by one group of authors some-
times to reflect autonomic dysfunction induced by the
neurological injury.330 SAH is an independent risk factor
for development of fever without identifiable cause.331
The notion that fever kills neurons is gaining widespread
acceptance and is based on many clinical studies showing
the improvement in neurological outcome associated with
prevention of fever.
Mortality in patients who had hyperthermia within the
first 72 hours after stroke was 15.8% and the rate was
1% in patients who were normothermic during that time.
Hyperthermia that occurred with the first 24 hours after
stroke, without respect to infectious or noninfectious origin,
was independently related to a larger infarct volume; worse
neurological deficits and dependency 3 months postinjury.
Azzimondi and Bassein332 reported that fever of 37.9°C or
above proved to be an independent risk factor predicting a
worse outcome and patients with high fever were far more
likely to die with the first 10 days than those with lower
temperatures. A prospective study by Reith et al.333 of
390 consecutive cases of acute stroke classified patients into
three admission-temperature groups: hypothermic (36.5°C
or less), normothermic (36.6–37.5°C), and hyperthermic
(above 37.5°C). They showed that admission body temper-
ature was highly correlated with initial stroke severity, size
of the infarct, mortality and poor outcome. For a 1°C differ-
ence in body temperature, the relative risk of poor outcome
was more than doubled. This was supported by Ginsberg
and Busto334 who reported that fever in stroke patients that
occurs soon after the development of stroke is most strongly
associated with poor outcome. Body temperature was signif-
icantly higher in patients who died within 3 days after
admission compared with the rest of the study population.
Moreover, in ICH patients surviving the first 72 hours after
hospital admission, the duration of fever is associated with
poor outcome and seems to be a prognostic factor in these
patients. Dietrich et al. also reported that fever exposure
resulted in an increase in ischemic injury and infarct in
the injured brain, but the same fever exposure in noninjured
tissue did not result in any impact on the integrity of neu-
ronal tissue.335 A central reason for this neural tissue dam-
age may be related to a 7% to 13% increase in cerebral
metabolism for each increase of 1°C in core body tempera-
ture.328 In SAH, fever is associated with vasospasm and
poor outcome independently of hemorrhage severity or
the presence of infection. In TBI, early-onset fever may sig-
nal impending paroxysmal sympathetic activity character-
ized by episodic hyperadrenergic alterations in vital signs
such as tachycardia, tachypnea, hypertension, fever, dysto-
nia or posturing, and diaphoresis.336 The vast majority of
studies agree that avoidance of fever is valuable, possibly
decreasing ICU length of stay, mortality, incidence of hyper-
tension, elevated ICP, and tachycardia.327,337,338 However,
these findings are not consistent across studies.327,339 One
critical aspect to consider may be timing of fever. Geffroy
et al. found that patients who have an early fever are more
likely to have a less favorable survival than those without
early fever.340
Pharmacologic methods can be used to control fever.
Such modalities include acetaminophen341 and ibupro-
fen,342 although there is some evidence suggesting that ibu-
profen is not efficacious in the context of ischemic stroke.343
Acetaminophen’s value can be limited by hepatotoxicity
and the theoretical concern that it is an oxidizing agent that
even at subhepatotoxic levels may decrease glutathione to
lesson potentially helpful free radical scavenging pro-
cesses.344 Ibuprofen has issues with gastric ulceration and
bleeding.345
An alternative method is to use an hypothermia blanket
or indwelling hypothermia catheters.346 Both techniques
are based on a servo-controlled system wherein the cooling
bath temperature decreases when the patient’s tempera-
ture starts to rise. In our neurologic ICU we have generated
temperature curves as illustrated in Fig. 24.20, indicating
that it is possible virtually to eliminate fever from the
pathophysiology of severe brain injury. Notably, examina-
tion of this figure reveals a new vital sign, Tbathmin, indicat-
ing the minimum bath temperature that was needed to
prevent fever in a given patient. The Tbathmin level required
to commence an investigation for infection remains to be
elucidated.
GLYCEMIC CONTROL
Glucose is the predominant source of energy for the brain347
and its transport into astrocytes, microglia, and neurons is
facilitated by the transporters GLUT-1 and GLUT-3348; how-
ever, the underlying relationships between neuronal and
astrocytic glucose utilization have remained controversial
for decades. Both neurons and astrocytes have strong
demands for energy and are largely intolerant to inadequate
energy supplies. Thus, abnormalities in glucose shuttling
and metabolism may result in CNS pathologies.
Hyperglycemia has been associated with exacerbation
of brain damage with both head trauma and cerebral
ischemia.349–352 However, it is not a straightforward
issue. Clearly, neuronal damage after global cerebral
ischemia is exacerbated with hyperglycemia.352–356
 24 • Perioperative Management of Acute Central Nervous System Injury
Several explanations have been suggested for high glucose
levels after brain injury including stress and inflammatory
response, pituitary and hypothalamic dysfunction, preex-
isting diabetes and iatrogenic. Bosarge et al. in a study
of 626 patients with severe TBI reported that patients
with stress-induced hyperglycemia had 50% increased
mortality compared with nondiabetic hyperglycemia
patients, whereas diabetic patients who were hyperglyce-
mic did not have a significant increase in mortality, which
may suggest that stress-induced hyperglycemia may be of
greater importance in the acute phase of brain injury.357
Brain injury is followed by a systemic inflammatory
response, in which proinflammatory cytokines are
released, including IL-6 and TNF-α.358 Increased levels
of TNF-α have been associated with insulin resistance
and hyperglycemia.359 Moreover, inflammatory response
increased levels of corticotrophin-releasing hormone
(CRH), which stimulates the release of ACTH leading to
hyperglycemia. Preexisting diabetes mellitus in the setting
of severe TBI results in higher mortality and insulin-
dependent diabetes has been associated with even higher
mortality.360,361 Additional factors associated with peri-
operative hyperglycemia are surgical stress, anesthesia,
intravenous fluid choice, and possibly psychological
factors.362,363 Finally, another possible explanation is
the impairment of cerebral autoregulation. A recent retro-
spective study of 44 patients reported impaired cerebral
autoregulation (pressure-reactivity index [PRx] was
0.22 a.u.) with elevated glycemic levels in pediatric
patients who suffered from severe TBI.364
Patients who are hyperglycemic after trauma have an
increased ICU length of stay, mortality, and infection
rates.365 In a retrospective cohort study of 77 patients with
severe TBI, blood glucose 170 mg/dL (9.4 mmol/L) at the
time of ICU admission was an independent predictor of a poor
GCS score at 5 days postadmission.366 In another prospective
cohort of trauma patients, patients with admission glucose
>200 mg/dL had significantly increased mortality.367 In
ischemic stroke patients, serum glucose >140 mg/dL has
been associated with worse clinical outcomes.368–374
With focal cerebral ischemia, it is a good deal less clear.
There have been animal and human studies showing
whether the brain damage is worsened, not affected, or less-
ened with hyperglycemia.375–388,350,389–392 One report by
Prado et al.388 in rats suggested that the discriminating fac-
tor in whether brain damage is worsened with hyperglyce-
mia is the presence of collateral flow. Areas of the brain with
minimal collaterals were not affected or were improved with
hyperglycemia. Brain areas with a continued trickle of flow
sustained worsened brain damage. Presumably the contin-
ued substrate supply in oligemic (not ischemic) areas
allowed greater accumulation of organic acids in the cells
leading to worsening of brain damage.351,389 Unfortu-
nately, these observations are difficult to apply clinically
to patients with focal ischemia.
Even if low levels of hyperglycemia were deleterious, it
would not be straightforward to treat. Aggressive therapy
of hyperglycemia would impose a risk of hypoglycemia, with
deleterious effects.393 Thus, given the data in the recent
NICE-SUGAR trial, it seems that a reasonable approach is
to aim for a blood glucose of approximately 140–180 mg/dL
in all acutely ill hyperglycemic patients at risk of cerebral
383
ischemia. This range avoids marked hyperglycemia, while
minimizing the risk of both iatrogenic hypoglycemia and
other complications associated with a lower blood glucose
target. Careful monitoring of blood glucose is mandatory to
achieve the target range and avoid hypoglycemia. Once
the hyperacute illness has resolved, transitioning to longer-
acting insulin in the ICU has been shown to be safe in
patients who are being enterally fed.394 Once the hyperacute
phase has resolved, the intensity of glucose monitoring can
be lessened to match the lowered acuity such that SSI can
be used and somewhat less stringent goals achieved while
the patient is readied for discharge from the ICU setting.
Hyperglycemia has not been shown to have deleterious or
protective effects in two animal models of status epilepticus
(SE).395,396 The model used in Swan’s report396 produced
limbic system damage whereas Kofke’s report395 used a
model producing substantia nigra damage. Nigral damage
in this model is associated with hypermetabolic lactic acido-
sis,397 which should have been exacerbated with hypergly-
cemia. The fact that nigral damage was not exacerbated
with hyperglycemia suggests that metabolic acidosis may
not be an important factor in the development of brain dam-
age after seizure. An experimental study in rats demon-
strated that hyperglycemic animals with status epilepticus
had the most severe neuronal loss in the hippocampal area
CA3.398 Although evidence is controversial, these reports
still suggest the importance of intensively treating hypergly-
cemia in patients with SE. In general, target glucose goals
should be similar to those in the general critical care
population.
Cardiovascular
BLOOD PRESSURE EFFECTS ON ICP-PLATEAU
WAVES AND DETERMINATION OF THE BLOOD
PRESSURE OPTIMUM
In 1960, Lundberg62 monitored ICP in hundreds of patients,
identifying characteristic pressure waves. One type has been
identified as plateau waves, which are known to be associ-
ated with increased cerebral blood volume9 (Fig. 24.23).
Such waves occur when the ICP abruptly increases to
nearly systemic levels for about 15–30 minutes, occasion-
ally accompanied by neurologic deterioration. Rosner10
has provided data and a synthesis of the data that convinc-
ingly suggests that intracranial blood volume dysautoregu-
lation is responsible for plateau waves. He induced mild
head trauma in cats and subsequently intensively moni-
tored the animals after the insult. With normal fluctuations
in blood pressure, while in the normal range, he observed
that mild blood pressure decrements to approximately
70–80 mmHg preceded the development of plateau waves
(Fig. 24.24). Cerebral blood volume in normally autoregu-
lating brain tissue increases as a result of vasodilation with
decreasing blood pressure and, moreover, the increase in
CBV is nonlinear. There is an exponential increase in CBV
as blood pressure decreases to below 80 mmHg
(Fig. 24.25).399 A small decrease in blood pressure,
although in the normotensive range, produces exponential
384 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

VFP
80

mm Hg
60
40
20
0
rCBV
m1-8 100
110
1 100
CBV%

90
2 100

3 100
2 4
7 4 100
3 5
8
1 5 100
6
6 100

7 100

8 100
0 20 40 60 80 100 120 140 160 180
min
Fig. 24.23 Simultaneous recordings of regional cerebral blood volume (rCBV) and ventricular fluid pressure (VFP) during three consecutive plateau
waves. The rCBV was measured in eight regions over the left hemisphere. The mean changes in the eight regions are shown in the uppermost curve of
the rCBV diagram. Note that the rCBV and VFP curves show a very similar course during the three waves. (Reproduced by permission from Risberg J,
Lundberg N, Ingvar D. J Neurosurg 1969;31:303–310.)

100 with hyperventilation or other vasoconstrictive therapy,

Cerebral perfusion pressure
mmHg
1 min
0 of heterogeneous autoregulation (Fig. 24.26). In addition to
200
Systemic arterial pressure
mmHg
0 ICP, changes in blood pressure have no effect on ICP. How-
80
Intracranial pressure
mmHg
Pavulon 0.4 mg/v
0 ing venous pressure, which in turn acts to further worsen
Fig. 24.24 In an animal head trauma model, a seemingly trivial and
transient decrease in systemic arterial blood pressure in the setting of
borderline cerebral perfusion pressure (CPP) precipitates sufficient
cerebral vasodilation to increase the ICP markedly. Restoration of CPP is
associated with abolition of the plateau wave. (Reproduced by per-
mission from Rosner M, Becker D. J Neurosurg 1984;60: 312–324.)
increases in CBV in a setting of abnormal intracranial
compliance with the ICP at the elbow of the ICP-intracranial
volume relation (see Fig. 24.2). Thus, a small decrease in
blood pressure introduces an exponential CBV change
upon an exponential ICP relation such that ICP will
increase abruptly and significantly. Plateau waves
spontaneously resolve with a hypertensive response or
which will act to oppose the increase in CBV. Clearly, to
develop a plateau wave there must be a portion of the brain
with normally reactive vasculature in the setting of other
brain areas with a mass effect and elevated ICP, a situation
preventing and treating plateau waves, such data indicate
that it is probably important to maintain MAP in patients
with high ICP in the 80–100 mmHg range.
Conversely, hypertension can also increase ICP. Nor-
mally, within the normal autoregulatory range and normal
ever, with brain injury and associated vasoparalysis, blood
pressure increases mechanically produce cerebral vasodila-
tion to increase ICP400 (see Fig. 24.26).
Notably, the Lund group suggests that hypertension-
induced exacerbation of brain edema increases ICP. The
increase in ICP then acts to occlude venous outflow, increas-
the brain edema, constituting a positive feedback cycle ini-
tially started by arterial hypertension.44
Therefore it appears that both increasing and decreasing
blood pressure can increase ICP, suggesting the presence of
a CPP optimum for ICP. In the absence of any patient-
specific physiologic information this is probably about 80–
100 mmHg, although this has not been definitively deter-
mined experimentally (Figs. 24.26 and 24.27).
These considerations underlie a current controversy with
respect to blood pressure management in the context of ele-
vated ICP. One argument is that blood pressure should be
maintained high to ensure adequate CBF and minimize
the probability of plateau waves. The contrary argument
is for ample fluids and low blood pressure to promote CBF
primarily rather than pressure. It is this author’s opinion
 24 • Perioperative Management of Acute Central Nervous System Injury 385

Fig. 24.25 Vasodilation occurs at a logarithmic rate as cerebral perfusion pressure (CPP) is reduced. Intracranial pressure (ICP) will increase at a
proportional rate within each pressure range with the most rapid increase occurring below a CPP of 80 mmHg. CBV, Cerebral blood volume. (Rosner MJ,
Becker DP: The etiology of plateau waves: A theoretical model and experimental observations. In: Ishii S, Nagai H, Brock M. (eds) Intracranial Pressure V. Springer,
Berlin, Heidelberg; 1983:301. https://doi.org/10.1007/978-3-642-69204-8_49.).

Fig. 24.26 In the setting of heterogenous autoregulation in the brain, conditions may predispose to cerebral blood volume (CBV)-mediated increases in
intracranial pressure (ICP) with both increases and decreases in blood pressure. MAP, Mean arterial pressure.

that the preferred approach would be to induce the lowest
blood pressure that allows sufficient CBF as indicated by
repeated (preferably bedside) measurement. However, lack-
ing such technology, it seems best to aim for a CPP in the
80-mmHg range.
BLOOD PRESSURE MANAGEMENT
Blood pressure management is an important issue in most
neurologic ICU patients. Concern exists that systemic hyper-
tension may exacerbate cerebral edema or intracranial
386 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

CVR

CBF
CBF CBF

CVR

50 150 50 150
A CPP mmHg B CPP mmHg

ICP

C MAP
Fig. 24.27 Cerebral perfusion pressure (CPP) versus cerebral blood flow (CBF) and cerebrovascular resistance (CVR). (A) Blood flow is normally main-
tained constant through changes in CVR, depicted in the figure as changes in vascular diameter and therefore in cerebral blood volume (CBV). CBV
varies inversely with CPP. (B) With vasoparalysis caused by injury, CVR does not change with CPP variations such that CBF and CBV vary directly with CPP.
C In the situation of decreased intracranial compliance both of these factors in (A) and (B) may interact to increase ICP. Normally autoregulating tissue as
in (A) will predispose to CBV-mediated ICP elevation with decreasing blood pressure, whereas vasoparalyzed tissue (B) will predispose to CBV-mediated
ICP elevations with increasing blood pressure, leading to the notion of an ICP optimum (probably about 80 to 100 mmHg) with varying CPP.

hemorrhage or have deleterious cardiopulmonary effects
such as pulmonary edema or myocardial ischemia. Con-
versely, blood pressure decreases can lead to insufficient per-
fusion even at a pressure in the normal range of
autoregulation. Moreover, mild blood pressure decreases
have been implicated in the genesis of plateau waves. Sev-
eral important principles apply to management of blood
pressure in neurologic ICU patients and they are described
in the following sections.
Hypertension
When blood pressure is high, a central question that must
be addressed initially is whether the pressure is elevated
because of normal homeostatic mechanisms to maintain
adequate perfusion. For example, with conditions of inade-
quate brainstem perfusion, a compensatory hyperadrener-
gic state may occur resulting in increased blood pressure,
thus maintaining sufficient perfusion to maintain aerobic
metabolism in the brainstem. If a decision is made to
decrease blood pressure, then brainstem failure and death
may ensue.
Animal data with cerebral ischemia models provide strong
support for the notion that sympatholytic drugs should be
used to decrease blood pressure if cerebral ischemia is a pos-
sibility. Compared with hemorrhagic induced hypotension,
ischemic damage was decreased with the use of ganglionic
blockade with hexamethonium,401 central adrenergic block-
ade with alpha-2 agonists,402 and angiotensin converting
enzyme inhibition.403 Hemorrhaged controls were noted
to sustain an increase in exogenous catecholamine concen-
trations. To test the hypothesis that these catecholamines
contributed to brain damage some of the animals treated
with hexamethonium also received IV catecholamine infu-
sions. Reversal of hexamethonium brain protective effect
was observed in these animals (Fig. 24.28).401 Similarly,
brain protection has been observed in laboratory studies
with preischemic404 and preseizure405 treatment with
reserpine, a drug that depletes presynaptic catecholamine
stores. Finally, there is a report by Neil-Dwyer et al.406 in
which all subarachnoid hemorrhage patients receiving
therapy with phentolamine/propranolol were compared
with no sympatholytic therapy (Fig. 24.29). Subjects who
received sympatholytic therapy had significantly better
neurologic outcome than the controls. In addition, beta-
adrenergic blocking drugs have not been reported to produce
cerebral vasodilatation or increase ICP.407–409
Calcium channel antagonist drugs, which may have
brain protective effects, are also available for antihyperten-
sive therapy. Nimodipine and nicardipine, developed spe-
cifically for brain protection purposes, have been
assessed in numerous studies with several reports of their
conferring protection versus delayed ischemic brain dam-
age.410–416 They thus become reasonable choices for anti-
hypertensive drugs based solely on these observations.
They are vasodilators and can modestly increase
ICP.417,418 As vasodilators they may be expected to pro-
duce compensatory catecholamine release,419 and, based
on the previous discussion, this may obviate some of their
protective qualities. Intravenous nimodipine moreover has
been observed to induce abnormal cerebral autoregula-
tion (high PRx index) and to increase brain tissue PO2
when CPP is maintained,420 while others have reported
a temporary decrease in PbtO2.421 Whether this can alter
outcome remains debatable.
 24 • Perioperative Management of Acute Central Nervous System Injury 387

Group 1 Peripheral vasodilators such as nitroprusside, nitroglyc-

40 erin, and hydralazine all have the potential to induce cere-
bral vasodilatation and thus cause hyperemic intracranial
30 hypertension.422–425 Moreover, they are associated with
compensatory increase in peripheral catecholamines and
20
renin,419 factors that theoretically may make ischemic
brain damage worse.401,404 However, the lack of bradycar-
10
dia and bronchoconstriction associated with their use may
0
make them the optimal choice in some patients with these
n=10 conditions. If such a drug is chosen and the patient is at risk
of neurologic deterioration from ischemia or high ICP, close
Group 2
clinical observation is indicated. Any deterioration would
40 mandate discontinuation of the drug. Such concerns are
Neurologic outcome score

important for deciding between these three drugs. Although

30 hydralazine is convenient to use, it cannot be reversed at the
receptor and its effects can last hours. Thus, it may be pref-
20
*† *† *† *† *
erable to use nitroprusside in such situations because
adverse effects can be treated quickly by simply discontinu-
10 ing the infusion.
It should be clear that the choice of antihypertensive
0 agent in a patient at risk of cerebral ischemia is not straight-
n=12
forward. Therapeutic urgency, sympatholytic and brain
protective side effects, and potential to increase ICP are all
Group 3
40
important considerations in the choice of antihypertensive
drug (Table 24.7).
30 If it is deemed that blood pressure has to be decreased very
fast, e.g., within minutes, nicardipine in 100–500 μg
20 * * * *
boluses is very effective and safely titratable. Once the blood
pressure is reduced, a maintenance regimen of nicardipine
10 or another drug can be started. Alternatively, sodium nitro-
prusside can be started although it has a variety of deleteri-
0 ous side effects elaborated upon previously that put it lower
1 2 3 4 5 n=10 down the list of preference for antihypertensive agent in a
Days neurological patient. However, it is perhaps the most potent
Fig. 24.28 Neurologic deficit scores after incomplete focal cerebral and reliable antihypertensive drug available.
ischemia in rats over a 5-day examination period. Each bar represents Plateau waves, first reported by Lundberg62 and associ-
the neurologic score for each rate (*P <0.05 versus Group 1; † P<0.05
versus Group 3). The rats are ranked according to total outcome score
ated with neurologic deterioration, were demonstrated by
in descending order (0 ¼ normal). Cerebral ischemia was induced with Risberg to be associated with cerebral vasodilation.9 Rosner
occlusion of one carotid artery with hemorrhagic hypotension. Group 1 et al.10 reported that mild decreases in blood pressure to
rats received no vasoactive drugs; group 2 rats received preischemic 60–80 mmHg can be associated with plateau waves.
hexamethonium, and group 3 rats received hexamethonium plus
intravenous epinephrine and norepinephrine. Protection was
conferred by hexamethonium in a catecholamine-reversible manner.
(Reproduced by permission from Werner C, Hoffman W, Thomas C,
et al: Anesthesiology 1990;73:923–929.) Table 24.7 Antihypertensive drugs.
Brain
Potential to protective
One-year outcome Drug increase ICP side effects Sympatholytic
60 Nitroprusside +++ 0 0
50 Good
Number of patients

Disabled Nitroglycerin ++ 0 0
40 Dead
Hydralazine +++ 0 0
30 Enalapril + ++ +
20 Trimethophan 0 +++ +++
10 Labetalol 0 + +++
0 Propranolol 0 + +++
Control Treated
Group Esmolol 0 + +++
(P = 0.005)
Nifedipine ++ + 0
Fig. 24.29 Subarachnoid hemorrhage patients were randomly treated
with propranolol or placebo. Neurologic outcome was better in Nicardipine ++ +++ 0
patients undergoing β blockade. (Graph made from data provided by Clonidine +++ +++
Neil-Dwyer G, Walter P, Cruickshank J. Beta-blockade benefits patients
following a subarachnoid hemorrhage. Eur J Clin Pharmacol. 1985;28:25.). Considerations rated from none (0) to significant (+++)
388 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Presumably the decrease in blood pressure prompts vasodi-
latation in normally autoregulating tissue. The increase in
cerebral blood volume, which is an exponential function
versus cerebral perfusion pressure,10 superimposed on the
exponential ICP versus intracranial volume relationship,
is associated with an explosive hyperemic increase in
ICP—a plateau wave (see Fig. 23.24). This, then, introduces
the concern with use of any antihypertensive agent, aside
from specific, direct cerebrovascular effects, that normal
autoregulation may also increase ICP when cerebral perfu-
sion pressure decreases to about 80 mmHg or below.
Clearly, whenever hypotensive therapy is used in a
patient with altered intracranial compliance, edema, or
ischemia, very close and recurrent observation of the
patient is mandatory. Deterioration should prompt con-
sideration of one of the above processes with corrective
therapy and reconsideration of the need to decrease blood
pressure.
Hypotension Treatment and Induced Hypertension
When a patient is hypotensive, in addition to treating the
low blood pressure, efforts should also be made to ascertain
the cause of the hypotension. In head trauma patients, con-
sideration needs to be given to other injuries with hemor-
rhage or spinal shock. Loss of blood flow to the brain stem
can similarly be associated with hypotension, which can
be quite difficult to treat. In addition, usual nonneurologic
causes of hypotension in an ICU (e.g., pneumothorax, sepsis,
and cardiogenic causes) should also be considered.
When therapy to increase blood pressure is contemplated,
as may be done with vasospasm, the need for it must be seri-
ously considered. Excessive increases in blood pressure can
exacerbate cerebral edema.425–429 This presumably occurs
in brain areas with dysautoregulation and BBB disruption,
such that increasing blood pressure, rather than producing
vasoconstriction and no change in rCBF, causes vascular
distention, increased rCBF, and transudation of fluid across
the damaged BBB. In addition, increases in blood pressure
risk producing or exacerbating intracranial hemorrhage.
Catecholamines used to increase blood pressure are neu-
rotransmitters or are chemically similar to neurotransmit-
ters. It is thus to be expected, if they cross the BBB, that
neural effects will arise secondary to their use. Normally,
exogenously administered catecholamines do not cross
the BBB and have no effect on CBF on metabolism.430 How-
ever, it has been demonstrated that catecholamine infusion
in the presence of BBB disruption leads to increased blood
flow and metabolism.431 In subarachnoid hemorrhage
patients, catecholamine infusions produce a variety of dispa-
rate and unpredictable effects on CBF432 and adrenergic
blockade confers neurologic protection.406 Finally, cate-
cholamines have direct neurotoxic potential as indicated
by data showing neurotoxicity with application directly to
the cortex in vivo.433 Unfortunately, catecholamines are
the only clinically accepted routine means to increase blood
pressure pharmacologically in neurologic ICU patients.
Increasing preload to the heart is one nonpharmacologic
method to increase blood pressure. With crystalloid or col-
loid infusion, this is generally associated with hemodilution.
The effects of this on a patient’s status should be considered
when this is contemplated. The hemodilution may improve
flow to areas where microcirculation is compromised.
However, it may be associated with increased CBV
and hyperemic intracranial hypertension if hematocrit
decreases excessively with compensatory vasodilatation.
Whether to use crystalloid or colloid for this purpose
remains controversial. The BBB is functionally an osmome-
ter.434–439 Thus, the added trivial increase in osmolarity
with colloid is not a sufficient conceptual reason to use it
unless the BBB is expected to be permeable to electrolytes
and less so to colloid. Thus, it makes sense and is supported
by animal studies that iso-osmolar or slightly hyperosmolar
fluids should be used to decrease the possibility of increasing
brain edema secondary to fluid administration.
Some advocate the use of induced systemic hypertension
with high ICP to prevent plateau waves. As blood pressure
increases, incremental increases in vasoconstriction occur
in normally reactive tissue to decrease CBV and thus ICP.
However, the advantage of this therapy may be offset by
increased edema in injured brain regions.44
SAH is an entity particularly notable for catecholamine
effects (described later), but catecholamine effects also occur
with other intracranial processes including increased ICP,
stroke, head trauma, or any situation of compromised mid-
brain–hindbrain O2 delivery. Serum catecholamine levels
increase dramatically after SAH, notably peaking at the
same time as the peak incidence of post-SAH vasospasm
with symptom development corresponding to serum cate-
cholamine levels.440–443 This leads to the notion that hypo-
thalamic injury with excess catecholamine release may be
an important factor in the genesis of post-SAH spasm and
stroke,442 observations that may be relevant to other intra-
cranial processes previously elaborated. Several lines of evi-
dence further support this hypothesis:
1. The cerebral vasculature is invested somewhat with
adrenergic nerves. With SAH the adrenergic receptors
in the cerebral vessels decrease in quantity.403,444 This
suggests that denervation hypersensitivity may be
occurring such that the increase in humoral catechol-
amines with SAH produces spasm in hyperreacting
vessels.
2. Catecholamine release after SAH is sufficient to produce
electrocardiographic changes404,440 with ventricular wall
motion abnormalities405,433 and myocardial injury.445,446
3. Treatment of humans with SAH with beta and alpha
adrenergic antagonists is associated with an improve-
ment in neurologic outcome447 and electrocardio-
graphic abnormalities.448
4. In animal models, selective destruction of hindbrain
adrenergic nuclei with cephalad projections prevents
the development of vasospasm.445 Moreover, laboratory
studies indicate an important role for vasopressin in
vasospasm because vasospasm cannot be produced in
vasopressin-deficient rats.449
5. Animal data with cerebral ischemia models provide
strong support for the notion that catecholamines can
exacerbate cerebral ischemia. Compared with hemor-
rhage-induced hypotension, ischemic damage was
decreased with hypotension induced through the use
of ganglionic blockade with hexamethonium450, central
adrenergic blockade with alpha-2 agonists451, and
angiotension-converting enzyme inhibition.452 Hemor-
rhaged controls were found to sustain an increase in
exogenous catecholamine concentrations. To test the
 24 • Perioperative Management of Acute Central Nervous System Injury
hypothesis that these catecholamines contributed to
brain damage, some of the animals treated with hexame-
thonium also received IV catecholamine infusions.
Reversal of the hexamethonium brain protective effect
was observed in these animals (Fig. 24.28).450
6. Brain protection has been observed in laboratory studies
with preischemic452 and preseizure453 treatment using
reserpine, a drug that depletes presynaptic catechol-
amine stores.
7. Application of catecholamines directly to nonischemic
cortical tissue has also been observed to have neurotoxic
potential.454 In addition, IV administration can exacer-
bate brain swelling after head trauma although this is
most probably a direct effect of blood pressure on a dys-
autoregulating brain (see Fig. 24.27) rather than a man-
ifestation of biochemical neurotoxicity.455
OPTIMAL HEMOGLOBIN LEVEL
Anemia is generally well tolerated neurologically except at
extreme levels. This indicates the enormous cerebrovascular
reserve that, in health, is in place to compensate for this and
similar physiologic stresses. Observations in rodents by
Borgstrom et al.456 indicate that decreasing Hb levels pro-
duce an increase in CBF that is initially primarily a result
of decreased viscosity, but as Hb continues to decrease to
below 10 gm% active vasodilation arises (Fig. 24.30). If
the brain vasculature is already maximally vasodilated
because of other stresses, such as hypoxemia or low cerebral
perfusion pressure, then the anemic stress may not be well
tolerated and produce hypoxic/ischemic brain damage.
For patients with acute neurological injury, anemia has
been identified as a potential cause of secondary injury
and is associated with worse neurologic outcomes and
increased in-hospital mortality. Acute anemia may cause
secondary injury via multiple suggested mechanisms,
600
Viscosity
500
Measured
400
CBF
Vasodilation
300
200
100
0
Hb 16 12 9 6
Hb
Fig. 24.30 Rats underwent isovolemic anemia with measurement
of change in global cerebral blood flow (CBF). The theoretical CBF that
would arise solely from changes in viscosity is indicated by the viscosity
curve. The CBF measurement follows this line until Hb falls to less
than 10, below which active vasodilation was observed. (Adapted
from Borgstrom L, Johannsson H, Siesjo B: Acta Physiol Scand
1975;93:505–514.)
389
including but not limited to tissue hypoxia, inflammation,
free-radicals, disruption of blood-brain barrier (BBB) func-
tion, vascular thrombosis, cerebral hyperemia, and
impaired cerebral autoregulation. However, most of the cur-
rent evidence does not support red blood cell administration
to correct anemia after brain injury.
Neurophysiologic Effects of Anemia
As many as half of patients who suffer from some degree of
acute brain injury require transfusion of blood products dur-
ing the first hours after admission because of acute ane-
mia.457–459 This anemia can be caused by active
hemorrhage, repeated phlebotomy, hemodilution, reduced
hematopoiesis, systemic inflammation, etc.460
Hemoglobin plays a major role in brain oxygenation as
the delivery of oxygen (DO2) to the brain is the product of
the arterial content of oxygen and cerebral blood flow
(DO2 ¼ CaO2  CBF), where CaO2 ¼ (Hb  arterial O2
sat [SatO2]  1.39) + (0.003  PaO2) and CBF is deter-
mined by cardiac output and cerebral vessel size.
In the setting of decreased oxygen concentration during
acute anemia, activation of different compensatory mecha-
nism counteracts the reduction in hemoglobin. This effect is
mediated by a sympathetically mediated increase in cardiac
output, heart rate, and stroke volume through aortic che-
moreceptor activation.461,462 In addition, there is a reduc-
tion in systemic vascular resistance and blood viscosity
and an enhanced oxygen extraction capacity.463 Moreover,
cerebral vasodilation occurs because of an increased pro-
duction of nitric oxide (NO) by endothelial cells, astrocytes,
and neurons to improve CBF.464 In the setting of acute brain
injury, these normal compensatory responses may be
impaired due to the loss of normal cerebral autoregula-
tion465, ultimately leading to the brain’s inability to vasodi-
late progressively during episodes of acute anemia and
reduced CaO2.
The association between anemia and poor neurological
outcomes after brain injury is extremely inconsistent. Some
observational studies have shown worse outcomes in
patients suffering from anemia and TBI,459,466,467 while
others have failed to show such association.458,468–470
Transfusion of PRBCs has the potential benefit of restoring
hematocrit and blood oxygen-carrying capacity, but it has
been associated with increased risk of multi-organ failure
including respiratory failure, infection, thromboembolic
events, and death.459,471–475 In addition, RBC transfusion
has been linked to decreased functional outcomes, impaired
cerebral autoregulation, and increased ICU length of
stay.468,471,476,477 Studies have shown that, for most criti-
cally ill patients, there is no advantage in maintaining a
higher hemoglobin concentration.478–480
The overall effects of anemia on the traumatized brain
may depend on several factors including the fine balance
between the harmful or protective factors of blood transfu-
sion. Although the optimal hemoglobin level in TBI patients
remains unclear, a liberal transfusion strategy (transfusion
when hemoglobin <10 g/dL) has not shown benefits in
patients with moderate to severe TBI and therefore is not
recommended.459 One recent RCT, using a factorial design,
compared the effects of erythropoietin and two hemoglobin
transfusion thresholds (7 vs 10 g/dL) on neurologic recov-
ery after TBI.481 Favorable neurological outcome was
43% for the Hb transfusion threshold of 7 g/dL and
390 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
33% for 10 g/dL (P ¼ 0.28). An individualized strategy to
base transfusion on a given patient’s vascular reserve to
accommodate anemia has not yet been reported.
Most current guidelines recommend a restrictive trans-
fusion strategy. There is clear clinical agreement that
hemoglobin <7 g/dL should be treated with PRBC trans-
fusion.482–485 Current clinical practice guidelines from
trauma and critical care specialties recommend a target
hemoglobin of 7–9 g/dL.483,485 The American Society of
Anesthesiologists486 and the American Association of Blood
Banks482 recommend the use of a restrictive transfusion
threshold approach. Despite this evidence, there is strong
physiologic support in preclinical studies and human data
to recognize the patient’s cerebrovascular reserve in making
transfusion decisions. Thus, despite these recommenda-
tions, the practitioner should make an individualized deci-
sion regarding blood transfusion, which should ideally be
based on each patient’s hemodynamic profile.
Perioperative Management of
Adults With Acute Spinal Cord
Injury
Anesthesia for patients who suffered an acute SCI can be
extremely challenging not only because of neurologic man-
ifestations of the injury but also because of the possible pres-
ence of cardiopulmonary complications and autonomic
instability. The sudden loss of motor, sensorial, and auto-
nomic functions predisposes the patient to dramatic hemo-
dynamic, respiratory, and vasomotor changes. Thus,
prompt assessment and management of these changes are
crucial to improve short- and long-term outcomes. As with
intracranial injury, the spinal cord may suffer from impaired
autoregulation making it susceptible to secondary insults.
Since potential watershed perfusion areas exist along its
anterior and posterior blood supply distribution, secondary
injury resulting from hypoperfusion and hypoxia must be
identified and treated promptly.
SPINAL SHOCK
Spinal shock refers to the abnormal physiologic state that
occurs immediately after an SCI and is manifested by loss
of spinal cord function below the injury level, with associ-
ated absent bladder and bowel control, areflexia, flaccid
paralysis, and anesthesia.487 Immediately after injury, there
is an intense sympathetic discharge that causes transient
hypertension. This period is followed by neurogenic shock,
which is part of the spinal shock syndrome consisting of
hemodynamic instability and loss of sympathetic tone,
and it is more commonly seen with complete cervical injury
than thoracolumbar lesions.488 Neurogenic shock consists
of four stages and develops over a period of weeks to months.
(Table 24.8).
CARDIOVASCULAR COMPLICATIONS
SCI can present with a wide variety of cardiovascular
manifestations including hypotension, bradycardia, and
hypothermia. The predominance of parasympathetic
activity is the cause of these manifestations. Impaired sym-
pathetic tone decreases systemic vascular resistance (SVR),
therefore decreasing venous return to the heart with subse-
quent hypotension. Orthostatic hypotension can be severe
after SCI below T6. Avoidance of hypotension is critical
because it may result in spinal cord hypoperfusion. Brady-
cardia is the most common arrhythmia seen after SCI, sec-
ondary to the loss of cardioaccelerator fibers at the level of
T1–T4, and may require atropine and/or pacing therapy.488
Almost every patient with SCI has resting HR < 60 beats/
min and close to 75% have less than 45 beats/min. The inci-
dence of bradycardia is higher with cervical spine injuries
and is most commonly seen around day 4 after the injury,
with complete resolution of cardiac electric abnormalities
after 4 to 6 weeks.489
In patients with a SCI above T5–T7, splanchnic innerva-
tion is intact. Therefore, distended intraabdominal hollow
viscera can cause excessive sympathetic discharge. This
phenomenon is called autonomic dysreflexia and is most
commonly seen in patients with chronic spinal cord injury,
but can be seen as early as 2 weeks after an SCI.490 It is char-
acterized by reflex vasoconstriction below the lesion and
vasodilation above, followed by baroreceptor reflex brady-
cardia. Symptoms include paroxysmal hypertension with
an increase in SBP >20%, bradycardia, flushing, blurred
vision, headache, and diaphoresis.491 It can be quite severe,
leading to myocardial infarction, seizures, and intracerebral
hemorrhage. Autonomic dysreflexia should be treated
immediately with the discontinuation of triggering stimuli
and hypertension should be managed with the use of quick
onset intravenous agents such as labetalol, nitrates, or cal-
cium channel blockers such as nicardipine.
PULMONARY COMPLICATIONS
SCI patients are at high risk of respiratory complications
including respiratory failure, mucous plugs, pneumonia,
atelectasis, pulmonary edema, and embolism. The respira-
tory complications following SCI vary depending on the
level and type of injury and preexisting respiratory status.
High cervical injuries affect the diaphragm and accessory
muscles, and up to 80% of patients with lesions above C4
have concomitant respiratory complications. Patients with
complete lesions often have a flaccid chest wall, hypoxia,
and hypercarbia from hypoventilation that usually require
airway protection. Patients with lower cervical lesions usu-
ally progress to respiratory failure within 3–5 days.492
MISCELLANEOUS
Patients with SCI are at increased risk of gastric content
aspiration on induction of anesthesia. In addition, gastric
delayed emptying, ileus, and acalculous cholecystitis can
occur as part of the spinal shock.493–495 Hyponatremia is
commonly present as a result of disruption of the sympa-
thetic pathways that regulate the renin–angiotensin sys-
tem.496 Urinary retention leading to bladder distention is
a common stimulus for autonomic hyperreflexia. Foley
catheters should be monitored intraoperatively to avoid
catheter kinking. Temperature dysregulation as a result
from the sympathectomy can lead to hypothermia.497
 24 • Perioperative Management of Acute Central Nervous System Injury
Table 24.8 Four-phase spinal shock model.
Phase Day 1 Areflexia resulting from the loss of excitatory
I input
Phase Day 1 to 3 Return of spinal reflexes when nerve endings
II develop supersensitivity
Phase Day 3 to Hyperreflexia
III 1 month
Phase 1 month to Progressive spasticity
IV 1 year Classic autonomic dysreflexia develops
during this phase
Therefore, core temperature should be monitored closely
during anesthesia, and fluid warmers and forced-air warm-
ing blankets used as needed.
ANESTHETIC MANAGEMENT AND CONSIDERATIONS
Anesthesiologists are involved in the perioperative care of
SCI patients at various stages of the treatment including ini-
tial airway management, ICU, and surgical care. Any
patient sustaining significant traumatic injuries to the head
and face, penetrating injuries in proximity to the spinal cord,
crush injuries, blunt trauma, and deceleration/acceleration
injuries should be assumed to have an unstable cervical
spine until proven otherwise. Initial anesthetic manage-
ment involves limiting any further injury to the spine and
spinal cord. Respiratory failure should be identified rapidly,
and any patient with obvious respiratory distress such as
cyanosis, apnea, severe paradoxical breathing pattern, or
airway obstruction should be intubated without delay. This
should be accomplished via either an orotracheal or naso-
tracheal approach with two-person in-line manual stabiliza-
tion. Presence of cranial and extracranial injuries are
common and can modify the anesthetic management.498
Presence of life-threatening intracranial hypertension or
thoracoabdominal trauma with hemodynamic instability
should be addressed before cervical spine therapy.
Preoperative evaluation should be as complete as time
and urgency allows. For elective procedures, a comprehen-
sive and coordinated anesthetic plan involving the surgeon
and anesthesiologist must be formulated in advance to
address the need for neurophysiologic monitoring, optimal
approach to secure airway, positioning, need for “wakeup
test,” and fluid management. Whenever possible, patients
should be evaluated for a preexisting neurologic deficit. This
evaluation needs clear documentation for comparison with
postoperative neurologic examination.
Airway Evaluation
The airway of a patient who presents for spinal procedures
requires meticulous assessment, including mouth opening,
dentition, presence of other facial injuries, head trauma,
blood in the airway, and the patient’s level of cooperation.
The patient may present with the C-spine immobilized with
a halo, a soft/hard collar, or other devices that may affect
the ability to mask ventilate or intubate the trachea. The
presence of a full beard may make mask ventilation more
difficult. Mallampati classification should be documented.
Several alternative means of endotracheal intubation
391
should be available and planned ahead in the event of a dif-
ficult airway. Patients with systemic diseases such as rheu-
matoid arthritis or cervical myelopathy are at increased risk
of further injury if a controlled approach is not performed.
Monitors
American Society of Anesthesiology (ASA) standard moni-
tors (5-lead EKG, pulse oximetry, end-tidal CO2, tempera-
ture, noninvasive blood pressure) are used in all patients
undergoing spinal surgery. A preinduction arterial line
should be placed in patients with high-cervical or thoracic
injuries as hemodynamic lability is commonly encountered.
In addition, arterial line can be utilized to guide fluid man-
agement by means of dynamic tests of fluid responsiveness
such as pulse pressure variation and stroke volume varia-
tion.499 There is debate regarding monitoring for venous
air embolism because the risk increases in procedures with
surgical incision >5 cm above the heart level, extensive sur-
gical spine instrumentation, and bony excision. Thus, for
procedures in which the surgical site is elevated above the
level of the heart and when associated with extensive blood
loss and hemodynamic instability requiring vasoactive sup-
port, a central venous catheter should be considered.500,501
Adequate venous access should be obtained before final
positioning, including at least two large bore IV lines for
multilevel procedures and instrumentation.
Premedication should be administered carefully in
patients with acute SCI because any sedatives might worsen
an otherwise already tenuous respiratory status. In general,
premedication is optional and should be prescribed at the
discretion of the anesthesiologist. A small dose of midazolam
may be considered if the patient is experiencing significant
anxiety. Analgesia with short acting opioids can be consid-
ered for pain management.
Induction of Anesthesia. Patients with thoracic and high
cervical injuries are at risk of intraoperative hypotension as
a result of induction agents, hypovolemia, and sympathetic
denervation. To date, no definitive evidence favors an anes-
thetic approach over another in patients with SCI. However,
careful blood pressure and oxygenation monitoring are vital
to prevent secondary injury to the spinal cord. For bradycar-
dic patients, a small bolus of ephedrine or glycopyrrolate can
be given to prevent hypotension/bradycardia. Nondepolar-
izing neuromuscular blockers can be safely used unless
there is planned intraoperative neuromonitoring. Succinyl-
choline use is usually avoided because of the risk of life-
threatening hyperkalemia seen in patients with SCI and
ACh receptor upregulation after 48 hours.502
Airway Management. Patients with cervical spine disease
have an increased incidence of difficult laryngoscopy by
approximately 20%.503 In particular, patients with
occipito-atlantoaxial disease have higher incidence of diffi-
cult laryngoscopy than those with lower cervical spine dis-
ease. The best single radiographic predictor of a difficult
airway is reduced separation of the posterior elements of
C1–C2 on lateral views, whereas the Mallampati classifica-
tion is the most accurate clinical predictor.503 To date, no
technique for airway management has been shown to be
superior to others for prevention of neurologic deterioration
in patients with an unstable cervical spine. However, the
392 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

technique chosen should reflect the clinical situation,
patient factors, and the expertise of the anesthesiologist. Air-
ways can be compromised in patients with SCI as a result of
several factors such as associated head injuries with/with-
out altered mental status, facial trauma, retropharyngeal
hematomas, etc. Experienced staff and a difficult airway cart
should be immediately available. If trouble is encountered,
the difficult airway algorithm for patients with SCI should
be followed (Fig. 24.31).
Manual in-line stabilization has shown to decrease but
not to eliminate C-spine motion during airway instrumenta-
tion.504 However, it should be used in all patients with acute
cervical or high thoracic SCI, unless the patient presents to
the operating room with a fixation device (i.e., Halo system).
During this maneuver, the assistant should apply enough
force to counter forces applied during laryngoscopy in order
to maintain a neutral spine, WITHOUT applying traction.
Unopposed traction carries risk of excessive spinal distrac-
tion and should be avoided.504 If a hard collar is in place,
manual in-line stabilization should be performed. Only after
stabilization is achieved, another operator can remove the
anterior portion of the cervical collar to allow extra range
of motion during mouth opening. Once the airway is
secured, the collar should be reapplied. Although, manual
in-line stabilization is recommended, a prior study found
that the rates of failed intubation are higher when manual
in-line stabilization is performed. It increased the rate of
failed intubation at 30 seconds (50% with in-line stabiliza-
tion vs 5.7% without). All patients who failed intubation
were successfully intubated when in-line stabilization was
released.505 Therefore, its use should also be based on the
urgency of the situation in order to avoid delays in securing
the airway.
Hemodynamic Management. Blood pressure should be
monitored closely to prevent any episodes of hypotension
that can predispose the already injured spinal cord to sec-
ondary injuries. As mentioned before, spinal cord

Assess airway and oxygenation

Apnea/respiratory distress Adequate

Emergency airway Elective airway

Intubation in most efficient Radiographic evaluation of

manner cervical spine
• Maintain MILI without • CT scan
traction • ±3-view plain
• Avoid neck extension or radiographic series
vjaw thrust • ±MRI

Airway Secured? Results

Yes No Normal Abnormal

Radiographic evaluation Mask ventiltion Cautious oral • Awake or asleep

of cervical spine or LMA intubation FOI-MILI
• VAL-MILI
• CT scan • Avoid jaw • Direct • Blind nasal
• ±MRI thrust/chin lift laryngoscopy intubation-MILI
• VAL • Surgical airway
• Asleep FOI

Inadequate ventilation

ASA difficult airway algorithm

• Jet ventilation
• Surgical or percutaneous airway
• Retrograde intubation
• Reconsider other options (ILMA, video-assisted
laryngoscopy, light wand, intubating stylet)

Fig. 24.31 Difficult airway algorithm for patients with spinal cord injury.
 24 • Perioperative Management of Acute Central Nervous System Injury
autoregulation is impaired after SCI. Thus, spinal cord per-
fusion is dependent on MAP and it is autoregulated over a
wide range of blood pressure. Currently, the proper blood
pressure level that should be achieved after a SCI has not
been established. The American Association of Neurological
Surgeons guidelines for BP management include mainte-
nance of a MAP of 85 to 90 mmHg for 5 to 7 days after acute
cervical SCI and avoidance of a systolic BP (SBP) below
90 mmHg, both as level 3 (optional) recommendations.506
Intravascular volume after acute SCI is insufficient to
maintain adequate blood pressure because of excessive
vasodilation resultant from sympathectomy. Thus, active
resuscitation with IV crystalloids, colloids, and blood prod-
ucts as necessary must be a priority. Although isotonic
crystalloid is the initial fluid of choice during SCI resuscita-
tion, experimental preclinical studies have shown hyper-
tonic saline to be useful in decreasing spinal cord edema
and inflammation.507 Fluid resuscitation should be guided
with invasive monitoring such as an arterial line and pos-
sibly a pulmonary artery catheter in cases where signifi-
cant pulmonary edema and hemodynamic impairment
are suspected. Pulse pressure variation (PPV) and stroke
volume variation (SVV) are derived from arterial line trac-
ing and can provide a measure of the patient’s volume sta-
tus during positive pressure mechanical ventilation to help
guide fluid administration.499 In the supine position, PPV
>11%–13% predicts that the patient will respond to a fluid
challenge with an increase in cardiac output. However, in
the prone position, variability in intrathoracic and intra-
abdominal pressures alter venous return limiting the
accurate assessment of PPV. Therefore, PPV trends rather
than absolute values should be used to guide fluid resus-
citation.508 Careful fluid administration is advised in order
to avoid further cardiorespiratory damage in patients
with neurogenic pulmonary edema resulting from the
initial sympathetic discharge and/or myocardial dys-
function. In addition, acid-base status, lactate levels, esti-
mated blood loss, and urine output are used to guide
fluid resuscitation.509
In the event of failure to maintain target BP with IV fluids
only, vasoactive agents can be utilized. Their use should be
guided with invasive hemodynamic monitoring including
arterial cannula and central venous access as needed. The
vasopressor agent of choice should be a potent α-agonist
such as phenylephrine or norepinephrine. However, the
ideal vasopressor must be chosen and adjusted (as needed)
based on the patient’s overall hemodynamic profile and pre-
existing cardiac function, because sudden increases in SVR
and afterload can precipitate left ventricle failure. Recent
evidence suggests that in cases of SCI above the cardioacce-
lerator fibers, norepinephrine might be the preferred agent
because it could slightly improve spinal cord perfusion. In
a prospective study of 11 patients with cervical and thoracic
SCI, norepinephrine was able to maintain MAP with a lower
intrathecal pressure (17 mmHg vs 20 mmHg), and a
slightly higher spinal cord perfusion pressure (67 mmHg
vs 65 mmHg), compared with dopamine.510 In cases of
lower SCI, phenylephrine might be the agent of choice
because peripheral sympathectomy and vasodilation often
require a pure vasoconstrictor. If the goal is to achieve a cer-
tain MAP level quickly, norepinephrine is probably the
agent of choice because it has mild to no β-2 agonism
393
activity, thereby decreasing the possibility of peripheral
vasodilation (Table 24.9). If the decision is taken to use a
pure α-agonist such as phenylephrine, the anesthesiologist
should be aware of the risk of reflex bradycardia, which can
further worsen preexisting bradycardia in patients with
high-level cervical SCI. Epinephrine has some proarrhyth-
mic activity and should be avoided unless physiologic and
echocardiographic evidence indicate that the patient would
benefit from its added inotropic support.
ANESTHESIA FOR ENDOVASCULAR THERAPY IN
ACUTE ISCHEMIC STROKE
Stroke is one of the leading causes of mortality and morbid-
ity around the world. A large body of evidence confirms that
the most important factor in the management of acute
ischemic stroke (AIS) is the timely restoration of blood flow
by means of thrombolytic therapy and/or endovascular
therapy. From the anesthesiologist’s perspective, the most
important role in the management of AIS is to allow the
prompt initiation of the procedure, through constant com-
munication and coordination of care with the neurointer-
ventionalist and stroke specialists. Many studies have
demonstrated the benefit of endovascular therapy (EVT)
in AIS (MR CLEAN,511,512 SWIFT PRIME,513 EXTEND-
IA,514 REVASCAT,515 ESCAPE,516 DAWN trial517). For
the purposes of this chapter, we will focus on anesthetic
management during endovascular therapy.
The main initial goals are to perform an initial ABC eval-
uation and to determine the need for urgent intervention,
ensure medical stability, and quickly reverse any condition
that can be contributing to the neurologic deficit. Important
aspects of acute stroke evaluation and management include
the following:
▪ Assessing vital signs and ensuring stabilization of airway,
breathing, and circulation.
▪ Obtaining a rapid but accurate history and examination
to help distinguish stroke mimics and other disorders in
the differential diagnosis of acute stroke.
▪ Obtaining urgent brain imaging (with CT/CTA or MRI)
and other important laboratory studies, including car-
diac monitoring during the first 24 hours after the onset
of ischemic stroke.
▪ Managing volume depletion and electrolyte disturbances.
▪ Checking serum glucose. Low serum glucose should be
corrected rapidly. It is reasonable to treat hyperglycemia
if the glucose level is >180 mg/dL with a goal of
keeping serum glucose levels within a range of 140 to
180 mg/dL.
▪ Assessing swallowing and preventing aspiration.
▪ Optimizing head of bed position. For patients with
intracerebral hemorrhage, subarachnoid hemorrhage,
or ischemic stroke who are at risk of elevated intracranial
pressure, aspiration, cardiopulmonary decompensation,
or oxygen desaturation, we recommend keeping the
head in neutral alignment with the body and elevating
the head of the bed to 30 degrees (Grade 1C). For patients
with stroke who are not at high risk of these complica-
tions, we suggest keeping the head of the bed in the posi-
tion that is most comfortable.
394 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 24.9 Common vasopressors and inotropic agents used in the neurologic ICU.
Receptor
Drug type activated Indications Comments Initial Dosage
INOTROPIC AGENTS
Dobutamine α, β1, β2 Acute decompensated heart failure, Can decrease SVR and provoke 2.5–10 μg/kg/min
Cardiogenic shock, septic shock with hypotension.
depressed cardiac function Tolerance may occur with
prolonged administration
Milrinone Phosphodiesterase Increase CO in decompensated heart failure Reduce dose if low CrCl 0.25–0.75 μg/kg/min
III inhibitor Adverse effects: hypotension,
arrhythmias, thrombocytopenia

VASOPRESSORS
Epinephrine α, β1, β2 First-line agent in septic shock Risk of dysrhythmias and 2–5 μg/kg/min
Anaphylactic shock myocardial ischemia.
Adverse effects: Children: 0.03–2 μg/
tachyarrhythmias, hyperglycemia, kg/min
lactic acidosis, hypokalemia

Norepinephrine α, β1 First-line agent in Septic Shock with low SVR May increase oxygen 2–5 μg/min
consumption OR 0.02–0.06 μg/kg/
Risk of dysrhythmia and min
myocardial ischemia
May decrease intestinal perfusion
and increase lactate levels

Phenylephrine α Rapid MAP increases May decrease CO 10–100 μg/min

# outflow tract gradient in patients with May cause reflex bradycardia 0.1–1 μg/kg/min
obstructive hypertrophic cardiomyopathy Not indicated for septic shock
No β effect, therefore less Children: 0.03–0.1 μg/
arrhythmogenic kg/min
Ephedrine α, β1, β2 IV: Postanesthesia-induced hypotension Can stimulate release of IV: 5–25 μg slow IV
endogenous norepinephrine push, may repeat
after 5–10 min

Vasopressin V1 Refractory hypotension in septic shock Not first-line agent in shock 0.04 units/min
Diabetes insipidus May decrease splanchnic
perfusion and increase gut Children: 0.3–2
ischemia milliunits/kg/min

Dopamine Dopa, α, β1 variable Dopa: 1–3 μg/kg/min

α: 3–10 μg/kg/min
β: 10–20 μg/kg/min

CO, Cardiac output; CrCl, creatinine clearance; ICU, intensive care unit; SVR, systemic vascular resistance.

▪ Evaluating and treating the source of fever, if present; for
patients with acute stroke, it is advisable to maintain
normothermia for at least the first several days after an
acute stroke (Grade 2C).
Planning the Anesthetic
In addition to performing a careful preoperative evaluation
whenever possible, it is advised for the anesthesiologist to
maintain constant communication with the neurointer-
ventionalist to avoid delays in care. Preoperative evalua-
tion should be focused and concise. In general, the
stroke specialist can provide some basic clinical informa-
tion to guide the anesthetic plan. Neurologic examination
by the anesthesiologist should include at least GCS in order
to determine need for airway protection. In addition, pres-
ence of neurologic deficit at baseline may alter the anes-
thetic plan. It is important to recognize whether the
patient has a history of fall/trauma in order to take C-spine
precautions if endotracheal intubation is warranted.
Neuroimaging studies should be discussed with the stroke
specialist to determine whether patient is at risk of life-
threatening conditions that may require immediate man-
agement. AIS patients commonly have cardiopulmonary
comorbidities that may modify the initial anesthetic plan
such as congestive heart failure, which limits the patient’s
ability to remain flat during the EVT. If a prior transtho-
racic echocardiogram is available, it should be reviewed
to guide fluid and anesthetic management. Its absence
should not delay the initiation of therapy. Electrolyte
and endocrine abnormalities should be corrected where
possible. Hypo- and hyperglycemia must be corrected
to maintain glucose <180 mg/dL. Use of anticoagu-
lants, t-PA, and/or laboratory evidence of coagulation
abnormalities should be sought. Although rarely seen,
the anesthesiologist must be aware of tPA-induced ana-
phylaxis risk.518
 24 • Perioperative Management of Acute Central Nervous System Injury
Anesthesia Type. EVT has become the current gold
standard of care for management of acute ischemic
stroke involving the anterior circulation. Its benefit has
been largely demonstrated in multiple RCTs and
meta-analyses.515,519,520 However, some questions
remain unanswered in endovascular practice, including
the modality of anesthesia that will yield the best clinical
outcome. The vast majority of retrospective studies have
shown superior neurologic outcomes with monitored
anesthesia care (MAC) over general endotracheal
anesthesia (GETA).512,521–543 However, most of these
retrospective studies experienced selection bias, and the
GETA group consistently showed higher National Insti-
tutes of Health Stroke Scale (NIHSS) admissions and more
posterior circulation strokes with little involvement of
anesthesiologists in authoring the reports. In addition,
general anesthesia in some trials was entirely at the dis-
cretion of the treating team and there is no report of formal
anesthetic protocols. A recent better but not optimally
designed prospective RCTs such as GOLIATH,534
SIESTA,535 and ANSTROKE536 have placed more atten-
tion on anesthetic protocols, hemodynamic variables,
and specified criteria to prevent hypo- or hypercarbia.
Most of current literature suggests a trend toward worst
neurologic outcome with GETA, and this conclusion is
based on the following variables: (1) the possibility of treat-
ment delay with GETA because of the need for intubation;
(2) transient hypotension and hemodynamic instability
associated with the commonly used anesthetics; (3) neuro-
protection/neurotoxicity from anesthetic agents used; and
(4) ventilation mode leading to hyper- and/or hypocarbia.
Notably many of these concerns are easily addressed when
the available anesthesiologists have ample experience with
emergency anesthesia in unstable patients and, most impor-
tantly, understand the urgency of EVT.
Despite the existence of very high-quality trials demon-
strating the beneficial effect of EVT, many questions remain
unanswered regarding the type of anesthesia that should be
used during EVT. More importantly, very inconsistent
results have been yielded in what are considered to be
advantages of one modality of anesthesia over the other
(Table 24.10). Based on current literature, the decision to
Table 24.10 Advantages of different anesthetic techniques
on management of AIS.
GETA MAC
▪ Less risk for patient movement ▪ Shorter time to treatment
during the critical components initiation
of the EVT, and thus higher ▪ Less risk for intraoperative
patient safety due to a lower hypotension
risk of vascular injury such ▪ Less risk for post-op respiratory
as perforation or dissection. complications
▪ Faster and more effective ▪ Allow intermittent neurologic
intervention by improved assessment during and sooner
stability in road mapping and after EVT
device placement
▪ Adequate oxygenation and
ventilation with less risk for
aspiration.
▪ Improving patient and
neurointerventionalist
comfort
AIS, Acute ischemic stroke; EVT, endovascular therapy; GETA, general
endotracheal anesthesia; MAC, monitored anesthesia care.
395
pursue GETA or MAC should be highly individualized, based
on the patient’s overall medical condition because no clear
advantage to either approach has been demonstrated. In
our experience, patients with impending respiratory failure
and/or inability to protect airway, gastric aspiration, poor
neurologic examination based on admission GCS, inability
to lay supine, and/or high risk of seizures, should receive
GETA. In addition, GETA may be preferable in the unco-
operative or agitated patient or when hemodynamic insta-
bility exists.
Blood Pressure Goals. Optimal blood pressure goals have
not been clearly defined but, in general, maintaining SBP
between 140 and 180 mmHg and DBP <105 mmHg
during all the stages of the procedure is recommended,
regardless of prior t-PA administration.537 Continuous
blood pressure is recommended and an arterial line should
be placed whenever possible without delaying therapy. If
there is a need to maintain target blood pressure with
vasoactive medications, the anesthesiologist should con-
sider the overall hemodynamic profile and decide on the best
pharmacologic agent.
After vessel recanalization, the anesthesiologist should
revise blood pressure goals with the neurointerven-
tionalist because some evidence suggests the brain tissue
may be at risk of hyperperfusion and/or hemorrhagic
transformation.538,539
Oxygenation and Ventilation. As previously mentioned,
the avoidance of secondary insults in acute brain injury
such as hypoxia and hypo- or hypercarbia should be
avoided. Hypocapnia induces cerebral vasoconstriction,
which can lead to decreased blood flow to an already com-
promised penumbral tissue,540 and hypercarbia can pro-
mote cerebral vasodilation with intracranial hypertension.
The Society of Neurosciences in Anesthesiology and Critical
Care recommend maintaining SpO2 >92% and PaO2
>60 mmHg, and minute ventilation should be adjusted to
maintain PaCO2 between 35 and 45 mmHg. Additionally,
hyperoxia (PaO2 >300 mmHg) should be avoided because
prior studies have associated its development with increased
in-hospital mortality and increased oxidative stress.242,541
Fluid and Glucose Management. Intravascular volume
depletion is frequent in AIS, especially in elderly patients.
In general, isotonic crystalloids should be used to resuscitate
an AIS patient.542 In general, it is best to avoid hypotonic
fluids because they may exacerbate cerebral edema in acute
stroke and are less useful than isotonic solutions for repla-
cing intravascular volume. In addition, it is best to avoid
fluids containing glucose, which may exacerbate hypergly-
cemia. However, fluid management must be individualized
on the basis of cardiovascular status, electrolyte distur-
bances, and other conditions that may alter fluid balance.
Hypoglycemia can cause focal neurologic deficits that can
mimic stroke symptoms, which must be corrected immedi-
ately to a goal of >70 mg/dL.543 Diabetes mellitus is
extremely common in patients suffering from AIS. Serum
glucose >140 mg/dL has been associated with worse clini-
cal outcomes in AIS.368–374 It is recommended to monitor
continuously serum glucose intraoperatively and maintain
between 140 and 200 mg/dL.537
396 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
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study. Lancet Neurol. 2009;8:802–809.
552. Herrmann O. Fast-track intubation for accelerated interventional
stroke treatment. Neurocrit Care. 2012;17:354–360.
553. Abou-Chebl A. North American SOLITAIRE stent-retriever acute
stroke registry: Choice of anesthesia and outcomes. Stroke.
2014;45:1396–1401.
554. Hubert GJ, Miiller-Barna P, Haberl RL. Unsolved issues in the man-
agement of high blood pressure in acute ischemic stroke. Int J Hyper-
tens. 2013;2013:1–5.
555. Leonardi-Bee J, Bath PMW, Phillips SJ, et al. Blood pressure and
clinical outcomes in the International Stroke Trial. Stroke. 2002;33:
1315–1320.
556. Potter J, Mistri A, Brodie F. Controlling hypertension and hypotension
immediately post stroke (CHHIPS)-a randomised controlled trial.
Health Technol Assess. 2009;13:1–73. iii, ix-xi.
557. Robinson TG. Effects of antihypertensive treatment after acute stroke
in the Continue or Stop Post-Stroke Antihypertensives Collaborative
Study (COSSACS): A prospective, randomised, open, blinded-endpoint
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558. Qureshi AI. Acute hypertensive response in patients with stroke:
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559. Komatsu R, You J, Mascha EJ. Anesthetic induction with etomidate,
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560. Nogueira RG. Predictors of Good Clinical Outcomes, Mortality, and
Successful Revascularization in Patients With Acute Ischemic Stroke
Undergoing Thrombectomy: Pooled Analysis of the Mechanical
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Trials. Stroke. 2009;40:3777–3783.
560. Davis MJ. Anesthetic management and outcome in patients during
endovascular therapy for acute stroke. Anesthesiology. 2012;116:
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562. Jauch EC. Guidelines for the early management of patients with acute
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563. Young WL. Anesthesia for endovascular neurosurgery and interven-
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 24 • Perioperative Management of Acute Central Nervous System Injury
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 25 Prevention and Treatment of
Gastrointestinal Morbidity
ANDREW ISKANDER, EHAB AL-BIZRI, ROTEM NAFTALOVICH, and TONG J. GAN
Undergoing general anesthesia for an elective operation has
become exceedingly safe and is now rarely associated with
mortality. With the improvements in perioperative screen-
ing, risk reduction, and intraoperative management, we
can now focus on and improve the quality of postoperative
recovery. For example, gastrointestinal morbidity is fre-
quent after elective surgery. In the past decade, there has
been a vast increase in the understanding of the risk factors
and therapeutic modalities associated with postoperative
nausea and vomiting and with postoperative ileus. Further
study has targeted interventions to specific patient popula-
tions to reduce the risk for these complications. This chapter
will highlight several common causes of gastrointestinal
morbidity and provide strategies to reduce the risk for
adverse gastrointestinal outcomes. Using this information
will allow the clinician to improve the quality of postopera-
tive recovery, increase patient satisfaction, and decrease the
length of hospital stay.
Aspiration of Gastric Contents
INCIDENCE, ETIOLOGY, AND PATHOGENESIS
The aspiration of gastric contents under anesthesia is for-
tunately a rare event but one that can be associated with
serious morbidity and even mortality. Despite a greater
understanding of the risk factors, prevention, and man-
agement, there has been no appreciable decrease in its
incidence.1 The consequences of aspiration include bron-
chospasm, laryngospasm, aspiration pneumonitis, aspira-
tion pneumonia, and the acute respiratory distress
syndrome.
Historically, the syndrome of aspiration pneumonitis was
first described by Mendelson in 1946 in a group of obstetric
patients undergoing general anesthesia.2 He was also the
first to describe the role of the acidity of gastric contents in
the pathogenesis of this syndrome. Installation of gastric con-
tents into the lung was indistinguishable pathologically from
the effect of the introduction of 0.1 N hydrochloric acid.2
Later, it was shown that neutralization of gastric acid prior
to aspiration reduced the damage to the lungs. In experimen-
tal studies, the degree of pulmonary injury increased signifi-
cantly with a decrease in pH and an increase in volume.3
The commonly cited values of a gastric volume of 0.3 to
0.4 mL/kg and a gastric pH of lower than 2.5 for the devel-
opment of aspiration pneumonitis come from animal studies
that involved the direct installation of acid into the lungs
of Rhesus monkeys.4,5 However, gastric contents are not
purely liquid and the presence of particulate matter can
cause inflammation and lung injury, even with a pH higher
than 2.5.6,7 Also, the volume of gastric fluid present does
not seem to correlate to the risk for aspiration or the amount
aspirated, Many appropriately fasted patients have gastric
volumes that exceed 0.4 mL/kg and demonstrate no evi-
dence of aspiration.8,9 Extrapolating gastric volume to the
potential aspirated volume is therefore speculative at best,
and it is further complicated by the difficulty of accurately
measuring gastric volumes. The Cochrane Database review
on perioperative fasting found some studies that show an
increase in gastric emptying with the ingestion of clear
fluids.10
The anatomic and physiologic mechanisms that prevent
reflux include the upper esophageal sphincter (UES), the
lower esophageal sphincter (LES), and the laryngeal reflexes.
Alteration of any of these can increase the risk of aspiration.
The LES forms a barrier between the stomach and the esoph-
agus that prevents aspiration. When gastric pressure
exceeds the LES barrier pressure, aspiration is possible.11 A
decrease in the LES pressure is the most significant physio-
logic derangement in patients who aspirate during anesthe-
sia and in those who suffer from gastroesophageal reflux
disease (GERD). Many of the drugs used in anesthesia can
alter the LES pressure, thus affecting the risk for aspiration.
In general, opiates, anesthetic induction agents, volatile
anesthetics, and anticholinergics all cause a decrease in
LES pressure, whereas cholinergics, prokinetics, and alpha
agonists all increase LES pressure (Table 25.1).11
The UES is best considered a region of increased pressure
in the peristaltic wave formation of the hypopharyngeal
region.12 Classically, the cricopharyngeus is considered
the largest contributor to the UES. However, there are large
contributions from the thyropharyngeus (itself a part of the
inferior pharyngeal constrictor) and direct contributions
from the proximal esophagus. The contributions belie the
interplay between the apparatus involved in airway control
and deglutition that are altered when aspiration is
encountered.
The cricopharyngeus is often the focus of most discussions
regarding the prevention of aspiration in the preoperative
period. It extends around the pharynx and in healthy con-
scious adults it prevents the entrance of gastric contents
from the esophagus into the hypopharynx. The tone of
the UES, like that of the LES, is altered by many of the
anesthetic induction agents as well as by neuromuscular
blockers and sleep. These factors may combine and further
411
412 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Table 25.1 Perioperative drugs that lower the tone of the
lower esophageal sphincter.
Drug class Example
Anticholinergics Glycopyrrolate, atropine
Catecholamines Dopamine
Volatile anesthetics Isoflurane, desflurane, sevoflurane
Opioids Morphine, fentanyl, sufentanil
Induction agents Propofol, thiopental
increase the risk for aspiration.13 Of particular importance is
the effect of residual neuromuscular blockade on the UES. In
a study using fluoroscopy and manometry, it was shown
that at a train-of-four (TOF) ratio of 0.8, resting UES and
pharyngeal muscle tone was decreased significantly.14
These investigators were also able to demonstrate alter-
ations in swallowing and found discordant activity of the
pharyngeal muscles and the UES. These alterations in UES
and pharyngeal tone could be clinically significant and
could lead to an increased risk of aspiration in the
postoperative period.
RISK FACTORS
The best defined risk factor for aspiration is an emergent
operation. There are several theories as to why this should
be the case. First, patients scheduled for emergent surgeries
are not appropriately fasted and thus have increased gastric
volumes. The sympathetic response to pain also decreases
gastric motility.15 Second, any opiate administered to such
patients in the preoperative period will slow gastric empty-
ing.16 Finally, traumatic brain or spinal cord injuries have
been shown to cause gastroparesis.
Late-term pregnancy, with its alterations in gastric
morphology, increases in intra-abdominal pressure, and
increases in progesterone levels, predisposes patients to
passive regurgitation. There is controversy, however, over
whether there is a delay in gastric emptying in parturient
women.17 Obstetric labor is also known to delay gastric
emptying. This most likely results from the effect of pain
and the administration of central neuraxial opiates, both of
which are known to slow gastric transit time.18 In addition
to having these physiologic and anatomic factors, parturient
women may also have increased upper airway edema and
tissue mass, which may necessitate multiple attempts to
perform a laryngoscopy and a longer duration of that
procedure, leaving the pregnant patient with an unprotected
airway for a longer time than a nonpregnant patient.
Obese patients are also thought to be at higher risk of aspi-
ration. Although no decrease in the rate of gastric emptying
has been demonstrated, the airway difficulties of obese
patients could place them at increased risk of aspiration
for the same reasons as pregnant patients.19
Other systemic diseases such as scleroderma, diabetes
mellitus type I, and Parkinson disease are all known to cause
either delays in gastric emptying or alterations in the LES,
leading to an increased risk of aspiration (Box 25.1).
RISK REDUCTION
Recent work has begun to look at data that point to prevent-
able causes of aspiration in the operating room, and focus
has been on the practitioners.20 The element of human
error is being examined because it is the most preventable
risk factor. The paucity of a proper level of knowledge
regarding the causes, especially when paired with the inap-
propriate decision-making that can come from lack of either
experience or inadequate training, are the most significant
elements of human error.
Knowledge of the risk factors for aspiration allows the cli-
nician to alter the anesthetic plan to reduce the periopera-
tive risk for this condition. The clinician can use four broad
strategies to facilitate this. First, decrease the chance of gas-
tric contents entering the hypopharynx. Second, inhibit the
passage of the contents from the pharynx and esophagus
into the trachea and lungs. Third, alter the pH of the gastric
fluid (by the use of histamine-2 [H2] blockers, proton pump
inhibitors, and particulate antacids). Finally, decrease the
volume of gastric fluid.
The most common way to prevent the gastric contents
from entering the hypopharynx, trachea, and lungs is by
using cricoid pressure, first described by Sellick in 1961.
The anatomic theory behind this maneuver is that pressure
on the circular cricoid ring will occlude the esophagus
against the fifth cervical vertebrae, thus inhibiting gastric
contents from entering the tracheobronchial tree.21
Although this technique is attractive in theory, its applica-
tion has many pitfalls. There is evidence that the application
of cricoid pressure can cause a decrease in LES tone, perhaps
through a mechanoreceptor-mediated reflex mechanism.22
The suggested force of 44 newtons (N) of pressure has been
shown in endoscopic studies to cause cricoid deformation,
airway closure, and increased difficulty in ventilation.23
Further, most anesthesia assistants misapply the cricoid
pressure (with variations in force between 10 and 90 N),
which can lead to difficulties in visualizing the glottic open-
ing.24 The maneuver itself is not without risk and there have
been reports of esophageal rupture when cricoid pressure
has been applied to a patient who is vomiting.25
Box 25.1 Diseases and conditions known to
increase the risk of aspiration.
Pain
▪
▪ Pregnancy
▪ Trauma
▪ Diabetes
▪ Head injury or altered level of consciousness
▪ Spinal cord injury
▪ Scleroderma (or CREST syndrome [acronym for calcinosis,
Raynaud phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia])
Parkinson disease
▪
▪ Obesity
Amyotrophic lateral sclerosis
▪
▪ Zenker diverticulum
▪ Pyloric stenosis

Alteration of the pH of gastric fluid is the most common
pharmacologic method to reduce morbidity should aspira-
tion occur. The three classes of drugs used to accomplish this
goal are H2-receptor blockers, proton pump inhibitors
(PPIs), and nonparticulate antacids. None of these has been
subjected to a rigorous clinical trial. With the actual event
rate of aspiration being so small, surrogate measures such as
gastric fluid volume have been used instead, but some ques-
tion the use of gastric fluid volume as a clinically significant
endpoint.26
H2-receptor antagonists are commonly used agents to
increase gastric pH. They bind the histamine type 2 receptor
on gastric parietal cells and inhibit gastric acid secretion.
Pharmacologic features of these drugs that should be recog-
nized, however, include the lack of correlation between acid
suppression and peak plasma concentration, significant
interindividual variation in the degree of acid suppression,
and the development of tolerance.
PPIs are a newer class of medications that form a covalent
bond with the H+,K+-ATPase of the parietal cell. To be effec-
tive in increasing gastric pH in the preoperative period, these
medications must be given the night before and the morning
of surgery.27
Many head-to-head studies of the H2-receptor antago-
nists and PPIs have shown an increase in gastric pH and
a decrease in gastric volume.28 Whether these surrogate
endpoints are clinically relevant has engendered much
debate. Even if a reduction in morbidity or mortality could
be demonstrated, the number needed to treat (see later)
would be too large to recommend widescale adoption of this
practice for all patients. In fact, the American Society of
Anesthesiologists (ASA) 2017 task force has not endorsed
the use of H2 antagonists for patients who are not at risk
for aspiration.29
Nonparticulate antacids (e.g., sodium citrate, sodium
bicarbonate) have been shown to increase the pH of gas-
tric fluid but to have no effect on gastric volume. These
agents are attractive because they increase gastric pH
rapidly, making their use with the emergency surgical
patient more feasible than that of the PPIs or H2 blockers.
Nonetheless, these agents should only be used in patients
with an increased risk for pulmonary aspiration. As
noted by the ASA in its 2017 guidelines, they should
not be used routinely in the preoperative setting before
general anesthesia, regional anesthesia, or procedural
sedation.
NPO GUIDELINES
Anesthetics and sedatives—used in general anesthesia,
regional anesthesia, and monitored anesthesia care—are
known to reduce the airway protective mechanisms. Reduc-
tion of aspiration risk starts with following fasting guide-
lines. These guidelines are primarily based on gastric
physiology and apply to patients having elective procedures
during all types of anesthesia. As mentioned previously,
studies have shown that particulate matters, acidic contents
with pH of lower than 2.5, and large gastric volumes of
greater than 0.3 to 0.4 mL/kg, are associated with worse
outcomes.5
25 • Prevention and Treatment of Gastrointestinal Morbidity 413
After reviewing the patient’s medical records, interview-
ing the patient and performing physical examination, the
anesthesiologist should take into consideration the ASA
physical status, age, sex, type of surgery, potential of difficult
airway, consideration of GERD and other gastrointestinal
(GI) motility and metabolic disorders (e.g., diabetes melli-
tus). Subsequently, both educating the patient in advance
prior to the surgery date and choosing plain language or
more detailed language based on the patient’s mental status
play a crucial role in patient compliance with fasting
requirements. Having noncompliant, nonfasted patients
on the day of surgery puts them at unnecessary increased
risk of aspiration. Decision to proceed or delay the procedure
at that time can be based on the amount and type of food
ingested and the effects of delaying the procedure.
Clear liquids include water, juices without pulp, coffee or
tea without milk, and carbohydrate drinks. Alcohol is pro-
hibited. These liquids are allowed for up to 2 hours prior
to the procedure with no restriction of the volume of the
clear liquid. This is based on evidence that patients who
were allowed clear fluids up to 2 hours prior to their surgery
had similar gastric fluid volumes and pH when compared
with those who fasted longer.30 Fasting for several hours
puts the patient at the consequence of hypoglycemia and
hypovolemia, particularly in the pediatric population. Thus
drinking clear carbohydrate-rich liquids should be encour-
aged up until 2 hours prior surgery. It may also reduce
thirst, hunger, and anxiety prior to surgery,31 particularly
when prolonged nil per os (NPO) times are caused by delays
in the nature of unpredictable scheduling of operation times.
The ingestion of a light meal (such as toast with a clear
liquid) on the morning of surgery and its relation to gastric
volume and emptying has been investigated. Although gas-
tric volume was not increased, particulate matter was still
present in the stomach up to 4 hours after ingestion,29
which is particularly worrisome because particulate mate-
rial in the lung elicits a profound inflammatory response.
Gastric emptying time is longer with larger meal weight,
higher calorie content, and higher fat content. Heavy meals
(such as those containing fried foods) took up to 9 hours to
exit the stomach. The ASA taskforce on perioperative fast-
ing has therefore recommended that a period of 6 hours
elapse before the conduct of general anesthesia in patients
who have had a light meal and up to 8 hours for those
who have consumed a meal that contains fatty foods.29
Enteral tube formula often contains carbohydrates, pro-
teins, and fat. Therefore, it is considered a fatty meal32
and should be stopped 8 hours before elective surgeries.
Exceptions may include postpyloric tube feeds.33
The presence of chewing gum in the preoperative period
deserves mention. In recent studies, the presence of chewing
gum upon initial encounter with the patient has been
thought to increase gastric fluid volumes and decrease pH
of that fluid, thereby increasing the risk for aspiration events
and sequelae. Although it appears that chewing gum is
associated with statistically notable increases in intragastric
fluid, the increase does not appear to be enough to increase
the risk of aspiration of that fluid.34 Furthermore, there does
not seem to be an increase in the acidity of the fluid. It can be
argued that patients who chew gum up to the time of the
surgery can proceed to the operating room35 because of
414 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
the minimal effects of chewing gum on gastric volume and
pH. Nonetheless, chewing generates saliva and stimulates
gastric secretion and is therefore not recommended within
2 hours prior to surgery. On the other hand, swallowing a
piece of chewing gum is considered equivalent to ingestion
of solid food, which may necessitate delaying the surgery for
6 hours.34
Patients can continue their routine medications on the
morning of surgery with a sip of water or a clear liquid, pref-
erably up to 2 hours from time of surgery.
These guidelines, however, apply only to patients without
GI pathology. Certain populations pose extra risk of pulmo-
nary aspiration. For example, long-standing diabetes melli-
tus can cause delayed gastric emptying and these patients
may benefit from a longer fasting duration. In contrast, in
both obese patients and women who are not in labor, gastric
emptying is normal and standard fasting guidelines can be
followed. Pediatric patients can follow the standard guide-
lines, with additional guidelines for breast milk and infant
formula. Children can have breast milk up to 4 hours and
infant formula up to 6 hours prior to the surgical procedure.
One study found that 70% of patients fasted for longer than
the recommended time thereby further increasing the risk of
hypoglycemia and hypovolemia.36
As mentioned previously, pregnant patients are a group
for whom preoperative fasting has been extensively investi-
gated. Parturients are a unique subset of patients because
they might need an operative intervention at some time dur-
ing the course of their labor, but keeping them NPO for a
procedure that might not occur is not practical. Most obstet-
ric units allow patients clear fluids (including gelatin) while
in labor, recognizing that this may place them at increased
risk for aspiration should they require a regional or general
anesthetic.
MANAGEMENT STRATEGY
The spectrum of clinical problems encountered when a
patient aspirates ranges from asymptomatic aspiration,
bronchospasm, laryngospasm, aspiration pneumonitis, aspi-
ration pneumonia, and acute respiratory distress syndrome.
The initial management of the patient who has aspirated
focuses on suctioning the oropharynx of any aspirated
material and on urgent airway control (Fig. 25.1). Once
the airway has been secured, a tracheal suction catheter
should be passed down the endotracheal tube to try to
remove any particulate matter from the lungs. At this point,
a decision must be made as to whether surgery should pro-
ceed. Several factors influence this decision, such as the
duration of the case, the emergent nature of the procedure,
and the patient’s respiratory stability. Early hypoxemia,
bronchospasm, or high peak airway pressures are all signs
that portend an aspiration event, and they are likely to
worsen over the ensuing several hours. Clinicians should
have a low threshold for canceling elective cases in this sce-
nario. Emergent cases (when most aspiration events occur)
pose more of a problem, and many times the anesthesiolo-
gist is left little choice but to proceed with the case, knowing
the potential for a worsening pulmonary status.
Aspiration of gastric contents may result in a severe
chemical burn of the tracheobronchial tree with an ensuing
inflammatory response. The lung injury is usually biphasic:
initially (in the first 1–2 hours) the gastric fluid has direct
acidic effects on the alveoli and then, approximately 4 to
6 hours later, the condition is worsened by the migration
of neutrophils and the inflammatory cytokines that are
liberated. Several adhesion molecules, complement, tumor
necrosis factor-α, and a myriad of other mediators are
responsible for this delayed reaction, which can be demon-
strated histologically as an acute inflammatory response.
Because the stomach is acidic, the gastric contents are
usually sterile, and early pneumonia of the patient who
has aspirated is uncommon. Patients who have a bowel
obstruction and aspirate feculent material are clearly more
likely to have bacterial contamination of their lungs. Inter-
estingly, increasing the gastric pH with H2 blockers may
increase the rate of colonization of the stomach by patho-
genic bacteria, increasing the risk of early pneumonia.37
As emergent cases are the ones most involved, when
deciding the course of action in the case of aspiration it is
important to be mindful of the substance involved. Aspira-
tion of fluid usually involve barium, water, or the last
ingested content. As discussed previously, these are not bac-
teriogenic in themselves and can be suctioned through the
endotracheal tube if suspected. If these patients are followed
after the aspiration event and there appear to be no notable
sequelae, observation can be appropriate.38
If the aspirate is particulate, other considerations should
be made. If the matter is larger, it may be lodged in the cen-
tral airway related to the glottic airway and trachea. These
situations manifest as difficulty ventilating the patient with
rapid desaturation. If the matter is smaller and is able to pass
unilaterally, the patient may present with increased airway
pressures, wheezing, air-trapping, and more gradual desa-
turation. In these cases, flexible or rigid bronchoscopy
should be considered for removal of whatever inciting mate-
rial can be retrieved.39
Despite the lack of evidence of efficacy, prophylactic anti-
biotics are commonly prescribed for patients who have
aspirated. This is not recommended, as the early institution
of antimicrobial therapy serves only to select for resistant
organisms. The exception is the patient in whom the aspi-
ration has occurred in the setting of a small bowel obstruc-
tion or those in whom gastric colonization is suspected.
The development of a fever, radiographic infiltrate, and
leukocytosis often prompts clinicians to initiate antibiotics.
This is also discouraged because the clinical patterns of
aspiration pneumonitis and pneumonia overlap signifi-
cantly. Antibiotics should be given only in those cases
where the pneumonitis persists for 48 hours or where there
is documented evidence of infection. Documenting the
infection has the further advantage of allowing the clini-
cian to tailor the antibiotic regimen and of reducing the
incidence of selecting for resistant organisms. Should anti-
biotics become necessary, broad-spectrum agents active
against both gram-positive and gram-negative organisms
are suggested. Empiric anaerobic coverage is not usually
necessary. Levofloxacin, ceftazidime, ceftriaxone, and
piperacillin-tazobactam are all good first-line agents to
treat this condition. Treatment regimens should continue
for 7 days, with a switch to oral antibiotics if the patient
appears to improve clinically. It should be noted that
 25 • Prevention and Treatment of Gastrointestinal Morbidity 415

Patient at risk of
aspiration:
Full stomach
Pregnancy
Trauma
Diabetes
Pain
Head injury
GERD

No
Yes

No change in
anesthetic
management
Emergency
surgery?

No Yes

• PPI or H2 blocker • Nonparticulate

• Pre-op fasting for antacid
up to 8 hours • RSI with CP
depending on
nature of meal
• RSI with CP

Patient
aspirates

No Yes

Awake extubation • Suction hypopharynx and

at end of case, tracheobronchial tree,
with full return of ⫾bronchoscopy
neuromuscular • 100% oxygen
function • Bronchodilators prn
• Based on patient's
clinical status and need
for surgery, decision to
Steroids:
proceed with case
No benefit,
between anesthetist and
potentially
surgeon
harmful
• Ventilate with
ARDSNet protocol

Fig. 25.1 Algorithm for the treatment of the patient at risk of aspiration. GERD, Gastroesophageal reflux disease; PPI, proton pump inhibitor; RSI with CP,
rapid sequence induction with cricoid pressure.

evidence is lacking for the appropriate duration of treat-
ment in these patients.
For several decades, steroids have been a mainstay of
treatment for aspiration pneumonitis despite a lack of evi-
dence showing their benefit. Theoretically, corticosteroids
should help to reduce the inflammation caused by the aspi-
ration event. One prospective placebo-controlled study
showed an earlier improvement in radiographically evident
aspiration pneumonitis, but these patients had longer stays
in the intensive care unit (ICU) and had no change in overall
outcome.40
Very few patients develop an aspiration syndrome serious
enough to result in acute respiratory distress syndrome
(ARDS). If the anesthesiologist suspects ARDS, the manage-
ment is largely supportive and early transfer to an ICU is
recommended.41 While awaiting transfer, the ventilatory
strategy used in the ARDSNet trial has been shown to
decrease mortality in this condition.42 This study demon-
strated that using a low tidal volume approach of 6.2 mL/
kg ideal bodyweight, with the goal of limiting mean plateau
pressures to 25 cm H2O, mortality was decreased from
39.8% when tidal volumes of 11.8 mL/kg were used com-
pared with 31.0% when lower tidal volumes were used.
In fact, the trial was stopped in the fourth interval analysis
as a result of the apparent efficacy in the lower tidal volume
regimen group.
416 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Postoperative Nausea and
Vomiting
BACKGROUND AND INCIDENCE
Postoperative nausea and vomiting (PONV) is a relatively
common condition, occurring in 20% to 30% of patients.43
In certain high-risk populations, the incidence can
approach 70%. The etiology of PONV is multifactorial, with
patient, surgical, and anesthetic factors playing a role (Box
25.2). PONV is among the 10 most undesirable outcomes
for surgical patients, and Gan and colleagues found that
patients were willing to pay up to $100 at their own expense
to avoid it.44 Universal antiemetic prophylaxis is not cost
effective; however, identifying high-risk patients allows
cost-effective antiemetic prophylaxis to be used in the most
economical fashion.
In general, the management of PONV includes: (1) the
identification of patients at risk; (2) the reduction of baseline
risk factors; (3) the appropriate prophylaxis of PONV on the
basis of risk stratification; and (4) the treatment of estab-
lished PONV in patients who did not receive antiemetics
or in whom prophylaxis with antiemetics failed. Published
guidelines on the recognition and management of PONV
are periodically updated drawing from evidence-based
efforts to address this issue adequately. The latest guidelines
were published in 2014.45 This document was composed by
an international panel of experts who reviewed the evidence
for prophylaxis and treatment of PONV and, by rating the
level of evidence (I to V), were able to suggest recommenda-
tions based on the strength of this evidence (Box 25.3).
RISK FACTORS
Several scoring systems have been developed to try to iden-
tify patients at high risk. The most commonly cited patient
risk factors for PONV are female sex, need for opioids for
postoperative pain, younger age, duration of anesthesia,
nonsmoking history, and a history of either PONV with prior
anesthetics or motion sickness. The presence of none, one,
two, three, or four risk factors leads to an incidence of
10%, 21%, 39%, 61%, or 79%, respectively.46
Box 25.2 Risk factors for postoperative nausea
and vomiting (PONV).
Patient factors
▪ because this reduces the stress related to having these pro-
▪ Female sex
▪ History of PONV
▪ History of motion sickness
▪ Nonsmoking history
▪ Anesthetic factors
▪ Opioids
▪ Volatile anesthetic agents
High-dose neostigmine
▪
▪ Nitrous oxide
▪ Surgical factors
▪ Emetogenic surgery (breast, ear-nose-and-throat, laparoscopic,
intra-abdominal, gynecologic, strabismus)
Long surgical procedures
▪ one or two interventions in adults that are deemed to be
Box 25.3 Evidence-rating scales for the
management of postoperative nausea and
vomiting.
Level of evidence based on study design
I. Large randomized, controlled trial, n  100 per group
II. Systematic review
III. Small randomized, controlled trial, n< 100 per group
IV. Nonrandomized, controlled trial or case report
V. Expert opinion
Strength of conclusion or recommendation
A. Good evidence to support the conclusion or recommendation
B. Fair evidence to support the conclusion or recommendation
C. Insufficient evidence to recommend for or against
Surgical factors may also play a role in the development of
PONV. An increase in surgery time is directly correlated
with an increase in PONV. Furthermore, ear-nose-and-
throat (ENT), strabismus, gynecologic, and laparoscopic
surgery have all been associated with an increase in the risk
of PONV.47 The recent PONV consensus guidelines on the
prevention and treatment of PONV note that the type of sur-
gery as a risk factor for PONV is still debated.45 Special men-
tion was made for the possibility that regardless of the type of
surgery performed, if the surgical time is prolonged, the pro-
longed exposure to opioids and inhalational agents can in
themselves explain increased emetogenicity.
The type of anesthetic can also influence the likelihood of
PONV. Nitrous oxide and opioids have been the most consis-
tently implicated agents in the development of this condi-
tion. However, more recent data suggest that nitrous
oxide increases the risk only minimally.48 In the IMPACT
study by Apfel and colleagues,48 TIVA with propofol with-
out volatile anesthetic demonstrably reduced the risk. Fur-
thermore, the consensus is that in order to reduce the risk of
PONV, regional anesthesia (because of its opioid-sparing
effects), the use of NSAIDs, and adequate intraoperative
hydration as much as 30 mL/kg all contributed to a decrease
in the incidence of PONV.
Recognition of the baseline risk factors in children is also
discussed because age is an independent risk factor. These
risk factors include duration of surgery greater than
30 minutes, age greater than 3 years, strabismus surgery,
personal or family history of PONV. Regional techniques
in children were noted to be of particular benefit even
though most are under general anesthesia, presumably
cedures performed. This results in a reduction in the use of
opioids with the apparent reduction in perioperative nausea,
as well as reduction in postoperative drowsiness with a
decreased need for rescue analgesia.
MANAGEMENT OF PONV
After the assessment of the patient’s baseline risk of PONV
and reduction of baseline risk factors for PONV, the guide-
lines advocate a multimodal, cost-effective approach to
the management of PONV. This centers around providing

a moderate risk for PONV and three or four antiemetics for
those in the high-risk group.
Pharmacologic Prophylaxis and Treatment
The four major receptor classes that have been implicated in
the generation of PONV are serotonergic (5-HT3), choliner-
gic, dopaminergic (D2), and histaminergic (H2). Box 25.4
summarizes the different methods used to treat PONV.
Numerous studies have looked at the various antiemetics
both alone and in combination for the treatment and pro-
phylaxis of PONV, and numerous meta-analyses have
examined both the number needed to treat (NNT) and the
number needed to harm (NNH) to determine which antie-
metic regimen is the most efficacious. With respect to the
antiemetics, the NNT is the number of patients who would
have to be treated with a particular drug to prevent an epi-
sode of nausea or vomiting that would have occurred had
the drug not been administered. The NNH is the number
of patients who would have to receive the drug and demon-
strate an adverse event that would not have occurred had
they not received the medication.
5-HT3 Receptor Antagonists. The 5-HT3 receptor
antagonists ondansetron, granisetron, dolasetron, and
Box 25.4 Options available for the management
of postoperative nausea and vomiting.
Pharmacologic techniques
A. Monotherapy
1. Older generation antiemetics
a. Phenothiazines: aliphatic (promethazine, chlorpromazine),
heterocyclic (perphenazine, prochlorperazine).
b. Buterophenones: droperidol, haloperidol.
c. Benzamides: metoclopramide, domperidone.
d. Anticholinergics: scopolamine.
e. Antihistamines: ethanolamines (dimenhydrinate, diphen-
hydramine), piperazines (cyclizine, hydroxyzine, meclizine).
2. Newer generation antiemetics:
a. Serotonin (5-HT3) receptor antagonists: ondansetron,
granisetron, dolasetron, tropisetron, ramosetron, and
palonosetron.
b. NK-1 receptor antagonists (aprepitant)
3. Other antiemetics: dexamethasone, propofol, ephedrine
B. Combination of two or more of the above antiemetics
1. 5-HT3 receptor antagonists + droperidol
2. 5-HT3 receptor antagonists + dexamethasone
3. Other combinations
Nonpharmacologic techniques
1. Acupuncture
2. Acupressure
3. Laser stimulation of the P6 point
4. Transcutaneous acupoint electrical stimulation
5. Hypnosis
Additional measures with potential antiemetic effects
1. Supplemental oxygen
2. Benzodiazepines
3. Adequate hydration
4. Good pain relief
5. α-2-Adrenergic agonists
Multimodal approach
25 • Prevention and Treatment of Gastrointestinal Morbidity 417
tropisetron, ramosetron and palonosetron bind very specif-
ically to their receptors in the chemoreceptor trigger zone
and have a very favorable side-effect profile. They are virtu-
ally devoid of the sedative effects commonly seen with other
antiemetics, making them ideal for the ambulatory surgery
setting.49
Ondansetron was the first agent in this class to be mar-
keted in the United States, and it is the most widely used
agent in this class. It is a much better antivomiting agent
than antinauseant, and it is most effective when given
toward the end of surgery.50,51 The recommended dose of
ondansetron is 4–8 mg, and the NNT is 5–6. Common side
effects include headache (NNH ¼ 36), dizziness, flushing,
elevated liver enzymes, and constipation.
Granisetron has been used in both the treatment and pro-
phylaxis of PONV. For prophylaxis, a dose of 1.0 mg has
been recommended, although more recent studies have
found that lower doses are efficacious, especially when com-
bined with dexamethasone. For established PONV, a dose of
only 0.1 mg has been found to be efficacious52
Palonosetron is a newer 5HT3 antagonist that can be
given once at the beginning of surgery.53 It demonstrated
slightly greater efficacy in prevention of PONV than
ondansetron.54
Dopamine Receptor Antagonists. Droperidol. Droper-
idol has been used extensively in the past for the treatment
of PONV. It is as effective as ondansetron in the prevention
of PONV (with an NNT of 5). The advantage of droperidol
over the other antiemetic agents is in its duration of action,
which can extend up to 24 hours even though its half-life is
only 3 hours.55
In 2001, the US Food and Drug Administration (FDA)
issued a “black box” warning for droperidol based on 10
case reports of QTc-interval prolongation and the develop-
ment of torsades de pointes when doses of less than
1.25 mg were used.56 It is important to note that these case
reports span over 30 years of use of droperidol and that the
estimated incidence of cardiac adverse events is somewhere
in the range of 6.7/1 million. Furthermore, no case reports
have appeared in peer-reviewed journals linking droperidol
to torsades, QTc prolongation, or cardiac arrest in the doses
commonly used in the prevention and treatment of PONV.
This is impressive considering all the other drugs used dur-
ing the course of a general anesthetic that could prolong the
QT interval. When considering the multimodal approach to
PONV, the consensus guidelines consider butyrophenones
such as droperidol to be a cost-effective component. Even
in children, after other medications have failed and the
patient is being admitted to the hospital, droperidol should
be considered because it remains safe in the doses adminis-
tered. The doses typically used were no more likely to cause
QTc prolongation than ondansetron.57
Metoclopramide. Metoclopramide has been used for
years in the treatment of chemotherapy-induced nausea
and vomiting in doses of 10 to 20 mg in adults. Its use in
the treatment of PONV is much more controversial. Despite
widespread use, approximately 50% of the studies per-
formed with metoclopramide have shown it to be no more
effective than placebo. A meta-analysis of all the metoclo-
pramide studies has identified a NNT of between 9 and
10. The PONV consensus panel could not recommend the
418 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
use of metoclopramide as an antiemetic, but there was no
consensus on this issue.
Anticholinergics and Antihistaminergics. The most
commonly used cholinergic for the treatment of PONV is
scopolamine. The transdermal preparation when applied
either the night before or 4 hours before the conclusion
of surgery has been shown to have an NNT of 3.8.58 Some
of the drawbacks of this drug, however, include dry
mouth, visual disturbances, dizziness, and agitation (with
NNHs of 5.6, 12.5, 50, and 100, respectively).52 Other dis-
advantages of scopolamine include the long time for its
peak effect (2–4 hours) and its associated medical
contraindications.59
Antihistamines are also commonly used for the treatment
of PONV. Their use is limited by various side effects, such as
sedation, urinary retention, blurred vision, and dry mouth.
They have also been shown to delay recovery-room dis-
charge. However, the NNT compares well with other anti-
emetics with a prophylactic NNT of 6 for a dose of 1 to
2 mg/kg for dimenhydrinate, and a NNT of 5 for established
PONV.60
Other Antiemetics. Dexamethasone. Dexamethasone
has long been used as an effective antiemetic for chemother-
apy patients. Its use has been studied in the surgical popu-
lation and it has been found that in doses ranging from 2.5
to 10 mg, its NNT was 4.3 (level IIA evidence for use).50 It
appears that dexamethasone is most effective when given
prior to the induction of general anesthesia. There are no
reported side effects when dexamethasone is used in antie-
metic dosages for short duration; however, some patients
complain of a burning perineal pain when the drug is
injected. It has been hypothesized that this reaction is
caused by the phosphate ester of the corticosteroid, because
perineal irritation has been described with hydrocortisone-
21-phosphate sodium and prednisolone phosphate.61
Propofol. When compared with volatile anesthesia, pro-
pofol total intravenous anesthesia (TIVA) has been associ-
ated with a decreased risk of developing PONV (level IIIa
evidence).62 This risk reduction seems to be most prominent
in the early postoperative period, and it is not present if pro-
pofol is used only as a bolus for the induction of anesthesia.
Recently, it has been discovered that subhypnotic doses of
propofol can be used to treat established PONV. The doses
required to achieve this antiemetic effect are several magni-
tudes lower than those needed for sedation and
anesthesia.63
Benzodiazepines. Benzodiazepines have been used for
the treatment of PONV when other forms of treatment have
failed. This evidence is based only on small randomized trials
and, as such, was graded as level IIIB by the PONV consen-
sus task force. Alpha-2-adrenergic agonists have also been
found to reduce the incidence of PONV in adults and chil-
dren (level IIIA). It is thought that their anesthetic and
opioid-sparing effects might explain their usefulness in this
condition.64
Neurokinin-1 antagonists. Another emerging phar-
macologic strategy is neurokinin-1 (NK-1) inhibitors. The
NK-1 antagonist class of drugs acts on the final common
pathway from the emetic center. These compounds are
known to inhibit the effects of substance P in the brainstem
regions associated with emesis. In humans, NK-1 receptor
antagonists are effective for the prophylaxis and treatment
of PONV. In one study of women undergoing gynecologic
surgery, the NK-1 receptor antagonist CP-122,721 pro-
vided better prophylaxis against vomiting than ondanse-
tron. The combination of both agents also significantly
prolongs the time to administration of rescue antiemetics
compared with either drug alone and is associated with a
very low incidence of emesis (2%). Cost may, however, be
an issue when considering routine use of these newer drugs
for PONV. Aprepitant is the only drug of this class approved
in the United States for chemotherapy-induced nausea and
vomiting, and emerging data suggest it has excellent effi-
cacy for preventing emesis.65
Nonpharmacologic Therapies
The use of nonpharmacologic therapies, such as acupres-
sure, acupoint stimulation, transcutaneous nerve stimula-
tion, and acupuncture (at the P6 point), have been
reviewed.67 These therapies have shown a significant
reduction in PONV when compared with placebo. When
acupuncture techniques were compared with conven-
tional antiemetics (not including the 5-HT3 antagonists),
there was a comparable decrease in the incidence of
PONV. A recent placebo-controlled study comparing the
use of transcutaneous acupoint electrical stimulation
and ondansetron showed comparable results between
these two strategies and significantly superior results to
placebo.68 These nonpharmacologic approaches are inter-
esting, but the lack of familiarity with the techniques by
most practitioners and the need for additional equipment
limit their use.
STRATEGY FOR THE PREVENTION OF PONV
In the most recent Consensus Guidelines cited previously,
the recommendations centered on the importance of appro-
priate risk-assessment of the patient and the measured risk
of PONV in each patient encounter. The importance of
proper evaluation of the patient, consideration of the sur-
gery to be performed, and the risk-benefit analysis of each
intervention including medication profiles must always be
undertaken.
PONV is frequently encountered in anesthesia, but it is
not cost effective to provide prophylaxis with antiemetics
for all patients. Instead, a risk stratification of patients
should be undertaken that includes patient, anesthetic,
and surgical risk factors. On the basis of the presence of
these risk factors, different levels of prophylaxis can be sug-
gested. The treatment of established nausea and vomiting
depends on what type of antiemetic (if any) the patient
has received.
Patients who have no risk factors (neither surgical nor
patient related) for the development of PONV should not
receive prophylaxis, because this has been shown to be
not cost effective, unless vomiting might compromise the
patient in some way (e.g., because of raised intracranial
pressure or a wired jaw). Those patients with risk factors
for PONV should receive prophylaxis according to the
algorithm in Fig. 25.2. Those patients at the highest risk
of PONV (i.e., those who have had PONV repeatedly in
the past) should receive double prophylaxis, and
 25 • Prevention and Treatment of Gastrointestinal Morbidity 419

Risk factors
for PONV
No
B
Clinical risk factors
No need • Female sex
for prophylaxis • Emetogenic surgery
A • Nonsmoker
Hx of PONV • Need for post-op opioids
• Hx of motion sickness

General risk reduction strategy

• Regional anesthesia
• Adequate hydration
• Avoid N2O
• Avoid high-dose neostigmine

Prophlyaxis for PONV

A on one A on one occasion A on more than one occasion

occasion or plus ⱖ 1 factor from B plus ⱖ 1 factor from B
2 factors from B or ⱖ 3 factors from B

5-HT3 antagonist 5-HT3 antagonist ⱖ2 antiemetics

⫹ dexamethasone plus TIVA with
Droperidol propofol
5-HT3 antagonist
Dexamethasone ⫹ Droperidol

Promethazine 5-HT3 antagonist

⫹ acupuncture
Scopolamine

Acupuncture
Treatment for PONV

PONV with or
without prophylaxis

5-HT3 antagonist ⫹ second agent or triple 5-HT3 antagonist ⫹ second agent or

No prophylaxis therapy including 5-HT3 antagonist when triple therapy with 5-HT3 antagonist
or PONV occurs ⬍6 hours post-op plus two other agents when PONV

5-HT3 antagonist Do not repeat Use antiemetic from

initial therapy different class
Droperidol
May repeat 5-HT3
Dexamethasone Use antiemetic of antagonist and droperidol
different class
Promethazine
Propofol in PACU

Fig. 25.2 Algorithm for reduction of risk for postoperative nausea and vomiting (PONV). Prophylaxis depends on both patient and surgical risk factors. A
treatment strategy for established PONV based on the presence or absence of prophylaxis is presented at the bottom of the figure. PACU, Posta-
nesthesia care unit; TIVA, total intravenous anesthesia.

consideration should be given to performing the surgery
under a regional anesthetic technique. Should this not
be practical, a general risk-reduction strategy should be
considered, including reducing opioid dosage by using
multimodal analgesia, ensuring adequate hydration,
avoiding high-dose neuromuscular reversal agents, and
the use of propofol for induction and maintenance of anes-
thesia (level IIIA evidence).
The focus on clinician practices as part of an overall strat-
egy to mitigate the risk of PONV has led to many efforts that
aim to compare different anesthetic strategies. There are
studies that posit the increased risk of PONV in patients
when volatile anesthetics were used over propofol based
TIVA.69 However, the use of newer formulations of etomi-
date does not appear to increase the incidence of PONV in
the perioperative period when compared with propofol for
420 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
induction with volatile agent-based maintenance.70 Intra-
venous ketamine is also proving to be a useful adjunct in
management of perioperative pain, with a notable reduction
in PONV.71
The use of nitrous oxide has also been scrutinized as a
cause of PONV.72 In a large meta-analysis, Fernandez-
Guisasola et al. note that the avoidance of nitrous oxide
was demonstrated to reduce the risk of PONV, but probably
only in those groups considered to be at higher risk (namely
women). This improvement was also deemed only modest
by the authors.
More recently, the association of preoperative hydration
with improved postoperative outcomes has garnered sup-
port.73 By allowing patients to consume carbohydrate liq-
uids up to 2 hours prior to surgery as mentioned in the
updated NPO guidelines, the incidence of PONV has been
shown to be reduced.
TREATMENT OF ESTABLISHED PONV
Evidence supporting a definitive treatment for those patients
with established PONV (with or without prophylaxis) is less
clear. The patient in whom prophylaxis has failed presents a
difficult problem. Factors such as the use of postoperative
opioids, blood entering the throat, or a mechanical bowel
obstruction should be ruled out before the institution of
pharmacologic therapy. In those patients in whom prophy-
laxis has failed, the use of an agent from another class is
recommended (level IIA to IVB, depending on the prophy-
laxis). In the trials for rescue therapy, the 5-HT3 receptor
antagonists are the most commonly studied medications.
As seen when their role is prophylaxis, their antiemetic
effect is stronger than their antinauseant effect. There is
no reported dose–response effect and smaller doses of these
agents have therefore been used. The recommended doses
are ondansetron, 1 mg; dolasetron, 12.5 mg; granisetron,
0.1 mg; and tropisetron, 0.5 mg.66
The data on the efficacy or the optimal dosage of the other
agents for the treatment of established PONV are limited.
This is because to obtain the required number of patients
who actually experienced PONV, the number that would
need to be recruited would have to be quite large.
Of note, the treatment of PONV that is deemed the result
of opioid administration at any time in the perioperative
encounter may be addressed using low-dose opioid antago-
nist, naloxone or naltrexone, without reducing analgesic
effects of opioid administered.74
Postoperative Ileus
Postoperative ileus (POI) is an impairment of GI motility
after abdominal or other forms of surgery. It is characterized
by the lack of bowel sounds, accumulation of gas and fluids
in the bowel, abdominal distention, and intolerance to
enteral feeding.75 This condition generally lasts for 3 to
5 days and is usually self-limiting. POI should be differenti-
ated from mechanical small bowel obstruction because the
etiology and management are very different.
Reducing length of hospital stay is paramount in the
current climate of health-care cost minimization. POI
serves only to lengthen the average stay after a laparot-
omy from 3 to 10 days. This is associated with increased
costs and the potential for other morbidity such as delayed
mobility, delayed absorption of food and medications,
and the increased risk of infectious and pulmonary
complications.
ETIOLOGY
Normal bowel motility depends on many factors, including
the enteric and central nervous systems and hormones.
Motility of the small intestine and the stomach also depends
on whether or not the patient has fasted. The perturbation
of gastric motility in the postoperative period is likewise
the result of many interrelated and overlapping factors.
In the normal state, the balance between the excitatory
parasympathetic and inhibitory sympathetic nervous sys-
tems is such that antegrade motility is preserved. Increased
activity of the sympathetic nervous system (which is com-
mon in postoperative states because of pain and the stress
response) causes activation of the α-2-adrenoreceptors
on cholinergic neurons, which leads to a dominant para-
sympathetic effect on the intestines, thereby reducing
motility.76
Nitric oxide (NO) also plays a role in the development of
POI and it is the most important nonadrenergic noncholi-
nergic neurotransmitter. NO plays an inhibitory role with
respect to bowel motility. Administration of an NO synthase
inhibitor reverses the lack of bowel motility caused by sur-
gical manipulation in rats.77
The release of endogenous opioids secondary to surgical
trauma of the abdomen may have a role in the development
of POI. In animal studies, the infusion of an endogenous opi-
ate peptide has been shown to slow bowel motility. The role
played by these endogenous opioids in humans is question-
able because the administration of synthetic opioids proba-
bly dominates.
The stress response to the surgery may also play a role
in the development of POI. Hypothalamic liberation of
corticotrophin-releasing factor (CRF) is the most important
factor in this response. Exogenous administration of CRF is
known to slow gastric emptying and the infusion of a CRF
antagonist partially prevents POI in rats.78
Intuitively, the inflammatory cascade that is initiated
with surgery should also play a role in the development of
POI. The resultant edema and liberation of cytokines along
with hypovolemia and underperfusion of gut mucosa con-
tribute to this pathogenesis.
In the end, the development of POI is most probably
caused by multiple overlapping factors. This is demonstrated
by the lack of any antagonist to the previously mentioned
factors to reverse or to prevent POI.
Role of Postoperative Opioids
Opioids are the most common and efficacious treatment for
postoperative pain. Their use, however, is associated with a
decrease in intestinal transit time. In 1972, opioid receptors
that affect bowel motility were discovered in the GI tract.
The central opioid receptors also play a role in bowel motil-
ity. The site in the GI tract where opioids have their most

profound effect is the colon. Opioids increase the basal mus-
cle tone in the colon to the level of spasm, thereby reducing
the propulsive forces. This slows the passage of feces
through the lumen, which causes drying and hardening
of the contents, further slowing passage.79
Role of General Anesthesia
Administration of anesthesia to patients alters bowel
motility. Induction agents, NO, and inhalation agents
have all been implicated. Of these, NO is the best
described. Diffusion of this gas into the bowel lumen dis-
tends the bowel and has been shown to cause a delay in
the return of gastric function. Its use also results in longer
hospital stays when compared with an air–oxygen mix-
ture.80 It should be noted, however, that in patients
without a baseline risk of PONV, NO does not appear to
increase the incidence.81
PREVENTION AND TREATMENT OF POSTOPERATIVE
ILEUS
Nonpharmacologic Methods
Nasogastric Drainage. Decompression of the stomach by
a nasogastric (NG) tube has been the mainstay of therapy
for POI since the late 1800s. Although this therapy does
reduce patient discomfort, there is no evidence that it has-
tens the return of normal motility. Among patients who
were given a colonic resection, no difference in duration
of ileus or hospital stay was observed between those who
received a NG tube and those who did not.80 Routine place-
ment of nasogastric tubes may delay recovery of normal GI
tract function and should be discouraged.
Early Enteral Nutrition. Despite widespread adoption of
enhanced recovery principles that encourage early intake,
many patients are still maintained in an NPO status after
a major laparotomy. Traditionally, patients are not fed
until after bowel sounds return. Unfortunately, this prac-
tice might be flawed because the lack of bowel sounds is
less pathologic than it is a response to fasting. The pres-
ence of food in the GI tract stimulates the release of hor-
mones that initiate intestinal propulsive activity. Early
enteral nutrition has therefore been proposed as a safe
and effective way of preventing or reducing the duration
of POI, and the maintenance of NPO status may be detri-
mental to the patient. Fasting causes a catabolic state at a
time when patients need to be anabolic. Furthermore,
translocation of bacteria and endotoxin across the para-
cellular space from the gut lumen into the circulation
may be responsible for the development of postoperative
infections and multiple organ dysfunction syndrome.82
There is some evidence that early enteral feeding reduces
this translocation. Some studies also show a decrease in
the duration of POI when early enteral nutrition is imple-
mented. Recent trials, however, have shown no change in
the duration of ileus or hospital stay.83 Still, it is important
to note that in all of these trials, early nutrition was not
associated with any adverse effects, challenging the
dogma that patients should fast until the return of bowel
sounds.
25 • Prevention and Treatment of Gastrointestinal Morbidity 421
Postoperative Fluid Administration. The amount and
type of fluid administered in the perioperative period also
plays a role in the development and duration of POI. When
a goal-directed fluid protocol titrated to esophageal Doppler
cardiac output was used in patients undergoing major sur-
gery, those who received fluid optimization demonstrated a
decrease in the rates of PONV, an earlier return of bowel
function, and a shorter hospital stay.84,85 Indices of tissue
perfusion such as gastric pH and base excess are correlated
with the development of postoperative complications, and
titrating therapy might therefore be expected to reduce GI
morbidity. On the other hand, some studies have demon-
strated that excess fluid in the perioperative period is asso-
ciated with the development of POI. Theoretically, this
may be the result of the development of bowel wall edema
and subsequent dysfunction. In a study by Moretti and
coworkers, it was shown that the administration of intrao-
perative colloid was associated with a decrease in the
amount of GI complications.66 The clinician is thus faced
with a dilemma of how much fluid to give. It would seem
prudent, therefore, to optimize fluid administration by titrat-
ing to specific endpoints such as gastric pH, base excess, or
(if it is available) esophageal Doppler cardiac output
(see later).
Mobilization. There is no known benefit to immobilization
after surgery but there are many potential hazards. In the-
ory, early postoperative ambulation should help induce gas-
tric motility and this is commonly practiced. Unfortunately,
this has not been demonstrated in clinical studies.69 Despite
a lack of benefit to the GI system, the reduction in the inci-
dence of deep vein thrombosis and postoperative pulmonary
complications (such as atelectasis and pneumonia) argue
for its continued use as part of facilitated recovery from
surgery.
Coffee. Coffee consumption after colectomy has been shown
to be associated with a statistically significant reduction in
time to first bowel activity. Additionally, time to tolerance
of solid PO intake, time to first flatus, and length of hospital
stay were all reduced in the coffee group.86 The small sample
size however limits the ability to draw generalizations.
Chewing gum. More recently86 chewing gum immediately
postoperatively has garnered attention as a gastrointestinal
propulsive strategy. In a Cochrane review by Li et al., there
was a noted decrease in time to first flatus, decrease in time
to first bowel movement and reduction in the length of hos-
pital stay.88
Pharmacologic Therapies for the Treatment of POI
The effects of various drugs on POI are listed in Table 25.2.
Agents Acting on the Autonomic Nervous System. As
mentioned previously, normal GI motility depends on a del-
icate balance between the sympathetic and parasympa-
thetic nervous systems. The enhanced activity of the
sympathetic nervous system in the postoperative state is
very likely a factor contributing to POI. This has led several
investigators to suggest that the alteration of this balance
with agents that act on the adrenergic or cholinergic
422 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 25.2 Drug effects on postoperative ileus. been conducted and their potential benefit is therefore
unproven.
Effect on
postoperative Opioid Antagonists. The presence of both endogenous
Drug Mechanism of action ileus
and exogenous opioids is known to play a role in postoper-
Atenolol, esmolol, β-Receptor antagonist Decreased or none ative bowel dysfunction. The administration of opioid antag-
propranolol onists is therefore an attractive intervention to decrease
Dihydroergotamine α-Receptor antagonist Decreased or none morbidity. The ideal therapeutic agent would be one that
antagonizes only the peripheral opiate receptors in the GI
Neostigmine Acetylcholinesterase Decreased or none
inhibitor tract but is not able to cross the GI lumen to affect central
receptors causing increased postoperative pain. Several
Erythromycin Motilin agonist None compounds accomplish this, including alvimopan and
Cisapride Acetylcholine and Decreased or none methylnaltrexone.
serotonin receptor Alvimopan is a μ-receptor antagonist that has been stud-
agonist ied in a randomized controlled trial of patients undergoing
Metoclopramide Cholinergic stimulant, None colonic resection or abdominal hysterectomy. It was found
peripheral dopamine that patients given 6 mg alvimopan 2 hours before major
antagonist abdominal surgery had a decrease in the median time to first
Cholecystokinin Prokinetic peptide None flatus and bowel movement of about 18 hours. Patients in
Vasopressin Defecation stimulant None the treatment group were also ready for hospital discharge
1 day earlier than those given placebo.90
From Mythen MG. Postoperative gastrointestinal tract dysfunction. Anesth Methylnaltrexone is a quaternary derivative of the
Analg 2005;100(1):196-204. μ-receptor antagonist naltrexone that is poorly lipid sol-
uble and does not cross into the central nervous system.
nervous systems might have a role in the prevention or It has recently been investigated in humans, demonstrat-
treatment of POI. ing an improvement in colonic motility in patients
Some older evidence indicates that the cholinergic ago- receiving elective colon surgery and given postoperative
nists of the muscarinic receptor, such as bethanechol, car- morphine.91
bachol, and methacholine, would stimulate gastric
motility via intestinal receptors. More recent and larger Nonsteroidal Anti-Inflammatory Agents. The prosta-
studies have focused on the role of cholinesterase inhibi- glandin is another pathway that plays a role in POI and is
tors such as neostigmine in the treatment of ileus. Several subject to pharmacologic modification. The initial step in
studies have shown neostigmine to be effective in the prostaglandin synthesis is catalyzed by the enzyme cycloox-
reduction of the duration of ileus.89 However, neostigmine ygenase (COX). There are two isoforms of COX, designated
has some significant untoward side effects, such as the COX-1 and COX-2. COX-1 is constitutively expressed and
development of profound bradycardia and bronchorrhea, is necessary for platelet aggregation, maintenance of renal
that mandate its being given in a monitored setting, which function in hypovolemic states, and gastrointestinal protec-
is not always possible or cost effective. Higher doses of neo- tion. COX-2 is inducible and responsible for the inflamma-
stigmine (>2.5 mg) are also associated with an increase tion, pain, and fever seen after tissue trauma.
in PONV. Prostaglandins E2 and I2 lower the threshold for stimula-
Adrenergic blockade is another attractive pharmacologic tion of afferent nerves by noxious chemical stimuli such as
target for the treatment of POI. However, as with agents histamine and bradykinin. Some prostaglandins also
that act on the cholinergic system, sympathetic blockade decrease smooth muscle activity in the GI tract and thus
of postoperative patients is associated with sufficient delete- increase transit time. Inhibition of prostaglandins is thus
rious cardiovascular effects to make its administration another way of potentially reversing POI. Ketorolac (a non-
impractical in the clinical setting. selective COX inhibitor) administered preoperatively was
shown to reverse the delay in gastric transit seen in patients
Prokinetic Agents. Metoclopramide has been in use for with POI.92 The authors hypothesized that the inhibition of
over 40 years for the treatment of PONV and is used as all prostaglandin synthesis resulted in the dominant inhib-
a prokinetic (see earlier section on Dopamine Receptor itory effects being reversed.
Antagonists). It has both central and peripheral sites of One of the potential drawbacks of using nonselective
action. The peripheral sites of action cause an increase COX inhibitors on postoperative patients is the potential
in gastric contractions, increased gastric emptying, and for the increased risk for GI ulceration and bleeding, the
increased transit time in the GI tract. It has been exten- potential for increased blood loss secondary to the effects
sively studied with several different clinical endpoints on platelet aggregation, and the detrimental effects of renal
and has not been shown to reduce the severity, duration, function. These drawbacks led to the development of
or incidence of POI. Side effects such as dystonic reactions selective inhibitors of COX-2 such as celecoxib, rofecoxib,
and prolongation of the QTc further limit its use in clinical and valdecoxib. There have been no published studies on
medicine. their effect on POI.
Recently, many studies have linked COX-2 inhibitors to
Laxatives. Historically, laxatives are also widely used in the an increase in adverse cardiac events such as myocardial
treatment of POI. However, blind randomized trials have not infraction, stroke, congestive heart failure, and cardiac

death.93 It is thought that because of the selective inhibi-
tion of prostacyclin synthesis with no effect on thrombox-
ane A2 synthesis, a prothrombotic state is created when
these drugs are administered. It is important to note that
these studies were on patients who were taking COX-2
inhibitors long term for the prevention of colorectal adeno-
mas. What role these agents might play in the incidence of
perioperative myocardial infarction with short-term use
has not been studied but is probably not of significant clin-
ical magnitude.94
It is likely that any beneficial effect of nonsteroidal anti-
inflammatory drugs (NSAIDs) on bowel motility and the
incidence of POI is more a result of their opioid-sparing effect
than of prostaglandin balance. Their contribution to a mul-
timodal approach to postoperative pain is significant. With
the previously noted adverse cardiac effects of the COX-2
inhibitors and the effects of nonselective NSAIDs on plate-
lets, renal function, and GI ulceration, the use of these drugs
will have to be better defined with more studies on their risk-
to-benefit ratio.
Multimodal Analgesics. The use of nonopioid agents to
reduce perioperative opioid consumption and correspond-
ingly limiting the incidence of opioid-related side effects
have been the main strategy as part of an Enhanced Recov-
ery After Surgery (ERAS) program. In a summary of various
ERAS protocols used in 15 academic centers around the
country,95 common nonopioid analgesics include acet-
aminophen, celecoxib, and gabapentin as part of the preop-
erative regimen. Lidocaine infusions, ketamine and
ketorolac as well as regional blocks were used most com-
monly intraoperatively.
Epidural Analgesia. Epidural analgesia is perhaps the
ideal method of reducing the incidence of postoperative
bowel dysfunction. It reduces the amount of parenteral
opioid used, and implementing a blockade of the thoraco-
lumbar sympathetic nervous system while leaving the cra-
niosacral parasympathetic nervous system intact creates a
favorable balance, promoting GI motility. There is also evi-
dence to show that epidurals increase GI blood flow and
that local anesthetics themselves have anti-inflammatory
properties.76
In recent years, more attention has been given to the less-
conventionally accepted function of local anesthetics offer-
ing benefit to surgical patients.96 In addition to the conven-
tionally understood function on sodium channels, the
antimicrobial97 and platelet function enhancing proper-
ties98 of local anesthetics is gaining more attention.
Notably, the benefit of epidural analgesia on GI motility
appears to be significant only when the catheter is placed
above the level of the 12th thoracic vertebrae. There
appears to be less effect when a lumbar epidural is placed
for abdominal surgery.
In a large meta-analysis of epidural local anesthetic
administration versus intravenous opioid-based analgesic
regimens for postoperative ileus,99 there is a decrease in
time to return of gastrointestinal transit in the epidural
cohort. There was a correlation with the concentration
of the local anesthetic used. Furthermore, there was no dif-
ference in the incidence of postoperative nausea or
anastomotic leaks.
25 • Prevention and Treatment of Gastrointestinal Morbidity 423
GOAL-DIRECTED THERAPY AND
GASTROINTESTINAL OUTCOME
The administration of fluids to surgical patients is quite var-
iable between centers and across the decades. The initial
thought in the 1950s and 1960s was that because of the
obligatory water and sodium conservation that occurred
after surgical trauma, fluid restriction was required, as first
proposed by Moore.100 This view was later challenged by
Shires and colleagues, who introduced the concept of
third-space losses.101 Their recommendation was that this
third-space fluid be replaced aggressively with crystalloid
administration. This theory was supported by studies during
the Korean War in which it was shown that aggressive fluid
resuscitation led to improved outcomes in trauma patients.
Modern clinical practice has been more influenced by Shires
because patients are often resuscitated with fluid in excess of
their deficit. Preoperative fasting and bowel regimens can
make patients have a fluid deficit at the beginning of
anesthesia.
The type of surgery itself often influences how much fluid
patients receive. It is not uncommon for patients undergo-
ing abdominal aortic reconstructive surgery to receive 4
to 6 L of fluid (in addition to the replacement of blood loss).
The same aggressive fluid regimen, however, has been
shown to be detrimental in flap surgery, where the increase
in venous pressure secondary to postoperative edema
decreases flap survival.
As demonstrated in the RELIEF study,102 “dry” and “wet”
strategies can both lead to postoperative complications and
morbidity. A fluid replacement regimen that is conservative
has the potential for a decrease in cardiac output and in per-
fusion to the splanchnic bed. This can lead to intestinal aci-
dosis, POI, and the translocation of bacteria and endotoxin
into the vascular system, potentially causing sepsis or mul-
tiple system organ failure.
On the other hand, the use of an aggressive, or wet,
approach to fluid replacement is known to increase bowel
edema, decrease the tolerance for enteral feeding, and
increase the incidence of POI. The liberal administration
of fluid is also known to increase the venous pressure in
the intestines (secondary to the edema) and therefore to
cause a decrease in splanchnic oxygenation by reducing
the perfusion pressure. This can also lead to the transmigra-
tion of bacteria and endotoxin into the circulation. Further-
more, some data suggest that the administration of
vasopressors and inotropes to the surgical103 patient with
the goal of maximizing oxygen delivery can improve
outcome.
The clinician is thus faced with choosing the fluid replace-
ment strategy that will best improve outcome and lessen GI
morbidity. The concept of goal-directed therapy—that is,
titrating fluid and vasoactive medications to specified
clinical and hemodynamic endpoints— was first proposed
by Shoemaker and Bland, who found that the hemody-
namic patterns of patients who did not survive major sur-
gery were different from those of survivors.104 They found
that those patients who died after major surgery had lower
cardiac indices, oxygen consumption, and oxygen delivery.
They speculated that nonsurvivors had an oxygen debt and
that this was the cause of their death. This led to the practice
of identifying supranormal physiologic goals to be achieved
424 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
in these high-risk patients to avoid the oxygen debt and
potentially reduce mortality. Although the idea is contro-
versial, variations of this therapy have been shown to be
effective in reducing the postoperative mortality of selected
high-risk patients.103 This practice has largely been sup-
planted by trying to maintain normality of cardiac index,
oxygen delivery (DO2), and volume of oxygen consumption
(VO2), and by looking at other indices of tissue perfusion
such as gastric mucosal pH and central mixed venous oxy-
gen saturation (ScvO2).
ROLE OF FLUID COMPOSITION
The debate regarding whether crystalloid or colloid is the
better replacement fluid began shortly after the introduction
of colloids. Colloid proponents point to the increased edema
and large volumes of fluid that are required in surgical
patients as evidence of the inferiority of crystalloids. Crystal-
loid proponents suggest that hemostatic effects and the
potential of anaphylactic reactions to colloids limit their
use. Most of the studies comparing crystalloids and colloids
have been conducted on critically ill patients in the ICU or
on patients undergoing resuscitation from trauma and have
not looked specifically at GI outcome. Perhaps the right
question is not being asked in the crystalloid-versus-colloid
debate. Measuring the quality of outcomes from resuscita-
tion using secondary endpoints such as incidence of PONV,
POI, postoperative edema, and length of stay might be more
practical.66
In a study with patients who underwent major noncar-
diac surgery, patients were randomized to receive 6% hetas-
tarch66 in either a balanced salt solution, normal saline, or
lactated Ringer solution. Hemodynamic targets such as
blood pressure, heart rate, and urine output were main-
tained within a predefined range. Patients in the colloid
group had less PONV and less need of rescue antiemetics.
They also reported less severe pain, periorbital edema, and
double vision.58 This study did not consider length of stay
or incidence of POI.
Conclusions
Modern anesthetic practice has made mortality after elec-
tive surgery in healthy patients an exceedingly rare event.
The goal of today’s anesthesiologist is to improve the quality
of recovery by avoiding aspiration and reducing the inci-
dence of PONV and POI. When applied in a systematic fash-
ion, several interventions, such as PONV prophylaxis and
goal-directed fluid therapy, have been shown to decrease
patient morbidity and length of stay. These outcomes are
becoming increasingly important in today’s cost-saving cul-
ture. However, further research is needed to define strate-
gies that can decrease the GI morbidity associated with
anesthetic practice.
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426 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
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 26 Prevention and Management
of Deep Vein Thrombosis and
Pulmonary Embolism
IAN J. WELSBY and KATHLEEN CLAUS
Venous thromboembolism (VTE), including deep vein
thrombosis (DVT) and pulmonary embolism (PE), is a com-
mon, preventable perioperative complication occurring in
up to 5% of noncardiac surgical patients.1 Even when trea-
ted, DVT can lead to long-term consequences, including
chronic edema, dermatitis, venous stasis ulcers, and post-
thrombotic syndrome.2 Another complication of DVT, pul-
monary embolism, carries 15% mortality,3 and acute phase
survivors may develop pulmonary hypertension.4 Preven-
tion and treatment of VTE are therefore exceedingly
important.
Pathophysiology
The three mechanisms for venous thrombosis were origi-
nally described by Rudolph Virchow in 1856: hypercoagul-
ability, stasis, and injured endothelium, known as Virchow
triad.5 Initially, in response to endothelial injury or stasis,
platelets begin aggregating and subsequently activate pro-
coagulant factors while simultaneously inhibiting those
that promote fibrinolysis. This process commonly begins
in the calf veins, most notably the soleal vein, and almost
exclusively occurs within the venous valves.5,6 More recent
research has also focused on the role neutrophils play in clot
formation.7,8
Several risk factors, both inherited and acquired, can
increase VTE risk. Common inheritable causes of hypercoa-
gulable states include non-O blood group, deficiencies of pro-
tein C and protein S, factor V Leiden deficiency, antithrombin
III deficiency, and prothrombin G20210A.6,9 In addition,
methylene tetrahydrofolate reductase 677T and hyperhomo-
cysteinemia also have increased risks of clotting. Both protein
C and protein S are vitamin K–dependent natural anticoag-
ulant proteins that are activated by thrombi via thrombomo-
dulin and work in concert to inhibit the activation of factors V
and VIII. When deficient, patients have a 10-fold increase in
the risk of developing VTE. Factor V Leiden is a mutated form
of factor V, which prevents protein C from binding and
thereby leads to a procoagulant state. This can occur in both
heterozygous and homozygous forms, the latter of which is
associated with an incidence of venous thrombosis 80 times
that of the general population. Antithrombin III is a protein
that under normal conditions binds to and inactivates both
factor II (thrombin) and factor X. Interestingly, deficiency
of antithrombin III can be both inherited and acquired.
The acquired form is associated with increased excretion as
428
seen in renal failure, decreased production (which occurs
in liver failure), and increased consumption as can happen
in severe trauma. It may also be deficient after major surger-
ies, most specifically those requiring cardiopulmonary
bypass. The prothrombin gene mutation (G20210A) leads
to higher levels of prothrombin in the blood and therefore
enhances the risk of clotting. The presence of antibodies to
antiphospholipid also has a 10-fold higher risk of developing
venous thrombosis. Finally, non-O blood groups express
higher levels of FVIII and vWf conferring a smaller increase
in VTE risk.
Acquired risk factors for the development of VTE are var-
ied and consist of age greater than 40 years, prior VTE, var-
icose veins, malignancy, major surgery,10 increased surgical
duration,11 prolonged anesthesia,12 trauma, sepsis, preg-
nancy, major fracture, obesity, prolonged immobility/paral-
ysis, stroke, inflammatory bowel disease (IBD), estrogen use,
and congestive heart failure, among others.9 Certain hema-
tologic conditions can also create a hypercoagulable state
and are associated with VTE. Examples are thrombotic
thrombocytopenic purpura (TTP), hemolytic uremic syn-
drome (HUS), polycythemia vera, heparin-induced throm-
bocytopenia (HIT), and various other myeloproliferative
disorders or malignancies. Although pregnancy is associ-
ated with an increased risk of VTE, men are more likely to
develop recurrent VTE.
Prevention
The Caprini Score is a validated risk assessment tool devel-
oped to stratify patients into very low, low, moderate, and
high-risk groups for developing DVT and thereby to guide
the choice of prevention strategy.12,13 It designates point
values to various risk factors, such as: age; type of surgery;
body mass index (BMI); presence of malignancy, lung dis-
ease, cardiac disease (myocardial infraction, congestive
heart failure), and IBD; stroke; hip, pelvis, or leg fracture;
and inherited coagulopathies, among others. It then creates
an estimate of VTE risk based on the total point value. It is
important to note that this method was only validated for
general, abdominal–pelvic, bariatric, vascular, and plastic/
reconstructive surgery patients; however, it can be applied
to other surgical populations. For patients who fall into the
very low category, the risk of VTE without any prophylaxis
is <0.5%, and for those who fall into the high-risk category,
this increases to 6%.13
 26 • Prevention and Management of Deep Vein Thrombosis and Pulmonary Embolism
For patients who are at very low risk of VTE, the Ameri-
can College of Chest Physicians recommends neither
mechanical nor chemoprophylaxis for DVT and instead sug-
gests early ambulation as a means for prevention.9 For those
at low risk of VTE, recommendations are to utilize mechan-
ical prophylaxis alone. Mechanical prophylaxis includes
both elastic compression stockings and sequential compres-
sion devices (SCDs). Compared with no prophylaxis, studies
have demonstrated that elastic stockings reduce the rate of
both asymptomatic and symptomatic DVT by 31%–65% but
can be associated with skin complications.14,15 SCDs are
intermittent pneumatic compression devices, which pro-
mote blood circulation through the veins of the legs, and
have been shown to have a 60% reduction in the rate of
VTE in various trials, although compliance can be diffi-
cult.15 Preference is usually for SCDs over compression
stockings. Once patients enter the moderate and high-risk
categories for VTE, chemoprophylaxis becomes the pre-
ferred method; however, the risk of bleeding must also be
considered.
Patients at moderate to high risk of developing VTE
should receive chemoprophylaxis as long as their risk of
bleeding is acceptably low. Low molecular weight heparins
(LMWHs; i.e., enoxaparin, dalteparin) and unfractionated
heparin are the preferred agents for pharmacologic preven-
tion based on guidelines. In high-risk patients, it is suggested
to add mechanical prophylaxis. If patients are moderate to
high risk but have a significant risk of bleeding, mechanical
prophylaxis can be used as a sole agent until it is safe to start
pharmacologic prophylaxis. If chemoprophylaxis is indi-
cated but there are contraindications to either LMWH or
unfractionated heparin (UFH), fondaparinux, dabigatran,
or aspirin may be utilized instead.
Regular surveillance with Doppler ultrasound and pro-
phylactic placement of inferior vena cava (IVC) filters have
been described as methods of screening and prevention of
VTE. They are not routinely recommended but remain a
rare option.15
Diagnosis
The Wells score is a validated tool used to assess the pretest
probability of a patient having a DVT. It was initially studied
in patients with a suspected first DVT and assigns point
values to various clinical findings, such as recent immobil-
ity, localized tenderness, calf swelling, pitting edema, recent
or active cancer, and stratifies patients into low, moderate,
and high probability of DVT. The modified Wells score incor-
porates previous DVT into the algorithm and distinguishes
patients as either unlikely or likely to have a DVT. Perfor-
mance of diagnostic tests to confirm the presence of DVT
should only be undertaken after determining a patient’s
probability of having a DVT.
In patients for whom the Wells score identifies a low prob-
ability of DVT, recommendations are to perform a D-dimer
test. A low D-dimer level effectively rules out the possibility
of a DVT. If the D-dimer is elevated or if the patient would be
expected to have an elevated D-dimer for any other reason,
ultrasonography should be performed.16 In those with mod-
erate probability of DVT, D-dimer is nonspecific and ultra-
sound is preferred.
429
DIAGNOSIS OF DEEP VEIN THROMBOSIS
Doppler ultrasound is now the most common tool for detect-
ing DVTs, because it is highly accurate in detecting symp-
tomatic DVT (sensitivity of 93% for acute, symptomatic,
below the knee DVT), noninvasive, and easily repeatable.
Its sensitivity and specificity are much less for asymptomatic
DVT but it still remains the test of choice. Ultrasonic findings
suggestive of acute DVT are enlarged affected veins, lack of
intraluminal echoes, reduced compressibility, and lack of
significant collaterals.
According to the American College of Chest Physicians
Guidelines, contrast venography, which involves injecting
contrast into a foot vein and observing proximal filling, is
the gold standard for diagnosing DVT. However, given its
cost, invasive nature, need for contrast, and overall limited
availability, it is not commonly used. An alternative to this is
CT venography, which similarly injects contrast to evaluate
leg vein filling, but instead utilizes an arm vein for the
injection site.
Other, now outdated, tests for diagnosis of DVT include
radiolabeled fibrinogen uptake testing and impedance
plethysmography.
DIAGNOSIS OF PULMONARY EMBOLISM
The method of diagnosis for pulmonary embolism depends
on the clinical presentation of the patient as well as the pre-
test probability of the patient having a PE. For those who
are hemodynamically unstable, recommendations favor
initial resuscitation, intubation, and mechanical ventila-
tion as needed; transthoracic echocardiography may note
signs of right ventricle (RV) strain or failure. If the patient is
at high risk of PE, empiric anticoagulation is suggested. In
patients at low or moderate risk of PE who are successfully
resuscitated, guidelines suggest following the same
approach at definitive diagnosis used for those who present
with initial hemodynamic stability. Finally, for patients in
whom hemodynamic stability cannot be obtained and a
definitive diagnosis is not possible, a presumptive diagnosis
of PE can be made based on the presence of RV strain on
echocardiogram or DVT on lower extremity compression
ultrasonography.
Pretest probability is important to consider not only for
DVT, but also PE. The Wells score or Modified Wells score
can be used and in outpatients further supplemented by
the Pulmonary Embolism Rule-out Criteria (PERC) rule,
which evaluates the likelihood of PE in patients with a Wells
score <2. This can help identify patients for whom the risk of
testing for PE outweighs the risk of PE and consists of eight
criteria: age <50 years, pulse <100, oxygen saturation of
95% or higher, no hemoptysis, no estrogen use, no prior
DVT or PE, no unilateral leg swelling, and no surgery or
trauma requiring hospitalization in the preceding 4 weeks.
A V/Q scan detects PE in approximately one-third of
patients with the disease. In order to diagnose PE, there
must be a segmental or subsegmental perfusion defect with
normal ventilation. Although a highly sensitive test (98%),
it has poor specificity (10%) and is not considered the gold
standard for diagnosis. However, it can be valuable in
patients in whom CT angiogram is contraindicated (i.e.,
contrast allergy, renal failure) or inconclusive.
430 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

CT pulmonary angiogram (CTPA) is the gold standard for
diagnosing PE. A positive CTPA will demonstrate a filling
defect within the pulmonary arteries. It is both sensitive
and specific (>90%) and also allows alternative diagnoses
to be discovered.
Pulmonary angiography is a historical test with inferior
accuracy compared with CTPA and has increased
procedural risk.
Magnetic resonance pulmonary angiography (MRPS) is
rarely performed despite its high sensitivity and specificity
because of the lack of technology and expertise and because
of time constraints.
Treatment of Venous
Thromboembolism
Choosing an anticoagulant requires consideration of many
factors. Factors such as renal function, risk of bleeding,
adverse reactions, ease of use, cost, and the need for moni-
toring should be considered. Table 26.1 lists the most
common anticoagulants used as therapy for VTE, and
Fig. 26.1 shows their location of action within the coagula-
tion cascade. The rate of recurrent thrombosis without ade-
quate anticoagulation is 29%–47%, but falls to 5%–7% if
appropriate treatment is administered.
UFH works by binding antithrombin III and increasing its
activity against factors IIa, Xa, and IXa. Prophylactic dosing
is typically 5000 units administered subcutaneously every 8
to 12 hours. Heparin has been shown to reduce the risk of
DVT by one-third and the risk of fatal PE by 50%. When
given intravenously as an infusion, heparin can be used
therapeutically in the treatment of both DVT and PE. The
infusion rate should be titrated to an activated partial
thromboplastin time (APTT) value of 2–2.5 times normal
or a heparin level of 0.3–0.7 units/mL.
LMWH includes both enoxaparin and dalteparin. It is
formed by depolymerization and fractionation of standard
heparin and can be administered subcutaneously at both pro-
phylactic and therapeutic doses. Compared with UFH, LMWH
has similar efficacy against VTE but with better bioavailability
and lower risk of bleeding complications. Its elimination is

Table 26.1 Medications Used in Prophylaxis and Treatment of DVT/PE.

Use in Route of Renal Special
Category Medication DVT/PE Administration Dose Reversal Considerations Considerations
Anti-thrombin Unfractionated Prophylaxis, Subcutaneous Prophylaxis: Protamine Negligible
Activation Heparin treatment (SC), 5,000 units SC sulfate
Intravenous (IV) every 12 or
8 hours
Treatment: 80
units/kg or
5,000 unit bolus
followed by
infusion to
maintain aPTT
corresponding
to heparin level
of 0.3-0.7 IU/mL
activity. SC
treatment
dosing also
available
Anti-thrombin Enoxaparin Prophylaxis, SC Prophylaxis: 40 Protamine Contraindicated Preferred
activation, (Lovenox), treatment mg SC daily (for sulfate in renal anticoagulant in
Factor Xa normal renal provides impairment pregnant
inhibition (Low function) partial patients or
molecular Treatment: 1 reversal patients with
weight mg/kg SC BID or cancerrelated
heparins) 1.5 mg/kg daily DVT
Dalteparin Prophylaxis, SC Prophylaxis: Protamine Contraindicated
(Fragmin) treatment 5,000 units SC sulfate in renal
daily provides impairment
Treatment: 200 partial
units/kg SC daily reversal
(max 18,000
units daily)
Vitamin K Warfarin Treatment Oral Varying doses to Vitamin K, Negligible Requires
Antagonism (Coumadin) maintain INR 2-3 FFP, monitoring
(VKA) Prothrombin of INR
Complex
Concentrate
Has many
drug-drug
interactions
 26 • Prevention and Management of Deep Vein Thrombosis and Pulmonary Embolism 431

Table 26.1 Medications Used in Prophylaxis and Treatment of DVT/PE—cont’d

Use in Route of Renal Special
Category Medication DVT/PE Administration Dose Reversal Considerations Considerations
COX inhibition Aspirin Prophylaxis Oral 81 mg PO daily None
Factor Xa Fondaparinux Prophylaxis, SC Prophylaxis: Recombinant Contraindicated Prophylactic use
Inhibition (Arixtra) treatment 2.5 mg SC daily Factor VIIa if renal contraindicated
Treatment: impairment in patients
<50 kg – 5 mg < 50 kg
SC daily 50-100
kg – 7.5 mg SC
daily > 100 kg –
10 mg SC daily
Rivaroxaban Treatment Oral 15 mg BID x 21 Andexanet Requires dose Not for use
(Xarelto) days, then 20 alpha adjustment in in pregnancy
mg daily renal
impairment
Apixaban Treatment Oral 10 mg BID x7 Andexanet Requires dose Not for use
(Eliquis) days, followed alpha adjustment in in pregnancy
by 5 mg BID (2.5 renal
mg daily after impairment
6 mo)
Edoxaban Treatment Oral 60 mg daily if Likely Requires dose Not for use
(Savaysa) >60 kg 30 mg andexanet adjustment in in pregnancy
daily if < 60 kg alpha renal
(following 5-10 pending FDA impairment
days of approval
parenteral
anticoagulation)
Betrixaban Prophylaxis Oral 160 mg initial Likely Requires dose No longer
(Bevyxxa) dose following andexanet adjustment in available in US
by 80 mg daily alpha renal
pending FDA impairment
approval
Direct Bivalirudin Treatment IV 0.15-2 mg/kg/h, None Utilized in
Thrombin titrate to PTT patients with or
Inhibition 1.5-2 times at high risk for
normal HIT
Desirudin Prophylaxis SC 15 mg SC every None Requires dose New warning
12 hours adjustment in against spinal/
renal epidural
impairment hematoma has
caused it to be
discontinued in
the US
Argatroban Prophylaxis, IV 0.2-2 mcg/kg/h None Utilized in
treatment Titrate to aPTT patients with or
1.5-3x normal at high risk for
HIT
Dabigatran Treatment Oral 150 mg BID Idarucizumab Contraindicated
(Pradaxa) (following 7 (Praxbind) in renal
days of impairment
parenteral AC)

independent of the dose and compared with heparin it has
significantly less antiplatelet activity and less complement
activation. Another benefit is that is does not require frequent
laboratory monitoring. However, whereas heparin is safe in
patients with renal failure, LMWH should be avoided.
Warfarin, a vitamin K antagonist, functions by inhibiting
protein C and S, as well as factors II, VII, IX, and X. Using
warfarin alone without heparin is associated with a hyper-
coagulable state for the first 24 to 48 hours because of its
depletion of factor VII and protein C, which can lead to skin
necrosis, especially in patients deficient in protein C. Tradi-
tionally, warfarin is dosed until a therapeutic international
normalized ratio (INR) of 2 to 3 is reached with a concom-
itant heparin infusion to ensure adequate anticoagulation
during the process. The duration of warfarin therapy is deter-
mined by the cause of VTE and history of prior thromboem-
bolic events.
Novel oral anticoagulants (NOACs) have been developed
in an effort to create efficient, safe anticoagulants with no
need for monitoring. Targets of the coagulation cascade
include both factor Xa and thrombin. Medications inhibiting
factor Xa to prevent thrombin formation include rivaroxa-
ban, apixaban edoxaban, betrixaban, and fondaparinux.
Both fondaparinux and the newer agent, betrixaban, are
432 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Intrinsic pathway
XII XIIa Tissue factor
XI XIa
IX IXa VIIa
VIIIa
Warfarin
X Xa
V Va
Prothrombin (II)
Activated protein C
Warfarin Fibrinogen (I)
Protein S
Protein C + thrombomodulin
Fig. 26.1 Coagulation cascade and site of action of anticoagulants. LMWH, Low molecular weight heparin; UFH, unfractionated heparin.
approved for prophylaxis of VTE. Rivaroxaban, apixaban,
edoxaban, and fondaparinux are all utilized in the treatment
of diagnosed VTE. NOACs targeting thrombin itself are dabi-
gatran, argatroban, bilvalirudin, and desirudin. Of these,
argatroban and desirudin are approved for prophylaxis,
and dabigatran, argatroban, and bivalirudin are used for
treatment. Bivalirudin and argatroban are the main agents
used for anticoagulation in patients diagnosed with or at
high risk of HIT.
IVC filters are not recommended as prophylaxis against
PE but can be utilized in patients with known DVT who have
previously failed anticoagulation or have contraindications
to anticoagulation, such as hemorrhage or thrombocytope-
nia. Risks of placing an IVC filter include bleeding, device
misplacement, thrombus dislodgement, caval thrombosis,
filter migration, device failure, and vessel erosion.
Thrombolysis is another potential treatment for VTE and
can be achieved either systemically or via catheter guid-
ance. Studies have shown that routine use of systemic
thrombolytic therapy has no advantage over standard
anticoagulation for DVT, but it does increase the risk of
major bleeding complications to 1 in 5 patients, with 3%
of patients receiving systemic tPA experiencing devastating
intracranial hemorrhage.17 Its use is therefore limited to
early intervention where it has been shown to decrease
the rate of development of post-thrombotic syndrome.
Catheter-guided thrombolysis for DVT is not regularly per-
formed, but when used to treat PE it can reduce both right
heart strain and pulmonary hypertension.
Extrinsic pathway
Warfarin
VII
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Fondaparinux UFH
LMWH
Antithrombin
Thrombin (IIa) Bivalirudin
Desirudin
Dabigatran
Fibrin (Ia) Argatroban
XIIIa
Fibrin clot
Mechanical thromboembolectomy, or surgical clot
retrieval, is an option for the treatment of both DVT and
PE. Indications for pulmonary embolectomy include failure
of aggressive medical management, persistent hypoxemia,
and persistent hypotension. Pulmonary embolectomy is
associated with high mortality of up to 30% in patients
who have not suffered cardiac arrest and up to 70% in
patients who have.
A newer technique, termed ultrasound assisted catheter
directed thrombolysis (USAT), has been growing in popular-
ity for the treatment of submassive PE in patients at interme-
diate risk of receiving systemic thrombolysis. This approach
uses a catheter to direct ultrasound beams at emboli within
the affected pulmonary arteries in order to increase throm-
bus permeability for subsequent catheter-guided tPA infu-
sion over the next several hours. In 2013, the ULTIMA
study evaluated outcomes of patients undergoing USAT
and demonstrated a more rapid improvement in RV dilation
with USAT therapy compared with standard heparinization
without a significant increase in complications.17
Complications of Treatment
The most feared complication of anticoagulation is major
and life-threatening bleeding.
Risk factors that increase the chance of experiencing
bleeding while on therapy include advanced age, previous
 26 • Prevention and Management of Deep Vein Thrombosis and Pulmonary Embolism
bleeding, known cancer, renal and liver disease, thrombocy-
topenia, anemia, diabetes, previous stroke, recent surgery,
frequent falls, and alcohol abuse, among others. Those
patients at low risk of bleeding have a <1% chance of bleed-
ing per year. This increases twofold for those at moderate
risk and eightfold for those at high risk of bleeding.18
An easy way to estimate a patient’s risk of bleeding while
on anticoagulation is the HAS-BLED score, which takes into
account several of the known risk factors listed.
Other complications of anticoagulation include treatment
failure (e.g., heparin nonresponders) or heparin-induced
thrombocytopenia (HIT). Patients suspected of having HIT
should immediately have heparin products discontinued
and switch to a nonheparin anticoagulant.
Reversal of Anticoagulation
In the event that a patient on anticoagulation suffers major,
life-threatening bleeding or requires urgent surgery, rever-
sal of anticoagulation may be indicated. Protamine sulfate
is used to reverse unfractionated heparin and can be
partially effective in the reversal of LMWH. For warfarin,
reversal can be achieved with prothrombin complex
concentrates, which contain vitamin K–dependent factors,
and with vitamin K itself and fresh frozen plasma. Of the
direct thrombin inhibitors, only dabigatran has an approved
reversal agent. Idarucizumab, or Praxbind, is the Fab
fragment of a monoclonal antibody, which sequesters dabi-
gatran, restoring hemostasis for up to 24 hours. Recently,
the reversal agent andexanet alpha, a decoy factor X
molecule, was approved for the reversal of apixaban and riv-
aroxaban in individuals with life-threatening bleeding.
Other antidotes are currently being studied.
Special Considerations
CANCER
Malignancy is a well-known risk factor for the development
of VTE and leads to an almost 10-fold increase in the rates of
thromboembolism. The risk of developing DVT and subse-
quent PE differs based on the type of cancer, with pancreatic
cancer having the highest risk.19 Tumor-specific, anatomic,
patient-specific, and therapy-related factors all play a role in
the increased risk of VTE in cancer patients. This has led to
the development of unique scoring systems to evaluate clot-
ting risk. In general, prophylactic VTE therapy is only
recommended for inpatients and those patients with either
previous DVT or at high risk as outpatients (e.g., following
surgical procedures).19
PREGNANCY
Pregnancy increases the risk of thrombosis through multiple
different mechanisms leading to four- or fivefold increased
risk compared with the general population. Physiologically,
pregnancy itself induces a hypercoagulable state from hor-
monal changes that predispose patients to forming blood
clots. In addition, impaired venous return from an enlarged
uterus is also considered a risk factor in developing VTE. In
433
pregnant patients with diagnosed DVT, 80% occur in the left
leg.20 It is important to note that the rate of pelvic and iliac
vein thrombosis is increased in pregnancy and is not easily
evaluated by traditional Doppler ultrasonography.
OBESITY
Obesity (BMI >30 kg/m2) also increases the chance of devel-
oping VTE by two or three times compared with the general
population. This is suspected to be influenced by a chronic
inflammatory state and decreased mobility. A 2012 study
demonstrated elevated factor VIII levels in obese patients,
associated with APC resistance and therefore increased
chances of thrombotic events.21
RENAL IMPAIRMENT
Chronic renal disease has also been shown to contribute to
an increased propensity for clot formation. Several studies
have demonstrated an increased risk of VTE in patients with
stage 3 or greater chronic renal disease compared with
those without, and a decreased GFR has been shown to
be directly correlated to the rate of VTE.22 The presence of
hypoalbuminemia and antithrombin loss may also be
relevant. In addition, renal impairment requires more care-
ful consideration of which anticoagulant to use for both
prophylaxis and treatment of VTE, because many of the
available options are renally cleared and relatively contrain-
dicated in this patient cohort. Table 26.1 lists the agents
used for prophylaxis and treatment of VTE and implications
for their use in renal impairment.
LIVER IMPAIRMENT/COAGULOPATHY
Although it is often stated that because of their elevated
INR, patients with liver disease are anticoagulated and at
increased risk of bleeding events, this is not necessarily
the case because the liver also synthesizes protein C, protein
S, and antithrombin. Decreases in the levels of these proteins
may lead to thrombotic phenomena rather than bleeding. It
can be exceedingly difficult to determine whether a patient
with liver disease is at higher risk of clotting or bleeding
given their known abnormalities in coagulation studies.
In such patients, the use of rotational thromboelastometry
or traditional thromboelastometry may be particularly help-
ful in determining their ability or propensity to form clots.
TRAUMA
Trauma is known to increase the risk of thrombosis signifi-
cantly, with up to more than 50% of trauma patients devel-
oping DVT.23,24 Orthopedic injuries of the lower body, such
as pelvic, femoral, or tibial plateau fractures, as well as major
head and spinal cord injuries seem to have the highest risk.24
ORTHOPEDICS
Patients undergoing lower extremity orthopedic procedures
are at exceedingly high risk of developing DVT, with an esti-
mated risk of up to 60%.25–28 A recent 2016 meta-analysis
by Venker et al. demonstrated that although newer
434 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
anticoagulants may reduce the risk of developing VTE in
arthroplasty patients, with the exception of apixaban, they
also increased the risk of bleeding events.29
CRITICALLY ILL
Critically ill patients are considered at high risk of develop-
ing VTE, given their prolonged immobility and high inflam-
mation states. Up to 10% of these patients will develop VTE
during their hospital stay, even when prophylaxis is used.30
In conclusion, VTE represents a common and serious, yet
preventable, surgical complication. It is therefore important
to assess a patient’s risk of perioperative thromboembolism
so that an appropriate form of prevention may be prescribed.
References
1. Eikelboom JW, Kearon C, Guyatt G, et al. Perioperative aspirin for pre-
vention of venous thromboembolism: The perioperative ischemia
evaluation-2 trial and a pooled analysis of the randomized trials. Anes-
thesiology. 2016;125(6):1121–1129.
2. Anderson Jr FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated
Annual Numbers of US acute-care hospital patients at risk for venous
thromboembolism. American Journal of Hematology. 2007;82(9):
777–782.
3. Bikdeli B, Sharif-Kashani B. Prophylaxis for venous thromboembolism:
A great global divide between expert guidelines and clinical practice?
Semin Thromb Hemost. 2012;38(2):144–155.
4. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE
disease: Antithrombotic therapy and prevention of thrombosis, 9th ed:
American college of chest physicians evidence-based clinical practice
guidelines. Chest. 2012;141(2 Suppl):e419S–e494S.
5. Malone PC, Agutter PS. Deep venous thrombosis: The valve cusp hyp-
oxia thesis and its incompatibility with modern orthodoxy. Med
Hypotheses. 2016;86:60–66.
6. Christiansen SC, Lijfering WM, Næss IA, et al. The relationship
between body mass index, activated protein C resistance and risk of
venous thrombosis. J Thromb Haemost. 2012;10:1761–1767.
7. Martinod K, Wagner DD. Thrombosis: Tangled up in NETs. Blood.
2014;123(18):2768–2776.
8. Fuchs TA, Brill A, Wagner DD. Neutrophil Extracellular Trap (NET)
impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012;
32(8):1777–1783.
9. Anderson Jr FA, Spencer FA. Risk Factors for Venous Thromboembo-
lism. Circulation. 2003 Jun 17;107(23 Suppl 1):I9–16.
10. Albayati MA, Grover SP, Saha P, et al. Postsurgical inflammation as a
causative mechanism of venous thromboembolism. Semin Thromb
Hemost. 2015;41(6):615–620.
11. Kim JY, Khavanin N, Rambachan A, et al. Surgical duration and risk of
venous thromboembolism. JAMA Surg. 2015;150(2):110–117.
12. Mlodinow AS, Khavanin N, Ver Halen JP, et al. Increased anaesthesia
duration increases venous thromboembolism risk in plastic surgery:
A 6-year analysis of over 19,000 cases using the NSQIP dataset. J Plast
Surg Hand Surg. 2015;49(4):191–197.
13. Caprini JA. Risk assessment as a guide to thrombosis prophylaxis. Curr
Opin Pulm Med. 2010 Sep;16(5):448–452.
14. Ho KM, Tan JA. Stratified meta-analysis of intermittent pneumatic
compression of the lower limbs to prevent venous thromboembolism
in hospitalized patients. Circulation. 2013;128(9):1003–1020.
15. Mannucci PM, Franchini M. Classic thrombophilic gene variants.
Thromb Haemost. 2015;114(5):885–889.
16. Horner D, Hogg K, Body R. Should we be looking for and treating iso-
lated calf vein thrombosis? Emerg Med J. 2016;33(6):431–437.
17. Kucher N, et al. Randomized, Controlled Trial of Ultrasound-Assisted
Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmo-
nary Embolism. Circulation. 2014;129:479–486.
18. Mackman N. New insights into the mechanisms of venous thrombosis.
J Clin Invest. 2012;122(7):2331–2336.
19. Buesing KL, Mullapudi B, Flowers KA. Deep venous thrombosis and
venous thromboembolism prophylaxis. Surg Clin North Am. 2015;95(2):
285–300.
20. Bates S, et al. Chest: Antithrombotic Therapy and Prevention of
Thrombosis, 9th Ed: ACCP Guidelines. CHEST. 2012;141(2):
e351S–e418S (Suppl).
21. Bovill EG, van der Vliet A. Venous valvular stasis-associated hypoxia
and thrombosis: What is the link? Annu Rev Physiol. 2011;73:
527–545.
22. Wattanakit K, Cushman M, Stehman-Breen C, et al. Chronic kidney
disease increases risk for venous thromboembolism. J Am Soc Nephrol.
2008;19:135.
23. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thrombo-
embolism. Chest. 2001;119(Suppl 1):132S–175S.
24. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous
thromboembolism after major trauma. New England Journal of Medicine.
1994;331:1601.
25. Smith NL, Harrington LB, Blondon M, et al. The association of statin
therapy with the risk of recurrent venous thrombosis. J Thromb Hae-
most. 2016;14(7):1384–1392.
26. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molec-
ular-weight heparin for extended venous thromboembolism prophy-
laxis after total hip arthroplasty: A randomized trial. Ann Intern Med.
2013;158(11):800–806.
27. Warwick D, Rosencher N. The “Critical Thrombosis Period” in Major
Orthopedic Surgery: When to Start and When to Stop Prophy-
laxis. Clinical and Applied Thrombosis/Hemostasis. 2010;16(4):
394–405.
28. White RH, Zhou H, Romano PS. Incidence of symptomatic venous
thromboembolism after different elective or urgent surgical proce-
dures. Thromb Haemost. 2003;90:446.
29. Venker BT, Ganti BR, Lin H, et al. Safety and efficacy of new anti-
coagulants for the prevention of venous thromboembolism after hip
and knee arthroplasty: A meta-analysis. J Arthroplasty. 2016;32(2):
645–652.
30. Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in
medical-surgical critically ill patients: prevalence, incidence, and risk
factors. Crit Care Med. 2005;33:1565.
 27 Perioperative Management
of Bleeding and Transfusion
STEVEN ELLIS HILL and DAISUKE FRANCIS NONAKA
Introduction
Transfusion therapy is necessary and can be lifesaving in
surgical patients. However, despite being the standard of
care for blood loss and anemia, it has never undergone
the rigorous, randomized testing required of a new thera-
peutic agent, including assessment of adverse events and
risk assessment. Since the outbreak of acquired immuno-
deficiency syndrome (AIDS) in the 1980s, it has become
apparent that the full extent of the risk of allogeneic trans-
fusion therapy is unknown. In the 2000s, the British
National CJD Surveillance Unit identified 48 individuals
who received a blood component from 15 donors who later
developed variant Creutzfeldt-Jakob disease (vCJD).1 One of
these individuals developed symptoms 6.5 years after a
transfusion of packed red blood cells (PRBCs) from an
asymptomatic donor and died of vCJD in December
2003. A decade later, investigators in Brazil described
two patients who tested positive for Zika virus after receiv-
ing platelet transfusions.2 The donor was asymptomatic at
the time of donation, but later was confirmed to be infected
with Zika virus after developing rash, retro-orbital pain,
and bilateral knee pain. Considering these risks, it becomes
apparent that alternatives to transfusion must be devel-
oped in combination with blood conservation measures.
The goal of these measures should be to limit transfusion
to clinical scenarios in which allogeneic blood product
administration is clearly necessary to maintain adequate
oxygen delivery and reduce mortality.
PATIENT BLOOD MANAGEMENT AND
PREOPERATIVE EVALUATION
Patient blood management (PBM) is a process designed to
optimize the risk-to-benefit ratio of allogeneic blood compo-
nent administration and improve patient outcomes. Accord-
ing to the Society for the Advancement of Blood
Management, the four pillars of PBM include interdisciplin-
ary blood conservation strategies, management of anemia,
optimization of perioperative coagulation, and patient-
centered decision making.3 PBM requires an integrated pro-
gram of preparation, reduction of blood loss, and elimination
of unnecessary allogeneic transfusion.4 Although the bene-
fit to patient outcome and cost reduction has been docu-
mented in the literature,5 implementation of an effective
PBM program is challenging. In order to realize the benefits
of PBM, infrastructure necessary for the diagnosis and treat-
ment of anemia in the preoperative period prior to major
elective surgery is essential.6
When the concept of PBM is simplified, the major compo-
nents of the program are geared toward preventing clini-
cally significant levels of anemia in the perioperative
period. While autologous predonation of PRBC has been
recommended in the past for noncardiac surgical proce-
dures with significant intraoperative blood loss such as total
joint replacement and spine surgery, the cost and question-
able efficacy of this technique has resulted in decreased uti-
lization.7–9 Autologous predonation can result in lower
hemoglobin at the time of surgery, off-setting any potential
benefit. Predonation is also subject to the risk of clerical
error and results in significant wastage of predonated units.
Preoperative anemia is an independent risk factor for
mortality in both cardiac surgery10 and major noncardiac
surgery.11 Without adequate red blood cell mass prior to
a major operation, intraoperative blood conservation strat-
egies are limited and allogeneic blood transfusion is almost
assured. In a national audit of patients undergoing elective
orthopedic surgery in the United States, 35% of patients had
hemoglobin levels <13 g/dL at the time of preadmission
testing with one-third of these patients testing positive for
iron deficiency.12 Treatment of reversible causes of anemia
requires assessment up to 28 days prior to surgery with
delay of elective cases for anemia treatment in order to opti-
mize outcome.5 Without the ability to input, assess, and
treat patients more than 7 days prior to major surgery,
an opportunity to avoid unnecessary transfusion and limit
cost is missed. In conjunction with plans for early input into
enhanced recovery pathway programs as part of an
expanded Preoperative Evaluation Clinic, anemia detection
and treatment as well as preparation for intraoperative and
postoperative PBM are recommended. If done comprehen-
sively, cost-savings from this approach will be realized for
the institution, patients will avoid allogeneic transfusion,
and excess utilization of the blood supply will be curtailed.
Preoperative Assessment of
Bleeding Risk
COMMON DISEASE STATES ASSOCIATED WITH
EXCESSIVE BLEEDING
Hepatic Insufficiency
Patients with hepatic failure have an increased risk of peri-
operative hemorrhage as a result of factor deficiency and
portal venous obstruction. In the event of portal venous
obstruction, development of esophageal varices and poten-
tial venous engorgement around the operative field can
435
436 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
produce enhanced blood loss. Deficiencies of liver-dependent
factors, including factors II, VII, IX, and X, result in a coa-
gulopathy most frequently characterized by prolongation of
the prothrombin time (PT). Vitamin K may be indicated in
the preoperative period if malnutrition is a component of the
coagulopathy in a patient with liver failure. On the other
hand, factor deficiency resulting from inadequate hepatic
synthesis is likely to be unresponsive to vitamin K, and direct
repletion of clotting factors with fresh frozen plasma (FFP) or
prothrombin complex concentrate may be necessary to pre-
vent life-threatening hemorrhage. However, patients with
hepatic insufficiency also have anticoagulant deficiency
and conventional repletion of factors can easily lead to over-
correction and thrombotic complications.
Accelerated fibrinolysis probably also plays a role in the
coagulopathy seen in patients with liver failure. This accel-
eration is evidenced by D-dimer levels that are normal or
slightly elevated in severe liver disease. One mechanism
for the increased fibrinolysis in patients with chronic liver
failure is the reduced clearance of tissue plasminogen acti-
vator (t-PA).13 Another potential mechanism is related to
decreased synthesis of hepatic regulating plasma proteins.
Alpha-2-antiplasmin is a hepatically synthesized enzyme14
that may be deficient in liver failure resulting in increased
plasmin activity.15 Alpha-2-antiplasmin inhibits plasmin-
mediated fibrinolysis by rapidly inactivating circulating
plasmin and by crosslinking to fibrin, making clots that
are resistant to plasmin degradation. Although plasminogen
(the precursor to plasmin) and alpha-2-antiplasmin are
both synthesized in the liver, alpha-2-antiplasmin is present
in lower concentrations than plasminogen and may be
depleted even when plasminogen is not. Another liver-
synthesized molecule, fibrinogen, may also become depleted
in liver failure and may merit measurement.16,17 Despite
that, pure fibrinogen deficiency is uncommon.
Platelet count is often low in liver failure as a result of
either splenic sequestration or increased consumption. Nev-
ertheless, the hemostatic effect of platelets may still be clin-
ically near-normal because of elevated levels of von
Willebrand Factor (vWF). The synthesis of ADAMTS13, a
vWF-cleaving protease, is decreased in liver failure thus
leading to higher than normal vWF activity and platelet
adhesion.18
Renal Failure
The most common blood clotting abnormality in uremic
renal failure is platelet dysfunction. The defect is a function
of uremia and is not intrinsic to the platelets. Therefore,
transfusion of allogeneic platelets is not indicated except
for patients with documented low platelet counts. Primary
treatment for uremic platelet dysfunction is treatment of
the underlying renal failure, with dialysis if necessary. Des-
mopressin (DDAVP; 1-deamino-8-D-arginine vasopressin)
may help platelet function by stimulating endothelial cell
release of vWF.19 A one-time dose of 0.3 μg/kg delivered
intravenously may be indicated to help offset life-
threatening hemorrhage while efforts are made to correct
the underlying uremia.20
Clotting Factor Deficiency
Deficiency of individual clotting factors can be the result of
inherited defects such as those found in hemophilia A (factor
VIII) and hemophilia B (factor IX). Deficiency can also result
from acquired deficiencies, such as the abnormal platelet con-
sumption occasionally observed in patients after cardiopul-
monary bypass. A history of excessive bleeding with prior
surgical or dental procedures or development of hemarthrosis
should raise awareness of a possible bleeding diathesis. Treat-
ment of specific clotting factor deficiencies requires identifica-
tion and replacement of the missing factors. Both factor VIII
and factor IX are available as recombinant products that are
effective but expensive. In general, more than 40% of normal
clotting factor activity is required to prevent bleeding and
higher levels may be necessary to stop active bleeding.21
Patients with vitamin K deficiency or those who have
experienced a warfarin overdose usually respond to vitamin
K administration within 12 to 24 hours. Intramuscular,
subcutaneous, or intravenous administration of 10 mg of
vitamin K often corrects the prothrombin time to an Inter-
national Normalized Ratio (INR) of less than 1.3. Smaller
doses of 1 to 2 mg allow partial correction in the absence
of active bleeding for patients who need reinstitution of war-
farin. Acute treatment of life-threatening hemorrhage from
vitamin K deficiency or warfarin overdose may be treated
with prothrombin complex concentrate (PCC).
Platelet Deficiency
Deficiency of platelet number or function has multiple
potential etiologies, many of which require interventions
other than transfusion. Primary bone marrow failure or
drug-induced bone marrow suppression can cause a defi-
ciency in platelet production. Conversely, immune-
mediated mechanisms, mechanical destruction, or drugs
can cause a deficiency because of increased platelet con-
sumption. Idiopathic thrombocytopenic purpura (ITP) is
caused by presence of a platelet antibody of unknown etiol-
ogy. This condition does not respond well to transfusion and
is treated with steroids and/or large doses of intravenous
immune globulin when there is life-threatening bleeding.
Patients with chronic ITP may be treated with immune sup-
pression or splenectomy. Thrombotic thrombocytopenic
purpura (TTP) is a syndrome characterized by a pentad of
fever, thrombocytopenia, microangiopathic hemolytic ane-
mia, central nervous system dysfunction, and renal failure.
TTP is most likely the result of an inborn or acquired defi-
ciency of a plasma protease that normally cleaves vWF mul-
timers.22 Presumably, when vWF multimers are not cleaved
they promote spontaneous aggregation of platelets in the
circulation, producing thrombi rich in platelets and vWF,
with a resultant consumptive deficiency. Patients with
TTP usually maintain a normal fibrinogen level and a nor-
mal disseminated intravascular coagulation (DIC) screen.
This condition must be treated aggressively with plasma-
pheresis or plasma exchange; patients have an 80% chance
of survival if treated early and aggressively. Awareness and
identification of this condition in the perioperative period is
essential, given the increased usage of drugs known to be
offending agents. Important drugs that can cause acquired
TTP include ticlopidine, quinine, clopidogrel, and calci-
neurin inhibitors such as cyclosporine A.
In addition to the disruptive processing of vWF seen with
TTP, deficient production and function of vWF, as seen with
von Willebrand disease (vWD), also lead to excessive bleed-
ing perioperatively. Although not an intrinsic platelet

disorder, vWD leads to a reduction in the adhesion and
aggregation of platelets. This condition is frequently diag-
nosed in patients with a history of abnormal bleeding asso-
ciated with surgical and dental procedures, who often
present with an elevated PTT. Appropriate therapy of this
condition requires identification of the disease type through
an activity assay in conjunction with input from a hematol-
ogy specialist. Patients with type 1 vWD are most effectively
treated by the administration of DDAVP in a dose of
0.3 μg/kg.23 This therapy is most useful in patients who
have vWF that is stored and can be released. Other types
of vWD respond to administration of cryoprecipitate that
is rich in vWF. Cryoprecipitate is rich in the “labile” clotting
factors VIII, XIII, and vWF and is also a concentrated source
of fibrinogen for patients with fibrinogen deficiency who are
unable to tolerate large volumes of FFP. Cryoprecipitate is
prepared by flash-freezing plasma and thawing it at 1°C
to 6°C. The cold insoluble portion of the thawed plasma is
expressed off the top, collected into separate collection bags,
and refrozen to become the cryoprecipitate product.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a spectrum of
diseases resulting from the formation of antibodies against
platelet factor 4 (PF4) and heparin complexes in response
to heparin therapy. The incidence of HIT has been reported
to be as low as <1% while other studies have report rates
approaching 5%.24 Heparin administration may lead to a
modest decline in platelet count a couple of days after expo-
sure, but this phenomenon is attributed to a nonimmune
interaction between heparin and platelets and is not consid-
ered true HIT. HIT typically leads to thrombocytopenia
5 days after heparin exposure, which is the time required
to form PF4/heparin complex antibodies. However, HIT
can develop immediately in patients with recent heparin
exposure and preexisting PF4/heparin antibodies. These
preexisting antibodies are not permanent, and a study has
shown that serum levels become undetectable at a median
of 50 to 85 days.25 Life-threatening HIT is characterized by
bleeding associated with a low platelet count or “white clot”
thrombosis caused by abnormal platelet aggregation.
Because of the frequency with which heparin is used in
the hospitalized patient population, vigilance for the forma-
tion of this potentially lethal adverse drug reaction must be
maintained. Diagnosis is made by the detection of antibodies
and clinical findings indicating HIT.
The 4Ts scoring system is a method using clinical param-
eters (thrombocytopenia, timing of platelet decrease,
thrombosis, and other causes of thrombocytopenia) to
assess the probability of HIT.26 A low probability 4Ts score
has a very robust negative predictive value; however, an
intermediate or high probability 4Ts score only has modest
positive predictive value.27 A 4Ts score of at least interme-
diate probability should be followed by a PF4-heparin
enzyme-linked immunosorbent assay (ELISA) test. This test
takes only a couple of hours to complete and has high sen-
sitivity to rule out HIT, but also has a high incidence of false-
positive results and low specificity. After a positive PF4-
heparin ELISA test, a serotonin-release assay (SRA) should
be performed, which is the gold standard.24 One downside of
the SRA is it must be performed at a specialized laboratory
and thus takes several days to obtain the results.
27 • Perioperative Management of Bleeding and Transfusion 437
Because the PF4/heparin ELISA is relatively nonspecific
and SRA results are frequently not immediately available,
initiation of therapy may need to proceed on the basis of
clinical suspicion while awaiting definitive diagnosis. If
HIT is suspected, heparin therapy must be discontinued
and other agents used for anticoagulation.24 Direct throm-
bin inhibitors, including argatroban and bivalirudin, are
acceptable alternatives to heparin therapy but lack the
safety benefit of reversibility with protamine. Bivalirudin
has been successfully used for patients with HIT on cardio-
pulmonary bypass. However, because no reversal agent
exists for bivalirudin, postoperative bleeding after cardiac
surgery is frequently excessive until the bivalirudin is
cleared. For patients with a vague history of heparin-
induced thrombocytopenia without life-threatening bleed-
ing or thrombotic complications, the use of heparin for
anticoagulation during cardiopulmonary bypass may still
be the safest therapy. If antiplatelet antibody titers are not
detectable with screening, bolus-dose heparin therapy prior
to bypass with prompt reversal at the end of bypass may be
indicated. The advice of a consulting hematologist is recom-
mended to assist with the risk-to-benefit analysis of short-
term heparin exposure in a patient with a history of HIT.
Low molecular weight heparin can also stimulate antiplate-
let antibodies and should not be used for patients with sus-
picion of HIT. If long-term anticoagulation is required for a
patient with HIT, administration of therapeutic warfarin
therapy is recommended. However, warfarin should be
started and adjusted to therapeutic levels while other forms
of anticoagulation are in place and already at therapeutic
levels. Warfarin has the potential to inhibit production of
the antithrombotic, vitamin K–dependent factors protein
C and protein S prior to therapeutic depression of factors
II, VII, IX, and X.
Tirofiban, a glycoprotein IIb/IIIa antagonist, has been
used successfully to inhibit platelet aggregation from HIT
during cardiopulmonary bypass. Koster et al. have pub-
lished a protocol where a bolus of tirofiban 10 μg/kg was
administered 10 minutes prior to cardiopulmonary bypass
cannulation followed by an infusion of 0.15 μg/kg/min.28
Heparin was given in a standard fashion with an activated
clotting time goal of >480 seconds. The tirofiban infusion
was stopped 1 hour prior to coming off cardiopulmonary
bypass. After arrival in the intensive care unit, a recombi-
nant hirudin infusion was started for thromboprophylaxis.
As an alternative to medical management, plasmaphere-
sis has been used to remove heparin/PF4 antibodies from
circulation and allow heparin administration safely for car-
diopulmonary bypass. Welsby et al. have described their
experience with 11 patients undergoing plasmapheresis
prior to cardiothoracic surgery.29 Nine patients had a pre-
and postprocedure PF4-heparin ELISA test, where six had
negative postprocedure ELISA results and the remaining
three patients had titer reductions between 48% and
78%. One patient underwent a second round of plasmaphe-
resis postoperatively for a possible acute, humoral rejection
after heart transplantation. None of the patients in this
study developed postoperative HIT.
The management of HIT is quite diverse. Confirmation
tests include the fast turnaround PF4-heparin ELISA, which
has high sensitivity but low specificity, and the SRA, which
is a send-out test, but has much higher specificity. The
438 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
treatment plan could include waiting for the heparin/PF
antibody to be naturally eliminated, using heparin alterna-
tives such as direct thrombin inhibitors, administering
platelet inhibitors, and performing plasmapheresis. The like-
lihood of HIT, with the timing and urgency of surgery and
the availability of resources at the clinician’s institution,
must all be assessed prior to moving forward with the best
plan for each patient.
Intraoperative Management
ANTICOAGULATION REVERSAL
Patients often require surgery while on therapeutic doses of
anticoagulants to manage chronic conditions such as pros-
thetic mechanical valves, ventricular assist devices, and
atrial fibrillation. The management of warfarin, a com-
monly used vitamin K antagonist, for elective surgery
involves stopping the medication 5 days prior to the proce-
dure.30 Patients who are considered high-risk for thrombus
formation should discontinue warfarin 5 days prior and
bridge with an alternative anticoagulant such as heparin
or enoxaparin.30 In the case of emergency surgery, warfarin
reversal can be accomplished in several ways: vitamin K,
FFP, or PCC. Vitamin K induces the synthesis of factors II,
VII, IX, and X and is best given intravenously and not orally
in the perioperative setting. Intravenous vitamin K has been
described to take more than 12 hours to bring down a
supratherapeutic INR to 2.0 in the majority of patients.31
Therefore vitamin K alone is not a suitable method to nor-
malize INR for emergency surgery.
FFP can be used to reverse the effect of warfarin by increas-
ing coagulation factor activity. However, the number of units
of FFP needed to lower the INR to a clinically reasonable level
is quite significant. Such a large-volume transfusion puts the
patient at increased risk of transfusion-related acute lung
injury, transfusion-associated circulatory overload, and
increased infection risk. Moreover, it is difficult to achieve
an INR <1.5 with FFP alone, because at this point the addi-
tional coagulation factors given through continued FFP
transfusion become diluted by the volume of the plasma prod-
uct. Current guidelines do not promote FFP as the preferred
agent for emergency warfarin reversal.32
PCCs contain vitamin K–dependent factors II, VII, IX, and
X, and are considered first-line therapy, with concurrent
administration of IV vitamin K, for emergency warfarin
reversal.32 In the United States, the most common PCC for-
mulation is the 4-factor Kcentra, which is also known as
Beriplex P/N (CSL Behring). In addition to the above-
mentioned vitamin K–dependent factors, Kcentra provides
the anticoagulant proteins C and S, antithrombin, and hep-
arin. Advantages of PCCs over FFP for emergency warfarin
reversal include decreased risk of pathogen transmission,
lower volume administration, and greater predictability in
reestablishing a normal coagulation state.33 Because of its
dependability in producing a procoagulant state, PCCs also
increase the risk of unwanted thromboembolism, which
needs to be balanced with its benefits. In addition, British
guidelines state that “PCC should not be used to enable elec-
tive or non-urgent surgery.”34
Oral anticoagulants that are not vitamin K antagonists
include factor Xa inhibitors (rivaroxaban, apixaban, and
edoxaban) and direct thrombin inhibitors such as dabiga-
tran. In a double-blind parallel group study, the factor Xa
inhibitor rivaroxaban was administered for 3 days to volun-
teers followed by 4-factor PCCs, tranexamic acid (TXA), or
saline.35 The study found that PCCs partially reversed the
prothrombin time and there was no reversal detected in
the TXA group. They also looked at bleeding time and vol-
ume, which showed no difference between the PCC, TXA, or
saline groups. Another crossover study had volunteers take
either rivaroxaban or the direct thrombin inhibitor dabiga-
tran, followed by 4-factor PCC (Cofact, Sanquin). They
found that in the rivaroxaban group, PCCs normalized
thrombin generation, but failed to do so in the dabigatran
group.36 Emerging studies continue to support the notion
that PCCs are a reasonable yet off-label option to normalize
the anticoagulant effect of factor Xa inhibitors, but not for
direct thrombin inhibitors. It is hypothesized that direct
thrombin inhibitors act too downstream of the coagulation
cascade for PCCs to have a meaningful effect.33
Instead of PCCs, idarucizumab is the agent of choice for
dabigatran reversal. The REVERSE study recently published
on the safety and efficacy of idarucizumab.37 It was a pro-
spective multicenter study that followed approximately
500 patients who either had uncontrolled bleeding or were
in need of an urgent procedure. The majority of these
patients either had intracranial or gastrointestinal bleeding.
They were administered a 5-g dose of idarucizumab, which
resulted in a complete reversal in 98% of patients with dura-
tion of anticoagulation reached 24 hours after the initial
dose. Adverse events such as thrombosis occurred at a lower
rate than that of PCCs.37
Andexanet alfa was developed as a reversal agent to fac-
tor Xa inhibitors. The ANNEXA-4 study enrolled 354
patients who suffered bleeding while on a factor Xa inhibi-
tor.38 They were given andexanet alfa and their antifactor
Xa activity levels were followed; in addition, they were clin-
ically assessed for hemostatic efficacy at 12 hours after their
andexanet alfa dose. The investigators found that 82% of
patients had good to excellent clinical hemostasis after
andexanet alfa administration. However, they concluded
that a drop in antifactor Xa activity level was not a predictor
of clinically significant hemostasis.38 Andexanet alfa also
reverses anticoagulation induced by heparin and enoxa-
parin.39 The mechanism of this reversal is andexanet bind-
ing to heparin-activated antithrombin’s anticoagulation
complex; the reversal is not andexanet inhibiting free hep-
arin or enoxaparin from binding to antithrombin.39
ANTIFIBRINOLYTIC THERAPY
Tranexamic acid (TXA) and aminocaproic acid (EACA) are
synthetic derivatives of lysine that downregulate fibrinolysis
by inhibiting plasmin production. In 2010, the Clinical Ran-
domization of an Antifibrinolytic in Significant Hemorrhage
(CRASH-2) trial described the analysis of 20,211 trauma
patients who were randomized to tranexamic acid or pla-
cebo within 8 hours.40 The primary outcome of death at
4 weeks after traumatic injury was significantly decreased
in the TXA group at 14.5% versus placebo 16.0% (RR
0.91, 95% CI 0.85–0.97, P¼ 0.0035). The causes of death
were divided into the following groups: bleeding, vascular
occlusion, multiorgan failure, head injury, and other causes.

Among these groups, only death by bleeding was signifi-
cantly reduced with TXA 4.9% versus placebo 5.7% (RR
0.85, 95% CI 0.76–0.96, P¼ 0.0077). This study could
not identify the reason or mechanism behind TXA reducing
all-cause mortality and death by bleeding. It may be pre-
sumed that the reason is TXA’s ability to reduce fibrinolysis;
however, blood transfusions were not significantly different
between the TXA and placebo groups (P ¼ 0.21). Extended
analysis performed on the CRASH-2 data found that admin-
istration of TXA less than 3 hours after injury was most
effective and that later administration was either ineffective
or possibly harmful.41
Two years later, the Military Application of Tranexamic
Acid in Trauma Emergency Resuscitation Study (MAT-
TERS) examined 896 patients who received at least 1 unit
of PRBC.42 This study was retrospective and observational
and found a 6.5% absolute risk reduction for death in the
TXA group versus the control non-TXA group. Additionally,
in patients who underwent a massive transfusion, this study
revealed a 13.7% absolute risk reduction for death in the
TXA group versus the non-TXA group. These findings were
interesting given the TXA group had higher Injury Severity
Scores and incidences of severe extremity injuries compared
with the non-TXA group. The study also found a statistically
significant decrease in hypocoagulable state in the TXA
group over controls, but higher rates of deep vein thrombo-
sis and pulmonary embolism.
Both CRASH-2 and MATTERs trials demonstrated the
benefit of antifibrinolytics administration in trauma
patients, but also indicated signs of possible harm. Although
the CRASH-2 trial did not show a significant difference in
vascular occlusive events with TXA administration,40 the
MATTERs trial revealed increased deep vein thrombosis
and pulmonary embolism.42 Additionally, the extended
analysis of CRASH-2 showed harm when TXA was given
too late.41 Such concern has led to the investigation of a
phenomenon called fibrinolysis shutdown, defined as state
of resistance to tissue plasminogen activator.43 Moore
et al. describe a three-group spectrum of fibrinolysis inten-
sity: hyperfibrinolysis, physiologic fibrinolysis, and fibrinoly-
sis shutdown.44 In their study of 180 patients, they found
that hyperfibrinolysis patients required more PRBC and
FFP, and there was a higher incidence of massive transfu-
sion. Mortality was the lowest in the physiologic fibrinolysis
group with hyperfibrinolysis and fibrinolysis shutdown hav-
ing higher mortality. The most frequent cause of death in
the hyperfibrinolysis group was acute blood loss, while for
the fibrinolysis shutdown group, multiple organ failure pre-
sumably from ischemia was the leading cause of death.
Because this study showed significant harm when patients
received an excess of antifibrinolytics leading to fibrinolysis
shutdown, the practice of routine administration of antifi-
brinolytics has been put into question. Current trends advo-
cate a more targeted use of antifibrinolytics based on
laboratory studies to maximize benefits and to mitigate risks.
INTRAOPERATIVE BLOOD MANAGEMENT
Appropriate triggers for transfusion of allogeneic red blood
cells in the perioperative period have been the subject of
extensive academic debate. According to the guidelines
for transfusion in the perioperative period published jointly
27 • Perioperative Management of Bleeding and Transfusion 439
by the Society of Thoracic Surgeons and the Society of Car-
diovascular Anesthesiologists in 2011, transfusion of alloge-
neic packed red blood cells is indicated for patients with a
hemoglobin level <6 g/dL or for patients with a hemoglobin
level between 6 and 10 g/dL with evidence of tissue ische-
mia.51 While not controversial, the wide range of hemoglo-
bin over which red blood cells were indicated in the presence
of tissue ischemia provided little solid clinical guidance for
most patients undergoing heart surgery. The benefit of
increasing oxygen carrying capacity with allogeneic red
blood cell transfusion versus the risk of an allogeneic red
blood cell transplantation remained largely up to provider
experience and practice patterns. Individual patient charac-
teristics that elevate risk of tissue ischemia such as preexist-
ing vascular insufficiency must also be considered when
selecting a hemoglobin level for red blood cell transfusion.
Regarding the effect of age of stored blood, the most recent
guideline reports that comparative outcomes of transfusing
old versus new blood products are equivocal.45
The level of hemoglobin at which allogeneic red blood cell
transfusion is necessary while a patient is anesthetized, par-
alyzed, and cooled on cardiopulmonary bypass is signifi-
cantly lower than in the postoperative period. In an
analysis of 10,179 consecutive patients with normal preop-
erative hemoglobin who underwent cardiac surgery with
cardiopulmonary bypass, Karkouti et al. found that a com-
posite outcome of death, stroke, and renal failure did not sig-
nificantly rise until hemoglobin fell to less than 50% of the
patient’s baseline.48 This data suggest that the percentage
fall in hemoglobin level is a better trigger for red blood cell
transfusion than an absolute hemoglobin level while on car-
diopulmonary bypass.
In randomized trial testing the noninferiority of a restric-
tive red blood cell transfusion strategy compared with a lib-
eral strategy for patients undergoing cardiac surgery
utilizing cardiopulmonary bypass with a moderate to high
risk of mortality, investigators in the Transfusion Require-
ments in Cardiac Surgery (TRICS) III trial concluded that
an intraoperative hemoglobin threshold of 7.5 g/dL was
not inferior to a higher threshold of 9.5 g/dL in the intrao-
perative and ICU period or 8.5 g/dL on the non-ICU ward.46
According to guidelines for management of bleeding in car-
diac surgery patients published in 2019, the Society of Car-
diovascular Anesthesiologists Task Force agreed that a
hemoglobin transfusion threshold of 7.5 g/dL is “clinically
reasonable and practical” for cardiac surgical patients.47
Noninferiority of a threshold lower than 7.5 g/dL following
separation from cardiopulmonary bypass has not been suf-
ficiently tested.
The most effective means of limiting allogeneic blood trans-
fusion is preservation of the patient’s own red blood cell mass.
Techniques such as limitation of unnecessary intravenous
fluid administration and reduction in cardiopulmonary pump
prime volumes limit dilution of red blood cells, platelets, and
clotting factors.
CELL SALVAGE
Cell salvage involves suction of shed blood from the opera-
tive field, which is then washed and resuspended in crystal-
loid for reinfusion. Cell salvage is currently widely used in
cardiac surgery and represents a low-risk method of
440 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
recovering red blood cells from the surgical field when not
on cardiopulmonary bypass as well as from the residual car-
diopulmonary bypass circuit following separation from
bypass. During this process, platelets and plasma proteins
are removed, but fresh autologous red blood cells are
preserved.
Meta-analysis performed at the end of the 1990s strongly
supported the use of perioperative cell salvage in orthopedic
surgery but was equivocal with regard to the efficacy in car-
diac surgery.49 In a 2009 meta-analysis of cell salvage use
in cardiac surgery, data from 2282 patients enrolled in ran-
domized clinical trials were combined for analysis.50 Using
cell salvage, exposure to allogeneic red blood cells was sig-
nificantly reduced as was exposure to any allogeneic blood
product. The volume of allogeneic blood products transfused
per patient was also significantly reduced by 256 mL (95%
CI: -416 to -95 mL, P ¼ 0.002).
A subanalysis of the Wang et al. study suggested that cell
salvage was only beneficial when used for shed blood or
residual cardiopulmonary bypass circuit blood. Therefore
cell salvage appears to be beneficial for the recovery of red
blood cells during the portions of cardiac surgery when
not on cardiopulmonary bypass, making the technique
complimentary to acute normovolemic hemodilution.
ACUTE NORMOVOLEMIC HEMODILUTION (ANH)
According to the 2011 Society of Thoracic Surgeons (STS)
and Society of Cardiovascular Anesthesiologists (SCA) Blood
Conservation Clinical Practice Guidelines, “Acute normovo-
lemic hemodilution may be considered for blood conserva-
tion but its usefulness is not well established. It could be
used as part of a multipronged approach to blood conserva-
tion. (Level of evidence B).”51 While this technique has been
used for many years, definitive evidence of efficacy is lack-
ing. As with many clinical interventions designed to reduce
transfusion, randomized controlled trials are limited.
Because allogeneic blood component transfusion is consid-
ered to be a standard of care, transfusion research trials
are complicated by the inability to remove investigator bias
and withhold transfusion in the treatment group deemed
necessary by the clinical team. Opponents of ANH will argue
that the procedure is time-consuming, distracting, risky,
and ineffective. Proponents will argue that in select popula-
tions where transfusion is likely, but limited to a need for 1–
2 units of PRBCs, the procedure allows avoidance of low-
volume transfusion. It is also believed to be inexpensive, safe
when performed by a trained team in the operating room,
and well accepted by patients.
Particularly in the arena of cardiac surgery with cardio-
pulmonary bypass, the risk-to-benefit ratio of ANH would
seem to be the most favorable for this technique. Whole
blood passed through the cardiopulmonary bypass machine
has a reduced clotting factor activity, a reduced platelet
count, and measurable thrombasthenia.52 By setting aside
units of whole blood for reinfusion following cardiopulmo-
nary bypass, not only will RBC mass be preserved, but each
unit of whole blood will provide one unit of fresh RBCs, one
unit of fresh plasma, and a single donor unit of autologous
platelets, potentially improving post-bypass hemostasis.
Following the HIV crisis in the 1980s, significant empha-
sis was placed on blood conservation research.
Meta-analysis performed at the end of the 1990s suggested
that ANH reduced the likelihood of exposure to allogeneic
blood.53 However, simply by using a perioperative transfu-
sion protocol guiding decision-making, the beneficial effect
of ANH was eliminated. This analysis was also criticized
for including studies from the 1970s that drove the study
conclusions. In 2001, Richard Weiskopf54 performed a
mathematical analysis to estimate the effect of ANH on
red blood cell mass preservation. Using elegant mathemat-
ical calculations, he concluded that ANH would indeed pre-
serve RBC mass, but only if the surgical blood loss exceeded
50% of the blood volume. He also calculated that it would
take a blood loss of 70% of the blood volume to save 1 unit
of packed RBCs from being transfused. In practice, this
would require an ANH harvest volume of 4 units of whole
blood and a blood loss approaching 2 L to preserve only 1
unit of RBCs based solely upon RBC mass preservation. A
subsequent meta-analysis in 2004 compared ANH with
other blood conservation techniques. Although hemodi-
luted patients were transfused between 1 and 2 units less
and had significantly less intraoperative bleeding, the risk
of allogeneic blood exposure was not significantly different
and the authors concluded that the safety of the procedure
is unproven and widespread use of ANH could not be sup-
ported.55 As a result, enthusiasm in the medical community
waned for this technique.
In 2015, Zhou et al. performed a subsequent meta-
analysis of 3819 patients in 63 studies comparing ANH
with controls in all types of surgery.56 A significant reduc-
tion in the volume of allogeneic RBC transfusion was iden-
tified and a reduction in risk of allogeneic exposure.
However, because of heterogeneity in the studies and a con-
cern for publication bias, the authors concluded that the
true efficacy of ANH is unproven. Critique of this study cited
the inclusion of small trials, absence of consistent
transfusion protocols, and variation in surgical type and
ANH technique as significant limitations making the study
inconclusive.57
Combining knowledge gained from decades of studies
regarding the need for large volume blood loss and the need
for a controlled environment to realize benefit and minimize
risk from ANH, cardiac surgical patients undergoing cardio-
pulmonary bypass would seem to be the best candidates for
ANH. When the volume of the cardiopulmonary bypass cir-
cuit is combined with surgical blood loss, the total tempo-
rary blood loss approaches 2 L. With the controlled
environment allowing time for gradual blood harvest under
general anesthesia, large harvest volumes up to 4 units of
whole blood are possible, making the total blood loss during
cardiopulmonary bypass mathematically favorable for sig-
nificant preservation of RBC mass. Setting aside fresh whole
blood that is not exposed to the cardiopulmonary bypass cir-
cuit would prevent decrement in clotting factor activity as
well as platelet number and function in the whole blood.
Infusion of fresh whole blood following separation from car-
diopulmonary bypass would then enhance coagulation and
improve hemostasis.
Recent analyses limited to cardiac surgery with cardio-
pulmonary bypass have yielded findings supporting ANH.
In a database study from the Michigan Society of Thoracic
and Cardiovascular Surgeons Quality Collaborative, 13,354
patients undergoing on-pump coronary artery and valve

surgery from 26 hospitals were analyzed.58 ANH patients
had a lower adjusted relative risk of allogeneic RBC transfu-
sion that improved with larger harvest volumes. ANH
patients also displayed a significantly lower risk of plasma
and platelet transfusion, risk-adjusted 30-day mortality,
and acute kidney injury. As a database study, selection bias
could not be excluded.
Subsequent meta-analysis including only randomized,
controlled trials of ANH in cardiac surgery also revealed a
signal favorable for the use of ANH. Twenty-nine trials
involving 2439 patients were included with findings of sig-
nificantly less allogeneic RBC transfusions in the ANH group
and a significantly higher allogeneic blood avoidance rate
with ANH. ANH patients also had less postoperative blood
loss.59 As with all conclusions provided from a meta-
analysis, the combination of data from a large number of dif-
ferent clinical trials with variation in technique, endpoints,
and quality can potentially limit the validity of the findings.
In a commentary of the Barile et al. study, it was noted that
the primary outcome was reported as a standardized mean
difference, instead of an absolute reduction in RBCs trans-
fused, and that assessment of patient outcome was also lack-
ing in the study. The significant differences identified also
resulted largely from older studies, suggesting that other
blood management techniques have eliminated the benefit
of ANH in recent years.60
In a recent single-center study by Henderson et al., 84
patients having undergone coronary artery bypass grafting
(CABG), aortic valve repair or replacement (AVR), or CABG/
AVR surgery with cardiopulmonary bypass and ANH with a
harvest volume of at least 2 units of whole blood (900 mL)
were propensity-matched for likelihood to receive allogeneic
transfusion with 84 patients undergoing the same proce-
dure with a harvest volume of 0–899 mL of whole blood.
Patients were excluded for age >80 years or <40 years,
body mass index >45, preoperative warfarin, P2Y12 inhib-
itor or direct oral anticoagulant (DOAC) therapy, cardiopul-
monary bypass time >4 hours or <40 minutes, emergency
surgery, hematocrit <27%, or platelet count <100 
109/L. Multifaceted blood conservation strategies were used
in both groups. There was no difference in adverse events
between groups. The rate-ratios for allogeneic transfusion
were significantly lower for patients undergoing high-
volume ANH for both RBC and non-RBC transfusion com-
pared with patients receiving either low-volume or no
ANH.61 This study strongly suggests that the use of high-
volume ANH in this select patient population is beneficial
for reduction of allogeneic transfusion.
The patient population refusing allogeneic transfusion
under any circumstance represents a group of patients for
whom all available means of blood conservation are maxi-
mized around the time of cardiac surgery in order to offer
the best chance for survival. Pattakos et al. published a com-
parison of outcomes between 322 patients refusing transfu-
sion and 322 propensity-matched controls.62 Postoperative
myocardial infarction, reoperation for bleeding, prolonged
ventilation, length of ICU stay, and length of hospital stay
were all reduced in the cohort of patients refusing transfu-
sion. One-year survival approached significant improve-
ment (P¼ 0.07) in the refusal cohort. In a series of 45
consecutive patients undergoing cardiac surgery and refus-
ing allogeneic transfusion, large-volume hemodilution was
27 • Perioperative Management of Bleeding and Transfusion 441
used for 37 of the 45 patients (not used for critical aortic ste-
nosis or off-pump CABG) as part of a comprehensive patient
blood management program. In the case series, 90-day mor-
tality was zero and hemoglobin levels were maintained
above 10 g/dL except while on cardiopulmonary bypass.63
Given the evidence to date, use of large-volume ANH for
selected patients undergoing cardiac surgery with cardio-
pulmonary bypass should be considered as part of a compre-
hensive patient blood management strategy. Study of
this technique in a large randomized, controlled trial is
warranted.
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PER977 on heparin and oral FXa inhibitors. Blood Adv. 2018;2:
2104–2114.
40. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on
death, vascular occlusive events, and blood transfusion in trauma
patients with significant haemorrhage (CRASH-2): A randomised,
placebo-controlled trial. Lancet. 2010;376:23–32.
41. Roberts I, Shakur H, Afolabi A et al: The importance of early treatment
with tranexamic acid in bleeding trauma patients: An exploratory
analysis of the CRASH-2 randomised controlled trial. Lancet 2011;
377:1096-101, 101.e1-101.e2.
42. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military Application of
Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs)
Study. Arch Surg. 2012;147:113–119.
43. Moore EE, Moore HB, Gonzalez E, et al. Postinjury fibrinolysis shut-
down: Rationale for selective tranexamic acid. J Trauma Acute Care
Surg. 2015;78:S65–S69.
44. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic
fibrinolysis, and fibrinolysis shutdown: The spectrum of postinjury
fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute
Care Surg. 2014;77:811–817 discussion 7.
45. American Society of Anesthesiologists. Practice guidelines for periop-
erative blood management: an updated report by the American Society
of Anesthesiologists Task Force on Perioperative Blood Management.
Anesthesiology. 2015;122:241–275.
46. Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell
transfusion for cardiac surgery. N Engl J Med. 2017;377:2133–2144.
47. Raphael J, Mazer CD, Subramani S, et al. Society of Cardiovascular
Anesthesiologists clinical practice improvement advisory for manage-
ment of perioperative bleeding and hemostasis in cardiac surgery
patients. J Cardiothorac Vasc Anesth. 2019;33:2887–2899.
48. Karkouti K, Wijeysundera DN, Yau TM, et al. The influence of baseline
hemoglobin concentration on tolerance of anemia in cardiac surgery.
Transfusion. 2008;48:666–672.
49. Huet C, Salmi LR, Fergusson D, et al. A meta-analysis of the effectiveness
of cell salvage to minimize perioperative allogeneic blood transfusion in
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fusion (ISPOT) Investigators Anesth Analg. 1999;89:861–869.
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cell saver during cardiac surgery: A meta-analysis of randomized trials.
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51. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of
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diopulmonary bypass. Clin Appl Thromb Hemost. 2016;22:505–511.
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1998;86:9–15.
54. Weiskopf RB. Efficacy of acute normovolemic hemodilution assessed as
a function of fraction of blood volume lost. Anesthesiology. 2001;94:
439–446.
55. Segal JB, Blasco-Colmenares E, Norris EJ, et al. Preoperative acute
normovolemic hemodilution: A meta-analysis. Transfusion. 2004;44:
632–644.
56. Zhou X, Zhang C, Wang Y, et al. Preoperative acute normovolemic
hemodilution for minimizing allogeneic blood transfusion: A Meta-
Analysis. Anesth Analg. 2015;121:1443–1455.
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58. Goldberg J, Paugh TA, Dickinson TA, et al. Greater volume of
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dilution reduces allogeneic red blood cell transfusion in cardiac sur-
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2745–2752.
 28 Prevention of Perioperative
Surgical Site Infection
Q. LINA HU and CLIFFORD Y. KO

Introduction incisional SSI involves only the skin or subcutaneous tissue,

Surgical site infections (SSIs) are now the most common
cause of hospital-acquired infections (HAIs), accounting
for approximately 20% of all HAIs in hospitalized patients.1
Approximately 160,000–300,000 SSIs occur each year in
the United States and 2%–5% occur in patients undergoing
inpatient surgery.2 SSIs are associated with worse out-
comes, including a 2- to 11-fold increase in the risk of mor-
tality.3 Although most patients recover from an SSI without
long-term adverse sequelae, 77% of mortality in patients
with an SSI can be directly attributed to the infection itself.4
Attributable costs of SSI vary depending on the type of oper-
ative procedure and the type of infecting pathogen, but SSIs
are believed to account for $3.5 to $10 billion annually in
health-care expenditures.2 On average, SSIs extend hospital
length of stay by 7–11 days and increase the cost of hospi-
talization by more than $20,000 per admission.5
All surgical wounds are contaminated by bacteria, but
only a minority result in clinical infections. In most patients,
an infection does not develop because innate host defenses
are quite efficient in eliminating contaminants at the surgi-
cal site. Development of SSI after surgery depends on com-
plex interactions between (1) patient-related factors such as
age, obesity, diabetes, host immunity, and nutritional status
(2) procedure-related factors such as placement of a foreign
body, duration of operation, skin antisepsis, and the magni-
tude of tissue trauma; (3) microbial factors that mediate tis-
sue adherence and invasion or that enable the bacterium to
survive the host immune response and to colonize or infect
the host concurrently; and (4) perioperative antimicrobial
prophylaxis.
Surgical Site Infection
CLASSIFICATION OF SSI
Classification of wounds can be based on the degree of bacte-
rial load or contamination that they contain. Since the land-
mark 1964 National Academy of Sciences’ National
Research Council study on the use of ultraviolet lights in
the operating room (OR), wounds have been classified by
the level of risk of contamination. The four categories are
clean, clean/contaminated, contaminated, and dirty/
infected.6 This classification of the degree of contamination
in the surgical site during surgery has become the traditional
system for predicting infection risk in surgical wounds.
SSIs are classified into three groups: (1) superficial inci-
sional, (2) deep incisional, and (3) organ/space. A superficial
a deep incisional SSI involves the fascia or muscular layers,
and an organ/space SSI involves any part of the body
opened or manipulated during the operative procedure,
excluding the previously mentioned layers. The criteria used
for defining an SSI are listed in Box 28.1. The identification
of SSI involves interpretation of clinical and laboratory data.
The Centers for Disease Control and Prevention (CDC) has
derived standardized surveillance definitions and these cri-
teria must be applied consistently when classifying an SSI.
MICROBIOLOGY
The risk of infection increases once the site has been con-
taminated with greater than 105 organisms per gram of tis-
sue.7 The bacterial burden necessary to cause infection is
significantly reduced when foreign material is in place
(i.e., only 100 staphylococci per gram of tissue when intro-
duced on silk sutures).8 Risk is also proportional to the
toxins produced by the specific pathogen because these
agents can facilitate host invasion, damage tissues, and
interfere with host defenses.9
The pathogens responsible for SSIs have not significantly
changed over time. Table 28.1 lists the distribution of
pathogens associated with SSIs. Staphylococcus aureus,
Escherichia coli, coagulase-negative staphylococci, and
Enterococcus faecalis represent nearly 50% of the pathogens
associated with SSIs. S. aureus is the most common SSI path-
ogen for most types of surgery, but E. coli is more prevalent
in abdominal surgery and Enterococcus species are most
prevalent in transplant surgery.10
SOURCES OF PATHOGENS
The primary source of SSI pathogens is the endogenous flora
of the patient’s skin, mucous membranes, or hollow vis-
cera.11 When the mucous membrane or skin is incised,
the exposed tissues are at risk of contamination with endog-
enous flora.12 These organisms are usually aerobic gram-
positive cocci (e.g., staphylococci). When an organ system
is entered, endogenous flora specific to it may be the source
of the pathogen (e.g., enteric flora such as E. coli or other
gram-negative rods when bowel surgery is performed).
Surgical pathogens can also be derived from exogenous
sources. Examples include surgical personnel (especially
members of the surgical team), the OR environment (includ-
ing air), and materials on the sterile field (such as instru-
ments, equipment, containers) during an operation.
Exogenous flora are primarily aerobes, especially gram-
positive organisms (e.g., staphylococci and streptococci).13,14

444

Box 28.1 Criteria for defining a surgical site infection.
Superficial incisional SSI
Occurs within 30 days after the operation, AND
▪ ▪
▪ Involves only the skin or subcutaneous tissue of the incision, AND
At least one of the following:
▪ examination, or imaging test
▪ Purulent drainage from the superficial incision
▪ Organisms isolated from an aseptically obtained culture or
nonculture-based microbiologic testing method of fluid or
tissue from the superficial incision or subcutaneous tissue
▪ Superficial incision that is deliberately opened by a surgeon,
attending physician, or other designee when the patient has at
least one of the following signs or symptoms: pain or tender-
ness, localized swelling, erythema, or heat unless the incision is
culture negative
▪ Diagnosis of superficial incisional SSI by the surgeon or
attending physician or other designee
Deep incisional SSI
▪ Occurs within 30 or 90 days after the operation according to
NHSN’s table of operative procedures, AND
▪ Involves deep soft tissues (e.g., fascial and muscle layers) of the
incision, AND
▪ At least one of the following:
▪ Purulent drainage from the deep incision
▪ A deep incision spontaneously dehisces or is deliberately
opened by a surgeon when the patient has at least one of the
SSI, surgical site infection.
From National Healthcare Safety Network, Surgical Site Infection (SSI) Event. Centers for Disease Control and Prevention; Atlanta: 2013, and available at
www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf.
Although S. aureus is usually from an endogenous source,
evidence suggests exogenous pathways as well.15 Fungal
SSIs are infrequent but can be endogenously or exogenously
derived.16 Nevertheless, there are over two dozen reports of
Candida infections in prosthetic joints, and a growing number
of studies report Candida infections after cardiac surgery.17–20
Although these infections are infrequent, they are associated
with serious problems, including a greater than 50%
mortality.21,22
RISK FACTORS
A risk factor is a characteristic statistically associated with,
although not necessarily causally related to, an increased
risk for a particular outcome. Risk factors for developing
an SSI after surgery can be broadly separated into
preoperative, intraoperative, and postoperative settings
and relate to patient, procedure, or facility factors
(Table 28.2).2,23,24 Nonmodifiable patient factors include
increasing age, recent radiotherapy, and preexisting or his-
tory of skin or soft tissue infection.2,24 Potentially modifiable
patient risk factors include glycemic control, alcohol, smok-
ing status, malnutrition, obesity, and immunosuppres-
sion.24 Procedure-related factors include emergency
surgery, surgical complexity, and wound classification.24
Facility risk factors include inadequate ventilation, increas-
ing OR traffic, and inappropriate sterilization of equipment.2
In this section, preoperative, intraoperative, and postopera-
tive preventative strategies for SSI will be examined in fur-
ther detail.
28 • Prevention of Perioperative Surgical Site Infection 445
following signs or symptoms: fever, localized pain or tender-
ness unless the site is culture negative
An abscess or other evidence of infection involving the deep
incision that is detected on gross anatomic or histopathologic
Organ/space SSI
▪ Occurs within 30 or 90 days after the operation according to
NHSN’s table of operative procedures, AND
▪ Involves any part of the body deeper than the fascial/muscle
layers (e.g., organs or spaces) that is opened or manipulated
during the operative procedure, AND
▪ At least one of the following:
▪ Purulent drainage from a drain that is placed into the organ/
space
▪ Organisms isolated from a culture or non culture based
microbiologic testing method of fluid or tissue in the organ/
space
▪ Organisms isolated from an aseptically obtained culture of fluid
or tissue in the organ/space
▪ An abscess or other evidence of infection involving the organ/
space that is detected on gross anatomical or histopathologic
examination, or imaging test
▪ Meets at least one criterion for a specific organ/space infection
site specified by NHSN
Prevention of Surgical Site
Infection
PREOPERATIVE SETTING
Patient-Related Factors
Diabetes Status and Control. Diabetes mellitus is a well-
known risk factor for adverse medical events. Historically,
increased risk for infection is thought to result from a com-
bination of the long-term effects of hyperglycemia (e.g.,
macrovascular and microvascular disease) and the poor
wound healing associated with neutrophil, complement,
and antibody dysfunction.25–29 However, more recent data
linking long-term blood glucose control and SSI risk have
been mixed. A retrospective Veterans Affairs National
Surgical Quality Improvement Program (VA NSQIP) study
reported that an elevated Hgb A1c (marker of long-term
glucose control) is associated with increased risk of
postoperative infections and that Hgb A1c less than 7%
was significantly associated with increased infectious com-
plications.30 However, subsequent studies using multivari-
able analysis suggest that perioperative hyperglycemia, as
opposed to elevated Hgb A1c, is associated with decreased
SSI risk.31–33 Interestingly, several studies show that periop-
erative hyperglycemia increases the risk of SSI in both dia-
betic and nondiabetic patients.34–37 These studies suggest
that short-term glucose control perioperatively may be
more important than long-term Hgb A1c control in
preventing SSIs.
446 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Table 28.1 Distribution of pathogens associated with Table 28.2 Risk factors for surgical site infection.
surgical site infections frequently reported to the National
Health-care Safety Network, 2011–2014. PREOPERATIVE SETTING
Patient-related factors
No. of % of Nonmodifiable
Pathogen pathogens pathogens Increased age
Recent radiotherapy
Staphylococcus aureus 30,902 20.7 Preexisting or history of skin or soft tissue infection
Escherichia coli 20,429 13.7 Modifiable
Diabetes
Coagulase-negative 11,799 7.9 Obesity
staphylococci Alcoholism
Current smoker
Enterococcus faecalis 11,156 7.5 Hyperbilirubinemia
Pseudomonas aeruginosa 8458 5.7 Malnutrition
Immunosuppression
Klebsiella (pneumoniae/ 7067 4.7
oxytoca) INTRAOPERATIVE SETTING
Bacteroides species 7041 4.7 Patient-related factors
Inadequate skin preparation
Enterobacter species 6615 4.4 Hair removal method
Poor glycemic control
Other Enterococcus species 6410 4.3
Proteus species 4196 2.8 Procedure-related factors
Procedure type
Enterococcus faecium 4140 2.8 Emergency
Higher procedure complexity
Candida albicans 3351 2.2 Higher wound classification
Viridans streptococci 2639 1.8 Longer procedure duration
Blood transfusion
Group B streptococci 1879 1.3 Breach in asepsis technique
Inappropriate antibiotic choice, timing, weight-based dosing, and
Serratia species 1857 1.2 redosing
Other pathogens 21,070 14.1 Inadequate gowning and gloving
Inappropriate surgical scrub
Total 149,009 100
Facility-related factors
Adapted from Weiner, L. M., et al. Antimicrobial-resistant pathogens associated Inadequate ventilation
with healthcare-associated infections: summary of data reported to the Increased operating room traffic
National Healthcare Safety Network at the Centers for Disease Control and Contaminated environmental surfaces
Prevention, 2011-2014. Infect Control Hosp Epidemiol 2016;37(11): Nonsterile equipment
1288-1301.
POSTOPERATIVE SETTING
Inappropriate postoperative antibiotics
Poor glycemic control

Smoking Cessation. Smoking is another well-known
risk factor for postoperative infectious complications.38–42
The etiology is complex but probably mediated through
three principal mechanisms: (1) tissue perfusion and oxy-
genation, (2) impairment of inflammatory cell functions
and oxidative bactericidal mechanisms, and (3) attenuation
of proliferative responses including reduced fibroblast
migration and collagen synthesis and deposition.38 The
effect of smoking is especially pronounced in cases in
which foreign materials or prosthetics are implanted.39
The negative effect of smoking on SSI risk has been dem-
onstrated across all surgical specialties, with current
smokers carrying the highest risk followed by former
smokers.40,42 The fact that former smokers have a higher
risk of SSI compared with those who have never smoked
demonstrates that the detrimental effect of smoking is pro-
longed or possibly even irreversible. Studies have shown
that inflammatory cell response and bactericidal mecha-
nisms improve after 4 weeks of abstinence from smoking,
but impairment of proliferative responses may persist.38
Nevertheless, smoking cessation has been shown to be
effective in reducing SSI risk and patients should be coun-
seled to refrain from smoking for a minimum of 4 to
6 weeks prior to elective surgery.41 The effect of nicotine
Adapted from Ban, KA et al. Executive summary of the American College of
Surgeons/Surgical Infection Society Surgical Site Infection Guidelines 2016
Update. Surg Infect (Larchmt) 2017;18(4):379-382.
replacement therapy on wound microenvironment and
healing is still poorly understood, but there is no evidence
to suggest detrimental clinical effects on postoperative
outcomes.41,43 Current opinion supports the use of nico-
tine replacement therapy as an aid to smoking cessation
before surgery.
Malnutrition. Preoperative malnutrition is a known risk
factor for poor outcomes following surgery. Nutritional fac-
tors play critical roles in regulating metabolic pathways and
immune system functions. A multicenter study found that
preoperative hypoalbuminemia was an independent risk
factor for SSI development after abdominal surgery.44 This
effect has also been shown in many other types of surger-
ies.45,46 However, there is no consistent evidence for malnu-
trition screening and nutritional optimization prior to
surgery. One Cochrane systematic review evaluated nutri-
tional supplementation in elderly patients recovering from

hip fracture that concluded that there is overall low-quality
evidence to support nutritional interventions before or soon
after surgery to prevent infectious complications.47
Procedure-Related Factors
Preoperative Bathing and Showering. Preoperative
antiseptic shower or bath reduces skin bacteria colonization
and decreases the risk of contamination at the surgical site.
In 1980, Cruse and Foord reported nearly double the SSI
rates among patients who did not shower (2.3%) compared
with those who showered with chlorhexidine (1.3%).48
Multiple subsequent studies have found that showering
with chlorhexidine-containing products lowered SSI
rates.49,50 However, a recent Cochrane systematic meta-
analysis of randomized controlled trials comparing preoper-
ative bathing with chlorhexidine did not find a statistically
significant reduction in SSIs compared with placebo con-
trols.51 The result may be in part a result of the highly
variable surgical patient population and lack of standardized
bathing protocols. There is some evidence to suggest
that chlorhexidine needs to dry on the skin for maximal
effect and repeated applications are superior to a single
shower.52,53 A recent randomized study showed that a stan-
dardized protocol of two or three sequential showers with
4% chlorhexidine gluconate with a 1-minute pause before
rinsing resulted in maximal skin surface concentration.54
Although the evidence for preoperative bathing as an inde-
pendent practice is inconclusive, it is important to note that
preoperative bathing as part of a larger bundle has been
shown to be beneficial in reducing SSIs.55,56
MRSA Screening and Decolonization. Nasal carriage of
S. aureus has been known as a risk factor for SSI for more
than half a century. In 1959, Williams reported an
increased risk of wound infection in patients with preoper-
ative nasal carriage of S. aureus and Weinstein found that
patients with preoperative colonization of nasal pathogens
were more than twice as likely to acquire an infection than
those patients with negative nasal cultures.57,58 Over the
past two decades, many studies have repeatedly demon-
strated the association of nasal S. aureus colonization with
higher risk of both methicillin-resistant S. aureus (MRSA)
and overall SSI among surgical patients.59–63 Unfortu-
nately, in the same time frame, the prevalence of MRSA
has dramatically increased with current incidence of posi-
tive MRSA screen at almost 7%.60
The use of MRSA bundles, including screening,
decolonization, contact precautions in the hospital, and
vancomycin-containing antibiotic prophylaxis, have been
shown to decrease SSI rates.56,64–66 Many decolonization
protocols have been developed and no single protocol is con-
sidered standard and supported by literature. Although a
Cochrane systematic review demonstrated that the use of
nasal mupirocin alone reduces S. aureus infection, a typical
decolonization protocol includes the use of 2% nasal mupir-
ocin twice daily for 5 days and bathing with chlorhexidine
gluconate at days 1, 3, and 5 preoperatively.64,67,68 Regard-
less of the exact components of the protocol, there is evi-
dence to suggest that the decolonization must occur close
to the time of surgery to be effective.69 Routine treatment
of all patients and personnel with nasal carriage of MRSA
has been carried out in some parts of Europe and Australia
28 • Prevention of Perioperative Surgical Site Infection 447
and has been proposed in the United States. However, sev-
eral institutions have found that mupirocin resistance
increased with this strategy.70,71 At this time, the American
Society of Health System Pharmacists recommends screen-
ing and nasal mupirocin decolonization for all patients
undergoing total joint replacement and cardiac procedures.
For all other procedures, hospitals should evaluate their SSI
and MRSA rates to determine whether implementation of a
screening program is appropriate.
Bowel Preparations. Preoperative bowel preparations for
colorectal surgery include the use of mechanical bowel
preparation (MBP) alone, oral antibiotics alone, or a combi-
nation of both. Although bowel preparations have been
shown to be beneficial in reducing SSIs, concern has been
raised about potential physiologic derangements related to
dehydration that may prolong postoperative recovery.72
Practice patterns with respect to bowel preparations have
evolved over time, but recently they have come full circle
to support the use of a combination of MBP and oral antibi-
otics.23 A 2011 Cochrane systematic review including 18
randomized studies and 5805 patients did not find statisti-
cally significant differences between MBP alone and no
MBP in terms of wound infections.73 Similarly, oral antibi-
otics or IV antibiotics alone are not effective.74–76 However,
multiple recent studies show that use of a combination of
both mechanical and oral antibiotic bowel preparations
results in lower rates of SSI, anastomotic leak, and Clostrid-
ium difficile infection.74,76–78
INTRAOPERATIVE SETTING
Procedure-Related Factors
Asepsis and Surgical Technique. Asepsis is defined as
the freedom from infection and the prevention of contact
with any microorganism that could cause infection. Aseptic
technique refers to the practices that are used by the surgi-
cal team to prevent infection during medical procedures.
The basic principles of aseptic technique prevent contami-
nation of the open wound, isolate the operative site from
the surrounding unsterile physical environment, and create
and maintain a sterile field in which the surgery can be per-
formed. Many factors come into play to affect asepsis in the
OR including the surgical scrub, appropriate gowning and
ungowning, gloving technique, site preparation to reduce
the normal flora of the patient, hair removal if necessary,
and surgical draping. Excellent surgical technique is critical
to reducing the risk for SSI and encompasses preventing
hypothermia, maintaining hemostasis, handling tissues cor-
rectly, preserving blood supply, avoiding entries into a hol-
low viscus, removing devitalized tissue, placing drains
appropriately, suturing appropriately, eradicating dead
space, and managing the postoperative wound.4
Hair Removal. Although the origin of the practice of
removing hair from the operative site has not been clearly
documented, this surgical practice dates back to at least
the 1850s at Bellevue Hospital in New York City and has
been an established practice since the beginning of the
20th century.79,80 Razor shaving is associated with disrup-
tion of skin integrity because of microscopic cuts and
448 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
abrasions that occur on the skin surface, liberating resident
dermal bacteria into the operative field, and making the skin
environment more favorable to bacterial proliferation.81,82
Seropian and Reynolds conducted the first prospective ran-
domized study to challenge this traditional practice and
found that SSI rate was nearly 10 times higher when hair
was removed by razors (5.6%) compared with depilatory
use or no hair removal (0.6%).83 A landmark 10-year pro-
spective study found that the SSI rate was higher when hair
was removed by electric clippers (1.4%) and highest when
hair was removed by razors (2.5%) compared with no hair
removal (0.9%).84 As such, hair removal is only recom-
mended when the hair will interfere with surgery and razors
are no longer recommended except in the scrotal area or the
scalp after traumatic injury.2,4 The timing of hair removal is
also important. Hair removal immediately prior to the oper-
ation is associated with decreased SSI rates when compared
with hair removal within 24 hours preoperatively.85–87 The
Guideline for Prevention of Surgical Site Infection advises
that if hair is to be removed, it should be done so immedi-
ately before surgery and preferably with electric hair
clippers.4
Skin Preparation. The primary aim of patient skin anti-
sepsis is to kill or incapacitate microorganisms and to reduce
the risk of postoperative infection. Although there is general
consensus that skin preparation is necessary prior to inci-
sion, the active ingredient in the scrub solution is the subject
of debate. Five commercially available antimicrobial ingre-
dients in the United States are approved antiseptic agents
for surgical site disinfection: alcohols, chlorhexidine gluco-
nate, iodine/iodophors, parachlorometaxylenol (PCMX),
and triclosan. Historically, antiseptic agents progressed from
the era of alcohol and carbolic acid to hexachlorophene and
PCMX, then to povidone iodine, followed by chlorhexidine
gluconate agents. Chlorhexidine gluconate, iodophors
(e.g., povidone-iodine), and alcohol-containing products
are currently the most commonly used agents, but there
have been no well-controlled studies to determine the supe-
riority of any agent. Chlorhexidine gluconate and iodophors
have broad spectra of antimicrobial activity. Compared with
iodophors, chlorhexidine gluconate has a greater microflora
reductive effect, greater residual activity after a single
application, and is not activated by blood or serum pro-
teins.88 However, most randomized trials comparing
chlorhexidine-based with iodine-based antiseptics have
been underpowered to detect differences in SSI rates.23,82,89
Current evidence suggests that alcohol-based preparations
are more effective in reducing SSI than aqueous prepara-
tions.89,90 Alcohol-based solutions have the most effective
and rapid-acting bactericidal effect, but this benefit is limited
by its lack of persistent antimicrobial effect. Some newer anti-
septic solutions attempt to prolong the bactericidal activity in
alcohol-based solutions with the addition of iodine or chlor-
hexidine. Although there is some evidence that
chlorhexidine-isopropyl alcohol is superior to iodine-
containing solution plus alcohol in preoperative skin flora
decontamination, no study has convincingly demonstrated
its superiority with regard to SSIs.88,89,91–93 Based on current
evidence, alcohol-based antiseptics should be used when
available. In the absence of alcohol preparations, chlorhexi-
dine might be superior to iodine.
Surgical Hand Scrub. Surgical hand scrubs have been
known to play a vital part in preventing surgical site infec-
tions for many years, beginning with the pioneering work of
Ignaz Philipp Simmelweiss and Joseph Lister in the 1860s.94
Six commercially available antimicrobial ingredients in the
United States are approved antiseptic agents for surgical
hand antisepsis: alcohols, chlorhexidine gluconate, iodi-
ne/iodophors, PCMX, hexachlorophene, and triclosan.
Although the data on the efficacy of microbial killing by
these antiseptics demonstrate decreased bacterial colony
counts on hands, the impact of the choice of scrub agent
on SSI risk has not been evaluated.95–99 Several studies
have found that alcohol-based antiseptics are more effective
than povidone-iodine or chlorhexidine in reducing micro-
bial counts.100 Historically, they were less frequently used
in the United States because of concerns about flammability
and drying of skin.101 However, alcohol-based preparations
for surgical hand antisepsis are gaining popularity because
they are waterless, involve less scrub time, have a broad
spectrum of activity, and do not require brushes.102 Chlor-
hexidine gluconate is a popular choice because of the persis-
tence of its effects. It has a strong affinity for skin and
remains active for over 6 hours and is not activated by blood
or serum proteins. In a study evaluating residual activity fol-
lowing hand disinfection, the greatest sustained activity was
achieved by alcoholic chlorhexidine.103 A recent Cochrane
systematic review found that alcohol scrubs reduce colony-
forming units (CFUs) compared with aqueous scrubs and
that chlorhexidine gluconate scrubs reduce CFUs compared
with povidone-iodine scrubs.104 However, the clinical rele-
vance of this surrogate outcome on SSI risk is unclear and
there is an overall low quality of evidence to support any one
antiseptic over another.
Factors other than the choice of antiseptic agent influence
the effectiveness of the surgical scrub, such as scrubbing
technique, duration of scrub, condition of the hands, and
techniques used for drying and gloving. Surgical hand anti-
sepsis protocols have traditionally required scrubbing with a
brush or sponge, but this practice is damaging to the skin
and results in increased shedding of bacteria from the
hands.105 Data now suggest that neither a brush nor a
sponge is necessary to reduce bacterial counts on the hands
to acceptable levels, especially when alcohol-based products
are used.105–107 With regards to duration of scrub time,
studies suggest that a scrub time of 2 or 3 minutes is as effec-
tive as the longer scrub time in reducing hand bacterial col-
ony counts.108–111 Recently, waterless surgical scrub
formulations have become commercially available. Studies
show that waterless chlorhexidine scrub is as effective as
traditional water-based scrubs and is acceptable in accor-
dance with each product’s instructions.23,112
Surgical Attire. Appropriate surgical attire helps contain
bacterial shedding and promotes environmental control
within the OR. Surgical attire typically refers to reusable
scrubs consisting of pants and shirt, and sterile gowns.
The term can also be extended to the disposable masks,
gloves, surgical caps and hoods, and shoe covers that are
utilized in the OR. Experimental data show that live micro-
organisms are shed from hair, exposed skin, and mucous
membranes, but there are no well-controlled clinical studies
evaluating the effect of surgical attire on SSI risk.4,113

Surgical scrubs consist of pants and a shirt. Policies for
laundering, wearing, covering, and changing scrubs vary
greatly across institutions. Recently, many formerly accept-
able practices, such as laundering scrubs at home and wear-
ing scrubs outside the operating suite, have been called into
question. However, there are no well-controlled studies
evaluating these practices as an SSI risk factor.4,114 Simi-
larly, an acceptable form of surgical caps has been a topic
of controversy in recent years. The rationale for surgical
caps is to reduce contamination of the surgical field by
organisms shed from the hair and scalp. However, no data
exists comparing cloth versus disposable hats and skull caps
versus bouffant hats. In response to these debates, a task
force convened by the American College of Surgeons
(ACS) Board of Regents released new guidelines on surgical
attire in 2016.115 These guidelines are based on profession-
alism, common sense, decorum, and available evidence.
They recommend that clean and appropriate professional
attire (not scrubs) be worn during all patient encounters
outside the OR. OR scrubs should not be worn at any time
outside the hospital perimeter. If they are worn outside the
OR within the hospital, they should be covered with a clean
lab coat or appropriate cover up. Scrubs and hats should be
changed at least daily or after dirty or contaminated cases
before subsequent cases, even if not visibly soiled. Visibly
soiled scrubs from any procedure should be changed as soon
as feasible and before speaking with family. Earrings and
jewelry worn on the head or neck should be removed or
appropriately covered during procedure and the mouth,
nose, and hair should be covered during all invasive
procedures.
Gowns and Drapes. The use of sterile gowns and drapes is
indicated to isolate the sterile field from contamination
because they provide a physical barrier between the sterile
field and the surrounding sources of microbial contamina-
tion such as skin and hair. Regardless of the many materials
used for gowns and drapes, the items should be impermeable
to liquids and viruses.116 To meet the standards of the
American Society for Testing Materials, the fabrics must
be reinforced with films, coatings, or membranes to prevent
breakthrough of fluids. Because such materials create
increased body heat and may be uncomfortable, surgeons
and staff must decide which materials should be selected
for their practice.117
Antimicrobial Prophylaxis. Antimicrobial prophylaxis
refers to a short course of an antibiotic administered prior
to the surgery.118 The goal of antimicrobial prophylaxis is
to reduce the number of organisms that could contaminate
the operative site to a level that will not overwhelm host
defenses. As early as 1961, it was shown that contami-
nants, including S. aureus, can be recovered from the oper-
ative site prior to closure.119,120 Burke demonstrated that
prevention of SSI required that antibiotics be at an effective
concentration in the tissue at the time of contamination.121
In 1969, Polk and Lopez-Mayor showed decreased rates of
wound and intra-abdominal sepsis among patients who
received antimicrobial prophylaxis prior to elective gastroin-
testinal tract surgery.122 Systemic antibiotics given after the
contaminating event had no appreciable effect on the natu-
ral history of infection.123 For antimicrobial prophylaxis to
28 • Prevention of Perioperative Surgical Site Infection 449
be fully effective, an appropriate antimicrobial agent should
be selected based on the type of surgery and the most com-
mon SSI pathogens for that surgery. Optimal prophylaxis
depends on adequate concentrations being present in the
serum, tissue, and wound during the entire time that the
incision is open and at risk of contamination. The agent
should be active against all potential contaminants and
should have the least effect on the normal flora of the body.
There are limited published data on the optimal dosing of
antimicrobial prophylaxis. Agents should be administered
based on the patient’s weight.2,4,124 In a study of obese
patients undergoing gastroplasty, patients who received 1
g of cefazolin had blood and tissue levels of cefazolin consis-
tently below the minimum inhibitory concentration for
gram-positive and gram-negative organisms and had higher
incidence of SSI compared with patients who received 2
g.124 Studies also support redosing with antibiotics during
surgery to maintain adequate tissue levels based on the
agent’s half-life or for every 1500 mL estimated blood
loss.2,125
The initial dose of antibiotic should be infused so that its
bactericidal concentration is established in serum and tis-
sues by the time the skin is incised and so that it remains
at a therapeutic concentration until the incision is closed.
Classen found that SSI rates ranged from 0.6% to 3.8%
depending on the timing of the infusion. The highest rates
were seen when antibiotics were infused more than 2 hours
before and again 3 hours after the incision. Rates were low-
est at 0.6% among patients who were infused within 2 hours
prior to incision.126 A more recent trial demonstrated sim-
ilar results where SSI risks were lower with shorter interval
between antibiotic infusion and surgical incision.127 How-
ever, other studies indicate that no statistically significant
differences in SSI with strict administration windows.128
In 2003, the Medicare National Surgical Infection Preven-
tion Project (SIPP) committee reviewed all published surgi-
cal antimicrobial prophylaxis guidelines and concluded that
the infusion of the first antimicrobial dose should begin
within 1 hour before incision or within 2 hours for fluoro-
quinolones or vancomycin.125 There was no consensus that
the infusion must be completed before incision.
Special Considerations: MRSA Prophylaxis
The routine use of vancomycin for antimicrobial prophy-
laxis is not recommended for any kind of surgery. However,
CDC guidelines suggest that vancomycin can be considered
in certain clinical situations, such as when a cluster of
MRSA infections has been detected.4 The threshold to sup-
port the decision to use vancomycin has not been scientif-
ically defined. Additionally, there is no evidence that
routine use of vancomycin will result in fewer SSIs than
when other agents are used, even in institutions with per-
ceived high rates of MRSA infection. A study at an institu-
tion with a perceived high rates of MRSA infections
randomized cardiac surgery patients to cefazolin or vanco-
mycin and found no statistically significant differences in
SSI rates.129 However, cefazolin-treated patients who later
developed an SSI were more likely to be infected with
MRSA, and vancomycin-treated patients were more likely
to be infected with methicillin-susceptible S. aureus.129 A
more recent study similarly found that use of vancomycin
alone in MRSA-negative patients was associated with a
450 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
higher risk of methicillin-sensitive S. aureus SSI.130 Studies
also indicate that lack of vancomycin prophylaxis is not
associated with MRSA SSI risk.131 Conversely, in patients
who are MRSA-negative preoperatively, treatment with
vancomycin prophylaxis is a risk factor for conversion to
MRSA-positive status.132 For these reasons, routine
administration of vancomycin antibiotic prophylaxis in
MRSA-negative patients is not recommended. Vancomy-
cin might be considered an appropriate agent in patients
known to be colonized by MRSA. According to the recent
Society for Health-care Epidemiology of America guide-
lines, the colonization status of patients at high risk of car-
riage of MRSA should be routinely determined at the time
of admission.133
Wound Protectors. The concept of using a physical bar-
rier to cover the surgical wound edges has been well-
studied over the decades. However, data linking wound
protectors with reductions in SSI are mixed.134–137 The
ROSSINI (Reduction of Surgical Site Infection Using a
Novel Intervention) trial was a large, multicenter random-
ized trial evaluating wound protector use in patients
undergoing laparotomy for any emergency or elective pro-
cedures and failed to demonstrate significant benefit in SSI
reduction.134 However, many other prospective, random-
ized trials have demonstrated substantial reductions in SSI
rate with the use of plastic wound edge protectors.135–137
One meta-analysis pooled data from six RCTs and reported
a significant decrease in SSI rates with wound protector
use.138 Although the evidence for wound protector use
is mixed, their use is generally supported and their benefit
may be more pronounced in more defined patient popula-
tions, such as patients undergoing elective colorectal
surgery.23,137
Antibiotic Sutures. Inflammation of the surgical site
because of the presence of a foreign body, whether it be a
prosthesis, a drain, or suture material, can increase the risk
of infection. Extensive research compares different types of
suture material and infection risk. In general, monofilament
sutures are associated with the lowest infection rates.4
Recently, numerous studies have evaluated the effect of
antibiotic sutures on SSI and have found decreased SSI rates
with use of triclosan antibiotic sutures compared with stan-
dard sutures.139 These findings are confirmed by systematic
review and meta-analysis on the subject.140,141
Wound Closure. As previously described, all wounds can
be classified into four major categories: clean, clean/con-
taminated, contaminated, and dirty/infected. This classifica-
tion of the degree of contamination in the surgical site has
become the traditional system for predicting infection risk
and for recommending the type of closure. Classically, pri-
mary closure is recommended for clean and clean/contam-
inated wounds and delayed primary closure or open wound
management are recommended for contaminated and dirty
wounds. A prospective randomized trial that compared pri-
mary closure with delayed primary closure reported lower
wound infection rate in the delayed primary closure
group.142 However, a systematic review evaluating eight
randomized clinical trials comparing primary closure with
delayed primary closure concluded that all studies were at
high risk of bias with marked deficiencies in study design
and outcome assessment.143 Although the studies reported
reduced SSI risk with delayed primary closure, the effect was
no longer significant after accounting for heterogeneity.143
In the setting of damage-control laparotomy, one study
found that primary closure was associated with an
increased risk of intra-abdominal SSI compared with open
wound management; however, they also found that 85%
of primary closure patients did not develop an SSI and were
spared the morbidity of managing an open wound.144
Perioperative Normothermia. Hypothermia causes
numerous adverse outcomes, including morbid myocardial
events, coagulopathy with increased blood loss and transfu-
sion requirement, postoperative wound infections, and pro-
longed hospitalization.145–148 The primary connection
between thermoregulation and postsurgical resistance to
infection is that hypothermia triggers thermoregulatory
vasoconstriction, which, in turn, decreases tissue oxygena-
tion. This effect was demonstrated as early as 1996 in a ran-
domized, double-blind, controlled trial, which showed that
warming patients for at least 30 minutes preoperatively sig-
nificantly reduced SSI rates in colorectal surgery.145 The
benefit of perioperative warming has been replicated in mul-
tiple randomized controlled trials in both short and long sur-
gical cases.149,150 For longer cases, ongoing temperature
monitoring and warming measures intra- and postopera-
tively are indicated.150
Perioperative Supplemental Oxygen. There is general
support for the use of supplemental oxygen in the perioper-
ative setting in patients with normal pulmonary function.
Although some randomized trials have found no benefit
or even potentially deleterious effects of supplemental oxy-
gen, most demonstrate that use of supplemental oxygen
with 80% FiO2 (fraction of inspired oxygen) during and after
general anesthesia is beneficial compared with 30%
FiO2.151–155 These findings were confirmed in a meta-
analysis that concluded that supplemental oxygen led to a
significant reduction in SSI risk.156
Perioperative Glycemic Control. Although many of the
long-term effects of diabetes cannot be reversed, evidence
suggests that improving glucose control can improve immu-
nologic function and postoperative outcomes.157 In fact,
short-term glycemic control in the perioperative setting is
arguably more important than long-term diabetic control
in preventing SSIs.31,32 There appears to be a dose-response
relationship between serum glucose level and SSIs, with
patients with serum glucose of less than 130 mg/dL with
the lowest SSI rate.35 Interestingly, although diabetic
patients had higher rates of adverse events compared with
nondiabetic patients in general, perioperative hyperglyce-
mia posed a greater risk of adverse events in nondiabetic
patients compared with diabetic patients.36 The authors
hypothesized that this paradoxical effect may be a result
of the underuse of insulin in nondiabetic patients and the
higher level of tolerance of hyperglycemia in diabetic
patients. Multiple randomized trials also demonstrated that
strict glycemic control with glucose targets in the 100 to
150 mg/dL range is superior to liberal glycemic con-
trol.23,158,159 However, target rates below 110 mg/dL are

associated with adverse outcomes, probably related to hypo-
glycemic episodes, without incremental benefit in reducing
SSI risk.2,160 In general, perioperative management of gly-
cemic control to maintain glucose levels between 110 and
150 mg/dL is considered acceptable for SSI prevention.2,23
Facility-Related Factors
The OR, a controlled environment designed for the per-
formance of surgical procedures, is the most highly regu-
lated of all the patient service areas in the hospital. Its
operation and maintenance are governed in the United
States by the state department of health, the Joint Com-
mission, recommendations from the CDC, the American
Institute of Architects, and clinical practice guidelines
developed by professional organizations such as the
American College of Surgeons, the American Society of
Anesthesiologists, and the Association of Operating Room
Nurses. Together, these associations and organizations
have outlined strict controls for the design and mechanical
function of the OR.
Ventilation. Microorganisms in the air of the OR can be a
potential source of surgical wound contamination. Multiple
case studies have traced local epidemics of streptococcal SSIs
to airborne transmission from OR personnel.161–163 Accord-
ingly, the American Institute of Architects (AIA) has pub-
lished guidelines for suggested ventilation parameters,
including maintenance of temperature between 68°F
(20°C) and 73°F (23°C), relative humidity between 30%
and 60%, and 20 to 25 total air exchanges per hour (of
which three must include fresh air).164 The CDC addition-
ally recommends that airflow is directed and balanced to
maintain positive pressure in the OR rooms with respect
to corridors and adjacent areas, that air be introduced at
the ceiling and exhausted near the floor, and that all HVAC
systems have two filter beds in series.4
Laminar airflow with high-efficiency particulate air
(HEPA) filters has been shown to be useful primarily in
orthopedic and implant surgery, where infection rates have
been significantly reduced.165 Laminar airflow is designed to
move particle-free air (ultraclean) over the sterile field at a
uniform velocity of 0.3 to 0.5 μm/sec. The ultraclean recir-
culated air passes through HEPA filters and can be directed
vertically or horizontally in the room.166 A large prospec-
tive, randomized multicenter study compared ultraclean
air, antimicrobial prophylaxis, and ultraclean air combined
with antimicrobial prophylaxis in total hip and knee
replacement procedures. Although the results show that
SSI rates decreased significantly with combination of anti-
microbial prophylaxis and ultraclean air, similar effects
were seen with only antimicrobial prophylaxis.167 A smaller
study in spine surgery found a significant difference in SSI
rates between ultraclean air and conventional groups even
with use of prophylactic antibiotics.168 However, there is a
minimal amount of data to support the use of ultraclean air
in other nonorthopedic surgical areas.169,170
Traffic Control. Traffic within the operating suite must be
controlled to ensure that only authorized personnel are
entering restricted zones, to maintain the separation of
clean from dirty areas, and to segregate clean equipment
areas from contaminated workrooms. Surgical attire is
28 • Prevention of Perioperative Surgical Site Infection 451
required for moving around in semirestricted zones such
as hallways, offices, or supply rooms that are adjacent to
an OR, and a face mask is required when entering a room
while a procedure is in progress. Attempts are made to limit
the number of personnel in an OR during a procedure.
Although there is evidence to suggest that the level of con-
tamination is proportional to the number of personnel in the
OR, it is unclear whether there is a link between increased
number of personnel and increased SSI risk.171,172 Never-
theless, OR traffic should be controlled to decrease the bac-
terial load of the room by negating both air turbulence and
bacterial shedding by personnel in the room.170,172,173
Cleaning Environmental Surfaces. Environmental sur-
faces are not routinely implicated in surgical site infections.
A randomized study compared cleaning ORs with Wet-Vac
routinely between cases and only after contaminated cases
and found significant differences in surface contamination
but not in postoperative wound infections.174 However,
OR telephones have been identified to be a potential reser-
voir for SSI-causing bacteria.175 In general, it is important
to maintain a hygienic work environment in the OR. Rou-
tine cleaning of environmental surfaces should be per-
formed between cases and at the end of the workday by
hospital housekeeping staff trained in the proper techniques
of OR cleaning. The decontamination process should begin
at the highest level in the room (light tracks, ceiling fixtures)
and progress downward to the level of shelves, tables, kick-
stands, and the floor. The Occupational Safety and Health
Administration (OSHA) requires the environmental clean-
ing of all surfaces that have come in contact with blood
or body fluids.176
Microbiologic Sampling. According to the CDC Guide-
line for the Prevention of Surgical Site Infections, there
are no standardized parameters for the evaluation and
comparison of microbial counts from air sampling or envi-
ronmental cultures in ORs.4 Therefore, routine culturing of
the OR environment is not recommended. Microbiologic
sampling of the environment should take place only if an
epidemiologic investigation is being conducted that impli-
cates some areas as a potential source of an outbreak or
a cluster of infections.
Sterilization of Surgical Instruments. Nondisposable
surgical instruments must undergo physical cleaning fol-
lowed by sterilization. Sterilization methods included steam
under pressure, hydrogen peroxide gas plasma, vaporized
hydrogen peroxide, ethylene oxide, or some other ethylene
oxide-containing mixture.177 The most critical issue in
instrument reprocessing is the required monitoring of the
functional parameters (time, temperature, and pressure)
of the sterilization process. Microbiologic and chemical test-
ing of sterilization methods must be performed on a sched-
uled basis. Protection of the sterility of surgical instruments
from time of sterilization until the time of use is critical. Ster-
ilized equipment is generally wrapped in sterile coverings,
which are routinely inspected for holes to identify inappro-
priately sterilized or contaminated contents. However, a
study found that holes smaller than 1 cm were often missed
by visual inspection, suggesting that more a rigorous tech-
nique may be required.178
452 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Flash Sterilization. Flash sterilization is the processing of
patient care items by steam sterilization when the item is
intended for immediate use in a patient procedure. This sit-
uation arises when a critical instrument has been inadver-
tently dropped or another necessary piece of equipment is
urgently needed. Flash sterilization is not appropriate for
implantable items and it is not to be considered for the con-
venience or time-saving of the OR schedule. The problems
with flash sterilization include a lack of biologic monitoring,
an absence of protective packaging, an increased possibility
of contamination, and shortened or minimal sterilization
cycles. In steam sterilization, the parameters of time, tem-
perature, and pressure are critical for adequately reproces-
sing a surgical instrument.4 The use of rapid biologic and
chemical indicators has been evaluated and found to be
acceptable.179 It is advisable, however, that flash steriliza-
tion be restricted to specific times and events.
POSTOPERATIVE AND POSTDISCHARGE SETTING
Postoperative Antibiotics
The majority of the published evidence demonstrates that
antibiotics after wound closure are unnecessary. A variety
of clinical studies have found no difference in SSI rates when
single-dose and multiple-dose regimens have been com-
pared.4,180–182 Extended use beyond the operation may be
associated with adverse events, such as Clostridium
difficile colitis and the emergence of resistant bacterial
strains.2,183,184 As such, the SIPP committee guidelines rec-
ommend discontinuation of antibiotics within 24 hours
after the operation.125 An exception in which the optimal
duration remains controversial is in cardiothoracic surgery.
The American Society of Health-System Pharmacists
(ASHP) recommends continuation of antimicrobial prophy-
laxis for up to 72 hours following cardiothoracic surgery,
although this recommendation is based on expert opinion
and the authors acknowledge that prophylaxis for less than
24 hours may be appropriate.181
Postoperative Showering
There is little guidance about when sterically dressed
wounds can get wet by showering or bathing postopera-
tively. Although traditional teaching encourages waiting
48 hours after surgery before showering, but there are no
data to suggest higher SSI rates with early showering (as
early as 12 hours after surgery) compared with delayed
showering (more than 48 hours after surgery).185 However,
the only randomized trial on this topic was at high risk of
bias and no conclusive evidence can be drawn.186 Timing
of postoperative showering should be determined at the dis-
cretion of the operating surgeon.
Surveillance
The Joint Commission has identified nosocomial infection
rates as an indicator of the quality of care in hospitals.
Accredited hospitals must perform surgical site surveillance
by systematic review of surgical patient charts, microbiol-
ogy culture results, pharmacy data, radiology reports, com-
munications from surgeons and nurses, and other sources of
reliable information, such as pathology reports, autopsy
reports, clinic visit reports, emergency room reports, and
quality improvement databases operated by individual sur-
gical services. To calculate meaningful SSI rates, data
should be collected on all patients undergoing a surgical
procedure of interest. Surveillance is best performed by an
individual trained in hospital epidemiology and infection
control (e.g., the infection control practitioner) who is
guided by the practices of the Association for Professionals
in Infection Control and Epidemiology. Monitoring of inpa-
tient and outpatient surgeries should be performed with
post-discharge surveillance. Currently there is no consensus
on the best method of postdischarge surveillance and hospi-
tals may choose methods that best fit their unique mix of
procedures, personnel resources, and data needs.4 CDC’s
National Health-care Safety Network (NHSN) collects and
disseminates SSI rates compiled voluntarily from more than
17,000 health-care facilities representing all 50 states.10
The CDC uses the data that are reported by participating
hospitals to estimate the magnitude of nosocomial infection
problems in the United States and to monitor trends in infec-
tions and risk factors.
Prion Disease and the
Operating Room
Prion diseases such as Creutzfeldt-Jakob disease (CJD),
variant Creutzfeldt-Jakob disease (vCJD), and bovine spongi-
form encephalopathy (BSE) (or mad cow disease) represent a
unique infection control problem because prions exhibit an
unusual resistance to conventional chemical and physical
decontamination methods. Because the CJD prion is not
readily inactivated by conventional disinfection and sterili-
zation procedures, and because of the invariably fatal out-
come of CJD, the procedures for disinfection and
sterilization have been both conservative and controversial
for many years.
BSE is a progressive neurologic disorder of cattle first iden-
tified about three decades ago in Europe. By 2005, more
than 184,000 cattle cases had been confirmed. When trans-
mitted to humans through BSE-contaminated food, BSE pro-
duces the fatal neurodegenerative disease known as vCJD.
There have been two cases of BSE in cows in the United
States, one of which was known to have come from Can-
ada.187 Three other cases of BSE-infected cows were identi-
fied in or linked to Canada.188 In April 2002, the Florida
Department of Health and the CDC announced the occur-
rence of a likely case of vCJD in a Florida resident believed
to have contracted it years before in England.189
Iatrogenic cases of prion disease have occurred as a result
of direct inoculation of prion particles during surgical proce-
dures in the hospital setting.190 The first documented base
occurred via an infected corneal transplant in 1974.191
More than 450 cases of iatrogenic transmissions have been
identified worldwide in the past decade.192 Although the
majority of these cases resulted from contaminated human
growth hormone and cadaveric dura mater grafts, contam-
inated surgical instruments have been cited as a source.193
In 2001, the Joint Commission reported two incidents at
accredited hospitals where 14 patients may have been

exposed to CJD through instruments used during brain sur-
geries on patients of unsuspected cases of CJD.194 Between
1998 and 2012, 19 incidences of suspected CJD exposure
via contaminated surgical instruments have been reported
to CDC, of which two were in ophthalmologic surgeries
and 17 were in neurologic surgeries.195
Recommendations to prevent transmission of infection
from medical devices contaminated by the CJD prion have
been based primarily on prion inactivation studies.196 Com-
monly used methods for disinfection and sterilization may
not adequately denature the prion particles.197 Recommen-
dations for enhanced cleaning and sterilization (274°C for
18 minutes) of instruments used on patients suspected of
having or confirmed to have CJD have been provided by
the World Health Organization (WHO) and are cited in
the APIC disinfectant guidelines.198 As prion diseases con-
tinue to increase in the United States and Europe, the poten-
tial for human-to-human iatrogenic spread of vCJD will
probably increase. Infected individuals, like the rest of the
population, will undergo medical and surgical procedures.
Extending disinfectant protocols in the medical setting
may be a strategy that deserves further investigation.
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 29 Perioperative Protection of the
Pregnant Woman
RICHARD C. MONTH
Introduction
Maternal safety surrounding nonobstetrical surgery, labor,
and delivery has been seen as one of the greatest triumphs of
20th century medicine. Within living memory, nearly 1% of
women in the United States died during or in the immediate
aftermath of childbirth. As recently as 1900, maternal mor-
tality was six to nine per 1000 live births, and of those 1000
births, 100 infants died before the age of 1 year.1,2 From
1900 through 1997, maternal mortality declined almost
99%, to less than 0.1 reported deaths per 1000 live births
(7.7 deaths per 100,000 live births in 1997).3,4 Environ-
mental interventions, improvements in nutrition, advances
in clinical medicine, improvements in access to health-care,
improvements in surveillance and monitoring of disease,
increases in education levels, and improvements in stan-
dards of living contributed to this remarkable decline.1
However, despite these significant improvements, a star-
tling trend has arisen. Between 2000 and 2014, maternal
mortality has steadily risen in the United States; the United
States now has the highest maternal mortality among
industrialized nations and is one of the only such nations
to have a maternal mortality that continues to climb
(Fig. 29.1).5,6 Clearly, significant preventable causes of
maternal death still persist. Here, we attempt to offer recom-
mendations toward what authorities consider best practice
in an effort to stem the tide and improve maternal morbidity
and mortality in the perioperative and peripartum periods.
Causes of Maternal Morbidity and
Mortality
Since 1952, the most thorough and reliable data on mater-
nal mortality have come from the Confidential Enquiry into
Maternal Death, now called Confidential Enquiry into
Maternal and Child Health (CEMACH),7,8 and the Centers
for Disease Control’s Maternal Mortality Survey.9 However,
more recent data are available from the World Health Orga-
nization,10 with the most recent period covering data from
2003–2009 (Fig. 29.2). The WHO reviewed a total of over
60,000 deaths from 115 countries. Among both developed
and developing countries, obstetric hemorrhage remains
the most common direct cause of maternal death, with rates
of 16.3% and 27.1% of deaths respectively. The majority of
hemorrhage deaths continue to occur in the postpartum
period and do not appear to be decreasing in frequency
worldwide. In developed nations, embolic events were the
second-leading direct cause of death with hypertensive
diseases third (13.8% and 12.9% respectively), and in devel-
oping regions, hypertensive diseases and sepsis (14% and
10.7%) were second and third. In both developed and d;eve-
loping regions, indirect causes of maternal death, primarily
preexisting medical conditions, comprise a large proportion
of all deaths (24.7% and 27.5% respectively).
Anesthetic Causes of Morbidity
and Mortality
Serious anesthesia-related complications are thankfully
rare in the perioperative and peripartum period. Histori-
cally, perioperative mortality fell significantly through the
1980s and 1990s, although it regressed slightly in the
beginning of the 2000s to a rate of about 1 in 20,000.7
The overwhelming majority of these deaths were a result
of failures in airway management: unidentified esophageal
intubation and hypoventilation. Obesity, aspiration, and the
lack of capnography were commonly associated with these
deaths.
With the expansion of regional anesthesia use in these
patients, the risk of anesthesia mortality has decreased sig-
nificantly. The Society for Obstetric Anesthesia and Perina-
tology’s Serious Complications Repository Project reviewed
more than 257,000 anesthetics between 2003 and 2009
and identified 157 serious complications, 85 of which
were deemed to be anesthesia-related (Fig. 29.3).11 No
anesthesia-related deaths were reported in this group; how-
ever, comparatively common severe complications included
failed intubation, with an incidence of 1:533 and high neur-
axial block, with an incidence of 1:4336. Other routinely
discussed complications of obstetric anesthesia were signif-
icantly less common: serious neurologic injury, with an
incidence of 1:35,923, epidural abscess/meningitis, with
an incidence of 1:62,866, and epidural hematoma, with
an incidence of 1:251,423 are all comparatively rare.
Thromboembolism and
Thrombophilia
Pregnancy and its hormonal changes are known to promote
coagulation.12–14 Clotting factors increase with gestational
age and, together with rapid myometrial contraction
at delivery, help prevent excessive blood loss. Platelet
production, consumption, and activation increase. Throm-
boelastography demonstrates accelerated clot formation,15
which further increases the risk of thromboembolism in
459
460 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Fig. 29.1 Estimated mortality in the United States, Canada, France, and the United Kingdom, from 2000 to 2015, in deaths per 100,000 live births.
(Adapted from MacDorman MF, Declerq E, Cabral H, et al. Is the United States maternal mortality rate increasing? Disentangling trends from measurement
issues. Obstet Gynecol. 2016;128(3):447–455; GBD 2015 Mortality and Cause of Death Collaborators. Global, regional, and national life expectancy, all-cause
mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet
2016;388:1459–1544.)

Fig. 29.2 Top causes of maternal

death in developed and developing
regions of the world. (Adapted from
Say L, Chou D, Gemmill A, et al. Global
causes of maternal health: a WHO sys-
tematic analysis. Lancet Glob Health.
2014;2(6):e323–e333.)

Fig. 29.3 Anesthesia-related inci-

dence of various serious complica-
tions. (Adapted from D’Angelo R,
Smiley RM, Riley ET, et al. Serious
complications related to obstetric
anesthesia: the Serious Compilations
Repository Project of the Society for
Obstetric Anesthesia and Perinatology.
Anesthesiology 2014;120:1505–1512.)

pregnancy. Risk factors associated with maternal thrombo-
embolism include older age, immobility, prolonged travel,16
surgery, family history, patient history, oral contraceptive
use, and obesity.17 Risk factors for thromboembolism in
pregnancy are outlined in Fig. 29.4.
With the continually significant risk of embolic disease in
pregnant patients, recent recommendations have widely
expanded the use of thromboprophylaxis; the California
Maternal Quality Care Collaborative’s Maternal Venous
Thromboembolism Toolkit recommendations include signif-
icant expansions in the use of prophylactic and therapeutic
heparins in the antepartum, peripartum, and postpartum
periods.18
Thrombophilia is emerging as an important cause of
maternal thromboembolic risk. It is found in up to 17% of
white North Americans. Thrombophilia can be divided into
three general categories: familial, acquired, and mixed.
Familial causes include protein C, protein S, and anti-
thrombin III deficiencies, as well as factor V Leiden and
prothrombin gene polymorphism. Conditions that increase
the risk of thrombophilia include antiphospholipid anti-
bodies and lupus anticoagulant. Mixed thrombophilia risk

Fig. 29.4 Risk factors for venous
thromboembolism in pregnancy and
the peripartum period. (Adapted from
RCOG Green-top Guideline No. 37a
April 2015. Available: https://www.rcog.
org.uk/globalassets/documents/guide
lines/gtg-37a.pdf)
includes methylene tetrahydrofolate reductase polymor-
phism and hyperhomocysteinemia. Genetic thrombophilia
is associated with other complications of pregnancy such
as gestational hypertension, intrauterine growth restriction
(IUGR), placental abruption, and stillbirth.19–21 In one
study,20 52% of women with severe gestational hyper-
tension and associated problems also had thrombophilia.
Preventing these thrombophilia-related side effects has
proven to be difficult; antepartum dalteparin prophylaxis
has shown no effect in preventing thromboembolic events,
pregnancy loss, or placenta-mediated pregnancy complica-
tions in patients with thrombophilia in pregnancy.22
Hypertensive Disorders
of Pregnancy
Chronic hypertension complicates between 1% and 5% of
pregnancies. It is defined as a blood pressure greater than
140/90 mmHg that either predates pregnancy or develops
before 20 weeks of gestation. Gestational hypertension
develops after 20 weeks of gestation and complicates
between 5% and 10% of pregnancies. Gestational hyperten-
sion may reflect a familial predisposition to chronic hyper-
tension or it may be an early manifestation of preeclampsia.
29 • Perioperative Protection of the Pregnant Woman 461
Preeclampsia is the most common disease that is unique
to human gestation, occurring in 6% to 8% of pregnancies.
In developed regions 12.9 % of deaths and 14% in develop-
ing regions were attributable to hypertensive disorders of
pregnancy, most commonly preeclampsia. Diagnostic cri-
teria are listed in Fig. 29.5 and include hypertension and
symptoms of end-organ dysfunction.
The etiology is unknown, but the defining feature of pre-
eclampsia is vasospasm affecting organs throughout the
body. Cellular damage can be seen in endothelium, platelets,
and trophoblasts. Vasoactive amines and prostaglandins are
then released. Blood vessel narrowing and decreased elastic-
ity are associated with increased vascular resistance.
Women who become preeclamptic, unlike those with a nor-
mal pregnancy, do not lose sensitivity to angiotensin and
catecholamines. Uterine Doppler studies show evidence of
high vascular resistance and flow abnormalities.23
An immune reaction involving trophoblast material and
basement membrane, prostacyclin imbalance, and vascular
nitric oxide dysfunction have all been suggested as impor-
tant parts of the puzzle. A genetic analysis of its aspects is
underway.20,21 General risk factors for the development of
gestational hypertension can be found in Table 29.1.
As hypertensive disorders of pregnancy remain a signifi-
cant cause of maternal morbidity and mortality, significant
462 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
efforts have been made to improve, standardize, and expand
appropriate and early care for gestational hypertension and
preeclampsia. Core to these efforts are to standardize ante-
partum care and to monitor closely those at elevated risk
of preeclampsia, early evaluation and treatment of all hyper-
tension in pregnancy, early implementation of magnesium
sulfate therapy for the treatment of preeclampsia, and
improved education for patients and health-care profes-
sionals in both identification and treatment strategies.24
MANAGEMENT OF MATERNAL HYPERTENSION AND
PREECLAMPSIA
Obstetric maternal monitoring should be done in all women
with gestational hypertension and preeclampsia. The aim in
gestational hypertension is to watch for progression to pre-
eclampsia and to treat as early as possible.25 In women with
severe features of preeclampsia, the goal is to detect and
avoid organ dysfunction.26
Fig. 29.5 Diagnostic criteria for pre-
eclampsia (Adapted from American
College of Obstetricians and Gynecol-
ogists; Task Force on Hypertension in
Pregnancy. Hypertension in pregnancy.
Report of the American College of
Obstetricians and Gynecologists’ Task
Force on hypertension in pregnancy.
Obstet Gynecol. 2013;122(5):
1122–1131.)
Antepartum outpatient management of preeclampsia
can be considered for select patients without severe fea-
tures who have access to routine follow-up appointments,
can adhere to their treatment plan, and have demon-
strated fetal wellbeing and maternal stability.27 The fetus
should be evaluated routinely (at least twice per week)
by nonstress test or biophysical profile, and the mother
should have routine blood pressure evaluation and labo-
ratory studies, including complete blood count with plate-
let count, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), lactate dehydrogenase (LDH),
and serum creatinine.26
Management of patients with preeclampsia at term, pre-
eclampsia with severe features, or patients with worsening
disease demands immediate hospitalization. Patients with
preeclampsia without severe features are routinely delivered
at 37 weeks. Patients with severe features who have
reached 34 weeks’ gestation are also routinely delivered;
patients who are less than 34 weeks are typically monitored

as inpatients with close observation, the goal being to
postpone delivery until 34 weeks.28
Magnesium Sulfate
The use of magnesium sulfate is considered a best practice for
the control of seizures in preeclampsia and eclampsia.26,29
The MAGPIE Trial (Magnesium Sulfate for the Prevention
of Eclampsia), a large, worldwide, placebo-controlled study,
looked at this drug’s effectiveness (see Fig. 29.10, later)30
The nearly 10,000 women in 33 countries who were
recruited had exhibited at least two blood pressure readings
of greater than 140/90 and had at least 1+ proteinuria. Of
these, 4999 received an intravenous (IV) loading dose of 4 g
and then maintenance dosages of 1 g/h intravenously or 5 g
intramuscularly every 5 hours, and 4993 women received a
placebo. There were fewer eclamptic seizures among women
given magnesium sulfate than among those receiving pla-
cebo (40 [0.8%] vs 96 [1.9%]). Maternal mortality was
lower among women given magnesium sulfate than among
those given placebo (11 [0.2%] vs 20 [0.4%]). Of interest,
one-third of the patients in this trial received nifedipine while
receiving magnesium, and the rates of hypotension among
these women were not higher than the rates seen in the
placebo group.
Labetalol, Hydralazine, and Nifedipine
Hydralazine given intravenously had been recommended for
over 30 years to control severe hypertension in pregnancy.
However, in 11 trials involving 570 participants, hydralazine
was compared with other antihypertensives for controlling
severe hypertension in pregnancy.31 The authors found that
parenteral hydralazine is not the drug of first choice for acute
severe hypertension later in pregnancy because it is associ-
ated with more maternal and perinatal adverse effects than
other drugs, particularly IV labetalol or oral or sublingual
nifedipine. The trials compared IV hydralazine with other
antihypertensives such as IV labetalol or oral sublingual
nifedipine. Labetalol and nifedipine compared with hydral-
azine caused less hypotension, fewer cesarean sections, less
placental abruption, and fewer low Apgar scores. Hydralazine
was 3.2 times more likely to be associated with maternal
hypotension than labetalol and nifedipine. Neonatal brady-
cardia was more common in the labetalol group, but only
one neonate required treatment. A clinical advantage of
nifedipine is that it is given by mouth; nursing staff may give
it on an as-needed basis (every 30 minutes).32 Caution is
advised because an interaction between calcium channel
blockers and magnesium sulfate has been reported to produce
profound maternal muscle weakness, as well as maternal
hypotension and fetal distress.33
Other Antihypertensives
Clonidine and prazosin have been used with good results for
preeclampsia, but no large clinical trials are available.34
Sodium nitroprusside (SNP) infusions have been recom-
mended for acute hypertensive crisis and to attenuate or
treat hypertension associated with the induction and emer-
gence of general anesthesia. It is rapid acting and somewhat
unpredictable, usually requiring an intra-arterial catheter
to avoid overshoot. Although effective, SNP is associated
with cyanide toxicity in large doses.
29 • Perioperative Protection of the Pregnant Woman 463
Newer drugs may have a significant role to play in man-
aging hypertensive emergencies in the pregnant patient.
Nicardipine has been used as a replacement for SNP; it is
a short-acting dihydropyridine calcium channel blocker
given by IV infusion. Although there were originally con-
cerns that adding nicardipine to magnesium may precipi-
tate significant refractory hypotension, recent studies
have not shown this to be the case.35,36 Clevidipine is a
newer intravenous calcium channel blocker with similar
action to nicardipine; however, specific studies in pregnancy
are lacking.
Central Monitoring
Because the overwhelming majority of women with gesta-
tional hypertension have adequate left ventricular func-
tion and normal pulmonary artery pressures, clinicians
must weigh the risk of central monitoring (central ven-
ous catheterization or pulmonary artery catheterization)
against the usefulness of any additional information
beyond that of standard monitoring and hemodynamic
data. There are no large randomized trials showing
improved maternal outcome with or without pulmonary
artery monitoring in severe preeclampsia; in fact, with
the increasing data calling into question the utility of pul-
monary artery catheterization in the critical care popula-
tion, as well as the growing adoption and acceptance of
point-of-care ultrasound practices including bedside trans-
thoracic echocardiography, the use of pulmonary arterial
catheterization has decreased significantly.37 The Ameri-
can Society of Anesthesiologists (ASA) taskforce on obstet-
ric anesthesia states: “It is not necessary to routinely use
central invasive hemodynamic monitoring for severe pre-
eclamptic parturients.”38–51
Anesthetic Considerations in the Management
of Hypertensive Disorders of Pregnancy
Old obstetric concerns that epidural and spinal analgesia in
preeclampsia could lead to sudden maternal hypotension
with maternal and fetal deterioration38 have not been
borne out. Although no large randomized trial or meta-
analysis addresses the effect of an anesthetic on maternal
outcome in preeclampsia, several small trials, some pro-
spective and randomized, are available for review. Thirteen
trials involving 544 women with preeclampsia who
received either regional or general anesthesia have been
published.39–51 Three trials involved laboring preeclamptic
patients. Ten trials involved preeclamptic patients who
received a cesarean section, five of which compared
regional anesthesia with general anesthesia. One trial
compared spinal with epidural block in patients with
severe preeclampsia. Two trials looked solely at spinal
anesthesia and general anesthesia techniques. Overall,
the incidence of maternal hypotension in these series
was not considered to have an adverse clinical effect on
either maternal or fetal outcome. In trials where general
anesthesia was used, four trials40,41,43,45 found peri-
induction hypertension difficult to control, whereas
two46,50 found the incidence and severity of hypertension
to be clinically acceptable. One series found the incidence
of hypotension to be less in preeclamptic patients receiving
spinal anesthesia than among healthy women.51
464 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Thrombocytopenia and Coagulopathy
Historically, a platelet count of less than 100,000/μL was
considered an absolute contraindication to neuraxial anes-
thesia; this stance is no longer supported by the available
science. The ASA Practice Guidelines now recommend that
even the decision to order an intrapartum platelet count
should be “individualized and based on a patient’s history…
physical examination, and clinical signs.”38 No “safe” plate-
let count for neuraxial anesthesia has been identified by any
professional organization; however, there is growing experi-
ence with thrombocytopenic patients with platelet counts
down to 70,000/μL that imply safety. Experience below
70,000/μL is limited by a lack of data.52 The decision
whether to place neuraxial anesthesia in the presence of
thrombocytopenia should take into account not only the
absolute platelet count, but the rate and direction of change
and an assessment of platelet function.
Fluid Management and Pulmonary Edema
IV fluid management is part of standard anesthetic care. In
patients with preeclampsia, this should be done with certain
precautions. Decreased colloid oncotic pressure, increased
hydrostatic pressure, and damaged capillary endothelium pre-
dispose to development of pulmonary edema. The incidence of
pulmonary edema in pregnancy is 80–500 per 100,000 preg-
nancies. It is responsible for about 25% of pregnancy-related
transfers to the intensive care unit. The causes of
pregnancy-related pulmonary edema can be divided into toco-
lytic (36%), fluid overload (31%), gestational hypertension
(26%), infection (4%), and other (3%).53 Approximately 3%
of preeclamptic patients develop pulmonary edema, with
30% occurring before the birth and 70% occurring in the first
3 postpartum days. Maternal mortality may be as high as 10%
and perinatal mortality as high as 50%. Those with fluid over-
load identified as the probable etiology had a significantly
greater mean positive fluid balance (6022  3340 mL).
The parturient is predisposed to pulmonary edema in that
blood volume, hydrostatic pressure, and cardiac output
increase, whereas colloid oncotic pressure decreases. In pre-
eclampsia, pulmonary blood pressure and blood flow
increase even further, colloid oncotic pressure decreases
more, and capillary endothelium sustains damage. If lym-
phatic flow is impaired (e.g., by pulmonary tissue swelling
and inflammation), the chances for symptomatic pulmo-
nary edema increase still further. In a few cases, when pre-
eclampsia has not been treated, cardiac failure exacerbates
these conditions even further.
In patients with diastolic blood pressure greater than
100 mmHg, the recommendation is to perform the block
accompanied by judicious use of vasopressors and intrave-
nous fluid, as needed. It is usually possible to care for most
of these patients without a central venous or pulmonary
monitor. The use of supplemental intravenous 25% albu-
min, recommended in the past, is not widely used now.
Decreasing vital capacity and a decrease in oxygen satura-
tion by pulse oximetry may be indicative of developing
pulmonary edema.
Cardiac Disease in Pregnancy
The differential diagnosis for sudden hemodynamic deterio-
ration in a pregnant woman includes thromboembolic dis-
ease, hemorrhage, sepsis, preeclampsia, and cardiac disease.
Maternal cardiac disease causes approximately 16% of all
maternal deaths.54 The most common single cause of
maternal mortality is cardiac disease. Cardiomyopathy,
myocardial infarction, and aortic dissection are the most
commonly reported conditions, with chronic and acquired
diseases such as pulmonary hypertension, and valvular
and congenital diseases being less common.55
Preexisting cardiac disease carries significant risk as preg-
nancy progresses. The Cardiac Disease in Pregnancy (CAR-
PREG) Studies ventured to quantify the risk of preexisting
cardiac diseases by identifying predictors of adverse events
in women with heart disease (Fig. 29.6).56 A score, the
CARPREG II score, was then derived from these findings
Fig. 29.6 Predictors of adverse events in pregnant
women with heart disease. (Adapted from Silversides
CK, Grewal J, Mason J, et al. Pregnancy outcomes in
women with heart disease: the CARPREG II study. J Am
Coll Cardiol. 2018;71(21):2419–2430.)

Fig. 29.7 The Cardiac Disease in
Pregnancy (CARPREG II) score and
interpretation. (From Silversides CK,
Grewal J, Mason J, et al. Pregnancy
outcomes in women with heart dis-
ease: the CARPREG II study. J Am Coll
Cardiol. 2018;71(21):2419–2430.)
by assigning a point score to 10 predictors and assessing risk
of new cardiac events, including maternal cardiac death,
cardiac arrest, sustained arrhythmia requiring treatment,
left-sided heart failure, stroke or transient ischemic attack,
cardiac thromboembolism, myocardial infarction, and vas-
cular dissection. The CARPREG II scoring system and car-
diac event risk with each point total is shown in Fig. 29.7.
CARDIOMYOPATHY
Peripartum cardiomyopathy occurs in 1 in 1500 to 1 in
4000 deliveries. There is no clear medical cause and onset
can be 1 month prior to up to 5 months after delivery.57
Multiparity, older age, African heritage, and birth of twins
appear to result in a higher incidence of cardiomyopathy.58
Authorities still do not agree on an etiology, although viral
and immune responses have been implicated.59
With peripartum cardiomyopathy there is usually no his-
tory of heart disease, and the onset of signs and symptoms is
nonspecific and easily confused with normal changes of
pregnancy, such as breathlessness, or with a viral chest
infection. Easy fatigue, dyspnea, and ankle edema can be
normal or abnormal. Therefore, clinicians should not ignore
a patient who has dyspnea at rest or orthopnea, paroxysmal
nocturnal dyspnea, chest pain, nocturnal cough, pulmo-
nary rales, jugular venous distention, or regurgitant mur-
mur. The electrocardiogram is often nondiagnostic,
although findings may be consistent with cardiomegaly
and include arrhythmias and ST changes. An echocardio-
gram remains the strongest diagnostic tool (Box 29.1).60
Box 29.1 Diagnostic criteria for peripartum
cardiomyopathy.
All four of the following:
1. Heart failure within the last month of pregnancy or the first
5 months postpartum;
2. Absence of prior heart disease;
3. No determinable cause;
4. Strict echocardiographic indication of left ventricular
dysfunction:
a. Ejection fraction <45% and/or fractional shortening <30%
and
b. End-diastolic dimension >2.7 cm/m2
Adapted from Hibbard JU, Lindheimer M, Lang RM. A modified definition
for peripartum cardiomyopathy and prognosis based on echocardi-
ography. Obstet Gynecol 1999;94:311–316.
29 • Perioperative Protection of the Pregnant Woman 465
Patients with peripartum cardiomyopathy are best
followed by a cardiologist familiar with the changes of
pregnancy. Therapy includes diuretics, salt restriction,
and volume overload avoidance. Vasodilation is aided
with hydralazine, nitrates, or amlodipine. Angiotensin-
converting enzyme (ACE) inhibitors are avoided because
of reported teratogenic effects, fetal renal failure, and
death.61 Amiodarone and verapamil are rarely used
because of their potentially deleterious fetal effects.62 Most
calcium channel blockers are associated with negative ino-
tropy,63 but carvedilol may improve overall survival rate in
parturient women with dilated cardiomyopathy, and per-
haps in patients with peripartum cardiomyopathy.64 The
use of intravenous immune globulin has been used success-
fully in some with peripartum cardiomyopathy.65 Patients
with low ejection fractions (35%) may be given thrombo-
prophylaxis with unfractionated or low-molecular-weight
heparin.
Delivery of the fetus, if viable, improves cardiac function
in most women with cardiomyopathy. Labor can be induced
safely in most cases if cardiac stabilization can be achieved.
Early consultation with an anesthesiologist is ideal. Less
blood loss, lower infection rate, decreased surgical stress
and occurrence of respiratory complications, and improved
hemodynamic stability are advantages of vaginal delivery.
The addition of a regional block decreases the variation in
blood pressure, decreases the preload and afterload on the
heart, and provides ideal conditions should instrumental
delivery be required.
Cesarean delivery may be necessary if the mother is
unstable or fetal indications are present. For cesarean sec-
tion, either regional block or general anesthesia is an accept-
able approach, depending on the patient’s coagulation
status and ability to cooperate. In patients with symptom-
atic cardiomyopathy, direct arterial and central venous
monitoring are advised. Some very ill patients who are gasp-
ing for breath may require induction in the sitting position,
converting to supine once consciousness is lost. Etomidate
for induction is advised if myocardial function is impaired.
Some of these patients will require respiratory and inotropic
support postoperatively and intensive medical care will be
necessary. No large-scale studies on anesthesia outcomes
exist, but descriptions of anesthesia with satisfactory out-
come are available.66,67 In patients with severe myocardial
impairment, a left ventricular assist device (LVAD) may be
necessary, and consideration should be given to transplan-
tation if ventricular function does not improve.68 Those who
improve usually do so within 6 months after pregnancy.68
Mortality from peripartum cardiomyopathy ranges from
466 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
18% to 56%,59 and persistent cardiomegaly is associated
with an 85% mortality.57
MYOCARDIAL INFARCTION
Myocardial infarction is rare in this population; it occurs in
about 1 in 10,000 deliveries.69 Risk factors include
increased age, diabetes, smoking, hypertension, cardiomy-
opathy, and obesity. However, 78% have no apparent risk
factors.70 Myocardial infarction is more common during
the third trimester of pregnancy and mortality is high if it
occurs within 2 weeks of delivery. Symptoms are classic,
including anginal-type chest pain, diagnostic electrocardio-
graphic changes, and increased cardiac-specific plasma
enzymes. Labor may mask these symptoms and muscle cre-
atinine kinase is normally elevated. Chest pain can also be
caused by hemorrhage/shock, sickle cell crisis, severe pre-
eclampsia, pulmonary embolism, and aortic dissection.
Immediate treatment may include oxygen therapy, sub-
lingual nitroglycerin, aspirin, systemic heparinization, and
coronary angiography with possible stenting.71 Tissue plas-
minogen activator (TPA) and assessment for emergency
coronary artery bypass graft (CABG) have also been sug-
gested.71,72 TPA and anticoagulants predispose to increased
bleeding in the immediate postpartum period and are not
advised during that period. These drugs also increase the
risk of bleeding associated with regional block.
If possible, the use of ergot alkaloids, such as methylergo-
novine, should be avoided in these patients. Reports of
peripartum myocardial infarction following ergot adminis-
tration are frequent.73–75 If ischemia occurs, it is usually
rapid and treatment with sublingual or intravenous nitro-
glycerin is recommended.75
AORTIC DISSECTION
Although rare, aortic dissection is associated with severe
hypertension and inherited disorders such as Marfan syn-
drome. If symptoms are present, intrascapular or chest pain
are most common. Increasing severity is associated with
signs of cerebral, cardiac, renal, or limb ischemia and heart
failure caused by aortic regurgitation or hemopericardium.
Vaginal delivery with regional block and postpartum repair
of descending aortic dissections is advocated if the fetus is
viable. For ascending lesions, repair with the fetus in situ
has been attempted for patients with fetuses before
28 weeks’ gestation. If the fetus is viable and because of
the life-threatening nature of nonoperative treatment
(80% mortality76), surgical repair and concomitant cesar-
ean delivery should be anticipated.
Anesthetic goals include a reduction in pressure-flow gra-
dient across the dissection. Epidural analgesia is suggested
to reduce the wall tension, mean arterial blood pressure,
and vessel shear stresses (cardiac output) seen in labor.77
For cesarean delivery, general anesthesia may be necessary
if anticoagulation increases the risk of regional block.78 The
risk of hypertension during induction of general anesthesia
is well known and arterial and central venous lines are
therefore recommended to provide beat-to-beat control of
blood pressure and volume control as needed.
CHRONIC CARDIAC DISEASE
As previously discussed, patients with significant prepreg-
nancy cardiac disease are at much higher risk of peripartum
cardiac events.56 Women with a history of cardiac disease in
previous pregnancies or congenital heart disease with prior
cardiac surgery can be identified, assessed, and counseled
before becoming pregnant. In some cases, such as when
severe pulmonary hypertension or Eisenmenger physiology
is involved, pregnancy termination may be advised.79
Ready assessment and communication between cardiolo-
gist, obstetrician, and anesthesiologist should be the norm.
The New York Heart Association functional class may not
predict how the patient will adapt to pregnancy and regular
echocardiographic assessment of the mother and fetal
assessment are desirable.
CONGENITAL HEART DISEASE
Because of improvements in diagnosis, treatment, and sur-
gical therapy, women with repaired congenital heart dis-
ease (CHD) are reaching childbearing age in increasing
numbers, and there is widespread encouragement in the lit-
erature for them to consider pregnancy.55 Pregnancy in
women with CHD not complicated by Eisenmenger syn-
drome is associated with low mortality.80 However, poten-
tial risk factors for maternal morbidity include poor
maternal functional class, poorly controlled arrhythmia,
heart failure, cyanosis, significant left heart obstruction,
and a history of cerebral ischemia. Cyanosis is a risk factor
for fetal and neonatal complications. A second modified risk
score has been developed, considering the unique chal-
lenges of both corrected and uncorrected congenital heart
disease; risk of major pregnancy complications in these
patients range from 2.9% to 70%, and the scoring system
and breakdown are available in Fig. 29.8.81 Medical or sur-
gical termination of pregnancy in intermediate- or high-risk
patients requires careful monitoring and should be done in a
regional adult congenital heart disease center.82
Pulmonary Hypertension
Primary pulmonary hypertension, which is rare, affects
young women by reducing nitric oxide and prostacyclin
synthesis and increasing endothelin and thromboxane
production in the pulmonary vessels causing pulmonary
arterial pressures in excess of 25 mmHg. Histologically,
medial thickening and intimal fibrosis are seen. There is
no clear etiology. The chief problem is the cardiopulmo-
nary system’s inability to adapt to the increased intravas-
cular volume and hyperdynamic state of pregnancy. The
greatest risk is in the peripartum period and the majority
of maternal deaths occur in the first week after delivery,
usually from right ventricular failure that manifests as
increasing shortness of breath, cough, easy fatigue, occa-
sional hemoptysis, cyanosis, and fainting. Echocardiogra-
phy and right heart catheterization are useful in
differentiating the symptoms from pulmonary embolism.
Treatment includes high-flow oxygen and pulmonary

Fig. 29.8 The modified risk score for
cardiac complications in women with
congenital heart disease. (Adapted
from Drenthen W, Boersma E, Balci A,
et al. Predictors of pregnancy compli-
cations in women with congenital
heart disease. Eur Heart J 2010;31(17):
2124–2132.)
vasodilators such as nifedipine, prostacyclin, and nitric
oxide. Anticoagulation may be necessary.
If pregnancy is carried toward viability and the maternal
condition does not improve, delivery is achieved as soon as
possible (32 to 34 weeks). During this time, the obstetri-
cian and the anesthesiologist work to avoid conditions that
increase pulmonary vascular resistance (pain, hypother-
mia, hypoxia, hypercarbia, acidosis, high intrathoracic
pressure, excessive use of catecholaminergic drugs). It is
also important to maintain right ventricular preload, left
ventricular afterload, and right ventricular contractility.
Although there was concern that cesarean delivery was
associated with increased maternal mortality,83 it is now
clear that this was a function of patient selection, because
cesarean delivery has been shown not to worsen patient
outcomes.84 As such, cesarean delivery is the recom-
mended delivery management, because it avoids the
catecholamine surges associated with labor and the
autotransfusion associated with vaginal contractions.
Elective cesarean delivery also allows for careful, multidis-
ciplinary planning and preparation of anesthesia,
optimization of hemodynamics, and development of
contingency plans.85
Notwithstanding this careful planning, anesthetic man-
agement remains challenging. There are no large-scale
series, but growing consensus among experts is to recom-
mend regional anesthesia in patients where the procedure
allows avoidance of general anesthesia.85 The mother
must be monitored closely, and a preblock arterial line is
strongly recommended. Decisions for further invasive
monitoring should be made on a case-by-case basis.
Decreased systemic vascular resistance may be treated
with volume replacement and appropriate doses of phenyl-
ephrine or ephedrine. While phenylephrine has been impli-
cated in worsening pulmonary vascular resistance (PVR),
in patients with chronic pressure overload PVR is usually
fixed, such that concern for additional vasoconstriction is
likely misplaced; there are no human data showing the
superiority of one vasopressor over another.86 Oxytocin
for induction of labor and postpartum hemostasis is recom-
mended, with the caveat that it can cause peripheral vaso-
dilation and may slightly elevate pulmonary vascular tone.
Prostaglandins such as carboprost are potent pulmonary
vasoconstrictors and should be avoided in patients with
pulmonary hypertension.
29 • Perioperative Protection of the Pregnant Woman 467
Reduction of Perioperative
Anesthesia Risk
MATERNAL HYPOTENSION DURING
REGIONAL BLOCK
During the 1940s, spinal shock (after spinal anesthesia) was
the most common anesthetic cause of maternal mortality in
the United States.87 The discovery, physiologic description,
and avoidance of the supine hypotensive syndrome, the dis-
cussion and use of intravenous hydration before and during
block placement, and the judicious use of vasopressors such
as phenylephrine, ephedrine, and norepinephrine have been
thought to attenuate, if not eliminate, hypotension as a
maternal risk during regional, especially spinal, anesthesia.
Although the utility of intravenous preload and coload and
left uterine displacement has been called into question in
recent years, their consideration has clearly led to improve-
ments in regional anesthesia-induced hypotension.
Vasopressor Selection: Ephedrine Versus
Phenylephrine Versus Norepinephrine
Since the 1960s, ephedrine had been recommended as the
vasopressor of choice during pregnancy, primarily because
it maintained maternal blood pressure with the least
decrease in uterine blood flow,88 and prophylactic ephed-
rine has been recommended to avoid spinal hypotension
during induction for cesarean section.89 A multitude of
studies and reviews have supported these early studies that
prophylactic ephedrine prevents or decreases the intensity
and incidence of spinal hypotension during cesarean section
but does not significantly change neonatal parameters.90–99
Phenylephrine was considered only a last-resort drug to
treat maternal spinal hypotension because of feared effects
on decreasing uteroplacental perfusion, based in large part
on early studies of metaraminol, a mechanistically similar
drug, in ewes.88 However, more recent systematic reviews
of phenylephrine versus ephedrine have not demonstrated
these effects.100 Not only were ephedrine and phenyleph-
rine found to be equally effective in prevention and treat-
ment of maternal hypotension (RR, 1.00; 95% CI, 0.96 to
1.06), women given phenylephrine had neonates with
higher umbilical arterial pH values than those given ephed-
rine (weighted mean difference, 0.03; 95% CI, 0.02 to
468 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
0.04), with a trend toward significance. This contradicts the
traditional belief that ephedrine is the best clinical choice for
treating maternal hypotension caused by spinal anesthesia
for cesarean section. Very quickly, practice began shifting;
now, it is common practice to utilize phenylephrine as a
first-line vasopressor for regional anesthesia-induced hypo-
tension. In addition, prophylactic phenylephrine infusions
for cesarean delivery under regional anesthesia have
become commonplace, because they have been shown to
decrease the incidence, frequency, and magnitude of hypo-
tension compared with repeat boluses.101
With growing use of prophylactic phenylephrine, a signif-
icant reduction in cardiac output has been noted.102 This
reduction in cardiac output has been primarily attributed
to a reduction in heart rate because in several studies stroke
volume remained unchanged.102,103 Although this reduc-
tion in cardiac output is of unclear clinical significance,
alternatives have been sought to mitigate or eliminate the
reduction in cardiac output that occurs with phenylephrine.
Norepinephrine, like phenylephrine, has strong α1 agonism,
but unlike phenylephrine, it also has mild β1 agonism,
which reduces the incidence of bradycardia compared with
phenylephrine. Comparisons of phenylephrine and norepi-
nephrine infusions for hypotension prophylaxis in cesarean
delivery have shown that norepinephrine has similar effi-
cacy for maintaining blood pressure compared with phenyl-
ephrine, with better maintenance of maternal cardiac
output and heart rate and similar neonatal outcomes.104
These data suggest that phenylephrine, ephedrine, and nor-
epinephrine are all reasonable choices for mitigation of
regional-induced hypotension depending on the clinical sce-
nario. Although phenylephrine remains the drug of choice
among many obstetric anesthesiologists, there is a growing
contingent that routinely uses norepinephrine.
Fluid Management: Preload Versus Coload
In 1950, the first data were published from humans demon-
strating profound hypotension in pregnant women who
were given total or near total sympathectomies while kept
supine without fluid loading or vasopressor therapy.105
Although some contemporary studies showed that 1 to
2 L of crystalloid before spinal block for cesarean section
decreased the incidence of hypotension and did not result
in maternal fluid overload,106 intravenous preloading
became commonplace prior to administration of spinal
anesthesia. When this “truism” was revisited in the
1990s, however, others suggested that pre-block IV fluid
loading was not as effective as once thought.107,108 This
led to significant disagreement over the value of prespinal
fluid-loading.
In 2002, a Cochrane analysis of 229 studies found 25 tri-
als (of 1477 women) that met inclusion criteria.109 They
found that 4 of 15 interventions reduced the incidence of
hypotension under spinal anesthesia for cesarean section:
(1) crystalloid versus control, (2) preemptive colloid admin-
istration versus crystalloid, (3) ephedrine versus control,
and (4) lower limb compression versus control. Ephedrine
was associated with dose-related maternal hypertension
and tachycardia, as well as fetal acidosis of uncertain clini-
cal significance. This Cochrane analysis concluded that
these interventions reduced but did not prevent hypotension
during spinal anesthesia for cesarean section.
A second Cochrane analysis from 2004 looked at 22
studies of prehydration before regional block for labor
and found seven trials that included 473 participants
who met the criteria.110 It concluded that “IV preloading
prior to traditional high-dose local anesthetic blocks may
have some beneficial fetal and maternal effects in healthy
women. Low-dose epidural and combined spinal epidural
(CSE) analgesia techniques may reduce the need for
preloading.”
To what degree these beneficial effects are clinically sig-
nificant remains controversial. A 2010 review found that
the rate of hypotension remained high with both the pre-
loading (62.4%) and the coloading group (59.3%).111 These
authors recommend what has become the practice of a
growing proportion of anesthesiologists: “It is unnecessary
to delay surgery in order to deliver a preload of fluid. Regard-
less of the fluid loading strategy, the incidence of maternal
hypotension is high.” A multimodal strategy for managing
hypotension should be undertaken: prophylactic vasopres-
sor to counteract the anticipated reduction in systemic vas-
cular resistance in addition to fluid administration with a
goal of euvolemia.
Obesity
Obesity is widespread to the point of being called an epi-
demic by the American College of Obstetrics and Gynecol-
ogy.112 The World Health Organization (WHO) and the
National Institutes of Health (NIH) define normal weight
as a body mass index (BMI) of 18–24.9, and a BMI of
25–29.9 is considered overweight. Obesity is a BMI of 30
or more, with class II obesity as BMI of 35–39.9, and class
III (extreme obesity) as greater than 40.113,114 Obesity is
very common and it is becoming more so; the most recent
National Center for Health Statistics report states that
39.6% of all Americans, and 41.1% of American women,
are obese. This has been steadily increasing over the past
two decades (Fig. 29.9).115 Obesity in pregnancy notably
increases the risk of diabetes, hypertensive disorders, throm-
boembolic complications, and cephalopelvic disproportion,
increases cesarean delivery rate, and leads to an increase
in anesthetic morbidity and mortality.116 In addition, class
I and class II obesity is associated with an increased risk of
gestational hypertension, preeclampsia, and gestational dia-
betes mellitus, compared with a BMI of less than 30.117–121
Operative and postoperative problems associated with obe-
sity during pregnancy include excessive blood loss, opera-
tive time greater than 2 hours, wound infection, and
endometritis.122–124
Anesthetic risk is increased in many categories for the
obese parturient. Technical difficulty with regional block
and the induction of general anesthesia resulting in failed
airway management, aspiration, and postoperative hypo-
ventilation are well documented.124–126 In some US studies,
anesthesia mortality has been associated with maternal
obesity in 80% of cases reported.127 It has been recom-
mended that all women with a body mass of more than
35 kg/m2 should receive an anesthetic assessment on
admission, including an airway examination and discussion
with the patient and surgeon regarding the best anesthetic
approach. Especially important are IV access, the

Fig. 29.9 Increasing prevalence of obesity in adults in the United States, 1999–2000 through 2015–2016. (From the National Center for Health Statistics,
October 2017.)
consideration of an early working epidural, and a discussion
of how to approach emergency surgery.128
The increase in bariatric surgery has raised questions
about its effect on future pregnancies. Bariatric surgery is
associated with iron, vitamin B12, folate, and calcium defi-
ciencies. These patients are advised to wait 12 to 18 months
after surgery before conception to avoid the rapid weight-loss
period. These patients should be evaluated for nutritional
deficiencies and supplementation before becoming pregnant.
Airway Management
The closed claims review of obstetric complications found
claims for anesthetic causes of maternal death accounting
for 30% of cases in the 1970s, 15% in the 1980s, and
12% in the 1990s. They attributed this to the marked
decrease in use of general anesthesia for cesarean delivery.
In addition, aspiration pneumonitis decreased from 9% of
claims in 1970 to 1% of claims in the 1990s. Although
direct evidence is not available, it is suggested that a
decrease in the use of general anesthesia and an increase
in the use of gastric emptying drugs, pH neutralizing efforts,
and appropriate induction techniques may well have con-
tributed to this decrease.129,130
The risk of maternal mortality with general anesthesia is
nearly seven times higher than with regional block. A sig-
nificant proportion of this risk is probably associated
with difficult intubation. The rate of failed intubation is
1-in-390 for nonobstetric general anesthesia in the preg-
nant patient and 1 in 443 for cesarean delivery, and these
rates have not changed significantly in three decades.131
This is compared with a failed intubation rate of 6 in
100,000 in the general population.132 These differences
in intubation failure rate are in no small part a result of
29 • Perioperative Protection of the Pregnant Woman 469
the physiologic changes of pregnancy, including a signifi-
cant decrease in functional residual capacity, significant
increases in oxygen consumption and airway edema/friabil-
ity, and an increase in aspiration risk. In addition, general
anesthesia is often chosen in emergencies when there is less
time for patient preparation, when a regional block fails or
because of relative contraindications to regional anesthesia
(HELLP, coagulopathy). In planning for the difficult airway
in the pregnant patient, the American Society of Anesthesi-
ologists Difficult Airway Algorithm133 and other algorithms
more specific to the pregnant patient are highly important
to review (Fig. 29.10).134 In addition, many authorities rec-
ommend drills or practice of lost airway events, which
would include advanced planning.
ADVANCED PLANNING FOR THE DIFFICULT AIRWAY
Advanced planning for the obstetric difficult airway includes
the following steps:
1. Prior to needing it, put together a “difficult airway” cart
for labor and delivery. This should, at a minimum, include
the following and should be checked on a routine basis:
a. Tracheal tubes in a range of sizes from 5.0 to 7.0.
b. Videolaryngoscope.
c. Eschmann stylet or other intubating stylet or catheter
d. Supraglottic airway devices, such as laryngeal mask
airways, including at least one that may act as a con-
duit for endotracheal intubation.
e. Equipment necessary for both awake and asleep
fiberoptic intubation, including a fiberoptic scope,
camera and monitor, and appropriate equipment
and pharmacologic agents.
f. Surgical cricothyroidotomy or needle cricothyroidot-
omy kit with the ability to jet ventilate.
470 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction

Algorithm 1 Pre-induction planning and preparation

Safe obstetric Team discussion
general anaesthesia

Rapid sequence induction

Consider facemask ventilation (P 20 cmH

Laryngoscopy Verify successful tracheal intubation

Success
(maximum 2 intubation attempts; 3 intubation and proceed
attempt only by experienced colleague) Plan extubation

Fail

Algorithm 2 Declare failed intubation

Obstetric failed Call for help
tracheal intubation Maintain oxygenation
Supraglottic airway device (maximum 2
attempts) or facemask
Success Is it essential / safe
Fail to proceed with surgery
immediately?*
Algorithm 3 Declare CICO
Can’t intubate, Give 100% oxygen No Yes
can’t oxygenate
Exclude laryngospasm – ensure
neuromuscular blockade
Front-of-neck access Wake§ Proceed with surgery§

Fig. 29.10 Obstetric Anaesthetists’ Association and Difficult Airway Society guidelines for the management of difficult and failed tracheal intubation in
obstetrics. (Reproduced from 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;70:1286–1306, with permission from Obstetric Anaesthetists’ Association
/ Difficult Airway Society.)

2. Review difficult airway algorithms. Consider drills as
necessary to ensure understanding of all who may be
involved in the emergency airway scenario.
3. Recommend prophylactic regional anesthesia for
patients at high risk of difficult airway in an effort to
avoid general anesthesia and endotracheal intubation.
4. If endotracheal intubation is anticipated, administer
aspiration prophylaxis as soon as possible; have extra,
experienced hands available at induction of general
anesthesia.
5. If after induction of general anesthesia you cannot
ventilate, wake the patient if possible.
6. If surgery must proceed, place a supraglottic airway,
elevate the head of the bed, and consider maintaining
cricoid pressure throughout the procedure. Metoclopra-
mide (to increase gastroesophageal sphincter tone) and
glycopyrrolate (as a drying agent) may also be consid-
ered. After the acute emergency (such as after delivery
of the fetus), further intubation attempts may be consid-
ered; otherwise consider spontaneous ventilation.
Unrecognized esophageal intubations continue to be a con-
cern in obstetric patients. Efforts to rule out esophageal intu-
bation have been intensified and include the following:128
1. Maintain oxygenation as a priority.
2. Always suspect the tube may not be in the trachea.
3. Visualize the tube directly between the cords.
4. Feel the lung recoil in the ventilation bag.
5. Look at the chest and abdominal movement.
6. Listen in the axillary line and epigastrium.
7. Use capnography.
8. Monitor oxygen saturation.
9. Allow succinylcholine to wear off and observe sponta-
neous respiration.
Peripartum and Postpartum
Hemorrhage
Hemorrhage is still the leading cause of maternal mortality.
Its early signs may be obscured by normal physiologic
changes or by infection. The substantial uterine blood flow
at term allows serious hemorrhage to progress to shock more
rapidly. Risk factors for intrapartum and postpartum hemor-
rhage include uterine atony (prolonged labor or oxytocin
augmentation, polyhydramnios, infection, grand multiparity,
multiple gestation, fetal macrosomia, and, rarely, inhaled
potent anesthetics), retained placenta, lacerations, fibroids,
placenta previa, abruption, placenta accreta, and coagulopa-
thy. In recent years, abnormal placentation, including pla-
centa accreta, increta, and percreta, has increased in
incidence to as high as 1 in 540 pregnancies. This increase
is associated with an increasing number of cesarean deliver-
ies. The most important risk factor for placenta accreta is pla-
centa previa, and there is a correlation with the number of
previous cesarean sections (Fig. 29.11).135 Other risk factors
include maternal age over 35 years, placenta overlying pre-
vious uterine scar, previous multiple pregnancies, uterine
scar, and previous dilatation and curettage.
 29 • Perioperative Protection of the Pregnant Woman 471

Fig. 29.11 Placenta previa with prior

uterine incisions: effects on incidence
of placenta accreta. (From Clark SL,
Koonings PP, Phelan JP. Placenta
previa/accreta and prior cesarean
section. Obstet Gynecol 1985;66:89–92.)

Fig. 29.12 Contents of the California Maternal

Quality Care Collaborative hemorrhage toolkit.
(From Lyndon A, Lagrew D, Shields L, et al. Improving
healthcare response to obstetric hemorrhage. Califor-
nia Maternal Quality Care Collaborative Toolkit to
Transform Maternity Care. Developed under contract
#11-10006 with the California Department of Public
Health; Maternal, Child and Adolescent Health Division;
published by the California Maternal Quality Care
Collaborative; 2015.)

Ensuring a standardized response has significantly References

reduced morbidity and mortality resulting from obstetric
hemorrhage; hospitals utilizing the California Maternal
Quality Care Collaborative Obstetric Hemorrhage toolkit
have seen a 20.8% reduction in severe maternal morbidity
in the 6 months after implementing the toolkit as opposed to
only 1.2% in those who did not.136,137 The contents of the
toolkit are outlined in Fig. 29.12.
Other techniques for women at risk of intraoperative and
postpartum hemorrhage include erythropoietin-induced
erythrocyte production, autologous donation, and preoper-
ative isovolemic hemodilution and intraoperative cell saver
use.138 In addition, the use of antifibrinolytics such as tra-
nexamic acid has been shown to reduce significantly the
risk of death and hysterectomy caused by hemorrhage.139
Postpartum hemorrhage has been successfully treated
with Sengstaken–Blakemore tube tamponade and B-Lynch
suturing.
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bidity from hemorrhage using a state perinatal quality collaborative.
Am J Obst Gynecol. 2017;216(3):298.e1–298.e11.
138. Esler MD, Douglas MJ. Planning for hemorrhage: Steps an anesthesi-
ologist can take to limit and treat hemorrhage in the obstetric patient.
Anesthesiol Clin North Am. 2003;21:127–144.
139. WOMAN Trial Collaborators. Effects of early tranexamic acid
administration on mortality, hysterectomy, and other morbidities in
women with post-partum haemorrhage (WOMAN): An international,
randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:
2105–2116.
 30 Preservation of Fetal Viability
During Noncardiac Surgery
VICTORIA BRADFORD and ROBERT GAISER
Caring for the pregnant patient who requires a surgical pro-
cedure is challenging. The effects of anesthetics on the
developing fetus continues to evolve and issues concerning
the pregnant patient have changed. The most important
point to remember when performing anesthesia on the preg-
nant patient requiring surgery is that this procedure will
involve caring for two patients with the mother being the
primary patient and the fetus being the secondary. Gener-
ally, optimal care of the mother provides good care for the
fetus. This premise supersedes any other concern but does
not negate consideration of anesthetic effects on the fetus
and the physiologic changes of pregnancy.
Should the Pregnant Patient
Undergoing Surgery During
Pregnancy Be Tilted?
If a pregnant patient undergoes surgery in the supine posi-
tion, there is the concern of the supine hypotensive syn-
drome. In this position, the gravid uterus compresses the
aorta, decreasing blood flow to the uterus, and the vena
cava, reducing venous return. The syndrome occurs when
the gestation is greater than 20 weeks. Angiographic stud-
ies were performed in term pregnant women demonstrating
the compression.1 Femoral arterial and venous pressures
were measured, with an increase in femoral venous pres-
sure and a decrease in femoral arterial pressure when the
pregnant patient was placed in the supine position. In
100 term pregnant patients, 41% of the patients had a
decrease in blood pressure of 10% or more when assuming
the supine position.2 An increase in heart rate accompanied
this decrease. Adjusting the position to left lateral position
returned the hemodynamics to baseline. A full lateral posi-
tion was not necessary; rather, hemodynamics returned to
baseline with a tilt as little as 20–30 degrees. Many argue for
the greatest tilt possible.3 The subsequent research in lateral
tilt led to the practice of tilting the patient or using a wedge
for left uterine displacement during surgery in pregnant
patients. Several adverse effects from supine positioning
have been described such as fetal acidosis and decreased
delivery of oxygen to the fetus.
Twenty healthy women with a term gestation fetus had
their stroke volume, arterial pressure, and cardiac output
determined in various positions.4 In the standing position,
there is no aortocaval compression and the cardiac output
is the greatest. In the left lateral position of 45 degrees, car-
diac output was greatest with the left position compared
with the right lateral position. In 32 term pregnant women,
cardiac output, stroke volume, and heart rate were mea-
sured using bioimpedance cardiography.5 Cardiac output
and stroke volume were the greatest when women were
in left lateral tilt of 15 degrees, with cardiac output being
the lowest when women lay on their back (CO 7.0 L/min
versus 6.5 L/min). Using suprasternal Doppler, cardiac out-
put was measured in 157 nonlaboring term pregnant
patients who were in 0 degree, 7.5 degrees, 15 degrees,
and full lateral tilt.6 Cardiac output increased until 15
degrees left lateral with no statically significant increase
when going from 15 degrees to full lateral tilt. The degree
of aortocaval compression varies among pregnant patients,
with not all patients being equally affected.
The concept of aortocaval compression has been chal-
lenged.7 Using magnetic resonance imaging, the aorta
and vena cava in term pregnant women were examined.
The positions of the women were supine, 15-degree, 30-
degree, and 45-degree tilt. The table was not tilted, rather
a wedge foam was used. The vena cava was compressed
with the patient in the supine position. The compression
did not improve with a 15-degree tilt; and it did not improve
until a 30-degree tilt was achieved. The only means to pre-
vent compression of the vena cava is to have the patient
tilted to 30 degrees, a position in which it is not possible
for surgeons to operate. Furthermore, in the supine position,
the aorta was not compressed. The results of this study sug-
gest aortocaval compression is only caval compression in
the supine position. A subsequent study confirmed these
results. In women undergoing elective cesarean delivery,
there was no difference in umbilical cord pH as long as blood
pressure was maintained at baseline regardless of whether
the patient was placed supine or with a 15-degree tilt
(Table 30.1).8
Body weight has a negative correlation with the umbilical
cord pH of the neonate born to mothers during spinal anes-
thesia.9 In a retrospective study of 5742 women undergoing
elective cesarean delivery during spinal anesthesia, body
mass index (BMI) had a negative correlation with umbilical
cord pH. For every 10-unit increase in BMI, the umbilical
cord pH decreased by 0.01 and the base deficit increased
by 0.26 mmol/L. Those pregnant patients with a BMI of
40 kg/m2 or greater had a mean umbilical cord pH of
7.22.10 In this group, 7.7% of the morbidly obese patients
had an umbilical cord pH <7.10. Aortocaval compression
may be exaggerated in obese pregnant patients. Examining
anesthetic outcomes in 142 morbidly obese pregnant
patients receiving spinal anesthesia revealed a greater inci-
dence of profound hypotension in the morbidly obese preg-
nant patients. Also, guidelines for cardiopulmonary
resuscitation for the pregnant patient recommend chest
475
476 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Table 30.1 Effect of patient position on fetal/maternal
outcomes.
Position Maternal cardiac output Umbilical cord pH
Supine 8.0 L/min 7.28
15-degree tilt 9.0 L/min 7.28
Tilting the table to 15 degrees improves cardiac output but has no negative
effect on the neonate as long as pressure is maintained with phenylephrine.
(Data from Lee, AJ et al. Left lateral table tilt for elective cesarean delivery
under spinal anesthesia has no effect on neonatal acid–base status:
A randomized controlled trial. Anesthesiology 2017;127:241–249.)
compressions be performed at a rate of 100/min at a depth
of 2 inches and a compression:ventilation ratio of 30:2 with
left uterine displacement being maintained manually.11
Although left uterine displacement is recommended for
surgery during pregnancy, it is not mandatory. If the sur-
geon is unable to perform the procedure with uterine dis-
placement, it is acceptable to accomplish the surgery with
the patient in the supine position as long as pressure is
maintained.
Does Anesthesia During
Pregnancy Have an Effect on
the Fetus?
It is estimated that 1 in 500 pregnant patients will require
surgery not related to the pregnancy.12 The greatest con-
cern for the pregnant patient is the effect of the anesthetic
agents on the fetus, both in regard to teratogenicity and
to learning. All anesthetic agents have been implicated as
teratogens in animal studies. However, the animal model
does not replicate the clinical situation because exposure
is greater than would be used clinically. For a teratogenic
effect to occur, the mother must be exposed to a given level
of drug for a specific period at a specific point in the gesta-
tion. To assess the teratogenicity of general anesthesia, pop-
ulation studies must be used.
When considering teratogenesis, surgery during the first
trimester is the major focus because this time period is when
the organs of the fetus are being formed. Snider and Webster
were the first to study the effects of anesthesia and surgery
during pregnancy.13 These authors evaluated the medical
records of 9073 women who delivered infants between
July 1959 and August 1964. Of these women, 147 women
(1.6%) had surgery during pregnancy. There was no increase
in congenital anomalies in the group who received surgery;
note that none of the drugs used at that time are currently
used. Brodsky and colleagues had a different approach, mail-
ing a questionnaire to dentists and dental assistants to iden-
tify pregnant women who underwent surgery during
pregnancy and to identify pregnant patients who had occu-
pational exposure to nitrous oxide or volatile agents.14 They
identified 287 women who had surgery during pregnancy. Of
these women, 187 had surgery during the first trimester.
A large number, 3624 women, had occupational exposure
only. There was no major difference in the incidence of con-
genital anomalies in infants born to women who had surgery
during pregnancy compared with a control group who did
not have surgery. Furthermore, there was no increase in con-
genital anomalies in infants born to women with occupa-
tional exposure. Using health insurance data from the
province of Manitoba, Duncan and colleagues confirmed
the previous results.15 Mazze and Kallen performed the larg-
est study by examining cases from three Swedish health-care
registries for the years 1973 to 1981.16 These authors iden-
tified 5405 women who underwent surgery during preg-
nancy. Of these women, 65% received general anesthesia
and 2248 had surgery during the first trimester. The authors
found no increased incidence of congenital anomies. Another
approach is to perform a case control study. Of the 20,830
pregnant women who had offspring with a congenital anom-
aly, 31 patients had surgery and anesthesia.17 This percent-
age did not differ from the 35,727 women who had babies
without defects, 73 had surgery during pregnancy. There
was no higher incidence of surgery and anesthesia for any
congenital anomaly.
Although none of the previous studies was able to link
anesthesia and surgery with a congenital anomaly when
performed during pregnancy, these studies must be
repeated because the choice of intravenous agents, inhala-
tion agents, and neuromuscular blockers change. The
anesthetic agents used for anesthesia currently differ from
those included in the study by Mazze and Kallen. In a study
of 6,486,280 pregnant women admitted between 2002
and 2012, 47,628 of these women had surgery during
pregnancy. There was no increase in congenital anoma-
lies. However, this study confirmed previously held convic-
tions. Surgery and anesthesia during pregnancy,
particularly abdominal surgeries, increased the risk of still-
birth, preterm delivery, and prolonged hospital stay.18
Although the risk of surgery during pregnancy is low,
there is a higher risk of infection, primarily urinary tract
infection.19
Despite these data, the status of nitrous oxide as a repro-
ductive toxin continues to be debated. Nitrous oxide is a
teratogen in animals. It inhibits methionine synthetase,
an enzyme necessary for folate metabolism.20 Despite the
previous studies, other authors have postulated a link. Kal-
len and Mazze reexamined their database and noted six
infants who had neural tube defects.21 This number is much
higher than the expected number, 2.2 (an incidence of 1 per
1000 births). The authors postulated nitrous oxide as a pos-
sible cause, although the numbers and exposure do not sup-
port this proposition. Another study examined infants born
with central nervous system defects in Atlanta between
1968 and 1980 who were matched to controls by race,
birth hospital, and period of birth.22 Of the 694 mothers
of infants with central nervous system defects, 12 reported
first-trimester anesthetic exposure (34 of 2984 control
mothers reported such exposure), yielding an odds ratio of
1.7 (confidence interval [CI], 0.8 to 33; not statistically sig-
nificant). However, when examining infants with hydro-
cephalus and eye defects, the odds ratio increased to 39.6
(CI, 7.5 to 208.2). Although the odds ratio suggests statis-
tical significance, it is important to examine the actual inci-
dence. There were eight infants with this defect, three of
whom had a first-trimester exposure to anesthetic agents.
This result is more due to a small number and inappropriate
application of statistics.

Table 30.2 Drugs for which the US Food and Drug
Administration recommends a label warning regarding
development of the neonatal brain when used during the
third trimester.
Sevoflurane
Desflurane
Isoflurane
Etomidate
Ketamine
Lorazepam
Methohexital
Midazolam
Pentobarbital
Propofol
Halothane
In 2016, the US Food and Drug Administration (FDA)23
released a statement regarding anesthetic use in children
and pregnant women: “repeated or lengthy use of general
anesthetic and sedation drugs during surgeries or proce-
dures in children younger than 3 years or in pregnant
women during their third trimester may affect the develop-
ment of children’s brains.” The FDA then said that it is prob-
ably safe after research review. In 2017, the statement was
updated to include information about neuronal loss in ani-
mal models and lengthy or multiple exposures “may nega-
tively affect brain development.”24 This statement brought
the potential of anesthetic-related neurotoxicity to the fore-
front and led many to wonder how it would affect clinical
practice (Table 30.2).
In 1999, Ikonomidou and colleagues reported that
N-methyl-d-aspartate (NMDA) receptor blockade in devel-
oping rats induced increased neuronal apoptosis in an
age-dependent fashion, with the most vulnerable time cor-
responding to a human 20–22-week gestational age
fetus.25 Coupled with findings that in the fetal rat brain,
alcohol, a gamma-aminobutyric acid (GABAA) receptor
agonist, induced neuronal degeneration, the question of
anesthetic-induced neurotoxicity was raised.26 NMDA
receptor antagonism and GABA-potentiation implicated
drugs such as ketamine and inhaled anesthetics as potential
neurotoxins because the observed neuronal degeneration
was in excess of the physiologic apoptosis that occurs in
brain development. Jevtovic-Todorovic et al. anesthetized
7-day-old rats for 6 hours with isoflurane, nitrous oxide,
and midazolam. Rats exposed to the three anesthetic drugs
displayed deficits in learning and spatial memory. On histo-
pathology examination of brain sections, large sections of
neuronal apoptosis were identified in the anesthetic exposed
group.27 Proposed mechanisms of this degeneration include
anesthetic induced calcium overload, mitochondrial dam-
age, and impaired myelogenesis leading to impaired synap-
tic transmission and potentiation.28
Dexmedetomidine was investigated as a potential modu-
lator of general anesthetic induced neuronal apoptosis. In
several studies, it appeared to decrease neuronal apoptosis
following isoflurane and ketamine exposure in fetal sheep
and monkeys.29,30 The T-REX clinical trial is currently
enrolling children under 2 years of age undergoing a
30 • Preservation of Fetal Viability During Noncardiac Surgery 477
general anesthetic for longer than 2.5 hours. The patients
are randomized to sevoflurane or sevoflurane-remifenta-
nil-dexmedetomidine and then undergo IQ testing at the
age of 3 years to assess whether the combination anesthetic
technique is associated with better neurodevelopmental
outcome.31
With this new evidence, researchers investigated
whether the rodent model of anesthetic induced neuronal
apoptosis could be similar to nonhuman primates. Newborn
rhesus monkeys exposed to continuous ketamine infusions
displayed increased neuronal apoptosis and persistent
deficits in learning, motivation, and cognitive develop-
ment.32,33 Further research in rhesus monkeys showed that
multiple, but not single, exposures to isoflurane and sevo-
flurane were associated with increased anxiety behaviors
to stressors several months later.34,35
Applying animal data to clinical obstetric and pediatric
anesthesia is challenging. In many animal models, healthy
animals were anesthetized and no surgery was performed,
which is quite unlike clinical practice. There is also vari-
ability between the ages of animals, anesthetic technique,
and the level of monitoring used to detect hypoxia, hyper-
carbia, and hypotension. Clinical application of the findings
is also difficult because no single structural change after
anesthesia was tied to specific behavioral findings; studies
identified affected regions in the cortex, hippocampus, and
thalamus.28
Further work on the role of general anesthesia exposure
in pregnant women and children has been carried out by
retrospective, ambidirectional, and randomized control tri-
als. Early research mostly consisted of retrospective
population-based studies to investigate a link between gen-
eral anesthesia and diagnosis of learning disability, aca-
demic performance, or results of neuropsychological
testing. Sprung and colleagues examined records of children
in Olmsted County, Minnesota, to compare exposure to
either general or regional anesthesia for cesarean delivery
or vaginal delivery and found no difference in rates of later
diagnosis of learning disability.36 Several large population-
based cohort studies in Australia, Denmark, and the
Netherlands found no differences in average academic
scores; however, children exposed to anesthesia were
over-represented in the lowest scoring percentiles.37–40
Among studies using clinical diagnosis as the outcome mea-
sure, results are conflicting. DiMaggio and colleagues exam-
ined a birth cohort in New York and concluded that
anesthetic exposure compared with no anesthetic exposure
was associated with increased risk of diagnosis for behav-
ioral or developmental disorder.41 However, others found
no difference in ADHD diagnosis with a single exposure
but did conclude there was increased risk with multiple
exposures.42–44
Limitations of research based on diagnosis of learning dis-
ability or academic records include confounding variables
such as maternal education, socioeconomic status, absen-
teeism, and conditions that may predispose the child to
anesthetic exposure and a diagnosis of learning disability
such as premature birth.45 Using neuropsychologic testing
as a primary outcome measure allows researchers to
decrease such confounding variables. Further analysis of
an Australian cohort found no difference in behavior or cog-
nitive ability among children exposed to general anesthesia
478 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
aged 3–10 years.23 However, a smaller study found children
exposed to general anesthesia under the age of 4 years
scored lower in language comprehension and IQ testing
and on MRI scan had lower gray matter density in the cor-
tex than those with no exposure.46
To address limitations of retrospective analysis and to study
children undergoing anesthesia with modern techniques, the
multisite Pediatric Ambidirectional Neurodevelopment
Assessment (PANDA) study used a sibling-matched cohort
of healthy children undergoing inguinal hernia repair before
the age of 36 months.47 The PANDA study found no signif-
icant difference in verbal, spatial, executive function, and
memory. When adjusted for sex, there were no differences
in language scores. Final results of another ambidirectional
long-term cohort study, the Mayo Anesthesia Safety in Kids,
are pending because children who received anesthesia before
the age of 3 years are being followed and tested until the age
of 19 years.48 The General Anesthesia compared with Spinal
anesthesia (GAS) trial is a randomized control trial that
examined 722 infants under 60 weeks’ postconceptual age
undergoing inguinal hernia repair. The infants received
either spinal anesthesia or sevoflurane general anesthesia
with the primary outcome being IQ testing, with full results
being published after the study subjects undergo further test-
ing at the age of 5 years.35 At 2 years old, there was no dif-
ference in five domains of testing including language, motor,
social, cognitive, and adaptive.49
As a result of confounding factors of variability in anes-
thetic technique, monitoring, socioeconomic status, sex,
health status, and surgical effects, it is difficult to say defin-
itively whether general anesthetics are neurotoxic. In addi-
tion to pediatric anesthesia, anesthesia for fetal surgery
must be considered because often high doses of inhaled
anesthetics are used to maintain uterine relaxation. For this
reason, the International Fetal Anesthesia Database, a reg-
istry of fetal anesthetic outcomes, has been established.50
Randomized control trials and sibling-matched cohort stud-
ies decrease some of these confounding variables, but diffi-
culties remain in the design of a study of healthy infants
undergoing long anesthetics or to control for postprocedural
sedation in an intensive care unit.47
If there is an effect on neurodevelopment caused by gen-
eral anesthetics, the risks of anesthesia must be weighed
against the real risks of delaying a necessary procedure such
as repair or palliation of congenital heart disease. Further-
more, many infants are not undergoing operations for trivial
reasons and it may be riskier, for example, to delay myrin-
gotomy because chronic otitis may lead to hearing loss and
a resulting potential language delay. Results from the ran-
domized controlled trials and further research are awaited
and they are expected to add more valuable information
for clinicians and all those caring for pregnant and pediatric
patients.
Management of Hypotension
During Surgery on Pregnant
Patients
The purpose of the placenta is to deliver oxygen and nutri-
ents to the developing fetus. Uteroplacental perfusion is
provided by the uterine and ovarian arteries as they join
and penetrate the myometrium to form the arcuate arteries.
In the nonpregnant state, uterine blood flow accounts for
less than 5% of the cardiac output. During pregnancy, uter-
ine blood flow increases progressively, reaching approxi-
mately 500 to 800 mL/min (10% of the cardiac output)
at term.51 Uterine blood flow is directly proportional to
the mean maternal arterial pressure and inversely propor-
tional to uterine vascular resistance. Thus, it is important
to maintain arterial blood pressure and to prevent increases
in uterine vascular resistance. By maintaining arterial pres-
sure, oxygen delivery to the fetus is ensured.
Wollman and Marx were the first to demonstrate the
importance of avoiding hypotension when caring for preg-
nant patients.52 Their original intent was to examine the
effect of crystalloid prehydration on the incidence of
hypotension after spinal anesthesia. In this study, no vaso-
pressors were administered. In patients who developed
hypotension, the Apgar scores of the infants were lower,
infants look longer to initiate respiration, and the umbilical
cord pH was lower (a reflection of decreased uterine blood
flow). These authors confirmed that hypotension is not well
tolerated by the fetus. Given that maternal hypotension is
bad for the fetus, the rapid return of maternal blood pressure
to baseline is desirable. When treating hypotension, the
anesthesiologist may use a direct agonist (such as phenyl-
ephrine, which binds directly to the alpha receptor) or an
indirect acting sympathomimetic (such as ephedrine, which
acts by causing the release of norepinephrine). The indirect
acting drugs have both alpha and beta effects. When treat-
ing maternal blood pressure with either of these drugs, their
effect on both maternal blood pressure and uterine blood
flow must be considered. If the drugs result in vasoconstric-
tion, the increase in blood pressure may not be sufficient to
negate the effect on uterine artery vascular resistance.
The first study comparing different drugs for the treat-
ment of blood pressure examined 14 pregnant ewes under-
going 80 treatments.53 All the sheep received both general
and spinal anesthesia and uterine blood flow was measured
in all animals. The authors studied metaraminol (an alpha
agonist), ephedrine (an indirect acting drug), and mephen-
termine (an indirect acting drug). In this model, a decrease
in blood pressure resulted in a direct, proportional decrease
in uterine blood flow. All three drugs increased blood pres-
sure and uterine blood flow. However, mephentermine and
ephedrine increased it much more than metaraminol. The
authors concluded that spinal anesthesia decreases mater-
nal blood pressure and uterine blood flow. Indirect acting
agents restore uterine blood flow to a greater extent. The
clinical conclusion from this study was that if vasopressors
are required, drugs whose mode of actin lies in cardiac stim-
ulation rather than peripheral vasoconstriction should be
used. This study was the one that initiated the recommen-
dation that ephedrine should be used for the treatment of
hypotension during pregnancy. In another sheep model
study, uterine blood flow was unaffected with ephedrine,
reduced 20% with mephentermine, and reduced 62% with
methoxamine.54 This study confirmed the recommendation
for ephedrine.
Ephedrine remained the standard of treatment for hypo-
tension until 1988, when intravenous ephedrine was com-
pared with intravenous phenylephrine to treat hypotension

resulting from epidural anesthesia. In this study, parturients
undergoing cesarean section were randomized to receive
either ephedrine 5 mg or phenylephrine 100 μg to treat
hypotension.55 An impedance cardiograph was used to
measure stroke volume, ejection faction, and end-diastolic
volume. Both vasopressors restored maternal blood pres-
sure. Also, there was no difference in Apgar score or umbil-
ical cord pH. More importantly, there was no difference in
stroke volume and ejection fraction between the two med-
ications. The major points from this study were that the
cardiac effects of ephedrine were not as important and that
the effects of phenylephrine were not as detrimental as
previously thought.
The previous study examined cesarean section during epi-
dural anesthesia. A similar study was conducted using spinal
anesthesia.56 In this study, there was no difference in mater-
nal blood pressure or neonatal Apgar score. However, the
umbilical cord pH was higher in the phenylephrine group
(7.33 vs 7.28). Subsequent studies comparing the two med-
ications confirmed this finding.57 There was no benefit to
phenylephrine but also no detriment; either vasopressor
resulted in similar maternal effects on blood pressure and
neonatal effects on umbilical cord pH and Apgar score in
women with preeclampsia.58 In another study, Doppler echo-
cardiography showed no difference in cardiac output
between phenylephrine and ephedrine when used to treat
hypotension occurring during spinal anesthesia.
Subsequent studies have confirmed this statistically sig-
nificant, but probably clinically insignificant, difference in
umbilical cord arterial pH.59 The hypotension alone cannot
be responsible for the additional acidosis. It has been postu-
lated that the difference is a result of ephedrine gaining
access to the fetus, increasing catecholamine levels. This
increase in catecholamine levels leads to an increase in oxy-
gen consumption and an increase in lactate concentration.
A quantitative, systematic review of studies comparing
phenylephrine and ephedrine was conducted.60 Seven ran-
domized controlled trials were identified with a total of 292
patients. There was no difference between phenylephrine
and ephedrine in the ability to correct maternal hypoten-
sion, but a higher incidence of maternal bradycardia
occurred if phenylephrine was used. In regard to the neo-
nate, there was no difference in the incidence of true fetal
acidosis, but neonates whose mothers received phenyleph-
rine had higher umbilical arterial pH values if the mother
did not have preeclampsia.
Phenylephrine may be administered as intermittent bolus
or as a continuous infusion. There is no difference between
the two methods with regard to the effect on the neonate.61
A continuous infusion results in less variability in maternal
blood pressure and less nausea and vomiting.62 The use of
norepinephrine for the treatment of hypotension has been
investigated.63 The benefit of norepinephrine is less depres-
sion on maternal heart rate and cardiac output. It seems to
have no effect on the fetus and is a viable alternative. An
international consensus statement was prepared on the
management of hypotension during cesarean section.64
This statement advocates the use of α-agonists for the pre-
vention and the treatment of hypotension. Phenylephrine is
currently recommended because of the number of studies
supporting its use. Ephedrine is also appropriate combined
with phenylephrine if the heart rate is low.
30 • Preservation of Fetal Viability During Noncardiac Surgery 479
Clearly, the choice of vasopressor for treating hypotension
in pregnant patients has undergone much study and
change. All of the studies have been conducted in women
undergoing cesarean delivery. When discussing surgery
during pregnancy, it must be assumed that the same prin-
ciples apply. The initial thought that ephedrine was the bet-
ter agent was based on an animal model. Subsequent study
on parturients did not support this finding. In fact, a statis-
tically significant, but clinically insignificant, difference in
umbilical arterial pH was found for phenylephrine. Either
drug is acceptable for the treatment of hypotension,
although a continuous infusion of phenylephrine results
in less maternal nausea and vomiting.
Monitoring Fetal Heart Rate
During Nonobstetric Surgery
The purpose of fetal heart rate (FHR) monitoring is to ensure
that the fetus is well oxygenated. In the fetus, the brain mod-
ulates the heart. It is thought that hypoxemia is reflected in
the FHR. During nonobstetric surgery, the FHR may only be
monitored externally. The external monitor uses a Doppler
device. When it is placed on the maternal abdomen and
located over the fetal heart, a computerized program inter-
prets and counts Doppler signals. Continuous FHR monitor-
ing was begun in 1972. By 1988, over half of all laboring
women received it and by 1998 this figure was 84%.65
Current trends support a nearly universal use of FHR
monitoring during labor.
In 1997, the National Institute of Child Health and
Human Development proposed definitions for the interpre-
tation of the FHR.66 This group classified decelerations
(a decrease in the FHR) on the basis of their occurrence
in relation to a uterine contraction: with early contractions,
the nadir occurs with the peak of the contraction; later, the
onset and nadir occur after the onset and peak of the con-
traction; variable, an abrupt decrease in FHR with no rela-
tion to the uterine contraction. The other important
criterion in evaluating the FHR is baseline variability, which
is usually classified as the peak-to-trough amplitude in beats
per minute (bpm). Variable decelerations were associated
with umbilical cord compression.67 The association of
depressed neonates with late decelerations led to the pro-
posed mechanism of uteroplacental insufficiency, whereas
pressure on the neonate’s head inducing a decrease in heart
rate led to the association of head compression and early
deceleration.
The purpose of FHR monitoring is to ensure the well-
being of the fetus. A normal tracing (i.e., a baseline of
110 to 160 bpm, regular rate, presence of accelerations,
presence of variability, and absence of periodic decelera-
tions) is generally associated with a healthy, well-
oxygenated fetus.68 However, sometimes the tracing is
not perfect. Fetal heart patterns that accurately predict
asphyxia have not been specified. A nonreassuring tracing
as an indication of fetal hypoxia has a false–positive rate
greater than 99%.69 During surgery, the uterus is usually
quiescent. Given the lack of uterine contractions, there
should be no decelerations noted. The inhaled agents relax
the uterus.70 The inhaled agents will also cross the placenta,
480 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Fetal heart rate during surgery
140
105
70
35
0
Fig. 30.1 The fetal heart during surgery is typically between 120 and
140 beats per minute (bpm) with no beat-to-beat variability.
causing a loss of FHR variability (Fig. 30.1).71 The typical
FHR pattern during surgery is a flat tracing with an FHR
of 120–140 bpm. Bradycardia is abnormal and requires
intervention, such as delivery. The American College of
Obstetricians and Gynecologists recommends docu-
mentation of the FHR before and after surgery if the fetus
is viable.72 If the fetus is viable, the decision to perform
intraoperative monitoring is based upon the location of sur-
gery and on availability. At a minimum, the fetal heart mon-
itoring and contraction monitoring should be performed for
a time period prior to and after the surgical procedure.
Do Pregnant Patients Undergoing
Nonobstetric Surgery Have Full
Stomachs?
Pregnant patients are considered to have full stomachs; if
general anesthesia is needed in a laboring patient, it is
induced by a rapid-sequence technique. Also, patients pre-
senting for cesarean delivery are frequently administered
histamine (H2)-blockers, metoclopramide, and oral nonpar-
ticulate antacids to prevent the development of pneumonitis
if they should aspirate. Although these practices have
become standard for cesarean delivery, they have not
become the standard for surgery during pregnancy. The evi-
dence on which these recommendations are based is
controversial.
In 1946, Mendelson reported 66 cases of aspiration of
stomach contents during obstetric anesthesia.73 Of these
patients, five patients aspirated solid material, 21 patients
did not have a witnessed aspiration but were diagnosed at
a later time, and 40 patients aspirated liquid material.
The focus was on these 40 patients because they had a wit-
nessed aspiration of liquid contents. These patients had a
stormy course for 36 to 48 hours, but all survived. The term
Mendelson syndrome was used to describe the pneumonitis
accompanying aspiration. Researchers have focused on
quantifying the volume and pH of a solution required to
cause fatality from aspiration in the animal model. This
research led to the development of strategies to reduce gas-
tric volume and to increase gastric pH.74
Parturients are believed to be at risk of aspiration because
of the physiologic changes of pregnancy. The enlarged gravid
uterus displaces the stomach cephalad. This displacement
alters the angle of the gastroesophageal junction, decreasing
the competence of the gastroesophageal sphincter. The
uterus also displaces the pylorus upward and posteriorly,
resulting in delayed gastric emptying. Elevated concentra-
tions of progesterone decrease gastrointestinal motility and
food absorption. These changes facilitate the occurrence of
gastric reflux and heartburn in as many as 70% of pregnant
women.75 Furthermore, the placenta secretes gastrin, a hor-
mone that increases the acidity of the stomach contents.76
The question is whether these changes place the pregnant
woman undergoing nonobstetric surgery at risk of regurgi-
tation and aspiration of gastric contents during induction
or maintenance of general anesthesia.
The introduction of ultrasound for the evaluation of gas-
tric contents has been applied to pregnant patients. The
stomach contents of 32 women who were pregnant and
who were in the third trimester of gestation were evaluated
after being nil by mouth (NPO), drinking, and eating.77 The
investigators were therefore able to detect those individuals
who had consumed liquids or solids. More importantly, no
patient who was NPO had a full stomach. These results were
confirmed in a study in which pregnant patients who pre-
sented for elective cesarean delivery and who were NPO
had their stomach contents compared before and after deliv-
ery.78 Pregnant patients who were not in labor did not have
stomach contents when examined using ultrasound.
Finally, in a study examining laboring patients, 10 patients
had to be excluded because of preexisting stomach contents
despite being NPO.79 Pregnancy does not make a “full
stomach”; labor may.
Use of 100% Oxygen During
Nonobstetric Surgery
The fetus is well adapted for a low blood oxygen concentra-
tion. Fetal hemoglobin accounts for 65% to 85% of the fetus’
hemoglobin. Fetal hemoglobin has an increased affinity for
oxygen (a shift to the left in the oxygen saturation curve),
binding to it more avidly than adult hemoglobin. Further-
more, the fetus has a much higher hematocrit, typically
45%, allowing an increased oxygen-carrying capacity.
The purpose of using a high inspired oxygen concentration
is to increase oxygen transfer to the fetus. Intraoperative
fetal oxygen saturation was compared in 24 women under-
going cesarean section using sevoflurane with either 100%
oxygen, or 50% oxygen/50% nitrous oxide. Intraoperative
fetal oxygen saturation was 57% in the 100% group and
43% in the 50% group.80 Also, umbilical vein and artery
PaO2 were higher. In a randomized study comparing mater-
nal inspired oxygen concentrations of 30%, 50%, or 100%,
there was no difference in arterial concentrations of oxygen
between the 30% and 50% groups. An inspired oxygen con-
centration of 100% resulted in the greatest umbilical arte-
rial and venous oxygen concentrations.81
An inspired concentration of 100% oxygen results in the
greatest level of fetal oxygen. This level is not sufficient to
cause retinopathy of prematurity. Despite this lack of effect
on the fetal eye, other toxic reactions to oxygen are possible.
Approximately 2% of the oxygen molecules in mammalian

mitochondria form superoxide free radicals.82 Oxygen-free
radicals have been implicated in the pathogenesis of inflam-
matory, toxic, and metabolic insults, ischemia-reperfusion
injury, carcinogenesis, and atherosclerosis. Although
oxygen-free radicals have not been implicated in having
any impact on the fetus, it has been shown to affect the new-
born. Forty-four healthy parturients undergoing cesarean
delivery during spinal anesthesia were randomized to
breathe either 21% or 60% oxygen.44 Direct detection of
free radicals is difficult because of the brief life span. In this
study, lipid hydroperoxides, the products of free radicals
were measured. There was a higher umbilical arterial and
venous oxygen concentration in the 60% group. There were
also greater concentrations of lipid peroxides in the fetus.
Lipid peroxide concentrations were much greater in the
umbilical vein than in the umbilical artery, suggesting that
the main site of free radical actively was the placenta.83
Administering a high concentration of inspired oxygen
induces free radical generation in the fetus. The clinical rel-
evance of this increase is uncertain. Future research may
reveal an adverse effect.
Increasing the maternal inspired oxygen concentration
increases fetal oxygenation. This increase is not needed
because the fetus has a high hematocrit and a high per-
centage of fetal hemoglobin. These changes make the
fetus well adapted for a lower maternal oxygen concen-
tration. A high maternal inspired oxygen concentration
increases fetal oxygen-free radicals. Free radicals have
been implicated in certain diseases but have not been
shown to harm the fetus. It seems prudent to maintain
mothers undergoing nonobstetric surgery at an inspired
oxygen concentration necessary to maintain an oxygen
saturation of 95% to 99%.
Should Hyperventilation Be
Avoided in Pregnant Patients
Undergoing Nonobstetric
Surgery?
An increase in minute ventilation represents one of the more
profound physiologic adaptations to pregnancy. During the
first trimester, altered chest wall dynamics and enhanced
diaphragmatic excursion produce a significant increase in
tidal volume. As pregnancy progresses, progesterone levels
rise, stimulating central respiratory centers and further aug-
menting tidal volume. Ultimately, minute ventilation
increases by 45% above prepregnant levels. As a conse-
quence, the pregnant patient experiences a mild, chronic
respiratory alkalosis, and typical arterial carbon dioxide ten-
sion ranges from 28 to 32 mmHg (Box 30.1).84
Unlike the mild respiratory alkalosis characteristic of
pregnant patients, the arterial carbon dioxide tension of
the fetus typically approaches or surpasses 40 mmHg.
The difference in carbon dioxide tension between mother
and fetus creates a transplacental concentration gradient,
favoring elimination of carbon dioxide from the fetal unit
to the maternal circulation. Mild degrees of hypercarbia
are well tolerated by both mother and fetus; elimination
of carbon dioxide from the fetus decreases when there is
a significant increase in maternal carbon dioxide tension.
30 • Preservation of Fetal Viability During Noncardiac Surgery 481
Box 30.1 Typical blood gas in third trimester.
Due to an increase in tidal volume and respiratory rate, pregnant
patients hyperventilate. There is little alkalosis due to renal
compensation.
▪ pH: 7.43
▪ PaCO2: 33 mmHg
▪ PaO2: 104 mmHg
▪ HCO3: 21 mmHg
Respiratory acidosis in the fetus initiates a downward spiral
of fetal cardiac depression and hypotension.85
Maintenance of normocarbia in the parturient undergo-
ing general anesthesia typically demands subtle manipula-
tion of minute ventilation. Laparoscopic surgery in the
pregnant patient presents greater challenges. For several
decades, the general surgical community avoided laparo-
scopic procedures during pregnancy with untoward effects
arising from the creation of pneumoperitoneum with car-
bon dioxide underscoring this reluctance.86 In 1992, the
first successful, nonobstetric-related laparoscopic procedure
was performed during pregnancy.87 Although many early
cases argued its safety, others suggested caution. An initial
report suggested an increase in fetal loss among women
undergoing laparoscopic procedures compared with a
matched cohort undergoing laparotomy. It was postulated
that the increased carbon dioxide levels predisposed both
the mother and the fetus to unrecognized respiratory acido-
sis and increased fetal loss. Subsequent study did not support
the increase in fetal loss.
The management of maternal and fetal hypercarbia varies.
Fetal respiratory acidosis is avoidable if the maternal–fetal
concentration gradient for carbon dioxide elimination is pre-
served.88 To maintain an appropriate transplacental concen-
tration gradient during abdominal insufflation, pregnant
ewes were hyperventilated to maintain normocarbia. In
these situations, an increase in fetal carbon dioxide was
not observed. Using a similar approach, there was no fetal
hypercarbia during abdominal insufflation if maternal car-
bon dioxide tension is maintained within normal limits.89
Unlike previous studies, both arterial and end-tidal carbon
dioxide were monitored. There was a significant gradient
from arterial to end-tidal carbon dioxide during abdominal
insufflation, with end-tidal carbon dioxide grossly underesti-
mating arterial concentration.90 Based on these results, end-
tidal carbon dioxide monitoring was considered inadequate,
with the recommendation that arterial concentrations of car-
bon dioxide should be obtained by blood gas analysis.
A significant discrepancy between end-tidal and arterial
carbon dioxide tension was observed in other studies.91–93
Given the deleterious effects of maternal hypercarbia, some
authors have recommended placement of arterial catheters
for monitoring carbon dioxide concentrations through
blood gas analysis. In pregnant patients undergoing laparo-
scopic surgery who have a low pre-insufflation gradient, it
remains low during abdominal insufflation. A lower alveolar
dead space in pregnant patients most probably accounts for
this discrepancy.94 End-tidal carbon dioxide monitoring is
adequate for the pregnant patient undergoing laparoscopic
surgery.
482 PART III • Preservation of Organ Function and Prevention and Management of Perioperative Organ Dysfunction
Normocarbia should be maintained during surgical pro-
cedures performed during pregnancy. Monitoring carbon
dioxide levels with end-tidal levels is adequate for manage-
ment of pregnant patients; invasive monitoring is not
required.
Risk of Preterm Labor or
Miscarriage in Nonobstetric
Surgery
Surgery during pregnancy increases the risk of premature
labor and miscarriage, especially if the procedure is intra-
abdominal or intrapelvic. In the first study to examine preg-
nancy outcome, a questionnaire was mailed to 30,272
female dental assistants regarding surgery during preg-
nancy and occupational exposure to anesthetic agents.14
Occupational exposure resulted in an increase in spontane-
ous abortion in the first trimester (8.6/100 pregnancies vs
5.1/100 pregnancies) and in the second trimester (2.6/
100 pregnancies vs 1.4/100 pregnancies). There was an
increase in spontaneous abortion in those women who
had anesthesia and surgery during the first trimester. The
rate for spontaneous abortion decreased during the second
trimester, although surgery was associated with a propor-
tionally greater risk for fetal loss compared with the first tri-
mester. The confounding variable in this study was that all
participants worked. Stress and increased time in an upright
position increases the risk of both of these complications.
This increased risk was further verified when health
insurance data from the province of Manitoba (1971
to 1978) were reviewed.16 This database identified
2565 women undergoing nonobstetric surgery and then
matched them to those not undergoing surgery. There were
181 abortions in the surgical group (7.1%) and 166 in the
nonsurgical group (6.5%). Surgery and anesthesia during
pregnancy did not increase the risk of abortion. There
was a significant increase in abortion in those women
who received general anesthesia (relative risk, 1.58; CI,
1.19 to 2.09). When further analyzed, the cause was linked
to the site of surgery rather than to the anesthesia. Gyneco-
logic surgery had the greatest risk and all of these proce-
dures were performed using general anesthesia.
Since these two studies were published, advancements
have been made in anesthetic agents and surgical tech-
niques. Anesthetic agents have shorter half-lives and less
residual effect. Surgical techniques are now less invasive.
It is unclear whether the previous incidences of miscarriage
and preterm labor are still applicable. A retrospective review
of all cases of nonobstetric abdominal surgery from 1991 to
1998 at the Women’s Hospital at the University of Southern
California identified 106 cases of nonobstetric abdominal
surgery (88 laparotomy and 18 laparoscopy).95 The inci-
dence of preterm delivery was 18%, which was not different
from the institutions’ general incidence of 16%. Further-
more, there was no difference in pregnancy loss, suggesting
no difference in preterm delivery or miscarriage in the sur-
gical group compared with the nonsurgical group. A total of
6.5 million pregnancies were studied in which 47,638 had
surgery during pregnancy between 2002 and 2012. In this
cohort of patients, the authors estimated that every 287
surgical procedures has one additional stillbirth, every 31
surgeries had one additional preterm labor, and every 25
operations was associated with cesarean delivery.96 Despite
these results, appendectomy, the most frequently performed
surgical procedure during pregnancy, has a higher inci-
dence of premature labor and miscarriage.97
A review of 54 articles concerning nonobstetric surgery
was conducted for a total 12,452 patients.98 The reported
incidence of miscarriage was 5.8% and the incidence of pre-
term labor was 8.2%. These percentages do not differ from
the reported percentages in the general population. Still, it is
difficult to evaluate because of the lack of a control group.
The most frequent surgical procedure during pregnancy is
appendectomy. There was a high percentage, 4.6%, of labor
resulting from the surgery. The incidence of premature
labor and delivery was higher for appendectomy than for
other medical conditions. It appears that the effects of acute
appendicitis and surgery on the patient are more severe
than, and different from, other acute conditions requiring
surgery during pregnancy.
With regard to long-term follow-up of the infant, the data
are extremely sparse. Only one study examined infants
whose mothers had surgery during pregnancy.99 These
infants were evaluated 1 to 8 years after laparoscopic sur-
gery during the 16th to 28th week of gestation. There
was no evidence of developmental or physical abnormalities
in the infants.
Initially, surgery during pregnancy increased the risk of
miscarriage and preterm labor. With the development of
newer, less invasive surgical techniques and of improved
anesthetic agents, the risks of both of these complications
are no different from the risks in those who have not had
surgery. It is important to counsel pregnant patients that
there is a risk of miscarriage and preterm labor, but it is more
caused by surgical location (abdominal or pelvic) rather
than the anesthetic agents.
Conclusions
Caring for pregnant patients requiring surgery is challeng-
ing because the provider is caring for two patients simulta-
neously. Optimal care of the mother provides the best care
for the fetus. Recent concerns have developed regarding the
effect of anesthetic agents upon learning when the fetus is
exposed during the third trimester. Surgery during preg-
nancy does not increase the risk of preterm labor unless it
is intra-abdominal. The treatment of hypotension is impor-
tant and the current recommendation is to use alpha ago-
nists. Left uterine displacement is important to prevent
compression of the vena cava; the amount of tilt possible
that allows for surgery to proceed is insufficient to prevent
compression of the vena cava. The use of fetal monitoring
is at the discretion of the obstetrician. Finally, surgery dur-
ing pregnancy is relatively safe for mother and fetus with the
risk higher for intra-abdominal procedures.
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72. American Obstetricians and Gynecologists. Nonobstetric surgery dur-
ing pregnancy. No 696. Obstet Gynecol. 2017;129:777–778.
73. Mendelson CL. The aspiration of stomach contents into the lungs dur-
ing obstetric anesthesia. Am J Obstet Gynecol. 1946;52:191–204.
74. James C, Modell J, Gibbs C, et al. Pulmonary aspiration: Effects of vol-
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75. O’Sullivan GM, Sutton AJ, Thompson SA, et al. Noninvasive measure-
ment of gastric emptying in obstetric patients. Anesth Analg. 1987;66:
505–511.
76. Attia RR, Ebeid AM, Fischer JE, et al. Maternal, fetal, and placental gas-
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ultrasound assessment of gastric content in the third trimester of preg-
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titative ultrasound assessment of the gastric antrum before and after
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measurement of antral area for estimating gastric fluid volume in par-
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 31 Cardiac Surgery
PINGPING SONG, MICHAEL HOLMES, and G. BURKHARD MACKENSEN
Each year, more than 500,000 cardiac surgery procedures
are performed in the United States, and, until recently, this
number continued to grow annually.1 Cardiac surgical
patients are routinely admitted to the intensive care unit
(ICU) for monitoring of recovery from anesthesia and sur-
gery, optimization of hemodynamics, weaning from ventila-
tory support, and monitoring for possible complications. The
ICU has emerged as the dominant area where the complex
transition from the operating room to sophisticated care
occurs. With high volumes of cardiac surgery procedures,
the postoperative care of these patients accounts for a signif-
icant percentage of ICU admissions at many institutions.
Cardiothoracic surgery intensive care units (CT-ICUs) have
evolved as a separate entity from the general surgical ICU as
management for cardiac surgery patients has become
streamlined and algorithm driven. Critical care is best man-
aged when the service is designed for a homogeneous pop-
ulation with a circumscribed set of medical and surgical
issues.
Traditionally, cardiac surgery patients remained in the
ICU for a few days before discharge to the ward or step-down
unit. Over the past decade, ICU management has changed
in response to changing patient populations, new surgical
and anesthetic techniques, and the penetration of managed
care. Patients presenting for cardiac surgery are signifi-
cantly older as the number of patients undergoing angio-
plasty and stenting procedures increases. Aggressive
medical therapy and nonsurgical revascularization tech-
niques also result in patients presenting for surgery at more
advanced stages of disease and with substantially more
comorbidities. Furthermore, given the current market of
health maintenance organizations (HMOs) and other cost-
containment strategies, there is an ongoing trend toward
enhanced recovery after cardiac surgery (ERAS), promoting
an earlier return to normal activities. These initiatives aim
for reduction of complications, accelerated care (e.g., fast
track), clinical care pathways, and earlier discharge from
intensive care.2,3
With the development of minimally invasive cardiac
surgery, warm bypass, and off-pump bypass techniques,
cardiac surgeons have altered the requirements for conven-
tional postoperative recovery. The overall trend has been to
move away from the high-dose, opioid-based anesthetic
techniques of the past to newer forms of balanced anesthesia
with shorter-acting induction agents (propofol and etomi-
date), volatile agents (isoflurane and sevoflurane), and
reduced doses of opioids allow accelerated patient recovery
from anesthesia. This trend has been accompanied by an
adoption of multimodal postoperative analgesia including
intravenous nonsteroidal analgesics and regional anesthe-
sia (both nerve and fascial blocks). Consequently, intensi-
vists need to develop strategies to manage this ever-
changing patient population in an efficient and cost-
effective manner while maintaining quality and minimizing
morbidity and mortality. Effective postoperative manage-
ment depends highly on each patient’s preoperative status,
intraoperative events, and condition on ICU arrival.
Although the majority of institutions utilize the surgical
ICU or specialized CT-ICU for postoperative care, avoidance
of ICU admission altogether may be the future for selected
patient populations: some institutions utilize step-down
units or short-stay intensive care for the weaning process
and high-dependency care.4,5
Transport and Initial Assessment
The transport of the freshly operated cardiac surgery patient
from the operating room to the ICU is not without risks and
should be as smooth as possible.6 Problems encountered
during transport include acute changes in physiology (with
hypovolemia being the most prevalent), sudden awakening,
or serious bleeding. Once surgery is complete and the
patient is stabilized in the operating room, the patient is
transported to the ICU while still emerging from anesthesia.
To improve comfort and safety, the patient is routinely mon-
itored (electrocardiography [ECG], invasive blood pressure
[BP] monitoring, and pulse oximetry) and maintained on
sedation with short-acting agents such as propofol or dex-
medetomidine supplemented with opioids when needed.
This allows the patient to wake up gradually in the ICU
while the intensivist team continues to monitor organ per-
fusion and postoperative complications.
ICU ADMISSION
During the transition of care from the anesthesiologist to the
ICU team, the intensivist must become familiar with the
patient’s medical history and intraoperative course. Ideally,
the multidisciplinary hands-off process should follow a
structured checklist and involve members from the anesthe-
sia team, the surgical team and the ICU team. Preoperative
and intraoperative events vary in magnitude and duration
but typically result in a myocardium of reduced contractility
and compliance, which affects the postoperative manage-
ment and eventual outcome.7–9 Essential data include indi-
cation for surgery, preoperative cardiac function and major
comorbidities, details of the surgical procedure (arterial and
venous coronary bypass grafts, valves repaired or replaced,
aortic surgery, etc.), duration of cardiopulmonary bypass
and cross-clamp, difficulties weaning from bypass, and
post-bypass cardiac function assessment. It is also important
to know the patient’s individual response to fluid adminis-
tration and vasoactive agents, the number and position of
487
488 PART IV • Early Postoperative Care
chest drains, requirement of cardiac pacing, and hemostasis
before chest closure. Extra caution should be paid to the “re-
do” procedures (repeat sternotomy or thoracotomy). They
are technically more challenging and tend to result in
greater blood loss and higher complication rates. Finally,
the amount and type of fluid and blood products adminis-
tered, the expected postoperative course, and specific post-
operative guidelines (BP targets, time for weaning from
ventilator support, initiation of anticoagulation, etc.) should
be communicated to the ICU team.
Upon the patient’s arrival in the ICU, the clinician should
carefully note the position of the endotracheal tube and per-
form an inspection of all surgical sites, drains, and indwell-
ing catheters. Important physical examinations focusing
specifically on potential complications of cardiac surgery
include pupillary response, pulmonary auscultation, cardiac
auscultation, chest tube output, and urinary output.
Patients may be hypothermic upon arrival, thus tempera-
ture should be rapidly assessed and warming initiated if nec-
essary. A 12-lead ECG provides valuable information
regarding baseline cardiac rhythm and potential ischemia.
An admission chest radiograph (CXR) effectively checks
for adequate positioning of all tubes and lines and provides
assessment of lung volumes, pulmonary edema, and poten-
tial operative complications such as pneumothorax and
hemothorax.10 CXR also provides a baseline cardiac silhou-
ette for later comparison if cardiac tamponade were to
develop. The extent of hemodynamic monitoring depends
on the patient’s perioperative condition, intraoperative
course, and anticipated complications after cardiac surgery.
At a minimum, patients should have an arterial line, a cen-
tral venous pressure (CVP) line, and a urinary catheter. The
utility of pulmonary artery catheters (PAC) remains debat-
able. Since Connors and colleagues initially questioned the
utility of PAC in critically ill patients,11 there have been
numerous studies investigating the effect of PAC in various
patient populations with different conclusions on patient
outcome. Despite the lack of consensus, there is report of
increased PAC use in cardiac surgeries from 2010 to
2014.12 A recent cohort analysis using propensity match
demonstrates that PAC use was associated with decreased
cardiopulmonary morbidity, decreased hospital length of
stay, and increased risk of infection. There was no difference
on the 30-day mortality between the PAC group and the
control group.13 The increased utilization of intraoperative
Microvascular bleeding
Platelet count Celite TEG
with/without heparinase
TEG R ⬎2 × hTEG R Platelet count ⬍100K
and MA ⬍45 mm
Protamine Platelets
1. 2.
Fig. 31.1 Algorithm for transfusion in cardiac surgery based on the results of platelet count, thromboelastography (TEG), and fibrinogen levels. EACA,
ε-aminocaproic acid; FFP, fresh-frozen plasma; hTEG, heparinase-activated TEG; LY30, lysis index at 30 min; MA, maximum amplitude; R, reaction time.
(Adapted with modification and permission from Shore-Lesserson L, Manspeizer HE, DePerio M, et al. Anesth Analg 1999;88:312-319.)
transesophageal echocardiography (TEE) has resulted in
PAC being less frequently used during the surgery. How-
ever, in the immediate postoperative period, PAC data
may guide therapy in patients with severe pulmonary
hypertension, right heart failure, low cardiac output (CO),
end-stage renal disease requiring renal-replacement ther-
apy, or patients with severe diastolic dysfunction.
Routine laboratory analysis on admission includes arte-
rial blood gases (ABG), electrolytes, complete blood count
(CBC), and coagulation parameters. ABG and electrolyte
data provide insight toward acid-base derangement, intra-
vascular volume status, and optimization of ventilator sup-
port. The plasma levels of potassium and magnesium need
to be kept above 4.0 and 2.0 mmol/L, respectively, to min-
imize the incidence of cardiac dysrhythmias.14–18 Potas-
sium repletion may not be successful without restoration
of magnesium stores.17 The ABG, hemoglobin/hematocrit,
and electrolytes tests should be obtained every 4 to 8 hours
or more frequently when clinically indicated, until when the
patient’s condition has stabilized and the data can be
obtained less frequently. As blood loss and marked inflam-
mation associated with cardiovascular surgery may result
in significant derangements in hemoglobin, platelets, and
clotting factor activity, a CBC and standard coagulation tests
are necessary to guide transfusion therapy. If significant
coagulopathy is initially suspected on arrival in the ICU from
high chest tube output, an activated clotting time may also
be used as a rapid point-of-care test to check for adequate
reversal of heparin given during surgery. The incorporation
of thromboelastography (TEG) or rotational thromboelasto-
metry (ROTEM) as a point-of-care monitor into a trans-
fusion algorithm allows more specific diagnosis of
coagulopathy and reduction of indiscriminate transfusion
practices (Fig. 31.1).19
Respiratory Management
MECHANICAL VENTILATION
Immediate changes in respiratory function as a conse-
quence of cardiac surgery and CPB include significant
decreases in vital capacity, total lung capacity, and func-
tional residual capacity, as well as significant atelectasis.
There is also increased pulmonary edema correlating with
TEG or Fibrinogen
hTEG R ⬎20 mm TEG LY30 ⬎7.5% Alpha angle ⬍45 degrees
Fibrinogen ⬍100 mg/dL
FFP EACA Cryoprecipitate
3. 4.
 31 • Cardiac Surgery 489

the length of CPB. These disorders probably stem from a mix Table 31.1 Criteria for extubation after cardiac surgery.
of surgical stress, complete deflation of the lungs during car-
diopulmonary bypass, and incisional pain. In patients General criteria Awake and follow commands; adequate
analgesia
undergoing coronary artery bypass grafting (CABG), the
average period of postoperative mechanical ventilation used Hemodynamically stablea: MAP >65 mmHg,
to be between 1 and 2 days when high-dose, opioid-based CI >2 L/min/m2
anesthetics were used.20 With the modern balanced anes- Normal acid-base status: pH 7.32
thetic technique, the “fast track” clinical care pathway tar-
Chest tube drainage <50 mL/h
gets early extubation, with the average mechanical
ventilation time ranging from 6 hours or less to 24 hours Urine output >0.5 mL/kg/min
postoperatively.21–25 Compared with late extubation Core temperature >36°C, no shivering
(>24 hours postoperatively), early endotracheal extubation
Airway criteria Intact cough and gag reflex
after cardiac surgery has been shown to reduce both the ICU
and hospital length of stay, to be more cost efficient, to Neuromuscular blockade fully reversed
improve left ventricular function, and to decrease cardiopul- Pulmonary secretions manageable
monary morbidity.22,23,26
Traditionally, ventilation with high tidal volume (10 mL/kg Chest radiograph within expectations
or more) was used to reduce atelectasis. However, current Gas exchange PaO2 >70 mmHg on 40% FIO2; PaCO2 <50 mmHg;
evidence suggests that lower tidal volume (6–8 mL/kg ideal criteria PEEP at 5 cm H2O
body weight) is beneficial, with the goal of reducing baro- No signs of respiratory distress:
trauma and volume trauma in the lungs that were already f/VT <100 on PSV or T-piece;
susceptible to injury by surgical stress. Lower tidal volume RR 10–30/min
has been shown to provide higher success rate of ventilator- NIF  -25 cmH2O
free at 6 hours after cardiac surgery as well as a lower inci-
FVC >10 mL/kg
dence of reintubation.27 On the contrary, high tidal volume
is a risk factor for organ failure and prolonged ICU stay after a
Vasopressors, inotropes, and circulatory assist devices (intra-aortic balloon
cardiac surgery.28 Positive end-expiratory pressure (PEEP) is pump) are permitted as long as there is no escalation of support.
generally started at 5 cm H2O and titrated up to adequate CI, Cardiac index; FIO2, fraction of inspired oxygen; FVC, forced vital capacity;
f/VT, respiratory rate/tidal volume; MAP, mean arterial pressure; NIF,
oxygenation. Whereas high versus low PEEP strategies are negative inspiratory force; PaCO2, partial pressure of arterial carbon dioxide;
debatable throughout critical care practice, lower PEEP in PaO2, partial pressure of arterial oxygen; RR, respiratory rate.
postoperative cardiac surgery patients may facilitate impro-
ved hemodynamics as long as adequate alveolar recruit-
ment and oxygenation is maintained. Since hyperoxia
(PaO2 >120 mmHg) is detrimental to organ function with (Box 31.1) are evaluated for further confirmation. An alter-
worse clinical outcome as a result of production of oxygen-free native weaning strategy is to attempt SBTs every 30 minutes
radical species and subsequent inflammatory responses,29,30 it as the patient continues to recover from anesthesia until a
is critical to reduce the fraction of inspired oxygen (FIO2) as certain set criterion is satisfied (see Table 31.1). Both
quickly as possible as long as adequate oxygenation is main- methods are safe and neither has any clear advantage over
tained (PaO2 >60 mmHg). The partial pressure of arterial the other. Most patients undergoing cardiac surgery with
carbon dioxide (PaCO2) should be titrated to compensate for normal pulmonary function preoperatively do not require
any concurrent metabolic acidosis, with the goal of a normal- a gradual wean from the ventilator. If the patient has
ized pH. When criteria for extubation are met, patients can be remained stable during recovery from anesthesia and has
transitioned to pressure support ventilation (PSV) mode. Early
extubation after admission to the ICU is an essential compo-
nent of fast-track protocols.
Routinely, weaning from ventilatory support can start
Box 31.1 Factors predicting successful weaning
once the patient starts to breathe over the rate set on the ven- from mechanical ventilation.
tilator. Weaning should not be aggressive until the patient
meets certain established criteria (Table 31.1).31,32 These Mechanical
criteria relate to the patient’s neurologic, cardiac, respira- Respiratory rate <25/min
tory, and renal status. They define an awake, normothermic, Vital capacity >12–15 mL/kg
and hemodynamically stable patient who most likely will not Maximal negative inspiratory pressure -25 cm H2O
need to return to the operating room for surgical bleeding. Minute ventilation (Vm) <10 L/min
One method of weaning is to reduce the rate set on the ven- Respiratory rate (f) / tidal volume (VT) ratio <105
tilator gradually until the patient is consistently triggering Gas Exchange
breaths, after which the ventilator can be switched to a pH 7.35
low level of pressure support (generally 5 cm of PEEP and PaO2 >60 mmHg with FIO2 <40%
5 cm of support) for a formal spontaneous breathing trial PaO2/ FIO2 ratio >200
(SBT). The patient who can maintain a reasonable gas PAO2 - PaO2 <350 mmHg
exchange and is not tachypneic after 30 minutes on pressure
support is ready to have the endotracheal tube removed. At FIO2, Fraction of inspired oxygen; PAO2, partial pressure of alveola oxygen;
some institutions, the patient’s pulmonary mechanics PaO2, partial pressure of arterial oxygen.
490 PART IV • Early Postoperative Care
no significant pulmonary disease, a rapid decrease in venti-
lator support to minimal levels can be safely instituted under
close observation, and the patient can be evaluated for extu-
bation. The method of removal from ventilatory assistance
varies between institutions depending on the characteristics
of the individual ICU.
LONG-TERM VENTILATION AND WEANING
The occurrence of respiratory complications and the dura-
tion of endotracheal intubation have been shown to corre-
late with mortality in patients who have undergone cardiac
operations.33,34 Because mechanical ventilation can have
life-threatening complications, it should be discontinued
at the earliest possible time. It is important to realize that
prolonged intubation time may lead to respiratory tract
mucociliary dysfunction, diminished clearing of secretions,
atelectasis, delirium, and ventilator-associated pneumo-
nia.26,35 The process of discontinuing mechanical ventila-
tion, termed weaning, is one of the most challenging
problems in intensive care, and it accounts for a consider-
able proportion of the workload of ICU staff.36
Most cardiac surgical patients are expeditiously weaned
from mechanical ventilation, but up to 6% of all patients
undergoing CABG surgery require mechanical ventilation
for more than 1 day and approximately 2% remain on
the ventilator for more than 2 weeks.20 Identification of pre-
operative risk factors limiting the ability to wean from
mechanical ventilation has been difficult, but common fac-
tors include advanced age, marked neurologic deficits, acute
renal failure with volume overload, limited perioperative
cardiac function, unstable hemodynamics, and sepsis.37,38
Other intraoperative and postoperative predictors of failure
to wean include prolonged CPB, preexisting pulmonary dis-
ease (e.g., chronic obstructive pulmonary disease [COPD]),
diaphragmatic paralysis, malnutrition, and high oxygen
requirements.39–41
The difference in oxygen consumption between sponta-
neous and total mechanical ventilation can be substan-
tial.42 Routine preoperative pulmonary function tests
have failed to serve as predictors for prolonged mechanical
ventilation.43 Risk stratification with established scoring
systems has led to mixed results when predicting the length
of endotracheal intubation after cardiac surgery.44,45
Methods used to wean from mechanical ventilation include
synchronized intermittent mandatory ventilation (SIMV),
PSV, and T-piece trials with spontaneous breathing. Until
the early 1990s, all weaning methods were considered
equally effective, and the intensivist’s judgment was
regarded as the critical determinant.46 This has changed
with the results of randomized controlled trials that revealed
that the period of weaning is up to three times longer with
SIMV compared with SBTs.47,48 SBTs may be as short as
30 minutes and appear to be as effective when performed
once a day as several times a day.48,49
Protocol-driven weaning from mechanical ventilation or
automated weaning protocols may facilitate the challenging
task of weaning.24,31 Scheduled assessment of respiratory
mechanics may also predict successful weaning. Among
patients who cannot be weaned, disconnection from the
ventilator is followed almost immediately by an increase
in respiratory rate and a fall in tidal volume.50 The
respiratory rate/tidal volume (f/VT) ratio, also known as
the rapid shallow breathing index, has been used with some
success as a predictor of failure to wean. An f/VT ratio
greater than 105 resulted in 95% of patients failing to wean,
whereas an f/VT ratio less than 105 resulted in a weaning
success of 80%.40 In a randomized trial, a two-stage
approach to weaning—systematic measurement of predic-
tors, including f/VT, followed by a single daily trial of spon-
taneous breathing—was compared with conventional
management.51 Although the patients assigned to the
two-stage approach were generally sicker than those
assigned to conventional weaning, they were weaned twice
as rapidly. This approach was not only cost effective but also
lowered the incidence of complications when compared
with conventional management.
In addition to the increase in respiratory effort, an unsuc-
cessful attempt at spontaneous breathing causes consider-
able cardiovascular stress.37 Patients can have substantial
increases in right and left ventricular afterload, with
increases of 39% and 27% in pulmonary and systemic arte-
rial pressures, respectively,52 most probably because the
negative swings in intrathoracic pressure are more extreme.
While most patients demonstrate improved hemodynamics
with weaning of positive pressure ventilation secondary to
improved preload and cessation of sedation, such afterload
increases may be very poorly tolerated in those with severe
heart failure. One of the most common reasons for failure to
wean is pulmonary edema, which worsens gas exchange
and increases the work of breathing. The correct diagnosis
is made with a careful clinical examination, assessment of
net fluid balance, and review of a chest radiograph. The eti-
ology of the pulmonary edema will guide therapy. Careful
attention to fluid balance and aggressive diuresis or use of
ultrafiltration as indicated for patients with good cardiac
function are essential components of therapy. Patients with
poor cardiac function and pulmonary edema need afterload
reduction and/or inodilator therapy in combination with
diuresis in preparation for successful extubation.
Long-term management of failure to wean is facilitated
by performing a tracheostomy, which allows reduced
sedation, better pulmonary toilet, and utilization of intermit-
tent ventilation, but carries the risk of higher rates of
mediastinitis.53,54 A comparison of open versus bedside per-
cutaneous dilatational tracheostomy in cardiothoracic sur-
gical patients revealed no significant clinical differences but
the potential for significant cost savings with the latter.55
Stabilization Phase
PERFUSION PRESSURE
Adequacy of tissue perfusion and CO can routinely be
assessed with the clinical evaluation of heart rate (HR),
heart rhythm, BP, skin perfusion, capillary refill, and urine
output.56 A patient with good skin perfusion and normal
values for mean arterial blood pressure (MAP), HR, and
urine output probably has a normal CO and sufficient tissue
perfusion. However, these parameters remain insensitive for
dysoxia (abnormal tissue oxygen utilization) and are consid-
ered to be poor surrogates of markers for oxygen delivery at
the tissue level, because tissue oxygenation is determined by

the net balance between cellular oxygen supply and oxygen
demand. Indirect measures of tissue perfusion and oxygen-
ation include the calculation of oxygen delivery or the mea-
surement of mixed venous oxygen saturation (SvO2). SvO2
can be readily measured either intermittently from blood gas
analysis or continuously with a fiberoptic PA catheter. The
importance of monitoring arterial lactate levels in critically
ill patients has been advocated, and concentrations of
greater than 2 mmol/L are generally considered a biochem-
ical marker of inadequate oxygenation.57,58 However, one
must keep in mind that administration of beta-adrenergic
inotropes may create a type-B lactic acidosis through
increased glycolytic activity in skeletal muscles, which
can confound the use of rising lactate to detect hypoperfu-
sion. Other methods to assess tissue perfusion include near-
infrared spectroscopy, gastrointestinal tonometry, and
direct monitoring of tissue oxygenation with miniaturized
implantable Clark electrodes.59–61 A recent study compared
using normal capillary refill time (CRT) with serum lactate
level as a resuscitation target in patients with septic shock.
There was 8.5% of risk reduction of 28-day mortality in the
CRT group compared with the lactate group; however, there
was no significant difference between the two groups.62 In
clinical practice, the combination of both direct monitoring
of tissue perfusion and indirect biomarkers may provide best
resuscitation strategy in critically ill patients.
BLOOD PRESSURE
One of the most dynamic physiologic variables during the
first hour of postoperative ICU care is the MAP, which
changes rapidly as a result of dynamic alterations in preload,
afterload, and ventricular function.63 Fluid shifts and veno-
dilation results in decreased preload, while arteriolar vaso-
dilation from widespread inflammation and sedatives
results in decreased afterload. Myocardial stunning from
ischemia, cardiopulmonary bypass, or deep hypothermic
circulatory arrest may result in both poor ventricular com-
pliance and contractility. Arrhythmogenic disturbances
may also have significant effects on MAP. Bradycardia
can result from conduction system edema, surgical damage,
or drug effects, whereas atrial fibrillation or other losses of
atrioventricular synchrony impede filling of stiff, postopera-
tive ventricles. Although hypotension has no concrete def-
inition, the general consensus is that a MAP goal of 60 to
80 mmHg is ideal and that a systolic BP of less than
90 mmHg or a MAP of less than 60 mmHg denotes hypo-
tension. However, the patient’s baseline BP must be consid-
ered because that determines the range of autoregulation
for end organs such as the brain or kidney. In older adult
patients and those with preexisting cerebrovascular or renal
disease, a higher MAP may be required to perfuse ade-
quately tissue beds that are used to chronic hypertension.
Diastolic BP is a major determinant of myocardial blood
flow, therefore attention must be paid to diastolic BP if myo-
cardial ischemia is evident. Occasionally, the cardiac sur-
geon may request a lower BP target if they deem the risk
of bleeding to be particularly high. Such cases demand a
careful balance of ensuring adequate organ perfusion while
also minimizing bleeding risk.
Hypovolemia is the most common cause of hypotension
in postoperative patients. Peripheral rewarming causes
31 • Cardiac Surgery 491
vasodilation, requiring expansion of circulating blood
volume for treatment. Ongoing bleeding requires intravas-
cular volume replacement. Diagnosis of hypovolemia
relies on clinical observation (vital signs, chest tube
output, urinary output), chest radiograph, and point of care
ultrasound (POCUS).
Although measurements of CVP and pulmonary capillary
occlusion pressure (PCOP) have been commonly used to
determine the need for fluid responsiveness, increasing data
suggest that both the absolute values and their trends can
be misleading, with poor negative and positive predictive
values.64 When used in appropriate clinical situations, more
accurate information is gained from dynamic indicators
such as pulse pressure variation (PPV), stroke volume var-
iation (SVV), and inferior vena cava (IVC) distensibility/col-
lapsibility.65 Because each of these methods attempts to
estimate the response of the cardiovascular system to a fluid
changes, the best confirmation of fluid responsiveness may
be an improvement in stroke volume (and thus CO) mea-
sured by a PA catheter, echocardiography, or carotid
velocity-time-integral (VTI) immediately after the applica-
tion of a small amount of crystalloid or a passive leg raise
test. Patients who do not respond to small amounts of fluid
are unlikely to respond to more volume.66
The best resuscitation fluid to use in cardiac surgery
patients depends upon the clinical scenario. Patients in
hemorrhagic shock from rapid blood loss require rapid
transfusion of blood products, initially given at 1:1:1 ratios
of packed red blood cells, plasma, and platelets to reduce
coagulopathy. Frequent measurements of hemoglobin,
platelets, prothrombin time (PT), partial thromboplastin
time (PTT), and fibrinogen will help guide initial therapy,
while the use of TEG or ROTEM may provide further insight
to the function of the coagulation cascade as a whole and
provide accurate assessment of further product needs.67
Patients who are deemed volume responsive but have
normal blood counts and coagulation parameters and are
without significant amounts of active bleeding are probably
better served by resuscitation with crystalloids to avoid the
risk of transfusion reactions, infections, and immunomodu-
lation associated with blood products. As to the choice of
crystalloid, recent evidence suggests that the use of lactated
Ringer and Plasmalyte as opposed to normal saline results in
the avoidance of a hyperchloremic metabolic acidosis and
improved renal outcomes.68 The use of colloid-containing
fluids in resuscitation continues to be a topic of debate.
Although the use of colloids may result in the need for less
fluid administration to achieve clinically significant results,
they are much more expensive, have not shown consistent
benefits in large clinical trials of critically ill patients, and
have the theoretical risk of distributing oncotically active
substances throughout the body where they act as a nidus
for the development of tissue edema. If colloid resuscitation
is chosen in the cardiac surgery population, the use of albu-
min is preferred over hetastarch because of associations
with increased renal injury from the latter.
Alternative diagnostic and therapeutic options need to be
considered if preload resuscitation is not successful in
improving MAP. Vasodilation with associated, often severe,
hypotension is a frequent complication occurring in up to
8% of patients after CPB and cardiac surgery.69 Although
the underlying mechanisms of this vasodilatory shock
492 PART IV • Early Postoperative Care
remain elusive, low ejection fraction and angiotensin-
converting enzyme inhibitor use have been identified as
predisposing factors, and anesthetic drugs, peripheral
rewarming, anemia, and variable degrees of a systemic
inflammatory response to the extracorporeal circuit may
also contribute.69–71 By directly measuring CO and CVP,
PA catheters allow the calculation of SVR and a rapid diag-
nosis of arterial vasodilation as the cause of low MAP. Before
aggressive measures to increase SVR are taken, it is impor-
tant to ensure that a patient is volume replete and has an
adequate cardiac contractility. Vasopressors may provide
an important temporizing measure to maintain coronary
perfusion pressure while these processes are being corrected
but should then be reevaluated.72 Common first choices of
agents include norepinephrine and vasopressin. The two
have been directly compared as a first-line vasopressor in
both the postcardiac surgical and septic populations.
Although mortality and primary composite outcomes were
similar between the agents, vasopressin resulted in less need
for renal replacement therapy and decreased rates of atrial
fibrillation. When high-dose norepinephrine (>0.1 μg/kg/
min) is required, arginine vasopressin has been proven use-
ful in increasing BP and reducing norepinephrine require-
ments, especially in patients undergoing placement of a
left ventricular assist device (LVAD).73,74 Phenylephrine is
another option if a pure vasoconstrictor is needed, while epi-
nephrine and dopamine are useful agents to provide both
inotropy and SVR support. In the case of severe, refractory
vasoplegia, methylene blue and hydroxocobalamin may be
useful to reduce arteriolar nitric oxide levels.75 When resort-
ing to these agents, be aware that methylene blue can cause
hemolysis in patients with G6PD deficiency and serotonin
syndrome in patients who take serotonergic medications.
Hydroxocobalamin likewise interferes with laboratory tests
that reply on colorimetric analysis and may cause blood-
leak alarms in dialysis machines.76 Regardless of the choice
of agent, when vasoconstrictors are used for a prolonged
period, it is essential to avoid hypovolemia because severe
peripheral hypoperfusion with gangrene may result.
Calcium increases BP without decreasing CO and has a
negligible effect on HR. However, routine use of calcium
to treat hypotension and low CO after cardiac surgery is con-
troversial. Bolus administration of calcium may impair
internal mammary artery (IMA) flow and potentially trig-
gers vasospasm.77 Furthermore, it is undesirable for ionized
calcium levels to be abnormally high, therefore repeated
administration should be guided by blood levels. Low blood
levels may result from citrate accumulation with rapid blood
product transfusion and can reduce vascular responsiveness
to catecholamines. Patients with a significant hepatic failure
are especially vulnerable to hypocalcemia from product
transfusion because of an inability to metabolize citrate rap-
idly. If ongoing blood product transfusion is needed, calcium
levels should be checked frequently to maintain normal ion-
ized calcium level.
Positive-pressure ventilation may produce relative hypo-
volemia, by eliminating the normal venous pressure gradi-
ent for filling the right atrium. Higher driving pressure and
PEEP will both impede the flow of blood into the chest, espe-
cially in the presence of hypovolemia and consequently low
filling pressures. This effect may be magnified in patients
with COPD because of dynamic hyperinflation, where air
trapping prevents full exhalation before the next breath is
delivered by the ventilator. The presence of intrinsic positive
end-expiratory pressure (auto-PEEP) is diagnostic of this
condition. Adjustment of ventilator settings to increase expi-
ratory time will help alleviate this problem. The develop-
ment of a tension pneumothorax as the result of chest
tube obstruction or occult intraoperative lung injury not
drained by a chest tube (usually the right side) can also
acutely compromise right heart filling. Assurance that
breath sounds are present and symmetric on arrival in
the ICU, as well as scrutiny of the initial postoperative chest
radiograph, will identify this potential complication and
guide the therapy (e.g., chest tube placement). Thoracic
ultrasound is also very sensitive for the diagnosis of pneu-
mothorax in the hands of a trained operator. It may allow
diagnosis in an unstable patient faster than waiting for a
chest radiograph.
Some patients present with postoperative hypertension
instead of hypotension in the ICU.78 Systemic BP needs to
be controlled to a MAP range of 70 to 80 mmHg because
an excessive MAP may augment bleeding and create exces-
sive afterload, subsequently myocardial contractility and
compliance are compromised and myocardial oxygen
demand increases. Postoperative hypertension may be
caused by hypoxia, hypercarbia, pain, inadequate sedation,
or shivering. Before therapy with vasodilating agents is ini-
tiated, these causes need to be ruled out. Nitroprusside and
nitroglycerin are routinely used and alternative medications
include nicardipine, labetalol, hydralazine, and esmolol. The
vasodilation provided by propofol may also be helpful to
modify BP rapidly in an intubated patient. Nitroprusside is
widely used because it acts rapidly and can be easily titrated
to effect and in response to sudden changes in preload and
afterload. However, its use has been associated with the
need for compensatory volume replacement, reflex tachy-
cardia, cyanide toxicity, and methemoglobinemia. The hall-
mark of intravenous nicardipine is arterial specificity, which
allows precise titration of BP without affecting the intravas-
cular volume.79,80 This property is significant in periopera-
tive hypertension, because arterial vasoconstriction with
varying degrees of intravascular hypovolemia is a central
characteristic of those patients. Nicardipine results in
decreased mean arterial pressure and systemic vascular
resistance, as well as an increase in CO, but it does not affect
filling pressures.80,81,82
CARDIAC OUTPUT
The routine use of continuous or intermittent measure-
ments of calculated hemodynamic indices is not necessary
for low-risk patients undergoing elective CABG.83 When
PA catheters are used in high-risk or complex cardiac sur-
gical patients, the target cardiac index (CI, equal to CO
per body surface area) is greater than 2.0 L/min/m2. Opti-
mization of the CI is aimed at maximizing the pumping
capacity of the cardiovascular system. A decreasing CI
should be addressed before signs of overt hypoperfusion
and tissue hypoxia develop, even if the baseline CI was
low. Clinical measures of right and left ventricular perfor-
mance, such as preload or volume status, afterload (SVR),
HR, and myocardial contractility, are essential to guide
therapy toward a stable hemodynamic status.56 Blood,

crystalloids, or colloids may be infused to increase preload.
CI can also be improved by optimizing afterload with a vaso-
dilator such as nitroprusside. With an optimized preload and
afterload, CI can sometimes be increased by atrial or atrio-
ventricular (AV)-sequential pacing using epicardial pacing
wires at a higher rate over the intrinsic HR. If preload
and afterload are optimized, stroke volume (SV) would nor-
mally remain the same and a higher HR would increase the
CI. If the target CI of greater than 2.0 L/min/m2 is not
achieved with optimization of preload, afterload, and HR,
inotropic agents are usually required to improve cardiac
contractility. There do not appear to be significant differ-
ences in patient outcome among the commonly used ino-
tropes, but cardiac surgeons and intensivists often have
personal preferences based on familiarity with the agent
and clinical experience. One critical distinction to make in
a hypotensive patient is between the relative intravascular
hypovolemia from vasodilation during warming and the
hypovolemia secondary to bleeding. Myocardial contractil-
ity may further diminish during the immediate postopera-
tive period63, mandating continued inotropic support or
augmentation of support with mechanical assistance (e.g.,
intra-aortic balloon pump [IABP]).
An array of inotropic agents exists, including epineph-
rine, milrinone, dobutamine, and dopamine. Intimate
knowledge of each drug’s inotropic, vasodilatory or vaso-
constrictive, and chronotropic profile is warranted to
achieve the desired effect. Combinations of inotropic and
vasoconstrictive agents are selected when significantly
reduced contractility is associated with severe hypotension.
This is typical for phosphodiesterase inhibitors such as mil-
rinone that often provide the wanted inotropic effect but not
without significant vasodilation. Therefore, norepinephrine
or vasopressin may be required in combination with milri-
none to address the typical postoperative vasodilation that
is related to the milrinone. Combining milrinone and epi-
nephrine allows utilizing their different inotropic actions
together with the vasoconstrictive effect of epinephrine for
the treatment of hypotension. If the need for milrinone is
anticipated in the operating room, it is ideally started during
CPB to avoid a loading dose with its inherent hypotension.
In addition to its inotropic effect, milrinone also provides
lusitropy, which is beneficial in patients with severe diastolic
dysfunction. Dopamine may be selected as an alternative
choice agent either to increase CO or to allow weaning of
epinephrine, but it might result in excessive tachycardia
and increase the risk of atrial fibrillation. Dobutamine is gen-
erally associated with a positive chronotropic response and
may be a good choice to increase CO if pulmonary artery
pressures are elevated and baseline HR is low.84
MODES OF MECHANICAL SUPPORT
Mechanical circulatory support (MCS) is either initiated
preemptively in the operating room or provided in the ICU
when low CO persists despite adequate preload, optimal sys-
temic vascular resistance, and maximal inotropic support.
Forms of short-term MCS include IABPs, single-catheter
microaxial pumps (Impella, [Abiomed Inc., Danvers, MA]),
multicatheter extracorporeal pumps (TandemHeart
[Cardiac Assist Inc., Pittsburgh, PA], CentriMag [Thoratec,
Pleasanton, CA]), and venoarterial extracorporeal life
31 • Cardiac Surgery 493
support (VA ECLS). Long-term, “durable” devices include
implantable LVADs and the total artificial heart (SynCardia
[SynCardia Systems, Inc, Tucson, AZ]). A detailed descrip-
tion of these devices and their management is outside the
scope of this text, but a brief summary is presented.
The decision to initiate MCS must be individualized for
each patient. Persistent low CO and hypotension in con-
junction with an elevated SVR, fluid nonresponsiveness,
inadequate response to inotropes, and signs of tissue hypo-
perfusion should generally prompt consideration of MCS
options. A potentially helpful tool is the cardiac power index
(CPI), which normalizes cardiac power output to body sur-
face area (BSA) with the following formula: CPI ¼ (MAP 
CI)/451. CPI has been found to be correlated with mortality
in cardiogenic shock in multiple studies. Retrospective data
suggest that values below 0.34 watts/m2 at the time of
device implantation are associated with increased 90-day
mortality.85 CPI below that level should thus suggest rapid
initiation of mechanical support.
Once the decision to undertake MCS is made, the specific
device is chosen in consultation with surgical and interven-
tional cardiology teams. If right heart function is deemed
adequate, commonly used left-sided devices are the IABP
and Impella. An IABP increases coronary perfusion pressure
by inflation during diastole and also reduces afterload by
deflation during systole. The resulting improvement in myo-
cardial oxygen supply and decrease in demand has the
potential to increase CO significantly. However, the device
requires sinus rhythm without marked tachycardia for
proper inflation timing at aortic valve closure, as well as a
patent aortic valve (no more than mild aortic regurgitation
present). It also provides very little direct hemodynamic sup-
port. Impellas, on the other hand, pump blood directly from
the left ventricle (LV) into the ascending aorta and do so
regardless of HR or rhythm. Current evidence does not sup-
port a mortality benefit of one device versus the other in
undifferentiated cardiogenic shock. If needed, higher flow
rates may be achieved through the use of extracorporeal
centrifugal devices that utilize separate inflow and outflow
cannulas such as the CentriMag and TandemHeart. These
devices may also be configured to provide right ventricular
support (CentriMag) or offer full biventricular support
(TandemHeart).
If biventricular failure is present, temporary MCS is best
provided by VA ECLS. Venous and arterial cannulas may
be placed centrally in the operating room or peripherally
at the bedside. By removing blood from the right atria,
pumping it through an oxygenator, and reinjecting it into
the arterial system (the aorta in central cannulation; usu-
ally the femoral artery in peripheral cannulation), VA
ECLS allows temporary, near-total unloading of a failing
cardiopulmonary system. Like all other continuous flow
support devices, adequate flows are highly preload depen-
dent and afterload sensitive. Common complications
include bleeding, thrombosis, and limb ischemia. VA ECLS
may also lead to LV distension, with corresponding LV
thrombus formation and wall ischemia, if there is lack of
LV unloading and native contractility remains poor.
Options for LV unloading include Impella, IABP, atrial sep-
tostomy, or direct surgical vent via apex or left atrium.86
Peripheral cannulation has the further complication of dif-
ferential hypoxia, where poorly oxygenated blood from the
494 PART IV • Early Postoperative Care
lungs is ejected out of a recovering ventricle and competes
with well-oxygenated blood from the femoral cannula,
potentially causing hypoxic conditions in the right side
of the aortic arch. Detection is facilitated by monitoring
pulse oximetry and arterial blood gas from the right upper
extremity.
Weaning from temporary support devices in the post-
cardiac surgery setting is facilitated by transesophageal
echocardiography (TEE). Device flow can be gradually
decreased while paying careful attention to ventricular
function and hemodynamic values. Be aware that most
devices have minimum recommended flow settings to pre-
vent thrombosis and flows should not be decreased below
such levels unless immediate decannulation is planned.
Although the bedside intensivist is unlikely to be
involved in the decision to place long-term, durable sup-
port devices, a knowledge of their function, management,
and common complications is necessary during their post-
implantation ICU stay. LVADs draw blood from an inflow
cannula at the LV apex and reinject into an aortic outflow
cannula. They may be placed as a bridge to heart trans-
plant (BTT), bridge to recovery, or destination therapy
(DT). While first generation LVADs produced pulsatile
flow, modern third generation devices produce continuous
flow via a centrifugal pump utilizing a magnetically sus-
pended impeller. The HeartMate 3 (Abbott, Abbott Park,
IL) and Heartware HVAD (Medtronic, HeartWare, Miami
Lakes, FL) are the two centrifugal devices currently on
the market. The HeartMate II is a second generation, non-
pulsatile, axial flow device, which until recently was the
preferred device for DT. Currently, HeartMate 3, HVAD
and HeartMate II are all devices approved by the Food
and Drug Administration for both BTT and DT. One nota-
ble complication of LVAD placement is right heart failure,
which may occur as a result of both altered morphology
and contractility from intraventricular septal shifting, as
well as because of increased right ventricular preload sec-
ondary to an increase in CO and thus increased venous
return. Careful attention should be given to CVP, PA pres-
sure, and signs of venous congestion in the immediate
postimplantation period. Treatment is through inotropes,
diuresis, pulmonary vasodilators, and reduction of pump
speed to minimize septal shift. Other complications include
device thrombosis, infection, and hemolysis.
Postoperative Complications
BLEEDING
Patients undergoing cardiac surgery with CPB frequently
have a variety of derangements of hemostasis (with striking
interpatient variability poorly explained by clinical, proce-
dural, biologic, and genetic markers) that frequently result
in transfusion of allogeneic blood products.87 More than 12
million units of allogeneic red blood cells (RBCs) are
administered in the United States annually, with more than
2 million units administered to patients undergoing cardio-
vascular surgery.88 Institutions vary significantly in periop-
erative blood conservation and transfusion practices for
cardiac surgery patients. Depending on the institution,
between 27% and 92% of CABG patients are transfused,
and the number of units of packed cells received ranges from
0 to 4.88,89 Patients undergoing repeat sternotomy for car-
diac surgery are approximately three times more likely to
receive a perioperative transfusion than those undergoing
primary cardiac surgery.90 Transfusion-related complica-
tions have decreased significantly in the last 10 to 15 years
but still remain a concern.
The transfusion of allogeneic RBCs has recently been
described as a risk factor for decreased long-term survival
after CABG surgery.91 Another recent study showed that
the storage duration of perioperatively transfused RBCs is
associated with an increased risk of both short-term in-
hospital and long-term out-of-hospital mortality, indepen-
dent of the number of transfusions administered and other
confounding factors.92 Other risks include hepatitis C infec-
tion (approximately 1 in 50,000), transmission of the
human immunodeficiency virus (less than 1 in 500,000),
major ABO group incompatibility (less than 1 in 33,000),
and minor transfusion reactions (approximately 1 in 5).93,94
According to the American Society of Anesthesiologists
(ASA), the cost of transfusion therapy approaches $5 to
$7 billion per year in the United States, with up to 25% of
RBC transfusions judged to be unnecessary. The ASA
strongly advocates judicious use of blood products and
has published a set of practice guidelines.93 Although prac-
tice guidelines are imperfect and must not replace clinical
judgment, the ASA guidelines provide a scientifically based
model to assist decision making. However, in the cardiac
surgical patient population, the ASA guidelines fail to
account for platelet dysfunction known to occur after
CPB. When major bleeding occurs in this patient group,
platelet transfusion is indicated even when platelet count
is greater than 100,000.95
Unfortunately, practice guidelines such as those from the
ASA and the College of American Pathologists do not seem
to change old transfusion habits and inappropriate use of
blood products has not been curtailed, especially in the car-
diac surgical population.95 One possible reason for lack of
success is that the time delay until coagulation results
return from the laboratory makes directed transfusion ther-
apy difficult in a bleeding patient. In response to this prob-
lem, several rapid assay devices are being developed. When
combined with goal-directed transfusion algorithms, such
point-of-care tests may improve care and limit unnecessary
transfusions.96 These algorithms usually incorporate some
measure of platelet function, coagulation factor activity,
and fibrinolysis as the stimulus for therapy. Although not
perfect, thromboelastography appears to be a key compo-
nent of such algorithms. Because its negative predictive
value is greater than 90%, a normal TEG implies with
greater than 90% certainty that a bleeding patient needs
to return to the operating room and a surgical bleeder will
be found. Incorporation of TEG produced a significantly
reduced rate of reoperation for bleeding in a single-center
study.96
Other strategies for limiting blood product requirements
show some benefit in clinical trials. Antifibrinolytic therapy
decreases the incidence of excessive postoperative bleeding
caused by fibrinolysis.97–99 Effective antifibrinolytic agents
include ε-aminocaproic acid (Amicar [numerous sources]),
tranexamic acid, and aprotinin. Aprotinin is the only agent
with class A level 1 evidence for reduction in rates of

transfusion and return to operating room to control bleed-
ing after heart surgery. However, because of its increased
risk for thrombosis and renal dysfunction, aprotinin was
withdrawn from the market in 2007.97 Amicar and tra-
nexamic acid have been shown to reduce total blood loss
and decrease the number of patients who require blood
transfusion during cardiac surgery.101,102 In the 2011
update to The Society of Thoracic Surgeons and the Society
of Cardiovascular Anesthesiologists Blood Conservation
Clinical Practice Guidelines, antifibrinolytic agents were
strongly recommended (level of evidence A) for blood
conservation.103
Intraoperative autologous hemodilution has also demon-
strated a blood-sparing effect in some studies,104 but postop-
erative use of cell salvage has not proven to be effective in
limiting the use of blood products in cardiac surgery.105
Reinfusion of shed mediastinal blood may be associated
with a greater frequency of wound infection and is not
recommended.106
In current postoperative practice, hemostasis is assessed
by measuring the amount of blood draining out of the chest
tubes. Prothrombin time and activated partial thromboplas-
tin time are normally slightly elevated after cardiac surgery.
An activated clotting time may also be used as a point-of-
care test for adequate reversal of heparin given during sur-
gery. As outlined earlier, the incorporation of TEG as a
point-of-care monitor into a specific transfusion algorithm
allows a more specific diagnosis of bleeding problems and
a reduction of indiscriminate transfusion practices. Fresh
frozen plasma (FFP) is not required when there is no signif-
icant drainage from the chest tubes; if drainage from the
chest tube exceeds 400 mL in the first 2 hours and 100
to 150 mL/h after the first 2 hours, FFP is probably required
to stop the bleeding. Infusion of 10 mL/kg of FFP normally
restores the coagulation factors to an adequate level. It is
also important to consider platelet transfusion in a bleeding
patient after CPB even if the platelet count is greater than
100,000/μL, because platelet function might be impaired
as a result of exposure to CPB. Cryoprecipitate is added when
the fibrinogen level is low.
In cases of severe ongoing bleeding despite transfusion of
blood products, prothrombin complex concentrate (PCC)
can be considered. The PCC contains relatively high levels
of factors II, IX, and X, and in some preparations, inactive
or activated form of factor VII. Compared with plasma,
PCC is administered in much smaller volume, is free of trans-
fusion reactions associated with plasma, and acts faster. PCC
was originally approved for emergency reversal of warfarin
or novel oral anticoagulants (NOAC) therapy when anti-
dotes are unavailable. The off-label use of PCC for microvas-
cular bleeding attributed to coagulation factor deficiencies
has recently shifted from rescue therapy to earlier and even
first-line therapy in some centers. Currently there is insuffi-
cient evidence to recommend a universal transition toward
the use of PCCs in lieu of plasma therapy for microvascular
bleeding associated with cardiac surgery. When used, the
inactive PCC (Kcentra; CSL Behring, King of Prussia, PA)
is recommended over activated factor concentrates such
as recombinant activated factor VII (rFVIIa, NovoSeven)
or anti-inhibitor coagulant complex (FEIBA, Shire, Dublin,
Ireland) because of concern for thromboembolic complica-
tions associated with the latter.100
31 • Cardiac Surgery 495
The chest tubes need to be evaluated on a regular basis to
avoid clogging by blood clots. When there is a sudden
decrease in drainage from the chest tubes, the intensivist
should exclude the possibility of concealed bleeding in the
mediastinum and pericardial sac, which can lead to cardiac
tamponade. If the response to blood transfusion is not
satisfactory, exploratory sternotomy should be seriously
considered.107,108
CARDIAC DYSRHYTHMIA
Transient alterations in HR or conduction may contribute to
postoperative hypotension or low CO. When BP or CO is
marginal, augmenting the HR should be considered, even
if it is already in the normal range. Abnormal patterns
within the first 24 hours include transient bradyarrhyth-
mia, sinus tachycardia (>110 beats/min), and, in cases of
valvular surgery, junctional tachycardia with atrioventric-
ular interference or even heart block. Significant ventricular
dysrhythmias are rare but if present may present a chal-
lenge to treat.
Bradyarrhythmia is common after cardiac surgery, and
atrial and ventricular epicardial pacing wires are typically
placed to facilitate temporary pacing in the immediate post-
operative period. Optimal pacing modalities have been
investigated.109 Dual-chamber pacing maximizes CO over
a wide range of AV delay (100 to 225 milliseconds). Condi-
tions impairing diastolic filling (ventricular hypertrophy,
cardiomyopathy, fibrosis) may benefit by extending the
AV delay.
The rate of pacemaker dependency after cardiac surgery
varies between studies and is approximately 1% after CABG,
2% after primary valve replacement, 7% after repeat valve
replacement, and 10% after orthotopic heart transplant
(OHT).110–112 Identified risk factors include annular calcifi-
cation, older age, preoperative left bundle branch block, and
increased CPB time. The etiology of bradyarrhythmia
includes ischemia, edema, and irreversible surgical destruc-
tion of the conducting system. Recovery from the reversible
causes can be considerably delayed. Permanent pacemakers
are typically implanted for symptomatic sinus node dysfunc-
tion or AV block lasting beyond the fifth postoperative day.
In the long term, up to 40% of patients with sinus node dys-
function and up to 100% of patients with complete AV block
past day 5 remain pacemaker dependent.
For heart transplant patients, chronotropic medication
may avoid the need for a permanent pacemaker.112,113
Sinus node dysfunction is five times more likely than AV
block to result in permanent pacemaker implantation in this
group. Both types of dysfunction can be significantly
reduced with bicaval rather than biatrial anastomoses.112
Atrial dysrhythmias (primarily atrial fibrillation [AF]) are
by far the most common complication after cardiac surgery,
with an incidence consistently reported to range between
27% and 40% and with little change over the past 2
decades.114 AF most commonly occurs 2 to 3 days after sur-
gery and can increase hospital stay, risk of stroke, risk of
neurocognitive deficits, and mortality.114–118 Those who
have undergone valvular surgery are at greatest risk.
Patients with preexisting AF may return from the operating
room in sinus rhythm and soon revert back to AF. If an atrial
epicardial lead is in place, an atrial electrocardiogram can
496 PART IV • Early Postoperative Care
be conducted when the rhythm or conduction cannot
otherwise be diagnosed.119 Use of adenosine is another option
for diagnosis and possible therapy when the atrial arrhythmia
is not AF.120 The exact pathogenesis of postoperative AF
is unclear. Structural changes in the atria, reduced threshold
for dysrhythmia generation, and a hyperadrenergic state
after CPB and surgery are all suggested as mechanisms.
Associated risk factors for the development of AF include
advanced age, history of atrial fibrillation or chronic obstruc-
tive pulmonary disease, prolonged CPB and aortic cross-
clamp times, left atrial enlargement, cardiomegaly, valve
surgery, and postoperative withdrawal of a beta blocker or
an angiotensin-converting enzyme (ACE) inhibitor.114,118,121
Pharmacologic prophylaxis against AF is controversial.
Prophylactic therapy includes supplemental magnesium,
potassium, and use of beta blockade in the perioperative
period to reduce the incidence of AF.122,123 The American
College of Cardiology and American Heart Association task
force consensus recommendations for prevention and man-
agement of AF are summarized in Box 31.2.124,125 In the
largest trial of amiodarone in patients undergoing CABG
surgery or valve replacement or repair surgery reported to
date, prophylactic amiodarone was shown to reduce effec-
tively the incidence of postoperative AF.126 Management
of postoperative supraventricular tachycardia (SVT)
depends on the patient’s clinical condition. If appropriate,
a 12-lead ECG and an atrial rhythm strip via the atrial pac-
ing electrodes aid diagnosis of the exact rhythm. Postoper-
ative therapy of AF includes the correction of electrolyte
abnormalities, empirical administration of magnesium
and potassium, and amiodarone or beta blockade. If phar-
macologic restoration of sinus rhythm fails or if hemody-
namic instability merits immediate synchronized direct
Box 31.2 Recommendations for prevention and
management of postoperative atrial fibrillation.
Class I
▪ Treat patients undergoing cardiac surgery with an oral beta
blocker to prevent postoperative atrial fibrillation (AF), unless
contraindicated. (Level of evidence: A)
▪ In patients who develop postoperative AF, achieve rate control
by administration of atrioventricular nodal blocking agents.
(Level of evidence: B)
Class IIa
▪ Administer sotalol or amiodarone prophylactically to patients at
high risk of developing postoperative AF or those who do not
tolerate beta blockade. (Level of evidence: B)
▪ In patients with recurrent or refractory postoperative AF, it is
reasonable to restore sinus rhythm by administration of anti-
arrhythmic medications or direct-current cardioversion. (Level of
evidence: B)
▪ It is reasonable to administer antithrombotic medication in
patients who develop postoperative AF that persists more than
48 hours. (Level of evidence: B)
Reprinted with permission from Fuster V, Ryden LE, Cannom DS, et al:
ACC/AHA/ESC 2006 guidelines for the management of patients with
atrial fibrillation. Developed in collaboration with the European Heart
Rhythm Association and the Heart Rhythm Society. Reprinted with
permission Circulation 2006;114:e257-e354. © 2006 American Heart
Association, Inc.
current (DC) cardioversion, electrical cardioversion is
attempted with an initial energy of 200 J for AF and 50
to 100 J for atrial flutter. Restoration of sinus rhythm rather
than simple rate control is the ultimate goal. After AF lasts
more than 48 hours (sustained or paroxysmal AF), or AF of
an unknown duration, it is reasonable to initiate anticoagu-
lation despite the recent cardiac surgery.
Premature ventricular complexes or ventricular
arrhythmias are also common after surgery and often asso-
ciated with electrolyte imbalances or may be introduced
during pulmonary artery catheter placement. Other causes
include hemodynamic instability, hypoxia, hypovolemia,
ischemia, myocardial infarction, acute graft closure, proar-
rhythmic effects of inotropic drugs, and effects of antiar-
rhythmic drugs.117 Sustained ventricular dysrhythmias
after cardiac surgery are uncommon, with an incidence
of about 1%.118 Initial treatment of hemodynamically sig-
nificant ventricular dysrhythmias is immediate defibrilla-
tion and administration of amiodarone or lidocaine.
Prognosis of postoperative frequent premature ventricular
complexes and nonsustained ventricular tachycardia in
patients with normal ventricular function is no different
from controls. However, patients with nonsustained
ventricular dysrhythmia and an LV ejection fraction of less
than 40% demonstrate 75% mortality at 15-month follow-
up.117 Patients with sustained ventricular dysrhythmias
have a poor short- and long-term prognosis, with hospital
mortality of 50%.119 An additional 20% of the survivors
have cardiac death within 24 months.120 These poor
outcomes merit aggressive therapy, particularly in the
higher-risk patient with LV dysfunction. All electrolyte
abnormalities should be corrected quickly. Ventricular
fibrillation and pulseless ventricular tachycardia require
immediate defibrillation or cardioversion in accordance
with advanced cardiac life support (ACLS) guidelines. Syn-
chronized DC cardioversion with 200 to 360 J is used for
symptomatic sustained ventricular tachycardia with a
pulse. Stable sustained monomorphic ventricular tachycar-
dia may be treated initially with intravenous antiarrhyth-
mic medication. Procainamide may be infused at a rate of
30 to 50 mg/min up to a maximum dose of 17 mg/kg or
a widening of the QRS complex by 50%. The loading dose
is followed by an intravenous continuous infusion of 1 to
4 mg/min. Dosage reductions are appropriate for older
adult patients and patients with congestive heart failure
or hepatic dysfunction. Lidocaine or amiodarone are good
alternatives, especially in patients with LV dysfunction.
For patients with ventricular epicardial wires in place,
conversion of stable ventricular tachycardia using overdrive
ventricular pacing may be attempted by burst pacing the
ventricle at rates greater than the native rate. Acceleration
of the ventricular tachycardia may sometimes end in ven-
tricular fibrillation and it is important to have a defibrillator
immediately available.
Long-term management of patients with dysrhythmia
depends on the severity of the condition. With sustained ven-
tricular dysrhythmias, electrophysiologic testing is per-
formed to evaluate whether antiarrhythmic medication or
implantation of an implantable cardioverter-defibrillator
(ICD) may be beneficial to the patient. A recent study demon-
strated that ICD is superior to drug therapy for patients with
hemodynamically significant ventricular arrhythmias.122

CARDIAC TAMPONADE
The clinical features of tamponade (unlike those of the more
classical “primary” tamponade) after cardiac surgery are
not specific and this can delay diagnosis. In practice, the
threshold for investigation must be low, and echocardiogra-
phy (both transesophageal and transthoracic) has been
invaluable in the detection and localization of pericardial
collections.123,124 Clinical and hemodynamic findings
include hypotension, low CO, low urine output, and elevated
CVP. This may be accompanied by a sudden decrease in
drainage from the chest tubes.126 Concealed bleeding in
the mediastinum and pericardial sac after excessive postop-
erative bleeding is the most likely etiology for cardiac tampo-
nade after cardiac surgery. Immediate reopening of the chest
and evacuation of the clot usually provides dramatic hemo-
dynamic improvement. Cardiac tamponade typically occurs
within the first 12 hours after cardiac surgery, although
delayed-onset tamponade may present a week or more later,
especially when patients are anticoagulated.127
POSTOPERATIVE MYOCARDIAL INFARCTION
The risk of a postoperative myocardial infarction (MI) exists
from immediately postoperatively through hospital dis-
charge and thereafter. Postoperative myocardial ischemia
as a result of incomplete revascularization or acute occlu-
sion of either the native coronaries or the bypass grafts
can result in a low CO state. This condition is diagnosed
by new segmental wall motion abnormalities on TEE or
regional ECG changes. However, high peak enzyme level
of postoperative creatine kinase MB (CK-MB), especially
when 20 times the upper limit of normal (or more), is a
stronger predictor of adverse outcomes than postoperative
Q-wave myocardial infarction and also predicts increased
mortality in this population.128,129 Troponin I levels gener-
ally exceed those seen in myocardial infarction in noncar-
diac surgery settings.129,131 A combination of serial ECGs
and enzyme profiles often helps with the diagnosis, but spe-
cific diagnostic criteria do not exist. Inotropic agents tend to
be less effective and are arrhythmogenic in ischemic areas.
Nitroglycerine, milrinone, or an IABP may sufficiently
improve myocardial perfusion, but reexploration (with or
without diagnostic angiography) remains the definitive
approach for an occluded bypass graft.
ACUTE KIDNEY INJURY
Acute renal impairment and renal failure are still significant
medical problems, occurring in 7.2% of all hospital patients
and 30% of those admitted to an ICU.132,133 The incidence
of acute renal failure (ARF) requiring dialysis after cardiac
surgery is approximately 1% to 4%. Significant postopera-
tive worsening of renal function is observed in approxi-
mately 7% of patients, and approximately 15% of these
patients require dialysis. The importance of postoperative
renal dysfunction lies in its consistent association with
increased rates of in-hospital mortality, perioperative cost,
and length of stay in the ICU, even after adjustment for other
contributing factors.134–137 Patients with renal dysfunction
are also more likely to be discharged to an extended-care
facility, with its associated financial and emotional costs.138
31 • Cardiac Surgery 497
Many issues related to postoperative renal protection are
similar to those discussed for the intraoperative period (e.g.,
ensure adequate renal perfusion and avoid nephrotoxins). A
number of agents including dopamine, fenoldopam (a selec-
tive dopamine-1 receptor agonist), diuretics (furosemide,
mannitol), and nesiritide (a natriuretic peptide) have been
proposed to be renoprotective. Nevertheless, current data
do not support their use for prophylaxis against renal injury
in cardiac surgery.
Unfortunately, once renal dysfunction has occurred,
there are no specific therapies for its amelioration; treatment
is supportive only by means of ensuring adequate renal per-
fusion and avoiding nephrotoxins. In the absence of effective
treatment strategies to reverse renal injury, the major
emphasis is on prevention (see Chapter 17). Identification
of risk factors plays an important role in renal protection dur-
ing cardiac surgery. One of the most powerful postoperative
predictors of renal dysfunction is depressed cardiac function
after CPB. Postoperative evidence of myocardial dysfunction,
including low CO state and need for inotropic support, is asso-
ciated with a twofold to fourfold increased risk of renal injury.
Prolonged positive-pressure ventilation, preexisting cyto-
megalovirus infection, and postoperative sepsis present addi-
tional risk of renal dysfunction and acute renal failure.
Monitoring kidney function remains a challenge and no
single test evaluates all renal activity. Despite its nonlinear
relationship with glomerular filtration rate (GFR), the test
for serum creatinine is most commonly used to assess peri-
operative renal function. Plasma creatinine reflects a state of
equilibrium between creatinine production and excretion
and is influenced by sex, weight, and especially age. Creatine
clearance and fractional excretion of sodium are probably
better reflections of true renal function.
While the search for clinically proven renal protective
drugs continues, current perioperative management of
the cardiac surgical patient should include measures to
ensure minimal renal stress, such as maintenance of ade-
quate perfusion and intravascular volume and the preven-
tion of hypoxemia. Although no firm evidence supports the
use of any drug to protect the kidney, several “renal protec-
tive” regimens have been proposed. These include dopa-
mine, fenoldopam (a selective dopamine-1 receptor
agonist), diuretics (furosemide, mannitol), and nesiritide
(a natriuretic peptide).
The proposed mechanism of renoprotection by dopamine
is through the activation of peripheral dopaminergic recep-
tors (DA1) with a “renal dose” of 0.5 to 3.0 μg/kg/min,
resulting in the DA1-mediated natriuretic, diuretic, and
renal vasodilating properties. Although dopamine has been
shown on animal models to provide significant improve-
ments in renal function after renal injury, human clinical
studies have not demonstrated a similar benefit. Dopamine
increases global renal blood flow without augmenting med-
ullary blood flow and therefore does not prevent medullary
hypoxia. Significant complications such as tachycardia,
atrial fibrillation, myocardial ischemia and intestinal ische-
mia are associated with intravenous dopamine, even at low
dosages.139 The 2012 KIDGO guidelines recommend
against using dopamine to prevent ischemic acute tubular
necrosis.
The potential usefulness of selective DA1-receptor ago-
nists, such as fenoldopam and dopexamine (not available
498 PART IV • Early Postoperative Care
in the United States), as renal protective agents has yet to be
determined. The largest randomized controlled trial per-
formed on fenoldopam in postcardiac surgery patients with
AKI found no difference in the need for RRT or mortality
compared with the placebo. Furthermore, fenoldopam use
was associated with a higher incidence of hypotension.140
Meta-analyses showed that among patients treated with
fenoldopam, there was a decrease in AKI and an increased
incidence of hypotension, and there was no significant effect
on RRT or mortality. 140 Given that most studies were small
and the definition of AKI was variable between studies,
there is not enough evidence to support the systematic
use of fenoldopam in cardiac surgery. Similarly, existing evi-
dence is inconsistent and insufficient to recommend dopex-
amine for renoprotection for either high-risk surgical or
critically ill patients.140
The rationale underlying renoprotection from diuretics
relates to the induced diuresis and natriuresis and the
decreased likelihood of tubular obstruction by casts after a
renal insult. This may retain tubular patency and avoid oli-
guria or anuria and the need for dialysis. Osmotic diuretics,
such as mannitol, also reduce tubular swelling to achieve
this goal, but a secondary proposed protective property
unique to loop diuretic agents, such as furosemide, is a
reduction in medullary tubular oxygen consumption and
a proposed antioxidant effect. Animal models of myoglobi-
nuric and ischemic renal failure demonstrate a protective
effect from mannitol. However, with the exception of useful-
ness in the setting of early myoglobinuric ARF and renal
transplantation, the clinical renoprotective effects of
mannitol have not been confirmed.138 There is similarly
no convincing clinical evidence to advocate the use of furo-
semide for renoprotection. Importantly, the increased urine
output from diuretics does not ensure improved renal func-
tion.139 In contrast, both furosemide and mannitol have
been incriminated in aggravating renal injury in some set-
tings. A deleterious property common to the use of all
diuretics is that they can induce dehydration if intravascu-
lar volume status is not carefully monitored. Although there
is some evidence that oliguric renal failure can be converted
to nonoliguric renal failure by the use of diuretics, there is no
proof that the reduced mortality seen with nonoliguric renal
failure applies to patients receiving diuretics after cardiac
surgery.
Nesiritide, a natriuretic peptide, has been proven to be of
benefit in the treatment of decompensated heart failure and
may have potential in the treatment of postoperative
patients with congestive heart failure and concurrent renal
dysfunction. Natriuretic peptides block tubular reabsorption
of sodium, vasodilate afferent arterioles, and inhibit the
renin-angiotensin system. Nevertheless, at this point, its
benefit is not clear and its expense and the risk associated
with its use (severe hypotension) may outweigh any benefit
derived.
Intensive insulin therapy had been shown to reduce acute
renal failure requiring renal replacement therapy (RRT) in
an early trial.141 However, the later NICE-SUGAR (Normo-
glycemia in Intensive Care Evaluation Survival Using Glu-
cose Algorithm Regulation) trial compared patients
receiving intensive insulin therapy (target blood glucose
level of 81–108 mg/dL) with a conventional glucose control
(target blood glucose of <180 mg/dL). There was no
difference in the percentage of patients requiring RRT or
in the duration of RRT.142
Absolute indications for initiating renal replacement ther-
apy include fluid overload, refractory hyperkalemia or aci-
dosis, and severe uremic symptoms.
NEUROLOGIC COMPLICATIONS
Neurologic injury after cardiac surgery ranges from inca-
pacitating or life-ending stroke and coma to encephalopa-
thy, delirium, and neurocognitive decline, which have
been described by many investigators.143–146 Although
stroke after cardiac surgery is an important concern for both
short- and long-term disability, more subtle neurologic def-
icits such as encephalopathy and neurocognitive dysfunc-
tion are also associated with an increase in medical costs
and a decrease in short- and long-term cognitive function
and quality of life.143,147 Successful strategies for perioper-
ative cerebral protection begin with accurate individual
patient risk assessment. Although studies differ somewhat
as to all the risk factors, certain patient characteristics con-
sistently demonstrate an increased risk of neurologic injury
associated with cardiac surgery. The factors representing
key predictive variables in a recently validated model
include advanced age, history of symptomatic neurologic
disease, prior CABG surgery, vascular disease, unstable
angina, diabetes, and pulmonary disease.148
Appropriately, most current strategies aimed toward risk
reduction involve intraoperative and preventive measures.
However, tailoring anesthetic technique to allow earlier
postoperative awakening may play a significant role in
the assessment and treatment of patients with postoperative
neurologic dysfunction.149 Patients remaining comatose
after surgery require early attention and the initiation of
diagnostic steps. Metabolic abnormalities, drug side effect
or overdose, and a primary central nervous system injury
need to be ruled out. Management includes withholding
of all sedatives, opioids, and muscle relaxants, and assess-
ment of peripheral neuromuscular function. An early com-
puterized tomographic (CT) or magnetic resonance imaging
(MRI) scan to rule out structural lesions or cerebral hemor-
rhage is warranted if the patient is stable enough for the test.
Electrophysiologic assessment includes electroencephalog-
raphy (EEG) and evoked potential monitoring. Early assess-
ment may also allow immediate intervention.
Postoperative delirium occurs in 32% to 73% of all
patients undergoing cardiac surgery, and the incidence var-
ies with patient risk factors, type of surgery, and method of
assessment.151,152 Delirium has been associated with
increased 5-year mortality after surgery.152 Initial manage-
ment includes reassurance and reorientation of the patient,
and adequate pain control. Certain medications have been
associated with increased risk of delirium and should be
avoided. These medications include benzodiazepines, cer-
tain opioids (meperidine), anticholinergics (scopolamine),
ketamine, and metoclopramide, etc. Dexmedetomidine has
been shown to decrease the incidence of delirium in elderly
patients after noncardiac surgery.153 For patients who
remain agitated and confused, haloperidol might be useful.
However, prophylactic haloperidol is not recommended to
prevent delirium. When agitation persists despite repeated
doses of haloperidol (up to 5–10 mg total dose),

dexmedetomidine infusion can be considered to treat the
persistent delirium.
POSTOPERATIVE FEVER AND INFECTIONS
Infection rates in patients undergoing cardiac surgery tend
to be higher than those in patients undergoing general sur-
gery.150 A number of factors are involved, including pro-
longed operative time, presence of indwelling catheters,
deleterious effects of CPB on the immune system, poor tissue
perfusion, hyperglycemia, and implantation of foreign mate-
rial. The magnitude of the problem is significant, with one
series reporting 71% of perioperative site cultures in patients
undergoing open heart procedures as positive.153,154
The overall incidence of postoperative infections has been
reported to be between 2% and 20%, resulting in signifi-
cantly prolonged hospitalization and substantial cost
increases.155–157
Severe infectious complications include sepsis and deep
sternal wound infections (DSWI) with associated mediasti-
nitis. DSWI is one of the most devastating infectious compli-
cations of cardiac surgery. It occurs in about 1% to 2% of
cardiac operations, with resulting mortality approaching
10%.158 Clinical features include redness and tenderness
over the sternum, wound drainage or discharge (70%–
90% of cases), inability to wean from vasopressor or venti-
lator support, sternal instability, fever, and leukocytosis.
Antibiotic therapy should be guided by culture results,
but debridement and flap closure achieve healing in most
cases. Indications for reoperation depend on the depth
and severity of the infection. Risk factors for DSWI include
diabetes, obesity, peripheral artery disease, tobacco use, low
CO, use of bilateral internal mammary artery grafts, and
reoperation for control of bleeding.159 A recent study sug-
gested that uncontrolled hyperglycemia in diabetic patients
after cardiac surgery, and not diabetes per se, is the true risk
factor for DSWI.158 Furthermore, this study demonstrated
that tighter control of blood glucose levels throughout the
perioperative period (levels maintained below 200 mg/dL)
independently decreased the risk of DSWI by 66%. In
2009, the Society of Thoracic Surgeons published updated
guidelines that recommended maintaining blood glucose
levels at less than 180 mg/dL during surgery and immedi-
ately postoperatively to prevent complications, especially
deep sterna wound infections.160
Septic complications are difficult to predict or to diagnose
early in the immediate perioperative period after cardiac
surgery. The proinflammatory state, triggered by CPB,
induces a number of changes that may mimic a septic pic-
ture. Fever and temperatures exceeding 38.5°C are com-
mon during the first 24 hours after cardiac surgery,
occurring in nearly 40% of patients. This often represents
a spectrum of physiologic insults such as the activation of
inflammatory cascades from CPB, pulmonary atelectasis,
and overly aggressive rewarming. There is some suggestion
that scores such as the Acute Physiologic and Chronic
Health Evaluation II (APACHE II) score or the EuroSCORE,
or markers such as procalcitonin may help predict a signif-
icant infection.161–163 Until the predictive value of these is
confirmed, it is reasonable to treat increased temperatures
symptomatically with an antipyretic drug during the first
24 hours after surgery. This appears to be even more
31 • Cardiac Surgery 499
important because postoperative hyperthermia has been
associated with significant complications such as cognitive
dysfunction.164 If the patient is febrile beyond 24 hours, cul-
ture of urine, blood, and sputum as well as a white cell count
check should be obtained. Common infectious causes of
fever after cardiac surgery include sternal wound infection,
urinary tract infection, pneumonia, catheter sepsis, and
loculated areas of contaminated blood accumulation (e.g.,
pericardial, pleural, retroperitoneal, and leg wound spaces).
Early antibiotic treatment is warranted if the patient has
prosthetic material (valve or graft) or a preexisting infection
(such as bacterial endocarditis). Nosocomial infections are
associated with prolonged lengths of hospitalization, the
development of multiorgan dysfunction, and increased in-
hospital mortality.165
Gastrointestinal Complications
Gastrointestinal (GI) complications occur in about 2.5% of
patients undergoing cardiac surgery, are associated with a
high mortality (up to 33%), and account for nearly 15%
of all postoperative deaths.164 The most common GI compli-
cation after cardiac surgery is upper GI bleeding, usually
from gastric or duodenal ulcer. Ileus, pancreatitis, and mes-
enteric ischemia can also occur.166 The proposed mecha-
nism is splanchnic hypoperfusion during CPB or
embolization to the splanchnic circulation during aortic
manipulation. Mortality is high in patients who develop
mesenteric ischemia. In a recent large study of 11,058
patients undergoing cardiac surgery, six independent pre-
dictors for GI complications were identified.165 These
include prolonged mechanical ventilation, postoperative
renal failure, sepsis, valve surgery, preoperative chronic
renal failure, and sternal wound infection. Other factors
such as CPB time, ischemic time, and use of IABP are only
marginally important. Monitoring for GI complications with
a high level of vigilance and instant diagnosis and treatment
of GI complications are important means to decrease asso-
ciated morbidity and mortality. Prophylactic measures such
as stress ulcer prophylaxis, optimization of postoperative
hemodynamics, adaptation of early extubation protocols
(e.g., fast tracking), and early mobilization might all contrib-
ute to prevent serious GI complications. Prevention of peri-
operative infections and renal dysfunction, as well as tight
control and monitoring of perioperative anticoagulation,
should also be considered.
Fast-Tracking
In the past, cardiac surgery patients were traditionally
maintained on sedation and mechanical ventilation until
the morning after surgery. It was believed that the cardio-
vascular and other organ systems needed recovery time
from the profound physiologic disturbances induced by
CPB. More recently, clinical care pathways have been suc-
cessfully introduced for cardiac and thoracic procedures.167
The idea of early extubation and minimization of ICU time,
often termed fast-tracking, has been suggested for many
years.168 The overall need for improved cost effectiveness
in all areas of health-care has supported the trend for early
500 PART IV • Early Postoperative Care
weaning from ventilator support and a shortened ICU and
hospital length of stay after cardiac surgery.169 Further-
more, organizational features of ICUs have been shown to
have a major impact on clinical outcomes170 and on the
duration of mechanical ventilation.
This new trend is made possible with innovative surgical
and anesthetic techniques as well as improved postoperative
sedative and analgesic agents. Shorter CPB time, improved
myocardial protection, and modifications of balanced anes-
thetic technique allow extubation within 2 to 3 hours post-
operatively.171,172 Changes in surgical and anesthetic
techniques include use of warmer core temperatures, reduc-
tion in invasive monitoring, and lower dosage of intraopera-
tive opioids and benzodiazepines. Use of short-acting opioids
and sedatives, such as remifentanil, propofol, and dexmede-
tomidine, and nonsedating analgesics, such as acetaminop-
hen and NSAIDs (non-steroidal anti-inflammatory drugs),
as well as use of regional anesthesia for postoperative pain
control, has hastened recovery from anesthesia and sur-
gery.173–175 User-friendly changes in ICU infrastructure,
such as preconfigured management protocols and comput-
erized physician order entries (CPOE), have enabled rapid
transit of patients through the ICU.
Recent studies have demonstrated the safety and efficacy
of extubation in the operating room for selected adult car-
diac surgical patients, with significant decrease in ICU
length of stay, hospital length of stay, and cost reduction.176
A risk scoring system that outlines the successful predictors
of operating room extubation can be used to guide the deci-
sion making.177 No benefit exists for prolonged ventilation
(>24 hours) after CABG in low-risk patients and such prac-
tice may be deleterious.176 Reintubation in conventionally
weaned patients results in increased mortality and morbid-
ity, including longer ICU length of stay, longer ventilator
dependency, a higher incidence of nosocomial pneumonia,
and a prolonged period of rehabilitation.178,179 However,
fast-track patients requiring reintubation do not seem to
experience the same morbidity,173 probably because of differ-
ences in the indications for reintubation in the two groups.
Different criteria exist for selecting suitable fast-track
patients. Patients considered suitable for fast-tracking have
a low probability of needing circulatory or respiratory sup-
port postoperatively and an absence of significant comorbid-
ity, corresponding with a low preoperative risk stratification
score (e.g., the EuroSCORE).180 Other important consider-
ations include the patient’s clinical condition after weaning
from CPB181 and on arrival in the ICU.182 Factors associated
with failure of early extubation include advanced age,
requirement for inotropic or IABP therapy, persistent hypo-
thermia, bleeding, and rapid atrial dysrhythmias.
Off-pump coronary artery bypass (OPCAB) procedures
are CABG surgeries performed with partial to full heparini-
zation of the beating heart and without the support of CPB.
Routine immediate extubation and fast-tracking of patients
undergoing OPCAB appear to be feasible and are probably
safe. Maintenance of normothermia, use of balanced anes-
thetic technique, and strict adherence to clinical care path-
ways appear to be essential in that patient population, and
early extubation might even help to reduce certain compli-
cations of surgery.183,184 Some authors found that port-
access and minimally invasive valvular surgery, such as
OPCAB surgery, result in shorter lengths of ICU and hospital
stays, faster return to normal activity (4 weeks vs 9 weeks)
when compared with conventional median sternotomy,
fewer blood transfusions, and lower rates of AF in the
port-access group.185–187
Cost reduction is a major driving force behind accelerated
recovery.188 Short-stay intensive care after CABG surgery
(maximum of 8 hours of ICU treatment) compared with con-
ventional ICU care was documented as a safe and cost-
effective approach in a recent prospective trial in Europe.
Cheng and coworkers reported a significant decrease in aver-
age ICU and hospital costs per patient by 53% and 25%,
respectively, by introducing a fast-track recovery protocol,
without change in morbidity.22 Other benefits included a
15% increase in case volume and a decrease in cancellation.
Besides potential cost reductions, early extubation offers
increased patient satisfaction, earlier interaction between
patient and relatives, earlier mobilization, earlier return to
normal diet, improved pulmonary function with less postop-
erative pneumonia,189 and improved perioperative mental
status. More recent data from Cheng and colleagues confirm
the notion that fast-track cardiac anesthesia and surgery is a
safe practice that decreases resource use after patient dis-
charge over a 1-year follow-up period.190
Because ICU costs rank second to operating room costs,
early extubation protocols and fast-track recovery to allow
earlier ICU and hospital discharge are economically appeal-
ing. There is strong evidence that fast-track management
with early extubation is safe, efficient, and cost beneficial
in both coronary and valvular patients. For optimal success
in the fast-track model, the most important element is to
facilitate the process of postoperative care coupled with
intraoperative anesthetic management aiming for early
extubation. Improvements in surgical and anesthetic tech-
niques coupled with improved preoperative risk stratifica-
tion and protocol-driven ICU care have allowed many
medical centers to implement fast-tracking protocols suc-
cessfully, and this trend is unlikely to be reversed.
Summary
There is increasing discussion of expanding existing ERAS
protocols to cardiac surgery patients with the ultimate goal
of improving patient care by creation of pathways, guide-
lines, and initiatives. Another model for expanding the
implementation of pathways that has gained traction refers
to the Perioperative Surgical Home. Although these con-
cepts are complementary, it is improved coordination and
decreased variability in the delivery of care that will improve
quality of perioperative care and service while ultimately
lowering costs.
Independent of the institutional approach, postoperative
management of today’s complex cardiac surgery patients
requires a well-prepared and vigilant ICU team with atten-
tion to detail, a multimodal monitoring infrastructure, and
implementation of institutional clinical care pathways.
These patients undergo major physiologic stress with limited
perioperative reserve, making effective ICU care essential to
their recovery. Detailed knowledge of the patient’s preoper-
ative history and baseline condition, instant and accurate
assessment of the physiologic impact of perioperative events,
immediate interpretation of trends in invasive monitoring
data, and reasoned clinical judgment and initiation of ther-
apy are required for optimization of patient care. Advances

in ongoing research and discovery, together with improved
risk stratification and continuous improvement of clinical
care pathways, will allow perioperative physicians to pro-
vide optimized care at a tolerable cost with improved
outcomes.
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 32 General Thoracic Surgery
THOMAS K. VARGHESE, JR
The focus of this chapter is on concepts in the perioperative
period germane to general thoracic surgery. Areas that will
be covered include preoperative pulmonary reserve assess-
ment, prevention of postoperative pulmonary complications
with emphasis on smoking cessation and the current evi-
dence for use of incentive spirometry, prevention of arrhyth-
mia, and a comprehensive assessment of the role for
enhanced recovery protocols in thoracic surgery. Although
the majority of the discussion centers on lung resection,
the principles detailed in this chapter can be applied
to the perioperative aspects of any general thoracic surgical
procedure.
Before ordering diagnostic tests to assess surgical risk, the
following should be carefully considered:1
1. Will the test results sufficiently alter the estimate of
surgical risk derived from history & physical (H&P), and
will the surgery be canceled, postponed, or changed in
nature?
2. Will the test results lead to possible changes in the
perioperative management to help improve outcomes?
3. What is the cost of the test?
4. What is the risk of the test itself?
Preoperative Pulmonary Function
Assessment
Lung function, the ability of the lungs to provide oxygen to
the body and to remove carbon dioxide, is a critical factor in
a patient’s perioperative well-being. Assessment of the pul-
monary reserve is an important element of risk stratifying
and determination of eligibility of patients for lung resection.
The comprehensive assessment of pulmonary reserve to
determine eligibility for lung resection encompasses three
areas: pulmonary function tests, exercise capacity, and pre-
dicted postoperative value (amount of lung reserve after
resection).
PULMONARY FUNCTION TESTS
Spirometry measures the volumes that an individual can
breathe in and out, whereas diffusion capacity measures
the functional ability, specifically measuring gas diffusion
within the lungs (ability of exchange of CO2 for O2). Accord-
ing to guidelines from the European Respiratory Society
(ERS) and European Society of Thoracic Surgeons (ESTS),
both spirometry (specifically FEV1 [forced expiratory vol-
ume in 1 second]) and the assessment of the diffusion capac-
ity of the lungs (DLCO) are the most important for assessing
preoperative pulmonary function status.2
Although prior guidelines from the American College of
Chest Physicians (ACCP) in 20073 and the British Thoracic
Society (BTS)4 were selective about use of DLCO assessment,
numerous recent studies have demonstrated that reduced
DLCO levels constitute an independent risk factor for
increased mortality and perioperative complications, even
in patients with normal FEV1.5–10
Assessment of Pulmonary Function Tests (PFTs)
▪ If both FEV1 and DLCO are greater than 80% of predicted
levels, no further testing is needed.
▪ When at least one of the parameters (FEV1 or DLCO) is
less than 80% of predicted level, the next step is to assess
the patient’s exercise capacity.
EXERCISE CAPACITY
The most precise test amongst the exercise assessments is
the cardiopulmonary exercise test (CPET). CPET may be per-
formed on a treadmill or on a cycloergometer.11 The mea-
surement of exercise capacity is peak oxygen uptake
expressed by the VO2 max parameter. Reduced VO2 max
results in an increased risk of postresection complications.12
Specific values of importance:
▪ Greater than 75% predicted value or >20 mL/kg/min:
safe to proceed to resection;
▪ Less than 65% predicted value or <16 mL/kg/min:
resection not recommended.
Criticism of CPET has been directed at both the difficulty of
doing the test and the exorbitant cost. Other low-cost
methods for assessment of exercise capacity include the 6-
minute walk test (6MWT), shuttle walk test, and stair
climbing test.
The distance covered during 6MWT has best been corre-
lated with VO2 values in lung transplantation patients but
has less correlation with complications after lung resec-
tion.13 During the shuttle walk test, patients walk between
two points 10 meters apart and increase their pace (speed)
by a signal during the test. The distance covered during this
test correlates well with VO2 max for the majority of
patients.14 Those patients who walk less than 250 meters
are at significantly increased risk of complications after lung
resection.4
During the stair climbing test, patients climb flights of
stairs, with assessment of both distance and number of
floors. Patients who climb less than three floors are twice
as likely to suffer from complications, have 13-fold increased
mortality, and 2.5-fold increased costs of treatment, com-
pared with those who are able to climb five floors of stairs.15
All patients who are able to climb more than five floors of
stairs are able to undergo even a pneumonectomy safely.
505
506 PART IV • Early Postoperative Care
PREDICTED POSTOPERATIVE VALUES
After assessment of PFTs and exercise capacity, the final step
is the calculation of the predicted postoperative values of
FEV1 and DLCO. The formula used incorporates the number
of bronchopulmonary segments removed at the time of
resection. The number of bronchopulmonary segments
per lobe:
Right lung: upper lobe (3), middle lobe (2), lower lobe (5)
Left lung: upper lobe (5–3 apical + 2 lingula), lower lobe (4)
Formula:
Predicted postoperative ðPPOÞ value
¼ Preoperative value
ð19 excised number of segmentsÞ 19
Historically, PPO values greater than 50% were ideal.
With improvement in surgical and critical care practices,
PPO values of 40% are acceptable and can be considered
even as low as 30% if the care is at centers of excellence
who have robust experience taking care of high-risk
patients.2,3
Special Considerations
For patients with marginal pulmonary reserve needing a
pneumonectomy for eradication of disease, additional
assessment with ventilation–perfusion (VQ) scans can help
determine regional function. VQ scans are also helpful for
those patients with heterogenous distribution of lung dis-
ease (e.g., upper lobe predominant emphysema; area-
specific bronchiectasis).2
Prevention of Postoperative
Pulmonary Complications
Once a decision is made to go forward with surgical inter-
vention, the focus shifts toward optimization of patient
health before surgical intervention, safe and efficient con-
duct of the operation, and prevention of postoperative com-
plications. Although all three are components of enhanced
recovery protocols, we will now discuss steps toward pre-
vention of postoperative pulmonary complications (PPCs).
These steps include:
▪ Stop smoking, 6 to 8 weeks before elective surgery, but
can be safely done if quit date at least 3 weeks before
surgical date.
▪ Undergo a preoperative exercise regimen, including deep
breathing and strong cough practice.
▪ Optimize medications for chronic obstructive pulmonary
disease (COPD) and other lung diseases. This may
include use of bronchodilators, inhaled or oral steroids,
and antibiotics to treat bacterial infections of the lungs.
▪ Delay surgery and treat pneumonia with culture-specific
antibiotics, as well as effective use of chest physical
therapy.
▪ Maximize nutrition before elective surgery.
OPTIMAL TIMING OF SMOKING CESSATION
Across the globe, 230 million adults undergo major surgery
annually, with cardiorespiratory complications amongst the
most devastating complications.16 Approximately 30% of
patients undergoing surgery are smokers at the time of their
surgery and it is well known that smoking is associated with
an increased risk of postoperative complications, the stron-
gest correlation of which is for respiratory complications.17
The optimal duration of smoking cessation prior to sur-
gery has been one of debate. Historically based on two
cohort studies from the Mayo Clinic on coronary artery
bypass patients, initial recommendations advised a mini-
mum of 8 weeks of smoking cessation prior to surgery.18,19
A major textbook of anesthesiology in the 1990s incorrectly
extrapolated that smoking cessation less than 8 weeks was
associated with increased complications because in the
cohort studies there was a nonsignificantly increased rate
in that group.20,21 Several studies then emerged demon-
strating brief preoperative smoking cessation was not asso-
ciated with increased pulmonary risk.22
A systematic review of five perioperative smoking cessa-
tion trials demonstrated preoperative smoking cessation
reduced a broad composite of postoperative complications.23
These preoperative smoking cessation programs were posi-
tively associated with long-term (12 months) smoking ces-
sation. The trial data did not provide guidance on optimal
timing of smoking cessation. The closest guidance of mini-
mal duration of effective smoking cessation prior to surgery
comes from a 2011 meta-analysis that concluded the avail-
able evidence (an assessment of several studies that admit-
tedly had heterogeneity of the types of surgeries and
definition of pulmonary complications) supported smoking
cessation at least 3 to 4 weeks prior to surgery.24 This
assessment is supported physiologically by the time it takes
for pulmonary benefits of smoking cessation to manifest.
However, it should not be forgotten that surgery is a pow-
erful opportunity and motivation for smoking cessation
and hence other than the first 48 to 72 hours after smoking
cessation where there may be increased bronchorrhea, any
amount of time may indeed be a good enough amount of
time for smoking cessation prior to surgical intervention.21
USE OF INCENTIVE SPIROMETER
PPCs are mostly seen in abdominal, cardiac, and thoracic
surgery, and can lead to high rates of morbidity, mortality,
increased hospital costs, and prolonged hospital stay.25–27
PPCs encompass atelectasis, pneumonia, tracheobronchitis,
bronchospasm, exacerbation of COPD, acute respiratory
failure, and prolonged mechanical ventilation (longer than
48 hours).28,29
When assessing PPCs, the major contributory factors
include shallow breathing and monotonous tidal volumes
in the postoperative period.30 Anesthesia, opioids, and
splinting from postoperative pain contribute to this ventila-
tion pattern.
As a result, physical therapy techniques of lung reexpan-
sion have been recommended as strategies to prevent and to
treat PPCs, as well as to recover ventilatory function in the
postoperative period. Techniques such as deep inspiration,
incentive spirometry (IS) and positive airway pressure

exercises stimulate the generation of a large and sustained
increase in the transpulmonary pressure, with consequent
expansion of collapsed alveolar units in order to prevent
and/or to treat PPCs.31,32
In the 1960s, intermittent positive-pressure breathing
(IPPB) was commonly used to prevent postoperative pulmo-
nary complications. However, further scrutiny determined
that there was no evidence of benefit to advocate for its
widespread use.33,34 Amidst this controversy emerged the
incentive spirometer introduced by Bartlett et al. Based on
the concept that yawning might generate pulmonary ben-
efits for postoperative patients, they designed a device for
patients to emulate a yawning-like sustained maximal inspi-
ration in order to prevent atelectasis.30
Several systematic reviews and meta-analyses have been
conducted on the use of IS in the perioperative period and
the results are mixed. Thomas and McIntosh assessed the
efficacy of IS, IPPB, and deep-breathing exercises in the pre-
vention of PPCs in patients undergoing major abdominal
surgery.35 The authors concluded that IS and deep-
breathing exercises appear to be more effective than no ther-
apy to prevent PPCs, but there was no evidence to determine
which was better. Overend et al.36 conducted a systematic
review on the use of IS for preventing PPCs and found that in
35 of 46 studies they could not accept the conclusions
because of flaws in methodology. Of the remaining 11 stud-
ies, only one demonstrated any positive effect and in that
study, IS, IPPB, and deep breathing were equally effective
compared with no treatment. In the systematic review by
Carvalho et al.37 the authors were by and large under-
whelmed by the results of IS. Analyzing only studies that
evaluated the effect of IS in patients undergoing abdominal
surgery, there was no significant difference when compared
with other interventions. The results in cardiac surgery
were similarly lacking.
Additional Cochrane reviews for coronary artery bypass
grafting38 and upper abdominal surgery39 did not demon-
strate any significant evidence for the use of IS. Agostini
and Singh40 conducted a systematic review of IS after tho-
racic surgery, where they concluded that the physiologic
evidence does support IS use after major thoracic sur-
gery. A novel program that had IS as a component (the
I COUGH program41) demonstrated reduction in postoper-
ative pneumonia and unplanned intubations. Individual
component contribution was not measured because the
intervention occurred as a bundle (IS, coughing, deep
breathing, oral care [brushing teeth and mouthwash twice
a day], getting out of bed three times daily, and head of bed
elevation).
Prevention of Arrhythmia
Atrial fibrillation (AF) has been reported to occur in 12%–
44% of patients after pulmonary and esophageal surgery.42
Risk factors for postoperative include male sex, increasing age,
magnitude of lung resection, magnitude of esophagus resec-
tion, history of congestive heart failure, underlying lung dis-
ease, preoperative episodes of AF, length of procedure, and
procedures associated with postoperative pericardial inflam-
mation as a result of dissection around the atria.43,44 In terms
of types of surgery, those operations with the highest rates of
32 • General Thoracic Surgery 507
postoperative AF are pneumonectomies, extrapleural pneu-
monectomies, and adult lung transplants.45,46
The onset of AF most commonly occurs on postoperative
days 2 and 3.42 The risk of postoperative AF subsequently
decreases over the course of a month until it reaches preop-
erative risk of AF.
Recently the Society of Thoracic Surgeons compiled
evidence-based practice guidelines on the prophylaxis and
management of AF associated with general thoracic sur-
gery.47 This was a synthesis of the available clinical trials,
cohort studies, and case reports, stratified by categories of
recommendation based on the evidence. The recommenda-
tions spanned the categories of prevention of postoperative
AF, treatment of postoperative AF, and use of anticoagula-
tion therapy. Guideline recommendations included the
following:
PREVENTING POSTOPERATIVE ATRIAL FIBRILLATION
▪ Patients taking beta blockers preoperatively should
continue to take them without missing doses in the post-
operative period (dose adjustment may be needed if epi-
dural is used).
▪ Dilitiazem prophylaxis is reasonable in most patients
undergoing major pulmonary resection who are not tak-
ing beta blockers preoperatively.
▪ Magnesium supplementation is reasonable to augment
the prophylactic effects of other medications.
▪ Amiodarone prophylaxis can be used, but strict dosing
protocols are needed. Amiodarone should not be used
after pneumonectomy.
▪ Use of postoperative beta blockers can be considered in
select cases to treat AF, but use is more limited because of
side effects.
▪ Flecainide and Digoxin should not be used for
prophylaxis.
TREATMENT OF POSTOPERATIVE ATRIAL
FIBRILLATION
▪ Hemodynamically unstable AF should be electrically
cardioverted.
▪ Hemodynamically stable and symptomatic AF should
be chemically cardioverted, with electrical cardioversion
if chemical cardioversion fails.
▪ Hemodynamically stable and asymptomatic or accept-
able symptomatic AF should receive a trial of rate control
lasting 24 hours before cardioversion (chemical then
electrical).
▪ Hemodynamically stable, continuous or recurrent, par-
oxysmal postoperative AF after adequate levels of chem-
ical cardioversion agent may be considered for an
attempt at electrical cardioversion.
CHOICE OF AGENT FOR TREATMENT
Rate Control
▪ For rate control, a selective β1-blocking agent is the
initial drug of choice in the absence of moderate to
severe COPD.
508 PART IV • Early Postoperative Care
▪ If moderate to severe COPD or bronchospasm is present,
dilitiazem is the drug of choice.
Rhythm Control
▪ For chemical cardioversion in the setting of continuous
or recurrent paroxysmal postoperative AF, the recom-
mendation is for intravenous (IV) followed by oral (PO)
administration of amiodarone.
▪ For mechanically ventilated patients, preexisting lung
disease, or after pneumonectomy, avoid the use of
amiodarone.
▪ Once initiated and successful, antiarrhythmic therapy
should be continued for a minimum of 1 week up to a
maximum of 6 weeks. (Most current protocols advocate
a 1-month duration of therapy.)
Use of Anticoagulation Therapy
▪ Anticoagulation is recommended in those patients with
postoperative AF and two or more risk factors for stroke
(age greater than 75 years, impaired left ventricular
function, hypertension, prior stroke, or prior transient
ischemic attack), and who have postoperative AF that
lasts more than 48 hours.
▪ For those with fewer than two risk factors for stroke and
AF that persists or recurs for more than 48 hours, 325 mg
of aspirin should be used.
▪ Anticoagulation therapy once initiated should be con-
tinued for 4 weeks after return of sinus rhythm.
Enhanced Recovery After Thoracic
Surgery
Enhanced recovery after surgery (ERAS) addresses the
entire patient journey from referral to discharge. The prin-
ciple of ERAS is that individual components may have a lim-
ited effect on outcome in isolation, but they act
synergistically when applied in combination to reduce sur-
gical stress and hasten recovery.48 The elements of ERAS
have been known for decades. For thoracic surgery, in addi-
tion to the traditional components of ERAS, the most rele-
vant modifiable risk factors are the management of chest
tubes, pain control, and social support plans.49,50 A recent
systematic review and meta-analysis demonstrated that
ERAS pathways in lung cancer surgery are associated with
reduced complications, shorter length of stay, and cost
savings.51
The 2019 guidelines for enhanced recovery after lung
surgery compiled evidence-based recommendations of the
ERAS society and ESTS.48 Specific details about ERAS pro-
tocols pertinent to successful perioperative outcomes in tho-
racic surgery are as follows:
▪ Preoperative counselling helps to set expectations about
surgical and anesthetic procedures, which in itself may
help to increase patient understanding, diminish fear,
fatigue and pain, and thus enhance early discharge.52
▪ Nutritional components of ERAS include preoperative
fluid and carbohydrate loading (up to 3 hours before sur-
gery), and early postoperative restarting of oral diet and
oral nutritional supplements (ONS).53 Malnutrition is an
important modifiable risk factor for adverse outcomes
after major surgery. Because the vast majority of
pulmonary rehabilitation programs for patients with sig-
nificant COPD emphasize nutritional supplementation,
ONS is recommended and improves patient quality of life
and muscle function.54 Additionally, cancer patients
should be screened for malnutrition with appropriate
interventions initiated once it is identified in the preoper-
ative setting.
▪ Alcohol is associated with perioperative morbidity and
mortality and should be avoided for at least 4 weeks
before surgery in patients who abuse alcohol.
▪ Anemia should be identified and corrected for iron defi-
ciency and any underlying disorder before surgery.
Where possible, blood transfusion or erythropoiesis-
stimulating agents should not be used to correct preop-
erative anemia.
▪ Although recent systematic reviews and meta-analyses
have determined that rehabilitation is beneficial, the
wide heterogeneity of studies (duration, intensity, struc-
ture, patient selection) precludes the ability to determine
the protocol for maximal benefit.55–57
Early ERAS protocols recommended epidural analgesia
▪
as an essential part of the bundle for pain management.
With recognition of increased adverse events such as
hypotension, urinary retention, and muscular weakness
associated with epidurals, alternative agents have
emerged as agents of choice. Paravertebral blocks pro-
vide somatic and sympathetic blockade of nerves that
lie in the paravertebral space. Recent randomized studies
suggest that paravertebral blocks are more effective at
reducing respiratory complications compared with tho-
racic epidurals and after the first few hours provide
equivalent analgesia.58–60
▪ During the postoperative phase, a multimodal analgesic
regimen should be used with the aim of minimizing the
use of opioids. Acetaminophen in combination with non-
steroidal inflammatory drugs is more effective than
either drug alone.
▪ In lung resection surgery, patients are prone to develop
interstitial and alveolar edema with fluid administration.
Preexisting lung disease, prior chemoradiation, one-lung
ventilation, direct lung manipulation at the time of sur-
gery, and ischemia–reperfusion injury can all increase
the risk of lung injury. As a result, volume restriction
of IV fluids is advocated, with a goal of perioperative fluid
balance of less than 1500 mL (20 mL/kg/24 hours).61 In
the postoperative period, attention is kept on fluid bal-
ance and PO intake should be resumed as soon as it is
clinically safe to do so.
▪ Early mobilization is a core component of ERAS in the
postoperative period.
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the incidence and risk of intraoperative and postoperative complica-
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352–358.
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resection surgery of the lung. Eur J Cardiothorac Surg. 2001;20:688–693.
44. Murthy SC, Law S, Whooley BP, et al. Atrial fibrillation after esopha-
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52. Egbert LD, Battit GE, Welch CE, et al: Reduction of postoperative pain
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510 PART IV • Early Postoperative Care
53. Collins PF, Elia M, Stratton RJ. Nutritional support and functional
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498–504.
 33 Major Abdominal Surgery
JESSICA Y. LIU and JYOTIRMAY SHARMA
Introduction
Major abdominal surgery encompasses a broad range of
operations with a wide variety of procedures that fall under
this category. The perioperative management after a low-
risk procedure such as a herniorrhaphy is going to be differ-
ent from the management following a high-risk procedure
such as a pancreaticoduodenectomy. The majority of
patients undergoing major abdominal surgery often present
with cancer and other medical comorbidities and are put at
an elevated risk of a large number of medical and surgical
perioperative complications. There are a significant number
of factors that make up the risk profile of patients undergo-
ing major abdominal surgery (Fig. 33.1). This elevated risk
results from the problem of a significant surgical stress
response in older patients with minimal functional or phys-
iologic reserve.
An evidence-based practice that has been gaining
momentum in recent years is Enhanced Recovery After Sur-
gery (ERAS). ERAS are evidence-based protocols that seek to
standardize perioperative management and have been
shown to improve outcomes such as rates of surgical site
infections, decrease length of stay, and lower health-care
costs. ERAS protocols consist of process measures that
aim to decrease the physiologic stress response to surgery
and maintain postoperative physiologic function.
In this chapter, we will explore several areas of perioper-
ative management uniquely associated with major abdom-
inal surgery. We will address prevention of pulmonary
complications, fluid management strategies, nutrition, and
surgical site infections (SSIs). The prevention and treatment
of delirium, deep venous thrombosis, and urinary tract
infections (UTI) are important in the management of
patients following major abdominal surgery and are covered
in depth in the other chapters in this textbook.
Pulmonary Management
Patients undergoing major abdominal surgery in particular
have an elevated risk of developing pulmonary complica-
tions. These include hypoxemia during induction of
anesthesia and atelectasis after extubation. Patients under-
going surgery in the upper abdomen and bariatric surgery
represent the higher risk cohorts for perioperative pulmo-
nary complications. The closer the operative procedure is
to the diaphragm the more likely respiratory compromise
is, because postoperative pain will inhibit deep breaths
and increase splinting.
REDUCING POSTOPERATIVE PULMONARY
COMPLICATIONS
Induction of general anesthesia involves the administration
of sedative hypnotic drugs and neuromuscular blockers to
secure the airway through translaryngeal placement of a
cuffed plastic (endotracheal) tube. The major early compli-
cations of this process include aspiration of gastric contents,
hypoxemia, and failure to obtain an adequate airway. Pre-
oxygenation is widely used to reduce the risk of hypoxemia
as a result of airway complications (Fig. 33.2). The principle
behind preoxygenation is replacing the nitrogen content of
the lungs with oxygen to increase apneic time (i.e., the time
between administration of drugs that halt respiration and
the restoration of ventilation). However, at the other end
of the spectrum, the overuse of oxygen leading to hyperoxia
can also cause damage because of oxygen free radicals and
increased atelectasis.1 Oxygen should be titrated to produce
normal saturations and arterial oxygen levels, avoiding
hyperoxia with prolonged periods of high inspired oxygen.2
Other potential problems that occur with induction of
anesthesia include decreased functional residual capacity
(FRC) and atelectasis. Both neuromuscular blockade and
anesthesia induced by sedative hypnotic agents cause signif-
icant reduction (16%–20% in the supine position) in FRC.3
Atelectasis is caused by high inspired oxygen tension
(absorption atelectasis) and also results from compression
of pulmonary tissue by the heart, particularly the left lower
lobe and the juxtadiaphragmatic region (compression atel-
ectasis).4,5 The combination of loss of FRC and compressive
and absorptive atelectasis commonly results in postintuba-
tion hypoxemia and increased airway pressures.6
Prolonging apneic oxygenation (the time from onset of
apnea until hypoxemia develops) and preventing atelectasis
on induction of anesthesia can help prevent some of these
problems. Evidence suggests that patient positioning may
have a significant impact on the apneic duration in high-risk
profile patients, such as pregnant women and the morbidly
obese.7,8 Intubating patients with the head elevated or in
reverse Trendelenburg position is recommended in the
majority of patients. Postoperative patient positioning also
plays a role in reducing pulmonary complications. The
transport of critically ill patients in the semirecumbent posi-
tion is associated with a lower incidence of nosocomial
pneumonia,9 and maintaining head of bed elevation in
mechanically ventilated patients has been demonstrated
to increase end expiratory lung volume and reduce respira-
tory complications.10 In non-critically ill patients, patient
positioning with maintaining head of bed elevation has
been demonstrated to reduce postoperative pulmonary
511
512 PART IV • Early Postoperative Care

Airway obstruction Delirium

Hypercarbia Dehydration

Hypoxemia Hypoperfusion

Major abdominal
surgery
Pulmonary embolism Over-resuscitation

Deep venous thrombosis Surgical site infection

Loss of physiologic
Malnutrition Delayed recovery
reserve

Fig. 33.1 Overview of the risk profile of patients undergoing major abdominal surgery.

Low-risk Medium-risk High-risk

patient patient patient

Emergency surgery Morbid obesity

3rd trimester pregnancy Low FRC
Abdominal hypertension

Option Head-up or Ramp position

reverse Trendelenburg
position
Op
tio
n

Standard Standard CPAP preoxygenation

preoxygenation preoxygenation

Option Consider PEEP following

PEEP following intubation
intubation

Consider CPAP following

CPAP in extubation and
recovery room in recovery room

Fig. 33.2 Preoxygenation for prevention of atelectasis. CPAP, Continuous positive airway pressure; FRC, functional residual capacity; PEEP, positive
end-expiratory pressure.

complications, especially pneumonia, after major abdomi-
nal surgery.11
Lung protective ventilation strategy during surgery with
low tidal volumes (4 to 5 mL/kg), positive end-expiratory
pressure (PEEP) (6 to 8 cm H2O) and lung recruitment
are associated with improved outcomes.12 There is
considerable evidence that mechanical ventilation with
high tidal volumes that cause alveolar stretching can initi-
ate ventilator-associated lung injury. Although lung protec-
tive strategies have been routinely accepted in the
postoperative phase of care, their usage intraoperatively
remains suboptimal.

Other postoperative interventions including head of bed
following major abdominal surgery have been demon-
strated to reduce pulmonary complications such as pneu-
monia. These include early mobilization, utilizing regional
anesthesia, incentive spirometry, oral hygiene, and smok-
ing cessation.11,13 These interventions have been shown
to function best as a pulmonary bundle, and all contribute
individually toward improving postoperative pulmonary
outcomes and should be utilized in postoperative major
abdominal surgery patients.11,13 Many of these compo-
nents also align with ERAS recommendations. Early mobi-
lization includes mandatory ambulation in the early
postoperative period with “enforced” time out of bed
ambulating or in a chair. Prolonged bed rest or immobili-
zation postoperatively is associated with decreased ventila-
tion, atelectasis, and increased rates of pneumonia,14,15
and early mobilization has been shown to decrease rates
of chest complications.16 The use of regional anesthesia
such as epidural use also has significant benefits to postop-
erative pulmonary function. Epidural use both reduces opi-
oid use, which has been demonstrated to reduce rates of
pneumonia and pulmonary complications,17,18 and
improves postoperative oxygenation and lung
function.19,20
PULMONARY MANAGEMENT AFTER BARIATRIC
SURGERY AND IN THE MORBIDLY OBESE
A unique population frequently seen in major abdominal
surgery is the morbidly obese, especially those undergoing
bariatric procedures. Morbidly obese patients have signifi-
cantly more atelectasis than nonobese patients, and atelec-
tasis in the obese persists for a longer duration when
compared to normal weight patients (Fig. 33.3).21 Postop-
erative patient positioning with the head of bed elevated
helps to prevent this atelectasis in obese patients21 and
early mobilization leads to lung recruitment and should
be encouraged. Obese patients have also been associated
with a higher risk for aspiration caused by increased gas-
tric and esophageal pressures, as well as increased work of
breathing because of reduced FRC and expiratory reserve
volume (ERV).22 Morbid obesity is also associated with
dramatic reductions in total respiratory system compli-
ance,23 which leads to significantly increased perioperative
risk in terms of primary and secondary respiratory failure.
Positive pressure ventilation should be utilized in any
obese patients at induction and following intubation and
especially with warning signs for insufficient ventilation,
such as desaturation, tachypnea, tachycardia, or hyper-
carbia (Fig. 33.2).
Because of these unique physiologic issues, medications
used for anesthesia, such as sedative drugs, and postopera-
tive analgesia for pain control promote obstruction of the
upper airways and may lead to postoperative hypoxemia.24
Recommendations for postoperative analgesia management
following abdominal surgery in the obese and bariatric sur-
gery include multimodal pain management strategies and
utilizing regional and local anesthesia techniques such as
epidurals and local wound infiltration (bariatric). Reducing
the consumption of narcotics by utilizing nonopioid
33 • Major Abdominal Surgery 513
20
Nonobese
Obese #
*
15
Atelectasis (%)
#
*
10
5 *
#
0
Before induction After extubation 24 h after
extubation
Fig. 33.3 Percentages of pulmonary atelectasis in morbidly obese
compared with nonobese patients, shown at three stages: before
anesthesia induction, after extubation, and 24 hours later. (Redrawn
from Eichenberger A, Proietti S, Wicky S, et al. Morbid obesity and post-
operative pulmonary atelectasis: An underestimated problem. Anesth
Analg 2002;95:1788–1792.)
alternatives such as non-steroidal anti-inflammatory drugs
(NSAIDs) helps reduce the risk of postoperative hypox-
emia.25,26 If patient-controlled analgesia is being utilized,
bolus dose rather than continuous infusion is recom-
mended, especially in patients with obstructive sleep apnea
(OSA).27 Additionally, the use of local wound infiltration
with laparoscopic surgery has successfully assisted with
minimizing opioids and improving patient comfort.28 In par-
ticular, longer acting agents such as ropivacaine or levobu-
pivicaine have been demonstrated to be more effective than
short-acting agents such as lidocaine.29 In those undergo-
ing open surgery, thoracic epidural analgesia has been asso-
ciated with improved lung function and faster recovery of
spirometric values in obese patients.30
OSA occurs in up to 70% of morbidly obese patients
undergoing bariatric surgery.31 Obese patients should be
screened for OSA using the STOP-BANG questionnaire pre-
operatively.32 Immediately following surgery, patients with
OSA should be monitored with continuous pulse oximetry
and respiratory rate monitoring. The treatment for OSA is
noninvasive positive pressure (NIPP) support, with contin-
uous positive airway pressure (CPAP), with or without
inspiratory pressure support (biphasic positive airway pres-
sure [BiPAP]), and there should be high vigilance postoper-
atively for the need to use CPAP or BiPAP in these patients
in addition to routine oxygen supplementation (Fig. 33.4).
NIPP use is indicated for hypoxia when oxygen saturation
reaches below 90% in the postoperative period.33 All
patients with a diagnosis of OSA should receive CPAP or
BiPAP in the recovery room (this is titrated to response)
and at night while they sleep. Patients treated with home
CPAP therapy at baseline should continue their CPAP post-
operatively and may even need slightly higher CPAP values
because of the respiratory effects of perioperative medica-
tions.34,35 Oxygen therapy should be used cautiously
because its use has been associated with a higher risk of
514 PART IV • Early Postoperative Care

Risks Timing in perioperative period Management strategies

Difficulty with INDUCTION Ramp position

intubation

CPAP preoxygenation
Postintubation
hypoxemia
Recruitment maneuver
following intubation
INTRAOPERATIVELY
Atelectasis

Intraoperative
High oxygen PEEP
Right-to-left shunt
requirement

Place nasal airway

Hypoxemia IMMEDIATELY Extubate to CPAP
POSTOPERATIVELY

Postextubation NIPPV in PACU

airway obstruction

Opioid-sparing
analgesia strategy
Airway obstruction

NIPPV postop night

Narcosis Hypoventilation POSTOPERATIVELY

Hypercarbia Monitor ventilation

Hypoxemia

Asystole

Fig. 33.4 Risks and management strategies for patients with obstructive sleep apnea/hypopnea syndrome or morbid obesity undergoing major
surgery. CPAP, Continuous positive airway pressure; NIPPV, noninvasive positive-pressure ventilation; PACU, postanesthesia care unit; PEEP, positive
end-expiratory pressure.

apnea and hypopnea in patients with OSA postopera-
tively.36 The risk of postoperative respiratory failure and
airway obstruction in patients with OSA (in particular,
those with an apnea–hypopnea index >30) cannot be
overemphasized.
Fluid Management
Perioperative fluid management is a complex process
involving the patient’s preexisting disease, preoperative vol-
ume status, physiologic reserve, degree of perioperative
stress, and perioperative fluid losses. Fluid management dur-
ing all phases of care are frequently influenced by external
variables with abdominal surgery. For example, preopera-
tively, the use of mechanical bowel preparations or func-
tional barriers to hydration such as esophageal cancer
can influence fluid status. Intraoperatively, operative case
duration varies greatly and can lead to insensible losses,
or varying degrees of intraoperative blood loss, which can
impact hemodynamic status. Postoperatively, the patient’s
ability to tolerate fluids influences fluid resuscitation. Fluid
management following major abdominal surgery can be a
challenge and requires unique adaptation for each patient.
Because Chapter 16 in this textbook addresses perioperative
fluid management, we will focus on specific factors that
impact fluid management in patients undergoing major
abdominal surgery.
Perioperative care is characterized by dramatic changes
in fluid and electrolyte content and distribution in the var-
ious fluid spaces in the body. These changes are predictable
and follow a characteristic pattern of a biphasic ebb-and-
flow. Initially, after an injury or a surgical incision, there
is significant peripheral vasoconstriction, a shunting of
blood from the periphery to the midline to preserve vital
organs, and a drop in body temperature. The second phase,
the hypermetabolic (or flow) phase, occurs within hours
and is characterized by a dramatic increase in cardiac

output, driven by catecholamines, vasodilation, increased
capillary permeability, and an increase in temperature. A
period of fluid sequestration occurs because of the extrava-
sation of fluid that follows widespread capillary leak; urinary
output falls and tissue edema may become evident. Eventu-
ally, a state of equilibrium arrives, usually day 2 postopera-
tively, when active sequestration stops. This is followed by a
phase of diuresis during which the patient mobilizes fluid
and recovers. The clinician must be aware of the stages of
the stress response when deciding whether to administer
fluid and electrolytes. Additionally, extensive fluid shifts
are to be expected in the perioperative period, and it may
be worthwhile to obtain a preoperative weight to have a
baseline goal for the patient’s postoperative diuresis.
Patients undergoing abdominal surgery are usually
entering surgery dehydrated secondary to preoperative fast-
ing, the use of mechanical bowel preparations, or their pri-
mary disease (e.g., esophageal cancer). This leads to varying
preoperative hydration deficits amongst different patients.
Various anesthesia society guidelines are now supporting
the use of clear liquids fluids up to 2 hours and solid food
up to 6 hours before induction of anesthesia, which has
been demonstrated to reduce insulin resistance and patient
discomfort and has less impact on intravascular volume,
especially for patients who received a mechanical bowel
preparation.37 This has led to reduced intraoperative
requirements; however, after undergoing mechanical bowel
preparations significant fluid and electrolyte derangements
can still occur.37 Although general guidelines can be fol-
lowed (Fig. 33.5), preoperative fluid administration should
be individualized to replace preoperative intravascular defi-
cits rather than following a formula.
Intraoperatively, the goal is to maintain a near zero fluid
balance38 without significant weight gain of 2.5 kg or more.
Excessive crystalloid has been shown to increase the risk of
Patient fasting Oral fluid up to
preoperatively
Fluid fasting
duration known?
Yes No
Administer BSS @ Administer
2 mL/kg/h fasting BSS @ 30 mL/kg
preinduction preinduction
No hydration
required
Fig. 33.5 Replacing dehydration losses by prehydration. BSS, Balanced salt solution; GI, gastrointestinal; NS, normal saline.
33 • Major Abdominal Surgery 515
pulmonary complications39 and lead to prolonged ileus in
patients undergoing abdominal surgery.38,40,41 Postopera-
tively, following most major abdominal surgery, early oral
intake including fluids and solids is encouraged.42–44 Pro-
vided that patients tolerate oral intake and are encouraged
to drink adequate amounts of water (approximately 25–
35 mL/kg of water per day),45 the early discontinuation
of routine intravenous (IV) fluids has been recommended
for most major abdominal surgeries.2 Following the discon-
tinuation of IV fluids, urine output and other clinical
markers of hydration should be monitored to assess for
any need to restart fluids.
Postoperative Nausea and
Vomiting and Ileus
Postoperative nausea and vomiting (PONV) affects 25% to
35% of surgical patients and has an even higher incidence
in patients undergoing major abdominal surgery with an
incidence as high as 70% following colorectal surgery.46
Its etiology is often attributed to the combined use of inha-
lational anesthesia medication, nitrous oxide, and opioid
medications for postoperative pain control. Patients with
a history of PONV or motion sickness have a higher likeli-
hood of developing postoperative PONV.47 In an effort to
reduce the incidence of PONV, anesthesiologists are now
more frequently utilizing antiemetic prophylaxis and reduc-
ing the use of inhalational anesthetics in exchange for med-
ications like propofol.48 Additional evidence has shown that
minimizing preoperative fasting, utilizing preoperative car-
bohydrate loading, and maintaining adequate hydration
in patients postoperatively have assisted with decreasing
PONV.49
Significant
preoperative
2 h preop fluid deficit
Bowel obstruction
Bowel preparation
Yes Patient currently on
intravenous fluids?
Lower GI or No Upper GI
intra-abdominal loss
loss
Administer Administer 0.9% NS
BSS 30 mL/kg deficit 30 mL/kg deficit
plus 1000 mL for losses plus 1000 mL for losses
516 PART IV • Early Postoperative Care
An inevitable consequence following major abdominal
surgery and a leading cause of PONV is the development
of a postoperative ileus. Postoperative ileus involves tran-
siently delayed recovery of gastrointestinal function follow-
ing surgery and has been attributed to reduced intestinal
smooth muscle contractility caused by the inflammatory
response and edema from bowel manipulation and stress
from surgery.50 Ileus has been associated with higher rates
of complications and prolonged hospital length of stay, and
risk factors for ileus include increasing age, poor preopera-
tive nutritional status, opioid use, long operative duration,
emergency surgery, and excessive fluid use.50 Patients’
responses to ileus vary greatly, with some patients remain-
ing asymptomatic and able to tolerate oral intake while
others experience significant gastrointestinal symptoms
with an inability to tolerate oral intake for several days.
Several strategies have been demonstrated to accelerate
the return of bowel function to reduce the duration of post-
operative ileus, and these are commonly found components
of ERAS pathways. Opioids have been shown to reduce gut
motility and to exacerbate postoperative ileus, and thus opi-
oid sparing pain management strategies have been associ-
ated with reducing the duration of postoperative ileus.
Multimodal pain management utilizing NSAIDs and
regional anesthesia such as epidurals and nerve blocks
has been shown to decrease the time of return of gastroin-
testinal function and improve pain control.51,52 Goal-
directed fluid management, with avoidance of over-
resuscitation has also been shown to reduce edema and
to decrease ileus with faster return of flatus.41,53 Early mobi-
lization has also been shown to improve gastrointestinal
function and to reduce ileus.16
Historically, nasogastric intubation use has been prophy-
lactically placed during abdominal surgery and kept in place
postoperatively until passage of flatus.54 However, there has
been strong evidence to demonstrate that routine use of
nasogastric tube (NGT) decompression following abdominal
surgery should be avoided and that the NGT should be
removed before reversal of anesthesia.55 There has been
no demonstrated benefit to routine prophylactic use of
NGT in multiple different patient populations undergoing
various types of major abdominal surgery,56 even including
following gastroduodenal and pancreatic surgery.42,56
Avoiding NGT use has been associated with earlier return
of bowel function55,57–59 and reduced rates of fever, atelec-
tasis, and pneumonia.58 However, delayed gastric emptying
can still occur and there is a higher incidence of emesis with-
out routine NGT use,55,57,58 therefore significant emesis
should be treated with insertion of a NGT to avoid fatal aspi-
ration.60,61 Despite this complication, the benefit of routine
NGT use does not outweigh the risks and routine prophylac-
tic NGT use is not recommended.
Nutrition
During the stress response, the demand for substrate to fuel
tissue repair and leukocyte activity results in increased
energy expenditure (evident as an increase in oxygen
consumption and CO2 production), increased substrate
turnover with protein catabolism, and enhanced glycogen-
olysis and gluconeogenesis to provide energy for the process.
Perioperative malnutrition is reported to impair wound
healing and anastomotic strength and believed to increase
infectious risk.62 The four basic goals of perioperative nutri-
tional therapy include provision of metabolic substrate,
retardation of the loss of lean body mass and physiologic
reserve, improvement in wound healing and immune func-
tion, and prevention of fluid and electrolyte disturbances.
Prior to major abdominal surgery, it is important for
patients to be screened for nutritional status and those
found to be at risk should be given nutritional support.
Many patients undergoing major abdominal surgery, espe-
cially for cancer, are at a high risk of having significant
unplanned weight loss prior to surgery and are often mal-
nourished. The addition of oral supplements may help mal-
nourished patients achieve nutritional goals both prior to
surgery and during their recovery postoperatively when
they are back at home.63 Ideally in the significantly mal-
nourished, beginning nutritional supplementation 7–
10 days preoperatively has the greatest effect and has been
shown to reduce the risk of anastomotic leaks and infectious
complications.64 With the obesity epidemic, overweight or
obese patients are often actually malnourished and are hid-
ing underlying muscle wasting, and this patient population
should not be overlooked with preoperative nutrition
screening. Bariatric surgery patients in particular require
a nutritional evaluation, specifically checking selective
micronutrient measurements (bariatric surgery ERAS),
and those undergoing gastric bypass and malabsorptive pro-
cedures, such as biliopancreatic diversion, require an even
more extensive nutritional evaluation.65
The standard practice of fasting from midnight is no lon-
ger recommended prior to surgery for patients undergoing
major abdominal surgery. While this was previously
thought to ensure an empty stomach and reduced risk of
pulmonary aspiration, two meta-analyses, including a
Cochrane review, demonstrated no reduction in gastric con-
tents or change to pH of gastric fluid between patients fast-
ing since midnight compared with those allowed to take in
clear fluids until 2 hours before surgery, and no increase in
complication rates.66,67 Imaging studies have actually dem-
onstrated complete gastric emptying from clear liquids
within 90 minutes of intake.68 Fasting from midnight has
been shown to increase patient discomfort, insulin resis-
tance, and reduce patients’ intravascular volume, especially
in those undergoing mechanical bowel preparation.37 Sev-
eral anesthesia societies are now recommending clear fluids
to be allowed until 2 hours before surgery and solid food
until 6 hours before surgery.69,70 In addition to allowing
clear fluids, the ingestion of a carbohydrate loaded clear
fluid 2 to 3 hours before surgery is thought to help maintain
a metabolically fed state in patients through surgery. There
has been evidence to suggest that preoperative intake of a
carbohydrate treatment reduces preoperative thirst, hun-
ger, anxiety, and plays a role in reducing postoperative insu-
lin resistance.67,71,72 Additionally, two meta-analyses have
found that preoperative carbohydrate loading in patients
undergoing major abdominal surgery was associated with
reduced length of stay.73,74
Following surgery, enteric feeding is effective when ther-
apy can be successfully initiated and maintained and is pref-
erable to the IV approach. Patients fed enterally have been
shown to have fewer complications such as reduced

infectious complications, improved nutritional markers, and
shorter length of stay.75,76 Historically, following abdominal
surgery patients were not fed until patients passed flatus.
However, new evidence does not support this practice. Early
feeding postoperatively has been associated with reduced
length of stay and reduced complications and does not dem-
onstrate any increase in rates of complications such as eme-
sis, NGT reinsertion, SSIs, anastomotic dehiscence, or
mortality.44 However, caution should be used in patients
with delayed gastric emptying who have documented gas-
troparesis or are taking prokinetic agents. Additionally,
patients scheduled for gastrointestinal operations, patients
with a previous Whipple procedure, patients with achalasia,
and patients with neurological disease with dysphagia have
a higher risk of delayed gastric emptying.2
Postoperative patients following most major abdominal
surgery should be able to drink immediately following
recovery from anesthesia and advance to a regular diet as
tolerated, which allows for spontaneous enteral consump-
tion of calories.77 Studies on “immunonutrition” diets with
special dietary components aimed at enhancing immune
function, such as glutamine, omega-3 fatty acids, arginine,
and nucleotides, have had mixed results thus far and require
further study.
Surgical Site Infections
SSIs are the second most common cause of nosocomial
infection.78 Up to 20% of patients undergoing major abdom-
inal surgery will develop an SSI. The Centers for Disease
Control and Prevention (CDC) estimate that approximately
500,000 SSIs occur annually in the United States.79
Patients who develop SSIs have longer and costlier hospital-
izations than patients who do not develop such infections.
They are twice as likely to die, 60% more likely to spend time
in an ICU, and more than five times more likely to be read-
mitted to hospital.80 This translates to significant increases
in health-care costs. Programs that reduce the incidence of
SSIs such as SSI prevention bundles or the use of ERAS can
substantially decrease morbidity and mortality and reduce
the economic burden for patients and hospitals. SSIs are
covered in Chapter 28, but we will focus on the aspects of
SSI specific to major abdominal surgery.
Many patients undergoing major abdominal surgery will
undergo procedures that entail entry into a hollow viscus
under controlled conditions and thus should receive antimi-
crobial prophylaxis. The CDC has developed guidelines for
prevention of SSIs, and Table 33.1 shows the four classes
of surgical wounds: class I (clean), class II (clean-
contaminated), class III (contaminated), and class IV
(dirty-infected). Antibiotic prophylaxis is indicated for most
clean–contaminated and contaminated (or potentially con-
taminated) operations (Fig. 33.6). Patients undergoing class
IV (dirty–infected) operations should not receive antimicro-
bial prophylaxis. They should receive therapeutic antimi-
crobials directed at anticipated organisms based on the
anatomic location and clinical situation surrounding the
injury. In such scenarios, therapeutic agents are started
at the time of injury or suspected infection, often before
the patient presents to the operating room.
33 • Major Abdominal Surgery 517
Table 33.1 Surgical wound classification.
Class I/Clean: An uninfected operative wound in which no
inflammation is encountered and the respiratory, alimentary, genital, or
uninfected urinary tract is not entered. In addition, clean wounds are
primarily closed and, if necessary, drained with closed drainage.
Operative incisional wounds that follow nonpenetrating (blunt) trauma
should be included in this category if they meet the criteria.
Class II/Clean–contaminated: An operative wound in which the
respiratory, alimentary, genital, or urinary tracts are entered under
controlled conditions and without unusual contamination. Specifically,
operations involving the biliary tract, appendix, vagina, and
oropharynx are included in this category, provided no evidence of
infection or major break in technique is encountered.
Class III/Contaminated: Open, fresh, accidental wounds. In addition,
operations with major breaks in sterile technique (e.g., open cardiac
massage) or gross spillage from the gastrointestinal tract, and incisions
in which acute, nonpurulent inflammation is encountered are included
in this category.
Class IV/Dirty–infected: Old traumatic wounds with retained devitalized
tissue and those that involve existing clinical infection or perforated
viscera. This definition suggests that the organisms causing postoperative
infection were present in the operative field before the operation.
From Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of
surgical site infection. Infect Control Hosp Epidemiol 1999;20:250-278,
available at http://www.cdc.gov/ncidod/dhqp/pdf/guidelines/SSI.pdf.
Antimicrobial prophylaxis is directed against the most
likely infecting organism, and the distribution of organisms
following major abdominal surgery differs from other opera-
tion types (Table 33.2). Skin organisms such as staphylococci
and streptococci are the most likely pathogens in surgeries
that do not enter a chronically colonized body cavity. Ceph-
alosporins are effective against many gram-positive and
gram-negative bacteria. Cefazolin is generally viewed as the
antimicrobial of first choice in clean operations. A full thera-
peutic dose of cefazolin (1–2 g depending on volume of distri-
bution) should be given to adult patients no more than
30 minutes before skin incision. Prophylaxis for operations
involving the lower gastrointestinal tract should include cov-
erage against gram-negative enteric bacteria and bowel
anaerobes, particularly Bacteroides fragilis. Antimicrobial pro-
phylaxis after wound closure is unnecessary.79 Prolonged
administration is associated with the emergence of resistant
bacterial strains and other complications, including catheter-
related bloodstream infections, pneumonia, multidrug-
resistant organisms, and antibiotic-associated colitis. Clostrid-
ium difficile colitis is increasing in frequency and severity.81
Disruption of the normal balance of gut flora results in over-
growth of the enterotoxin-producing C. difficile. Therefore,
antimicrobial prophylaxis should be discontinued within
24 hours of the end of surgery (Table 33.3).
Conclusion
Prevention of additional complications such as delirium,
thromboembolic events, and urinary tract infections is a
major goal of appropriate perioperative care following major
abdominal surgery. Prevention strategies for these compli-
cations are covered elsewhere in this book and are impor-
tant in the perioperative management of patients
following major abdominal surgery.
518 PART IV • Early Postoperative Care

Wound Wound Wound Wound

Class I Class II Class III Class IV

Prophylactic antibiotics Prophylactic antibiotics Therapeutic antibiotics

not indicated indicated indicated

Antibiotics given Nonantimicrobial

within 60 minutes interventions
of incision

Antibiotics redosed Glycemic control Oxygen therapy

as necessary blood glucose FiO2 ⬎0.8
during surgery ⬍140 mg/dL

Enteral Maintenance of
Antibiotics
nutrition normothermia
discontinued at
wound closure

Supplemental fluid
blood transfusion

Fig. 33.6 Preventing surgical site infections in major abdominal surgery. Wound class I (clean), class II (clean–contaminated), class III (contaminated),
and class IV (dirty–infected). FIO2, Inspired oxygen tension.

Table 33.2 Distribution of pathogens associated with surgical Table 33.3 Recommendations for perioperative antimicrobial
site infections (SSIs) following abdominal surgery reported to treatment.
the National Healthcare Safety Network, 2011–2014.
Antibiotic timing Infusion of the first antimicrobial dose should
No. of % of begin within 60 minutes before the surgical
Pathogen pathogens pathogens incision is made.

Staphylococcus aureus 6922 9.1 Duration of Prophylactic antimicrobials should be

prophylaxis discontinued within 24 hours of the end of
Escherichia coli 14,955 19.6 surgery.
Coagulase-negative 3273 4.3 Screening for β- For operations in which the cephalosporins
staphylococci lactam allergy represent the most appropriate antimicrobials
for prophylaxis, the medical history should be
Enterococcus faecalis 7197 9.4 adequate to determine whether the patient has
Pseudomonas aeruginosa 4469 5.9 a history of allergy or has had a serious adverse
antibiotic reaction. Alternative testing
Klebsiella (pneumoniae/ 4318 5.7 strategies (e.g., skin testing) may be useful in
oxytoca) patients with reported allergy.
Bacteroides species 5690 7.5 Antimicrobial The initial antimicrobial dose should be
dosing adequate for the patient’s weight, adjusted
Enterobacter species 3475 4.6 dosing weight, or body mass index. An
Other Enterococcus species 4692 6.1 additional dose of antimicrobial should be
given intraoperatively if the surgery is still
Proteus species 1473 1.9 continuing two half-lives after the initial dose.
Enterococcus faecium 3451 4.5 From Bratzler DW, Houck PM, Richards C, et al. Use of antimicrobial prophylaxis
Candida albicans 2736 3.6 for major surgery: Baseline results from the National Surgical Infection
Prevention Project. Arch Surg 2005;140:174-182.
Viridans streptococci 1849 2.4
Group B streptococci 291 0.4
Serratia species 333 0.4
Other pathogen 11,183 14.7
Total 76,307 100

Adapted from Weiner, L. M., et al. Antimicrobial-resistant pathogens

associated with healthcare-associated infections: summary of data reported
to the National Healthcare Safety Network at the Centers for Disease
Control and Prevention, 2011–2014. Infect Control Hosp Epidemiol 2016;37
(11): 1288-1301.

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81. Morris AM, Jobe BA, Stoney M, et al. Clostridium difficile colitis: An
increasingly aggressive iatrogenic disease? Arch Surg. 2002;137(10):
1096–1100.
 34 Major Orthopedic Surgery
LISBI RIVAS, RYAN D. SCULLY, TAMMY JU, JAMES DEBRITZ, and BABAK SARANI
The United States is experiencing considerable growth in
its elderly population. In 2050, the population of elderly
people aged 65 years and over is projected to be 83.7
million, almost double the estimated population in 2012.1
As a result, an increasing portion of health-care resources
will be used by the “baby boomer” generation. In the United
States, approximately 505,000 hip replacements and
723,000 knee replacements were performed in 2014.2
It is expected that an increasing number of both elective
and urgent orthopedic procedures, such as joint replace-
ments and complex fracture repairs, will be required in older
patients with multiple comorbid conditions. Therefore the
number of orthopedic patients who may require postopera-
tive critical care management is expected to increase. The
critical care provider must be familiar with issues unique
to these patients.
Several factors have been shown to impact morbidity and
mortality in orthopedic patients. For hip replacement sur-
gery, age has been established to be an independent predic-
tor of mortality where patients older than 80 years of age
have a mortality rate 38% higher than those less than
59 years of age.3,4 Patients with an American Society of
Anesthesiologists (ASA) 3, preexisting pulmonary or car-
diac conditions, renal insufficiency, or diabetes mellitus also
have higher morbidity.3,4 Finally, patients undergoing spine
operations have the potential for unique postoperative com-
plications, which will be discussed separately.
Although many studies have documented the utility and
benefits of joint replacement and spine surgery, there con-
tinues to be a paucity of large randomized clinical trial data
on interventions to minimize postoperative complications
after these procedures. The recommendations in this chap-
ter are based mostly on small case series, meta-analyses, and
retrospective reviews. This chapter will focus on the care of
patients undergoing total joint or spine surgery and will not
discuss care of the multiply injured trauma patient.
Care After Total Joint Arthroplasty
Several issues are unique to patients after total joint arthro-
plasty. These include venous thromboembolic disease, fat
embolism, and complications related to the intraoperative
use of cement.
VENOUS THROMBOEMBOLIC DISEASE
Deep venous thrombosis (DVT) and pulmonary embolism
(PE) are generally considered to be a single clinical entity
referred to as venous thromboembolic disease (VTED). It is
estimated that 80% to 90% of pulmonary emboli originate
as lower extremity, pelvic, or caval DVTs. Certain orthopedic
procedures such as total joint arthroplasty are associated
with a very high rate of DVT.5–7 The reasons for this are
most likely related to the extensive soft tissue dissection,
inflammatory reaction in proximity to major blood vessels,
and prolonged extremity immobility required after such pro-
cedures. The incidence of asymptomatic, venographically
evident DVT in postoperative total joint arthroplasty
patients is approximately 50% to 80% without chemopro-
phylaxis, but the majority of these thrombi resolve sponta-
neously with no clinical sequelae.6–8 Although there is
minimal data with sufficient follow-up to know precisely
the incidence, prevalence, or timeline for the development
of these symptoms, studies have shown that patients who
undergo total knee replacement have a much higher risk
of symptomatic DVT (10%–15%) than those undergoing
total hip replacement (3%–4%).9,10 Symptoms of DVT
include edema, pain, erythema, or, less commonly, ulcera-
tion of the lower extremity. Asymptomatic DVT refers to
thrombi that are evident only by screening imaging, such
as conventional CT venography or duplex ultrasound.
The risk of fatal PE is the same whether patients have symp-
tomatic or asymptomatic DVTs (<1%).
Although medical society guidelines have been estab-
lished,5 recommendations regarding venous thromboembo-
lism (VTE) prophylaxis can be applied uniformly to most
orthopedic patients. The evidence available is low quality
mainly because of the lack of adequate power, or random-
ized, blind, and controlled studies comparing one modality
with another for the prevention of VTED. Most studies eval-
uating the efficacy of one VTE prophylaxis agent against
another for the prevention of DVT have been nonblinded
or nonrandomized. Studies evaluating various agents for
the prevention of PE would be difficult to execute because
of the low incidence of fatal PE. For example, a randomized
prospective trial with an 80% power to demonstrate a 5%
difference in efficacy of mechanical versus pharmacologic
prophylaxis for prevention of PE would require 45,000
patients.11
Total Hip Arthroplasty
Studies evaluating the efficacy of pharmacologic versus
mechanical (e.g., foot pumps or sequential compression
devices) prophylaxis against DVT after elective hip surgery
have yielded conflicting findings. Small studies have
shown that mechanical devices alone are efficacious in
preventing asymptomatic DVT, but compliance with the
use of these devices is highly variable.12,13 Other studies
have shown that pharmacologic prophylaxis is superior
to mechanical prophylaxis for the prevention of VTE,14–16
but these studies are low quality due to imprecision and
high risk for bias. Regarding the different pharmacologic
agents, low-molecular-weight heparin (LMWH) has been
521
522 PART IV • Early Postoperative Care
compared with other anticoagulants. When compared with
unfractionated heparin (UFH), patients who received LMWH
had fewer incidence of pulmonary embolism, DVT, and major
bleeding events. Compared with patients who received a
vitamin K antagonist (VKA), those who received LMWH
had fewer deep vein thromboses but reported increased
bleeding events.17–19 The data on factor Xa inhibitors (FXaI)
such as fondaparinux, rivaroxaban, and apixaban are mixed,
but overall seem to suggest a similar efficacy as LMWH for
prevention of VTE and also a similar risk profile for bleed-
ing.20–22 Evidence on dabigatran, a direct thrombin inhibitor,
is also conflicting. When compared with LMWH, some
randomized controlled trials showed inferior efficacy while
others revealed comparable efficacy with similar bleeding
rates.21,23 To date, the data on aspirin for VTE prophylaxis
are mixed. Two large nonrandomized control trials compared
antiplatelet agents with LMWH, whereas one study found
no significant difference in PE and symptomatic DVT between
the two treatments, the smaller study found a higher rate
of PE in the antiplatelet group.24,25 When comparing
antiplatelet agents with VKA, one randomized control trial
compared the use of intermittent pneumatic compression
(IPC) alone, IPC with aspirin, and IPC with VKA, and found
no differences in incidence of VTED between the three
groups.13
Although the rates of asymptomatic DVT are similar for
patients with hip fractures and those undergoing elective
joint surgery, patients with hip fractures have a significantly
higher rate of fatal PE (4%–10%).5,26 The reason for this dif-
ference is unknown and the exact site of the fracture (sub-
capital vs intertrochanteric) does not appear to affect the
rate of VTED.26 One small randomized control trial compar-
ing aspirin with IPC alone, found no difference in VTE
events.27 However, pharmacologic intervention has been
shown to be far superior to placebo alone.28 Low-dose
unfractionated heparin has been shown to be efficacious
in preventing VTED in small uncontrolled studies.29,30 Sim-
ilarly, LMWH and warfarin have also been shown to be
effective in larger studies.30–32 For hip fracture patients, fon-
daparinux has been shown to have higher efficacy than
enoxaparin for the prevention of VTE, with conflicting
results regarding the risk of bleeding complications.33,34
The Agency for Health-care Research and Quality (AHRQ)
published the largest meta-analysis so far regarding
prevention of VTE in major orthopedic surgeries, including
hip fracture surgery. They compared different classes of
chemotherapy agents.
This review concluded that the data are insufficient to
assess the risks and benefits of these different interventions.35
Total Knee Arthroplasty
As is the case for total hip arthroplasty, there are conflicting
data regarding the various prophylactic regimens for VTED
after total knee replacement. It is generally accepted that
mechanical devices are less efficacious than pharmacologic
agents in preventing asymptomatic DVT after knee arthro-
plasty.36,37 Several randomized controlled trials comparing
LMWH with warfarin for the prevention of VTE after total
knee replacement have failed to show a difference in PE rate,
but LMWH was associated with less DVTs but slightly
higher increase in bleeding events.38–40 In recent years
there has been growing evidence supporting the use of FXaI
after total knee arthroplasty.41–43 In a meta-analysis, Balk
et al. found that FXaI were the most efficacious intervention
in preventing DVT following total knee replacement,
followed by the combination of LMWH and mechanical pro-
phylaxis. As with previous studies, there were no differences
between the rates of symptomatic DVT and fatal PE, most
probably a result of inadequate study power to detect such
a difference. Aspirin has also been compared with other che-
moprophylaxis agents. When compared with FXaI, one ran-
domized control trial showed fewer total DVTs with FXaI
and no difference in symptomatic DVT when compared with
aspirin.44 Other studies comparing aspirin with VKA and
LMWH found similar results with no significant difference
in total or symptomatic DVT with either group.44–46
Recommendations for Prophylaxis Against VTED
Prophylaxis against VTED is currently based more on the
danger of PE than on prevention of DVT. Previous studies
from the 1970s cited the incidence of fatal PE after joint
replacement surgery to be higher than 2% to 3% despite
some form of prophylactic anticoagulation.47,48 Based on
these papers, such operations were considered to be “high
risk” for VTED and either mechanical or pharmacologic pro-
phylaxis was encouraged. However, more recent studies
have documented an incidence of fatal PE to be only
0.05% to 0.2%, regardless of whether prophylaxis of any
modality is used.8,11,49 Possible reasons for the significant
decrease in the rate of fatal PE include improved surgical
and anesthetic techniques with shorter operative times,
faster discharge of patients from the hospital (resulting in
earlier mobility), and improved rehabilitation techniques.
Because the incidence of fatal PE is extremely low, some
have suggested that pharmacologic prophylaxis is not war-
ranted. They argue that the incidence of fatal PE is nearly
equal to the incidence of complications from therapy (e.g.,
bleeding) and that pharmacologic intervention has not been
shown to be more efficacious than mechanical measures
alone in preventing symptomatic DVT or PE.50 Further-
more, the vast majority of deep venous thromboses resolve
spontaneously, and thus the risk of bleeding associated with
pharmacologic intervention may not be justified. Others,
however, note that nonfatal PE and DVT carry substantial
morbidity, such as heart strain, respiratory embarrassment,
and thrombophlebitis, and thus the risk associated with
pharmacologic prophylaxis is justified.
Patients in the intensive care unit (ICU) have limited
opportunity for movement because of either the nature of
their critical illness or the need for continuous monitoring.
Thus it is possible that these patients will have a higher rate
of fatal PE and stronger consideration should be given to
providing both mechanical and pharmacologic prophylaxis
against VTED.
After these guidelines were published, the use of aspirin
for VTE prophylaxis in elective knee and hip arthroplasty
has been looked at by many studies. One meta-analysis com-
paring aspirin with other chemoprophylaxis agents, either
alone or in combination with mechanical prophylaxis,
found a low rate of VTE with a low risk of bleeding. These
results were limited by the low quality of the studies, there-
fore they concluded future randomized controlled trials
should investigate the efficacy of aspirin.51 A more recent
meta-analysis by Balk et al. showed that the combination

of antiplatelet drug plus mechanical devices had a lower
odds of DVT compared with antiplatelet drug alone, UFH
heparin, and VKA.35
The current guidelines, published in 2012, from the Col-
lege of Chest Physicians Consensus Conference on Preven-
tion of VTE in orthopedic surgery patients recommend
pharmacologic prophylaxis to guard against VTED after
total joint replacement surgery.6 LMWH is the agent of
choice for the prophylaxis against VTED and agents such
as fondaparinux, apixaban, dabigatran, rivaroxaban, UFH,
adjusted-dose warfarin, or aspirin are considered second line
agents (Table 34.1). Similarly, The American Academy of
Orthopedic Surgeons (AAOS) also recommends pharmaco-
logic prophylaxis against VTE after hip/knee joint arthro-
plasty. Mechanical and chemical prophylaxis combined is
recommended in patients with a past history of VTED.
FAT EMBOLISM SYNDROME
Fat embolism must be distinguished by the critical care pro-
vider from fat embolism syndrome (FES). Fat embolism
occurs in almost all patients who have suffered multiple
trauma or have had major orthopedic surgery, it is rarely
symptomatic, and it is most often diagnosed incidentally
on postmortem examination.52,53 On the other hand, FES
has a distinct triad of signs and symptoms with a variable
disease course.
Table 34.1 Recommendations of the Ninth American
College of Chest Physicians Consensus Conference on
Antithrombotic Therapy.
ELECTIVE TOTAL HIP OR KNEE ARTHROPLASTY
(USE AT LEAST ONE OF THE FOLLOWING)
Grade 1B Grade 1C
a
LMWH IPCD
Fondaparinux
Apixaban
Dabigatran
Rivaroxaban
LDUH
Adjusted-dose VKA
Aspirin
HIP FRACTURE SURGERY
Grade 1B
LMWHa
Fondaparinux
LDUH
Adjusted-dose VKA
Aspirin
a
LMWH is the preferred option in both elective joint arthroplasty and hip
fracture surgery. IPCD, Intermittent pneumatic compression device; LDUH,
low-dose unfractionated heparin; LMWH, low-molecular-weight heparin;
VKA, vitamin K antagonist.
34 • Major Orthopedic Surgery 523
Von Bergmann first described FES in 1873 while treating
a patient with a femur fracture.54 In the orthopedic popula-
tion, it occurs most often after joint replacement surgery
(1%–3% incidence) and in those with multiple long bone
fractures (5%–10% incidence).55 It is much more com-
monly seen in adults than in children because olein, a lipid
that is more abundant in the marrow of adults, is more likely
to produce emboli than palmitin and stearin, which are
found mainly in younger individuals.56 Prolonged bedrest
or delayed definitive fracture repair (greater than 48 hours)
has been shown to increase the incidence of FES. The overall
mortality has improved since the mid-20th century but
remains at 5% to 15%, although this figure may be an
underestimation of the true incidence of death resulting
from FES.53,57
FES is classically characterized by pulmonary, cerebral,
and cutaneous or retinal findings. The most severe manifes-
tations of FES are usually noted after trauma; it is unusual to
have severe multiorgan dysfunction resulting from FES after
joint replacement surgery. Signs and symptoms tend to
occur 12 to 24 hours after injury or operation and to worsen
between 72 and 96 hours after the initial insult. Nearly all
patients have some degree of pulmonary impairment,
tachypnea often being the first sign. Later findings are hyp-
oxemia and increasing requirements for supplemental oxy-
gen. Cerebral findings are present in 80% of patients and can
manifest as headache, agitation, confusion, or seizure.58
Finally, a petechial rash localized to nondependent regions
and the oral mucosa and possible retinal edema or hemor-
rhage occur in 40% of patients after 24 to 48 hours.59 The
rash tends to resolve after 1 week. Other nonspecific findings
may include tachycardia and fever. Mortality is most often
related to severe pulmonary dysfunction, whereas morbidity
is most often the result of cerebral complications.
The exact pathophysiology underlying FES remains
unknown. The two leading theories are mechanical and bio-
chemical and it is possible that the actual cause is a combi-
nation of both proposed mechanisms. The mechanical
theory states that intramedullary pressure exceeds venous
pressure and causes embolization of fat globules, which then
lodge in pulmonary capillaries. The resulting pulmonary
hypertension causes opening of the foramen ovale (if not
already patent) and allows arterial embolization of other
globules, which lodge in cerebral, retinal, and dermal arte-
rioles.55,60 Because there is a 12- to 24-hour latency in the
development of symptoms and there is no direct relationship
between the amount of embolized fat and pulmonary dis-
tress, the biochemical theory states that the embolized fat
globules initiate an inflammatory cascade in the lung lead-
ing to respiratory impairment and noncardiogenic pulmo-
nary edema.53,55 Cerebral impairment is postulated to be
caused by a similar mechanism.
Although scoring systems have been described,53,61 FES
remains mostly a clinical diagnosis because no test is sensi-
tive or specific enough to be of use. The critical care provider
must have a high index of suspicion to make this diagnosis
accurately. A near ubiquitous finding is hypoxemia. Many
patients have PaO2 values less than 50 mmHg on room
air within 72 hours. Accordingly, arterial blood gas analysis
is the only uniformly helpful test, although the results do not
differentiate FES from other causes of hypoxemia. Most
patients have a normal electrocardiogram. The chest
524 PART IV • Early Postoperative Care
radiograph is often normal initially and lags behind clinical
findings, much as is noted for acute respiratory distress
syndrome (ARDS). There are only isolated case reports
and small series on the use of high-resolution computed
tomography for the diagnosis of FES. These reports consis-
tently show bilateral ground-glass opacities and thickening
of the interlobular septa in nondependent regions of
the lungs, but these findings are not specific to FES.62,63
Other tests, such as urinalysis or evaluation of cerebrospinal
fluid or blood for fat cells or eosinophils, are too insensitive
to be helpful. For patients with respiratory embarrassment,
bronchoalveolar lavage (BAL) showing fat cells might
allow FES to be differentiated from other causes, but the
role of BAL has not been studied in large, prospective
trials.64
The treatment of FES is centered on definitive fixation of
all fractures and on respiratory support to maintain ade-
quate oxygenation. Studies evaluating therapies such as
alcohol and dextran have not shown them to be of bene-
fit.53,55,65 Additionally, reports on the usefulness of cortico-
steroids are conflicting. Corticosteroids were first used in the
1960s and their use today remains controversial, with some
studies suggesting that they may be harmful.55 It is thought
that corticosteroids may help by inhibiting the inflamma-
tory reaction seen with FES and by decreasing the rise in
plasma free fatty acids by inhibiting pulmonary lipase activ-
ity. A recent meta-analysis looked at the effect of corticoste-
roids in preventing FES in patients with long bone fractures.
Findings suggest that use of corticosteroids may be benefi-
cial in preventing FES and hypoxia but there was no differ-
ence in mortality.66 However, it is not possible to identify
patients at risk of FES, thereby making prophylactic therapy
not practical.
Currently, there is no consensus or recommendation on
whether corticosteroids should be prescribed or on the dos-
age to be used. Suggested doses of methylprednisolone have
ranged from 1.5 mg/kg every 8 hours for four doses, to 30
mg/kg every 2 hours for two doses, to 7.5 mg/kg every
6 hours for 12 doses.53
The overall approach to the patient with FES should be
based on ensuring adequate oxygen delivery to the periph-
eral tissues. Management involves restoring euvolemia, cor-
recting severe anemia, monitoring indices of perfusion, and
utilizing mechanical ventilation as necessary. On the basis
of current knowledge, the use of corticosteroids or other
medical therapies cannot be recommended.
COMPLICATIONS RELATING TO THE USE
OF INTRAMEDULLARY CEMENT
Traditionally, polymethylmethacrylate has been used to fix
prostheses implanted during total hip replacement surgery.
Most recently it is most commonly used in repair of spinal
fractures.67 Reports of severe transient hypotension or hyp-
oxemia related to the use of cement first appeared in 1970,
but the incidence has decreased from greater than 50% to
5%.57 The reason for this significant decrease in incidence
remains speculative because the cause of cement-related
hypotension has never been determined. The decrease
may be the result of improvement in anesthetic technique,
such as maintaining euvolemia and oxygenation, and also
the result of better prostheses, which decrease the incidence
of cement or fat (bone marrow) emboli. Cement-related
hypotension may be related to systemic release of poly-
methylmethacrylate with resulting systemic inflammation,
vasodilation, and cardiac depression.57 Hypoxemia may
result from air and fat emboli caused by forceful instillation
of cement into the medullary cavity of the femur. Intrao-
perative transesophageal echocardiography has demon-
strated numerous emboli traveling through the right
heart during cement and component insertion, but rela-
tively few patients manifest symptoms of pulmonary
embolism.68
It is not known what predisposes some patients to become
hypotensive or hypoxemic while most remain asymptom-
atic. Patients at high risk of developing cement-related com-
plications include older adults with cancer, patients with
preexisting cardiopulmonary conditions, patients undergo-
ing operations with a long-stem femoral component, and
patients with hypovolemia.69 Unfortunately, the factors
that have been shown to decrease the incidence of
cement-related complications are outside the direct control
of the intensivist and include maintenance of euvolemia
intraoperatively, lavage of the femoral canal, and placement
of a vent hole in the prosthesis.
Patients who develop complications related to the use of
cement most commonly present with isolated hypoxemia
that can last between 30 minutes and 48 hours.57,70 Most
often, these patients have a normal chest radiograph. The
need for mechanical ventilation depends on the patient’s
preexisting cardiopulmonary reserve, the severity of the
reaction to the cement, and other insults that may have
occurred intraoperatively (such as excessive bleeding, long
operative time, or inadequate resuscitation). Ries and col-
leagues showed a 28% increase in the pulmonary shunt
fraction after instillation of cement and further demon-
strated that it took up to 48 hours for the shunt fraction
to return to normal.70 These authors recommended evalu-
ating patients’ pulmonary function when use of cement is
planned during total hip replacement surgery. Significant
hypotension is noted in only 5% of patients and is usually
much more transient, often lasting less than 30 minutes.
All in all, cement-related complications should be consid-
ered as a diagnosis of exclusion, and physicians caring for
such patients postoperatively must exclude other causes
of persistent hypotension, such as myocardial infarction
or hypovolemia, even in patients who are at risk of
cement-related complications. Therapy is mainly supportive
and centers on ensuring adequate oxygen delivery.
Care After Spine Surgery
The types of procedures performed on the spine are varied
and becoming increasingly common. Lumbar fusion rates
doubled from 1979 to 1990, and the highest rise was seen
in those older than 60 years of age.71 The planned surgery
may involve single or multiple levels of vertebrae using an
anterior or posterior approach and may or may not require
instrumentation. Some procedures require an intraperito-
neal, retroperitoneal, or thoracic approach. Percutaneous
and minimally invasive procedures are becoming more
common. The indications for and physiologic consequences
of each approach will be discussed.

Although the various operations have a low morbidity
and mortality, the need for a postoperative ICU stay is
increased for patients older than 60 years, when there is
extensive decompression and fusion, with greater than 60
degrees in curvature of the spine (e.g., severe scoliosis),
for an anterior approach to the thoracic or lumbar spine,
and in the presence of other comorbidities.72 Comorbidities
associated with the need for postoperative ICU care include
preexisting myelopathy, pulmonary disease, cardiac or cor-
onary artery disease, renal impairment, and diabetes melli-
tus. Preexisting myelopathy and severe scoliosis can lead to
impaired pulmonary mechanics, significant pulmonary
hypertension, and right ventricular failure in those older
than 40 years.57 Furthermore, myelopathy often requires
more extensive surgical repair, resulting in increased oper-
ative time, increased blood loss, and multilevel fusion.
It is not known whether an anterior or posterior spine
fusion is more physiologically taxing to the patient. How-
ever, studies suggest that complications are more common
and severe after a posterior approach than with an anterior
approach.73–75 Nonetheless, patients may require ICU care
after an anterior approach because of the volume shifts and
possible respiratory dysfunction associated with violation of
the thoracic or peritoneal cavity. An anterior approach may
result in transiently worsening pulmonary function,
whereas a posterior approach is often better tolerated from
a cardiorespiratory standpoint.76 Complications of a poste-
rior approach to spinal fusion include bleeding, dural tear,
neurologic injury, or prolonged operative time; complica-
tions of an anterior approach include ileus, deep venous
thrombosis, or respiratory impairment (in cases involving
the thoracic vertebrae). The main advantage of the posterior
approach is the ability to visualize the posterior spinal ele-
ments (lamina, intervertebral disks, and spinal cord) with-
out opening a body cavity. The main disadvantage of this
approach is the limited operative field provided to the sur-
geon, which can make instrumentation and multilevel
fusion more difficult. Thus most patients requiring multile-
vel fusion or tumor resection undergo an anterior approach.
In this circumstance, the exposure can involve retroperito-
neal dissection only, or it can be much more invasive,
involving a thoracoabdominal approach. A combined ante-
rior–posterior approach is used most often when a large
correction is necessary (e.g., for scoliosis) or when an ante-
rior approach alone is insufficient to allow multilevel fusion
(e.g., for osteoporosis).
Spine surgery involving multiple levels can be especially
painful. Decompression of the neural elements often pro-
vides immediate pain relief to patients but the stripping of
paraspinal musculature during exposure causes acute sur-
gical pain. The implementation of a multimodal approach
to pain control centered on nonnarcotic medications has
led to improved outcomes across multiple categories of
orthopedic patients. A multimodal approach allows
improved pain control while minimizing the risk of opioid
side effects, such as respiratory depression, altered mental
status, constipation, ileus, and urinary retention. Some
studies have demonstrated decreased fusion rates with non-
steroidal antiinflammatory (NSAID) use after spine sur-
gery.77,78 However, level I and level II evidence has
demonstrated improved pain scores and decreased opioid
use without associated risk of pseudoarthrosis with
34 • Major Orthopedic Surgery 525
short-term perioperative NSAID use in spine patients.79 The
use of neuromodulatory agents such as gabapentin and
pregabalin is also helpful. A meta-analysis of seven studies
demonstrated significant decreases in pain and opioid use
without major side effects.80 Similarly, acetaminophen
should be routinely considered part of the pain regimen
unless contraindicated. Continuous local anesthetic infu-
sions postoperatively are another adjunctive therapy that
can improve pain control while decreasing opioid consump-
tion.81–83 Lastly, continuous low-dose intravenous infusion
of ketamine is highly effective in minimizing postoperative
narcotic requirement.
UNIQUE ISSUES AFTER SPINE SURGERY
Patients undergoing spine surgery, like other surgical
patients, are at risk of developing congestive heart failure,
arrhythmia, bleeding, and other common postoperative
complications. However, spine surgery patients have a par-
ticularly increased risk for cardiopulmonary dysfunction,
infection, and certain unusual complications, such as syn-
drome of inappropriate antidiuretic hormone (SIADH)
release, injury during intubation, and recurrent laryngeal
nerve injury.
Cardiopulmonary Dysfunction
Patients are at increased risk of hypoventilation after sur-
gery involving the thoracic or lumbar spine. Surgery involv-
ing the thorax is associated with a marked decline in the
1-second forced expiratory volume (FEV1), forced vital
capacity, and total lung volume.84 Severe atelectasis is
noted in 5% to 15% of patients, and 3% to 4% develop
pneumonia.71 Thoracoabdominal procedures are associated
with significant pain, which, if not treated appropriately,
can lead to hypoventilation. The severe pain can last as long
as 4 days,84 so many patients may benefit from either epi-
dural or patient-controlled analgesia (PCA) postoperatively.
Rarely, patients who have undergone a thoracoabdominal
approach may have phrenic nerve injury, which may be
transient (because of traction) or permanent. Unilateral
phrenic nerve injury manifests radiographically as elevation
of the ipsilateral hemidiaphragm and is often well tolerated
in individuals with only mild to moderate preoperative pul-
monary impairment. The rate of symptomatic DVT after
spine surgery is 0.5% in patients receiving either mechani-
cal or pharmacologic prophylaxis85 and Dearborn and col-
leagues found a 2% incidence of PE in such patients.86 PE is
rarely the cause of hypoxemia in patients who have under-
gone spine surgery and have received VTED prophylaxis.
Critical care providers must expeditiously exclude other
causes of hypoxemia in these patients.
Patients with severe scoliosis are at high risk of cardiac or
pulmonary failure in the perioperative period.57 The severe
angulation of the spine results in a restrictive pattern of
ventilation, with resultant hypercapnia, hypoxemia, and
pulmonary hypertension, especially in those older than
40 years.84 Accordingly, pulmonary or right ventricular
function may deteriorate acutely in the perioperative period,
particularly after aggressive fluid resuscitation. These
patients may benefit from cardiac performance monitoring
and may require pharmacologic support to maintain
adequate right ventricular function.
526 PART IV • Early Postoperative Care
Many patients with scoliosis have muscular dystrophy or
cerebral palsy. The majority of these patients have a cardiac
abnormality of some nature. Dysrhythmia and cardiac con-
duction defects have also been reported in up to 50% of
these patients.84 Such patients require telemetry postopera-
tively. In addition, many patients with muscular dystrophy
have involvement of the bulbar muscles and are therefore at
risk of aspiration postoperatively.
Acute Vision Loss
Spine patients are at risk of postoperative vision loss or dis-
turbance resulting from prolonged prone positioning. The
pathophysiology is thought to be related to inadequate vas-
cular perfusion of essential ocular structures such as the
optic nerve. Patients with ischemic neuropathy of the optic
nerve typically report painless but sudden loss of vision.
Ophthalmologic examination reveals swelling or pallor of
the optic disc. Other causes for vision disturbance should
be considered, such as corneal abrasion, stroke, and pitui-
tary apoplexy. Patients in the prone or lateral position for
an extended period of time may be at risk of orbital compart-
ment syndrome. This ophthalmologic emergency presents
with proptosis, conjunctival swelling, periocular edema,
and painful loss of vision. Direct compression of the eyes
causes venous congestion and increased orbital pressure,
which in turn leads to decreased perfusion. Prone position-
ing, use of the Wilson head frame, estimated blood loss
greater than 1.5 L, perioperative hypotension, and perioper-
ative transfusion may increase the risk of perioperative
vision loss. If postoperative vision loss is suspected, an oph-
thalmologist should be consulted immediately and hemody-
namic stability should be optimized.87
Intraoperative Blood Loss
Increased blood loss is expected in revision or prolonged
deformity correction surgeries. Perioperative allogenic blood
transfusion has been associated with surgical site infections
and urinary tract infections in lumbar spine surgery, prob-
ably caused by suppression of T-cell response. As in other
instances of hemorrhage, red blood cell transfusion alone
can deplete clotting factors. For large-volume blood transfu-
sions, subsequent plasma transfusion should be considered.
Perioperative core temperature control is essential. Mild
hypothermia can increase blood loss up to 16%.88 Antifibri-
nolytics, such as tranexamic acid and aminocaproic acid,
have greatly reduced the need for allogenic blood transfu-
sion in total joint arthroplasty. A meta-analysis of tranexa-
mic acid (TXA) used in spine surgery in 644 patients
concluded that the antifibrinolytic reduced total blood loss
by a mean of 219 mL. The authors also found a decreased
rate of transfusion with TXA.89 Some concern remains
regarding the effect of these agents on the fusion mass when
arthrodesis is performed.90
Infection
Patients undergoing thoracic or lumbar surgery have a
higher risk of infection than other surgical patients under-
going clean operations. Clean operations are nontraumatic
cases that do not involve violation of hollow viscera or
infected fields. Whereas discectomy with antibiotic prophy-
laxis is associated with a 1% risk of infection, fusion with
instrumentation is associated with a 3% to 8% risk,
depending on the number of levels fused and amount of
instrumentation needed.57 It is thought that the higher risk
of infection seen with increasing levels of fusion is the
result of greater dissection, operative time, and blood loss.
Other contributing factors include malnutrition, chronic
steroid use, and preexisting distant infections (e.g., of the
urinary tract).
Syndrome of Inappropriate Antidiuretic Hormone
Approximately 5% of patients undergoing spinal fusion
develop SIADH postoperatively.91 Risk factors for develop-
ing this complication include severe blood loss, intraopera-
tive hypotension, and rapid correction of the spine. The
cause remains uncertain and therapy is directed at mainte-
nance of normal serum sodium through water restriction.
Most often, the disorder is self-limiting. Partly because of
the very long operative time needed for single-stage correc-
tion, most patients with severe scoliosis are corrected in a
two-stage procedure. Depending on the operation planned,
the first stage can involve exposure and decompression of
the cord from either an anterior or a posterior approach.
The second stage, which is usually performed 5 to 7 days
after the first, may involve instrumentation and can also
be approached from either side. Dividing the operation into
two stages might protect against the development of SIADH
because blood loss and operative time for each operation are
minimized. However, many studies have shown that two-
stage procedures are actually associated with more net
blood loss, longer net operative time, and longer hospitaliza-
tion.92–95 In conclusion, the intensive care physician needs
to maintain a high index of suspicion for SIADH in the
patient who has undergone spine surgery and presents with
hyponatremia and high urinary sodium. Patients undergo-
ing two-stage procedures may require more ICU care than
those undergoing a single-stage operation.
Ileus and Colonic Pseudo-Obstruction
Ileus occurs in 3.5% of patients undergoing lumbar spine
surgery. The rate of ileus in anterior lumbar surgery is three-
fold higher than that of posterior lumbar surgery (7.5% vs
2.6%.).96 Preexisting gastroesophageal reflux disease, poste-
rior instrumentation, and opening wedge osteotomy are risk
factors for ileus in the spine patient. Other risk factors may
include patients with prolonged surgeries, multiple staged
surgeries, history of chronic pain, and delayed mobilization
postoperatively.97
It is critical that colonic pseudo-obstruction (also known
as Ogilvie syndrome) is distinguished from ileus. The patient
will present with obstipation in both instances, but the key
feature in the former is isolated distention of the colon. In
cases where a plain x-ray cannot distinguish between an
ileus and colonic pseudo-obstruction, a noncontrast CT scan
can be diagnostic. Although the exact cause of Ogilvie syn-
drome is not known, it is believed to be caused by autonomic
impairment and parasympathetic inhibition. Mechanical
distal colonic obstruction, such as a neoplasm, must be ruled
out. Once this has been ruled out, the treatment of choice is
intravenous administration of neostigmine. Colonoscopic
decompression is also an option when neostigmine is con-
traindicated or unsuccessful. It is important that subsequent
narcotics be stopped and that the patient be mobilized to
prevent recurrence of either disorder.

Superior Mesenteric Artery Syndrome
Superior mesenteric artery (SMA) syndrome is a rare but
known complication in patients undergoing spine surgery
for deformity correction. As the alignment of the spine is cor-
rected, the angle between the SMA and third part of the duo-
denum decreases. This narrowed angle may lead to external
compression of the duodenum by the SMA. This complica-
tion has been most associated with the pediatric or adoles-
cent scoliosis patient. Patients with SMA syndrome typically
develop abdominal pain, emesis, and bloating 5 to 10 days
postoperatively. Braun et al. identified multiple risk factors
for SMA syndrome: body mass index less than 25th percen-
tile for age, stiff thoracic curve, laterally displaced lumbar
curve, thoracoplasty, anterior approach, staged procedures.
The authors also emphasized the importance of nutritional
optimization preoperatively.98,99 Most patients with SMA
syndrome can be successfully treated with nasogastric tube
decompression, repositioning the patient to a prone or left
lateral position, and appropriate fluid and electrolyte
replacement. Laparotomy is reserved for patients who fail
medical management or who have deteriorating clinical
status and concern for bowel ischemia.
Conclusions
In summary, the number of patients older than 65 years
who require elective or urgent orthopedic surgery is
expected to increase. Often, these patients have significant
comorbidities that need to be addressed in the perioperative
period and they may require ICU care. In addition to the rou-
tine care of the postoperative patient, those undergoing
major orthopedic surgery have unique issues related to their
propensity for thromboembolic disease or cardiopulmonary
failure and to their need for pain management. Similarly,
those undergoing spine operations are at risk of atypical
postoperative complications. The astute critical care pro-
vider should be aware of these possible complications to
minimize morbidity and length of stay in this patient
population.
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 35 Solid Organ Transplantation
JANE LEE, SHYAMASUNDAR BALASUBRAMANYA, and VATCHE G. AGOPIAN
Solid organ transplantation is the surgical procedure in
which an organ is removed from a one body (donor) and
placed into another body (recipient). Solid organs that have
been successfully transplanted are liver, kidneys, pancreas,
intestine, heart, and lungs. Before organ transplantation
can be considered, there must be failure of the native organ.
Each organ failure is associated with specific morbidities and
for some organs the severity of these morbidities is associ-
ated with the recipient’s place on the candidate waiting list.
There is also an association with death that is either direct
(after complete organ failure) or indirect (from complica-
tions of organ failure). Some organs have a method of sup-
port that are advanced from a technological vantage point,
but biologically they are primitive and rudimentary. The
risks of these supportive therapies should be weighed
against the risks of surgery and immunosuppression. Ide-
ally, patients would have a choice and transplant physicians
would be able to guide them in their decision. However, the
demand for all organs outstrips the supply, engaging the
transplant physician in a complicated ethical dialogue on
a daily basis while patients wait on candidate lists. Each spe-
cialty has its own formula for determining who should
receive the next available organ, but all struggle with the
shortage of organs.
The organ shortage means that organ support is the only
option for many individuals awaiting transplantation. Xeno-
transplantation as a bridge remains a concept, not a reality.
Patients with chronic renal failure may spend years on
hemodialysis or peritoneal dialysis. Patients with diabetes
mellitus from endocrine pancreatic insufficiency are medi-
cally managed with insulin replacement therapy. Patients
with heart failure may be connected to ventricular assist
devices while they await their new heart. For respiratory
failure, support may culminate in noninvasive or invasive
mechanical ventilation, but it often starts with supplemental
oxygen therapy. Artificial liver support remains experimen-
tal. Patients with fulminant hepatic failure are more likely
than patients with chronic liver disease to benefit from liver
replacement therapy. The vast majority of patients with liver
disease, however, have chronic liver disease and develop
acute-on-chronic liver failure. Complications such as intrac-
table ascites and variceal hemorrhage are caused by portal
hypertension and are not corrected by treatment with an
artificial liver or a liver dialysis machine. Hepatic encephalop-
athy before or after a transjugular intrahepatic portosyste-
mic shunt (TIPS) may be amenable to artificial liver
support, but it is very unlikely that this therapy would
ever replace pharmacologic management with lactulose
and oral antibiotics. The development of total parental nutri-
tion (TPN) has increased the survival of short bowel patients;
530
however, when central venous access becomes an issue,
intestinal transplant is the only option for long-term survival.
Types of Donors
The quality of the donor organ as well as preoperative med-
ical history of the recipient must be known to manage a
postoperative transplant patient. Organs come from both
deceased and living donors. Donors may have been pro-
nounced dead by fulfilling brain death criteria (donation
after brain death or DBD) or by cardiorespiratory criteria
(donation after cardiac death or DCD).
The concept of brain death was created during the
infancy of transplantation; however, the practice of pro-
nouncing someone dead because of absent brainstem
function was already accepted in many cultures. The con-
troversy that still exists is brain death criteria may differ
by country.1 The brain-dead individual is ideal for organ
recovery because organs are removed under controlled cir-
cumstances. This limits warm ischemia time, which is when
organs undergo the greatest injury. Cold ischemia time is
the time after removal of the organ when it is cooled and
perfused with preservation solution. Presently, most organs
recovered for transplantation are DBD.2
The first heart and liver donors were people pronounced
dead by DCD, a method of retrieving organs for transplanta-
tion that is becoming popular again.3 When organs are
recovered from these donors, sometimes called non–heart-
beating donors, there is always a period of warm ischemia
depending on each transplant center’s preferences, render-
ing the organs less desirable for transplantation. However,
because the supply of organs is limited, donor organs that
are more marginal than desired are being transplanted into
patients. These organs, classified as expanded-criteria organs
(ECD), have specific donor or graft characteristics that
increase the probability of poor graft function postoperatively
and that are ultimately associated with poor graft or patient
survival. Recipients must consent to these marginal organs,
but this may be the only choice for many on a waiting list.
Many transplant experts believe that the only meaningful
answer to the organ shortage will come from increasing the
number of living donors. The first living donor was a living
related kidney transplant performed in Boston, Massachu-
setts, between identical twin brothers in 1954.4 The first
successful living donor liver transplantation was performed
between an adult and a child in 1989 in Brisbane, Australia,
and between two adults in 1994 in Tokyo, Japan.5 In the
United States, living donation increased until the first death
of a living liver donor in 2001.6 For a decade following this

tragedy, living donation decreased; however, according to
the Organ Procurement and Transplantation Network
(OPTN), there has been a slow increase in the recent years
largely because of organ shortages.
Immunosuppression
Advances in solid organ transplantation correspond with
the advancement of immunosuppression therapies. Many
of the early transplants may have been surgically successful,
long-term graft function and survival of patients was not
achieved until the development of calcineurin inhibitors.
The goal of immunosuppressive therapy in solid organ
transplant patients is to prevent rejection while limiting
the adverse effects of the drugs, which include direct drug
effects and secondary effects of immunosuppression (e.g.,
infection and cancer). The major classes of immunosuppres-
sive drugs are corticosteroids, antimetabolites, specific
lymphocyte-signaling inhibitors, and antibodies. Combina-
tion therapy decreases the likelihood of adverse effects.
Despite five decades of transplantation experience, achiev-
ing the delicate balance between immunosuppression to
prevent rejection of the transplanted organ and immuno-
competence to prevent opportunistic infections and cancers
remains a naive science. During the course of transplanta-
tion, different immunosuppressant medications are used in
different amounts and at appropriate times. In the initial
phase of organ transplantation, there are more cellular
and cytokine mechanisms that may lead to rejection; there-
fore, immunosuppression levels are maintained at a very
high level in the beginning. This is also called the induction
phase. Later, once recovered from organ transplantation,
patients can be maintained on less immunosuppression
medications called the maintenance phase. During episodes
of rejection, higher dosages of some of the maintenance
immunosuppression drugs may be used, or other drugs
may be used, or both. Immunosuppressant regimens for
the induction phase, maintenance phase, and rejection
episodes are not standardized, and they vary widely by
institution.7
Corticosteroids indiscriminately downregulate the imm-
une system, in particular, the expression and secretion of
many proinflammatory cytokines. It is ironic and telling
that this drug class, which has the least specificity for the
immune system, remains part of the scaffolding for all trans-
plant regimens. Corticosteroids are given in high dosages,
followed by a taper for induction and for the first episode
of acute cellular rejection in most paradigms.
The calcineurin inhibitors cyclosporine and tacrolimus
are the mainstays of immunosuppression. They work by
inhibiting the lymphocyte signaling pathways that lead to
interleukin-2 (IL-2) transcription. Cyclosporine and tacroli-
mus traverse the cell membrane and combine with cytoplas-
mic cyclophilin and FK binding protein (FKBP), respectively.
Either one of these complexes inactivates calcineurin, an
essential component of the enzyme complex that dephos-
phorylates nuclear factor for activated T cells (NFAT). NFAT
traverses the nuclear membrane and ultimately prevents
the transcription of IL-2. The major adverse effects in the
early postoperative period include both neurotoxicity and
nephrotoxicity. Both tacrolimus and cyclosporine cause a
35 • Solid Organ Transplantation 531
renal arteriolar vasoconstriction that may be reversible with
low-dose intravenous nicardipine.
A newer drug class of agents, the mTOR inhibitors siroli-
mus (rapamycin) and everolimus, work through different
cellular mechanisms. Like tacrolimus, these agents also bind
to FKBP and this complex then combines with mTOR
(which stands for molecular target of rapamycin) and pre-
vents protein translation from mRNA. Calcineurin is not
involved in this reaction. Sirolimus and everolimus do not
have the degree of neurotoxicity and nephrotoxicity seen
with the calcineurin inhibitors and they are often used
instead of, or in combination with, calcineurin inhibitors
when renal function is of concern.
Antimetabolites is another class of immunosuppressive
agent that is often used in combination with calcineurin
inhibitors and/or mTOR inhibitors. Azathioprine, a prodrug
that is converted to mercaptopurine, is an example. It is
nonspecific and affects all rapidly dividing cells. Because
lymphocytes are rapidly dividing cells, they are preferen-
tially affected, which decreases the immune response. Intes-
tinal cells divide rapidly and are injured by azathioprine,
leading to the adverse side effect of diarrhea. The more tai-
lored antimetabolites are mycophenolic acid and its prodrug
mycophenolate mofetil, which has greater bioavailability.
These drugs enzymatically inhibit the formation of the
nucleoside guanosine, preferentially in T and B cells, avoid-
ing some of the side effects of the azathioprine.
Antibody agents are used both for induction and for rejec-
tion. A polyclonal antibody called antithymocyte globulin is
prepared by injecting rabbits with human thymocytes. The
resulting antibody then attacks human T cells. It is often
used as rescue therapy when cellular rejection develops.
Basiliximab is a chimeric mouse–human monoclonal anti-
body to the IL-2 receptor of T cells. Basiliximab competes
with IL-2 to bind to the IL2 receptor on the surface of the
activated T lymphocytes and thus prevents the receptor
from signaling. This prevents T cells from replicating and
also from activating B cells, which are responsible for the
production of antibodies. Alemtuzumab is a monoclonal
antibody that binds to CD52, a protein present on the sur-
face of mature lymphocytes, but not on the stem cells from
which these lymphocytes are derived. After treatment with
alemtuzumab, these CD52-bearing lymphocytes are tar-
geted for destruction. All antibody therapies can cause the
release of cytokines and patients need to be monitored
closely during administration. Finally, physical removal of
antibodies can be performed with plasmaphorisis.
Liver Transplantation
Thomas Starzl completed the first successful human liver
transplant in 1967 after experimenting for 7 years with
dogs. More than 40 years later, over 1 million liver trans-
plants have been performed worldwide.8
RECIPIENT
Candidates for liver transplant have end-stage liver disease
as a result of multiple etiologies varying by global
region. According to United Network for Organ Sharing
(UNOS) and OPTN databases, nonalcoholic steatohepatitis,
532 PART IV • Early Postoperative Care
alcoholic hepatitis, and hepatitis C virus were found to be
the most commonly cited etiologies of chronic liver disease
in adult patients (18 years and older) in the United States.9
Allocation of livers is primarily determined by the severity of
disease according to Model for End-stage Liver Disease
(MELD) score, which consists of serum bilirubin, creatinine,
and International Normalized Ratio (INR) for prothrombin
time. It was initially developed to predict mortality within
3 months of surgery in patients who had undergone a trans-
jugular intrahepatic portosystemic shunt (TIPS) proce-
dure.10 The pediatric equivalent is the PELD, which also
takes into account albumin and growth failure. The morbid-
ity of liver cirrhosis include both direct and indirect factors,
which include coagulopathy, portal hypertension resulting
in ascites with possible spontaneous bacterial peritonitis and
gastrointestinal bleeding from varices, poor nutritional sta-
tus, adaptive immune dysfunction, cardiomyopathy, and
associated renal, pulmonary, and hematologic dysfunctions,
which consequently make these patients poor surgical can-
didates.11,12 Patients and their families should be well
informed about the mortality and morbidity of the albeit
life-preserving nature of a liver transplant.
DONOR
Liver grafts can be from DBD, DCD, or living donors and can
be used as a whole or partial graft. Graft function is deter-
mined by several donor-related risk factors for primary non-
function and initial poor function, which includes moderate
steatosis, cold ischemia time greater than 12 hours, and
donor age over 50 years.13 Warm ischemia time is also a
known risk factor, with 16%–26% increased risk of biliary
system complications in DCD grafts.14 Other donor-related
factors include duration of intensive care, renal function,
size/body weight index, hemodynamic stability, and blood
transfusions.15 Living donor grafts can be from the left lat-
eral or the right lobe depending on the size of liver needed for
the recipient. The risk of living donor death and complica-
tions are both 1%–2%.16
POSTOPERATIVE MANAGEMENT
The first attempted liver transplant was performed by
Thomas Starzl in 1963. The recipient was a child with bil-
iary atresia, who died intraoperatively because of massive
hemorrhage. Bleeding remains the first major concern after
the operation. The management of postoperative bleeding
after hepatic transplantation is similar to the management
of postoperative bleeding after any surgical procedure. The
first priority is to determine whether the bleeding is surgical
or nonsurgical. There is a heightened urgency after liver
transplantation, because survival of the graft or the patient
may be impacted by ischemic damage sustained in these
early hours. It must be rapidly determined whether there
is any surgical bleeding that would require reexploration.
A negative reexploration is likely to do less harm than graft
injury from poor perfusion. If the recipient is bleeding,
plasma and platelets should be given to raise the platelet
count and correct the coagulopathy. Procoagulant-like
substances including α-aminocaproic acid, desmopressin
(aqueous vasopressin), and recombinant activated factor
VII may be given, although data are lacking to support
the routine use of these agents. During this time, the recip-
ient must be monitored closely for the possible development
of abdominal compartment syndrome. Elevated peak airway
pressures may be the first clue to this diagnosis. If this pos-
sibility seems likely before the transplant operation is com-
plete, it may be worthwhile to leave the fascia open initially
and to only close the skin. Later, the fascia can be closed in a
staged second operation.
A careful record should be made of the operation, with
specific details of the events during reperfusion of the allo-
graft, such as the clearance of lactate, the appearance
and production of bile, and the need for hemodynamic
presser support. Because lactate is converted to pyruvate
in the liver, early clearance of lactate is evidence of graft
function, even if bile production is not observed. As liver
function improves, clearance of lactate increases. The more
common scenario of overproduction of lactate in a critically
ill patient, as pyruvate is shunted to lactate because of tissue
hypoxia, may also be present in the post-transplant patient.
Circulating lactate concentrations in liver transplant recip-
ients may represent either end of this metabolic spectrum.
Another marker of early liver function after transplantation
is the quality and quantity of bile measured through an
externalized biliary drain. Intraoperative vasoactive pressor
agent infusion is often necessary during allograft reperfu-
sion, and it is usually weaned within several hours postop-
eratively. An ongoing requirement for pressors to maintain
hemodynamic stability often implies graft dysfunction.
Circulating transaminase levels typically peak approxi-
mately 24 hours after operation. The release of these
enzymes is a manifestation of ischemic liver injury and reper-
fusion injury. If the transaminase levels continue to rise after
24 hours, or if encephalopathy does not clear, or a nonsurgi-
cal coagulopathy develops, or lactic acid does not clear, the
patient may have primary nonfunction (PNF) of the allograft
and needs a retransplant urgently. This diagnosis is one of
exclusion, however, and hepatic artery and portal venous
thrombosis must be ruled out by duplex ultrasonography
(US) first. Postoperative management has little or no impact
on this devastating complication.
Vascular complications may also be devastating in the
immediate postoperative period. The most common early
vascular complication is hepatic artery thrombosis (HAT).
Some advocate routine ultrasound to screen for this prob-
lem. Concern for HAT is heightened if the resistive index
(RI) on US is high, even if there is flow. The normal range
is 0.6 to 0.9, and a low RI value is most consistent with
HAT.17 If HAT is suspected on US, then the diagnosis should
be confirmed angiographically. Return to the operating
room for restoration of hepatic artery flow is dependent
on timing. In many cases, surgical correction still results
in biliary complications and eventual need for retransplan-
tation. When patients sustain HAT, biliary complications
are likely to occur in the future because flow to the bile can-
aliculi is dependent on the hepatic artery and not the portal
vein. Collaterals from the diaphragm that traverse the bare
area of the liver offer a second circulation route to the bile
canaliculi. These vessels are transected during the trans-
plantation. This phenomenon appears to be the reason that
hepatic artery occlusion is better tolerated in the non-
transplant patient than in the transplanted patient. Biliary
complications can include biliary strictures and the biliary

cast syndrome, which are often managed with endoscopic
stents and/or percutaneous drains. Immediate post-
transplant portal venous thrombosis is a less common but
more life-threatening complication. An urgent surgical res-
toration of portal flow should be undertaken. Another vas-
cular complication may be a technical error that causes
Budd–Chiari syndrome, which also needs surgical correc-
tion in the immediate postoperative period.
The liver is a forgiving organ for acute cellular rejection in
the immediate postoperative period and, when rejection
does occur, it is usually easily managed with corticosteroids.
Low-grade fever and elevated transaminase levels are often
clues, but a high index of suspicion and confirmation of the
diagnosis with a liver biopsy are frequently required.
In recipients who receive an ABO-compatible but non-
identical liver, there is the possibility of developing passen-
ger lymphocyte syndrome. In this scenario, a group O
organ is transplanted to a non–group O recipient or a group
A or B organ is transplanted to a group AB recipient. In this
syndrome, the transplanted donor lymphocytes promote
hemolysis. Biochemical features of this syndrome include
indirect hyperbilirubinemia and an elevated serum lactate
dehydrogenase concentration. The circulating haptoglobin
concentration may be low, but because haptoglobin is syn-
thesized by the liver, this test is unreliable in these circum-
stances. The direct antiglobulin test is positive. Hemolysis
resolves over the course of weeks to months.18
Many cirrhotic patients have renal dysfunction preoper-
atively and postoperatively. Recovery of renal function
may depend as much on preexisting renal function as on
any other factor, but the course of the operation and the
quality of the donor liver are also important factors. Hepa-
torenal syndrome usually resolves postoperatively, but
patients with preoperative renal dysfunction have a greater
chance of chronic renal failure postoperatively. Hepatorenal
syndrome can also evolve into acute tubular necrosis and
the line between the two disorders is not always distinct.
The pathogenesis of hepatorenal syndrome is not well delin-
eated and is most likely multifactorial. The end result is
splanchnic vasodilatation and intrarenal vasoconstriction.
Patients with hepatorenal syndrome have low urine sodium
concentration but do not respond to intravascular volume
expansion. Early renal replacement therapy with ultrafiltra-
tion may help the liver transplant patient who is suffering
from encephalopathy and fluid overload. However, enceph-
alopathy is rarely caused simply by azotemia. If the liver
transplant patient is fluid overloaded with normal arterial
and central venous blood pressures, further volume resusci-
tation is usually not effective in reversing oliguria.
Kidney Transplantation
Although the scientific story of transplantation began when
Alexis Carrel attempted transplantation of various organs in
animals, the clinical story began in 1954, when Joseph
Murray transplanted a kidney from one identical twin into
the other. Originally, it was believed that renal transplanta-
tion would confer only lifestyle benefits associated with free-
dom from dialysis, but it is now clear that there is a survival
advantage as well. Younger white patients without diabetes
mellitus seem to benefit the most in this regard.19
35 • Solid Organ Transplantation 533
RECIPIENT
Patients with end stage renal disease (ESRD) are referred for
kidney transplantation when the estimated glomerular fil-
tration rate (eGFR) is <30 mL/min/1.73m2 and is evaluated
by the transplant program to detect and treat coexisting ill-
nesses, which may affect perioperative risk and survival
after transplantation, as well as transplant candidacy.20
Generally, kidneys are allocated by basis of time on the wait-
ing list and HLA matching. In some regions, waiting time for
a cadaveric graft is up to 10 years; therefor the living donor
option is encouraged for most patients. Preoperatively, the
kidney transplant recipient is screened for electrolyte abnor-
malities. Potassium levels of <5.5 mEq/L are reasonable and
even a short dialysis session of 1–2 hours may be enough to
reduce the potassium levels acceptable for hemodynamic
control during anesthesia.21
DONOR
Kidney grafts can be from DBD, DCD, and living donors.
Deceased donor graft quality is assessed using the Kidney
Donor Risk Index (KDRI) scoring system.22 The original KDRI
accounted for 14 donor and transplant factors, each found to
be independently associated with graft failure or death; how-
ever, a modified scoring system is currently used by OPTN that
includes: donor age, history of hypertension, history of diabe-
tes, serum creatinine, cerebrovascular cause of death, height,
weight, donation after cardiac death, and hepatitis C virus sta-
tus. Cadaveric grafts for adult recipients can be a single kidney,
dual adult kidneys that are from extended criteria donors
(ECD), or en bloc dual pediatric kidneys.
Living donor graft can be from related donor or as a donor
exchange or chain. Living grafts have better graft function
and survival than cadaveric grafts. Donors are evaluated to
exclude major contraindications such as active malignancy,
hypertension with end-organ damage, and uncontrolled
psychiatric conditions. Other relative contradictions differ-
ing by center preferences includes advanced age, obesity,
pre-diabetes, some vascular diseases, substantial protein-
uria, and recent nephrolithiasis amongst others. Once
donors are accepted, CTA is performed to determine vascu-
lar anatomy of the kidneys. Most often, the left kidney is
selected for donation and laparoscopic donor nephrectomies
are the standard of care. Donors generally have an unevent-
ful postoperative course and have little risk of mortality
and morbidity from donation. Evidence suggests that
the 15-year relative risk of ESRD for a living donor is
0%–5%.23
POSTOPERATIVE MANAGEMENT
The major postoperative complication associated with kid-
ney transplantation is delayed graft function. Primary non-
function can occur as it does for livers after liver
transplantation and may necessitate transplant nephrec-
tomy (removal of the transplanted organ). Both oliguria
and increasing plasma creatinine concentration are signs
that indicate delayed graft function. The classic categoriza-
tion of renal dysfunction as prerenal failure, intrarenal fail-
ure, and postrenal failure remains useful for classifying the
etiology of delayed graft function.
534 PART IV • Early Postoperative Care
Prerenal delayed graft function can be caused by intravas-
cular volume contraction. The nephrotoxic effects of cyclo-
sporine or tacrolimus also can contribute to delayed graft
function. These immunosuppressive agents cause renal arte-
riolar vasoconstriction that can be distinguished from the
effect of intravascular volume contraction by the lack of
response to a volume challenge. An additional area of con-
cern is the vascular anastomoses. Postoperatively, both the
arterial and venous anastomoses may develop thromboses,
a vascular emergency that requires urgent ultrasound eval-
uation, leading to surgical reexploration as appropriate.
Venous thrombosis is more common than arterial thrombo-
sis, but either can endanger the survival of the allograft.
The most common cause of intrarenal delayed graft func-
tion is early cell-mediated rejection. Hyperacute (humoral)
rejection and accelerated acute (humoral and cellular) rejec-
tion are less common today than in the past because of sensi-
tive cross-matching techniques. Early cell-mediated rejection
is the most common form of rejection in the postoperative
period. However, it must be differentiated from acute tubular
necrosis (ATN), and a renal biopsy is the only definitive way to
do this. If the cause of delayed graft function is early cell-
mediated rejection, it is necessary to adjust and augment
the immunosuppressive regimen, and the most common strat-
egy is to increase the dose of corticosteroids and antilympho-
cyte antibody. Delayed graft function increases the risk of cell-
mediated rejection.24 Additionally, delayed graft function is
more likely to lead to allograft failure in patients with a 0-
antigen match than in those with a 6-antigen match.25
Another cause of intrarenal delayed graft function is
ATN. It is a common cause of renal dysfunction among hos-
pitalized patients, including renal transplant recipients. The
incidence of ATN after renal transplant is higher when the
organ came from a cadaveric donor rather than from a liv-
ing donor. Indeed, when ECDs are used, it may be appropri-
ate to increase the renal mass and give one patient both of
the donor’s kidneys. The logic of this approach has been well
documented in an animal model of renal transplantation.26
Postrenal causes of delayed graft function are often
related to the creation of an ureteroneocystostomy, which
may become evident because of leaks or obstruction.
Although stenting can be attempted to remediate these
problems, reexploration is often necessary. A leak may be
first noted because of delayed graft function, but it is some-
times diagnosed by the presence of fluid from a drain or the
wound that has a higher concentration of creatinine than is
present in plasma.
Lymphoceles and hematomas may also develop in a crit-
ical location or to a large size to cause both prerenal and
postrenal delayed graft function. These may develop to com-
press the graft’s vascular supply or ureter externally and
may require drainage. Drainage can be approached percu-
taneously or surgically by open or laparoscopic techniques.
Pancreas Transplantation
The first successful pancreas transplant was performed in
1966 by Richard Lillehei and William Kelly in Minnesota,
US. Until about 1990, the procedure was considered exper-
imental. Now it is a widely accepted therapeutic modality.27
Pancreas transplantation has seen a decline in the last
10 years with more technologically advanced and easy to
use methods of glucose monitoring and insulin delivery;
however, dual pancreas and kidney transplantation num-
bers have remained stable since the turn of the century.
RECIPIENT
Pancreas transplantation is considered as therapy only in
patients who have a history of frequent, acute, and severe
metabolic complications (hypoglycemia, hyperglycemia,
ketoacidosis) requiring medical attention, clinical and
emotional problems with exogenous insulin therapy that
are so severe as to be incapacitating, and consistent failure
of insulin-based management to prevent acute complica-
tions. Pancreas allocation policy is similar to the kidney allo-
cation policy taking into account time on the waiting list
and the suitability of HLA matching.28 Additional variations
occur for dual pancreas and kidney transplantations
because the kidney transplant can be from a cadaveric or
living donor. Pancreas transplant recipients are generally
young and healthy without other morbid medical condi-
tions; however, careful attention to metabolic derange-
ments need to be provided by anesthesia because surgery
can increase secretion of cortisol, catecholamines, gluca-
gon, and growth hormone affecting intraoperative glucose
control.29
DONOR
Pancreas grafts can be cadaveric whole grafts from DBD or
DCD donors or segmental grafts from living donors. Islets of
Langerhans transplantation into the liver can be an auto-
graft or allograft and is still experimental. It has been used
successfully to treat patients with chronic pancreatitis who
require a total pancreatectomy with autotransplantation of
islets. Deceased donor pancreas graft should be without
signs of acute pancreatitis, glandular edema, hematoma,
fatty infiltration and/or hardened consistency.30
POSTOPERATIVE MANAGEMENT
Pancreas transplantation has several surgical variations.
The location of the vascular anastomosis may be to the
external iliac vessels, aorta and IVC, or aorta and a portal
vessel. The exocrine drainage may be anastomosed directly
to the donor pancreas in the case of a segmental graft or
with a segment of donor duodenum in the case of cadaveric
graft to the recipient’s jejunum or bladder. Whatever the
technique, the postoperative management is the same with
the major postoperative complications being related to graft
failure, which includes vascular and enteric anastomotic
leaks, rejection, and pancreatitis.
Pancreatic function is difficult to monitor. Increasing cir-
culating glucose concentration is the best clinical marker of
pancreatic graft dysfunction. C-peptide can also be moni-
tored closely. If dysfunction is suspected in the first 2 weeks
after transplantation, arterial thrombosis must be in the dif-
ferential diagnosis. Doppler ultrasonography should be com-
pleted urgently. The presence of a necrotic pancreas can
lead to systemic inflammatory response syndrome and

secondary acute respiratory distress syndrome. It is often
wise to perform a transplant pancreatectomy rather than
risk the morbidity and mortality associated with these seri-
ous complications.
If an exocrine anastomotic leak is suspected, computed
tomography (CT) should be performed to look for extra-
luminal contrast or air and surgical repair is necessary.
Further therapy is dictated by the means used to achieve
drainage of the exocrine pancreas (enteric or bladder).
Revision of the duodenojejunostomy to a Roux-en-Y anas-
tomosis is a common approach to deal with an anastomotic
leak with an enteral drainage system. These leaks may
result in peritonitis from contamination of the peritoneal
cavity with gastrointestinal contents. For bladder drain-
age, decompression with a Foley catheter is usually suffi-
cient. A follow-up cystogram should be obtained when
the patient is better.
All patients develop some degree of pancreatitis after
transplantation. Routinely monitored amylase and lipase
levels should peak and begin to decline in the first several
postoperative days. If glucose control continues to be poor
and/or pancreatitis persist, cell-mediated rejection must be
gauged in the first weeks. After exclusion of other causes,
a pancreatic biopsy may become necessary. The possibility
of cytomegalovirus infection can be investigated at that time
and treated with antiviral therapy as necessary. Rejection
requires enhancement of steroids and the administration
of antilymphocyte thymoglobulin.
Intestinal Transplantation
The first attempted intestinal transplant in humans was in
1964 by Ralph Deterling in the United States. In the fol-
lowing two decades, further attempts were universally
met with failure as patients died of technical complications,
sepsis, and graft failure largely resulting from severe rejec-
tion and graft-versus-host disease. However, the discovery
of calcineurin inhibitors revolutionized the field and in
1988 Eberhard Deltz performed the first successful living
donor intestinal transplant in Germany and David Grant
performed the first successful cadaveric intestinal trans-
plant combined with a liver in Canada.31,32 In the United
States, nearly three thousand intestinal transplants have
been reported in the OPTN database. There are three types
of intestinal transplants: isolated intestinal graft, a com-
bined intestine and liver graft, and multivisceral graft,
which can include stomach, colon, liver, pancreas, and
kidney.33
RECIPIENT
The indication for intestinal transplant is intestinal failure
with failure of medical management. This includes loss of
venous access for parental nutrition, multiple episodes of
life-threatening sepsis, uncontrollable fluid and electrolytes
abnormalities, growth and development failure in children,
and TPN-induced liver disease. Etiologies of intestinal
failure differ by age and range from congenital diseases
(microvillus disease, Crohn disease, generalized Hirsch-
sprung disease, pseudo-obstruction), neonatal and pediatric
35 • Solid Organ Transplantation 535
bowel complications requiring multiple resections (necro-
tizing enterocolitis, gastroschisis, intestinal atresia, small
bowel volvulus), and adult abdominal catastrophes
(trauma, internal volvulus following gastric bypass, throm-
bosis of mesenteric vessels).34 Most intestinal transplants
are complex because of multiple previous abdominal surger-
ies. Candidates should be optimized preoperatively to limit
anesthesia complications from metabolic and electrolyte
imbalances. Additionally, intravenous and central venous
access should be well mapped out prior to transplantation
because many of these patients have poor veins from mul-
tiple peripheral and central venous lines.35
DONOR
Intestinal and multivisceral grafts should be from DBD or
living donors. Donors are ideally young otherwise healthy
with stable hemodynamics because the small bowel is
very sensitive to ischemic injury. Recipient’s antibody
profile is rigorously taken into account when considering
a donor graft because the intestine is a highly immuno-
genic organ and rejection is one of the most common
complication. Additionally, because intestinal recipients
may have had previous surgeries that may have resulted
in loss of abdominal domain, donor size matching is also
important.
POSTOPERATIVE MANAGEMENT
The surgical technique varies widely depending on the type
of graft, but all patients should have central line access,
nasogastric tube, feeding tube, ileostomy as well as other
standard drains and tubes for close monitoring and manage-
ment. Early surgical complications include infection, vascu-
lar thrombosis, bleeding, dehiscence, and fistula.36 The care
of the intestinal portion of the transplant is the same as any
other general surgery patient who had bowel surgery albeit
with a heightened suspicion for infection, anastomotic
dehiscence, and primary nonfunction. For a multivisceral
transplant, the care of the other organs is similar to that dis-
cussed previously for the specific graft. Ultrasound or CT
evaluations should be promptly performed for any suspi-
cious abnormalities in laboratory evaluations or concerning
physical examinations and explored surgically as indicated
by the imaging evaluations.
Acute rejection (AR) is the most common complication
that can be caused by or exacerbated by an already present
surgical complications. AR is a clinical diagnosis, which is
then confirmed with endoscopy through the ileostomy with
pathological evaluation of biopsies. A wide range of labora-
tory tests are routinely taken including weekly B-cell and
T-cell subsets, IgA, IgG, IgM, Calprotectin, ESR, CRP,
CMV, and EBV as well as the standard daily hematology
and chemistry labs to aid in the clinical diagnosis. Subtle
physical examination findings such as low-grade fevers
and/or high enteric output from NGT or ileostomy can also
indicate rejection. Cell-mediated AR is most common and
treated with increased levels of tacrolimus and steroid pulse
per institutional protocol. Other forms of immunological
complication are antibody-mediated rejection, graft versus
host disease, and inflammatory bowel disease.37,38
536 PART IV • Early Postoperative Care
Heart Transplantation
The French surgeon Alexis Carrel, in collaboration with
American physiologist Charles Guthrie, is credited with per-
forming the first canine heart transplant in 1905. American
surgeon James Hardy performed the first human heart
transplantation using a chimpanzee xenograft on January
23, 1964, at the University of Mississippi. The first
human-to-human heart transplant was performed in
1967 by South African heart surgeon Christiaan Barnard
in Cape Town, South Africa, but unfortunately, the patient
died 18 days later from complications arising from pneumo-
nia. Three days later, a New York heart surgeon Adrian
Kantrowitz performed the first pediatric heart transplant
at Maimonides Hospital in Brooklyn, New York, on an
18-day-old male infant. The infant survived only 6.5 hours
and died of severe metabolic and respiratory acidosis.
A month later, in 1968, Norman Shumway who was widely
regarded as the father of heart transplantation performed
the first adult human-to-human heart transplant in the
United States at Stanford Hospital using techniques he
had perfected in the laboratory with Richard Lower. The
recipient died of multiple systemic complications after
15 days. Over the next several years, poor clinical results
resulted in a worldwide moratorium on heart transplanta-
tion. However, as a result of the persistent and pioneering
efforts of Shumway with his colleagues at Stanford and
the emergence of a new immunosuppressive agent cyclo-
sporine, there was a resurgence of heart transplantation
in the 1980s as a viable therapy for end-stage cardiomyop-
athy. Currently, more than 2200 heart transplantations are
performed annually in the United States.39
RECIPIENT
Heart transplantation is considered the “gold standard”
therapy for refractory heart failure (HF). The relative scar-
city of donors has expanded the indication for and use of
mechanical circulatory assist devices such as ventricular
assist devices (VAD) and total artificial heart (TAH). Both
are used as a bridge to transplantation and destination ther-
apy.40 Pharmacological therapies, cardiac defibrillators, and
devices for cardiac resynchronization therapies have
improved the prognosis of patients with left ventricular
systolic heart failure.41 Unfortunately, in spite of the
combined use of the best therapies, heart failure progres-
sively advances in the vast majority of cases. In some
cases, patients become completely unresponsive to conven-
tional treatments to the extent that even surgical revascu-
larization,42,43 ventriculoplasty,44 and mitral valve surgery
are inadequate to rectify the underlying myocardial dys-
function.45,46 Patients with acute HF requiring inotropic
therapy (milrinone and/or epinephrine) have an approxi-
mately 6-month mortality of 25% based on clinical trials
and registries on acute HF.47–49
The typical clinical profile of a patient with refractory
heart failure often exhibits some of the following character-
istics despite optimal medical and pharmacological manage-
ment: (1) severe symptoms (New York Heart Association
[NYHA] Class III to IV); (2) episodes with clinical signs of
fluid retention and/or peripheral hypoperfusion; (3) objec-
tive evidence of severe cardiac dysfunction that can be
demonstrated by at least one of the following: left ventricu-
lar ejection fraction (LVEF) < 30%; restrictive mitral inflow
pattern at Doppler echocardiography; high left and/or right
ventricular filling pressures; and elevated B-type natriuretic
peptides; (4) evidence of systemic organ injury, in particular
renal and hepatic dysfunction, underlined by an increase in
creatinine and bilirubin levels; (5) severe impairment of
functional capacity demonstrated by either an inability to
exercise (a 6-minute walk test distance <300 meters) or
a peak oxygen uptake <12–24 mL/kg/min; and (6) history
of hospitalization related to heart failure in the previous
6 months.50 The prioritization of appropriate recipients for
transplantation is based on survival and quality of life
expected to be gained in comparison with maximal medical
and surgical alternatives. Highest priority is given to Status
IA. As of 2007, the patient distribution of status is 50% (IA),
36% (IB) and 14% (II).39
Since October 2018, the adult heart allocation for the
recipients is classified into statuses 1-6 based on the urgency
with which the recipients need a heart, with status 1 being
those who need a heart most urgently, status 6 being the
least urgent, and status 7 being inactive. On the other hand,
the pediatric heart allocation remains the same as prior to
October 2018 and has statuses 1A (most urgent), 1B (less
urgent) and 2 (least urgent). More specific details of the
statuses can be found on the Organ Procurement and
Transplantation Network (OPTN) website at https://
optn.transplant.hrsa.gov/learn/professional-education/
adult-heart-allocation/.
DONOR
Once a brain dead individual has been identified as a poten-
tial donor, the patient undergoes a rigorous screening reg-
imen. The cardiac surgeons and/or cardiologists of the
recipient team search for potential contraindications, deter-
mine the hemodynamic support necessary to sustain the
donor, and review the echocardiogram, electrocardiogram,
chest X-ray and arterial blood gas (ABG). Even when
adverse donor criteria are reported, a team is often dis-
patched to the hospital to evaluate the donor on site. The
final and most important screening of the donor occurs
intraoperatively at the time of organ procurement by the
cardiac surgical team. Direct visualization of the heart is per-
formed for evidence of right ventricular or valvular dysfunc-
tion, previous myocardial infarction, and myocardial
contusion. The coronary arterial tree is palpated for any
gross atherosclerotic disease. If the heart examination is
unremarkable, the recipient surgeon is notified and the
heart procurement is performed. Coronary angiography is
indicated in the presence of advanced donor age (tradition-
ally male donors >45 years of age and female donors
>50 years of age). Angiography should be performed if
there is a history of cocaine abuse or the donor has three risk
factors for coronary artery disease (CAD) such as hyperten-
sion, diabetes mellitus, smoking history, dyslipidemia, or
family history of premature CAD.51
POSTOPERATIVE MANAGEMENT
Postoperative care is determined in part by the medical state
of the recipient and in part by the quality of the donor organ.

Thus, the care of heart transplant recipients is dictated by
their hemodynamic status and degree of end-organ dysfunc-
tion prior to transplant.
Postoperative bleeding can be more of a concern in car-
diac transplant patients than in typical postcardiotomy
patients for several reasons. Transplant recipients may have
been therapeutically anticoagulated preoperatively and this
treatment may not have been reversed adequately prior to
sternotomy. Need for reoperation or prolonged time in the
operating room and on cardiopulmonary bypass (CPB)
can increase the risk of coagulopathy. Treatment of bleeding
caused by coagulopathy consists of administration of blood
products and clotting factors.
The goal of hemodynamic support is to maintain systemic
perfusion with an appropriate cardiac output (CO) while
preventing right heart failure or overload. Appropriate man-
agement requires the use of a pulmonary artery catheter to
evaluate CO and central venous and pulmonary artery
pressures.
The intact heart is innervated by antagonistic sympa-
thetic and parasympathetic fibers of the autonomic nervous
system. Transplantation necessitates transection of these
fibers during donor cardiectomy, with a consequent dener-
vated heart with altered physiology. Devoid of autonomic
input, the sinoatrial node of the allograft fires at an intrinsic
rate of 90–110 beats per minute. The allograft relies on
distant sites as its source of catecholamines and conse-
quently its response to stress (e.g., hypovolemia, hypoxia,
and anemia) is somewhat delayed. There is absence of a
normal reflex tachycardia in response to venous pooling
and thereby there is increased frequency of orthostatic
hypotension.
Denervation of the transplanted heart leads to loss of
autonomic nervous system modulation of heart’s electro-
physiologic properties. Sinus or junctional bradycardia
occurs in up to half of all transplant recipients. Risk
factors for sinus node dysfunction include prolonged
organ ischemia, angiographic nodal artery abnormalities,
bi-atrial anastomosis, preoperative amiodarone use, and
rejection. Atrial fibrillation, atrial flutter, and other supra-
ventricular arrhythmias have been reported in 5%–30%
of patients after heart transplantation.52 Supraventricular
tachycardia in transplant patients should be treated in
the same manner as in nontransplant patients but with
lower doses.
Donor myocardial performance is transiently depressed in
the immediate postoperative period. Allograft injury associ-
ated with donor hemodynamic instability and hypothermic
ischemic insult of preservation result in reduced ventricular
compliance and contractility.53 Infusion of inotropes includ-
ing epinephrine, milrinone, dobutamine, and norepineph-
rine is routinely initiated in the operating room. Because
of depletion of myocardial catecholamine stores with pro-
longed inotropic support of the donor, the allograft often
requires high doses of catecholamines. The inotropic sup-
port is often necessary for several days. In patients with pre-
transplant continuous flow VADs, the resulting vasoplegia
requires vasopressor support. Cardiac denervation has sev-
eral consequences including a chronotropic and inotropic
supersensitivity to exogenous catecholamines.54 Restora-
tion of normal myocardial function permits cautious wean-
ing of inotropic support within 5–7 days.
35 • Solid Organ Transplantation 537
Systemic hypertension should be treated to prevent
unnecessary afterload stress on the allograft. In the early
postoperative period, intravenous sodium nitroprusside or
nitroglycerin is administered. Preoperative renal insuffi-
ciency owing to chronic heart failure and nephrotoxic
effects of calcineurin–inhibitor-induced renal insufficiency
will usually resolve with a reduction in dose.
Early cardiac failure accounts for 20% of perioperative
deaths of heart transplant recipients.55 The cause of
primary graft failure is multifactorial. The most important
etiologies are myocardial dysfunction owing to donor insta-
bility, pulmonary hypertension, ischemic injury during
preservation, and occasionally acute rejection. Mechanical
cardiac support with an intra-aortic balloon pump, VAD,
or extracorporeal membrane oxygenation (ECMO) can
be used in patients who are resistant to pharmacologic
interventions; however, this has been associated with
increased mortality.56,57
Chronic right heart failure is frequently associated with
elevated PVR and the unprepared donor right ventricle
may be unable to overcome this increased afterload. Right
heart failure remains a leading cause of early mortality. Ini-
tial management involves pulmonary vasodilators such as
inhaled nitric oxide and nitroglycerin. Pulmonary hyperten-
sion refractory to this sometimes responds to PGE1 or pros-
tacyclin.58 IAPB and RVAD (temporary) can also be used in
patients unresponsive to medical therapy.59 ECMO support
for several days with an open chest has been successful to
allow time for graft recovery in cases of inadequate biventri-
cular function.
Cardiac allograft rejection is the normal host response to
cells recognized as non-self. The vast majority of cases are
mediated by the cellular limb of the immune response
through a cascade of events involving macrophages, cyto-
kines, and T-lymphocytes. Antibody mediated rejection
(AMR) also known as humoral rejection is less common
but more difficult to diagnose. Although 85% of episodes
can be reversed with corticosteroid therapy alone,60 rejection
is still a major cause of morbidity in cardiac transplantation.61
Right ventricular endomyocardial biopsy remains the
gold standard for diagnosis of acute rejection. Most fre-
quently used technique for orthotopic allografts is percuta-
neous approach through the right internal jugular vein.
Interventricular septal specimens are fixed in formalin for
permanent section, although frozen sections are performed
occasionally if urgent diagnosis is necessary. Biopsies are
performed initially 7–10 days in the early postoperative
period and then eventually at intervals of 3–6 months in
the first year. Suspicion of rejection warrants biopsies.
Peripheral blood gene expression profiling is an exciting
new tool for this field.62 The AlloMap test has been cleared
by the US Food and Drug Administration and widely imple-
mented since 2006 to help rule out acute cardiac allograft
rejection.63,64
Hyperacute rejection results from preformed donor spe-
cific antibodies in the recipient. ABO blood group and panel
reactive antibody screening have made this a rare complica-
tion. Onset of hyperacute rejection occurs within minutes to
several hours after transplant. Gross inspection reveals a
mottled or dark red, flaccid allograft and histological exam-
ination confirms the characteristic global interstitial hemor-
rhage and edema without lymphocytic infiltrate. Immediate
538 PART IV • Early Postoperative Care
plasmapheresis, intravenous immunoglobulin, and mecha-
nical cardiac support are instituted and retransplantation
may be the only successful strategy.
Lung Transplantation
The first clinically attempted lung transplant in humans
was reported by James Hardy and Watts Webb in 1963 fol-
lowed by others with short survival times, except for one
case by Fritz Derom in Belgium that same year. In 1986,
the Toronto Lung Transplant Program reported the first
truly successful single-lung transplantations for two
patients with pulmonary fibrosis. The same team went on
to perform several other firsts: the first successful double-
lung transplant, the first with an en bloc technique that
used a tracheal anastomosis, and the first bilateral sequen-
tial transplantation technique that not only improved air-
way healing, but also had the additional benefit of
avoiding cardiopulmonary bypass.65
RECIPIENT
Candidates for lung transplantation have end-stage lung
disease with a life expectancy of less than 2 years. Medical
management has not been able to help these individuals.
Exclusionary criteria include coexisting diseases that would
adversely affect survival after transplantation, such as sig-
nificant cardiac disease, cirrhosis, and malignancy. One-
year adjusted graft survival (2001) was 77% and has been
essentially unchanged over the past 9 years (75% graft sur-
vival in 1993). Patient survival was only slightly higher
than graft survival. Retransplantation is rare (2% in
2002). One- and 5-year patient survivals were 78% and
45%, respectively.66
Allocation of donor lungs is determined more by waiting-
list time than by geographic area and blood compatibility
issues. As a result, patients are often listed early in their
course and, if necessary, can become inactive on the list
without losing their previous place in line. Patients in their
40s, 50s, and 60s account for the majority of transplant
recipients. The largest cohort (between 50 and 64 years
old) represents nearly 56%. Lungs are allocated based on
the Lung Allocation Score (LAS) introduced in the United
States in 2005 and later in Europe and the rest of the
world.67 The LAS estimates the severity of each candidate's
illness and chance of success following a lung transplant. All
candidates are placed in order for compatible lung offers
according to their score: a candidate with a higher lung allo-
cation score will receive higher priority for a lung offer when
a compatible lung becomes available in the same geographic
zone. More specific calculation of the LAS can be found on
the UNOS website at https://unos.org/wp-content/uploads/
unos/Lung_Patient.pdf.
The major primary diagnoses are emphysema, idiopathic
pulmonary fibrosis, cystic fibrosis, alpha-1-antitrypsin defi-
ciency, and primary pulmonary hypertension. In 2002,
emphysema accounted for 39% of the lung transplants per-
formed. The majority of recipients are not hospitalized at the
time of transplantation. Recipients (from 2002 cohorts)
in the intensive care unit (ICU) immediately prior to
transplantation had significantly lower graft survival rates
at all time points, compared with non-ICU and nonhospita-
lized cohorts.66
Patients with emphysema should be considered for trans-
plantation when the postbronchodilator forced expiratory
volume in 1 second (FEV1) is less than or equal to 25% of
predicted. Single lung transplantation is most commonly
performed, although sequential double lung transplantation
is offered at some centers. Native lung hyperinflation may
occur in the immediate postoperative period, which can
be difficult to manage especially when the patient is on
mechanical ventilation. For this reason, patients with signif-
icant bullous disease are often offered double lung trans-
plants. Another option is lung volume reduction surgery
on the native lung to control the underlying disease.
Single lung transplantation is effective treatment for idi-
opathic pulmonary fibrosis (IPF). Decreases in lung compli-
ance and perfusion of the native lung helps to maintain
ventilation–perfusion (V/Q) matching of the transplanted
lung for IPF.
Primary pulmonary hypertension can be treated with
both single and double lung transplantation and, at times,
heart–lung transplant. Centers that advocate double lung
transplants argue that there is greater recovery of right
ventricular function because of maximal reduction in
PVR for primary pulmonary hypertension.67a
Timing a transplantation for patients with cystic fibrosis is
difficult. Malnutrition and colonization with resistant bacte-
ria and fungi complicate decisions about the timing, the
choice of single or double lung transplantation, and postop-
erative management.
The recipient operation can be done without the use of
CPB, but CPB is scheduled when the patient has pulmonary
hypertension and right heart failure. Single lung procedures
are done via thoracotomy with exposure of the left atrium,
transection of the bronchus and vascular structures, and
then anastomosis of the donor bronchus, left atrium, and
pulmonary artery. Double lung transplantation has evolved
into sequential single lung procedures via a sternotomy with
bilateral subcostal incisions.
DONOR
Lung graft can be from a living donor, DBD, or now with
renewed interest, DCD.68 Proper selection of the donor
organ is crucial when evaluating lung donors. Most cadav-
eric donors have undergone a traumatic or other stressful
situation that has resulted in extensive resuscitation and
mechanical ventilation. Trauma patients could have sus-
tained direct injury to the lung. Therefore, many potential
donors are excluded from donating lungs because of pulmo-
nary edema, pneumonia, contusions, or adult respiratory
distress syndrome (ARDS).69
Living-donor lungs account for a very small number of
transplants. Interestingly, the majority of living-donor lung
recipients are in the ranges of 11 to 17 years and 18 to
34 years, consistent with recipients having a diagnosis of
cystic fibrosis.
Harvesting of the lungs is accomplished via median
sternotomy with preservation of the organs with a cold pul-
moplegia solution via the main pulmonary artery with
simultaneous cardioplegic harvest of the heart.

POSTOPERATIVE MANAGEMENT
The focus in the following paragraphs is on the underlying
disease processes of patients being evaluated for lung or
heart–lung transplantation because the baseline pulmonary
disease plays a significant role in postoperative manage-
ment. The decision to do a single or double lung transplant
will affect the treatment strategy for both the native and the
transplanted lungs. In addition, surgical approaches, with
their intricacies, will alter management and pose different
problems.
The goals of postoperative care are the same for any
patient: appropriate ventilatory weaning and extubating,
early mobilization and nutrition, and prevention of infection
by limiting the use of invasive lines and unnecessary antibi-
otics. The goals of respiratory management are no different
from those of any ICU patient: ventilatory support to main-
tain adequate oxygenation and ventilation without causing
barotrauma or oxygen toxicity.
As discussed earlier, single lung transplantation for
patients with emphysema results in differential compliance
and V/Q mismatch. The native lung is more compliant than
the donor lung, resulting in air trapping and hyperinflation.
Overexpansion of the native lung shifts the lung toward the
mediastinum, further decreasing compliance to the allo-
graft. This phenomenon is more likely to occur when the
allograft is placed on the left side, because the native organ
(in the right thorax) is restricted from expanding in the cau-
dal direction by the liver. Reperfusion injury to the donor
lung may further compromise compliance to the allograft.
Therapies to combat such a V/Q mismatch include place-
ment of a double-lumen tube and independent ventilation
of the two lungs with lower tidal volumes and prolonged
expiratory times to the native lung. Positioning the donor
lung side upward may aid in improved ventilation to the
allograft. With resolution of pulmonary edema from reper-
fusion injury to the allograft, single-lumen tube placement
and unified ventilation can be successful and ventilatory
weaning can be initiated.70
Differential perfusion to both organs can also occur with
single lung transplantation for primary pulmonary hyperten-
sion. The donor lung in this situation has lower pulmonary
pressures resulting in preferential blood flow to the trans-
planted organ. The increase in circulating blood volume, in
turn, results in pulmonary edema to the allograft, further
contributing to a potentially edematous lung from reperfu-
sion injury. As with severe compliance differences, significant
perfusion mismatch may need to be managed by independent
ventilation of the two lungs with higher positive expiratory
pressures to the allograft. Increases in intra-alveolar pressure
will reduce the pressure gradient across the capillary bed and
help to control pulmonary edema.71
Patients who undergo double lung transplants usually do
not have significant issues with V/Q mismatch unless there
is a difference in ischemia or the preservation of one of the
two allografts. However, pulmonary edema from reperfu-
sion injury can occur in both lungs. This would manifest
as hypoxia and decreased compliance. The mechanisms of
reperfusion injury are believed to be caused by long ische-
mia time, poor organ preservation, or immune-mediated
injury. Long CPB times, large-volume resuscitation, and
extensive use of blood products can add to edema of the
35 • Solid Organ Transplantation 539
lungs. In managing this condition, it is reasonable to use
the same maneuvers as those used to support patients with
ARDS. All of these patients should be ventilated with low
tidal volume ventilation (6 mL/kg of patient’s ideal
bodyweight).72
All lung transplant patients require aggressive pulmo-
nary care including frequent suctioning, bronchodilators,
deep coughing, postural drainage, and incentive spirometry.
Ventilated patients may require daily bronchoscopy to
maintain good pulmonary toilet. Lung transplant patients
are kept in a state of relative hypovolemia with judicial
use of fluids, blood products, and inotropic support. These
therapies are maintained while minimizing prerenal azote-
mia and maintaining adequate end-organ perfusion. Aspira-
tion can be a deadly complication and needs to be avoided at
all costs. Aspiration precautions and swallowing evalua-
tions are part of general care. Patients receiving enteral
feedings should be maintained with head of bed elevation
at 30 degrees and have feedings stopped well in advance
of planned extubations.73
Anastomotic complications can have severe conse-
quences for the lung transplant patient in the early postop-
erative period. These can be described as partial or full-
thickness injuries ranging from necrosis and dehiscence to
ulceration and formation of granulation tissue. Delayed
complications include stricture formation and bronchoma-
lacia. The etiology of anastomotic complications is believed
to involve ischemia. Bronchial arteries, which are fed by the
aorta and intercostal arteries, are transected with procure-
ment of the lung and are not reestablished with surgical
implantation. The bronchial and tracheal anastomosis relies
on retrograde flow through the pulmonary artery to collat-
erals from the bronchial arteries. A lung donor bronchial
stump adds to the vulnerability of the anastomosis. Dissec-
tion and devascularization of the recipient’s main bronchus
up to the level of the carina further compromises anasto-
motic blood flow. Poor perfusion can be accentuated by
hypotension, use of high-dose vasopressors, hypovolemia,
poor organ preservation, long ischemia time, infection,
and immunosuppression.
Necrosis and dehiscence typically occur in the first few
weeks after transplantation. Circumferential and large
dehiscence must be treated as a surgical emergency, with
debridement and reanastomosis of the bronchus. Coverage
of the anastomosis with viable tissue and extensive drainage
to treat pleural and mediastinal contamination is necessary.
Localized areas of necrosis and dehiscence without pleural
communication can be treated conservatively. A removable
stent can be placed to act as scaffolding for secondary heal-
ing. Weeks to months later, stricture formation may result
from a healed necrotic or dehiscent area. Strictures are
managed by dilation or laser resection. Stenting with wire
or Silastic stents may be a necessary adjunct for the treat-
ment of strictures. Airway obstruction caused by granula-
tion tissue is usually remedied by laser ablation with stent
placement if there are recurrent and chronic problems.
Bronchomalacia is characterized by airway collapse with
obstruction on expiration. It can also be controlled with
stent placement to support the involved area of the
airway.74
Airway complications are reported to occur in 5% to 12%
of cases at experienced transplant centers. The sequelae of
540 PART IV • Early Postoperative Care
ischemia to the bronchial anastomosis are preemptively
treated by the surgical management of the anastomosis at
the time of implantation. Specifically, shortening of the
donor bronchus to two or fewer cartilaginous rings proxi-
mal to the upper lobe take-off minimizes the watershed area
of ischemia. Reinforcing the anastomosis with a vascular-
ized flap (omentum, pericardium, or intercostal muscle) also
helps prevent anastomotic leaks. An intussuscepting anas-
tomotic technique is performed at some transplant centers
to help to accommodate size mismatch between the donor
and recipient airway and to help to avoid extensive devas-
cularization of the bronchus.
Phrenic nerve injury is a potential intraoperative compli-
cation of lung transplantation. This is especially true in
cases of repeat thoracotomy because of extensive pleural
adhesions. Bilateral lung transplantation increases the risk
of nerve damage. Nerve damage may be temporary or per-
manent and can be caused by stretching, crushing, thermal
damage, or transection of the phrenic nerve. Phrenic nerve
paralysis is a devastating complication that interferes with
good pulmonary hygiene and may prevent independence
from the ventilator.74
Rejection as discussed here relates to the early postoper-
ative period. Hyperacute rejection occurs immediately on
reperfusion and is caused by preexisting antibodies to donor
tissue. It is a rare event because of the routine screening of
recipients and ABO matching. Acute rejection is a cell-
mediated process and can occur during the first 30 days
after transplantation. It is diagnosed by both clinical and
histologic criteria. In the early postoperative period, the his-
tologic criteria are not very distinct and are difficult to sep-
arate from infection or from reperfusion injury. Therefore,
the clinical presentation becomes crucial in the diagnosis.
Symptoms of acute rejection include dyspnea, fatigue, dry
cough, low-grade fever, malaise, and pulmonary infiltrates
without evidence of infection. Chronic rejection is mani-
fested by obliterative bronchiolitis. This complication is
caused by a fibroproliferative process that causes oblitera-
tion of tubular structures of the transplanted lung, similar
to coronary artery vasculopathy seen in the transplanted
heart.74
Infections
Many infections can develop in the solid organ transplant
(SOT) patient after weeks to months on immunosuppres-
sion. In the immediate postoperative period, however, it is
imperative to watch for the usual bacterial pathogens.
Many of these patients were very sick preoperatively and
are now susceptible to nosocomial infections, especially
hospital-acquired pneumonia, ventilator-associated pneu-
monia, catheter-associated urinary tract infections, and
catheter-related bloodstream infection. As a result of
prolonged hospitalization before transplantation, many of
the bacterial pathogens are resistant organisms and antibi-
otic therapies should be guided by definitive cultures and
sensitivities. Catheters and tubes of all types should always
be removed from patients as soon as possible. Indeed,
these necessary tubes may be more responsible for the
high incidence of postoperative infection than early
immunosuppression.
Prophylactic antibiotics are used against toxoplasmosis,
Pneumocystis pneumonia (PCP), fungal infections, and
viral infections in the early months after SOT. Toxoplas-
mosis and PCP are covered by the same prophylaxis antibi-
otic. Toxoplasmosis can be a life-threatening opportunistic
infection in all SOT with heart being the most frequently
affected organ. Either the infection is transmitted to the
recipient by an infected organ or it is a reactivation of a
latent seropositive infection in the recipient. The median
point of disease onset is estimated to be two months. PCP
has been known to become epidemic in several transplant
units worldwide with mortality as high as 60% and is
now classified as a fungus.75,76 Prophylaxis antibiotics
most frequently used are pyrimethamine-sulfadoxine, tri-
methoprim and sulfamethoxazole, co-trimoxazole, and
atovaquone. These drugs have various levels of myelosup-
pression and are often interchangeably used depending
on the patient’s tolerance profile. Length of prophylaxis
is dependent on risk of infection and can range from
1–12 months.77
Candida and Aspergillus species are the most frequent
causes of fungal infection followed by Cryptococcosis and
non-Aspergillus molds. Evidence suggests fungal prophylaxis
is most evidence-based for liver, intestine, and lung trans-
plant patients although most institution use fungal
prophylaxis for all transplants. Azoles such as fluconazole,
itraconazole, and voriconazole have been used among
transplant recipients. Some lung regimens include dual
therapy with aerosolized amphotericin B. Duration of ther-
apy varies with the type of organ with abdominal solid
organs ranging from 1 to 6 weeks and thoracic organs rang-
ing from 1 to 6 months.78
Viral infections are emerging as having the most
deleterious effects on SOT recipients. Cytomegalovirus
(CMV) is one of the major microbial pathogens in SOT,
but it is most notable in heart and lung transplanta-
tion.79 Ganciclovir and valacyclovir have been used as
prophylaxis for a duration of 3–12 months. Fortunately,
both antiviral agents provide prophylaxis against other
viral pathogens such as varicella-zoster virus (VZV)
and Epstein-Barr virus (EBV). Treatment of hepatitis B
virus (HBV) and hepatitis C virus (HCV) especially after
liver transplant is controversial. Some institutions will
give hepatitis B immunoglobulin (HBIG) followed by a
regimen of Retuximab when transplanting recipients
who have HBV. HCV drug treatments such as Zepatier
and Harvoni are highly effective at eradicating HCV
with the result that most patients are treated and cured
before transplant. HCV positive donors are a potential
source of organs and prophylaxis regimen are being
developed to use these ECD grafts safely.80 Finally, all
SOT recipients should receive yearly influenza virus vac-
cines and prompt treatment with oseltamivir for early
infections.81
Two organs deserve special mention in regard to bacterial
infection. First, the liver is prone to biliary infections, partic-
ularly after hepatic artery thrombosis. Abscesses may
require drainage. If the infection is confined to the liver,
retransplantation is a viable option. Second, pneumonia
in a transplanted lung could have disastrous consequences,
therefore these patients must be observed closely for any
signs and symptoms of pulmonary infection.

Conclusion
The solid organ transplant recipient requires unique postop-
erative care. The quality of the organ is determined by the
health of the donor and by postmortem factors such as
warm and cold ischemia time and events at the surgery,
including but not limited to, reperfusion. The preexisting
health of the recipient also plays a role postoperatively.
For patients with diabetes mellitus and renal failure, comor-
bid conditions include coronary artery disease. For the
patient with cirrhosis, years of muscle wasting may leave
the patient profoundly weak. Postoperative decisions that
would be appropriate for nontransplant patients may be
inappropriate for transplant patients. For example, transient
hypoxemia or hypotension might be tolerated in other
patients, but these problems can lead to early damage to
the graft in transplant recipients. It is easy to ignore these
issues in the early postoperative period but they are essential
to the long-term outcome of the graft and, of course, the
patient.
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 36 Multisystem Trauma
TIMOTHY J. DONAHUE and LILLIAN S. KAO
Care of patients with multisystem trauma is challenging.
Although well-defined constellations of injury exist, ulti-
mately each patient is unique in preinjury health, injury
complex, and postinjury management. Because many inju-
ries are managed nonoperatively, many patients have no
postoperative phase. However, some injured patients
require multiple operations, and the distinction between
postoperative care and preoperative care is blurred. The fun-
damental principles of care of the injured patient are similar
to those of the postsurgical patient. The trauma patient’s
stress response is a function of the severity of injury. The
postoperative or postinjury course of trauma patients should
be assessed with this paradigm in mind.
Initial evaluation of the injured patient should follow guide-
lines set forth by the American College of Surgeons Advanced
Trauma Life Support (ATLS) program. The ATLS paradigm of
primary, secondary, and tertiary surveys prioritizes the
ABCs—airway, breathing, and circulation—and ensures that
the most immediately life-threatening injuries are diagnosed
and treated before moving on to other injuries. The trauma
evaluation is rapid and comprehensive, utilizing physical
examination, vital signs, radiographs, and ultrasound. The
patient’s subsequent disposition—to the operating room,
interventional radiology suite, computed tomography suite,
intensive care unit (ICU), or general care floor—is based on
the findings of the primary and secondary survey.
Resuscitation
BALANCED RESUSCITATION
Historically, early trauma resuscitation involved large vol-
umes of crystalloid and the last decade has welcomed a
new concept in early trauma resuscitation. This change in
approach to the resuscitation of the injured patient stresses
a balanced resuscitation, using high ratios of red blood cells
(RBCs), plasma, and platelets that come close to that of whole
blood as early as possible in the care of trauma patients.
Whole blood itself has increasingly become available and
applied in both the prehospital and hospital setting. The Prag-
matic Randomized Optimal Platelet and Plasma Ratios
(PROPPR) Trial demonstrated that a 1:1:1 ratio of units of
plasma to platelets to RBCs is not only safe but effective.
Although not resulting in a mortality benefit at 24 hours
and 30 days, a 1:1:1 ratio compared with a 1:1:2 ratio
resulted in more patients achieving hemostasis and fewer
deaths resulting from exsanguination in the first 24 hours.1
Overaggressive crystalloid resuscitation accentuates
coagulopathy through dilution of blood components, adds
to acidosis through pH alteration, and exacerbates hypo-
thermia via installation of large volumes of cold solution.
In order to combat this, balanced resuscitation limits the
use of crystalloid in the early resuscitation of the critically
injured patient. In fact, the American College of Surgeons
Committee on Trauma has recently changed the ATLS
approach to limit initial crystalloid infusion from 2 L down
to 1 L before adding blood products.2
Another mainstay of balanced resuscitation is the con-
cept of permissive hypotension. This allows an adequate
but not normal blood pressure in order to preserve vital
organ function as well as prevent further hemodilution
and disruption of established clot in the patient with ongo-
ing hemorrhage. The literature is mixed but a recent meta-
analysis shows that permissive hypotension may not only
show a reduction in blood loss and blood product utilization
but also a survival advantage.3
Many centers have established massive transfusion proto-
cols that permit hospital blood banks to release rapidly stan-
dard quantities of uncrossmatched type O-negative red
blood cells, plasma, platelets and, increasingly, low titer
O-negative whole blood at regular intervals until hemor-
rhage is controlled. Despite being a strain on hospital blood
banks, such protocols appear to be justified by studies show-
ing decreased mortality as low as 15%, decreased overall
component usage, and avoidance of overuse.4–8 Scoring
systems, such as the Assessment of Blood Consumption
(ABC) score, designed to predict need for massive transfu-
sion, may help guide activation of such protocols. Trade-offs
include risks of transfusion reaction, transmission of blood-
borne diseases, and infectious and immune complications.
Hyperfibrinolysis has been recognized as a contributor to
ongoing coagulopathy. Although normally striking a balance
with thrombosis, increased fibrinolysis in some trauma
patients leads to clot breakdown while hemorrhage is still
ongoing. Tranexamic acid (TXA) has long been used to stem
bleeding in elective surgery. Within the last decade, the use of
TXA has been increasingly studied in trauma patients.
Although it remains controversial, there is evidence to sup-
port its early use in the bleeding trauma patient. The Clinical
Randomisation of an Antifibrinolytic in Significant
Haemorrhage-2 (CRASH-2) trial showed a small but signifi-
cant reduction in mortality and death secondary to bleeding
with TXA. Thrombotic events were not different between the
treatment and placebo groups. Late administration (>3 hours
after injury) of TXA showed an increase in mortality.9
CHOICE OF ICU RESUSCITATION FLUID
The fluid of choice for resuscitation after hemorrhage con-
trol in critically ill and injured patients is still controversial.
Crystalloid solutions are less expensive but are theoretically
less effective for maintaining intravascular volume.
Although colloid solutions are more expensive, they theo-
retically remain longer in the intravascular space relative
543
544 PART IV • Early Postoperative Care
to crystalloid, and thus smaller volumes are required for
infusion. Studies have not consistently shown one to be
superior to the other for ICU resuscitation. The largest pro-
spective randomized trial to address this issue is the Saline
versus Albumin Fluid Evaluation (SAFE) trial, which com-
pared normal saline with 4% albumin for resuscitation in
ICU patients.10 This trial showed no mortality benefit of
albumin over saline in a large cohort of ICU patients at
28 days. However, there was a lower amount of total fluid
utilized in the albumin group in the first 4 days, a decrease in
heart rate, and an increase in central venous pressure,
although no change in mean arterial pressure. Post hoc sub-
group analysis suggested that trauma patients in the albu-
min group may have fared worse than those in the saline
resuscitation group; nonetheless this was inconclusive
because this group also had a higher rate of death from trau-
matic brain injury.
Although the issue of crystalloid versus colloid has not
been settled definitively, it is clear that overresuscitation
can occur with any fluid and lead to a variety of complica-
tions, both immediate and delayed. Thus the choice of resus-
citation fluid is probably less important than the timing and
volume of resuscitation.
TRANSFUSION TRIGGERS
Anemia is common in the postinjury period, especially in
those injured patients admitted to the ICU.11 Transfusion
of blood products solely based on laboratory values should
be approached cautiously. When other factors are controlled
for, blood transfusion correlates with organ dysfunction,
mortality, and ICU length of stay.12,13 Studies in trauma
patients have suggested that blood transfusion is an indepen-
dent predictor of worsened outcomes in patients with solid
organ injuries.14 Large controlled trials in critically ill
patients have suggested that restrictive blood transfusion
practices (e.g., a hemoglobin transfusion trigger of 7 g/dL)
are equal or superior in mortality to more liberal transfusion
practices (e.g., a transfusion trigger of 10 g/dL).15 A smaller
body of literature suggests the same is true in the injured pop-
ulation. Post hoc analysis of the Transfusion Requirements in
Critical Care (TRICC) trial confirmed the safety of restrictive
transfusion practices in trauma patients.16 Both protocols
are similar in terms of mortality and incidence of multiple
organ dysfunction. A postinjury practice management
guideline is safe and cost effective.17 Although the transfu-
sion trigger for patients with active cardiac ischemia and
patients with head injury is not known, it is likely that most
other injured patients with hemorrhage control will not ben-
efit from liberal transfusion strategies. The concept of trans-
fusion threshold should be applied very carefully in the
trauma population: any threshold for transfusion presup-
poses control of hemorrhage. Stated more bluntly, transfu-
sion thresholds do not apply to patients who are still bleeding.
ENDPOINTS OF RESUSCITATION
Clinical judgment is an essential component of multisystem
trauma resuscitation. Not all endpoints are applicable to all
patients, and a global perspective of the patient’s status is
tantamount to the attention to minute details. Endpoints
can be classified as clinical, laboratory, or monitoring.
The initial assessment of the trauma patient begins with
evaluating and treating the ABCs, and the ongoing care
should ensure that the ABCs remain intact. Changes in
hemodynamics or oxygenation should prompt reassessment
of airway, breathing, and circulation, especially confirming
proper position and function of endotracheal tube, chest
tubes, catheters, monitors, and surgical drains. In the early
postinjury period, hypotension should be assumed to be
caused by hemorrhage until proven otherwise.
Traditional clinical indicators such as blood pressure,
heart rate, urine output, distal perfusion, and mentation
should be used as a starting point for assessing resuscitation.
Abnormalities of these basic signs should prompt thorough
physical examination and close monitoring of interventions
(blood component therapy, fluid challenges, analgesia, seda-
tion). Several caveats relevant to the injured patient should
be mentioned: tachycardia is nonspecific and may represent
hypovolemia, pain, agitation, presence of illicit substances,
or myocardial injury. On the other hand, tachycardia may
be absent or blunted in patients who were receiving beta-
blocker therapy before the injury. Regarding blood pressure,
essential hypertension is widely prevalent, and a “normal”
blood pressure may in fact represent relative hypotension
and hypovolemia. Finally, mental status may be altered
by hypoperfusion, brain injury, the presence of illicit sub-
stances, or baseline chronic encephalopathic diseases such
as dementia.
Laboratory studies are useful for assessing endpoints of
resuscitation. Postinjury acidosis, as manifested by persis-
tently elevated lactic acid or by base deficit (or persistently
low serum bicarbonate), suggests occult hypoperfusion or
devitalized tissue. Although the initial value (i.e., immedi-
ately on arrival to the trauma center) has correlation to out-
come,18 the trend over hours is more useful for assessing
treatments and predicting mortality.19 Persistent acidosis
is a grave sign. Failure to normalize serum lactic acid level
by 24 hours after injury is associated with worse outcome in
injured patients.19 Similarly, persistent base deficit corre-
lates with worse outcomes.20
Viscoelastic tests such as thromboelastography (TEG) and
rotational thromboelastometry (ROTEM) can also guide
blood component therapy and may be superior to conven-
tional coagulation tests such as PT/INR and PTT for guiding
the correction of coagulopathy.21 ProTime (PT) and acti-
vated partial thromboplastin time (aPTT) are usually per-
formed at 37°C. Thus in the normothermic patient,
abnormalities of PT and aPTT indicate clotting factor defi-
ciency. However, in the hypothermic patient, these studies
fail to assess the qualitative deficiency of coagulation and
thus underestimate coagulopathy. TEG may demonstrate
coagulopathy with improved fidelity irrespective of body
temperature. TEG measures the dynamics of clot develop-
ment, stabilization/strength, and dissolution. A prolonged
R-time may indicate the need for plasma transfusion. An
increased K-time or decrease in alpha angle may denote
hypofibrinogenemia. A low maximum amplitude reveals
low platelet function. LY-30 or lysis of clot at 30 minutes
is increased with hyperfibrinolysis and treatment with
TXA may be indicated. Component therapy may be directed
toward these coagulopathic findings as stated earlier.
Trauma patients who suffer deterioration of these indica-
tors should be presumed to have ongoing or uncontrolled

hemorrhage in the thorax, abdomen, retroperitoneum, and
extremities. After physical examination, chest radiograph
and focused abdominal sonography for trauma (FAST)
may help triage the chest and abdominal cavities by diagnos-
ing or excluding recurrent hemothorax or new hemoperito-
neum. Hemorrhage in the thorax, abdomen, or extremities
that is brisk enough to result in hypotension or acidosis often
requires control in the operating room. However, hemor-
rhage from hepatic lacerations, pelvic fractures, or retroper-
itoneal injury may be difficult to control in the operating
room and instead may require interventional radiology with
angiography for diagnosis and embolization for treatment.
Despite the vast cumulative experience with central
venous pressure (CVP) monitoring, the amount of objective
data available to guide clinicians in deciding which injured
patients to monitor are limited. CVP monitoring is probably
indicated for patients who have hemorrhage control but
have not responded appropriately to initial volume resusci-
tation or for patients with chronic cardiac and pulmonary
disease and low physiologic reserve. The endpoints are sim-
ilar to those of postsurgical patients. When CVP is unavail-
able, bedside ultrasonography may be used to assess inferior
vena cava diameter, respiratory variability and collapsibil-
ity, which can be a surrogate for right atrial pressures
and volume status.22
The pulmonary artery (PA) catheter remains controver-
sial in trauma patients. Although PA catheterization is the-
oretically attractive and commonly used, retrospective and
prospective studies of critically ill patients have not consis-
tently demonstrated that it has a mortality benefit compared
with central venous monitoring.23,24 Furthermore, these
studies typically have relatively small numbers of injured
patients, making results more difficult to apply to the
trauma patient. It is likely that the benefit of the PA catheter
is not in its presence or absence, but in how the clinician
uses the data that are available. Ultimately, the usefulness
of the PA catheter may lie in optimizing ventricular preload
and overall cardiac efficiency and in preventing over-
resuscitation.25,26
Many methods of assessing regional visceral perfusion
have been proposed as adjuncts to clinical examination, lab-
oratory studies, and central monitoring. Gastric tonometry
demonstrates good correlation with other indices of global
perfusion,27 but it has not found widespread clinical accep-
tance. Sublingual capnometry may also prove to be a useful,
noninvasive marker of perfusion.28,29 Esophageal Doppler
and surface ultrasound techniques have been investigated
as noninvasive means of assessing cardiac output and pre-
load, respectively.30 Further studies will clarify their roles in
achieving adequate resuscitation of the injured patient.
Special Considerations in Trauma
DAMAGE CONTROL
Borrowing from United States Navy vernacular, “damage
control” has become widely used in the care of the severely
injured patient.31–33 The paradigm involves rapid control of
exsanguinating hemorrhage and gastrointestinal contami-
nation, followed by resuscitation in the surgical ICU, then
a return to the operating room for thorough identification
36 • Multisystem Trauma 545
and definitive treatment of injuries when the patient has sta-
bilized. Sometimes, multiple cycles between surgical ICU
and the operating room are necessary, depending on the
extent of injury and physiologic stability. Some patients
have insufficient fascia in the abdominal domain after pro-
longed periods of damage control and require skin graft clo-
sure of the abdomen. Originally described for abdominal
injuries, damage control concepts have been extended to
the thorax, extremities, neck, and even the cranium.
Successful implementation of damage control requires
the coordinated efforts of the trauma surgeon, anesthesiol-
ogist, and surgical intensivist. When the source of bleeding
and contamination is suspected to be within the abdomen,
the surgical team begins with laparotomy and quickly packs
all quadrants of the abdominal cavity. Meanwhile, the anes-
thesiology team begins aggressive resuscitation of the
patient with blood and blood products. The surgical team
systematically explores the abdominal cavity. The goal of
the initial operation is rapid control of life-threatening hem-
orrhage and massive gastrointestinal contamination. Inju-
ries to major arteries are shunted; injuries to smaller
arteries and most veins (except suprarenal inferior vena
cava) are ligated; gastrointestinal injuries are quickly closed
primarily or resected with staplers without reestablishing
continuity; liver injuries are packed; splenic and renal inju-
ries are treated by splenectomy or nephrectomy, respec-
tively. The abdominal fascia is not closed. Rather,
temporary abdominal closure is performed, for which many
methods have been described. Patients with hepatic or pel-
vic injuries identified at the initial operation may require
diagnostic arteriography and embolization immediately
postoperatively. Among patients with hepatic injuries, the
therapeutic yield of interventional radiology is high.34
Surgery is followed by an ICU phase of damage control.
With hemorrhage and gastrointestinal contamination con-
trolled by the trauma team, the intensivist team is charged
with attaining physiologic “capture” of the patient. The goal
of this period is to prevent or reverse the lethal triad of hypo-
thermia, coagulopathy, and acidosis (Fig 36.1).
Several measures are available to prevent and treat hypo-
thermia. Straightforward measures decrease heat loss and
allow rewarming, albeit slowly, by increasing the tempera-
ture of the room and using blankets, warming lights, and
forced-air warming blankets. An intravenous fluid warmer
should be used. The ventilator circuit should have warmed
air. Warming pads, placed against the torso and extremities,
are highly effective for rewarming. Warmed fluid is circu-
lated through tubes in the pads. Although abdominal cavity
lavage with warmed fluid is described, it is unclear whether
Acidosis
Coagulopathy Hypothermia
Fig. 36.1 Lethal triad of hypothermia, coagulopathy, and acidosis.
546 PART IV • Early Postoperative Care

the rate of rewarming is better than other, less invasive

methods. The most rapid and invasive method of rewarming
is venovenous bypass, but its primary disadvantage is the
requirement for full systemic heparinization.
Acidosis is primarily caused by hypoperfusion and hypo-
thermia and should therefore correct when normothermia
and circulating volume are restored. Acidosis per se should
not be treated with bicarbonate solutions except to treat
myocardial irritability (i.e., pH <7.2). Coagulopathy is mul-
tifactorial, resulting from blood loss, consumption and dilu-
tion of platelets and clotting factors, accelerated fibrinolysis,
impaired function of blood components, hypothermia, and
hypocalcemia.35 As discussed previously, treatment along-
side rewarming and correction of acidosis continues with
blood product therapy until laboratory values of coagulation
tests or viscoelastic tests are corrected and/or clinically sig-
nificant hemorrhage is resolved.

RESUSCITATIVE ENDOVASCULAR BALLOON

OCCLUSION OF THE AORTA (REBOA)
REBOA is a technique that can be used during the initial
treatment of the trauma patient in hemorrhagic shock to
control truncal bleeding rapidly and temporarily for non-
compressible locations such as the abdomen and pelvis.
Another source of noncompressive hemorrhage is junc-
tional hemorrhage or hemorrhage at the junction of an
extremity with the torso of the body that is not amenable
to tourniquet application. REBOA should not be used in Fig. 36.2 Aortic zones: Zone I extends from the origin of the left
the exsanguinating patient with penetrating thoracic injury subclavian artery to the celiac artery; Zone II extends from the celiac
because this may hasten thoracic cavity bleeding and artery to the most caudal renal artery; and Zone III extends from the
should otherwise be controlled with open surgical tech- most caudal renal artery to the aortic bifurcation. Resuscitative endo-
niques. In placing a REBOA, the femoral artery is used to vascular balloon occlusion of the aorta (REBOA) deployment is limited
to Zones I and III. (From Bogert JN, Davis KM, Kopelman TR, Vail S, Pieri P,
introduce the balloon to the lumen of the aorta. A percuta- Matthews MR. Resuscitative endovascular balloon occlusion of the aorta
neous approach, when possible, is preferred; however, an with a low profile, wire free device: A game changer? Trauma Case Rep
open, surgical cut-down may be required. Once thoracic 2017; 7: 11–14.)
cavity bleeding has been excluded by ultrasound, plain film,
or tube thoracostomy, the intraaortic balloon is deployed
these complications. IAH exists when the pressure in the
just proximal to the diaphragmatic hiatus in zone 1 of the
abdomen is elevated without evidence of organ dysfunction.
aorta (Fig 36.2). For major pelvic or junctional hemorrhage,
ACS exists when abdominal hypertension causes organ dys-
the balloon is inflated at the level of the aortic bifurcation in
function or failure. IAH may be signaled by a rising central
zone 3. This temporary control allows a more definitive
venous pressure (CVP), high peak airway pressures or diffi-
approach to major vascular injuries.
culty generating tidal volume, oliguria or worsening renal
Proponents of REBOA regard this technique as less inva-
function, or by worsening or new onset of lactic acidosis.
sive than resuscitative thoracotomy and aortic cross clamp-
Risk factors for increased intraabdominal pressure (IAP)
ing in the chest. A retrospective study (n ¼ 31) at a busy
include major abdominal surgery or trauma, major burns,
level 1 trauma center showed that balloon inflation corre-
prone positioning, ileus or intestinal obstruction, acute pan-
lated with increased blood pressure and temporary hemor-
creatitis, decompensated cirrhosis with large volume asci-
rhage control in most patients.36 However, there have been
tes, hemoperitoneum, intraabdominal infections, large
no randomized trials comparing REBOA with other methods
volume crystalloid infusions, and blood transfusion of
of hemorrhage control. Furthermore, REBOA has been asso-
greater than 10 units.37
ciated with vascular complications necessitating additional
The World Society on Abdominal Compartment Syn-
procedures.
drome (WSACS) published consensus definitions and clini-
cal practice guidelines in 2013.38 They defined resting
INTRAABDOMINAL HYPERTENSION AND THE IAP at 5–7 mmHg in critically ill adults. IAH was defined
ABDOMINAL COMPARTMENT SYNDROME as a sustained pressure greater than 12 mmHg and was
divided into four grades of increasing pressures (Grade I,
Intraabdominal hypertension (IAH) and the abdominal IAP 12–15 mmHg; Grade II, IAP 16–20 mmHg; Grade
compartment syndrome (ACS) are well-recognized compli- III, IAP 21–25 mmHg; Grade IV, IAP >25 mmHg). ACS
cations of critically ill trauma patients. Injury, hemorrhage, is defined as primary when associated with injury or disease
ischemia, reperfusion, and resuscitation all contribute to in the abdominopelvic region and frequently requires early

surgical or interventional radiologic intervention. Second-
ary ACS develops as a result of conditions that do not orig-
inate from the abdominopelvic region such as ascites
secondary to volume overload. Recurrent ACS refers to
the condition in which IAH or ACS redevelops following pre-
vious surgical or medical treatment of primary or secondary
IAH or ACS.
In order to estimate IAP, the bladder pressure is typically
used as a surrogate. The bladder is filled with 25 mL sterile
saline and the bladder catheter tubing is clamped. The
patient should be supine and paralyzed to mitigate external
contributors to bladder pressure. The transducer is located
at the midaxillary line. The pressure of the system is then
transduced.
Noninvasive measures to treat IAH include improvement
of abdominal wall compliance by way of sedation, analgesia,
and neuromuscular blockade; nasogastric and rectal decom-
pression with evacuation of intraluminal contents; drainage
of abdominal fluid by paracentesis; judicious use of fluids,
diuretics, and/or dialysis to correct volume overload; opti-
mize ventilation to avoid increased intrathoracic pressures.38
Once ACS has been identified, immediate measures to
treat the underlying etiology must ensue. If primary ACS
is the cause, laparotomy and temporary abdominal closure
are required to reduce IAP and to restore perfusion. After
decompressive laparotomy, the abdominal fascia is left open
and a temporary abdominal closure is fashioned to cover the
viscera without exerting tension on the closure. Even so,
recurrent ACS in the open abdomen has been described.39
Even when treated, ACS is associated with increased
morbidity and mortality.40 There is growing appreciation
for the iatrogenic component of IAH and ACS,41 highlight-
ing the importance of reaching—but not exceeding—
resuscitation endpoints.42
OTHER COMPARTMENT SYNDROMES
Both blunt and penetrating mechanisms put tissue at risk of
compartment syndromes. Extremities—not only calves but
also thighs, buttocks, and upper extremities—should be
examined carefully for increases in tenseness. Extremities
with increased tenseness should be immediately evaluated
by a surgeon. The presence of a distal pulse that can be
detected by Doppler ultrasonography or palpated does not
rule out compartment syndrome. New onset of pain should
alert the physician, but pain is often already present and its
absence does not rule out compartment syndrome. Other
neurologic findings, such as motor or sensory deficits,
should prompt immediate surgical evaluation. Invasive
monitoring of compartment pressures may help establish
the diagnosis, but normal pressures may lead to a false sense
of security. In general, it is safer to act on a strong clinical
suspicion than to allow compartment syndrome to go
untreated. Wide fasciotomies should be performed immedi-
ately if compartment syndrome is diagnosed or clinically
suspected.
MANAGEMENT OF PATIENTS WITH BRAIN INJURY
Resuscitation of brain-injured patients deserves special
mention. Although clinical signs and laboratory studies
36 • Multisystem Trauma 547
are useful for global perfusion, head-injured patients with
severe head injury (Glasgow Coma score [GCS] 8) benefit
from more direct assessment of brain perfusion. Outcome
after head injury is markedly dependent on cerebral
perfusion. Hypotension and hypoxemia are to be
avoided at all costs. Even one brief episode of hypotension
(systolic blood pressure [BP] <90 mmHg) or hypoxemia
(PaO2  60 mmHg) is detrimental to long-term outcome
after head injury.43 The clinically relevant index of brain
perfusion is cerebral perfusion pressure (CPP), defined as
the difference between mean arterial pressure (MAP) and
intracranial pressure (ICP). Retrospective studies suggest
that failure to maintain CPP above 60 mmHg is associated
with worse outcome.44,45 ICP monitors can guide medical
therapies (e.g., fluids and/or pressors to increase CPP;
osmotic diuretic to decrease ICP). Maintaining ICP consis-
tently at less than 20 mmHg probably improved outcome
after brain injury.46 The Brain Trauma Foundation recom-
mends ICP monitoring in the following situations:
▪ Severe head injury (defined as GCS 3 to 8) with abnormal
computed tomography (CT) of the head at admission
(e.g., CT demonstrates hematoma, contusion, edema,
or compressed basal cisterns).
▪ Severe head injury with normal CT of the head at
admission and two or more of the following at admission:
age greater than 40 years, unilateral or bilateral motor
posturing, systolic BP less than 90 mmHg.
▪ At the physician’s discretion among conscious patients
with traumatic mass lesions.
Furthermore, the ICP transducer may have a ventricu-
lostomy catheter to allow drainage of cerebrospinal fluid
(CSF) and thereby decrease the ICP. CPP is increased by
increasing MAP (volume resuscitation, then vasopressor if
necessary) and/or by decreasing ICP (by an osmotic diuretic
agent such as mannitol or by drainage of CSF). The ideal
transfusion trigger for brain-injured patients is not known.
The traditional trigger is 10 g/dL, but this has recently been
challenged. Until more definitive studies are completed, it is
prudent to be more liberal in RBC transfusion when caring
for brain-injured patients. Hypertonic saline is a safe and
effective component of brain trauma resuscitation47 and
should be considered after colloid resuscitation. Deliberate
hyperventilation is indicated for acute control of ICP, but
it has no benefit as a sustained ICU therapy, because the
ICP control by hyperventilation is based on decreased cere-
bral blood flow.
Cerebral cortical oxygenation is being investigated as an
adjunct to ICP monitoring.48 These devices alert the clini-
cian to occult brain tissue hypoxia (partial pressure of oxy-
gen [PO2] <15 to 20 mmHg)—that is, ischemic brain tissue
despite adequate CPP. Further studies will clarify its role in
brain resuscitation.
In addition to these resuscitation measures, the Brain
Trauma Foundation has promulgated guidelines for the
management of severe TBI and early posttraumatic seizures
(PTS) prophylaxis. Although no recommendations have
been made for decreasing the incidence of late PTS, level
IIa recommendations suggest that phenytoin be used to
decrease the incidence of early PTS (within 7 days of injury)
when the overall benefit is felt to outweigh the
548 PART IV • Early Postoperative Care
complications associated with such treatment. However,
early PTS have not been associated with worse outcomes.
At the time the guidelines were published, there was insuf-
ficient evidence to recommend levetiracetam over phenyt-
oin regarding efficacy in preventing early posttraumatic
seizures and toxicity.49
VENOUS THROMBOEMBOLISM (VTE)
Injured patients are at higher risk of deep venous thrombosis
(DVT) and pulmonary embolism (PE) than either uninjured
patients or other groups of hospitalized patients. Meta-
analysis reveals an overall DVT rate of 11.8% and a PE rate
of 1.5% among all injured patients.50
Despite the frequency of thromboembolic complications,
there is significant controversy and variability in current
practice. Most trauma centers have developed standardized
approaches to prophylaxis for venous thromboembolic
events. Early mobilization is a simple prophylactic measure.
However, many patients are limited by their injuries or
mental status. Sequential compressive devices should be
considered in all patients without precluding wounds, frac-
tures, splints, and external fixators. Patients with risks fac-
tors for VTE and no contraindications should be given
chemical prophylaxis.
High risk patients are those anticipated to be hospitalized
>24 hours and have one or more of the following risk
factors:
▪ Anticipated immobilization >2 days
▪ Previous history of DVT, PE, or hypercoagulable disease
▪ Head injury with GCS < 8 or unable to respond to
commands
▪ Pelvic fracture
▪ Long bone fracture
▪ Spinal fracture
▪ Lower extremity venous injuries
▪ Cancer
▪ Obesity
▪ Multiple rib fractures
Many single-center studies have demonstrated efficacy of
one or more of the three most common prophylaxis mea-
sures—mechanical prophylaxis with sequential compres-
sion devices (SCD), low-dose unfractionated subcutaneous
heparin (SQH), and subcutaneous low-molecular-weight
heparin (LMWH). When subjected to meta-analysis, none
of the measures was statistically more effective than no pro-
phylaxis at all,51 but this meta-analysis was insufficiently
powered to exclude a true benefit of any of the therapies.
Among SCD, SQH, and LMWH, LMWH is probably the best
choice for DVT prophylaxis in injured patients who are not
at excessive risk for bleeding. A study from the University of
Michigan used data from the Michigan Trauma Quality
Improvement Project (MTQIP) database to conduct a com-
parative effectiveness study evaluating UFH versus LMWH
for the in-hospital outcomes of VTE, PE, DVT, and mortality.
They found that trauma patients who received LMWH as
their first dose of VTE prophylaxis had a significantly
reduced risk of VTE, PE, DVT, and mortality when compared
with UFH.52 LMWH may be more effective than SQH in pre-
vention of DVT with no increased risk for bleeding
complications. Contraindications to LMWH include renal
insufficiency or renal failure or the presence of an epidural
analgesia catheter. In these situations, unfractionated hep-
arin and intermittent compression devices are acceptable
alternatives.
For patients at high risk of thromboembolic events who
cannot undergo anticoagulation or tolerate additional
bleeding (e.g., patients with intracranial hemorrhage, pelvic
hematoma, ocular injury with hemorrhage, or injury to
liver, spleen, or kidney), prophylactic placement of an infe-
rior vena cava (IVC) filter is controversial. The Eastern Asso-
ciation for the Surgery of Trauma (EAST) guidelines
recommend consideration of IVC filter placement but the
American College of Chest Physicians (ACCP) recommend
against the primary use of IVC filters for VTE prophylaxis
and recommend SCDs and starting chemical prophylaxis
when the contraindication resolves.53,54 The long-term
sequelae of IVC filters are not known. A variety of removable
IVC filters exist and they may be considered in patients who
are deemed candidates for filter placement.
Other Postinjury Considerations
STRESS ULCER PROPHYLAXIS
Injured patients have an increased risk of stress ulcers and
prophylaxis is indicated for patients with high risk. Inci-
dence of gastrointestinal bleeding ranges from 1.5% to
8.5% in intensive care unit patients but may be as high
as 15% among patients who do not receive stress ulcer pro-
phylaxis. Mortality is significantly higher in ICU patients
who develop clinically apparent upper GI bleeding, 49% ver-
sus 9%.55 Risk factors include coagulopathy defined as a
platelet count <50,000 per m3, an International Normal-
ized Ratio (INR) >1.5, or a partial thromboplastin time
(PTT) >2 times the control value, mechanical ventilation
for longer than 48 hours, traumatic brain injury, spinal cord
injury, burns >30%, or a history of upper gastrointestinal
bleeding.55 A variety of treatment options exist (sucralfate,
histamine-2 receptor antagonists [H2RAs], and proton-
pump inhibitors [PPIs]). In the largest meta-analysis of 18
studies, PPI use prevented more upper GI bleeding events
than H2RAs without any impact on the rate of pneumo-
nia.56 Among mechanically ventilated patients, sucralfate
and H2RAs are effective for prevention of bleeding, with
H2RAs possibly slightly more effective.57 Some studies sug-
gest that sucralfate is associated with a lower rate of noso-
comial pneumonia,58 but others have been unable to show
a difference.59,60 Large randomized controlled trials are
warranted to elucidate the benefit of one regimen over
another and the relationship of stress ulcer prophylaxis
and infectious complications.
NUTRITION SUPPORT
Nutrition support is of utmost importance in the injured
patient once acute hemodynamic issues have been
addressed. Injured patients are often in a catabolic state
and have higher nutritional requirements than in the pre-
injury state. Both enteral nutrition and parenteral nutrition
have roles in postinjury care. The enteral route is preferred.

The Society of Critical Care Medicine and American Society
for Parenteral and Enteral Nutrition published guidelines for
the assessment and provision of nutrition support in criti-
cally ill patients.61 They recommend determining nutri-
tional risk for ICU patients and starting enteral nutrition
when possible and as early as 24 to 48 hours after admis-
sion. This should start in the hemodynamically stable
patient and be used with caution in patients on vasoactive
medications. Among critically ill patients, especially those
with abdominal injury, enteral nutrition is associated
with a lower rate of septic complications (pneumonia,
intraabdominal abscess, line sepsis) than the parenteral
route.62–65 About half of all patients cannot tolerate goal
enteral nutrition at 1 week postinjury. Parenteral nutrition
should be considered in patients who do not achieve at least
50% of goal enteral nutrition by postinjury day 7.
Enteral nutrition can be delivered by the intragastric or
postpyloric route. Neither route has been proven superior
in trauma patients in terms of mortality; however, the post-
pyloric route may reduce the risk of aspiration and pneumo-
nia. Because intragastric feeding is typically simpler, it
should be the first choice. Postpyloric feeds should be consid-
ered for patients at high risk of aspiration, especially patients
with head injury, in whom gastroparesis is common. Gastric
residual volumes were traditionally used to assess tolerance
but have since been disproven and are associated with a
decrease in calorie delivery.61 Other ways to assess toler-
ance include abdominal distension, pain, nausea, emesis,
diarrhea, constipation >3 days, and/or a large gastric bub-
ble seen on plain film of the abdomen. Enteral formulas with
various supplements (e.g., arginine, glutamine, fish oils)
have been studied in critical care populations, including
trauma patients, but no specific enteral formulation has
demonstrated consistently superior outcomes. Based on sys-
tematic review, guidelines have not formally recommended
enhanced enteral nutrition formulas but simply suggest
considering them.66 Rather, it appears that simply avoiding
starvation is the key to reducing septic morbidity in the
critically ill.
GLYCEMIC CONTROL
Hyperglycemia in trauma patients is associated with in-
creased infectious complications and mortality.67–70 Injured
patients with a serum glucose level greater than 200 mg/dL
have consistently demonstrated worsened outcomes: in-
creased ICU length of stay (and thus increased hospital length
of stay), longer duration of mechanical ventilation, higher
rates of infection, and higher mortality. However, the
optimal target range for glycemic control has been debated
over the past two decades—in particular, whether lower
glycemic targets are associated with improved outcomes.
The largest trial to date concerning glycemic control
was the multicenter Normoglycemia in Intensive Care
Evaluation Survival Using Glucose Algorithm Regulation
(NICE-SUGAR) trial, which randomly assigned 6104 medi-
cal and surgical ICU patients to either intensive insulin
therapy (target blood glucose level of 81–108 mg/dL
[4.5–6 mmol/L]) or conventional glucose control (target
blood glucose of <180 mg/dL [<10 mmol/L]).71 The
intensive insulin group had a higher mortality and higher
36 • Multisystem Trauma 549
incidence of severe hypoglycemia. However, a subgroup
analysis suggested a possible trend toward improved out-
comes with intensive insulin in trauma patients. None-
theless, a blood glucose target of 140 to 180 mg/dL (7.7–
10 mmol/L) rather than a more stringent target of 80 to
110 mg/dL (4.4–6.1 mmol/L) or a more liberal target (e.g.,
180–200 mg/dL [10–11.1 mmol/L]) is currently recom-
mended for ICU surgical patients.
INFECTIOUS COMPLICATIONS
Trauma patients often have gastric contents present at the
time of injury, placing them at higher risk of aspiration
pneumonitis and aspiration pneumonia, either from inabil-
ity to protect the airway or from rapid-sequence intubation.
“Ventilator bundles,” designed to reduce the risk of
ventilator-associated pneumonia (VAP), are commonplace
in the ICU. Within limits of the patient’s injuries and treat-
ments, mechanically ventilated trauma patients should
receive all such therapies to decrease the incidence of
VAP. Intubated trauma patients should have the head of
the bed at 45 degrees after thoracic and lumbar spine clear-
ance. Until then, or if spine injury is present, the patient
should be placed in reverse Trendelenburg position.
The incidence of catheter-related blood stream infections
is higher in trauma patients. This may reflect the less
than ideal conditions in which they are placed. These lines
should be removed or replaced with peripheral access as
soon as possible. Likewise, catheter-associated urinary tract
infections can be mitigated with early removal of bladder
catheters.
There is no role for routine antibiotic administration in
most patients. In patients requiring a laparotomy, a single
preoperative dose given within 1 hour of incision is appro-
priate. If hollow viscus injury is identified and repaired in a
timely fashion, there is evidence for limiting postoperative
antibiotics to 24 hours postoperatively.72 Longer courses
of antibiotics do not decrease rates of infection and abscess
formation. Antibiotic prophylaxis may be justified in some
open fractures.
ANALGESIA
Pain management in the trauma patient is similar to that of
the postoperative patient. Critically injured patients require
careful assessment of their pain. Whenever possible, opioid
based medications should be limited or avoided and a non-
opioid multimodal pain medication regimen should be fol-
lowed. The American Society of Anesthesiologists Acute
Pain Task Force Guidelines recommend the use of a multi-
modal pain management therapy plan, neuraxial/regional
blockade with local anesthetics, and an around-the-clock
regimen of cyclooxygenase (COX) inhibitors, nonsteroidal
antiinflammatory drugs (NSAIDs), or acetaminophen.73
Numerous studies have documented a strong relationship
between rib fractures and either respiratory complications
or mortality.74–76 Although rib fractures are debilitating
for all patients, older adult patients with rib fractures are
particularly susceptible. Some studies have suggested that
epidural analgesia is superior to patient-controlled analgesia
in patients with rib fractures,76,77 but others have found no
550 PART IV • Early Postoperative Care
benefit.75,78 Operative fixation of multiple rib fractures and
flail chest is gaining acceptance and may enhance pulmo-
nary mechanics and decrease complications such as pneu-
monia and death. Clinical trials are lacking and more
research is warranted in this field.
Summary
Multisystem trauma patients are heterogeneous in prein-
jury status, injury pattern, and postinjury management.
Some injured patients require no operative intervention,
whereas others require multiple operations. Thus for many
multiply injured patients, the early postoperative phase is an
aggregate of the early postinjury phase and a preoperative
phase. In all patients, resuscitation, treatments, and inter-
ventions should be rapidly implemented and frequently
reassessed. Judgment is required to select among the many
endpoints of resuscitation. The rapid arrival at a resuscita-
tion goal should not give way to iatrogenic over-
resuscitation, which has its own consequences. Damage-
control techniques have improved outcomes from severe
trauma, underscoring the importance of collaboration
among trauma surgeons, anesthesiologists, and intensivists.
Many evidence-based practices in postsurgical care and crit-
ical care have been applied successfully to postinjury care.
Ideally, all such practices are evaluated to improve the care
of patients with multisystem trauma.
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patients with severe trauma: The PROPPR randomized clinical trial.
JAMA. 2015;313(5):471–482.
2. American College of Surgeons Committee on Trauma: Advanced
Trauma Life Support (ATLS) Student Course Manual, ed 10. American
College of Surgeons, Chicago, 2018.
3. Tran A, Yates J, Lau A, et al. Permissive hypotension versus conven-
tional resuscitation strategies in adult trauma patients with hemor-
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 37 Neurosurgery
AMANDA L. FAULKNER and MICHAEL L. JAMES
After uncomplicated neurosurgical procedures, patients are
often admitted to an intensive care unit (ICU) for close obser-
vation. In the large majority of cases, this level of care is
warranted as a means to monitor the patient’s neurologic
function carefully and to expedite appropriate intervention
if necessary. Further, observation and evaluation of postop-
erative neurosurgical patients may be complicated by the
residual effects of the prior anesthetic and an ongoing need
for analgesia and sedation.
The Leapfrog Group has shown that the implementation
of basic intensive care practices can vastly improve
patient safety. One of these practices is choosing a hospital
with ICUs that are staffed at least 8 hours daily by
specially trained critical care physicians.1,2 Mirski and col-
leagues3 showed that treatment in a dedicated specialty
neurologic-neurosurgical ICU (NSICU) improved mortality
and disposition at discharge for patients with intracerebral
hemorrhage, compared with a similar cohort treated 2 years
earlier in a general ICU setting. Furthermore, critically ill
postoperative neurosurgical and neurologic patients who
are treated in the NSICU had shorter hospital stays and
lower total costs of care than a national benchmark. The
data suggest that a neuroscience specialty ICU staffed by
specialty-trained intensivists and nurses is beneficial.3 Only
a small fraction of patients require prolonged ICU stay after
craniotomy for tumor resection. A patient’s risk of pro-
longed stay can be predicted by certain radiologic findings,
large intraoperative blood loss, fluid requirements, and the
decision to keep the patient intubated at the end of surgery.4
For those patients requiring ICU resources beyond the first
4 hours, the interventions can be critical. It is, therefore,
crucial to have appropriate skills and resources readily
available.
In this chapter, we describe the methods we have imple-
mented in many NSICUs to improve outcome after neuro-
surgical procedures (Fig. 37.1). In basic terms, most
improvement in postoperative outcome is attained by recog-
nizing acute reversible neurologic injury and distinguishing
it from expanding intracompartmental mass lesions or
edema, and by preventing secondary neurologic insults
from decreased ventilation or cerebral hypoperfusion. We
summarize the care given to postoperative patients who
have undergone major neurosurgical procedures that carry
a higher risk for neurologic impairment.
Neurologic Support
FOCUSED NEUROLOGIC EXAMINATION
Postoperative neurosurgical patients require rapid initial
neurologic assessment. The Glasgow Coma Scale (GCS)
score is the most widely recognized assessment of cortical
552
function, consisting of motor, verbal, and eye opening
(arousal) responses (Box 37.1) The GCS offers simplicity
and reproducibility, but it is affected by other factors causing
cortical impairment such as sedatives, narcotics, tempera-
ture, glucose levels, and electrolyte imbalances; it also lacks
compensatory scores for intubated or aphasic patients.5
Regardless of a patient’s level of consciousness, an examiner
must evaluate cranial nerve and brainstem reflexes, includ-
ing pupil size and light reflex, eye deviation and extraocular
muscle movements, oculovestibular and oculocochlear
reflexes, facial symmetry/movement, gag reflex, and midline
tongue protrusion (see Box 37.1).
Spinal cord function can be assessed using reflexes, mus-
cle strength, and peripheral sensation. Triceps, biceps, bra-
chioradialis, patellar, and ankle reflexes are graded and
compared with the contralateral side. The standardized
motor strength grading is based on a scale of 1 to 5. Typi-
cally, flexor and extensor muscle groups in the proximal
and distal portion of each extremity are tested as an initial
screen, with further and more detailed testing of individual
muscles as warranted by the history or initial screen. If a
patient is unable to comply fully with the motor examina-
tion because of an alteration in level of consciousness, an
examiner may still observe some measure of muscle
strength based on spontaneous movement or withdrawal
from stimuli. Passively flexing and extending the extremities
can be used to assess the patient’s muscle tone.
A screening examination consists of light touch and pain
sensation attained proximally and distally in each extrem-
ity, as well as proprioceptive sense in the thumbs and great
toes. Stimulating the lateral sole assesses plantar responses.
Testing finger-to-nose and heel-to-shin maneuvers is used to
assess cerebellar function.
The results of the focused neurologic examination are
used as the basis for further monitoring, which requires
coordination between examiners as they assess neurologic
recovery. With the exception of some simple reflexes (which
are either present or not present), the neurologic examina-
tion is subjective, and variability can be expected to exist
between examiners; however, repeated examinations by
the same health-care professional are consistent and this
consistency is bolstered by knowledge of the clinical his-
tory.6 In summary, the intensive and intermediate nursing
care of postoperative neurosurgical patients is based on
the repeated observations of responses to the neurologic
examination.
POSTOPERATIVE IMAGING
Central nervous system imaging studies are often an exten-
sion of the neurologic examination, because they can be
used to assess anatomic lesions, which may then be related
 37 • Neurosurgery 553

Procedure
Craniotomy
Intradural lesion, spine

Yes Admit to neurologic intensive care for monitoring

No
Yes
New neurologic deficit? Imaging study
Yes
Negative Positive

Respiratory compromise No
Hemodynamic instability Continue monitoring Acute intervention

Yes Secure airway

No Respiratory compromise?
Maintain ventilation

No
Routine postanesthesia
Yes
recovery Hemodynamic compromise? Establish invasive monitoring

No CPP adequate?
Yes No

Continue overnight monitoring

Volume replacement
Vasopressors
Inotropes

Fig. 37.1 Early postoperative care for neurosurgery. CPP, Cerebral perfusion pressure.

Box 37.1 Focused postoperative neurologic examination.

Cortical function: Glasgow Coma Eye opening + motor response +
Score (GCS) verbal response ¼ GCS
Eye opening Brainstem function
Spontaneous 4
Speech 3 Reflexes
Pain 2 Pupillary light reflex
None 1 Ocular movements
Motor response Corneal reflex
Obeys commands 6 Facial grimace
Localizes 5 Gag
Withdraws 4 Cough
Flexes 3 Spinal cord function
Extends 2 Deep tendon reflexes
No response 1 Brachial
Verbal response Achilles
Oriented 5 Motor response
Confused 4 Hands
Inappropriate words 3 Toes
Incomprehensible sounds 2 Sensory
No response 1 Light touch

to neurologic dysfunction uncovered by the examination.
In the postoperative neurosurgical population, imaging is
useful for any of three reasons: (1) because the patient is
unable to arouse fully in a reasonable amount of time after
anesthesia, (2) because a neurologic deficit is seen postoper-
atively that was not seen preoperatively, or (3) because
a preexisting deficit is worse postoperatively than it was
preoperatively.
Computed tomography (CT) scanning, which provides
fast, detailed images by computerized analysis of circumfer-
ential radiographs, is the mainstay for urgent or emergent
evaluation of ventricular size, edema, hemorrhage, and
bony structures. The main advantage of CT is the speed with
which the scans can be obtained because patient compli-
ance may be limited in this population. Spiral CT scans pro-
vide three-dimensional (3-D) images (especially useful in
554 PART IV • Early Postoperative Care
examining vascular anatomy and cerebrospinal fluid [CSF]
flow), and perfusion CT scanning may give some measure
of regional cerebral blood flow. Additionally, with the
improved availability of portable CT scanners, reductions
in transportation-related morbidity and time to clinical
decision may be facilitated without compromise of image
quality.7–8
Magnetic resonance imaging (MRI) may be used in addi-
tion to or instead of CT to provide the highest anatomic
detail available. MRI uses pulse sequences of magnetic radio
waves to orient cellular nuclei in a particular direction;
computer analysis then converts the differences in radio
energy imparted by the subsequent relaxation of these
nuclei into excellent images that provide information on
gray and white matter structures, edema, CSF, hemorrhage,
blood–brain barrier integrity (with the use of gadolinium
contrast), and tumors. Newer pulse sequences allow 3-D
images of intracranial vasculature and perfusion studies.
The main disadvantage of MRI is the length of time it takes
to perform a study: complete imaging of the brain may take
up to 1 hour. Also, acquiring the images can be difficult in
the noncompliant or critically ill patient. Another disadvan-
tage is that the noise and closeness of the MRI machine
result in many patients’ needing to be sedated because of
claustrophobia and anxiety. For these reasons, MRI is usu-
ally reserved for situations in which CT is inadequate (e.g.,
for imaging in the posterior fossa), for non emergent detailed
imaging after intracranial tumor surgery, and for spinal
cord imaging.
Finally, conventional angiography remains the gold stan-
dard for vascular imaging. In the postoperative period, it is
mainly reserved for use after intracranial vascular surgery
when MR angiography or CT angiography is contraindi-
cated or of questionable efficacy.
POSTOPERATIVE INTRACRANIAL PRESSURE
MONITORING
Because the central nervous system is relatively incompress-
ible, postoperative intracranial pressure (ICP) may be
directly related to mean arterial pressure (MAP) after com-
pensatory mechanisms have been exhausted. Cerebral per-
fusion pressure (CPP) equals MAP minus the highest
downstream pressure, usually the ICP. If cortical function
is normal, CPP may be approximated by measuring MAP
when ICP is unknown. However, the central nervous
system is somewhat compartmentalized because of the
separation of the cerebral hemispheres and posterior fossa
by the dural reflections, and thus raising or lowering
the MAP may not directly raise or lower ICP in a linear
manner. Therefore, it is often necessary to monitor the
ICP invasively.
ICP should be monitored directly when its manipulation
involves prolonged attempts or when a degree of hydro-
cephalus might result in depressed neurologic function.
Historically, this has been done by ventriculostomy or cra-
nial bolt placement. However, newer ICP monitors can
evaluate regional oxygenation, temperature, and pres-
sure.9 These catheters may be used to guide management
of intracranial pressure, oxygenation, and cerebral meta-
bolic rate (CMR) but are largely not validated with out-
come data.10–12
MANAGEMENT OF POSTOPERATIVE
COMPLICATIONS
Immediately after a neurosurgical procedure, complications
include cerebral edema, hematoma, and seizures. Global
cerebral edema, as seen after head trauma, with associated
increases in ICP has been shown to have high mortality,
thought to be largely the result of decreased cerebral blood
flow (CBF).13 Although the regional edema seen at the sur-
gical site is not associated with the same risks or mortality,
postsurgical edema with neurologic compromise may be
caused by local or diffuse decrements in CBF and thus
may benefit from ICP management. The goals are to supply
the metabolic demands of the brain by maintaining perfu-
sion, oxygenation, and glucose. The treatment for elevated
ICP is first directed at the cause, which in this patient pop-
ulation is typically postsurgical edema, but it may include
intracerebral hemorrhage, cerebral venous occlusion, focal
ischemia or infarction, infection, or unresected tumor.
Management of ICP begins with supporting the viable
neuronal tissue until definitive therapy for the underlying
cause can be achieved. Maneuvers intended to decrease
ICP in the setting of cerebral edema range from hyperven-
tilation to calvarium removal; however, in the immediate
postoperative period, most interventions are meant to
reduce the volume of CSF or blood in the cranial vault.
Hyperventilation, routinely used to reduce CBF via cere-
bral vasoconstriction, can be achieved through increases in
tidal volume, respiratory rate, or both. Its disadvantages
include reducing CBF in concurrently ischemic brain, pre-
sumably because of associated vasoconstriction, decreasing
seizure threshold, rebound increase in ICP, and CSF acidosis
after cessation.14–17 Osmotherapy, aimed at shifting intra-
cranial fluid into the vascular compartment, utilizes hyper-
osmolar solutes such as mannitol or hypertonic saline to
reduce ICP.18 Although mannitol acts to promote osmotic
diuresis, it may also diffuse into areas of the brain where
the blood–brain barrier is no longer intact and theoretically
could cause worsening of regional edema.19 Likewise, infu-
sion of hypertonic saline with subsequent rapid increases
in serum sodium have been associated with irreversible
myelinolysis.18 Intravenous corticosteroids can be used to
actively treat the cause of cerebral vasogenic edema, as seen
in malignancies. High dosages may be necessary and may
be difficult to wean quickly.20 Finally, barbiturates have
been used to decrease ICP through lowering CBF and
CMR.21 In general, high dosages are required to induce
burst-suppression patterns on electroencephalogram.
Therefore, the blood pressure may need pharmacologic aug-
mentation with inotropes and/or vasoconstrictors.
Postoperative hematoma formation is another major
concern. The location of surgery best dictates how to mon-
itor the patient for this. Epidural hematoma formation
occurring after spinal surgery is usually indicated by
new and progressive neurologic symptoms in the extrem-
ities and demands immediate diagnosis with CT and with
surgical evacuation and decompression. Although the
postoperative development of intracerebral or epidural
hemorrhages is not unheard of, subdural hematoma for-
mation is more common after intracranial procedures
and may be signified by alteration in mental status, unilat-
eral neurologic signs, or failing to recover fully from anes-

thesia. Again, immediate imaging with CT and consider-
ation of evacuation is indicated.
Finally, seizures may complicate the early postoperative
course. The largest incidence study indicated that early
postoperative seizures may occur in as many as 17% of
cases, allowing for wide variation between inciting pathol-
ogies.22 Although many studies have found differing results
regarding seizure prophylaxis utilizing a myriad of antiepi-
leptic drugs (AEDs) including phenytoin, carbamazepine,23
valproic acid, phenytoin, phenobarbital, zonisamide, and
levetiracetam, a recent systematic review suggests that
there is inconsistent, low-quality evidence to suggest that
AEDs are effective in the reduction of early or late seizures
postcraniotomy.24 Current recommendations include the
use of perioperative antiepileptic drugs in patients with a
history of seizures or considerable preoperative cerebral
damage; these drugs should be continued indefinitely if post-
operative seizures occur or for several months if they do not.
The use of any medication should be weighed against its
side-effect profile and the patient’s comorbidities.
Respiratory Support
Airway and breathing are the initial concern in preventing
secondary neurologic injury and should therefore be inte-
gral to the initial assessment of any postoperative patient.
In the neurosurgical patient, control of both oxygen and
carbon dioxide is critical.
HYPOXIA AND HYPERCARBIA IN BRAIN INJURY
Hypoxia can be detrimental by two mechanisms. First, in
areas of the brain with cerebrovascular compromise, hypox-
emia may be poorly tolerated, with subsequent neuronal
infarction if not corrected. Second, hypoxemia may exacer-
bate intracranial hypertension. The normal compensatory
mechanism for hypoxia in the brain is vasodilation. This
seems to be a regional phenomenon25 and may be con-
trolled by regional factors.26,27 Therefore, it is reasonable
to assume that areas of maximal vasodilatation and decre-
mental blood flow will not tolerate additional hypoxemia,
because there may be few, if any, further compensatory
mechanisms available to the neuronal tissue. If further
vasodilatation is possible, however, subsequent cellular
damage may occur because of increases in intracranial pres-
sure, with consequent decrease in regional or global blood
flow and altered cellular structure, leading to further edema
and increases in ICP. Hyperoxia, on the other hand, is also
theoretically detrimental because of the abundance of free
radicals created as a result of ischemia and reperfusion.28,29
However, with the data available, it still seems most reason-
able to err on the side of too much oxygen rather than too
little.
Carbon dioxide has an even more profound effect on cere-
bral vasculature. CBF is linearly related to PaCO2 when it is
between 20 and 60 mmHg.17 Therefore, decrements or
increments in PaCO2 will either decrease or increase CBF,
respectively. This change in CBF has a direct effect on blood
volume and therefore on ICP. It would then seem that when
an increased ICP was detrimental, a lower PaCO2 would be
beneficial, as it would directly lower the ICP; however, the
37 • Neurosurgery 555
lower ICP is at the direct expense of blood flow, which is
exactly the parameter that the clinician is attempting to
maintain. The relation between ICP and PaCO2 is even more
complicated in the injured brain. When injured, the cerebral
vasculature loses autoregulation and increased PaCO2 may
not increase blood flow to injured areas because arterioles in
that area may be maximally dilated. There is also the theo-
retical issue of steal, as noninjured areas may increase their
blood flow with increases in PaCO2 at the expense of
maximally dilated areas of injured brain. On the other hand,
lowering ICP through decreases in PaCO2 may counterintu-
itively cause hyperperfusion of injured areas because vaso-
constriction does not occur as readily there as it does in
areas of normal brain where ischemia may otherwise
result.30,31
AIRWAY ASSESSMENT AND MANAGEMENT
Decreased Level of Consciousness. Reduced level of
consciousness (GCS <10) correlates with the need to protect
the airway by endotracheal intubation to prevent passive
aspiration and intermittent airway obstruction. This was
demonstrated in studies that used ICP monitoring after
acute hemispheric stroke, in which the development of
decreased level of consciousness was not correlated with a
rise in ICP but was more closely correlated with edema
and tissue shifts.32,33
Raised Intracranial Pressure. Patients presenting with
acutely raised ICP often require control of the airway as
the initial therapeutic intervention.34 Preventing hypox-
emia, hypercarbia, and acidosis can minimize secondary
neurologic damage from raised ICP. A decreased level of
consciousness (GCS <9) is associated with a decreased abil-
ity to protect the airway and suggests additional potential
benefit from mechanical hyperventilation to control raised
ICP.35 Potential cerebral herniation is associated with raised
intracranial pressure and brainstem injury, which impairs
airway reflexes, coughing, and ventilatory drive.36,37 How-
ever, laryngoscopy, hypoventilation, struggling, and the use
of succinylcholine without using a small dose of nondepolar-
izing muscle relaxant to prevent muscle fasciculation38
have been shown to raise ICP.
Brainstem Lesions. Brainstem disease may lead to several
well-defined disorders of breathing and require endotra-
cheal intubation. Patients with basilar artery infarction
may suffer from obstructive or mixed apnea or impaired air-
way reflexes, which lead to positional airway obstruction or
repeated aspiration. The dorsolateral medulla is primarily
responsible for the integration of effective rhythmic breath-
ing and as long as this area, which includes the nucleus
ambiguous and solitarius, is not affected by the ischemic
infarct, central respiratory control may be relatively normal.
Thus, even locked-in patients with rostral brainstem infarc-
tion may be left with a relatively normal respiratory drive if
infarction spares the dorsal lateral medulla.39 Disruption of
automatic breathing may result from damage to the lateral
medulla and pontine tegmentum caudal to trigeminal out-
flow. Lateral medullary stroke is most commonly the result
of occlusion of the distal vertebral or posterior inferior
556 PART IV • Early Postoperative Care
cerebellar artery, and large infarcts involving the dorsolat-
eral medulla may be associated with fatal apnea.40 These
patients may suffer from mild hypoventilation while awake,
which can be reversed voluntarily. Respirations may cease
entirely during sleep.
Spinal Cord Lesions. Priority is given to simultaneous air-
way assessment and management. Immobilization of the
spine must be ensured until definitive radiographic studies
are obtained. Listening for stridor caused by partial airway
obstruction and feeling for air movement can determine
adequacy of the airway. Patients who can speak without
stridor or hoarseness usually have unobstructed airways.
Some patients who demonstrate airway obstruction will
respond to a jaw-thrust maneuver; however, during this
process, spine manipulation must be avoided. Many patients
with cervical cord lesions will require at least temporary
endotracheal intubation. A significant proportion of spinal
cord injured patients have associated head injuries and
depressed levels of consciousness. Patients who are stupor-
ous or unconscious are at increased risk of developing aspi-
ration pneumonitis. In the patient with spinal cord injury,
this risk is compounded by gastrointestinal paresis that
develops soon after the injury.41 Patients with significant
chance for regurgitation and aspiration require intubation
or tracheotomy to protect their airway. Gastric atony
should be suspected and managed with nasogastric tube
suction until it resolves.42
SEDATION STRATEGIES
Once a decision has been made to reintubate or to continue
mechanical ventilation, the role of sedation becomes an
issue because agitation, increased physiologic stress, and
inadvertent airway extubation may impair neurologic
recovery. However, sedation hinders the neurologic exam-
ination and impairs functional monitoring. The perfect sed-
ative would allow complete cooperation from an alert,
awake, yet passive patient, would take effect immediately,
and would dissipate immediately when infusion is stopped.
The oldest agents are the barbiturates, such as thiopental.
Although thiopental’s efficacy is limited because tissue
redistribution causes prolonged sedation after cessation of
drug infusion, it has cerebral-protective properties by lower-
ing metabolic rate and decreasing ICP.21
Benzodiazepines (such as midazolam) are commonly
used. These gamma-aminobutyric acid (GABA)ergic drugs
cause sedation and amnesia. They retain some antiepileptic
properties, decrease cerebral metabolic rate, and can be rel-
atively short acting.43 They have the added benefit of being
reversible with flumazenil but at the expense of potentially
lowering the seizure threshold. The main disadvantages are
that benzodiazepine use is associated with delirium and
hypotension.
Short-acting opioids (such as fentanyl, alfentanil, or remi-
fentanil) may also be used for their sedative properties. They
have the added bonus of conveying analgesia (they do not,
however, consistently confer amnesia) and are also revers-
ible with naloxone. Patients remain fairly cardiostable after
dosing and opioids blunt respiratory responses such as dys-
pnea, coughing, or gagging in ventilated patients. These
drugs become more problematic with lengthier infusion
because all have context-sensitive half-lives (except remi-
fentanil). Remifentanil, however, can be quite expensive,
which, coupled with its propensity to reduce MAP and thus
CPP, may limit its use in the setting of prolonged postoper-
ative sedation. Nevertheless, neurosurgical patients may
benefit from its utility secondary to its rapid elimination
and similar safety profile; this affords a predictable time to
sedation elimination for rapid neurological assessment.44
Newer agents include propofol and dexmedetomidine.
Propofol is another GABAergic agent with both a very short
half-life and sedative-hypnotic properties. Its main benefit is
quick arousal times even with prolonged infusions. It may,
however, have detrimental hemodynamic effects and can be
rather expensive. Finally, dexmedetomidine, an alpha-2
agonist, grants both sedative and analgesic properties with
minimal amnesia. Some hemodynamic depression can be
seen (especially with bolus loading) and it also has a rela-
tively long half-life when compared with propofol. Never-
theless dexmedetomidine, unlike the other sedatives,
allows patients to be aroused from sedation with minimal
stimulation and there is little to no respiratory depres-
sion.45–47
Cardiovascular Support
CEREBRAL PERFUSION AND ARTERIAL BLOOD
PRESSURE
Under normal circumstances, cerebral blood flow is tightly
autoregulated on the basis of regional tissue oxygenation,
arterial carbon dioxide, cerebral glucose metabolism; there-
fore, oxygen delivery, glucose delivery, and carbon dioxide
elimination are maintained despite wide changes in arterial
pressure. However, after neuronal or vascular injury, as
seen in postsurgical changes, cerebral perfusion may be
uncoupled from autoregulatory mechanisms and, therefore,
will be tied directly to arterial blood pressure. In these cir-
cumstances, the arterial–intracranial pressure curve will
change to reflect linear increases in ICP because arterial
pressure increases until compensatory mechanisms are
overwhelmed, at which point ICP increases exponentially.
For these reasons, increased systemic arterial pressure
may exacerbate, or even cause, cerebral edema or hemor-
rhage just as decreased systemic pressure may worsen
ischemia. It may be necessary, then, to control systemic
arterial pressure within tightly defined parameters until
neuronal or vascular repair has been accomplished suffi-
ciently to reestablish cerebral blood flow autoregulation.
HYPERTENSION AND BRAIN INJURY
Postoperative neurosurgical patients often display varying
degrees of hypertension as they recover from anesthesia
and postsurgical changes to the brain. The essential ques-
tion is whether the elevated systemic arterial pressure is det-
rimental to (or, on the contrary, sustains) cerebral
perfusion. When the brain undergoes periods of relative
hypoperfusion, systemic arterial pressure may be elevated
to maintain adequate cerebral perfusion pressure. At some
point along this perfusion–pressure curve, additional sys-
temic pressure no longer increases cerebral perfusion but

instead begins to reduce blood flow because the surrounding
cranium is not compressible. It is often very difficult to deter-
mine immediately and empirically where along the pres-
sure–perfusion curve any individual patient is lying.
Therefore, it may be necessary to judiciously manipulate
the systemic arterial pressure while vigilantly monitoring
the patient for neurologic changes and for indications of
improvement or deterioration. Additionally, an estimation
of the potential for postsurgical complications (e.g., hemor-
rhage, edema) should be made to determine whether to
lower or to increase a patient’s arterial blood pressure. These
factors can make blood pressure manipulation precarious,
and clinical decisions are best made for individual patients
after considering all significant patient and surgical factors.
INOTROPES AND VASODILATORS
A variety of pharmacologic agents are at the disposal of
the intensivist when systemic arterial blood pressure must
be maximized in attempts to maximize cerebral perfusion.
Inotropes such as epinephrine, norepinephrine, dopamine,
dobutamine, and phenylephrine demonstrate varying
degrees of alpha- and/or beta-adrenergic agonism; a full dis-
cussion of all inotropes commonly employed is beyond the
scope of this chapter. As such, the selection of blood
pressure-augmenting agent is best made in the specific clin-
ical context in which it is to be used while weighing the
drug’s intended benefits with its expected side effects. Gen-
eral considerations include the patient’s comorbidities, par-
ticularly cardiac and renal function, as well as whether the
patient’s arterial pressure and cardiac output are best main-
tained or enhanced through alpha (i.e., peripheral) or beta
(i.e., cardiac) effects.
When induced hypotension is required, the clinician can
choose from vasodilators, angiotensin-converting enzyme
(ACE) inhibitors, and sympatholytics. Commonly utilized
vasodilators include nitroglycerin, sodium nitroprusside,
hydralazine, and nicardipine; however, in general, nitro-
glycerin and nitroprusside are avoided for the postoperative
neurosurgical patient because of their tendency to dilate
cerebral vasculature, which can raise intracranial pressure
and thus decrease cerebral blood flow. Nicardipine, a
calcium-channel blocker (CCB), can theoretically worsen
intracranial pressure, but it has been found to decrease sys-
temic arterial pressure reliably without clinically significant
intracranial pressure changes and it has the additional ben-
efit of potential cerebral protective properties.48 Similarly,
clevidipine, a newer third-generation CCB, has found favor
both intraoperatively and in the NSICUs because of its more
rapid onset and shorter half-life than nicardipine; in addition
to its rapid titratability, it may also be advantageous because
of the lower drug volume required to achieve an effect,
which may be particularly useful in critically ill, hypervole-
mic patients.49
ACE inhibitors have also been shown to decrease systemic
blood pressure and have additional benefits in patients with
cardiac comorbidities. The sympatholytics include beta-
adrenergic blockers (i.e., labetalol and metoprolol) and cen-
trally acting alpha-2 agonists (i.e., clonidine). Clonidine is
not routinely used in the immediate postoperative phase
because of its long-acting and sedative effects. However, it
has potential uses in patients with refractory or poorly
37 • Neurosurgery 557
controlled hypertension, ongoing drug abuse, or signs and
symptoms of narcotic withdrawal.50,51
Fluid and Electrolyte Support
HYPOVOLEMIA AND CEREBRAL PERFUSION
Hypovolemia may lead to hypotension and thereby worsen
ischemia because of decreased perfusion of organs. This is
also true in the brain. With regional brain injury and ische-
mia, cerebral blood vessels may be maximally dilated in an
attempt to maintain perfusion and lose autoregulation,
which ties perfusion directly to mean arterial pressure. In
states of hypovolemia, hypotension may be induced despite
compensatory mechanisms (decreased blood flow to periph-
eral tissues and nonessential organs, increased movement of
water intravascularly), thereby worsening ischemia in
poorly perfused neuronal tissue. Therefore, patients with
hypovolemia, whatever its cause, warrant aggressive fluid
resuscitation.
In the immediate postoperative period, hypovolemia is
most likely related to blood loss, intraoperative diuresis with
mannitol and/or furosemide, or inadequate resuscitation.
Blood loss, whether it occurred intraoperatively or is ongo-
ing postoperatively, should be replaced with crystalloid solu-
tion until a lowest limit of allowable hemoglobin is reached
(see later), at which point blood transfusion should begin.
Intraoperative fluid manipulation to decrease brain water
generally consists of osmotic diuresis with mannitol and/
or loop diuresis with furosemide. Use of either of these agents
can result in depletion of total body water in the postoper-
ative patient and potentially hypovolemia with resultant
hypotension. It then becomes necessary to replace body
water without worsening cerebral edema. In general, this
is done through the use of iso-osmolar fluid solutions, such
as normal saline, and 5% albumin.
The use of hyperosmolar saline solutions has been evalu-
ated during resuscitation. These solutions expand intra-
vascular volume with the benefit of a favorable osmotic
pressure gradient in the cerebral vasculature.52,53 However,
a potential disadvantage is the propensity to cause hyperna-
tremia with even modest amounts of volume.54 Thus, they
should be carefully titrated with frequent serum sodium
assessments.
Finally, colloids have long been used to increase intravas-
cular volume while attempting to avoid third-space loss.
These include both natural colloids (fractionated plasma
protein, albumin, and blood products) as well as synthetic
colloids (hetastarch). Although there is little evidence in
neurosurgical patients, the synthetic colloids are largely
avoided because of antiplatelet effects in vivo and concerns
about clinical bleeding.55,56 In general, fractionated plasma
protein colloids and albumin are chosen when there is con-
cern for excessive crystalloid use without indication for the
use of blood products.57,58
HYPONATREMIA, EDEMA, AND SEIZURES
Hyponatremia has been associated with delirium, cerebral
edema, and seizures. Usually, sodium levels below 120
mEq/L are required for hyponatremia alone to cause a
558 PART IV • Early Postoperative Care
significant decline in neurologic status. However, all cases of
hyponatremia merit attention and being evaluated for a
cause. The three major reasons for the development of
new-onset hyponatremia in the postoperative neurosurgical
patient are syndrome of inappropriate antidiuretic hormone
(SIADH), cerebral salt wasting, and inappropriate free water
administration.59
It is helpful to describe hyponatremia as it relates to intra-
vascular volume. SIADH most commonly falls in the
hypervolemic category, cerebral salt wasting in the hypovo-
lemic category, and dilutional in the euvolemic category.
An assessment of volume status should be made from
change in weight, the fluid balance record, or measurement
of ventricular filling pressure with central venous or pulmo-
nary capillary wedge pressure. It may also be helpful to
check the osmolarity of both serum and urine and to check
the urine sodium to make a distinction between the causes.
Both SIADH and cerebral salt wasting increase urine
sodium, differentiating them from dilutional causes. SIADH
is associated with a high (often very high) urine osmolarity,
while the urine osmolarity is typically normal in cerebral
salt wasting.
It is, of course, important to rule out other causes of hypo-
natremia (e.g., medication, renal failure, excess loss from
fever, diarrhea, or vomiting, or endocrine disorder such as
hypothyroidism or cortisol deficiency) because the treat-
ment is dictated by the cause. If free water is being given,
the practitioner should switch the intravenous fluid to an
iso-osmolar or a hyperosmolar salt solution, depending on
the degree of hyponatremia. SIADH is generally treated
by fluid restriction; however, this may be inappropriate in
the hemodynamically unstable patient. In this case, admin-
istration of hyperosmolar saline or the addition of extra
sodium to the patient’s diet may be more desirable. Cerebral
salt wasting is treated by replacing urine sodium lost with
normal or hypertonic saline. It is important to begin therapy
before reaching critically low serum sodium levels, as cor-
rection of hyponatremia should be performed gradually to
avoid the complication of central pontine myelinolysis.60
Usually, correction of 1 to 2 mEq/L/h is recommended, up
to 12 mEq/L/day.
ROUTINE FLUID MANAGEMENT
Unlike other tissues, which respond to both hydrostatic and
oncotic pressures, the brain’s water content is regulated
most by serum osmolarity, in large part because of the
blood–brain barrier.61 Therefore, to avoid the possibility of
producing or worsening cerebral edema, it is important to
avoid hypo-osmolarity in the serum. This is accomplished
by the administration of an isotonic intravenous fluid such
as normal saline or a balanced salt solution such as Normo-
sol. The use of colloid solutions is not recommended because
oncotic pressure is not as useful in regulating brain water.
Maintenance of euvolemia is imperative in the typical post-
operative neurosurgical patient because both hypovolemia
and hypervolemia may have detrimental side effects. Hypo-
volemia can lead to hypotension and, therefore, hypoperfu-
sion. Hypervolemia may increase intracranial pressure,
leading to hypertension or an edematous state. Finally,
dextrose-containing fluids are not recommended for routine
use because the presence of hyperglycemia has been shown
to worsen outcomes in cerebral injury and in general they
add to the amount of hypo-osmolar fluid administered.62
DIABETES INSIPIDUS (DI)
DI results from dysfunction of the pituitary gland through
primary causes or, more likely in the postoperative neuro-
surgical patient, from ischemia, tumor, or surgical manipu-
lation. It should be suspected when urine output is higher
than expected and serum sodium appears to be rising. DI
is the most common cause, behind iatrogenic causes, of
hypernatremia in the neurosurgical patient.63 The diagno-
sis is suggested by a large hypotonic urine volume in the
presence of hyperosmolar hypernatremia leading to a hypo-
volemic state. Treatment is aimed at replacing total body
water with hypo-osmolar salt solutions. This deficit should
be replaced over 24 hours at a rate no faster than 2 mEq/L/h
because too-rapid correction may result in seizures, delir-
ium, or cerebral edema, presumably from what the brain
perceives to be a hyponatremic state.64 Additionally, low
dosages of arginine vasopressin given by continuous infu-
sion are very effective in correcting both hypovolemia and
hyponatremia in patients with diabetes insipidus,65 brain-
injured patients,66 and children.67 Common protocols call
for administering 1 or 2 IU/L of arginine vasopressin in
hyponatremic fluid at hourly urine output rates plus 10%
to correct hypovolemia and hyponatremia gradually. Simi-
larly, a titratable infusion of 0.01–0.03 IU/h vasopressin
may be utilized while replacing urine output in a 1:1 ratio
with hyponatremic fluid.
Hematologic Support
ROLE OF ANEMIA IN CEREBRAL ISCHEMIA
Normovolemic anemia has been shown to increase cerebral
blood flow68 by increasing cardiac output and cerebral vaso-
dilation to ensure an adequate oxygen supply to the brain.
Decreased blood viscosity may also contribute to the increase
in cerebral blood flow.69 The compensatory increase cerebral
hemodynamics may be impaired by hypovolemia associated
with perioperative blood loss. However, if adequate intra-
vascular volume is maintained through the use of intrave-
nous crystalloids, even moderate anemia has little effect
on cerebral ischemia.70 In fact, it has not been shown that
even severe anemia (hemoglobin level <6 g/dL) can cause
long-term or permanent cerebral injury alone. Higher
hemoglobin levels may, in fact, be detrimental in some path-
ologic processes, as in subarachnoid hemorrhage–induced
vasospasm and diffuse axonal injury.29,71 It is also possible,
at least in theory, that normovolemic anemia may cause det-
rimental increases in cerebral blood flow in patients with
raised intracranial pressure, but this has not been studied.
Finally, only one human study has demonstrated adverse
effects of severe anemia (hemoglobin level <6 g/dL), consist-
ing of mild cognitive changes in healthy volunteers that
was readily reversible by increasing the amount of inspired
oxygen.72

The American Society of Anesthesiologists has published
guidelines for the administration of blood products, with
emphasis on patient-specific transfusion criteria in the set-
ting of prior blood transfusions, history of a known coagu-
lopathy or thrombotic event, and risk factors for organ
ischemia that might alter thresholds for transfusion. They
recommend first maintaining normovolemia by the use of
crystalloids and colloids; additionally, the application of
available pharmacologic therapies such as erythropoietin,
prothrombin complex concentrates, and antifibrinolytic
agents should be considered when appropriate to minimize
transfusions and their subsequent risks. Red blood cell
transfusions are recommended for hemoglobin levels
6–10 g/dL based upon an ongoing assessment of blood loss,
intravascular volume, end-organ perfusion imbalances,
and cardiac reserve. Fresh frozen plasma transfusions are
recommended for urgent reversal of anticoagulation,
known coagulation factor deficiencies (when specific con-
centrates are unavailable), microvascular bleeding in the
presence of an elevated prothrombin time (an interna-
tional normalized ratio [INR] >2, in the absence of hepa-
rin), and microvascular bleeding after the replacement of
more than one blood volume when PT or PTT cannot be
obtained. Platelet transfusions are recommended in surgi-
cal patients with platelet counts of less than 50,000/μL
or despite a theoretically adequate platelet count in the set-
ting of known of suspected platelet dysfunction; this might
be appropriate following cardiopulmonary bypass or when
undergoing surgery where minimal bleeding may cause
major damage, such as in neurosurgery.73 Aggressive cor-
rection of clotting abnormalities in actively bleeding
patients with fresh frozen plasma, platelets, and/or cryo-
precipitate, as indicated by clotting studies, seems good
clinical practice.
THROMBOPROPHYLAXIS
Deep venous thrombosis (DVT) has three classic antecedents:
venous injury, stasis, and hypercoagulability. The postopera-
tive neurosurgical patient is prone to many risk factors for
development of DVT, including trauma, immobilization,
tumors, acute stroke, estrogen use, obesity, age greater than
40 years, and acquired coagulopathy.74 Several mechanical
and chemical methods are used to prevent the development
of DVT. Pneumatic compression devices and compression
stockings have few contraindications and have proven effi-
cacy after a number of types of surgery, including neurosur-
gery.75 Additionally, mobility may be of benefit: for mobile
patients, an early ambulation strategy may be used and for
those in a nonambulatory state, passive motion exercise
may be utilized. Chemoprophylaxis with enoxaparin or
low-dose subcutaneous heparin have been proved valuable
in reducing the burden of thromboembolic events without
significant increases in bleeding occurrences; current meta-
analyses suggest that the benefits of chemoprophylaxis in
neurosurgical patients outweigh the risks.76 It is our practice
to use pneumatic compression devices with elastic compres-
sion stockings for every patient not on subcutaneous heparin.
Physical therapy and ambulation are encouraged in every
patient. Heparin is used in those patients with minimal risk
of intracranial hemorrhage formation.
37 • Neurosurgery 559
Gastrointestinal and Endocrine
Support
GLUCOSE AND CEREBRAL INJURY
Glucose is the main substrate of the brain and is actively
transported across the blood–brain barrier by a carrier-
mediated mechanism and by diffusional mechanisms that
can be affected by blood glucose levels. Hypoglycemia is
disadvantageous to ischemic brain, but hyperglycemia also
worsens cerebral ischemia and neuronal damage after
both head trauma and stroke.62,77 It is less clear how, or
at what level of hyperglycemia, global cerebral ischemia
becomes worse, and the data are even less clear when
applied to focal injury.78,79 It is thought that organic acid
accumulation in nonischemic areas may lead to cellular
injury.80 Another theory is that lactate production from
anaerobic metabolism in areas of ischemia worsens exist-
ing damage.81 Some data suggest that any amount of
hyperglycemia (serum glucose greater than 120 mg/dL)
may be detrimental.82 It is not clear whether maintenance
of normal glucose levels through insulin therapy improves
outcome, neurologic or otherwise. However, it is common
practice to keep serum glucose below 200 mg/dL in
patients with known, or at risk of, cerebral ischemia. It
is not uncommon to attempt to keep blood glucose in
the range of normal or less than 140 mg/dL, usually by
sliding-scale regular insulin injections or regular insulin
infusion protocols.
MANAGEMENT OF DIABETES MELLITUS
Patients with premorbid diabetes mellitus may have serum
glucose levels that are quite difficult to control. These
patients are very likely to benefit most from tight glycemic
control in the setting of cerebral ischemia, but studies sug-
gesting how to maintain the serum glucose, and to what
level, are scant. In our own practice, we routinely check
every patient’s serum glucose level every 6 hours after
admission for at least the first 24 hours, and patients are
placed in an insulin infusion nomogram after two consecu-
tive blood glucose readings greater than 200 mg/dL. It has
also become our practice to check glucose levels every
3 hours for the first 24 hours after admission or after begin-
ning feeding for patients who are thought to be at high risk
of glucose intolerance.
NUTRITION
Neuronal tissue undergoes very high rates of oxidative
metabolism with little or no stored energy, relying almost
solely on blood-delivered glucose. Glucose undergoes active
transport from the capillaries in areas with an intact blood–
brain barrier. Throughout the brain, glucose also enters
neuronal tissue through diffusion mechanisms. Areas of
the brain where the blood–brain barrier has been disrupted
(e.g., by ischemia) may be totally reliant on diffusion mech-
anisms for their glucose supply. It is critical that nutritional
demands be continually met in the critically ill. In the imme-
diate postoperative period, nearly all neurosurgical patients
560 PART IV • Early Postoperative Care
receive nothing by mouth until they have been fully
assessed and allowed to recover from the effects of anesthe-
sia and postsurgical changes. If they are then able to self-
feed, they are allowed a trial period, during which it is deter-
mined whether their nutritional demands can be adequately
met. If self-feeding is not feasible, nasogastric tube feedings
are initiated and a determination is made about the long-
term prognosis for adequate self-nutrition. If enteral nutri-
tion is not successful, (i.e., if there are persistent large resid-
ual volumes after feeding or continuing lack of bowel
sounds), parenteral nutrition via central venous catheters
should be considered.
POSTOPERATIVE NAUSEA AND VOMITING
It is common for neurosurgical patients, especially those
who underwent intracranial surgery, to have significant
nausea and vomiting. This may result from the effects of
anesthesia centrally or peripherally or from central effects
of the surgery itself. Nausea can be uncomfortable for the
patient and vomiting can be catastrophic in cases of crani-
otomy; the act of vomiting may lead to transient increases in
intracranial pressure and place the patient with potentially
already decreased airway reflexes at an increased risk of
aspiration. Nearly all antiemetics, including promethazine,
corticosteroids, droperidol, and serotonergic drugs (e.g.,
ondansetron), have some effect on postoperative nausea
and vomiting.83 Ondansetron has been shown to be partic-
ularly efficacious with respect to postoperative nausea
following craniotomy, if given as a prophylactic.84 Aprepi-
tant, a substance P antagonist, has also shown great effect
as a premedication in the neurosurgical population and may
be more efficacious than ondansetron when either drug is
combined with dexamethasone.85
Infectious Disease
INFECTIOUS RISKS OF NEURAXIAL DEVICES
Several neuraxial catheters may be encountered in the post-
operative neurosurgical patient, the most common of which
is placed via a ventriculostomy. The predominant concern of
any externalized neuraxial device is infection. Historically,
available literature has suggested that infection rates
rise quickly at approximately 1 week after placement86;
however, a recent meta-analysis has suggested that this
rate is lower than previously thought and may not be
associated with frequency of manipulation or duration of
catheter dwelling.87 In fact, according to Ramanan et al.,
studies prior to 2000 show a remarkably increased
ventriculostomy-associated infection rate; perhaps this
can be attributed to emphasis placed on infection prevention
modalities since that time. In the interim, a number of dif-
ferent strategies have been used to combat the ongoing con-
cern of infection associated with ventriculostomy, including
intrathecal antibiotic infusion, tunneling of the catheter,
and changing the catheter weekly.88 However, there are
limited data to suggest that any method actually improves
infection rates or patient morbidity or mortality, and each
approach has its disadvantages, including microbial resis-
tance and the risk of having to repeat the procedure.
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 38 Sepsis and Septic Shock
JAMES BURTON and MERVYN SINGER
Introduction
The Third International Consensus Definitions for Sepsis
and Septic Shock (Sepsis-3)1 recently defined sepsis as a
“life-threatening organ dysfunction caused by a dysregu-
lated host response to infection.” Sepsis is a medical
emergency with mortality rates of 18% to 29% in developed
countries2,3 and as high as 80% in low-income countries.3
In the United States alone there are reportedly 750,000
cases per year.4
History
The oldest reports of sepsis date back to 1600 BCE from a
papyrus discovered in Luxor, Egypt. This is probably a copy
of another dated 3000 BCE and is best described as a surgi-
cal treatise detailing 48 cases of traumatic lesions from
wounds, fractures, and dislocations exploring symptoms,
signs, follow-up, prognosis, and treatment.5 The actual term
“sepsis” is derived from the ancient Greek word “σηφις”
meaning decomposition of animal or vegetable matter. This
term was used in Homer’s Iliad to describe Hector’s body as it
lay in Achilles’ ship, “σηπω” (translates as “I rot”).5
The first theories of sepsis originate from Hippocrates
(460–370 BCE) who described the body humors: blood,
phlegm, yellow bile, and black bile. He theorized that distur-
bance of these humors resulted in disease, with blood and
yellow bile causing acute disease. This Hippocratic theory
remained the mainstay of sepsis understanding until the
19th century,6 despite Marcus Terentius Varro postulating
in 100 BCE the presence of “small creatures invisible to the
eye, fill the atmosphere, and breathed through the nose
cause dangerous disease.”7 Microorganisms were not recog-
nized until 1674 when Anthony van Leeuwenhoek built his
own compound microscope and made drawings of these
animalcules in the shape of “Spheres, Rods and Spirals”7
(Fig. 38.1). However, their role in disease was not identified
until 1897 when Louis Pasteur discovered streptococci in
the bloodstream of a patient with puerperal sepsis.7,8 Joseph
Lister (1827–1912) applied this concept of germ theory to
the use of carbolic acid on wounds, significantly reducing
rates of wound sepsis and death.
The concept that morbidity relates more to a dysregulated
host response than the infection itself was first described by
Lewis Thomas.9 In 1904, Sir William Osler noted: “Except
on few occasions, the patient appears to die from the body’s
response to infection rather than from it.”10
The first formal definition of sepsis was published by Roger
Bone and colleagues in 1992 to assist suitable patient enrol-
ment into drug trials.11 They considered sepsis to be a
combination of infection with two or more systemic
564
inflammatory response syndrome (SIRS) criteria; namely
temperature >38°C or <36°C, heart rate >90 bpm, respi-
ratory rate >20 bpm or PaCO2 <32 mmHg, and an abnor-
mal white blood count (>12 or <4  109/L or >10%
immature forms). “Severe sepsis” represented sepsis plus
organ dysfunction while “septic shock” was characterized
by severe sepsis plus hypotension or hypoperfusion. How-
ever, these authors did not provide formal clinical criteria
for dysfunction, hypotension, or hypoperfusion. A second
task force reporting in 2003 recognized the limitations
but lacked the evidence to recommend change.12 The
recent Sepsis-3 definitions,1 published in 2016, utilized
large hospital databases to identify hospitalized patients
with likely infection (850,000 episodes where cultures were
taken and antibiotics commenced) to characterize organ
dysfunction as a change in “Sequential [sepsis-related]
Organ Failure Assessment (SOFA) score” 2 related to an
episode of infection. Patients fulfilling these criteria carried
a 10% risk of hospital mortality. Septic shock is defined
as “underlying circulatory and cellular/metabolic abnor-
malities profound enough to substantially increase mortal-
ity.” It is characterized clinically by a requirement for
vasopressors to maintain a mean arterial pressure (MAP)
65 mmHg and hyperlactatemia (>2 mmol/L) despite ade-
quate volume resuscitation. This subgroup has an in-
hospital mortality greater than 40%. SIRS was dropped from
the sepsis criteria because it occurs in response to any
inflammatory insult and usually represents an appropriate
rather than pathologic response to infection.
Epidemiology
Sepsis remains a significant cause of mortality, morbidity,
and economic burden. Precise numbers are uncertain
because of prior inconsistencies in defining sepsis. Fleisch-
mann et al.13 recently suggested a global annual burden
of 31.5 million cases of sepsis with 5.3 million deaths.
Recent UK data identified sepsis as the cause of a quarter
of all ICU admissions and approximately 11,000 deaths
per annum14; mortality depended on the location of infec-
tion (e.g., 19.1% for genitourinary sepsis but 43% for respi-
ratory sepsis). Mortality increased with the number of organ
failures (18.5% for one to 69.9% for five affected organs).
Although various studies suggest an increasing incidence
but falling mortality,3,15 this probably relates in large
part to coding changes, reimbursement incentives, and
increased recognition.16 Nonetheless, mortality appears to
be improving, albeit at the same rate as other noninfective
critical illnesses.17 Unfortunately, long-term morbidity and
mortality remain high.18 The reported economic burden of
sepsis in the United States was $24.3 billion in 2007, costing
 38 • Sepsis and Septic Shock 565

Does this patient Rapid bedside assessment of possible

have Sepsis? organ dysfunction

Yes
Evidence of Organ Dysfunction:
qSOFA scoring:
1. RR 22 breaths / minute
2. Altered Mentation
3. Systolic BP 100 mmHg
Early treatment
qSOFA Score 30 day mortality
• Obtain blood cultures and other
microbiological specimens as appropriate 0 5.1%
• Measure lactate and reassess after 1 1.8%
treatment instituted
2 13.3%
• Give appropriate antibiotics and perform
source control 3 42.4%
• Fluid resuscitation to promptly restore
organ perfusion
• Add vasopressor if remains hypotensive
(MAP <60-65 mmHg) despite fluid
Renal Support:
• Up to 50% of septic patients develop an
acute kidney injury (AKI).
• AKI is defined as
® an increase in serum creatinine ≥
Cardiovascular Support: 26.5 mmol/L within 48 hours or
Maintain a Mean Arterial Pressure 60-65 ® an increase in serum creatinine ≥ 1.5
mmHg or higher if previously hypertensive fold from the baseline value in the
preceding 7 days, or
High cardiac output state?
® a urine volume <0.5 mL/kg/h for
- add vasopressor
(e.g. norepinephrine, vasopressin) more than 6 hours

Low cardiac output state? Indications for RRT include

- add agent with more inotropic activity ® Hyperkalemia resistant to medical
(e.g. epinephrine, dobutamine, management,
levosimendan) ® metabolic acidosis,
® fluid overload and
® uraemia

Respiratory Support:
• Supplemental Oxygen as required
• Escalation to Non-Invasive Ventilation
Rehabilitation:
• Mechanical Ventilation:
Early rehabilitation is now
® Keep Tidal Volumes 4-8 mL/Kg
recognized to both
® Minimise Airway Pressures to
prevent loss and
reduce risk of Barotrauma
encourage recovery of
® Consider use of Proning &
muscle bulk and strength
Paralyzing agents in severe ARDS
• Aim Neutral or Negative Fluid Balance
Psychological Impact:
Many survivors suffer
Nutrition: Glycemic Control from depression, delirium,
25-30 kCal/kg/day blood glucose levels should be hallucinations and post-
maintained below 10 mmol/L while traumatic stress disorder
Corticosteroids: avoiding hypoglycemia both during and after their
Meta-analyses have consistently shown hospital stay
that hydrocortisone as a bolus or
infusion does hasten shock reversal
Fig. 38.1 Flow diagram for the management of sepsis and septic shock. Starting with rapid recognition of the septic patient, early initiation of
appropriate antibiotics, and fluid resuscitation with supportive management.
566 PART IV • Early Postoperative Care
$50,000 per patient treated for sepsis. In the UK, the
average cost was £25,000 with an annual cost of £2.5
billion.3
In a comparison between the SOAP study conducted in
2002 and the ICON audit in 2012 a number of important
changes to the epidemiology of intensive care were identi-
fied over that 10-year period.19 Patients admitted to the
intensive care unit are now older (60.6  17.4 years in
SOAP 2002 vs 62.5  17.0 years in ICON 2012) and tend
to be sicker with an increased incidence of shock on admis-
sion (SAPS II Score [without age] 26.0  16.1 in SOAP vs
30.8  17.0 in ICON) but have an improved survival rate.
More patients admitted to intensive care have significant
comorbidities such as COPD (SOAP 10.8% vs ICON
15.3%) and were receiving chemotherapy (SOAP 0.8% vs
ICON 2.5%). Other important differences include a redu-
ced use of mechanical ventilation (SOAP 58.8% vs ICON
53.0%) suggesting a higher reliance on noninvasive
ventilation (NIV).
Sepsis is more common and serious in the elderly, but
other underlying patient risk factors include immunosup-
pression, which can be either endogenous (e.g., diabetes,
malignancy) or iatrogenic, related to corticosteroid, chemo-
therapy, or other immunosuppressive treatments. A prior
insult such as trauma or surgery can also predispose the
patient to secondary infection and sepsis. Apart from the
presence of various tubes (endotracheal, urethral) and
skin-breaching wounds, catheters and drains, a serious non-
infectious insult will also cause immunosuppression as will
the use of drugs such as sedatives, analgesics, and
catecholamines.20
Pathophysiology
INFLAMMATION
By definition, sepsis needs an infective source. The SOAP
study, conducted in multicountry intensive care units,
identified respiratory (68%) and abdominal (22%) as the
most frequent sites of infection. Laboratory identification
of an infecting microorganism was positive in 60% of cases;
30% had Staphylococcus aureus, 14% Pseudomonas species,
and 13% Escherichia coli.21
The infecting microorganisms contain pathogen-
associated molecular patterns (PAMPs), which are recog-
nized by the innate immune system. Examples include
Box 38.1 Procalcitonin.
Procalcitonin was discovered in 1975 as a precursor to Calcitonin. In
healthy people, it is produced almost solely by thyroid C cells after
transcription of the CALC-1 gene on chromosome 11. During these
healthy states, almost none of the protein is released into the sys-
temic circulation with very low levels only <0.05ng/mL. During
inflammation procalcitonin is synthesized via stimulation by lipo-
polysaccharides or inflammatory cytokines and expressed in more
cell types including white bloods cells, spleen, kidney, adipocytes,
pancreas, colon, and brain, all of which have mRNA expression in
hamsters.
From Vijayan A, Shilpa R, Vanimaya S, et al: Procalcitonin: A promising diagnostic marker for sepsis and antibiotic therapy. J Intensive Care 2017;5:51.
lipopolysaccharide (endotoxin) found exclusively in gram-
negative bacterial cell walls, lipoteichoic acid from gram-
positive bacteria, mannan from fungi, and single- or
double-stranded RNA from viruses.22,23 These are detected
by various extracellular and intracellular pattern recogni-
tion receptors (PRRs), of which toll-like receptors are the
best characterized.23 PRRs can also detect “self” molecules
originating from the host, which can also trigger a similar
host response. These molecules, termed damage-associated
molecular patterns (DAMPs) include heat shock proteins,
high mobility group (HMGB1) (Box 38.1), histones, mito-
chondria, and DNA.
Detection of PAMPs and/or DAMPs by PRRs activates
intracellular signal transduction pathways leading to an
inflammatory response. This usually involves activation of
NF-κB with increased production of proinflammatory cyto-
kines (such as TNF-α, IL-1, and IL-6) and multiple other
mediators including nitric oxide, eicosanoids, chemokines,
reactive species, and adhesion molecules.23 Some PPRs
assemble into intracellular molecular complexes on activa-
tion, forming inflammasomes that secrete potent proinflam-
matory cytokines such as IL-1β and IL-18. Inflammasomes
can trigger programmed cell death pathways via caspase-
mediated rupture of the plasma membrane (pyroptosis).
Anti-inflammatory mediators such as IL-10 are also
released simultaneously to control the degree of inflamma-
tion. Although proinflammatory mediators predominate
initially, they are subsequently superseded by anti-
inflammatory mediators to enable resolution of the inflam-
mation. For reasons still unknown, the normal checks and
balances controlling inflammation are overwhelmed, lead-
ing to the dysregulated host response that results in organ
dysfunction.
An important host defense mechanism is to prevent
spread of infection from the source. This is achieved by local
endothelial activation and formation of clots. Neutrophils
release extracellular traps (NETs) and platelets, endothelial
cells, and leukocytes release microparticles. The net result is
immunothrombosis whereby microbes are trapped within
thrombi, which then attract and further activate leukocytes
and prevent hematogenous spread.25 Consolidation within
the lung is also considered to be another means of prevent-
ing the spread of microorganisms beyond the affected
segments.
Although the inflammatory response is evolutionarily
conserved, systemic activation and injury can result in
Levels rise within 2–6 hours after infection and peak at 6–
24 hours. It also reduces to normal levels much faster than C-reactive
protein, giving a good indication of resolution. There are now
guidelines regarding which levels of procalcitonin correlate with
bacterial infection with levels <0.1 ng/mL being actively discour-
aged from using antibiotics to levels >0.25 ng/mL, which are
probably bacterial infections warranting antibiotic use.
Some studies have indicated that levels >2 ng/mL suggest the
patient is more likely to develop septic shock than those with levels
<0.5 ng/mL. Levels of PCT <0.1 ng/mL can be used to discontinue
antibiotics early.

dysfunction affecting organs distant from the site of infec-
tion.25 There is widespread activation of the endothelium
with increased production of vasoactive mediators—both
constricting and vasodilating—that result in marked het-
erogeneity of the microcirculation. Degradation of the gly-
cocalyx layer covering the endothelium, with shedding of
endothelial cells and loss of tight junctions between the cells,
results in increased capillary leak and the development of
tissue edema. Although some microregions may be hypoxic,
there is little visible cell death. Widespread immunothrom-
bosis can result in disseminated intravascular coagulation
(DIC); however, frank DIC is now rarely seen. Notwithstand-
ing a lack of widespread intravascular clots, there is an
increased prothrombotic milieu with marked thrombin
generation. Thrombin itself is a potent proinflammatory
stimulant.
CARDIOVASCULAR FUNCTION
The cardiovascular system is affected at all levels. The auto-
nomic nervous system is activated, with an imbalance
between sympathetic and parasympathetic limbs that usu-
ally results in tachycardia and an elevated cardiac output.
In sepsis there appears to be an uncoupling between cholin-
ergic signaling and the sinoatrial node, which may be
related to vagal activation producing an anti-inflammatory
response.26 Nevertheless, myocardial depression is com-
monplace with systolic and/or diastolic dysfunction being
frequently recognized. Multiple mechanisms are involved
in cardiac depression including down-regulation of
β-adrenergic receptors, decreased activity of post-receptor
signaling pathways, mitochondrial dysfunction, abnormal
actin–myosin cross-bridge formation, and perturbations of
intracellular calcium.23 Circulating cardiodepressants such
as TNF-α, IL-1β, and nitric oxide are contributory. Some
data also suggest a role for complement activation, IL-6
and TNF-α inhibiting myocardial fiber shortening, while
TNF-α also produces a dose-dependent reduction in left ven-
tricular ejection fraction.26 Sepsis-induced cardiomyopathy
has been associated with a reduced calcium current across
cardiomyocytes, reduced calcium sensitivity especially to
phospholamban and the ryanodine receptor, and reduced
density of L-type calcium channels, all of which can result
in reduced cardiac contractility.26 Nitric oxide (NO) is also
implicated with inducible NO synthase (iNOS) indirectly
inhibiting myocardial contractility. The interaction of NO
and superoxide radicals can exert inhibitory effects on the
mitochondrial respiratory chain and depress cardiac con-
tractility as a result.26 An increase in NO production with
low levels of the antioxidant glutathione is indicative of oxi-
dative and nitrosative stress. This has been associated with
reduced ATP levels in patients with septic shock. Reduced
cardiac contractility has been hypothesized to be akin to car-
diac hibernation, protecting cardiomyocytes from excessive
stress by limiting ATP production.27 Indeed, this could be
part of a wider cell hibernation and be responsible for mul-
tiple organ failure, particularly as histological evidence of
cell death is remarkably limited.
The vasculature is also affected by excess production of
mediators including eicosanoids, prostacyclins, and NO that
can either cause local vasoconstriction or vasodilation
38 • Sepsis and Septic Shock 567
(see later for microcirculatory heterogeneity). The net over-
all result is usually vasodilatation with loss of vascular tone
and often profound hyporeactivity to catecholamines.22
This, in combination with reduced cardiac contractility, is
responsible for the profound hypotension that can be seen
in septic shock. In such patients, normal compensatory
mechanisms have been overwhelmed despite high concen-
trations of circulating catecholamines and activation of the
renin–angiotensin system. The pathology generally lies
downstream, with decreased receptor density and impaired
signaling. Although vasopressin levels are elevated early in
the shock phase, a relative deficiency of vasopressin ensues.
Other hormones have also been associated with the reduc-
tion in vascular tone seen in septic shock including adreno-
medullin, which has both pleiotropic vasodilating and
cardiac depressant effects.28
The microcirculation is also abnormal in septic shock
with increased heterogeneity, potentially creating patho-
logic shunts.29 However, even though microregions of
hypoxia may exist within tissues during sepsis, there is min-
imal evidence of cell death in affected organs, even at post-
mortem examination. The direct contribution of the
abnormal microcirculation towards the causation of organ
dysfunction remains moot. Arguably, as discussed later, the
increased heterogeneity may be a response to decreased cel-
lular utilization of oxygen, perhaps protecting these “dor-
mant” cells from oxygen toxicity by decreasing local
oxygen supply. Although the degree of microcirculatory
abnormality and failure to improve after resuscitation are
associated with poor outcomes,30,31 no intervention specif-
ically targeting the microcirculation has yet shown out-
come benefit.
IMMUNOACTIVATION AND PARESIS
Despite the initial widespread activation of immune cells
and an exaggerated inflammatory response to sepsis,
immune cells taken from septic patients are hyporeactive
when stimulated ex vivo. Various mechanisms are postu-
lated, such as metabolic reprogramming. There is also a
depletion in the number of both T and B lymphocytes, with
often decreased levels of immunoglobulins, related to both
decreased production and increased destruction through
apoptosis. Neutrophils, on the other hand, undergo delayed
apoptosis. The resulting immune anergy places the critically
ill patient at increased risk of secondary or superimposed
infection.
Apart from autonomic effects on the circulation, cyto-
kines within the systemic circulation can access the
constitutively permeable areas of the carotid body chemore-
ceptors, vagal afferents, and certain cerebral regions. Vagal
cholinergic efferents are activated and these signal to the
innate immune system in the spleen and gut to inhibit
inflammatory cytokine production.
HORMONAL AND METABOLIC CHANGES
The initial inflammatory insult generates a stress hormonal
response with increased production of catecholamines, cor-
tisol, and glucagon. This response stimulates lipolysis and fat
utilization at the expense of glucose, with insulin resistance
568 PART IV • Early Postoperative Care
and hyperglycemia. These stress hormones are catabolic,
decreasing turnover of muscle protein yet increasing release
of muscle amino acids and lactate into the circulation to be
utilized by other organs as energy substrates. Although
hyperlactatemia may be related in part to poor tissue perfu-
sion and tissue oxygen insufficiency (anaerobic respiration),
increased aerobic respiration related to catecholamine-
driven acceleration of glycolysis is likely to be more relevant
when the rate of carbohydrate metabolism from gluconeo-
genesis and glycolysis exceeds the oxidative capacity of the
mitochondria.32 Pyruvate is produced from glucose faster
than it can be converted into acetyl CoA by pyruvate dehy-
drogenase (PDH). Pyruvate also accumulates through
increased protein catabolism with metabolism of amino
acids to pyruvate. With increased levels of pyruvate in the
cytosol, lactate dehydrogenase (LDH) converts it to lactate,
recycling NADH to NAD+. Adrenergic mediators activate β
receptors on the cell membrane, which increases cyclic
AMP in the cytosol. This, in turn, stimulates gluconeogen-
esis and glycolysis with subsequent activation of the Na+/K+
ATPase pump. This further activates glycolysis and produc-
tion of lactate.32 Muscle appears to a major producer of lac-
tate in septic shock.
Circulating levels of many other hormones also change in
sepsis, mainly to subnormal ranges during established sep-
sis. This includes thyroid and sex hormones, vasopressin,
and gut hormones. Downstream effects at receptor and
post-receptor levels for most of these hormones are poorly
described, other than for adrenergic vascular hyporespon-
siveness and insulin resistance.
The initial increase in total body oxygen consumption
and metabolic rate in response to infection is subsequently
followed by a decrease toward resting healthy baseline levels
during the established phase of sepsis and organ dysfunc-
tion, followed by a 60% increase in oxygen consumption
during the recovery phase.33,34 Although most of the body’s
oxygen utilization is directed toward “coupled” respiration
with aerobic production of ATP by mitochondria, a greater
proportion may possibly be diverted towards heat produc-
tion (“uncoupled” respiration).
ORGAN DYSFUNCTION
The findings in metabolic rate during the septic process
mentioned previously, in conjunction with the minimal
levels of cell death in most organs affected by sepsis35 imply
a functional shutdown rather than structural damage as an
underlying cause of organ dysfunction. While changes in
metabolism may be directly affected by hormonal changes
occurring in sepsis, such as the low T3 (triiodothyronine)
syndrome, there may also be direct negative feedback from
a reduced production of ATP by mitochondria. Multiple fac-
tors are recognized in sepsis including tissue hypoxia, partic-
ularly before resuscitation; excess production of NO, NO
metabolites such as peroxynitrite, and other reactive species
that can overwhelm antioxidant defenses and directly
inhibit and/or damage the electron transport chain and
other mitochondrial structures; transcriptional changes
with decreased expression of genes encoding mitochondrial
proteins resulting in decreased mitochondrial biogenesis;
the impact of hormonal and metabolic alterations;
alterations in substrate utilization, and increased uncou-
pling.36 The net result is a decrease in ATP turnover with
less energy substrate available for utilization by normal cel-
lular processes. Continued cell functioning would deplete
ATP levels and trigger cell death pathways with the result
that a reduction in metabolic rate, targeting pathways that
are not essential for cell survival, will potentially balance out
the reduced levels of ATP production. This will result in
maintained cell integrity and the potential to recover. How-
ever, the normal physiological and biochemical roles of the
cell cannot be fulfilled, which manifests clinically as organ
dysfunction or failure.37 Of note, many of the treatments
routinely used in sepsis such as antibiotics, catecholamines,
and sedatives can impact upon mitochondrial functionality
and biogenesis; as a result there may be an unwitting iatro-
genic contribution to delayed restoration of cell function
and organ recovery.
Mitochondrial dysfunction, microvascular and epithelial
abnormalities, and local inflammatory mediators are all
thought to contribute to the organ dysfunction witnessed
in sepsis. Altered renal and hepatic metabolism can affect
metabolism and excretion of drugs and this may further
contribute to organ dysfunction. Every organ system can
be affected, including the nervous system with both central
(encephalopathy) and peripheral (motor and/or sensory
neuropathy) manifestations; muscle dysfunction with loss
of muscle bulk and power; gut dysfunction with ileus or
diarrhea and decreased gut hormone activity (e.g., gastrin,
ghrelin); liver and renal dysfunction with decreases in syn-
thetic capability, metabolism, and excretory function. The
hematopoietic system is also affected with decreased pro-
duction of circulating cell constituents and increased con-
sumption of platelets and clotting factors.
Clinical Features
Sepsis can present in protean ways. There may be clinical
features pointing to the likely source of infection such as dys-
pnea, hypoxemia, and productive cough for a respiratory
source, or peritonism for abdominal sepsis. However, not
infrequently, and especially in the early stages, there may
not be a clear pointer to the site of infection. The septic
patient may present nonspecifically unwell with evidence
of organ dysfunction. The infected patient will often present
with two or more SIRS criteria such as pyrexia, tachycardia,
and neutrophilia, as described earlier, but this is not a pre-
requisite. One in eight patients in Australasian ICUs with
infection-related organ failure did not have the requisite
two or more SIRS criteria on admission.38 The converse is
often true: 20% to 40% of patients initially diagnosed and
admitted to ICUs as “septic” subsequently turn out to have
a noninfective critical illness.39,40
Various bedside scores such as NEWS (National Early
Warning Score), which uses seven criteria, and qSOFA
(Box 38.2), which uses three criteria, identify clinical
markers of unwellness such as abnormal levels of blood pres-
sure, respiratory rate, and conscious level.41 A high score
indicates those patients at increased risk of doing badly;
however, this should not be relied upon as a “rule-out.”
There is no perfect screening tool at present that offers both

Box 38.2 Quick sequential organ failure
assessment score (qSOFA).
qSOFA scoring
1. RR 22 breaths/min
2. Altered mentation
1. Systolic BP 100 mmHg
qSOFA score 30-day mortality
0 5.1%
1 1.8%
2 13.3%
3 42.4%
high specificity and sensitivity for detecting the septic
patient at risk of poor outcome.
LABORATORY FEATURES
There are no specific early diagnostics for sepsis. Laboratory
confirmation of infection is found in approximately 60% of
cases with blood culture positivity rates ranging between
15% and 30%. Newer molecular diagnostics for infection
will identify microorganisms far sooner than traditional cul-
ture techniques, but issues surrounding cost, over-
sensitivity, and false positive results resulting from sample
contamination need to be overcome.
Biomarkers such as neutrophilia and neutropenia, C-
reactive protein, and procalcitonin (Box 38.1) are all non-
specific for infection. Although useful in supporting a clini-
cal suspicion of infection, these biomarkers can both give
false negatives (especially if the patient cannot mount a host
response) and false positives (related to other noninfectious
inflammatory insults). Multiple efforts are being made to
find superior biomarkers of the host response to infection
for both “rule in” and “rule out,” including transcriptional
changes, various circulating mediators (or combinations
thereof), and proteomic and metabolomic analyses. None
has yet become established commercially.
Management
Sepsis and septic shock are medical emergencies and are still
associated with significant mortality and morbidity. Conse-
quently, prompt treatment is warranted with early, ade-
quate but not excessive resuscitation, plus administration
of appropriate antibiotics and early source control.
Multiple management challenges and questions remain.
For example, ongoing debate surrounds what constitutes
adequate but not excessive resuscitation, what optimal
blood pressure should be targeted for an individual patient,
and the true impact of early antibiotics.
ANTIBIOTICS AND INFECTION CONTROL
Intravenous antibiotics are recommended by international
guidelines to be given within 1 hour of admission to hospital
and identification of sepsis, immediately after blood cultures
and other relevant microbiological samples have been
38 • Sepsis and Septic Shock 569
taken. It is claimed that each hour’s delay in giving antibi-
otics is associated with significant increases in mortality and
worse outcomes.42–44 However, this particular dogma is
based on retrospective analyses, usually with complex sta-
tistical adjustments of preexisting databases, and often with-
out confirmation of infection or knowledge of antibiotic
sensitivity patterns. All prospective studies to date, includ-
ing a recent large randomized study investigating the utility
of pre-hospital antibiotics, have failed to show such an asso-
ciation.45,46 Although the absolute importance of each
hour’s delay can be challenged, especially if “time zero”
when infection or sepsis commences is unknown, it is
nonetheless rational to give antibiotics without
considerable delay.
Depending on local resistance patterns, it may be prudent
to commence empiric broad spectrum antibiotics that are
likely to be effective until the organism and its antimicrobial
sensitivities are identified, with subsequent switch and/or
de-escalation to a narrow-spectrum antibiotic. An empiric
antifungal and/or antiviral agent may be needed based on
risk factors (e.g., in a neutropenic patient following chemo-
therapy).47 The evidence base for combination therapy,
using two or more antibiotics aimed at the same organisms,
is currently inconclusive and may even be harmful.48,49
Similarly, while using an initial appropriate antibiotic also
appears rational, the evidence base for survival benefit is
also conflicting.43,44,50,51 Other outstanding questions that
remain unanswered are the optimal means of administering
antibiotics (e.g., intermittent bolus vs continuous infu-
sion52) not just to achieve therapeutic plasma levels but also
to improve outcomes, and the optimal course duration both
to ensure adequate microbial eradication and yet to avoid
the downsides of excessive antibiotic use such as develop-
ment of resistance, or fungal and Clostridium difficile over-
growth. Although a 7–10-day course is currently
recommended, the evidence base for this is surprisingly
weak and shorter courses appear adequate for many
conditions.40
The one area of infection management for which there is
clear consensus is the imperative for early and adequate
source control. This is particularly pertinent in the postop-
erative patient who may suffer, for example, from anasto-
motic leaks or wound infections with abscess formation or
necrotizing fasciitis. If suspected, appropriate investigations
and imaging should be conducted promptly followed by
urgent drainage or debridement.
CIRCULATORY SUPPORT
In terms of a specific early resuscitation regimen, the
previously endorsed Early Goal-Directed Therapy (EGDT)
strategy proposed by Rivers et al.53 was recently shown
not to offer any benefit over standard-of-care in three
separate multicenter studies (ARISE, ProCESS, and
ProMISe).54,55,56 EGDT comprised fluid resuscitation
 dobutamine  blood transfusion targeting a central
venous pressure of 8 to 12 cm H2O, a mean arterial pressure
65 mmHg, and a central venous oxygen saturation
70%. More recent guidelines47 suggest targeting a mean
blood pressure 65 mmHg using at least 30 mL/kg of intra-
venous crystalloid within the first 3 hours of admission.
570 PART IV • Early Postoperative Care
More fluid may be given as required or vasopressors if the
patient is unresponsive to fluid. However, the optimal
means of assessing volume resuscitation remains uncertain.
While dynamic assessment (e.g., monitoring the response to
a fluid challenge or a straight-leg raise) is superior to a static
measurement, this gauges fluid responsiveness but not
whether this is necessarily benefiting organ perfusion.
Nonetheless, failure to respond positively to a dynamic chal-
lenge does suggest that further fluid loading is probably
inadvisable. Various measures are used to assess fluid
responsiveness including changes in stroke volume, blood
pressure, pulse pressure variation, or stroke volume varia-
tion. All have limitations and potential methodological pit-
falls, although stroke volume monitoring is likely to be the
most accurate.
A higher MAP may be needed, particularly if the patient is
chronically hypertensive. Persisting hyperlactatemia may
be indicative of continuing tissue hypoperfusion. Although
such patients who remain hyperlactatemic are more likely
to fare badly, there is no strong evidence that normalizing
lactate as a primary therapeutic target offers outcome
benefit.47
The currently recommended first-line vasopressor for fluid-
resistant hypotension is norepinephrine (Box 38.3), with
vasopressin recommended as a second-line vasopressor.57
Epinephrine was, however, equally effective compared with
norepinephrine  dobutamine in two multicenter studies
assessing outcomes in shock patients.58,59 Dopamine has,
however, been shown to be inferior to norepinephrine.60
Although a post hoc analysis of the VASST trial61 suggested
superiority of vasopressin over norepinephrine in patients
requiring low-dose vasopressors, the recent VANISH study
found no outcome difference but did note a reduction in
the need for renal replacement therapy.62
For inotropic support, where there is significant myocar-
dial depression with a low cardiac output, options include
dobutamine,47 levosimendan, or milrinone. Although these
are pharmacologically appropriate, none has been shown in
multicenter studies to provide outcome benefit (e.g., LeoP-
ARDS study63). They can all cause tachyarrhythmias and
excessive vasodilatation and should therefore be used with
caution.
RESPIRATORY SUPPORT
Patients with sepsis frequently develop respiratory failure.
This may be directly related to an underlying pneu-
monic process (the lung being the commonest focus of
sepsis21), or to an acute respiratory distress syndrome
(ARDS) resulting from a distant source. In this syndrome
Box 38.3 Vasopressors in septic shock.
1st Line: Noradrenaline up to 1.0 μg/kg/min
2nd Line: Vasopressin up to 0.03 units/minute
3rd Line: If evidence of cardiac dysfunction dobutamine starting at
2.5 μg/kg/min up to 20 μg/kg/min infusion.
Consider hydrocortisone 200 mg/day in four divided doses in
vasopressor-dependent patients and in those where shock
occurred <12 hours.
there is excessive neutrophil accumulation and fibrin
deposition within the lung, epithelial and endothelial dis-
ruption, loss of surfactant with alveolar collapse, and a
marked increase in lung extravascular fluid manifests radio-
logically as a noncardiogenic pulmonary edema. The patient
may also be tachypneic from a metabolic acidosis related
to hyperlactatemia and/or renal failure, or from heart fail-
ure and diaphragmatic fatigue secondary to myocardial
depression.
Management is supportive with supplementary inspired
oxygen and either noninvasive or invasive respiratory sup-
port. After initial fluid resuscitation, a strict neutral or even
negative fluid balance should be adhered to (with furose-
mide as needed) because this has provided outcome bene-
fit.64 Hyperoxia should also be avoided as this can result
in direct damage to the lung and other organs through
excess generation of reactive oxygen species. A recent study
showed survival benefit when pulse oximetry oxyhemoglo-
bin saturation was targeted at 94%–98% rather than being
maintained above 97%.65 Fewer episodes of shock, liver fail-
ure, and bacteremia were also recorded.
Provision of respiratory support targets hypoxemic
and/or hypercapnic respiratory failure. This may be achie-
ved through the use of noninvasive techniques such as high
flow nasal oxygen, CPAP, or BiPAP, or invasive ventilation
with limitations of tidal volume (4–8 mL/kg ideal body
weight66) and airway pressures to reduce the risk of lung
barotrauma. For severe ARDS, other strategies such as
proning67 and use of paralyzing agents67 should be consid-
ered. No specific ventilator mode has been demonstrated to
be superior and strategies such as recruitment and high
PEEP have been recently reported to be harmful.68 Occa-
sionally, the respiratory failure may be so severe that extra-
corporeal membrane oxygenation (ECMO) support is
warranted. Clear evidence of outcome benefit for this strat-
egy, which carries a significant complication rate, is how-
ever lacking.
RENAL SUPPORT
Up to 50% of septic patients develop an acute kidney injury
(AKI). AKI is defined as an increase in serum creatinine
26.5 μmol/L within 48 hours or 1.5-fold from the base-
line value in the preceding 7 days, or a urine volume
<0.5 mL/kg/h for more than 6 hours.69 Risk factors for
developing AKI during sepsis include age, heart failure, liver
failure, chronic kidney disease, anemia, and nephrotoxic
agents including contrast dyes and antibiotics.70 The stages
of AKI are based on the RIFLE criteria (risk, injury, failure,
loss, end-stage renal failure).69
All patients should have an arterial line.
All patients will need a central venous catheter.
Targets of perfusion: mean arterial pressure (MAP) greater than or
equal to 65 mmHg or greater than or equal to 75 mmHg in
chronic hypertensive patients, urine output of greater than or
equal to 0.5 mL/kg/h and to normalize lactate in those with high
initial lactate.

Both in vivo and postmortem studies in patients with
sepsis-induced AKI reveal bland histologic changes with
focal areas of tubular injury but minimal cell death and min-
imal inflammatory infiltrate.70 These findings are out of
keeping with the profound functional abnormality seen
with the more severe forms of AKI. The main workload of
the kidney involves reabsorption of approximately 97% of
glomerular filtrate through the sodium pump. Sepsis-
induced AKI is often associated initially with hypotension
and hypovolemia, but these are not prerequisites. Even
post-resuscitation oxygen consumption falls; this is probably
a result of both mitochondrial dysfunction and microvascu-
lar shunting with reductions in glomerular blood flow. This
implies that AKI represents a functional shutdown that may
offer protection and the capacity to recover. The kidney itself
is poorly regenerative yet survivors of sepsis-induced AKI
rarely require renal replacement therapy providing the kid-
neys were normal pre-insult.
Management of AKI involves optimizing volemic status,
blood flow and perfusion pressure, discontinuing nephro-
toxic agents, minimizing high venous and intra-abdominal
pressures, and providing mechanical support (renal replace-
ment therapy [RRT]) as needed. Indications for RRT include
hyperkalemia resistant to medical management, metabolic
acidosis, fluid overload. and uremia.69 Continuous RRT
rather than intermittent dialysis is now generally used
because this offers more hemodynamic stability and allows
more gradual correction of fluid, electrolyte, and metabolite
abnormality. Outcome studies do not support either the
institution of early RRT for sepsis-induced AKI,71 nor the
use of high-volume filtration.72
NUTRITION
Critically ill patients are catabolic and lose significant
amounts of muscle bulk, which results in weakness, debil-
ity, and delayed recovery. However, other than for patients
with underlying malnutrition, there is no strong evidence
that early feeding provides outcome benefit. Several recent
multicenter trials73 found no outcome difference between
patients randomized to early enteral or parenteral
nutrition. Guidelines suggest parenteral nutrition can be
delayed until 5 to 7 days after admission if the patient is
not able to tolerate enteral feed and provided they are
not very malnourished.74 Hyperalimentation with provi-
sion of high calorie loads has been shown to be detrimen-
tal.75 At present, 25 to 30 kCal/kg/day is a recommended
nonprotein calorie target, although there is little hard evi-
dence to support this amount. There is also ongoing debate
regarding how much protein should be provided; some
authorities contend that high protein loads are beneficial
whereas others argue that this delays autophagy and slows
organ recovery. Multiple studies of different immunonutri-
ents, including glutamine, polyunsaturated fatty acids,
and L-arginine, have shown either no outcome benefit or
even detriment.
Other Organ Support and Therapeutic Strategies
Multiple other strategies have been tested in septic patients.
These will be briefly covered here but suffice it to say that no
new therapeutic has been successfully introduced in the last
38 • Sepsis and Septic Shock 571
two decades on the basis of positive multicenter, randomized
controlled trial data.
1. Immunomodulation. Despite promise in preclinical and
small-scale clinical studies, multiple antiendotoxin, anticyto-
kine (e.g., anti-TNF: tumor necrosis factor; IL-1ra:
interleukin-1 receptor antagonist) and other anti-
inflammatory strategies (including corticosteroids) have all
failed to show outcome benefit. A flawed understanding of
pathophysiologic mechanisms, inadvisable extrapolation of
early administration effects in animal models to use later (up
to several days) in patients, and a naive assumption that
“one size fits all” with respect to dose, timing, and duration
are probably responsible in large part for these repeated failures.
Advances in diagnostics reveal marked heterogeneity in the
patient’s biologic phenotype. Some patients reveal a more
pronounced hyperinflammatory response whereas others
may show significant immunosuppression, even at an early
stage of their critical illness. Administering an identical therapy
may be thus advantageous to some patients, but detrimental or
ineffective in others. Many discarded therapies may have been
advantageous to selected patient subsets; hopefully some of
these may be revisited in the light of greater understanding
and improved diagnostic capabilities. This would also include
the use of immunonutrients carefully targeted toward the
patient’s inflammatory/immune milieu. An increasing interest
is also being paid to immune-stimulatory approaches to boost
immune function in selected patients (e.g., with anti-PD1 [pro-
grammed cell death protein 1], IL-7 [interleukin-7], or GM-CSF
[granulocyte macrophage-colony stimulating factor].
A related approach involves removal of circulating
inflammatory mediators by extracorporeal techniques such
as plasma exchange (where filter membrane pore size is
approximately 2–3 times that of conventional renal replace-
ment therapy filters, thus enabling removal of larger mole-
cules, including those bound to albumin), or hemadsorption
onto bioactive membranes such as polymyxin, or onto poly-
mer beads. The threshold immunomodulation hypothesis
suggests that there is an equilibrium between the tissue
compartment and the blood compartment with cytokines
and that removal of these cytokines causes reduced concen-
trations at the tissue level.76
2. Hormonal Manipulation. Recognition that hormonal
imbalances are commonplace in sepsis has led to many
studies where hormones are either replaced or given at
supraphysiologic doses. Unfortunately, such studies have
generally proved ineffective or even harmful. For example,
administration of growth hormone led to a relative risk of
death of 2.4 (95% CI 1.6–3.5) versus placebo and, for those
who survived, growth hormone treatment resulted in lon-
ger length of stays in hospital and duration of mechanical
ventilation.77 In a trial of acute renal failure, patients with
the sick euthyroid syndrome, administration of thyroxine
produced a sustained reduction in thyroid-stimulating hor-
mone but was associated with a mortality of 43% versus
13% in placebo.78
Multiple trials have examined the role of corticosteroids.
Initially, high doses of methylprednisolone were investi-
gated but in recent years the focus has been on more
physiologic replacement dosing, usually with hydro-
cortisone  the mineralocorticoid fludrocortisone, because
572 PART IV • Early Postoperative Care
adrenal insufficiency is commonplace in sepsis. Although
vasopressor requirements are significantly reduced with
corticosteroids, most trials do not demonstrate any sur-
vival benefit.79 Post hoc analysis suggests the sicker cohort
of shock patients (as judged by norepinephrine dose) are
more likely to benefit. Meta-analyses have consistently
shown that hydrocortisone as a bolus or infusion does has-
ten shock reversal80 but there have been concerns about
secondary infection.79 Despite this lack of strong evidence,
corticosteroids are still used in up to 50% of ICU patients
admitted with sepsis.81
The stress response to critical illness releases high levels of
counterregulatory hormones that antagonize the effects of
insulin. In addition, downregulation of glucose transporters
and increased lipolysis (with a greater reliance on fat as an
energy substrate) all contribute further to insulin resistance.
The resulting hyperglycemia, exacerbated by early feeding,
is injurious to cells. The concept of tight glycemic control in
ICU patients improving outcomes82 could not be replicated
in large multicenter studies83; however, there is a general
acceptance that blood glucose levels should be maintained
below 10 mmol/L while avoiding hypoglycemia as shown
in the NICE-SUGAR trial 2009.83 This study also reported
a direct correlation between hypoglycemia and mortality
with severe hypoglycemia having an adjusted hazard ratio
for death of 2.10.84 Higher target ranges may, however, be
more beneficial in patients with poor control of their
diabetes.85
As mentioned earlier, vasopressin or analogues such as
terlipressin have been used successfully for septic shock with
outcome results equivalent to norepinephrine. A recombi-
nant angiotensin II preparation was recently shown to
spare norepinephrine dosing in septic shock and raise blood
pressure by at least 10 mmHg, or above 75 mmHg in 69.9%
of patients in vasodilatory shock.86
There has also been interest in beta blockade to overcome
the deleterious effects of excess catecholamines affecting
immune function, inducing a prothrombotic state, enhanc-
ing bacterial growth and virulence, and inducing myocardial
damage, muscle catabolism, and metabolic inefficiency. A
single-center randomized study of esmolol in septic shock
patients87 showed survival benefit and faster recovery of
myocardial, vascular, and renal function with reduced need
for vasopressors and fluid requirements. Similarly, vitamin D
(actually a hormone, not a vitamin) supplementation was
shown to give outcome benefit in a subset of septic patients
with severe vitamin D deficiency.88 Multicenter trials of beta
blockade and vitamin D are ongoing to see whether these
findings can be replicated.
Other Organ Supports
General supportive care is crucial for these critically ill
patients. This includes skin care and regular repositioning
to prevent pressure sores and thromboprophylaxis.
Although proton pump inhibitors and other gastric pro-
tectants have become a mainstay of clinical practice over
the last 2 decades, their utility is now being questioned in
new multicenter studies. First, significant upper gastro-
intestinal bleeding is far less common than in previous
years, mainly related to better overall care. Second, side
effects such as C. difficile overgrowth, nosocomial pneu-
monia, and effects on immune and mitochondrial function
suggest the benefit:risk ratio may be much more shifted
toward harm although many studies have had contradic-
tory results.89,90
The utility of other long-standing interventions such as
gastric motility agents is also being questioned.91 Motility
agents such as metoclopramide and erythromycin are both
associated with a number of side effects including QT
prolongation and tachyphylaxis.92 High gastric residual
volumes do not correlate with complications of gastrointes-
tinal feeding intolerance such as aspiration and pneumonia;
as such it is not recommended to stop enteral feeding with
volumes of <500 mL without other signs of feeding
intolerance.92
Early rehabilitation is now recognized both to prevent loss
and to encourage recovery of muscle bulk and strength.
Patients should be appropriately stressed but not allowed
to be overexercised and fatigued. Reductions in sedation
use have enabled patients to be awake earlier, move onto
spontaneous breathing modes, and start exercising sooner
with outcome benefits.93 These benefits also apply to cogni-
tive function.
The psychological impact of critical illness cannot be
underestimated. Many survivors suffer from depression,
delirium, hallucinations, and post-traumatic stress disorder
both during and after their hospital stay. Delirium is defined
as being a sudden and severe confusion with rapid changes
in brain function that occur with physical or mental ill-
ness.94 There are four domains described: disturbance of
consciousness, change in cognition, development over a
short period of time, and fluctuation over time. Patients
may have either hyperactive delirium with agitation and
confusion or hypoactive delirium where they appear out-
wardly withdrawn. Nonpharmacologic treatments for delir-
ium include repeated reorientation of the patient, noise
reduction, cognitive stimulation, use of vision and hearing
aids, music, adequate hydration, and early mobilization.
Pharmacological treatments include the use of low-dose
haloperidol or low-dose risperidone, avoidance of benzodiaz-
epines, and use of alpha-2 agonists such as clonidine or dex-
medetomidine. Sedative and analgesic use should be
minimized and titrated using regular scoring (e.g., RASS:
Richmond Agitation Sedation Scale) to ensure patient com-
fort, an appropriate level of awareness, but not excessive
sedation. This is a more appropriate strategy than daily
sedation holds.95
Cognitive decline, fatigue, weakness and neuropathy may
be long-lasting and severe.96,97 There is an increasing focus
on enhancing post-ICU recovery, which should begin while
the patient is in the ICU.
Future Directions
Clinical trials in sepsis and septic shock have been severely
hindered by the previous doctrine of “one size fits all” and
poor characterization of patient populations. The increasing
awareness of different groups of biologic phenotypes suggest
that management should be personalized to the individual
patient and titrated over time. Excess harmful levels of cir-
culating mediators and hormones should be attenuated.
However, this should not be overzealous, thereby removing
possible protective effects. Likewise, where immune function

or hormonal hypoactivity may be usefully boosted in some
patients, this should be titrated to protective but safe levels.
This requires rapid, ideally point-of-care, diagnostics to iden-
tify accurately the presence of infection and those patients
with impending sepsis in advance of obvious clinical deteri-
oration. Machine-learning algorithms may also be useful in
this regard.98 Theranostic biomarkers would also be needed
to identify suitable patients for a specific intervention and to
optimize dose titration and duration.
Modulation of metabolism and bioenergetics may prove
clinically useful but, again, timing is key. If the postulate
that organ failure represents a potentially adaptive meta-
bolic shutdown does indeed hold true, then metabolism
should not be reactivated prematurely. On the other hand,
reactivation at the right time may greatly facilitate rehabil-
itation of the critically ill patient by accelerating physical
and psychological recovery.
Continued work also needs to be undertaken into the ben-
efit:harm ratio of many of our current interventions. The
major outcome advances in critical care have been related
to less iatrogenicity, be it improved fluid balance, less baro-
trauma, less caloric intake, less sedation, and so forth. Opti-
mizing antibiotic use and ensuring good source control are
major questions that need addressing.
Finally, a holistic approach needs to be increasingly
adopted towards septic, critically ill patients. They currently
undergo severe physiologic, pharmacologic, and psycholog-
ical stress, which will impact not only how they cope with
the illness but also how they manage recovery.
Conclusions
Sepsis and septic shock remain common causes of mortality
and morbidity and continue to complicate surgical proce-
dures. Over the last few decades few interventions have
made a significant impact on mortality except for the timely
identification and administration of appropriate resuscita-
tion and infection control and avoidance of iatrogenic harm.
A personalized medicine approach is likely to yield improved
results for the varied therapeutic strategies being consid-
ered. A better understanding of the underlying mechanisms,
including a greater appreciation of adaptive and maladap-
tive changes, will also focus efforts on strategies that are
more likely to succeed. This is all the more pertinent when
it is recognized that sepsis and septic shock are umbrella
syndromes covering a wide array of different biologic
phenotypes based on the host characteristics, the invading
microorganism, and site of invasion, and that these change
over time.
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 39 Acute Respiratory Failure
CHARLOTTE SUMMERS, ROB S. TODD*, GARY A. VERCRUYSSE*, and
FREDERICK A. MOORE*
Definition
Respiratory failure occurs when the lungs fail to oxygenate
the arterial blood adequately and/or fail to prevent carbon
dioxide retention. Although the definition does not contain
any absolute values, an arterial O2 of less than 60 mmHg
and an arterial CO2 of more than 50 mmHg are often
regarded as of consequence. However, values should be con-
sidered in the context of an individual patient.
Hypoxemic Respiratory Failure
There are four main causes of hypoxemic respiratory failure:
1. Hypoventilation
2. Diffusion impairment
3. Shunt
4. Ventilation-perfusion (V/Q) mismatch
Of these, V/Q mismatch is the most frequently encoun-
tered.1,2 Most of these abnormalities improve with supple-
mental oxygenation, except for a shunt. A “true shunt”
develops when portions of the lung are perfused in total
absence of ventilation. The most frequent causes of a shunt
in the postoperative patient are consolidated pneumonia,
lobar atelectasis, and the later phases of the acute respira-
tory distress syndrome (ARDS).3,4 Other causes of hypox-
emic respiratory failure in the postoperative population
include pulmonary edema, chronic obstructive pulmonary
disease (COPD), pneumothorax, pulmonary embolism, and
pulmonary hypertension.3
Hypercapnic Respiratory Failure
The four basic mechanisms underlying hypercapnic respira-
tory failure are:
1. Inability to sense increasing arterial CO2
(hypoventilation)
2. Increased CO2 production
3. Increased dead space
4. Decreased tidal volume
The common causes of each in the postoperative patient
are listed in Box 39.1.2,3,5
*Inactive on 5e.
576
Acute Respiratory Failure in the
Perioperative Patient
Identification of risk factors for postoperative acute respira-
tory failure is helpful in that it identifies those patients who
may benefit from preoperative optimization and increased
postoperative vigilance. Many studies have been under-
taken to identify predictors of postoperative acute respira-
tory failure and other pulmonary complications. Nijbroek
et al. reviewed 21 different studies attempting to derive pre-
dictive scores and concluded that only the ARISCAT score
was adequately externally validated.6
The Assess Respiratory Risk in Surgical Patients in Cata-
lonia (ARISCAT) investigators conducted a prospective mul-
ticenter observational random-sample cohort study of 2464
patients undergoing non-obstetric procedures under gen-
eral, neuroaxial or regional anesthesia in southern Spain.7
The overall incidence of postoperative pulmonary complica-
tions (PPCs) was 5% and 30-day mortality was increased in
those who developed PPCs compared with those who did
not (19.5 versus 0.5%). Seven factors were found to be inde-
pendently predictive of the development of PPCs: low preop-
erative arterial oxygen saturations when breathing room air
and lying supine, acute respiratory infection associated with
a fever and the need for antibiotic therapy during the pre-
ceding month, age, preoperative anemia, upper abdominal
or intrathoracic surgery, a surgical duration longer than
two hours, and emergency surgery. The derived ARISCAT
score was able to classify patients as low (score <26), inter-
mediate (score 2–44) or high (score >45) risk for PPCs.
Although obesity and asthma did not emerge as indepen-
dent predictors, other studies have shown that preexisting
comorbidities are important contributors.8,9 However, their
importance may be lessened by preoperative optimization.
Subsequent investigators have validated the ARISCAT
score for predicting the risk of developing PPCs, including
a recent study of 1170 patients undergoing noncardiac sur-
gery, which showed that patients with intermediate and
high risk based on ARISCAT were found to have increased
risk of PPCs.10
Some factors can be optimized prior to undertaking
elective surgical procedures. Warner and coworkers docu-
mented that smoking cessation 8 weeks prior to elective
surgery led to a decreased incidence of postoperative acute
respiratory failure.11 Systematic review of the impact of
preoperative smoking interventions by the Cochrane
collaboration found that there was heterogeneity between
intensive and brief behavioral interventions, with signifi-
cant impact of intensive intervention on PPCs and wound
complications.12

Box 39.1 Common causes of type II respiratory
failure in postoperative patients.
Inability to Sense an Increasing PaCO2
▪ Anesthetic agents
▪ Benzodiazepines
▪ Narcotics
Increased CO2 Production
▪ Hypermetabolic states
▪ Fever
▪ Sepsis
▪ Multiple organ failure
▪ Burns
▪ Trauma
▪ Excessive carbohydrate intake
▪ Hyperthyroidism
Decreased Tidal Ventilation (VT)
▪ Post-traumatic flail chest
Increased Dead Space Ventilation (VD)
▪ Adult respiratory distress syndrome (ARDS)
There are also data suggesting that the manner in which
both emergency and elective surgical patients are mechan-
ically ventilated during surgery can be associated with the
development of PPCs. Several studies have shown that for
patients receiving tidal volumes less than 8 mL/kg IBW
(ideal body weight), increased driving pressure or peak
inspiratory pressure are associated with increased develop-
ment of PPCs.13,14 These findings have also been repro-
duced in an individual patient meta-analysis of data from
2250 patients from 17 clinical trials.15
The association between intraoperative tidal volume and
PPCs is less straightforward, but a meta-analysis of 2127
patients from 15 studies suggested that low tidal volume
ventilation is associated with a decreased incidence of PPCs,
but has no impact on mortality of length of hospital stay.16
However, this finding was not reproduced in more recent
clinical studies.13,14
POSTOPERATIVE FACTORS
After surgery, all patients are at risk of acute respiratory fail-
ure. Some of the more common etiologies are atelectasis,
bronchospasm, pulmonary aspiration, anesthetic effects,
pulmonary edema, pulmonary embolism, and ARDS.
ATELECTASIS
The term atelectasis is derived from the Greek words ateles
and ektasis, which mean incomplete expansion. Atelectasis
is defined as alveolar collapse with reduced intrapulmonary
air. It is the most common PPC, with radiographic evidence
in up to 70% of patients undergoing a thoracotomy or a
celiotomy.17 If left untreated, it can result in pulmonary
gas exchange alterations leading to severe hypoxemia and
acute respiratory failure. The mechanisms leading to atelec-
tasis are multifactorial and include alterations in ventilatory
39 • Acute Respiratory Failure 577
mechanics, changes in the mechanical properties of the tho-
racic wall, stagnation of bronchial secretions, and airway
obstruction.1
The alterations in ventilatory mechanics seen postopera-
tively include diminished vital capacity (VC), diminished VT,
increased respiratory rate, and diminished functional resid-
ual capacity (FRC), resulting in atelectasis. The primary
cause of these alterations is postoperative diaphragmatic
dysfunction.1,18 Stagnation of bronchial secretions is also
a mechanism leading to atelectasis. This problem is nor-
mally prevented by mucociliary clearance and coughing.
When these functions are inhibited, stagnation of bronchial
secretions occurs, and atelectasis can develop.1
Mucociliary clearance is significantly diminished during
mechanical ventilation.9 Coughing may be suppressed
secondary to mechanical ventilation, opioids, diaphrag-
matic dysfunction, pain, altered mental status, and air-
way obstruction. A final mechanism of atelectasis is
airway obstruction. In this case, atelectasis is either pas-
sive or absorptive. Passive atelectasis is secondary to
external or internal compression of a lung segment
(e.g., pneumothorax, hemothorax, abdominal distention).
Absorptive atelectasis occurs when the inhaled gas is rich
in oxygen and poor in nitrogen. In this instance, oxygen
diffuses rapidly into venous blood, leading to alveolar
collapse.9
Risk factors for atelectasis are shown in Box 39.2.1 The
type of surgical procedure performed has tremendous influ-
ence on the occurrence of postoperative atelectasis. Tho-
racic and upper abdominal surgeries pose a greater risk
for atelectasis than do other procedures. Several studies
have documented progressive deterioration of pulmonary
gas exchange during the course of thoracic and abdominal
surgeries.19,20 Likewise, cardiopulmonary bypass surgery
increases the risk of atelectasis more than other surgeries
(including noncardiac thoracic surgeries).21–23 In addition,
midline celiotomies have an increased risk of atelectasis rel-
ative to transverse or subcostal abdominal incisions.
Clinical Manifestations
Clinically, atelectasis ranges from asymptomatic to severe
hypoxemia and acute respiratory failure. The variability
in presentation depends on the rapidity of onset, the degree
of lung involvement, and the presence of an underlying pul-
monary infection. In the worst-case scenario with rapid
Box 39.2 Risk factors for atelectasis.
▪ Very young age (infants and young children)
▪ Obesity
▪ Smoking
▪ Preexisting pulmonary disease
▪ Dehydration
▪ Anesthetic agents
▪ Mechanical ventilation
▪ Types of surgery
▪ Cardiopulmonary bypass surgery
▪ Thoracic surgery
▪ Upper abdominal surgery
▪ Midline incisions
▪ Prolonged anesthesia
578 PART IV • Early Postoperative Care

onset, major airway collapse, and underlying infection, atel- Treatment

ectasis presents with sudden dyspnea, chest pain, cyanosis,
tachycardia, and an elevated temperature. On physical
examination, the patient often exhibits diminished chest
wall excursion, dullness to percussion, and diminished or
absent breath sounds. In the less severe presentations, ele-
vated temperature on the first postoperative day may be
the only manifestation of atelectasis.24
Diagnosis
The diagnosis of atelectasis is generally made from radio-
graphic findings of diminished lung volumes in the presence
of the aforementioned clinical manifestations. On chest
radiographs, findings indicative of atelectasis relate to vol-
ume loss and include displacement of the lobar fissure,
retracted ribs, an elevated hemidiaphragm, mediastinal or
tracheal deviation to the affected side, and over-inflation
of the unaffected lung. The exact radiographic findings
depend on which portion of the lung is involved and to what
degree, in addition to how the surrounding structures
compensate for the volume loss. On arterial blood gas
(ABG) analysis, significant atelectasis results in hypoxemia.
Atelectasis also may be identified by means of chest
computed tomography (CT) or lung ultrasound.1,24,25
For postoperative atelectasis, prevention is the key.26
Because tobacco use and underlying pulmonary disease pro-
cesses are predictors of postoperative atelectasis, preopera-
tive optimization is essential. Both smoking cessation and
improved bronchial toilet preoperatively should be encour-
aged. During anesthesia induction, the use of positive end-
expiratory pressure (PEEP) has been shown to be beneficial.
Rusca and coworkers documented significantly decreased
atelectasis and improved oxygenation by applying 6 cm
H2O of positive end expiratory pressure (PEEP) on induc-
tion.27 In addition to this, long-acting anesthetics and those
with significant post-anesthesia narcosis should be limited.1
During the postoperative period, a number of measures
can be taken to prevent atelectasis (Fig. 39.1). Control of
postoperative pain is critical. Insufficient analgesia results
in pleural and parietal pain, causing inadequate coughing
and expectoration. However, because narcotics depress
the cough reflex, excessive doses should be avoided.1,24,25
The traditional intermittent dosing of narcotics at 3- to
4-hour intervals is insufficient. The patient cycles from over-
dosing after administration (over-sedation with resultant
poor coughing and expectoration) to pain and anxiety
before receiving the next dose. This cyclical pattern may

• Adequate analgesia (i.e., patient-

controlled analgesia, epidural)
POSTOPERATIVE
• Elevated head of bed Intubated
SURGERY PATIENT
• Out of bed
• Humidified O2

Yes No
PREVENTATIVE

• IS, deep breathing exercises,

• Kinetic bed
and coughing
• Optimize PEEP
• Early ambulation

• Intermittent Chest physiotherapy • Bronchodilators for Chest physiotherapy IPPB if IS fails

deep breaths for lobar collapse wheezing for lobar collapse
• CPAP • Tracheobronchial/
Endotracheal
aspiration to enhance
coughing Consider intubation
• Mucolytics and postural FFB if lobar collapse
FFB if lobar collapse
drainage for thick persists
persists secretions
THERAPEUTIC

If progresses to acute
respiratory failure, go to
the Intubated arm

Fig. 39.1 Prevention and treatment algorithm for postoperative atelectasis. CPAP, Continuous positive airway pressure; FFB, flexible fiberoptic
bronchoscopy; IPPB, intermittent positive-pressure breathing; IS, incentive spirometry; PEEP, positive end-expiratory pressure.
 39 • Acute Respiratory Failure 579

be avoided by using patient-controlled analgesia (PCA).
Another alternative is neuroaxial or regional analgesia,
which is very effective. A meta-analysis supports the view
that postoperative atelectasis is decreased when patients
receive epidural opioids instead of systemic opioids.28
Just as pain control is critical, so is meticulous nursing
care. In non-intubated patients, several steps should be
taken to prevent atelectasis. Early ambulation and tech-
niques that encourage deep breathing are important.29–31
Incentive spirometry (IS) is the most widely used postop-
erative pulmonary therapy. Its purpose is to imitate the nat-
ural sighing or yawning that healthy individuals perform
regularly. The simplicity of IS and its lack of required person-
nel account for its popularity. A meta-analysis suggests that
IS, intermittent positive-pressure breathing (IPPB), and
chest physiotherapy are all equally efficacious in decreasing
PPCs after upper abdominal surgery.32 Chest physiotherapy
encompasses deep breathing and coughing, postural drain-
age, and chest percussion.
Continuous positive airway pressure (CPAP) can be used
as a last means in attempting to prevent intubation. In a
randomized controlled trial, Squadrone and colleagues
documented that CPAP decreases the incidence of PPCs
(including endotracheal intubation) in patients who develop
hypoxia after major elective abdominal surgery.33 If these
maneuvers are unsuccessful and the patient continues to
progress to acute respiratory failure, the patient should be
intubated and consideration given to whether a flexible
fiberoptic bronchoscopy may be of benefit.
ASPIRATION
Pulmonary aspiration of gastric contents is generally pre-
ventable with meticulous anesthesia technique and critical
care. Despite this, the incidence varies from 1 in every 3900
elective surgical cases to 1 in every 895 emergent surgical
cases. The number increases dramatically to 8% to 19%
during emergent intubations without anesthesia.1
Aspiration of gastric contents results in chemical pneumo-
nitis, which develops in four stages.1 Initially, the aspirate
causes mechanical obstruction of the airways, with distal col-
lapse. Obstruction alters ventilatory mechanics, leading to
increased shunt, loss of FRC, and increased work of breath-
ing. In the second stage, chemical injury occurs in response
to the acidity of the aspirate. The pattern of injury includes
mucosal edema, bronchorrhea, and bronchoconstriction,
all resulting in an increased risk of bacterial infection. The
third stage in the pathophysiology of aspiration is the inflam-
matory response. The release of tumor necrosis factor, inter-
leukin 1, leukotrienes, and thromboxane A2 contribute to
mucosal edema and bronchoconstriction resulting in lung
inflammation. The final phase is progression to infection if
appropriate interventions are not performed. Risk factors
for pulmonary aspiration are shown in Table 39.1.34–36
Clinical Manifestations
Hypoxemia is the most consistent finding in aspiration. In
addition, patients present with increased temperature,
tachypnea, tachycardia or bradycardia, cyanosis, and
altered mental status. On physical examination, the pulmo-
nary findings include crackles, rales, and decreased breath
sounds. The extent of these manifestations depends on the
degree of aspiration.1,24
Table 39.1 Risk factors for pulmonary aspiration.
Risk factor Clarification / Examples
Endotracheal intubation The cuff does not prevent
aspiration.
Decreased level of consciousness GCS<9, alcohol or drug
overdose/withdrawal,
excessive analgesics or
sedatives, chemical paralysis
Neuromuscular disease and Diabetic gastroparesis,
structural abnormalities of the Parkinson’s disease,
aerodigestive tract scleroderma,
gastroesophageal reflux
disease, esophageal cancer
Recent cerebrovascular accident Within 4–6 weeks
Major intra-abdominal surgery Less than 5 days postoperatively
Persistently high gastric residual GRV >500 mL
volume (GRV)
Prolonger supine positioning Spinal fractures
Persistent hyperglycemia Blood glucose >140 mg/dL
Modified from Metheny NA. Risk factors for aspiration. JPEN J Parenter Enteral
Nutr 2002;26(Suppl 6):S26-S31.
The outcome varies widely from asymptomatic to rapid
death.1 Fortunately, many patients improve rapidly within
several days without further treatment. A second subset of
patients improves initially and then deteriorates over the fol-
lowing 2 to 5 days. These patients develop increased tem-
perature, productive cough, and hypoxemia and progress
from aspiration pneumonitis to aspiration pneumonia.
The remaining patients do not improve from their initial
pneumonitis and progress to diffuse pulmonary infiltrates,
refractory hypoxemia, and ARDS.
Diagnosis
After a witnessed pulmonary aspiration, the diagnosis is
clear. However, in other situations, the diagnosis of aspira-
tion is based on the clinical symptoms and a high index of
suspicion. On laboratory evaluation, significant aspiration
results in hypoxemia and leukocytosis. Aspiration may also
be identified by means of chest radiography. There are no
pathognomonic radiologic features; however, infiltrates in
gravity-dependent lung regions are the most consistent find-
ing. The most common sites of infiltration are the superior
segment of the right lower lobe and the right middle lobe.
However, depending on the aspirate volume and the
patient’s position during aspiration, left and bi-lobar aspira-
tion is possible. Flexible fiberoptic bronchoscopy may also be
used for diagnosing aspiration.1,24
Treatment
As in atelectasis, prevention is the key. During the preoper-
ative assessment by the anesthesiologist, patients at risk of
aspiration need to be identified (Fig. 39.2). These include
patients requiring emergency procedures, patients with dia-
betes mellitus, and pregnant patients. In these instances, an
experienced anesthesiologist is required. If feasible, regional
anesthesia should be entertained. The American Society of
Anesthesiology have produced guidelines on the duration of
preoperative fasting required under various circumstances
(Table 39.2).37
580 PART IV • Early Postoperative Care

HIGH-RISK • Meticulous nursing care PREVENTIVE

PULMONARY • Elevated head of bed
ASPIRATION • Monitoring of feeding tubes
PATIENT • Jejunal enteral nutrition

• Humidified O2
• Discontinue tube Consider intubation if the patient continues THERAPEUTIC
feedings to deteriorate
• Airway suctioning

Particulate matter

Yes No

Bronchoscopy and lavage Aggressive pulmonary care

Ongoing clinical assessment

Secondary pneumonia Worsening/refractory ARDS

BAL and appropriate Treat according to ARDS clinical

antibiotic coverage management guidelines

Fig. 39.2 Prevention and treatment algorithm for pulmonary aspiration. ARDS, Acute respiratory distress syndrome; BAL, bronchoalveolar lavage.

Table 39.2 Preoperative fasting recommendations of hygiene. Nasogastric and orogastric tubes should be moni-
American Society of Anesthesiologists. tored closely because they may become displaced during the
Ingested material Minimum fasting period course of hospitalization.
Gastric feeding is a major risk factor for pulmonary aspi-
Clear liquids (water, fruit juices 2 hours ration and there appears to be no difference in risk between
without pulp, carbonated
drinks, tea and coffee without nasogastric/orogastric tubes and small-bore feeding
milk tubes.38 To avoid this problem, many clinicians advocate
postpyloric feeding. However, randomized controlled trials
Breast milk 4 hours
comparing gastric with postpyloric feeding have produced
Infant formula 6 hours conflicting results,39–45 possibly because most postpyloric
Non-human milk 6 hours feeding tubes are too short to go beyond the ligament of
Treitz. When the tube is too short, enteral nutrition is
Light meal, e.g., toast and clear 6 hours
fluids
administered into the duodenum and there is a high inci-
dence of duodenogastric reflux in patients at risk for aspira-
Fried foods, fatty foods or meat Additional fasting time (e.g. 8 or tion.40 Heyland and coworkers documented an 80% rate of
more hours) may be needed
reflux into the stomach, 25% into the esophagus, and 4%
Adapted from Practice guidelines for preoperative fasting and the use of into the lung when radioisotope-labeled enteral formulas
pharmacologic agents to reduce the risk of pulmonary aspiration: were fed through postpyloric feeding tubes in mechanically
application to healthy patients undergoing elective procedures: an ventilated patients in the intensive care unit.43 In post-
updated report by the American Society of Anesthesiologists Task Force on operative patients, Tournadre and colleagues demonstrated
preoperative fasting and the use of pharmacologic agents to reduce the
risk of pulmonary aspiration. Anesthesiology 2017;127:376-393.
gastroparesis and rapid uncoordinated duodenal contrac-
tions.46 These studies provide compelling evidence that duo-
After the surgical procedure, meticulous nursing care is denogastric reflux is present in postoperative and critically
required.1 The head of the bed should be elevated to 30 ill patients. Thus, with regard to aspiration risk, feeding into
degrees at a minimum; elevation to 45 degrees is better. the duodenum is not significantly different from feeding into
In addition, particular attention should be paid to oral the stomach in these patients. In addition to these findings,

there appears to be no difference in the rate of pulmonary
aspiration between patients with nasogastric feeding tubes
and percutaneous endoscopic gastrostomy (PEG) tubes.47
Once the diagnosis of aspiration is entertained, the resul-
tant hypoxemia should be addressed. Supplemental oxy-
gen via a nasal cannula or a face mask should be
administered until the diagnosis is confirmed. In severe
cases, patients may require intubation and positive-
pressure mechanical ventilation. If tube feeding is ongoing,
it should be discontinued. Suctioning should be performed
to clear the upper airway of any residual aspirate. The role
of bronchoscopy is limited to the retrieval of large particu-
late matter. The acidic aspirate is neutralized by pulmo-
nary secretions within minutes of aspiration, therefore
bronchoscopy and saline lavage are not required for the
aspiration of nonparticulate matter. The use of empiric
antibiotic coverage is not supported by current literature;
however, if a subsequent aspiration pneumonia is identi-
fied, antibiotic coverage should be tailored according to
the microbiological findings. Not only are empiric antibi-
otics not indicated in aspiration but they often select for
resistant organisms.1
PULMONARY EMBOLISM
In 1856, Virchow described a triad of conditions associ-
ated with the development of venous thromboembolism
(VTE): vessel intimal injury, venous stasis, and hypercoa-
gulability.48 Today, VTE remains a significant source of
morbidity and mortality after surgical procedures. The
most common and clinically significant forms of VTE
are deep vein thrombosis (DVT) and pulmonary embolism
(PE).49 PE is the most common preventable source of hos-
pital mortality.50
Venous thromboembolic disorders vary in incidence
depending on the type of surgical procedure being per-
formed; the highest rates are reported in urologic and ortho-
pedic procedures.51 Studies prior to 1984 documented a
15%–30% rate of DVT and a 0.2%–0.9% rate of fatal PE
among general surgical patients not treated with VTE pro-
phylaxis.52–54 The current risk of DVT and PE in general
surgical procedures is unknown because trials devoid of pro-
phylaxis are no longer ethical. The combination of individ-
ual predisposing factors and the specific type of surgery
determine the risk of DVT and PE in surgical patients. Risk
factors are shown in Box 39.3.55–60
Clinical Manifestations
The clinical manifestations of pulmonary embolism are highly
variable. The majority of emboli are asymptomatic. In those
that are symptomatic, the most common complaint is dys-
pnea, which is sudden in onset. Additional findings include
rales, pleuritic chest pain, and hemoptysis. Patients with mas-
sive pulmonary emboli often present with chest discomfort in
addition to anxiety and a sense of impending doom. In the
most severe form, massive embolic events involve complete
circulatory collapse, characterized by shock and/or syncope.10
The physical examination is often unremarkable, the most
common findings being tachypnea and tachycardia. Jugular
vein distention, a parasternal heave, a pulsatile liver, and a
loud S2 on cardiac can also be present.
39 • Acute Respiratory Failure 581
Box 39.3 Risk factors for venous thromboem-
bolism in general surgical patients.
Patient-Related Factors
▪ Genetic predisposition
▪ Increasing age
▪ Cancer
▪ Previous venous thromboembolism
▪ Obesity
▪ Smoking
▪ Varicose veins
▪ Estrogen-containing oral contraception or hormone
replacement therapy
▪ Pregnancy
Type of Anesthesia
▪ General anesthesia
Postoperative Care
▪ Immobilization
▪ Central venous catheterization
▪ Fluid resuscitation
▪ Transfusion
Diagnosis
A high index of suspicion is critical for diagnosing a PE.
A detailed history should be obtained specifically inquiring
about a history of VTE, preexisting medical conditions, and
other risk factors. On blood gas analysis, most patients are
hypoxemic. On the electrocardiogram (ECG), the most com-
mon finding is sinus tachycardia. Other common abnormal-
ities are anterior precordial T wave inversion, S1Q3T3 and
precordial ST segment elevation.61 The chest radiograph is
generally non-diagnostic; however, a wedge-shaped infiltrate
(Hampton’s hump) should heighten suspicion of a PE. Addi-
tional findings can include a prominent pulmonary artery
with decreased peripheral pulmonary vasculature (Wester-
mark’s sign).61
Measuring circulating D-dimer levels as an aid in diagnos-
ing DVT and PE has been recommended, but the role of this
test remains uncertain in this setting. The main problem
with this test is that D-dimer levels are elevated in multiple
medical conditions, including routine recovery from opera-
tions. As such, the specificity and positive likelihood ratios
are of little clinical value in diagnosing DVT or PE. Despite
these limitations, if the D-dimer is not elevated, the patient
does not have a PE.
More definitive diagnostic tools for PE include ventilation-
perfusion (V/Q) scans and CT pulmonary angiography. The
Prospective Investigation of Pulmonary Embolism Diagnosis
(PIOPED) study reviewed V/Q scanning as a diagnostic
modality for PE.62 Seventy-five percent of V/Q scans are
in the indeterminate category. Thus, V/Q scanning alone
is insufficient to either confirm or exclude the diagnosis of
PE. The D-dimer test and Doppler ultrasound may be useful
adjuncts in this situation.63,64
Since the 1990s, CT scans have become a routine means
of diagnosing PE. Advantages of the CT scan include its
582 PART IV • Early Postoperative Care
rapidity, widespread availability, and non-invasiveness. In
2005, Hayashino and colleagues performed a meta-analysis
of the diagnostic performance of helical CT scanning in com-
parison to V/Q scanning in suspected PE.65 On the basis of a
summary receiver operating characteristic (ROC) analysis,
they determined that when the V/Q scan is normal or
near-normal, the CT scan is superior in the diagnosis of
PE. However, in situations of high probability, the V/Q scan
is equivalent to CT scan for diagnosing PE.
Prophylaxis
Because of the inherent risk of DVT and PE in postoperative
patients, numerous modalities have been developed for pro-
phylaxis. Prophylactic measures are categorized by mecha-
nism of action as pharmacologic or mechanical. The most
commonly used pharmacologic measure is low molecular
weight heparin (LMWH).66 In the past, low-dose unfractio-
nated heparin was the pharmacologic standard of care for
VTE prevention; however, a number of disadvantages have
made it unattractive as a prophylactic agent. These include,
but are not limited to, nonspecific binding, low bioavailabil-
ity, anticoagulant and dose-response variability, resistance,
and heparin-induced thrombocytopenia (HIT). LMWH
overcomes the majority of these limitations with the excep-
tion of HIT.67
Mechanical measures include thromboembolism-
deterrent stockings (TEDS) and intermittent pneumatic
compression (IPC) devices, such as venous foot pumps
(VFP) and sequential compression devices (SCD). In
1986, the National Institutes of Health Consensus Devel-
opment Conference on the Prevention of Venous Throm-
bosis and Pulmonary Embolism endorsed IPC devices as
an effective prophylactic measure68 and the American
Society of Hematology 2019 guidelines for Management
of Venous Thromboembolism: Prevention of venous
thromboembolism in surgical hospitalized patients clinical
guidelines69 recommended IPC devices over no prophylaxis
rather than TEDS. In addition to the efficacy of IPCs, there
are few associated complications. Only isolated case reports
of pressure necrosis, peroneal nerve palsy, and compart-
ment syndrome have been documented.70,71 Mechanical
measures should be considered in patients with a high
bleeding potential. In addition, they should be considered
in combination with chemical prophylaxis to improve effi-
cacy in high-risk patients.69
The mechanism of action of intermittent pneumatic com-
pression devices is twofold. The first is mechanical: the
devices increase the velocity of venous return and decrease
venous stasis. The second mechanism is the systemic activa-
tion of the fibrinolytic system. Compression results in the
release of plasminogen activators, which are found in high
concentrations in the vaso vasorum.
In multiple trauma patients, when neither chemical nor
standard mechanical prophylaxis approaches are an option,
placement of an inferior vena cava (IVC) filter may be
considered.
Routine use of VTE prophylaxis is recommended for at-
risk surgical patients and the measures recommended vary
depending on the nature of the surgical procedure and the
bleeding versus thrombosis risk of individual patients.69
Treatment
Once the diagnosis of PE is seriously entertained, the treat-
ment is supportive. Treatment includes the administration
of oxygen, fluid resuscitation, and full anticoagulation.
For medical patients, rapid anticoagulation before the defin-
itive diagnosis is acceptable. However, this treatment strat-
egy should be avoided in the surgical population, where the
diagnostic uncertainty and bleeding potential are greater.
Quinlan and coworkers performed a meta-analysis of ran-
domized controlled trials comparing LMWH with intrave-
nous unfractionated heparin in the treatment of PE.72
This meta-analysis revealed that fixed-dose LMWH is as
effective and safe as intravenous unfractionated heparin
for the treatment of sub-massive PE. In this study, the rate
of bleeding, recurrent VTE, and mortality were not signifi-
cantly different between the two treatment arms. Other
modalities of PE treatment include thrombolytic therapy
and IVC filters and specialist opinions should be sought if
considered.
ACUTE RESPIRATORY DISTRESS SYNDROME
Acute respiratory distress syndrome is characterized by the
presence of refractory hypoxemic respiratory failure in the
presence of bilateral pulmonary infiltrates on chest radiogra-
phy. The diagnostic criteria were updated in the 2012 Berlin
criteria and it is now sub-classified into mild, moderate,
and severe depending on the degree of oxygenation deficit.73
Acute respiratory distress syndrome occurs in a bi-modal
distribution in the postoperative period, with early cases
occurring within 72 hours of the surgical procedure.
Surgical procedures, such as pulmonary thromboendarter-
ectomy, where pulmonary ischemia-reperfusion injury
occurs are associated with the development of ARDS within
72 hours of the procedure. Similarly, procedures that involve
the use of cardiopulmonary bypass, where the bypass circuit
can induces a systemic inflammatory cascade, are also asso-
ciated with an increased risk of ARDS in the early postoper-
ative period.74
A second peak of acute respiratory distress syndrome in
the postoperative patient occurs somewhat later and is a
well-recognized postoperative pulmonary complication.
Only two-thirds of ARDS occurring after esophagectomy
surgery are within the first 72 hours.75 Interestingly, it
has been observed that patients undergoing Ivor Lewis eso-
phagectomy are more vulnerable to the development of
ARDS between 1 and 10 days after the procedures than
patients undergoing major pulmonary resection.76 The
reported rates of pneumonia are also lower after major pul-
monary resection than after Ivor Lewis esophagectomy. In
this study, the intra-surgical blood loss, duration of one-lung
ventilation, and the release of circulating biomarkers did not
seem to explain the different rates of postoperative ARDS.
The authors postulate that the site of the esophageal anas-
tomosis and the risk of anastomotic leak may be causative
factors, but this requires further study.
There is no licensed pharmacotherapy for ARDS
anywhere in the world, despite several decades of clinical
trials. The gold standard clinical management is supportive
 39 • Acute Respiratory Failure 583

care with lung protective ventilation77 and conservative use
of intravenous fluids,78 and does not significantly differ for
the postoperative patient compared with ARDS from other
etiologies.
Principles of Management
The most common clinical presentation of all types of acute
respiratory failure is acute hypoxia.79 Early identification
and appropriate management are critical in limiting adverse
outcomes. In the non-intubated patient, evaluation includes
a physical examination, a review of recent events, an
inspection of any supplemental oxygen equipment, arterial
blood analysis, chest radiography, and an electrocardio-
gram (selectively). Following this, management should be
as indicated by the likely diagnosis.
In the intubated patient, the evaluation is more complex.
An algorithm for the approach to the hypoxic intubated
patient is found in Fig. 39.3.80 In this scenario, hypoxia is
defined as a 5% decrease in continuous pulse oximetry
(SpO2) or a 10% decrease in mixed venous oximetry
(SvO2). After identification of hypoxia, the supplemental
oxygen should be enhanced. The patient should be discon-
nected from the mechanical ventilator and hand venti-
lated. If there is a cuff leak, the tube should be repaired
or replaced. If there is difficulty bagging the patient, an
attempt at passing a suction catheter should be made.
Inability to do so confirms obstruction. If this cannot be
reversed by altering the patient’s head position, checking
the tube’s position, or deflating the cuff, the tube should
be replaced. If there is no evidence of obstruction, despite
bagging difficulty, a tension pneumothorax should be ruled
out. Assuming that the patient is hand ventilated easily,
the mechanical ventilator and its circuitry should be
inspected to exclude a mechanical flaw. Additional workup
at this time should include a physical examination, review
of recent events, blood gas analysis, a portable anteropos-
terior chest radiograph, and an electrocardiogram. Further
diagnostic studies should be guided by the findings in the
algorithm of Fig. 39.3.
Summary
Throughout this chapter, we have focused on the clini-
cally relevant issues regarding postoperative respiratory
failure. Initially, we addressed the pathophysiology of the
varying types of acute respiratory failure, then we identified
the preoperative, intraoperative, and postoperative predic-
tors of postoperative pulmonary complications including
respiratory failure. We then took an in-depth look at the
more common etiologies of acute respiratory failure: ate-
lectasis, pulmonary aspiration, pulmonary embolism and
the acute respiratory distress syndrome. Finally, we outlined
a practice approach to the acutely hypoxemic perio-
perative patient, that is outlined in the algorithm shown
in Fig. 39.4.

• Alter head position

Pass a suction catheter Obstruction • Check tube position Replace the tube
• Deflate the cuff

Difficulty bagging the No obstruction

patient Chest tube

Inspect:
ACUTE • Enhance supplemental O2
• O2 source Tension
HYPOXIC • Disconnect patient from the Physical examination
• Mechanical ventilator pneumothorax
EVENT ventilator and hand ventilate
• Circuitry

• ABG analysis
Endotracheal tube cuff leak Correct mechanical problems • Chest radiograph
• Electrocardiogram

Repair/replace the tube

Interventions or procedures New complications Progressive underlying disease

Fig. 39.3 Treatment algorithm for acute hypoxia in the intubated patient. ABG, Arterial blood gas.
584 PART IV • Early Postoperative Care

ACUTE RESPIRATORY FAILURE THERAPIES

Prevention is the key

O2 administration Pulmonary embolism Pulmonary aspiration Atelectasis

Inferior vena cava filter Fixed-dose low- • O2 administration • Out of bed

if not a candidate for
anticoagulation
molecular-weight • Discontinue tube feedings
heparin administration
• Airway suctioning
• Consider airway intubation
• IS, deep breathing exercises,
coughing, and early ambulation
if not intubated
• Kinetic bed and optimization
of positive end-expiratory
pressure if intubated

Particulate matter

No
Aggressive pulmonary
care (see Atelectasis)
Ongoing clinical assessment
• IPPB if IS fails
• Intermittent deep breaths
Yes and CPAP if intubated
• Bronchodilators for
wheezing
Bronchoscopy and lavage • Tracheobronchial
aspiration/suctioning
to enhance coughing
• Mucolytics/postural
drainage for thick
secretions
• Chest physiotherapy
for lobar collapse

Secondary pneumonia Worsening/refractory ARDS

• Consider intubation
BAL, and appropriate Treat according to • FFB if lobar collapse persists
antibiotic coverage ARDS clinical
management guidelines

Fig. 39.4 Overview algorithm for treatment of pulmonary embolism, pulmonary aspiration, and atelectasis. ARDS, Acute respiratory distress syndrome;
BAL, bronchoalveolar lavage; CPAP, continuous positive airway pressure; FFB, flexible fiberoptic bronchoscopy; IS, incentive spirometry; IPPB, inter-
mittent positive-pressure breathing.

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 40 Endocrine and Electrolyte
Disorders
PETER INGLIS, EUGENE W. MORETTI, and DUANE J. FUNK
Introduction
Perioperative electrolyte and endocrine disorders are dealt
with by anesthesiologists on a daily basis. With the rising
incidence of diabetes and obesity and their relation to
increased morbidity in the perioperative period, it is imper-
ative that clinicians are skilled in the management of these
disorders. This chapter discusses the management of these
conditions and other common endocrinological problems
such as thyroid disease and the controversy surrounding
perioperative steroid supplementation. Finally, this chapter
discusses the etiology and management of some of the more
commonly encountered electrolyte disturbances.
Endocrine Dysfunction
DIABETES MELLITUS
Diabetes mellitus is a metabolic disease characterized by an
absolute or relative lack of insulin from the pancreas. There
are three distinguished types. Although it can occur at any
age, Type I diabetes usually occurs in adolescence. It is
believed to result from the autoimmune destruction of
insulin-producing cells in the pancreatic islets. There is an
absolute deficiency in insulin production and these patients
are dependent on exogenous insulin administration for sur-
vival. Type II diabetes is caused by insulin resistance, thus
resulting in a relative deficiency of insulin. Its onset is typ-
ically in adulthood, although recent epidemiologic data sug-
gest that the mean age of onset is decreasing. Type II
diabetes results from a heterogeneous group of causes but
is usually associated with obesity and abnormal insulin
levels. Like many diseases today, there may also be a genetic
component.
Gestational diabetes is defined as carbohydrate intoler-
ance beginning in or first recognized during pregnancy. It
is believed to occur in 2%–9% of all pregnancies and is asso-
ciated with substantial rates of maternal and perinatal com-
plications, such as shoulder dystocia, bone fractures, nerve
palsies, and hypoglycemia. Long-term adverse health
outcomes reported among these infants include sustained
glucose intolerance, obesity, and impaired intellectual per-
formance. Gestational diabetes is a strong risk factor for
the subsequent development of diabetes in the mother.1
Diabetes is marked by long-term complications involving
the microvasculature and macrovasculature. This vascular
disease is manifested by retinopathy, neuropathy, and
nephropathy and constitutes a major risk factor of heart dis-
ease, stroke, kidney disease, blindness and nontraumatic
amputation. The etiology of these complications is multifac-
torial and includes glycosylation of proteins and sorbitol
synthesis as a result of glucose reduction, which functions
as a tissue toxin.
With respect to management of the perioperative patient,
diabetes itself is not as important an issue as the degree of
end-organ dysfunction that it causes.2–4 Several major trials
have shown that over the long term, tight glycemic control,
tight blood pressure control, and regular physical activity
can postpone the microvascular complications in both types
of diabetic patients.4a,4b What is less clear is the benefit of gly-
cemic control in the perioperative period.
In 1878, Claude Bernard described hyperglycemia in
response to hemorrhagic shock.5 It is now well known that
injury and stress can cause hyperglycemia as a result of
the secretion of glucagon, insulin resistance, and glucose
intolerance. This so-called “stress hyperglycemia” is evolu-
tionally preserved and provides the body with a rapid source
of energy in times of stress. For a long period of time, stress
hyperglycemia was tolerated as it was deemed to be an adap-
tive evolutionary response to stress. It was not until several
studies in both intensive care unit (ICU) and non-ICU patients
suggested a link between hyperglycemia and adverse out-
come that clinicians began treating hyperglycemia.6–8
There is evidence that perioperative hyperglycemia impairs
wound healing. Inadequate insulin action in the early post-
operative period leads to impaired hydroxyproline incorpora-
tion into the structure of healing wounds.9 Laboratory
studies in diabetic animals have demonstrated that, in
insulin-treated animals, repaired tissue could withstand up
to three times the mechanical force that separated the inci-
sion in non-insulin treated animals.10 An additional study
in a murine diabetic model revealed that blocking insulin
activity inhibited DNA and protein synthesis in wounds, thus
resulting in decreased fibroblast activation and collagen syn-
thesis and a reduction in capillary proliferation.11 There is
now greater recognition that glycemic control is crucial in
maintaining healthy tissue repair and regeneration in the
perioperative period.
Diabetic patients are also at higher risk of postoperative
wound infections. High glucose levels hinder immune func-
tion by increasing neutrophil adhesiveness, decreasing
phagocytic activity, and decreasing microbicidal function.12
Glycemic control is vital in the immediate postoperative
period when the patient is particularly vulnerable to infec-
tion. Raissas et al. prospectively studied diabetic patients
undergoing cardiac surgery. These patients were random-
ized to an aggressive insulin infusion or standard therapy.
587
588 PART IV • Early Postoperative Care
Tight glucose control during cardiac surgery was found to
improve leukocyte function significantly.13
There are several clinical studies supporting short-term
hyperglycemia and perioperative infection risk. One investi-
gation involving diabetic patients undergoing major vascu-
lar surgery or major abdominal procedures revealed that
diabetic patients had higher nosocomial infection rates
when their serum glucose values exceeded 220 mg/dL. Zerr
and colleagues found an association between infection risk
and the mean concentration of blood glucose on the first
postoperative day. In that study, the incidence of postoper-
ative wound infection was 1.3% among patients with glu-
cose levels between 100 and 150 mg/dL versus 6.7%
among patients with glucose levels between 250 and
300 mg/dL.14 In a prospective cohort of diabetic patients
undergoing coronary artery bypass graft (CABG) surgery,
those patients with mean glucose concentrations in excess
of 200 mg/dL within the first 36 postoperative hours were
more likely to develop infectious complications including
infections of their leg and chest wounds. In a similar pro-
spective study involving 2467 diabetic patients undergoing
cardiac surgery, a continuous insulin infusion resulted in
decreases in perioperative serum glucose levels consistently
less than 200 mg/dL, which led to a significant reduction in
the incidence of wound infection.15
Numerous studies on glucose control have been con-
ducted with patient populations ranging from the critically
ill, pregnant diabetics, diabetics undergoing cardiac surgery
with cardiopulmonary bypass, and in those with brain
injury and global central nervous system (CNS) ischemia.
Although some of these studies have demonstrated benefit
with tight glucose control, there is little evidence to indicate
that tight glycemic control may be of benefit to any
other group.
In 2001, Van Den Berghe and colleagues published their
seminal study on “Intensive Insulin Therapy in Critically Ill
Patients.”16 This shifted the paradigm from tolerating or
normalizing glucose levels to attempting to maintain “tight
glucose control” (blood glucose concentration between 80
and 110 mg/dL). Although the mortality reduction in this
single center study was impressive, 14 subsequent studies
demonstrated no benefit and the suggestion of harm with
this tight glucose control as a result of extremely high rates
of hypoglycemia.17,18
There is a lack of data on the intraoperative management
of hyperglycemia in diabetic patients. Based on the ICU stud-
ies on intensive insulin therapy, the safety and efficacy of
this therapy has been trialed in operative patients. The
majority of these studies have been undertaken on cardiac
surgical patients because of the benefit of glucose-insulin-
potassium infusions on mortality seen in acute myocardial
infarction (although this association has recently been
questioned).19,20
A systematic review and meta-analysis of the studies of
tight glucose control demonstrated an almost 50% decrease
in the odds of mortality when compared with conventional
glucose control (<220 mg/dL).21 This result was driven
almost entirely by one paper.22 The difficulty with interpret-
ing the evidence regarding the benefit of tight glucose con-
trol and cardiac surgery is the limited number of well
conducted clinical trials, the significant variability in the
target glucose levels, and reporting of outcome measures.
Cardiac surgery is plagued with intense periods of surgical
stress and therefore wide swings in glucose levels. Consider-
ing the intense fluctuation in glucose levels and the question
of harm in the ICU studies of tight glucose control, it would
seem prudent to avoid tight glucose control in this popula-
tion and aim for normoglycemia (blood glucose concentra-
tion <180 mg/dL).
In diabetic patients undergoing cardiac surgery with car-
diopulmonary bypass, there are sufficient data to recom-
mend maintaining a perioperative blood glucose level
below 180 mg/dL. In nondiabetic patients the data are
not as compelling and most anesthesiologists are satisfied
with a serum glucose level below 200 mg/dL especially in
view of a study that revealed that nondiabetic patients expe-
rienced hypoglycemia after cardiopulmonary bypass when
continuous insulin infusions where used intraoperatively
to maintain normoglycemia.23 Fig. 40.1 presents an algo-
rithm for perioperative glucose management in a both car-
diac and noncardiac surgery patients.
MEDICALLY SIGNIFICANT OBESITY
Obesity is defined by an abnormal accumulation of fat in
proportion to body size. Overweight persons, although still
technically obese, have a body-fat proportion that is inter-
mediate between normal and obese. The most recently pub-
lished United States data reveal that approximately 65% of
adults are above normal weight: about 30% are overweight
(BMI 25 to 30), 30% are obese (BMI 30 to 40), and 5% are
extremely obese (BMI 40).24 Minority populations have
seen a rise in the prevalence of obesity, with the highest
rates found in Native Americans, Hispanics, and African
Americans, and the lowest rates found in those of Asian
ancestry. Prevalence rates for obesity are also highest in
populations with less education and lower income levels.
Internationally, obesity rates are generally lower than those
in the United States, but even societies that traditionally had
the lowest prevalence of obesity are starting to observe rates
of weight gain that are beginning to meet or exceed those of
Western societies.25 Obesity has now become a major bur-
den on health-care systems and it has surpassed alcohol and
tobacco abuse in terms of health-care costs and resource
usage.26
Men aged 25–34 years with extreme obesity have a 12-
fold higher mortality and men aged 35–44 years with
extreme obesity have a sixfold higher mortality then non-
obese men in the same age group.27 In addition, obese
adults are at increased risk of other comorbidities such as
hypertension, diabetes mellitus, coronary artery disease,
and a variety of neoplastic diseases.
Preoperative Evaluation
Obesity and its complications present major challenges for
the anesthesiologist. For the morbidly obese patient, the
main concern for the anesthesiologist is the airway and
the cardiopulmonary system. Abundant soft tissue in the
upper airway makes the obese patient more susceptible to
obstructive sleep apnea and the development of hypoxemia
and hypercapnia. Obesity also significantly increases the
risk of a difficult tracheal intubation.28,29
Morbid obesity is the most common risk factor for
obstructive sleep apnea (OSA). Every increase in BMI of

No treatment
BG ⱖ250 mg/dL BG ⱖ600 mg/dL
and pH ⬍7.3 and OSM ⱖ320,
Treat as DKA, treat as HHS,
cancel elective cancel elective
surgery. surgery. Proceed
Proceed with with emergent
emergent surgery
surgery only only when
when pH and BG ⬍200
⫹ None: Maintain
K normalized
GIK solution: Insulin
1–2U/hr with D5W or D5
0.45NS at 75–100 cc/hr
with KCl 10–20 mEq/dL.
Maintain BG ⬍180 mg/dL.
Monitor BG hourly
Fig. 40.1 Algorithm for glucose control in cardiac and noncardiac surgery. With the exception of cardiac surgery, most diabetic and nondiabetic
patients need receive only insulin. Cardiac surgical patients and patients with type I diabetes require glucose and insulin. BG, Blood glucose; D5W, 5%
dextrose in water; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; ICU, intensive care unit; NS, normal saline; OSM, osmolarity.
two units increases the likelihood of coexisting OSA by
4%.30,31 The prevalence of OSA is 3% to 25% in morbidly
obese men and 40% to 78% in morbidly obese women, as
opposed to 2% in non-obese women and 4% in non-obese
men in the general US population.32
It is difficult to predict the presence of OSA based solely on
a clinical examination. The definitive diagnostic test for OSA
is polysomnography. It is, however, impractical to screen all
suspected OSA patients with polysomnography and this has
led to the development of clinical predictive tools.33
A good example is the STOP-BANG questionnaire devel-
oped by Chung et al., which has been shown to have con-
sistently high sensitivity for detecting OSA at different
severity levels (84% in mild OSA or above, 93% in moderate
or above, and 100% in severe).34 It consists of questions on
Snoring, Tiredness, Observed apnea, and high blood Pres-
sure and is combined with BMI >35, Age >50, Neck cir-
cumference > 40 cm, and male Gender. Like many
screening tools, the high sensitivity of the STOP-BANG score
allows users to rule out moderate to severe OSA if the scor-
ing tool ranks them as low risk, i.e., the negative predictive
value is good.
A subgroup of obese patients are susceptible to a syn-
drome called the obesity-hypoventilation syndrome (OHS).
This is characterized by chronic daytime hypoventilation
and chronic daytime hypoxemia (PO2 <65 mmHg) and is
easily detected by using room air pulse-oximetry. Sustained
hypercapnia (PCO2 >45 mmHg) in an obese patient with-
out significant chronic obstructive pulmonary disease
(COPD) is also diagnostic for this syndrome. These patients
often have BMI >40 kg/m2 and the likelihood of OHS
40 • Endocrine and Electrolyte Disorders 589
Hyperglycemia
BG ⱖ150 mg/dL
Cardiac Noncardiac
surgery surgery
Diabetes Diabetes
No
perioperative
BG ⬍200 mg/dL
Type I: Insulin infusion
Yes Yes 1–2 U/hr with D5W or D5
0.45 NS at 75–100 cc/hr.
Type II: Insulin only
(infusion or intermittent).
Maintain BG ⬍200 g/dL.
Glucose and K⫹ not
required. Monitor BG hourly
increases as the BMI increases. The underlying pathophys-
iology of this syndrome is unclear and patients on the
extreme end of this spectrum who have signs of cor pulmo-
nale are called “Pickwickian.” Pickwickian conditions are
associated with increased perioperative morbidity and mor-
tality and these patients may require more extensive preop-
erative testing and postoperative management.35
Because most clinically severe obese patients do not
undergo polysomnographic testing, the diagnosis and sever-
ity of OSA in a preoperative patient are most commonly
gleaned from patient history. For example, reports of con-
stant snoring, interrupted breathing during sleep, morning
headache, and daytime somnolence may be indicative of
OSA. Systemic hypertension, a BMI >35, and a neck
circumference >40 to 42 cm at the cricoid cartilage are con-
sistent with the diagnosis of OSA.36 At present polysomno-
graphic testing is indicated in severely obese patients who
continually snore, have daytime somnolence, or have
observed periods of interrupted breathing during sleep.
Unfortunately, there are no studies to suggest that this
approach is correct. In the setting of morbid obesity and
OSA without symptoms or signs of underlying pulmonary
pathology, tests for room air, blood gases, and pulmonary
function have no predictive value in optimizing postopera-
tive outcomes in severely obese patients.37–40 Fig. 40.2 pre-
sents an algorithm providing guidance on the preoperative
evaluation of patients with morbid obesity.
Treatment with Noninvasive Ventilation
Continuous positive airway pressure (CPAP) can reduce or
eliminate signs of sleep apnea. To be successful, the use of
590 PART IV • Early Postoperative Care

CPAP titration. It is important to point out that patients

BMI require a period of adaptation to the mask and device and
ⱖ35 not all patients can tolerate this treatment.
The amount of CPAP required varies depending upon
whether the sleep disorder involves rapid eye movement
(REM) or non-rapid eye movement (NREM) sleep. For exam-
Cardiac evaluation as per ple, a CPAP level that eliminates obstructive and hypoxic
ACC/AHA guidelines
depending on patient risk symptomology during naps may not be effective for night-
(high, intermediate, low), time sleep when REM occurs. Unfortunately, compliance
and risk of surgery (high, with CPAP is in the range of 50% to 80%. Therefore, it is
intermediate, low) important for the anesthesiologist to make inquiries of each
patient on an individual basis regarding the use of their
device.41,42
The use of CPAP to reduce complications associated with
Suspect OSA has recently come into question with the publication of
sleep apnea
a large randomized controlled trial that did not demonstrate
any benefit to CPAP therapy on reducing the rate of death
from cardiovascular causes, myocardial infarction, stroke,
or hospitalization for unstable angina, heart failure, or tran-
Clinical
probability sient ischemic attack.43
of positive In the preoperative setting it remains unclear whether
sleep test surgery should be delayed to optimize airway status and
oxygenation with CPAP therapy. One study failed to observe
any major postoperative respiratory complications in 14
Med to high patients treated with nasal CPAP for a period of 3 weeks
Low (adjusted neck (adjusted neck before surgery. However, in addition to a small sample size
circumference ⬍43 cm) circumference 43–48 and this study suffered from the lack of a control group. There-
⬎48 cm, respectively) fore, it could not be determined whether these complications
would have occurred without the intervention.44 Other
studies have shown that 3 weeks of CPAP therapy before
Severity of bariatric surgery improved the left ventricular ejection frac-
daytime tion and afterload in patients with severe obesity and heart
symptoms failure. Eight weeks of preoperative CPAP may be necessary
to treat hypertension (HTN) secondary to OSA.45,46 In the
postoperative setting, one study revealed that CPAP used
on the first night after surgery failed to improve oxygena-
None or Moderate Consider tion. The authors believed that this may have been because
mild or severe pulmonology the REM rebound does not occur until several days after
consult and
sleep study surgery.47
Bilateral positive airway pressure (BiPAP) provides posi-
tive pressure to the airway during both inspiration and expi-
Proceed to OR ration. With this modality spontaneous ventilation is
(see Fig. 40.3) further assisted with increases in airway pressure and flow.
Fig. 40.2 Preoperative management algorithm for patients with a
BiPAP may have its greatest use in patients who require a
body mass index (BMI) greater than 35. Preoperative testing should significant amount of CPAP or in those who have a severe
follow American College of Cardiology and American Heart Association underlying airway disease such as COPD. The effectiveness
(ACC/AHA) guidelines for cardiac disease. Decisions to consult a pul- of BiPAP in the general sleep apnea population remains
monologist can be based on clinical symptoms and an adjusted neck unknown.
circumference, which is calculated by measuring neck circumference in
centimeters and adding 4 cm if the patient is hypertensive and 3 cm for Cardiovascular Complications of Obesity
chronic snoring. OR, Operating room. (Modified from Flemons WW,
Whitelaw WA, Brant R, et al. Likelihood ratios for a sleep apnea clinical Morbid obesity is associated with a higher frequency of car-
prediction rule. Am J Respir Crit Care Med 1994;150[5 Pt 1]:1279-1285, and diovascular disease, including essential hypertension, pul-
Eagle KA. ACC/AHA Guideline Update for Perioperative Cardiovascular
Evaluation for Noncardiac Surgery. J Am Coll Cardiol 2002;39:542-553.)
monary hypertension, left ventricular hypertrophy,
congestive heart failure, and ischemic heart disease. There-
fore, many patients with morbid obesity will require a thor-
ough cardiac workup. Preoperative patients can be assigned
CPAP requires experienced respiratory care practitioners to a risk group based primarily on history and physical
and patient cooperation. Hence, it is not surprising that examination and the extent of surgery as per the American
use of CPAP results in failure postoperatively because it is College of Cardiology/American Heart Association (ACC/
often performed in sleepy and uncooperative patients who AHA) guidelines.48
have not been formally diagnosed with OSA. In addition, Cardiac output must increase 0.01 L/min to perfuse each
it is also provided by practitioners who are not skilled in kilogram of adipose tissue adequately. Not surprisingly,

obese patients often have hypertension, which can lead to
cardiomegaly and left ventricular failure. The mechanism
for the development of hypertension may be caused by
repeated episodes of desaturation and sleep arousals result-
ing in the activation of the sympathetic nervous system.
Although treatment of sleep apnea may result in improve-
ment of HTN, most often treatment cannot be initiated in
time for the planned surgery. Treatment of hypertension
should be based on current recommended guidelines for
patients without sleep apnea.
The association between obesity, sleep apnea, and
atherosclerotic cardiovascular disease remains incompletely
understood.49,50 Episodes of myocardial ischemia are not
temporally related to apneic episodes despite sleep studies
demonstrating myocardial ischemia in high risk individuals.
Myocardial ischemia in this setting could be caused by
increased activation of the sympathetic nervous system,
resulting in increased myocardial work and increased oxy-
gen demand. Oxygen demand can easily outstrip delivery in
this setting because of hemoglobin desaturation.51 OSA also
predisposes patients to congestive heart failure, arrhyth-
mias, and diastolic heart dysfunction.52–54
Chronic daytime hypoxemia can also result in pulmonary
hypertension, right ventricular hypertrophy, or right ven-
tricular failure. Anesthesiologists should consider the use
of echocardiography to evaluate right heart failure or pul-
monary hypertension in selected patients with clinically
severe obesity and OSA. However, data are lacking to sup-
port the widespread use of this modality at this time.
Deep Vein Thrombosis
Obesity is also an independent risk factor for deep vein
thrombosis (DVT) and pulmonary embolus. The estimated
incidence of DVT and pulmonary embolism in the postoper-
ative period after bariatric surgery is 2.6% and 0.95%
respectively.55,56 Venous emboli migrating to the pulmo-
nary circulation is a significant contributor to the 1% to
2% 30-day mortality after bariatric surgery. Most mortality
in the 30-day period after bariatric surgery is a result of pul-
monary embolism, and this cause of mortality is threefold
higher than anastomotic leak and subsequent sepsis.
Unfractionated heparin in a dosage of 5000 units adminis-
tered subcutaneously before surgery and then two times a
day until the patient is ambulatory has been shown to
reduce the risk of DVT.57 Enoxaparin in a dosage of
40 mg twice a day has also been shown to decrease the inci-
dence of complications arising from postoperative DVT.58
Intraoperative Concerns
In obese patients, the expiratory reserve volume (ERV) and
functional residual capacity are reduced to 60% and 80% of
normal respectively. ERV is the primary source of oxygen
reserve during apnea. Decreased apneic reserve and possibil-
ity of difficult mask ventilation has led some to suggest that
awake intubation is the safest way to secure the airway in
severely obese patients, indicating the potential for difficult
intubation.32 Because of the higher risk of aspiration in the
severely obese patient, most practitioners perform a rapid
sequence induction to secure the airway, but there is little
data to support this practice.
It has been shown that drugs used for analgesia
and neuromuscular blockade have increased volume of
40 • Endocrine and Electrolyte Disorders 591
distribution and prolonged elimination times in severely
obese patients. In one study involving eight obese patients
(mean weight 94 kg), the elimination half-life of sufentanil
was 208 minutes versus 135 minutes for eight control
patients (mean weight 70 kg).59 In a study examining
twitch recovery times of vecuronium, the twitch recovery
time was 38.4 minutes in obese patients (mean weight
93 kg) versus 17.6 minutes for non-obese patients (mean
weight 61 kg).60
Postoperative Concerns
It is absolutely essential postoperatively that obese patients
receive some form of continuous oxygen supplementation
and be maintained in the semi-recumbent or upright posi-
tion.61 If oxygen therapy alone is insufficient to maintain
adequate arterial oxygenation, it is recommended that
CPAP or BiPAP therapy be instituted. The issue of postoper-
ative disposition and monitoring of OSA patients is contro-
versial. Although it is known that patients with OSA are at
higher risk of complications, there is no evidence that higher
levels of postoperative monitoring reduce these risks, and
the latest guidelines from the American Society of Anesthe-
siology do not have specific recommendations for postoper-
ative monitoring of these patients.62,63
Recommendations
Data from well-designed randomized trials are lacking in the
perioperative care of morbidly obese patients. In particular,
there are no data to suggest that outcomes are improved if
coexisting conditions such as OSA are diagnosed and treated
prior to surgery. In addition, there are no data to reveal
whether the type of anesthetic administered has an impact
on perioperative outcomes. We do recommend polysomno-
graphic testing with CPAP titration in selected patients, and
more extensive cardiac testing in selected patients prior to
surgery. We also recommend that DVT prophylaxis begin
prior to anesthetic induction and early ambulation be
encouraged in the postoperative period. In addition to oxy-
gen supplementation, a low threshold for initiating non-
invasive ventilation in the postoperative period is recom-
mended for patients who are hypoxemic. Fig. 40.3 presents
an algorithm that provides guidance on the perioperative
airway and disposition planning for patients with clinically
significant obesity.
CORTICOSTEROID SUPPLEMENTATION
Since their introduction in 1949, corticosteroids have been
used for a myriad of clinical purposes and have revolution-
ized the treatment of inflammatory diseases. In fact, it was
not long after their initial use that Fraser and colleagues
reported the first case of adrenal insufficiency secondary
to withdrawal from glucocorticoid therapy.64 The following
sections review (1) the normal physiologic secretion of
glucocorticoids and the response to stress; (2) the alterations
in the hypothalamic-pituitary-adrenal axis (HPA) with
chronic steroid supplementation; (3) the incidence and diag-
nosis of adrenal insufficiency; (4) current recommendations
for identifying and treating patients who need perioperative
steroid supplementation; and (5) a review of corticosteroid
use in the treatment of sepsis and septic shock.
592 PART IV • Early Postoperative Care

Obese
patient with
OSA

General risk reduction strategy:

• Limit narcotic use
• Consider regional anesthesia

Perceived
ease of A/W
Easy or
intermediate Difficult

Perceived ease
Difficult Awake intubation
of ventilation

Easy

Asleep intubation Severity of OSA:

• Daytime hypercapnia
• Hypoxemia
• Evidence of right heart Severe
failure
• Pulmonary hypertension
• Other pulmonary
comorbidities

• Transfer to ICU intubated

• Extubate when fully awake with
Mild/Moderate stable hemodynamics
• Ensure adequacy of ventilation and
oxygenation prior to extubation

Intraoperative concerns:
• Duration of surgery
• Upper abdominal/thoracic Present
incision
• Significant fluid administration
• Unanticipated difficult A/W
• Difficulties with oxygenation/
ventilation during case

Absent

• Extubate in OR
• Observe in monitored setting overnight
• Use multimodal postoperative analgesia
• Limit narcotic use
• Consider noninvasive ventilation if
significant hypoxemia or hypercarbia
present in recovery room

Fig. 40.3 Intraoperative algorithm for managing obstructive sleep apnea (OSA). Decisions depend on factors such as airway difficulty, severity of OSA,
and intraoperative factors that might adversely affect gas exchange in the postoperative period. A/W, Airway; ICU, intensive care unit. (Data from
Benumof JL. Obstructive sleep apnea in the adult obese patient: implications for airway management. J Clin Anesth 2001;13:144-156.)

Normal Physiology
The zona fasciculata of the adrenal gland secretes approxi-
mately 5 mg/m2 of cortisol per day. For the average sized
person, this means the total normal cortisol production is
about 8.5 mg/day. Glucocorticoid receptors are present on
many different tissue types and play a key role in homeosta-
sis. Specifically, glucocorticoids are necessary for lipid, car-
bohydrate, and protein metabolism. Glucocorticoids also
facilitate catecholamine production and the maintenance
of normal blood pressure and affect cardiovascular homeo-
stasis.65 In healthy subjects, glucocorticoid secretion has a
diurnal variation with peak levels occurring between 4 AM
and 8 AM. The nadir of their secretion is between 2 AM
and 4 AM. Interestingly, this diurnal variation is lost in crit-
ically ill patients.66,67
With stressors such as critical illness, trauma, and sur-
gery, the normal physiologic response is an increase in
the level of adrenocorticotrophic hormone (ACTH), which
stimulates the adrenal gland to secrete cortisol. However,
there is considerable interindividual variation in the HPA
response to these stresses. Some of the variation is thought
to be the effect of anesthetics, endogenous and exogenous
opioids, age, and sleep.68 Of particular interest is emerging
data suggesting that a significant proportion of opioid trea-
ted chronic pain patients display a degree of adrenal sup-
pression.69 Furthermore, the amount of glucocorticoid
secreted depends on the amount of surgical stress. Minor
surgical procedures result in an adrenal secretion of approx-
imately 50 mg of cortisol per day, whereas major surgical
procedures produce between 75 and 150 mg of cortisol
per day.70 To put these levels in perspective, patients with
Cushing syndrome secrete an average of 36 mg/day of cor-
tisol.71 The daily production of cortisol during periods of
stress seldom exceeds 200 mg/day in normal subjects. This
suggests that this is the maximum dosage that should be
administered to patients thought to be at risk of postopera-
tive adrenal insufficiency.
Effect of Chronic Steroid Supplementation on the
HPA Axis
Adrenal insufficiency (AI) can be classified as either primary
(resulting from the destruction of the adrenal gland by
tumor, infection, or hemorrhage), secondary (resulting from
pituitary dysfunction), or tertiary (resulting from the thera-
peutic administration of glucocorticoids). By far, the most
common cause of AI is tertiary.72 Exogenous administration
of glucocorticoids results in the inhibition of the hypotha-
lamic and pituitary glands, which results in the atrophy
of the adrenal gland over time. Precisely how long it takes
for the adrenal gland to recover its function from the exog-
enous administration of glucocorticoids is the subject of
much debate. Studies have shown that the adrenal gland
can take as little as 2 to 5 days to recover its normal function
or as long as 9 months to a year.73
Diagnosis of Adrenal Insufficiency
The diagnosis of tertiary AI in a postoperative patient is dif-
ficult and subject to error. Both clinical and physical exam-
ination findings need to be supplemented with biochemical
testing to confirm the diagnosis.73 The typical history of
fatigue, anorexia, postural hypotension, and weight loss
40 • Endocrine and Electrolyte Disorders 593
seen in adrenally insufficient patients in the outpatient set-
ting is not relevant in the postoperative state. Surgical
patients most often present with an Addisonian crisis that
includes fever and hypotension unresponsive to fluid or
vasopressor support. The diagnosis is thus confounded by
typical postoperative mimics such as hypovolemic shock
or sepsis.
Biochemically, the classic findings of adrenal insufficiency
include hyponatremia and hyperkalemia. Hyponatremia
might be masked by the administration of perioperative
fluids. Hyperkalemia is often not present because of intact
mineralocorticoid secretion thanks to the renin-angioten-
sin-aldosterone system.73 The limitations of the physical
examination and baseline biochemical data therefore argue
for a more focused interrogation of the HPA axis either with
an ACTH stimulation test or with a random cortisol level.
Determining an adequate cortisol response in a postoper-
ative patient suspected of having adrenal disease is made
challenging by the previously mentioned interindividual
and procedural variability in cortisol levels. Ideally, a
threshold cortisol level could be defined, below which the
diagnosis of adrenal insufficiency could be made with a high
degree of certainty, and therapeutic replacement could be
initiated. There are currently no clear consensus values
used in the diagnosis of postoperative or critical illness
related adrenal insufficiency. A random cortisol value of
<10 μg/dL has appeared in older guidelines as a value below
which a diagnosis of adrenal insufficiency can be made.74
Patients whose cortisol level is above 34 μg/dL are unlikely
to have AI and need not be treated.
Further testing of the HPA axis can be accomplished with
the ACTH stimulation test. This involves the administration
of 250 μg of intravenous cosyntropin (a synthetic ACTH
analog) and the measurement of plasma cortisol levels at
baseline and at 30 and 60 minutes after administration.
Current guidelines suggest that a cortisol value of less than
18 μg/dL (assay specific) recorded at any of the time points
are needed to confirm adrenal insufficiency.75 These guide-
lines, however, are written for the diagnosis of primary adre-
nal insufficiency and not AI related to critical illness or
perioperative stress.
Unfortunately, anesthesiologists often do not have the
luxury of waiting for the results of specialized biochemical
tests when faced with a hypotensive patient in the operating
room or the recovery room who might have AI. One man-
agement option, should this situation arise, would be to
administer 8 mg of dexamethasone to the patient, as this will
adequately provide the “stress dose” required without inter-
fering with any subsequent testing of the HPA axis. Concur-
rently, a random cortisol level should be drawn to check for
the presence of AI.
Incidence of Adrenal Insufficiency
The reported incidence of tertiary AI in at risk surgical
patients ranges from 0.1 to 1 in 1000.68 Whether this rep-
resents an actual low incidence, under-reporting, or poor
recognition of this condition is unclear. Many patients
undergo major surgical procedures without perioperative
glucocorticoid coverage, or even without their baseline
therapeutic dosage, without sequelae.68 The likely explana-
tion for this is that these patients have normal HPA axis
function in response to stress.
594 PART IV • Early Postoperative Care
A collection of small studies has examined the outcomes
of omitting additional corticosteroid administration in times
of stress amongst patients who would be considered to have
corticosteroid induced impaired HPA axis. Bromberg and
colleagues prospectively studied 40 renal transplant
patients on long-term steroids for immunosuppression
who required hospital admission for surgical procedures
or acute illness. Despite no stress doses being administered
they found no clinically significant cases of adrenal
insufficiency.76
Glowniak and Loriaux studied patients taking at least
7.5 mg of glucocorticoid per day who underwent major sur-
gical procedures.77 There were no cases of clinically signif-
icant adrenal insufficiency found in either the treatment
(stress dosed) or control arm. In 2012 and 2014 Zaghiyan
et al. completed two studies involving steroid-treated
patients with inflammatory bowel disease requiring bowel
surgery. Based on these two studies they concluded that
continuing only daily home dose steroids perioperatively
was not more likely to yield additional cases of adrenal insuf-
ficiency than if patients were administered stress doses.78,79
Further, within these studies patients who had been treated
with steroids but were not actively taking them did not dis-
play AI features despite no perioperative steroid being given.
Despite this, adrenal crisis remains a rare yet feared and
potentially fatal complication in the perioperative period
and patients taking exogenous steroids are at risk. In light
of the rarity of adrenal insufficiency and the small size of
studies refuting the need for stress dose steroids, many prac-
ticing anesthesiologists retain a conservative approach.
Identifying patients at risk for adrenal insufficiency
The commonly agreed upon scenarios for which periopera-
tive stress dose steroids are indicated include patients who
take >20 mg prednisone equivalent per day for >3 weeks
or have clinical features of Cushing syndrome. Patients
who take less than 5 mg/day prednisone equivalent or
who have taken any dose for less than 3 weeks are consid-
ered to have intact HPA axes and do not require stress dose
steroids.80 Patients who take topical or inhaled steroids are
at extremely low risk of developing tertiary AI.73
A number of patient groups fall outside of these catego-
ries. Such patients form an intermediate group for whom
there is concern for HPA axis suppression but limited, if
any, evidence to support the practice of administering stress
dose steroids. For these patients the risk of harm with excess
steroid is a significant concern. Patients who fall into this
group include those who: (1) take between 5 and 20 mg
prednisone equivalent per day, (2) have received epidural
or intra-articular steroid injections in the past 90 days,
and (3) were treated but have stopped corticosteroid use
within the past year.81–85
Determining which of these patients, if any, need stress
dosing is a topic of much debate. No clear guidelines exist.
An attractive and much discussed approach is to perform
a 250-μg ACTH stimulation test preoperatively although
its use has not been shown to predict accurately which
patients will develop tertiary AI. It is also time-consuming
and costly, making it frequently impractical in the preoper-
ative setting. An alternative approach is to omit stress dos-
ing for these patients and administer a rescue dose of
hydrocortisone only if features of AI develop.
Perioperative Steroid Supplementation
Once the decision to administer stress dose steroids has been
made, the question then turns to dosage and duration.
Although several regimes exist in the literature, all are in
agreement that patients should take their usual daily dose
throughout the perioperative period and that stress dosing
should reflect the magnitude of surgical stress. In 2017 a
thorough review of the literature on this topic by Liu
included a suggested dosing schedule.80 This is presented
in Table 40.1.
As mentioned previously, identifying patients at risk of
tertiary AI by history alone is fraught with difficulties. None-
theless, focused questioning of patients with inflammatory
conditions (such as rheumatoid arthritis or inflammatory
bowel disease) for steroid use is simple, and the yield is
potentially high. Clinicians should also inquire about any
administration of epidural steroids in the previous 90 days,
because this has also been shown to suppress the adrenal
axis.81 Patients who take topical or inhaled steroids are at
extremely low risk of developing tertiary AI.73
The salient questions, however, are what dosage, by what
route, and what duration of therapy is sufficient in patients
at risk of tertiary AI. Previous recommendations of quadru-
pling the amount of steroid patients were receiving for stress
are: (i) antiquated, (ii) based only on case reports, and (iii)
have the potential for increasing morbidity such as wound
infections, gastrointestinal ulceration, altered glucose toler-
ance, and dysphoria.68 A rational approach to supplemen-
tation takes into account the magnitude of the insult as well
as the patient’s baseline steroid dose.
For all procedures, patients should receive their daily dose
of steroid preoperatively, either orally or parenterally.
Patients who are receiving 5 mg of prednisone per day or
less do not require steroid supplementation because they
continue to have an intact HPA axis. For minor surgical
stresses (Box 40.1), based on daily cortisol secretion, a target
of 25 mg hydrocortisone equivalent (Table 40.1) is sufficient
to overcome the surgical stress. If the postoperative course is
uncomplicated, the patient may return to their usual steroid
dose on postoperative day 1.
For moderate surgical stress, cortisol production rates
suggest that a target of 50 to 75 mg/day of hydrocortisone
or its equivalent should be administered for 1 to 2 days.
After this period, patients may return to their usual oral reg-
imen if they are tolerating and absorbing oral medications.
For major surgical stresses, 100 to 150 mg of hydrocorti-
sone equivalent per day for 2 to 3 days is required to avoid
Table 40.1 Recommended Perioperative Steroid Stress
Dosing.
Type of
Surgery Stress Dose
Minor or Hydrocortisone 50 mg IV before incision
moderate + 25 mg IV q8h 24 h
Major Hydrocortisone 100 mg IV before incision
+ 50 mg IV q8h  24 h then taper dose by half per day
until usual daily dose reached
q8h, Every 8 hours (Latin: quaque octa hora).
From Liu M, Reidy A, Saatee S, Collard C. Perioperative steroid management.
Approaches based on current evidence. Anesthesiology. 2017;127(1):166-172.

Box 40.1 Classification of surgical stresses.
Minor
▪ Inguinal hernia repair
▪ Colonoscopy
▪ Laparoscopic surgery
Moderate
▪ Open cholecystectomy
▪ Bowel resection
▪ Peripheral revascularization
▪ Joint replacement
Major
▪ Cardiopulmonary bypass
▪ Pancreaticoduodenectomy
▪ Esophagectomy
▪ Aortic surgery
From Salem M, Tainsh Jr RE, Bromberg J, et al. Perioperative glucocorti-
coid coverage. A reassessment 42 years after emergence of a problem.
Ann Surg 1994;219:416-425.
tertiary AI. This amount can then be discontinued on post-
operative day 3 with a return to the baseline regimen.
There are no data to support the contention that patients
who are receiving maintenance doses of steroids that exceed
the estimated stress requirements need higher perioperative
doses. That is, a patient who is receiving a maintenance dose
higher than the previously estimated stress requirement will
not need extra coverage during the postoperative period.86
These recommended regimens do not require a long taper-
ing because there is little or no evidence to support the
short-term (i.e., less than 48 hours) suppression of the
adrenal gland.
Corticosteroids and Sepsis
Although more commonly encountered by intensivists,
anesthesiologists are often involved in the care of patients
with sepsis and septic shock and much controversy has sur-
rounded the use of corticosteroids in this patient population.
High-dose methylprednisolone (30 mg/kg) had previously
been used but was subsequently linked to increased mortal-
ity and morbidity and ultimately abandoned as a practice
about 25 years ago.87 Since that time, the use of low-dose
corticosteroid (<400 mg/day) has gained traction as a treat-
ment option for sepsis and septic shock, but results of clinical
trials have produced conflicting results.
Four randomized controlled trials have been carried out
in this patient population with conflicting results. In
2002, Annane found that treatment with low-dose hydro-
cortisone and fludrocortisone conferred a significant mortal-
ity benefit among septic shock patients with demonstrated
adrenal insufficiency.88 In 2008 a study by Sprung found
no mortality benefit with low-dose corticosteroid treatment
in patients with sepsis and septic shock.89 A propensity
matching study by Funk in 2014 on this topic found a small
mortality benefit amongst the most ill patients.87 In 2018
two large independent trials addressing the issue of cortico-
steroid use in septic shock were published. Venkatesh found
no mortality benefit with the use of low-dose corticosteroid
and Annane did find a significant mortality benefit with the
use of corticosteroid and fludrocortisone.90,91
40 • Endocrine and Electrolyte Disorders 595
Two current guidelines address the issue of corticosteroid
treatment in sepsis and septic shock. The Society of Critical
Care Medicine 2017 recommend using low-dose hydrocor-
tisone (<400 mg/day) for at least 3 days only in patients
with volume and vasopressor unresponsive septic shock;
however, this recommendation is labeled conditional and
supported by only low quality evidence.74 The 2012 Surviv-
ing Sepsis Campaign Guidelines similarly suggest using
hydrocortisone at a dose of 200 mg/day for volume and
vasopressor refractory septic shock, although they also
acknowledge that the quality of evidence supporting this
recommendation is low.92
In conclusion, although evidence remains overall con-
flicting and weak, there appears to be agreement that treat-
ment with low-dose corticosteroid in severely ill septic shock
patients may have mortality benefit and is reasonable. The
role of fludrocortisone appears to have some promise but is
not yet fully researched.
Of particular interest to anesthesiologists, evidence
sources agree that the use of etomidate should continue
to be avoided in patients with septic shock.
THYROID DISEASE AND ANESTHESIA
Anesthesiologists are frequently faced with patients who
have preexisting hyperthyroidism or hypothyroidism. The
management of these patients during elective surgery is
straightforward and does not necessitate any change in
anesthetic technique. Problems arise, however, when
patients who are floridly hyperthyroid or hypothyroid pre-
sent for surgery. Patients who are not in a euthyroid state
should only be operated on for life-threatening illnesses.
The postoperative complications that arise in patients
who are not clinically euthyroid make elective surgery a
dangerous adventure. This section will address some of
the concerns of anesthetizing patients with untreated or
uncontrolled thyroid disease. Unfortunately, evidence-based
guidelines are not available because of the low incidence of
patients with acute thyroid dysfunction presenting for sur-
gery and the lack of controlled trials on management
strategies.
Hypothyroidism
Hypothyroidism is a relatively common condition that
occurs in 1% of all patients and in approximately 5% off
those over the age of 50 years.93 Females represent the vast
majority of patients. The most common (noniatrogenic)
cause of hypothyroidism is Hashimoto thyroiditis, which
is an autoimmune disorder caused by antibodies to thyroid
tissue. Patients with this condition should be screened for
other autoimmune diseases because they are often present.
The diagnosis and clinical management of these patients
has been reviewed recently.94
Some of the manifestations of overt hypothyroidism of
concern to the anesthesiologist are a decrease in the venti-
latory response to hypercarbia and hypoxia, impaired gas-
tric emptying, decrease in free water clearance, altered
ability to thermoregulate, and decreased cardiac output
and bradycardia. These patients have a slightly decreased
anesthetic requirement and opiates, induction agents, and
volatile anesthetic agents should therefore be titrated
accordingly.
596 PART IV • Early Postoperative Care
Myxedema coma is the most extreme form of hypothy-
roidism and anesthesiologists may encounter these patients
in the perioperative setting. Common precipitants of myx-
edema coma include trauma, burns, stroke, sepsis, amiodar-
one, and the postoperative state. The mortality from
myxedema coma is high (greater than 60%), but fortunately
this condition is exceedingly rare.
Clinical manifestations of this condition include a
decreased level of consciousness, coma, decreased cardiac
output, hyponatremia, hypoventilation, and hypothermia.
Myxedema coma is an endocrinological emergency and
attention should be focused on securing the patient’s air-
way, control of ventilation, and circulatory support, and
these patients should be transferred to an intensive care
unit. Despite an increase in total body water, these patients
are hypovolemic and subject to profound hypotension
should they become vasodilated. Thus external rewarming
is ill-advised because the resultant vasodilation that occurs
with rewarming could result in cardiovascular collapse.
Normothermia will be achieved with normalization of thy-
roid hormone levels. Hypotension should be treated with the
administration of warmed intravenous fluids. Vasoactive
agents should be used judiciously because they may precip-
itate arrhythmia. Hypoglycemia, which is often present,
responds well to glucose infusions. With the lack of a febrile
response or leukocytosis, broad spectrum antibiotics should
be initiated in patients without an obvious precipitant for
myxedema coma after appropriate cultures have been
obtained.
Definitive management of myxedema coma relies on the
administration of intravenous thyroid hormone. The proper
initiation of thyroid hormone replacement is controversial
with regard to the selection and dose of thyroid hormone
(either T4 or T3). In theory, T3 is the logical choice, because
it is the form of thyroid hormone active at the cellular level.
Further, T4 is converted to the active T3 by a deiodinase
enzyme, levels of which are depressed in myxedema coma.
This has led several investigators to suggest T3 as the logical
replacement choice. T3, however, is expensive, difficult to
obtain, and may precipitate arrhythmia. There are also no
controlled trials demonstrating improved outcome with
T3. Thus most investigators recommend the use of intrave-
nous T4 as the sole replacement hormone. A loading dose of
200–500 μg IV followed by 50–100 μg IV per day afterward
is suggested. Concomitant glucocorticoid therapy (hydro-
cortisone 50 mg IV every 6 hours) should also be initiated,
as the presence of AI in these patients is high. Cortisol levels
should be drawn prior to initiation of therapy and if random
levels greater than 25 μg/dL are found, glucocorticoid ther-
apy can be discontinued.93
Hyperthyroidism
Graves’ disease or thyrotoxicosis is the most common cause
of hyperthyroidism and is caused by the presence of autoim-
mune antibodies directed against the thyroid hormone
receptor. These autoantibodies cause stimulation of the
TSH receptor and result in excessive production of thyroid
hormone. Clinically, overt hyperthyroidism is manifest by
tachycardia, tremor, diarrhea, ophthalmopathy, and goiter.
The diarrhea might be severe enough to cause hypovolemia,
acid base abnormalities, and electrolyte disturbances. Anes-
thesiologists should pay particular attention to the size of the
goiter as it may be large enough to cause airway obstruction
upon induction of anesthesia. Historical features, such as
shortness of breath in a recumbent position, and supple-
mental tests, such as postural flow volume loops and com-
puterized tomography scans, should be evaluated prior to
anesthesia. An awake intubation with an armored tube
placed distal to the obstruction should be performed with
a large goiter. Extubation should occur in the operating
room or the ICU with optimal circumstances (complete
reversal of neuromuscular blockade and optimal level of
consciousness). Postoperatively after thyroidectomy for a
large goiter, the possibility of tracheomalacia and tracheal
collapse secondary to weakened tracheal rings warrants
close observation.
The progression of thyrotoxicosis to thyroid storm is also a
rare event. Most often, thyroid storm is caused by a thyroid
event such as thyroid surgery, iodinated radiocontrast dye
administration (Jod-Basedow effect), and withdrawal of
antithyroid drugs. Other common precipitants include sur-
gery, trauma, stroke, parturition, and severe infections.93
Physical manifestations of thyroid storm result from sympa-
thetic stimulation and include hyperthermia, altered mental
status, tachycardia, high cardiac output (that might develop
into heart failure), hypertension with a widened pulse pres-
sure, and arrhythmia.
The treatment of thyroid storm requires admission to an
intensive care unit and involves general support of the
patient, blocking the peripheral effects of thyroid hormone,
blocking synthesis of thyroid hormone, and treatment of
precipitating causes. Initial management involves inhibition
of iodine organification with the thioureas, propothiouracil
(PTU), or methimazole. PTU has the added advantage of
inhibiting the peripheral conversion of T4 to T3. PTU is
administered in a 600–1000 mg loading dose, followed by
1200 mg/day in four divided doses. If the oral route is
unavailable, PTU is also absorbed rectally. The next step
is to inhibit the secretion of preformed thyroid hormone
with iodine. PTU and methimazole only inhibit the forma-
tion of new thyroid hormone and have no effect on the
release of preformed hormone. Several hours should elapse
between the administration of the thioureas and iodine. If
iodine is given before organification blockade, it may
precipitate a substantial release of thyroid hormone (Jod-
Basedow effect).93 Stress dose steroids (hydrocortisone
100 mg IV three times daily) can also block the release of
thyroid hormone.
Simultaneous with the inhibition of thyroid hormone
release and synthesis, the peripheral effects of thyroid hor-
mone should be antagonized with the use of beta blockers.
Propranolol has been the most commonly used beta blocker
for this, but other more selective beta blockers such as met-
oprolol and esmolol can also be used. Beta blockers have the
additional effect of blocking the peripheral conversion of T4
to its active form T3.
Thyroid Hormone and Cardiac Surgery
The effects of thyroid hormone on the heart have long been
known. Furthermore, it is also well known that a low T3
state occurs after cardiopulmonary bypass resulting in a
low cardiac output and high systemic vascular resistance
state. Studies that have shown thyroid hormone to be a pos-
itive inotrope and a vasodilator have led to clinical studies

that assess its role in the treatment of this post-bypass
abnormality.
In adults undergoing coronary artery bypass grafting
(CABG), T3 levels decrease between 50% and 75% from
baseline and remain depressed for the first 1–4 postoperative
days. The precise reason why this occurs is not well known.
Proposed mechanisms include hypothermia and increased
IL-6 levels, both of which may cause decreased conversion
of T4 to T3, or a decreased half-life of T3.95
Initial clinical studies suggested that the administration of
T3 to patients undergoing CABG improved hemodynamics
and overall outcome. These initial studies were, however,
small in nature and based mostly on anecdotal experience.
These initial studies led to larger randomized placebo-
controlled trials. Most of them showed a decrease in the
need for inotropic support, but overall outcome was the
same between groups. Interestingly, in some of the studies
a lower incidence of atrial fibrillation was found. This is
unusual because this is one of the more common dysrhyth-
mias in patients with hyperthyroidism. Of note, none of the
studies performed to date show an increase risk of adverse
events in the treatment group. Despite the lack of clear out-
come benefit, a potential role for thyroid hormone in CABG
patients does exist and warrants further study.95
Alteration in the HPA axis resulting in hypothyroidism is
also commonly present in organ donors who have suffered
brain death. Studies where a protocol for hemodynamic sup-
port included replacement with thyroid hormone have
shown a decreased need for vasopressors and a substantial
increase in the number of organs transplanted. Thus, thy-
roid hormone replacement should be considered in any
hemodynamically unstable donor patient who is receiving
vasopressor therapy.96
SODIUM
Hyponatremia
Hyponatremia is defined as a serum sodium concentration
less than 135 mEq/L and it can occur in a hypotonic, hyper-
tonic, or isotonic state. Hypertonic hyponatremia (increased
plasma osmolality) is caused primarily by solutions such as
glucose or by mannitol, as seen in transurethral resection of
the prostate (TURP).
The most common type of hyponatremia seen in the peri-
operative setting or in the critically ill is hypotonic hypona-
tremia, which can occur in the isovolemic, hypervolemic, or
hypovolemic state. All three involve an impairment in the
excretion of renal water along with continued intake of
dilute fluid.
Isovolemic hyponatremia occurs with retention of water
in the absence of sodium, and there are no clinical signs of
edema. The most common postoperative cause of this con-
dition is syndrome of inappropriate antidiuretic hormone
(SIADH), which can be caused by pulmonary or cranial
neoplasms or infections, postoperative pain (secondary
to sympathetic activation), and drugs such as tricyclic
antidepressants or opiates.
Hypovolemic hyponatremia is commonly caused by gastro-
intestinal losses, third-space losses, or adrenal insufficiency.
Hypervolemic hyponatremia is characterized by edema-
tous states such as congestive heart failure, cirrhosis, and
40 • Endocrine and Electrolyte Disorders 597
renal failure. This state is characterized by sodium retention
with disproportionately larger amounts of water.
Management of Hyponatremia. When the serum sodium
level remains greater than 125 mEq/L, patients are usually
asymptomatic. Lower values usually result in symptoms,
especially if the hyponatremia has developed quickly.
Nausea, vomiting, visual disturbances, depressed level of
consciousness, altered mental status, seizures, disordered
reflexes, loss of thermoregulatory control, muscle cramps,
and weakness can be seen. Cerebral edema begins to man-
ifest at a sodium concentration of 123 mEq/L and, if it
progresses rapidly, it may lead to transtentorial herniation.
Cardiac symptoms occur at levels of less than 100 mEq/L
and can result in pulmonary edema, hypertension, and
heart failure.
It is recommended that the rate of correction of asymp-
tomatic hyponatremia be 0.6 to 1 mmol/L/h until the
sodium concentration is 125 mEq/L, using hypertonic
saline. Then, one half of the deficit should be administered
over 8 hours and the remaining half over 1 to 3 days. Con-
current treatment with furosemide is also recommended to
avoid volume overload. A further advantage to this combi-
nation is that furosemide treatment is equivalent to the
administration of one-half normal saline and thus aids in
the correction.96 Patients who have symptomatic hypona-
tremia should have their serum sodium concentration
raised by 3 to 7 mmol/L. Overly rapid correction of hypona-
tremia places patients at risk of osmotic demyelination. This
usually occurs when serum sodium is increased by more
than 12 mmol in a 24-hour period.
The sodium dosage for deficit correction can be based on
the following formula:
Dosage ¼ ðbodyweight  140 ½NaŠÞ  0:6
where the dose is in milliequivalents, the patient’s body-
weight is in kilograms, and [Na+] is sodium concentration in
milliequivalents per liter.
The treatment of hyponatremia involves two basic
pathways: raising the low sodium levels and at the same
time treating the underlying cause. Normal saline (308
mOsm/L) is usually sufficient in cases of hypovolemic hypo-
natremia, and fluid restriction works well in normovolemic
or edematous cases. Severe coma or seizures are most effec-
tively managed with hypertonic saline (513 mEq/L), fluid
restriction, and furosemide.
The vasopressin receptor antagonists tolvaptan (oral) and
conivaptan (IV) represent recent additions to list of manage-
ment options for hyponatremia. There is strong evidence
that these drugs are effective in raising serum sodium in
cases of hyponatremia caused by SIADH, heart failure,
and liver cirrhosis.97 Existing guidelines are in agreement
that vaptans are not indicated for the treatment of acute
hyponatremia or hyponatremia that is severely symptom-
atic.97 These medications act to increase serum sodium pri-
marily by blocking renal vasopressin-2 receptors and
subsequently limiting the recovery of free water.98 Despite
their ability to raise serum sodium, outcome data are scarce.
At present there are no data to support a mortality benefit
with the use of vaptans; however, some evidence exists
for improvement of mental, volume, functional, and respira-
tory status in selected patient populations.97 From an
598 PART IV • Early Postoperative Care
anesthesia perspective, no data exist on the use of these
medications in the perioperative period.
Vaptans are associated with significant adverse effects.
Overcorrection of sodium has been reported in as many as
23% of patients with the use of tolvaptan and although
these over-corrections did not lead to clinically significant
outcomes, the potential does exist for the development
of osmotic demyelination syndrome.99 Significant liver
enzyme derangement has also been observed with the use
of tolvaptan, which led to concerns about its use in patients
with liver cirrhosis.100
Outcomes. For the anesthesiologist, the challenge of man-
aging hyponatremia involves the presence of concomitant
hepatic, renal, or cardiac disease. Although acute hypona-
tremia is tolerated much better than chronic hyponatremia,
it is not necessary to restore the serum sodium level to nor-
mal before surgery. Cerebral edema is usually absent at a
level of 130 mEq/L. A large cohort study in 2012 by Leung
et. al found preoperative hyponatremia (defined as Na
<135 mmol/L) to be associated with increased 30-day mor-
tality risk, coronary events, wound infections, pneumonia,
and increased hospital stay.101 Increasing severity of hypo-
natremia was also found to be associated with increasing
risk. There are presently no data that show the level of
serum sodium that might increase anesthetic risk. The
lower sodium limit arbitrarily chosen by some authors is
131 mEq/L. Furthermore, simply correcting the hyponatre-
mia is unlikely to reduce risk because the sodium value
probably represents severe underlying disease, which
should be the target of preoperative intervention.
Hypernatremia
Hypernatremia is defined as a serum sodium concentration
exceeding 145 mEq/L. The primary difference between
hyponatremia and hypernatremia is that all patients with
hypernatremia are by definition hyperosmolar. In addition,
these patients are always free-water depleted. Total body
water (TBW) is considered to be approximately 60% of
the total bodyweight in kilograms.
The equation for an estimation of free-water deficit is as
follows:
Free water deficit ¼½0:6  patient’s weight
 ð1 ½140  patient’s ½NaŠŠÞ
where the patient’s bodyweight is in kilograms, and [Na] is
sodium concentration in milliequivalents per liter.
One of three circumstances must be present for hyperna-
tremia to occur: water loss, decreased water ingestion, or
over-ingestion of sodium.
Categories of water loss would include insensible losses
such as sweating, burns, fever, gastrointestinal losses,
and renal causes (central or nephrogenic diabetes
insipidus). A major cause of increased sodium ingestion
is usually iatrogenic, as might occur during the indiscrim-
inate use of sodium bicarbonate during cardiopulmonary
resuscitation.
Antidiuretic hormone (ADH) and thirst sensation as
sensed by the hypothalamic osmoreceptors are the two
basic mechanisms the body uses to combat the development
of hypernatremia. The body’s first response is to release
ADH, which occurs when the plasma osmolality exceeds
275 to 285 mOsm/kg, but thirst is the more important reg-
ulator. Severe hypernatremia will not occur unless the
patient is unable to ingest water or has a nonfunctional
thirst reflex.
Diabetes insipidus results from the absence of ADH (cen-
tral diabetes insipidus), or the inability of the renal tubules to
respond to ADH (nephrogenic diabetes insipidus). Common
etiologies of central diabetes insipidus include head trauma,
neurosurgery, hypoxic/ischemic insults, and neoplasia. All
these disorders are characterized by a lack of ADH. In
nephrogenic diabetes insipidus, the production and secre-
tion of ADH are normal, but renal responsiveness to it is
not. The most common etiologies are lithium toxicity,
hypercalcemia, and osmotic diuresis (seen in hyperglycemic
hyperosmolar nonketotic syndrome). A urine osmolality of
less than 300 mOsm/L and serum sodium greater than
150 mEq/L should make one suspect a diagnosis of diabetes
insipidus.
Management of Hypernatremia. Regardless of the etiol-
ogy of the hypernatremia, the symptoms are predominantly
neurologic. Headache, weakness, dizziness, irritability, and,
in severe cases, seizures and coma can be observed. In cases
of a TBW deficit, when dehydration is severe, hypotension,
decreased central venous pressure, tachycardia, and oli-
guria are manifested. Glomerular filtration rate is decreased,
and hence the blood urea nitrogen (BUN) and serum creat-
inine (Cr) are likely to increase. Peripheral edema is absent,
indicating decreases in TBW are responsible for the hyper-
natremia. In cases of total body excess of sodium, hyperten-
sion and edema can be part of the clinical presentation.
Treatment of hypernatremia is directed at treating both the
high sodium and the underlying disease. Patients with cen-
tral diabetes insipidus should receive supplemental ADH in
the form of desmopressin (DDAVP, a synthetic peptide with
ADH activity). In cases of hypernatremia caused by a TBW
deficit, free water must be replaced judiciously. The sodium
level should be lowered by 0.5 mEq/h, or 12 mEq/day, to
avoid the development of cerebral edema. The rate of free-
water repletion should be half the total deficit administered
in the first 12 to 24 hours, with slow correction thereafter.
Outcomes. For the anesthesiologist, managing hypernatre-
mia centers on hypotension, and secondarily on dehydra-
tion and drug-induced hypovolemia. These can be made
worse by positive pressure ventilation. These patients could
theoretically experience an enhanced sensitivity to nonde-
polarizing neuromuscular blockers because they have a
decreased volume of distribution for these drugs. When
there is an excess of total body sodium, the anesthesiologist
must be aware of an increased intravascular volume. A
2016 study by Ceconi et al. involving over 45,000 noncar-
diac surgical patients found that a preoperative Na value of
>150 mmol/L was independently associated with increased
mortality (odds ratio 3.4 [2.0–6.0]).102 With these data, it
seems reasonable to assign this value as a cutoff for proceed-
ing with elective surgery.
POTASSIUM
Potassium differs greatly from sodium in terms of body dis-
tribution. Approximately 98% of the body’s potassium

stores are intracellular. Total body and serum potassium
levels are under hormonal and renal regulation. Acute
changes in serum potassium levels are less well tolerated
than chronic changes, because chronic changes allow equil-
ibration of serum and intracellular stores over time to return
the resting membrane potential of excitable cells (cardiac
and CNS) to approximately normal levels.
Hypokalemia
Hypokalemia (<3.5 mEq/L) can be seen with decreased
intake, increased entry into cells (alkalosis, insulin, and beta
2 adrenergic administration), increased gastrointestinal or
urinary losses, and excessive sweating. Decreased serum
potassium levels may reflect large changes in total body
potassium stores. A decrease in the serum potassium of
1 mEq/L may represent a total body potassium deficit of
50–200 mEq. Hypokalemia can result in muscle weakness
and paralysis, rhabdomyolysis (seen with serum levels
<2.5 mEq/L), hyperglycemia, and renal dysfunction.
Between 10% and 50% of patients taking diuretic drugs
will become hypokalemic. However, many primary care
providers are reluctant to prescribe oral potassium supple-
mentation, even though patients taking diuretics experi-
ence some degree of hypokalemia.103,104
The most concerning manifestations of hypokalemia
involve the cardiovascular system. These can range from
autonomic neuropathy, decreased contractility, or distur-
bances in conduction that can result in serious life-
threatening arrhythmias. ECG changes include ST segment
abnormalities (usually depression) flattening or inversion of
the T wave, and gradual increase in the U wave ampli-
tude.105 These ECG changes almost always manifest when
the serum potassium level is <2.3 mEq/L.106 Morphologic
ECG changes do not correlate with the severity of potassium
depletion. In addition, although U waves are not specific for
hypokalemia, they are sensitive indicators of this condition.
Cardiac ischemia, left ventricular hypertrophy, and digitalis
use all increase the risk of arrhythmias from hypokalemia.
Treatment. The main principle in the treatment of hypoka-
lemia is that rapid administration is potentially harmful and
should only be administered in life-threatening situations.
The recommended replacement rate for a typical adult is
10 to 20 mEq/h with constant ECG monitoring.
Outcomes. There are no data revealing increased morbid-
ity or mortality in patients undergoing anesthesia with a
potassium level of at least 2.6 mEq/L. As a result, the deci-
sion to proceed with anesthesia or surgery in the face of
hypokalemia is multifactorial.107,108 The urgency of the
operation, acid base balance, medications history, onset,
and degree of the abnormality must all be taken into consid-
eration. Furthermore, there are retrospective data attribut-
ing considerable risk to potassium administration.109 In one
study involving a cohort of 16,048 hospitalized patients,
1910 of these patients were given oral potassium supple-
ments. Hyperkalemia contributed to death in seven of these
patients and the incidence of complications of potassium
therapy was 1 in 250.
Three separate studies examined the effects of modest
hypokalemia by prospectively examining the incidence of
arrythmias in patients with varying levels of preoperative
40 • Endocrine and Electrolyte Disorders 599
potassium.108,110 Vitez et al. found no difference in the inci-
dence of arrythmias among moderately hypokalemic
(K ¼ 3–3.4 mEq/L), severely hypokalemic (K < 2.9 mEq/L)
or normokalemic patients (K > 3.4 mEq/L).108 Another
study involving 2402 patients undergoing elective coronary
artery bypass grafting reported that a serum potassium level
less than 3.5 mEq/L was predictive of serious perioperative
arrythmias, intraoperative arrhythmia, and postoperative
atrial fibrillation/flutter.110
Although it is recommended that hypokalemic patients be
given some form of potassium supplementation before elec-
tive surgery, the evidence for this is uncertain. One study
administered 50 mg of hydrochlorthiazide to 21 patients
twice a day for 4 weeks. These patients had become hypoka-
lemic secondary to diuretic therapy and had no history of
demonstrable cardiac disease or other medication ingestion.
Ambulatory ECG recordings revealed ventricular arrythmias,
ranging from premature ventricular contractions (PVCs) to
ventricular tachycardia, in 33% of the patients. Potassium
repletion decreased the number of ventricular ectopic beats
per patient from 71.2 to 5.4 per hour.111
There are varying patient sensitivities to degree of potas-
sium depletion. Most studies have demonstrated complica-
tions resulting from moderate and severe potassium
depletion.103,111,112 However, even minor potassium deple-
tion can result in ventricular ectopy. The Multiple Risk Fac-
tor Intervention Trial involved 361,662 patients, more than
2000 of whom were given diuretics for hypertension. The
reduction in serum potassium was noted to be greater in
patients with PVCs.103
It is difficult to recommend a certain level of serum potas-
sium below which one should cancel elective surgery. Some
experts would recommend postponing elective surgery if the
serum level is below 2.8 mEq/L. However, the etiology of the
hypokalemia and the acuity of the hypokalemic state must
be considered. This takes on greater importance as more
data are emerging on the safety of hypokalemia and the
dangers of replacing potassium quickly in the hospital
environment.
Hyperkalemia
Hyperkalemia (>5.5 mEq/L) occurs from three major pro-
cesses: increased intake, decreased urinary excretion, and
transcellular shifts (diabetic ketoacidosis [DKA], acidosis,
beta-adrenergic blockade, succinylcholine administration,
digitalis overdose). Of particular importance to the anesthe-
siologist is the reperfusion of a large vascular bed after a
period of prolonged ischemia, as might occur during the
reperfusion of a newly transplanted liver. The acidosis in
the affected area causes an outflow of intracellular potas-
sium, hence upon reperfusion patients could receive a large
bolus of potassium that cannot be redistributed quickly,
which could result in fatal hyperkalemia. Factitious hyper-
kalemia can result from the lysis of cellular components,
particularly involving blood products. Adrenal insufficiency
is another potential cause of hyperkalemia (see later).
The most significant problem facing anesthesiologists in
managing the hyperkalemic patient involves abnormal car-
diac function. Hyperkalemia lowers the resting membrane
potential of cardiac conductive cells and decreases action
potential duration and upstroke velocity. In severe states
of hyperkalemia, this decreased rate of depolarization and
600 PART IV • Early Postoperative Care
repolarization in other areas of the myocardium produces a
progressive widening of the QRS complex that merges with
the T wave, resulting in a sine wave on the ECG.
The earliest manifestations of hyperkalemia are the nar-
rowing and peaking of the T wave. These are not diagnostic
of hyperkalemia, but T waves are almost always peaked
when serum potassium levels are 7 to 9 mEq/L. When potas-
sium levels exceed 6.7 mEq/L, the degree of hyperkalemia
and duration of a QRS complex correlate closely. As serum
potassium levels progress beyond 7 mEq/L atrial conduction
disturbances appear, such as a decrease in P-wave ampli-
tude and an increase in the PR interval. As levels approach
10 to 12 mEq/L progressive widening of the QRS complex to
sine wave, ventricular fibrillation, or even asystole may
occur.106
If significant ECG abnormalities are present, 5–10 mL of a
10% solution of calcium chloride should be administered
intravenously over 3–5 minutes to stabilize the myocardial
cell membrane. Calcium chloride’s salutary effects on the
myocardium last only 30 to 60 minutes. Other therapies
for hyperkalemia that should be initiated are insulin (10
units of Reg IV), glucose (50 g of 50%), sodium bicarbonate
(1 mmol/kg), and hyperventilation. Insulin, glucose, and
bicarbonate will lower serum potassium levels within 10
to 20 minutes, and the effects will last for 4 to 6 hours. Out-
side the operating room, dialysis, diuretics, B-adrenergic
agonists, and exchange resins are accepted therapies.
Acute hyperkalemia is more poorly tolerated than
chronic hyperkalemia. The most common cause of chronic
hyperkalemia is renal failure. It is recommended that any
patient with a serum potassium level >5.5 mEq/L should
undergo ECG evaluation preoperatively. It is difficult to rec-
ommend a serum potassium level above which one should
cancel elective surgery. Some experts recommend 5.9 mEq/
L as a safe cutoff because ECG changes start to become man-
ifest at levels of 6.0 mEq/L or greater. It is important to con-
sider dialytic therapy before elective surgery for potassium
levels exceeding 6.0 mEq/L, although data are also lacking
here. Most clinicians agree that clinical presentation and
ECG changes are the most important guides.
MAGNESIUM
After potassium, magnesium is the second most abundant
intracellular cation. Of total body magnesium, 99% is
intracellular (primarily in the skeleton) and only 1% is
extracellular. Of the total circulating magnesium (0.8–
1.2 mmol/L [1.9–2.9 mg/dL]), 50% is free and physiologi-
cally active. Serum magnesium is regulated primarily by
intrinsic renal mechanisms. Magnesium is an essential
cofactor in more than 300 cellular reactions, including
energy metabolism and maintenance of the Na+/K+-ATPase
pump. Magnesium also modulates vascular tone, is an
endogenous Ca2+ antagonist, and plays a role in nucleic
acid and protein synthesis.
Hypomagnesemia
Hypomagnesemia (<1.5 mEq/L) primarily arises from three
causes: (1) intracellular serum shifts, (2) gastrointestinal
losses, and (3) renal losses. Common causes of transcellular
shifts would include chelation by tissues during pancreatitis
and rhabdomyolysis, or insulin therapy. Excessive GI losses
can result from malabsorption, diarrhea, nasogastric suc-
tion, or fistulas. Chronic alcohol ingestion leads to sig-
nificant magnesium loss and most hospitalized patients
are hypomagnesemic. The most common cause of renal
wasting is drug toxicity. Cyclosporine, amphotericin B,
digitalis, aminoglycosides, and diuretics are frequently
implicated.
Hypomagnesemia affects multiple organ systems, includ-
ing the cardiovascular (arrythmias, vasospasm, angina),
neuromuscular (weakness, spasms, seizures, tetany), and
gastrointestinal systems (anorexia, dysphagia, nausea).
Treatment of hypomagnesemia depends on the acuity or
chronicity of the disorder. Acute hypomagnesemia should
be treated intravenously with magnesium sulfate. Hypo-
magnesemia is often accompanied by hypokalemia and
potassium should also be replenished. Treatment is gener-
ally with 1–2 mEq/kg of magnesium sulfate given over 8–
12 hours, with careful periodic assessment of electrolyte
levels. One concerning aspect of magnesium deficiency is
that cardiac arrhythmias can be seen with deficient stores
of magnesium not reflected in the serum levels. For acute
life-threatening cardiac arrhythmias, 2–4 g of magnesium
sulfate should be administered over 5 minutes, while closely
monitoring blood pressure and heart rate. Arterial pressure,
deep tendon reflexes, and serum magnesium concentration
should be monitored during symptomatic, life-threatening
replacement. In severe depletion without cardiac arrhyth-
mias, the period of administration can be extended from
5 minutes to 3 hours. Chronic asymptomatic magnesium
depletion is usually treated with oral magnesium.
Like most electrolyte abnormalities, the importance of
magnesium deficiency relates to the underlying pathophys-
iologic process causing the deficiency. Clearly associated
conditions such as alcoholism and malnutrition contribute
to anesthetic risk. There are no data relating to hypomagne-
semia, which itself contributes to the risk of anesthesia and
outcome.
There is a theoretical risk that low serum magnesium
levels could lessen the effectiveness of neuromuscular block-
ing agents, but this possibility has never been investigated.
There are data on the management of patients in coronary
care units showing that magnesium infusion can reduce the
incidence and severity of cardiac arrhythmias. There are
also data in the perioperative setting showing magnesium
may decrease the incidence of adrenergic mediated arrhyth-
mias, without interfering with the bronchodilating efficacy
of beta agonists, while at the same time contributing to the
bronchiolar smooth muscle relaxation.113
The role of magnesium in the setting of an acute myocar-
dial infarction has been studied extensively. The theoretical
benefits of this electrolyte on the myocardium are extensive.
First, magnesium plays a key role in the regulation of coro-
nary vascular tone. Second, it helps to stabilize the myocar-
dial membrane and reduce the incidence of dysrhythmias.
Finally, magnesium has been shown to decrease platelet
aggregation in vitro and in vivo. These properties have
made magnesium an attractive therapy for patients present-
ing with myocardial ischemia.
Small preliminary studies showed a significant mortality
decrease when patients were treated with magnesium. Sub-
sequent larger studies, however, have failed to duplicate
these early results. Thus at present magnesium replacement

is not recommended in the setting of myocardial ischemia
unless documented hypomagnesemia is present.114
Furthermore, while magnesium is used extensively in
cardiac surgery to reduce the incidence of both atrial and
ventricular dysrhythmias, there is some evidence that mag-
nesium might have an adverse effect on platelet function.
Although this effect has been demonstrated in a recent
study, there have been no studies to show that magnesium
causes increased bleeding during the post-bypass period.115
Thus, in the absence of data to show an increased risk of
bleeding, the use of magnesium is still recommended based
on its salutary effects on the myocardium in reducing
dysrhythmias.
Hypermagnesemia
Hypermagnesemia (>2.5 mEq/L) is extremely uncommon
in patients with normal renal function. Hypermagnesemia
is commonly seen after ingestion of magnesium-containing
antacids or laxatives in patients with renal failure. Lithium
intoxication, hypothyroidism, and adrenal insufficiency are
other causes. Importantly, clinical effects are not closely
related to serum measurements of magnesium. Central
and peripheral neuromuscular effects are the major compli-
cations of hypermagnesemia. These include altered mental
status, coma, decreased deep tendon reflexes, respiratory
muscle weakness, and paralysis.
Electrocardiographic changes associated with hypermag-
nesemia do correspond to serum levels. Between 5 and
10 mg/dL, depressed cardiac conduction, widened QRS
complexes, and prolonged P–Q intervals appear. Sedation,
hypoventilation, decreased deep tendon reflexes, and mus-
cle weakness appear at levels between 20 and 34 mg/dL,
with hypotension, bradycardia, and diffuse vasodilation
occurring between 24 and 48 mg/dL. Areflexia, coma,
and respiratory paralysis occur at 48 to 72 mg/dL.
Treatment. The removal of magnesium can be accom-
plished with fluid loading followed by diuresis. In life-
threatening cases, IV calcium can be administered to
reverse neuromuscular and cardiac membrane instability
while magnesium is removed via dialysis. Of prime impor-
tance to the anesthesiologist is determining the underlying
cause of hypermagnesemia. Euvolemia and the mainte-
nance of acid-base homeostasis are of critical importance
because they both contribute to hypermagnesemia. Because
hypermagnesemia potentiates the action of both depolariz-
ing and nondepolarizing muscle relaxants, it may be neces-
sary to decrease the initial doses of these drugs. Monitoring
with a peripheral nerve stimulator is essential. Cardiac
depression and vasodilation produced by anesthetic drugs
could be accentuated in the presence of hypermagnesemia.
The clinical significance of interactions between magne-
sium and anesthetic drugs has never been investigated. Out-
come data are lacking relating hypermagnesemia to
postanesthetic outcomes.
PHOSPHOROUS
Phosphorous in the form of phosphate is distributed in equal
concentrations throughout the intracellular and extracellu-
lar compartments. Of body phosphate 85% is present in
40 • Endocrine and Electrolyte Disorders 601
bone, 55% circulates as the free ion, 33% is in complexed
form, and 12% is protein bound. Normal serum phosphate
levels range from 1.3 to 8.0 mmol/L (12.3 to 7.6 mg/dL).
Serum phosphate is under the control of both the parathy-
roid gland and the kidney. Phosphate plays an integral role
in energy storage and is responsible for the high energy
phosphate bond in adenosine triphosphate and creatine
phosphate. Phosphate is a major component of nucleic
acids, phospholipids, and cellular membranes. It is also a
part of vital second messenger systems including cyclic
adenosine monophosphate and phosphatidylinositol. In
addition, it plays a critically important role in the
offloading of oxygen from hemoglobin as part of the 2,3-
diphosphoglycerate molecule.
Hypophosphatemia
Clinically significant hypophosphatemia occurs when serum
levels fall below 2 mg/dL and is considered severe when
serum phosphorous levels fall below 1.0 mg/dL. Major etiolo-
gies of hypophosphatemia include intracellular shifts, sepsis,
alkalosis, alcoholism (50% of hospitalized alcoholics), diabetic
ketoacidosis, and salicylate poisoning. Similar to magnesium
and calcium, low levels of phosphorous can have disastrous
neuromuscular complications, including respiratory muscle
paralysis, CNS changes, and skeletal myopathy. Hematologic
manifestations (hemolysis and impaired platelet function) are
seen less commonly.
As with all electrolyte disorders, the underlying etiology
should be clearly identified. This usually involves the sam-
pling of arterial blood gases and the measurement of ionized
calcium and magnesium and of serum and urinary phospho-
rous. A 24-hour urine phosphate level greater than 100 mg
when the serum phosphate level is less than 2 mg/dL is sug-
gestive of renal disease. Treatment includes intravenous
potassium phosphate (2.5–5.0 mg/kg every 6 hours). The
rate of administration should not exceed 0.25 mmol/kg over
4 to 6 hours to avoid hypocalcemia and tissue damage. It is
critically important to avoid hyperphosphatemia because of
the ensuing hypocalcemia that results from these elements
binding together. Calcium phosphate deposition can occur
in the eyes, heart, lung, vasculature, and kidneys and is seen
in long-term dialysis patients. For phosphorous levels greater
than 2 mg/dL, an oral sodium phosphate solution can be
used. This is usually limited to 30 mmol/day (1 g/day)
because of severe diarrhea.
Data are currently lacking on the management of hypo-
phosphatemia related to anesthetic outcome.
Hyperphosphatemia
Hyperphosphatemia (serum phosphate level >4.5 mg/dL)
can result from increased intestinal absorption, parenteral
administration, renal dysfunction, frank renal failure,
hyperthyroidism, or massive extracellular shifts, such as
seen in sepsis, hypothermia, or hyperthermia, rhabdomyol-
ysis, or tumor lysis syndromes. Clinical manifestations are
few and usually symptoms of the underlying cause predom-
inate. Hypoparathyroidism can cause hyperphosphatemia
in the presence of normal renal function. A rapid rise in
serum phosphate concentration can lead to severe hypocal-
cemia, and this can result in frank precipitation of calcium
and phosphate.
602 PART IV • Early Postoperative Care
First-line therapy includes the administration of phosphate-
binding antacids such as aluminum-containing antacids and
sucralfate, calcium citrate, or calcium carbonate. High rates of
IV fluids and acetazolamide are effective at increasing urine
phosphate excretion. Phosphorous intake should be restricted
to less than 200 mg/day. Dialysis is indicated in patients with
renal failure.
CALCIUM
Calcium is a ubiquitous cation that is involved in many cel-
lular functions. These include the duration and strength of
cardiac muscle contraction, smooth muscle contraction in
blood vessels airways and the uterus, and apoptosis.
Calcium also has an effect on platelet aggregation and
function.116-120
Calcium exists in the extracellular plasma in the free ion-
ized state as well as bound to other molecules. The majority
of bound calcium (80%) associates with albumin. Mathe-
matical formulae correcting for changing albumin concen-
trations can be inaccurate and therefore calcium should be
measured to ascertain accurate calcium concentrations ion-
ized.121 Of the total calcium 45% is biologically active and
exists in the ionized form with a normal concentration of
4.5–5.0 mg/dL.
Ionized calcium concentrations are affected by the pH of
the blood. An increase in one pH unit will decrease the ion-
ized calcium concentration by 0.36 mmol/L; thus it is not
surprising that patients with a metabolic alkalosis are usu-
ally hypocalcemic.122,123
Calcium homeostasis is maintained through the actions of
parathyroid hormone (PTH), calcitonin, and vitamin D act-
ing primarily on the bone, kidney, and gastrointestinal tract.
Hypocalcemia
Hypocalcemia is defined as a decrease in serum calcium
below 4.5 mg/dL. Its most common perioperative cause is
hypoparathyroidism after thyroid surgery. Hypocalcemia
can also arise from a variety of medical conditions, such
as pancreatitis, vitamin D deficiency secondary to malnutri-
tion, meningococcal sepsis, and critical illness in general.
Hypocalcemia can also be caused by shifts in intravascular
volume or dialysis. Here sudden increases in anions that
bind calcium (e.g., citrate and phosphate) can lead to
hypocalcemia.
Clinical manifestations of hypocalcemia include perioral
numbness, paresthesia, muscle cramps, and mental status
changes such as irritability. As hypocalcemia increases in
severity there are neuromuscular and cardiac findings,
including Chvostek’s (spasm of facial muscles elicited by tap-
ping the facial nerve anterior to the ear) and Trousseau’s
signs (carpal spasm produced by wrist pressure induced
by blood pressure cuff inflation for 3–5 minutes or by
tapping on the median nerve). Mental status changes,
seizures tetany, hypotension, and heart failure also may
occur.124,125
Acutely, hypocalcemia decreases cardiac function by
lengthening phase 2 of the cardiac action potential resulting
in prolongation of the ST segment and the QT interval on
the ECG. This is significant because QT lengthening is an
independent risk factor for cardiac arrhythmias and sudden
death. Patients who present to the hospital in cardiac arrest
are often hypocalcemic.126,127 Hypocalcemia can lead to
cardiac failure and in patients with underlying heart disease
who are on beta blockers, hypocalcemia can precipitate
severe cardiac failure.128,129 Although patients with long-
standing hypocalcemia may have normal cardiac function,
it is desirable to keep their calcium concentrations in the
normal range, especially in the setting of underlying heart
disease. The coexistence of other electrolyte abnormalities
such as alterations in magnesium concentration should also
be considered.130
Successful management of hypocalcemia involves first
correcting any underlying acid base derangements. When
plasma concentrations of calcium fall below 3.5 mg/dL or
when symptoms of hypocalcemia (hypotension, tetany)
manifest, treatment is recommended. Treatment consists
of intravenous administration of a calcium salt, either cal-
cium chloride (1.36 mEq/mL) or calcium gluconate
(0.45 mEq/mL). Calcium chloride (2.5 mg/kg IV) or calcium
gluconate (7.5 mg/kg IV) are equivalent in terms of
their ability to increase the calcium concentration. Calcium
is generally administered until serum calcium concentra-
tions approximate 4 mEq/L or the ECG tracing returns to
normal.131
The goal in the anesthetic management of the hypocalce-
mic patient is to identify the etiology of this condition, to
prevent any further decreases in the serum calcium concen-
trations, and to treat the adverse cardiovascular effects of
hypocalcemia.
Intraoperative hypotension may represent an exagger-
ated cardiac depression produced by anesthetic drugs in
the setting of hypocalcemia. Responses to nondepolarizing
muscle relaxants may be exaggerated in the setting of
hypocalcemia. Coagulation abnormalities, skeletal muscle
spasm, and laryngospasm may all accompany acute
decreases in the serum calcium concentration.
Rapid infusion of blood (e.g., 500 mL every 5 to
10 minutes), decreased metabolism or elimination of citrate,
cirrhosis of the liver, or renal dysfunction can all precipitate
hypocalcemia. There are few data to support the predisposi-
tion to citrate intoxication in the setting of hypocalcemia.132
Continuous ECG and blood pressure monitoring should be
continued in the perioperative period in all patients with
hypocalcemia.
At present there are no compelling data on the mana-
gement of perioperative hypocalcemia and anesthetic
outcome.
Hypercalcemia
Hypercalcemia is defined as a serum calcium concentration
greater than 5.5 mEq/L. It is most commonly caused by
hyperparathyroidism and malignant disorders that release
PTH-related peptide (PTHrp) from tumor cells. Granuloma-
tous diseases with pulmonary involvement (such as sarcoid-
osis), vitamin D intoxication and immobilization are less
common causes. In addition, drugs such as thiazide diuretics
and lithium can cause hypercalcemia.133,134
The clinical manifestations of hypercalcemia arise pri-
marily from the actions on the central nervous system, neu-
romuscular junction, heart, kidneys, and gastrointestinal
tract. The earliest signs and symptoms involve sedation
and emesis. Increased serum calcium concentrations
(7 to 8 mEq/L) interferes with renal concentrating ability

resulting in polyuria. Increased calcium concentrations can
contribute to the formation of renal calculi and eventually
oliguric renal failure. Serum concentrations exceeding
8 mEq/L result in cardiac conduction disturbances, such
as prolonged PR interval, widened QRS complexes, and
shortened QT intervals on the ECG tracing.
The cornerstone of treatment for hypercalcemia is
hydration with 0.9% NaCl, at a rate of approximately
150 mL/h.135 This serves to lower calcium concentration
by dilution and sodium inhibits the renal tubular absorp-
tion of calcium. Combining saline resuscitation with furo-
semide diuresis every 4 hours decreases the risk of volume
overload and aids in calcium excretion. A therapeutic goal
should be a daily urine output of 3 to 5 L. It is important to
assure ambulation in this setting to decrease the calcium
release from bone associated with immobilization. Hemodi-
alysis and bisphosphonate therapy can be used in life-
threatening cases of hypercalcemia to lower serum con-
centrations quickly. Calcitonin is effective for immediate
lowering of the serum calcium concentration, but its
effects are transient. Mithramycin is also effective in lower-
ing calcium concentrations in the setting of malignancy,
but thrombocytopenia, hepatotoxicity, and nephrotoxicity
limit its use.
Anesthetic management in the presence of hypercalce-
mia includes the previously mentioned saline resuscitation
and diuresis. Continuous monitoring of the ECG periopera-
tively is necessary to monitor for adverse effects of increased
calcium on cardiac conduction. Maintenance of acid-base
homeostasis should be of prime importance because alkalo-
sis could serve to lower the potassium concentration and
leave the actions of calcium unopposed. The actions of non-
depolarizing muscle relaxants are not well defined, but the
presence of skeletal muscle weakness in the state of hyper-
kalemia may necessitate decreasing the doses of these drugs.
CHLORIDE
Chloride is the major extracellular anion in the ECF and is
the major reabsorbable anion in the renal filtrate. It has rel-
evance for the anesthesiologist in relation to two distinct
acid-base abnormalities.
Hypochloremia
Hypochloremia (<96 mEq/L) results from excessive loss in
gastric secretions or urine resulting in hypochloremic alka-
losis. Chloride depletion results in reduced delivery of chlo-
ride to the collecting tubules resulting in limited bicarbonate
excretion secondary to the interdependence of bicarbonate-
chloride exchange. If less chloride is available for reabsorp-
tion, a greater amount of sodium must be reabsorbed with
bicarbonate through increased proton secretion. Thus met-
abolic alkalosis can generally be classified as chloride
responsive or chloride resistant.
A chloride-responsive alkalosis (urinary chloride <15
mEq/L) constitutes the majority of cases of metabolic alkalosis
in hospitalized patients. It results from gastric acid loss,
diuretic therapy, volume depletion, or renal compensation
for hypercapnia. Chloride replacement is the mainstay of
management in this condition. Because volume depletion is
a common etiology, 0.9% NaCl infusion is the most common
means of chloride replacement.
40 • Endocrine and Electrolyte Disorders 603
A chloride-resistant alkalosis (urinary chloride >25 mEq/L)
is rarely encountered by the anesthesiologist. It most com-
monly results from mineralocorticoid excess or potassium
depletion. The mainstay of therapy is potassium replacement
in the form of potassium chloride.
Hyperchloremia
Hyperchloremic (>106 mEq/L) acidosis is frequently encoun-
tered by the anesthesiologist in the perioperative setting. It
most commonly accompanies large volume administration
of 0.9% NaCl solution. It can also occur in the setting of acute
normovolemic hemodilution with a 5% albumin solution or a
6% hetastarch solution.136 Hyperchloremic acidosis is some-
times confused with dilutional acidosis.137 In hyperchloremic
acidosis, serum sodium should remain the same or possibly
increase because of chloride gain, most likely through NaCl.
In dilutional acidosis, the serum sodium decreases because of
the alteration of sodium and chloride in free water.
The clinical significance of hyperchloremic acidosis is
accumulating. Several studies of the critically ill have dem-
onstrated an increase in the risk of acute kidney injury and
mortality with the use of isotonic saline and its antecedent
hyperchloremia.138–140 In emergency department patients,
these adverse outcomes were not observed.141 However, in
patients undergoing noncardiac surgery, a recent retrospec-
tive propensity matched study did find that mortality was
increased with increases in serum chloride.142 With these
data, it is hard to argue for the use of normal saline in almost
any patient coming for surgery or requiring resuscitation.
The only patient population where normal saline would
be considered appropriate is the traumatically brain injured
patient or the patient presenting for neurosurgery. There is
a theoretical concern that the use of a slightly more hypo-
tonic fluid (such as Ringer’s lactate) in this patient popula-
tion may worsen cerebral edema.
Conclusion
As the prevalence of diabetes and obesity continues to
increase, endocrine and electrolyte disturbances will
become more common in the perioperative setting. The
manner in which the anesthesiologist addresses these disor-
ders can impact significantly on perioperative morbidity and
mortality. As scientific discovery advances the way we man-
age these conditions will continue to evolve.
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 41 Improving Pain and Outcomes
in the Perioperative Setting
NEIL RAY and THOMAS BUCHHEIT
The Growth of Unidimensional
Pain Assessment Tools
A subjective and personal experience, pain remains diffi-
cult to quantify within the confines of empirically based
medical tradition. Regardless of this challenge, however,
management still necessitates accurate and timely assess-
ment, particularly in the perioperative patient.1 The pro-
motion of pain as a fifth vital sign in the 1990s2,3 has
been criticized for its potential unintended consequences,4
however, this initiative also highlighted the limitations of
our assessment tools and encouraged the development of
improved methods to evaluate pain and its modifying
factors.
As the Numeric Rating Scale (NRS) and Visual Analog
Scale (VAS) became common standards for the regular
interval assessment of patients in the perioperative setting,
it was evident that these self-reporting tools were superior
to health professional estimates and minimized the impact
of cultural and racial bias.5 Multiple studies comparing the
NRS and VAS scales consistently demonstrated similar
sensitivities and superiority to the Verbal Rating Scales
(VRS) in their ability to detect differences in both acute
and cancer pain.6–8 Temporally-based assessments and
measurement of pain trajectory have also become increas-
ingly commonplace.9
However, it has become increasingly evident that single-
dimension pain tools lack the sophistication needed to guide
effective therapies. In fact, a large retrospective review of
medical records before and after the implementation of
the “Pain as the 5th Vital Sign” initiative did not find any
improvement in quality of pain care, especially with individ-
uals with severe pain documented on NRS.10 Clinicians and
investigators increasingly appreciated the impact of anxiety,
depression, addiction, and the psychosocial context of the
experience.11 For example, in the primary care setting,
the NRS was found to have only modest accuracy for iden-
tifying patients with clinically important pain, defined as
pain that interferes with function or intense enough to
require a physician visit.12 Single dimension pain tools were
inherently subjective and also not generalizable. Despite
qualifying descriptions, patient A’s pain score of 4 may
equate to patient B’s pain score of 6. These limitations in
the unidimensional assessment of perioperative pain neces-
sitated a new approach.
The Importance of
Multidimensional Assessment
In response to these shortcomings, a focus on multidimen-
sional assessment models has grown to evaluate properly
the complexity, the modifying factors, and the associated
disability of pain. Traditionally used in the chronic pain set-
ting, tools such as the McGill Pain Questionnaire and Brief
Pain Inventory (BPI) have been further validated in the
postoperative setting.13,14 The McGill Pain Questionnaire
provides a description of not only the intensity, but also
quality of pain a patient is experiencing and can be used
to monitor the efficacy of interventions and pain trajectory
(ideal for the perioperative setting). The BPI accurately
assesses pain severity and self-perceived functional limita-
tions. Similar to the McGill Pain Questionnaire, BPI can
monitor responsiveness to both behavioral and pharmaco-
logic interventions. Another tool, the Multidimensional
Affect and Pain Survey (MAPS) was designed to assess three
main clusters: somatosensory pain, emotional pain, and
well-being. The preoperative use of MAPS has shown to pre-
dict postoperative opioid usage.15 An additional instrument,
the Pain Catastrophizing Scale (PCS) is an important predic-
tor of functionality and disability. PCS scores measure cata-
strophic thinking related to pain and have been shown to
correlate significantly with postoperative pain scores, partic-
ularly during activity following various types of surger-
ies.16–18 Lastly, it is well known that concomitant
psychological factors such as anxiety and depression modu-
late the experience and perception of pain in the periopera-
tive period and the chronification of acute pain.19,20
Consistently, preoperative anxiety as measured by the Hos-
pital Anxiety and Depression Scale (HADS) and State-Trait
Anxiety Inventory have also been shown to correlate with
the severity of postoperative pain.16
An Increased Focus on
Perioperative Functional
Outcomes
The most valuable assessments in the perioperative period
may be those that measure function along with pain.6
The evaluation of functional limitation during required
607
608 PART IV • Early Postoperative Care

postoperative physical activities is noted as critical to the
recovery trajectory.21 For example, measuring whether
pain limits a patient’s ability to take deep breaths, cough
after thoracic surgery, or ambulate after orthopedic surgery
may be more important to overall outcomes than simply
measuring pain during rest. With a growing focus on
function and recovery along with the psychological com-
orbidities associated with pain, the use of these multidi-
mensional tools has assumed a prominent role in guiding
the prediction of pain in the perioperative period.22
Table 41.1 is a summary and comparison of common
multidimensional pain outcome tools that we recommend
to assess and predict pain more fully in perioperative period.
Table 41.2 provides appropriate clinical settings and popu-
lations for commonly used psychological assessment tools.
As shown, there are a variety of useful and predictive
tools that can be used in the perioperative period with the
opportunity to tailor choices to the particular needs of both
patient population and health system. We recommend the
use of these multidimensional pain assessments in conjunc-
tion with functional activity outcomes to assess complicated
patients properly in the perioperative setting.
Future Directions: Risk Predictive
Tools and Personalized Pain
Medicine
A critical aspect in improving perioperative outcomes is the
ability to identify patients at risk of delayed recovery or the
development of chronic postsurgical pain. This concept is
further supported by growing evidence that health-care uti-
lization is reduced with intensive multidisciplinary manage-
ment programs for patients on chronic opioids,23,24 a major
risk factor for chronic postsurgical pain.25,26 Systematic
identification of patients at risk is an important step in the
process of focusing resources where needed to improve
perioperative care.
Clinical Phenotyping: Cluster
Analysis
Beyond the multidimensional assessment instruments dis-
cussed, there are several perioperative risk predictive tools
that are based on systemic disease severity,27–29 as well
as organ-specific practice guidelines for surgical patients
with cardiac,30 liver,31 and renal disease.32 Research to date
has established that chronic opioid use25,26 and psycholog-
ical traits such as anxiety,33 depression,34 catastrophizing35
are associated with an exaggerated burden of chronic post-
surgical pain. In particular, the psychological constructs
such as catastrophizing and depression appear to be key
drivers of pain chronification and disability following sur-
gery.33,36–38 As nearly 50% of chronic pain patients have
a coexisting psychological disorder, it is intuitive that preex-
isting psychological status has a significant impact on the
incidence and severity of postsurgical chronic pain.
The importance of accurate diagnosis in painful condi-
tions has been highlighted in recent years.39 A granular
diagnostic approach has been successful in generating ther-
apeutic advances in other medical arenas40 and is a critical
step for the development of personalized pain therapies.41,42
Recent progress has been made with improved classifica-
tions of peripheral neuropathy43 and complex regional pain
syndrome,44,45 and diagnostic improvements are beginning
to drive disease-specific therapies founded upon mechanisti-
cally defined phenotypes.46,47

Table 41.1 Multidimensional pain assessment instruments.

Short Time to
Survey Population studied Validated populations forms complete Setting

McGill Pain General Primary TKA/THA; MSK and rheumatologic Yes 15–20 min Postoperative
questionnaire pain; low back pain; menstrual pain
Multidimensional Oncology patients None Yes 20–30 min Preoperative
effect and pain survey
Brief pain inventory Oncology patients, multiple Low back pain; joint pain; same-day surgery No 10 min Postoperative
languages and cultures patients

MSK, Musculoskeletal; THA, total hip arthroplasty; TKA, total knee arthroplasty.

Table 41.2 Psychiatric comorbidity assessment instruments.

Short Time to
Survey Population studied Validated populations forms complete Setting
Hospital anxiety and Outpatient medical Low back pain; noncardiac chest pain; No 2–5 min Preoperative
depression scale population cancer pain

Pain catastrophizing scale Healthy psychology Chronic MSK pain Yes 5 min Preoperative
students

MSK, Musculoskeletal.
 41 • Improving Pain and Outcomes in the Perioperative Setting
It is additionally evident that certain traits and psycholog-
ical comorbidities cluster together, creating the basis for
pain and symptom amplification.48 Utilizing validated ques-
tionnaire instruments and one psychophysical measure
(algometry to the trapezius) a methodology has recently
been developed that defines a phenotype “cluster” for
patients with subsequent chronic pain risk predictive capa-
bilities.49 Although to date this process has been used more
in patients with orofacial pain conditions, the methodologies
are not diagnosis or body region specific and promise great
utility when applied to the perioperative patient.
Genetic Risks Predictors
Our knowledge of the human genetic code50 and polymor-
phisms associated with specific chronic pain syndromes
has grown significantly in past decades.51–53 In addition
to risk prediction, initial hopes were that genetic profiling
would develop the foundation for individualized medicine,
optimizing therapy for each patient based on his/her spe-
cific genomic structure.54 There are clear associations
between inflammation, degenerative conditions, the per-
ception of pain, and individual genetic variability.55–57
Furthermore, there is evidence that genetic factors influ-
ence the trajectory of pain recovery following surgery.58
Genetic predictive capacity, especially following high
chronic pain risk surgeries such as amputation, thoracot-
omy, and mastectomy would be of significant value in
identifying, stratifying, and treating patients in need of
more intensive resources.59
Several candidate gene polymorphisms have been linked
to pain susceptibility. Notable examples include catechol-
O-methyltransferase (COMT) that modifies adrenergic
tone55 and the SCN9A gene that codes for the alpha-
subunit of a voltage-gated sodium channel (Nav1.7).60
SCN9A mutations have been noted in both gain of function
disorders such as erythromelalgia and paroxysmal extreme
pain disorder61,62 as well as loss of function conditions
such as congenital insensitivity to pain.51 Although the
implications of the SCN9A gene mutations are dramatic
when present, clinical therapeutics developed from candi-
date gene polymorphisms (SNPs) have remained
limited.54,57
In addition to candidate gene analyses, genome-wide
association studies (GWAS) have been used to improve
the study of the associations between disease and common
variants. This approach has led to insight for diseases such
as cancer63 and diabetes,64 however, GWAS findings gener-
ally only account for a fraction of the population attribut-
able risk of complex heritable traits65 and risk-predictive
abilities across the wide spectrum of surgical diseases and
procedures remain limited.66
The technique of polygenic risk scoring is now being uti-
lized in other medical arenas67 and is currently being inves-
tigated in an effort to strengthen genetic risk predictive
tools. These polygenic methodologies, based upon a compos-
ite index of intermediate phenotypes and gene polymor-
phisms, may provide significant advantages in the
identification of genetic risk factors and predictive tools for
the development of chronic postsurgical pain.
609
Biomarkers of Risk: Cytokine
Profiling
Research increasingly supports the important role of the
immune system and cytokine dysregulation in the develop-
ment and amplification of various chronic pain states.68,69
For instance, tumor necrosis factor (TNF) and interleukin-
2 (IL-2) are found to be significantly elevated in patients
with neuropathic pain conditions such as Complex
Regional Pain Syndrome (CRPS).70 The association
between a proinflammatory cytokine state and chronic
pain is additionally noted in studies of traumatic injury71
and osteoarthritis.72–74 The growing body of knowledge
around cytokine dysregulation and specific disease states
played an important role in the development of disease-
modifying therapies in conditions such as ankylosing spon-
dylitis,75,76 painful neuropathy,77,78 and arthritis,79,80
and will be critical for novel therapeutic approaches in
chronic pain. The important influence of inflammatory
cytokines in chronic pain is further supported by research
that shows improvements in proinflammatory cytokine
profiles that mirror the improvements in depression and
fatigue with successful treatment81 and that demonstrate
associations between catastrophizing and pain severity in
traumatically injured individuals.82 Research into these
unique biomarkers will continue to elucidate mechanisms
and facilitate the development of future risk–predictive
tools and tailored therapeutics.
Optimization
Pain outcome assessment and eventually prediction are
only one part of the overall story. The next step in truly
affecting outcomes is the optimization of modifiable factors
related to pain in patients prior to undergoing surgery. It has
been established that many economic and health-care uti-
lization outcomes such as increased length of stay, readmis-
sions, hospital costs, and decreased return to work are
associated with preoperative opioid use.83–85 Related to
health outcomes, one high-powered study additionally
found that chronic preoperative opioid users were signifi-
cantly more likely to undergo early total knee arthroplasty
revision.86
On a patient level, other studies have shown that preop-
erative opioid use is associated with increased postopera-
tive pain (both short and long term),87–90 increased
postoperative opioid requirements (both short and long
term),91,92 higher incidence of complications,93 and
decreased range of motion.94,95 One study by Menendez
et al. additionally demonstrated that preoperative opioid
dependence is significantly associated with increased mor-
bidity and even mortality.96 With preoperative opioids
often leading to higher operative opioid use, there are addi-
tional potential comorbidities such as acute tolerance,97
hyperalgesia,98 and increased risks of chronic postsurgical
pain.99
Because of these risks, there is a growing interest in pre-
operative optimization involving opioid weaning to improve
both patient and surgical outcomes along with economic
610 PART IV • Early Postoperative Care

and health-care utilization in these patients. Nguyen et al. these optimization techniques within the context of a
showed that patients with a 50% reduction in oral mor- patient-centered system of care will allow the matura-
phine equivalent prior to primary knee or hip arthroplasty tion of personalized perioperative pain interventions and
had greater improvements to their postoperative WOMAC, improved outcomes.
SF12 Physical Component, and UCLA activity scores com-
pared with those who did not wean. These patients also
had similar and equivalent changes in WOMAC, SF12 Phys-
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before total joint arthroplasty. J Arthroplast. 2016;31(9):282–287
Suppl.
 42 Postoperative Cognitive
Dysfunction and Delirium
MARK F. NEWMAN, MILES BERGER, and JOSEPH P. MATHEW
Introduction
Since the inception of anesthesia changed and expanded
surgery, some patients have experienced changes in cogni-
tive function postoperatively. Elderly patients are at higher
risk of these changes in neurocognitive function, probably
because of reduced cognitive reserve and increased cerebral
atherosclerosis. Changes in cognitive function are associ-
ated with impaired activities of daily living, which substan-
tially reduce the quality of life in elderly patients.1 Various
terms are used to describe changes in neurocognitive func-
tion after surgery, ranging from “postoperative delirium”
(POD) to “postoperative cognitive dysfunction” (POCD) or
“postoperative neurocognitive dysfunction” (POND). A
recent publication from the Nomenclature Consensus
Working Group recommends that “perioperative neurocog-
nitive disorders” be used as an overarching term for
cognitive impairment identified in the preoperative or post-
operative period. This includes cognitive decline diagnosed
before operation (described as neurocognitive disorder),
any form of acute event (postoperative delirium), and cog-
nitive decline diagnosed up to 30 days after the procedure
(delayed neurocognitive recovery) and up to 12 months
(postoperative neurocognitive disorder).2 For the purposes
of this chapter, focused on postoperative complications,
the term POCD is used to be consistent with the literature
quoted. It is likely that the recommendations of the nomen-
clature working group will help more clearly define the
timeline and incidence of POCD and delirium moving for-
ward; however, several of the current authors have
expressed concerns with the new recommendations.3
The pathophysiologic mechanisms that underlie postop-
erative delirium and POCD are key to defining potential
approaches to reduce their occurrence. Understanding the
etiology of these perioperative changes is complicated by
multiple factors. Clearly, anesthesia and surgery are rarely
conducted separately, therefore it is difficult to disentangle
their effects on cognition. Additionally, patients come to
the operating room with different levels of comorbid illnesses
that may affect cognition (such as cerebrovascular disease)
and different levels of protective factors that may promote
normal postoperative cognition (such as higher educational
status). The combination of these procedural and patient
factors define the key contributors to postoperative neuro-
cognitive issues.4,5
The safety of anesthesia and surgery has progressed over
several decades to the point that elderly and debilitated
patients may safely undergo increasingly complex procedures
with low risk of major morbidity or mortality; however, this
population is at increased risk of neurocognitive dysfunction.
This chapter discusses cognitive changes that are often seen
after anesthesia and surgery, how to determine which
patients are at risk of postoperative delirium and/or cognitive
dysfunction, and what clinicians can do to optimize postoper-
ative cognition. The recent consensus statement discussed
earlier has attempted to identify the clinical impact of cogni-
tive impairment associated with the perioperative period.2
Those reviews redefine POCD in terms of geriatric medicine
constructs so that the short-, medium-, and long-term
clinical and functional impact can be better appreciated or
anticipated.2,6
PERIOPERATIVE CENTRAL NERVOUS SYSTEM
INJURY OR DYSFUNCTION
Postoperative central nervous system (CNS) dysfunction
includes emergence delirium, emergence agitation, POD,
POCD, postoperative maladaptive behaviors, and postopera-
tive stroke. These diagnoses share similar features but can
be differentiated in part by their differential time courses
(Fig. 42.1).7,8 There is significant overlap in risk factors and
suspected etiology between postoperative delirium and POCD,
and delirium appears to affect the development of both early
postoperative cognitive dysfunction9,10 and longer-term cog-
nitive decline.11
POSTOPERATIVE DELIRIUM
Delirium is a disturbance in attention and awareness that
represents a change from baseline, accompanied by dis-
turbed cognition, and not caused by a preexisting disorder
or occurring in context of a severely reduced arousal level.12
Postoperative delirium rates range from 14%13 to greater
than or equal to 50%,14 perhaps reflecting differing levels
of delirium risk factors (e.g., older versus younger patients,
and others).15,16 Delirium rates are likely underreported in
routine clinical care.17
POSTOPERATIVE COGNITIVE DYSFUNCTION IN
CARDIAC SURGERY
Many studies have used preoperative and postoperative neu-
ropsychologic testing to assess POCD after surgery, with vary-
ing testing deficit thresholds used to define POCD. POCD at 1
to 3 months after cardiac surgery and noncardiac surgery
shows a wide range of reported incidence.18–20 Most studies
show postoperative cognitive dysfunction rates decrease over
time from 3 months to 1 year after surgery.19,21 A number of
613
614 PART IV • Early Postoperative Care
Time Frame of Delirium and POCD
Emergence Post-Op
Delirium Delirium
Pre-Op OR PACU 24-72 hours Post-Op
Fig. 42.1 One of the principal distinctions between postoperative (Post-Op) delirium and postoperative cognitive dysfunction (POCD) is the time frame
in which they are found. Emergence delirium occurs in the operating room (OR) or immediately after in the postanesthesia care unit (PACU). Post-
operative delirium occurs 24 to 72 hours after surgery. POCD is measured at weeks to months after surgery and anesthesia. Pre-Op, Preoperative.
(Reprinted with permission from Silverstein JH, Timberger M, Reich DL et al. Central nervous system dysfunction after noncardiac surgery and anesthesia in the
elderly. Anesthesiology 2007;106(3):622–628.)
factors are important for interpreting these studies. First,
with most neuropsychological testing, scores improve with
repeat testing during short intervals (learning effect). These
issues can be partly mitigated by including multiple individ-
ual tests to assess each cognitive domain and by using
methods such as factor analysis to create overall cognitive
domain scores.19,22 Thus, an optimal cognitive test battery
includes assessments that span different cognitive domains
and cognitive ability ranges.23Also, postoperative cognitive
changes in older adults occur superimposed on normal
age-related neurocognitive/ neurophysiologic changes,24,25
including preexisting neurodegenerative pathology. Since
Alzheimer’s disease-associated pathology begins decades
prior to observable cognitive deficits (such as memory impair-
ment),26,27 many older patients may have clinically silent
Alzheimer’s disease-associated neuropathology; these
patients are at increased risk of postoperative delirium6,28
and POCD.29,30 Many statistical or clinical thresholds have
been used to define cognitive dysfunction after surgery. Some
thresholds incorporate changes in one31 or two32 tests, some
rely on changes in larger cognitive domains, such as atten-
tion and verbal memory,19 and others measure global
change across an entire cognitive test battery.33 Depending
on the statistical thresholds and rules used to define it, POCD
may represent either a single-domain or multidomain deficit
in memory, executive function, or other affected areas. It is
unclear how long-term cognitive trajectories differ in more
detailed domain specific (memory versus executive function)
analysis. It is also important to consider the timing of preop-
erative and postoperative testing. Cognitive dysfunction early
after surgery is likely to be influenced by postoperative pain,
medications like opioids, and acute postoperative recovery.34
Global cognitive dysfunction 1 year after coronary artery
bypass graft (CABG), for example, was directly correlated
with worsened quality of life measures, and global cognitive
dysfunction and worsened quality of life 1 year after CABG
were associated with increased self-reported depressive symp-
toms (but not increased anxiety symptoms).35 A continued
correlation between overall cognitive dysfunction and quality
of life was also seen more than 5 years after cardiac surgery,
with a similar association between both measures and
Post-Op Cognitive
Dysfunction
Weeks-Months
self-reported depressive symptoms.36 This correlation
between POCD and quality of life was present across the full
range of cognitive dysfunction severity at 1 and 5 years after
surgery;35,36 even relatively minor postoperative cognitive
deficits were associated with reduced quality of life. Thus cog-
nitive dysfunction should be considered a syndrome with a
severity distribution.37,38 The idea that “subthreshold” post-
operative cognitive deficits may be significant for patients is
consistent with the emerging view in medicine that many dis-
ease processes represent a continuous spectrum rather than
dichotomous traits.
POCD ASSOCIATED WITH NONCARDIAC SURGERY
POCD, an accepted complication of cardiac surgery, has
been, until the last 20 years, less appreciated or defined after
noncardiac surgery. In 1998, the International Study of
Postoperative Cognitive Dysfunction (ISPOCD-1) evaluated
cognitive decline in 1218 elderly patients who underwent
major noncardiac surgery and found that cognitive dysfunc-
tion was present in 25% of patients 1 week after surgery and
in 10% of patients 3 months after surgery.39
To investigate further POCD after noncardiac surgery,
Monk et al. completed a prospective assessment of 1064
patients undergoing elective noncardiac surgery.40 This
assessment was divided among young (18–39 years of
age), middle-aged (40–59 years of age), and elderly
(60 years and older) patients. A group of 210 primary family
members were used as controls to provide a change
score similar to that used in the ISPOCD. The patients com-
pleted a battery of cognitive tests at baseline (preoperatively)
and at both 1 week and 3 months postoperatively.40
Fig. 42.2 shows the incidence of POCD at the hospital dis-
charge and 3-month postoperatively based on neuropsy-
chological evaluations. At hospital discharge, the
incidence of POCD was 36% in the young, 30.4% in the
middle-aged, and 41.4% in the elderly patients. The inci-
dence of cognitive decline was significantly lower in
middle-aged patients compared with elderly patients
(P ¼ 0.01), but was not different for young versus elderly
or young versus middle-aged patients. The incidence of
 42 • Postoperative Cognitive Dysfunction and Delirium 615

80

Percentage (%) of Patients with POCD

70

60

50

40
Control
30 Young
Middle-Aged
20 Elderly

10

0
Early Late
Postoperative Cognitive Testing Session
Fig. 42.2 Incidence of postoperative cognitive dysfunction (POCD) in adult patients after noncardiac surgery: Z score definition. (Modified from Monk TG,
Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108(1):18–30.)

cognitive decline was similar for control subjects of all age predictive factors for POCD at 3 months after surgery, only
groups at the first postoperative testing session: 4.1% in increasing age, lower educational level, and POCD at hospi-
young, 2.8% in middle-aged, and 5.1% in elderly patients. tal discharge remained significant in the multiple logistic
However, the differences in cognitive decline between regression analysis. The results of this trial indicate that
age-matched controls and patients were significant for all postoperative cognitive dysfunction is common in all age
age groups (P < 0.001).39 At 3 months after surgery, POCD groups at 1 week. However, at 3 months after surgery it
was identified in 5.7% of young, 5.6% of middle-aged, and is more common in the elderly with lower educational
12.7% of elderly patients. POCD was significantly higher achievement. Monk et al. not only reported on the incidence
in elderly compared to young or middle-aged patients of POCD, but also reevaluated patients at 1 year to collect
(P¼ 0.001). There was no difference in the incidence of mortality data. They found an increase in 3-month mortal-
POCD between age-matched control subjects and patients ity associated with POCD at discharge compared with those
in the young and middle-aged groups. However, elderly without POCD at discharge (P¼ 0.02). They also found that
patients exhibited a significantly greater incidence of cogni- patients with POCD at both discharge and 3 months have a
tive decline at 3 months after surgery compared with elderly significantly higher 1-year mortality rate than any other
control subjects (P< 0.001). Of the significant univariate group39,40 (Fig. 42.3).

12
*
10
1 Year Mortality Rate (%)

0
None Hospital 3 Months Hospital
Discharge Discharge + 3
Presence of POCD Months
Fig. 42.3 Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after
surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients
who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients
who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital
discharge and the late testing sessions). Hospital discharge + 3 months group was significantly different from the other 3 groups, P¼0.02*. (Reprinted with
permission from Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108(1):18–30.)
616 PART IV • Early Postoperative Care

PATHOPHYSIOLOGY OF NEUROCOGNITIVE interleukins IL-1 and IL-6, tumor necrosis factor (TNF)-α,
DYSFUNCTION AFTER SURGERY and damage-associated molecular pattern molecules such
as high mobility group box-1 and S100 calcium binding
In general, POCD is probably multifactorial.6 The risk factors proteins (Fig. 42.4).51 Systemic inflammatory mediators
and mechanism contributing to postoperative delirium and may also enter the brain as a result of postsurgical break-
postoperative cognitive dysfunction can be categorized in down of the blood–brain barrier.41,44,52–55 Blood–brain bar-
several ways. Patient risk factors are clearly defined by those rier dysfunction is frequently seen in older adults (even in
present before surgery and those present during and after the absence of surgery),56 and has been seen in 50% of
surgery and anesthesia (such as cardiopulmonary bypass patients after cardiac surgery.57 Furthermore, postoperative
or anesthetic dosage)6 (Table 42.1). These divisions are use- blood–brain barrier breakdown correlates with the degree of
ful because they help define targets for prediction or preven- cognitive dysfunction after cardiac surgery.58 Neuroinflam-
tion of POCD at a given time during perioperative care. It is mation has detrimental effects that are sufficient to cause
also important to recognize that some proposed risk factors deficits in cognition, memory, and behavior,59 and has been
and mechanisms may be modifiable while some may not be. implicated in conditions ranging from mood disorders to
Another way to categorize etiology is by potential patho- neurodegenerative disease and postoperative cognitive dys-
physiologic processes, such as inflammation, neuronal dam- function.37,60,61 Supporting the role of neuroinflammation
age, vascular damage/embolism, cerebral autoregulation in postoperative cognitive dysfunction are studies demon-
and oxygen delivery, neurodegenerative disease pathology, strating that genetic polymorphisms that modulate inflam-
and brain network dysfunction. These factors are clearly mation (e.g., in the genes CRP, SELP, GPIIIA, and iNOS)
overlapping and are discussed in the following sections. are associated with postoperative cognitive dysfunction
risk.62–64 Inflammation in cardiac surgery is exacerbated
INFLAMMATION by blood contact with foreign surfaces of the cardiopulmo-
nary bypass (CPB) circuit causing significant peripheral
Inflammation associated with surgery and anesthesia are inflammation, including multiple-fold elevations of the
thought to play a major role in delirium41,42 and postoper- proinflammatory cytokines interleukins 6 and 8 (IL-6, IL-
ative cognitive dysfunction.6,43–48 Tissue trauma during 8) also seen during noncardiac surgery.65,66 The classic
surgery leads to the release of injury-associated chemokines complement cascade can also be activated by heparin-
and cytokines.49,50 These mediators result in a systemic protamine complexes after CPB.67 Sternotomy and surgical
inflammatory response which leads to further release of incision also increases proinflammatory cytokine levels in
rats,68 and possibly in humans,69,70 although some studies
have not replicated these findings.71,72 Lastly, anesthetic
drugs themselves, both in cardiac and noncardiac surgery
Table 42.1 Modifiable, partly modifiable, and nonmodifiable can modulate inflammation. Inhaled anesthetics have
factors that may contribute to postoperative delirium and/or proinflammatory effects on microglia and opioids and hep-
postoperative cognitive dysfunction after cardiac surgery. arin can also modulate inflammation and monocyte func-
tion in vitro.73,74 Thus drugs given during surgery may
Preoperative/ have significant effects on the overall balance of pro-
postoperative Intraoperative
and anti-inflammatory cytokine levels and on patient
Modifiable (1) Preoperative blood (1) Use of outcomes.75 Taken together, these findings suggest that
pressure control cardiopulmonary exposure to anesthetics and other drugs during surgery,
bypass
(2) Preoperative (2) Temperature together with the effects of surgical trauma or other factors
glycemic control management such as the incision, median sternotomy, tissue damage,
(3) Sleep disruption/ (3) Surgery duration and ischemia reperfusion injury, may contribute to neuroin-
sleep apnea flammation and ensuing postoperative delirium and postop-
(4) Alcohol abuse (4) Arterial pressure
management
erative cognitive dysfunction. In rodent models, cardiac
(5) Postoperative (5) Glycemic control surgery causes more prolonged neuroinflammation and a
sedation, analgesia (6) Hemodilution wider spectrum of behavioral impairments than abdominal
and delirium surgery, although both surgery types reduced hippocampal
management neurogenesis rates and neurotrophic factor levels (such as
Partly (1) Patient frailty (1) Surgical approach brain-derived neurotrophic factor).76 Terrando found simi-
modifiable (2) Preoperative (i.e., median lar neuroinflammation and subsequent behavioral changes
cognitive function sternotomy versus after orthopedic surgery in mice,77 suggesting that common
(3) Preoperative lateral
neurocognitive thoracotomy), On mechanisms involving decreased hippocampal neurogen-
reserve versus Off CPB esis, spinal pain signaling, and central neuroinflammation
(4) Depression (2) Anesthetic dosage may lead to memory dysfunction after both orthopedic
and EEG responses and cardiac surgery. Blocking neuroinflammation45 and
Nonmodifiable (1) Patient chronic age (1) Direct myocardial microglial activation78 reduced postoperative memory defi-
injury cits in mouse models, although these interventions have yet
to be tested in humans. Several anti-inflammatory drug tri-
CPB, Cardiopulmonary bypass; EEG, electroencephalogram.
Modified from Berger M, Terrando N, Smith SK et al. Neurocognitive function
als have failed to prevent delirium or cognitive dysfunction
after cardiac surgery: from phenotypes to mechanisms. Anesthesiology. after cardiac surgery, including lidocaine,79 magnesium,17
2018;129(4): 829–851. complement cascade inhibitors,80 and postoperative
 42 • Postoperative Cognitive Dysfunction and Delirium 617

Fig. 42.4 Pathophysiologic mechanisms that may play a role in postoperative cognitive dysfunction (POCD) and/or delirium. Starting from the top, in
clockwise order, the pullout boxes represent cellular/molecular and synaptic mechanisms (such as Alzheimer’s disease-related pathology), cerebral
oximetry monitoring, anesthetic dosage, resolution of inflammation, vascular mechanisms (such as emboli), and blood–brain barrier dysfunction, which
may be involved in POCD and delirium. Additional physiologic variables that may be involved in POCD and delirium are described in the text.
APP, amyloid precursor protein; CNS, central nervous system; RBC, red blood cell. (Reprinted with permission from Berger M, Terrando N, Smith SK et al.
Neurocognitive function after cardiac surgery: from phenotypes to mechanisms. Anesthesiology. 2018;129(4): 829–851.)

acetylcholinesterase treatment.81,82 Intraoperative high-
dose steroids were also ineffective,12,83,85 perhaps because
steroids can also cause delirium and hallucinations86 that
may counterbalance their theorized cognitive improving
antineuroinflammatory effects. Intraoperative ketamine
treatment reduced delirium87 and cognitive dysfunction88
after cardiac surgery in small pilot studies, but did not
reduce delirium in a large multicenter randomized trial
(which included approximately both cardiac and noncar-
diac surgery patients).89 Dexmedetomidine also had no
effect on delirium incidence after cardiac90 surgery in a
recent multicenter randomized trial, although it had mixed
effects on delirium after noncardiac surgery;91,92 these
divergent results may be caused by differing dexmedetomi-
dine infusion rates and durations between these stud-
ies.90,91,92 The large predominance of negative study
findings may reflect the complexity of delirium and postop-
erative cognitive dysfunction, which may also underlie the
relatively greater success of multimodal interventions.93
Alternative strategies to more specifically target postopera-
tive inflammation may better prevent postoperative delir-
ium and postoperative cognitive dysfunction.
618 PART IV • Early Postoperative Care
EMBOLIC LOAD
Embolic load may also play a role in neurocognitive dysfunc-
tion after cardiac and noncardiac surgery. Direct manipula-
tion of the aorta during cardiac surgery often disrupts
atheromatous plaques. Increased intraoperative atheroma
burden has been seen in patients with postoperative cog-
nitive dysfunction (versus those without postoperative
cognitive dysfunction) at 1 week, but not at 3 or 12 weeks,
after cardiac surgery.33 Current guidelines recommend
epiaortic ultrasound evaluation of aortic plaque in patients
with increased stroke risk, including those with a vascular
disease history and those with other evidence of aortic ath-
erosclerosis or calcification.94 Aortic plaque disruption can
liberate microemboli that can travel to the brain. These
microemboli can be detected by transcranial Doppler ultra-
sound,95 although the majority of transcranial Doppler sig-
nals actually represent small gas emboli.96
Gaseous microemboli occur frequently in open chamber
cardiac valve cases, which has led many centers to flood
the open cardiac chamber with carbon dioxide, because car-
bon dioxide is more soluble than air and thus promotes the
resorption of gas emboli.97 However, a randomized trial
found that field flooding with carbon dioxide versus medical
air had no effect on cognitive function 6 weeks after
surgery.98
Microemboli can also be detected by postoperative
diffusion-weighted magnetic resonance imaging (MRI)99
although preoperative MRI scans are needed to differentiate
new microemboli from prior lesions. The percentage of
cardiac surgery patients with detectable microemboli vastly
outnumber the percentage with clear postoperative
stroke(s). Many experts refer to these emboli and diffusion-
weighted MRI abnormalities as “clinically covert
strokes,”6,100 because they are not associated with neurologic
abnormalities detectable in routine clinical examination.
Although it seems intuitive that embolic load to the brain
and resulting T2-weighted MRI white matter hyperintensities
would have detrimental neurocognitive effects, correlations
between embolic load and postoperative cognitive changes
have been inconsistent.94,101–103 This is complex and obser-
vational studies have found that these “clinically covert
strokes” are associated with future risk of stroke, cognitive
decline, and Alzheimer’s disease.104–107 Interaction between
embolic load, central neuroinflammation, and other variables
that may interact in synergistic ways to produce postoperative
neurocognitive dysfunction.
CEREBRAL BLOOD FLOW, AUTOREGULATION,
AND OXYGEN DELIVERY
Since the inception of CPB with nonpulsatile blood flow, low
perfusion pressure has been blamed for both stroke and
POCD. Further, an increasing percentage of our elderly sur-
gery patients (cardiac and noncardiac) have hypertension,
which can shift the normal autoregulatory range of cerebral
blood flow (classically thought to be 60 to 160 mmHg) and
thus increase risk of hypoperfusion. The actual autoregula-
tion range for any given patient is unknown and the lower
limit of autoregulation during CPB may vary from 45 to
80 mmHg.108 Newman et al. found significant cerebral
autoregulation impairments in 215 patients during cardiac
surgery, but no correlation with postoperative cognitive
dysfunction.109,110 Similarly, Joshi et al. found that up to
20% of cardiac surgery patients have impaired autoregula-
tion and these patients with “pressure passive” cerebral
blood flow had increased perioperative stroke rates.111 Fur-
ther, intraoperative cerebral autoregulation can dynami-
cally change in response to intraoperative physiologic
changes,112,113 suggesting the need for real-time cerebral
autoregulation measurement.
Studies examining the relationship between mean arte-
rial pressure (MAP) management and postoperative cogni-
tive change have shown varying results. For example,
maintaining intraoperative MAP within 80 to 90 mmHg,
rather than 60 to 70 mmHg, was associated with less post-
operative delirium and a smaller postoperative decrease in
mini mental status examination scores.114 Gold et al. found
that higher MAP targets (i.e., 80 to 100 mmHg versus 50 to
60 mmHg) were associated with lower cardiac and neuro-
logic complication rates (i.e., stroke):115 however, they
found no difference in postoperative cognition between
groups. Much of this variation, especially in stroke rate,
was later defined to be primarily associated with the degree
of aortic atheroma with pressure only being of substantial
effect in those patients with severe aortic atherosclerosis.116
Postoperative MAP values below the lower limit of autore-
gulation have also been associated with increased levels of
the glial injury biomarker glial fibrillary acidic protein,
emphasizing the importance of maintaining MAP within
the autoregulatory range.117 However, observational stud-
ies have found that maintaining blood pressure above the
upper limit of cerebral autoregulation is associated with
increased postoperative delirium rates,118,119 suggesting
that it may be important to avoid MAPs above, as well as
below, each patient’s autoregulatory range.
TEMPERATURE MANAGEMENT DURING
CARDIAC SURGERY
The cerebral metabolic rate of oxygen (CMRO2) is closely
associated with temperature, which led to the practice of low-
ering cerebral metabolic rate of oxygen utilization by induc-
ing hypothermia, thus reducing brain oxygen deprivation
and neurocognitive injury during reduced oxygen delivery
period. Hypothermia reduces neurologic injury in animal
models of focal cerebral ischemia and cardiopulmonary resus-
citation.120,121 Alternatively, hyperthermia increases cere-
bral metabolic rate of oxygen utilization and is associated
with worse neurocognitive outcomes and increased mortality
risk in numerous clinical situations.122–124 Thus studies have
examined whether lowering cerebral metabolic rate of oxy-
gen utilization by inducing hypothermia during CPB would
improve postoperative neurocognitive function. Early work
showed that patients who underwent normothermic (i.e.,
“warm” or greater than 35°C) CPB had a threefold higher
stroke incidence than those who underwent hypothermic
(i.e., “cold” or less than 28°C) CPB.125 Yet one randomized
trial found no benefit of hypothermia (i.e., 28°C to 30°C) ver-
sus normothermia (35.5°C to 36.5°C) during CPB on cogni-
tive change from before cardiac surgery to 6 weeks after
cardiac surgery.126 Nonetheless, the maximum postoperative
temperature after cardiac surgery was associated with cogni-
tive dysfunction severity 6 weeks after surgery,127

emphasizing the importance of avoiding postoperative hyper-
thermia. This concept may help explain data showing that
rewarming to a lower temperature (34°C versus 37°C) was
associated with lower cognitive dysfunction rates 1 week
after surgery and improved performance on the grooved peg-
board test (a manual dexterity and visuomotor processing
speed task) at 3 months after surgery,128 although there
was no overall cognitive benefit at 3 months after surgery.129
In essence, the early cognitive benefits of rewarming to a
slightly lower target in this trial128 may have been a result
of the prevention of postoperative hyperthermia. This group
also found no neurocognitive difference among CABG
patients randomized to undergo normothermic (37°C) CPB
or hypothermic (34°C) CPB without operating room rewarm-
ing in either group; avoiding central hyperthermia during
rewarming may therefore help optimize postoperative cogni-
tive function.129 Similarly, another recent randomized trial
found that achieving a lower core body temperature (via
external head cooling) during CPB was associated with less
cognitive dysfunction 10 days after cardiac surgery.130
Despite numerous studies,131,132 there is still debate about
temperature management during cardiac surgery.133,134
Current clinical recommendations simply call for avoiding
hyperthermia (arterial outlet blood temperature greater than
or equal to 37°C) during cardiac surgery and for a rewarming
rate less than or equal to 0.5°C/min once temperature
exceeds 30°C.135 Slow rewarming may help avoid cerebral
ischemia because rapid rewarming has been shown to cause
cerebral metabolic rate of oxygen utilization increases prior to
corresponding increases in CBF.136
GLUCOSE HOMEOSTASIS DURING
CARDIAC SURGERY
Neurocognitive function is typically unaltered by glucose
changes within normal physiologic limits.137–139 Because
many surgical patients have diabetes and the surgical stress
response can decrease peripheral insulin sensitivity and cause
hyperglycemia, studies have investigated the relationship
between intraoperative glucose management and postopera-
tive neurocognitive outcomes. One retrospective study found
that intraoperative hyperglycemia (i.e., glucose levels greater
than 200 mg/dL) was associated with worsened postopera-
tive cognitive function in nondiabetic patients, but not in dia-
betic patients.140 This is not surprising because diabetic
patients are often exposed to hyperglycemia, which causes
physiologic compensatory responses (such as glucose trans-
porter downregulation on brain capillaries) to reduce exces-
sive glucose influx into the brain.141 This adaptation helps
explain why intraoperative hyperglycemia may be more det-
rimental to the brains of nondiabetic patients. However, this
interpretation is challenged by the results of a large random-
ized trial (n¼ 381) showing that intraoperative insulin infu-
sion (up to 4 units/h) in nondiabetic patients did not improve
neurocognitive outcomes.142 The idea that hyperglycemia is
detrimental to the brain led to additional interventional stud-
ies examining whether tighter glucose control would
improve postoperative cognition. Yet, tight intraoperative
glucose control with a hyperinsulinemic–normoglycemic
clamp (glucose target 80 to 110 mg/dL) versus standard
therapy (glucose target less than 150 mg/dL) during cardiac
surgery was associated with increased delirium rates,143
42 • Postoperative Cognitive Dysfunction and Delirium 619
perhaps as a result of the increased hypoglycemia in the
intensive glucose control arm of this study. Another study
found that the use of glucose and insulin infusions to main-
tain serum glucose at 64 to 110 mg/ dL preserved auditory
learning and executive function after cardiac surgery,144 sug-
gesting that avoiding hyperglycemia may result in improved
postoperative cognitive function. These data suggest that it
may be equally important to avoid hypoglycemia and hyper-
glycemia in order to avoid postoperative delirium and postop-
erative cognitive dysfunction. The physiologic adaptations to
chronic hyperglycemia in diabetic patients suggest that
intraoperative glycemic control should be individualized.
Depression
Studying depression as it relates to cardiac surgery
shows that preoperative depression is associated with
decreased long-term survival postoperatively145 and also
predicts the development of postoperative cognitive dys-
function.146,147 The precise causal relationship between
preoperative and postoperative depression, quality of life,
and cognitive dysfunction remain to be defined.
GENETIC FACTORS
An intriguing development in the field of neuroprotection is
in the area of genetic predisposition or susceptibility in
surgery-associated cerebral injuries. The possibility that a
person’s genetic makeup might alter cognitive outcome
after cardiac surgery was first delineated in a 1997 study.148
In that study, the apolipoprotein E hypothesis was born, that
is, that patients possessing the Apo E4 allele had worse cog-
nitive outcomes after CPB. Although not all studies have
replicated this finding,149–153 the consideration that postop-
erative cognitive dysfunction and delirium may involve
mechanisms similar to those of Alzheimer’s disease has
led to further studies. These studies have found conflicting
results; overall it appears that ApoE4 carriers are not more
likely to develop early postoperative delirium or postopera-
tive cognitive dysfunction, but do have worse long-term
cognitive trajectories after cardiac surgery.154–159 This find-
ing could be related to the known long-term detrimental
effects of the ApoE4 allele on cognition,154 and/or to the
increased aortic arch atheroma burden seen in ApoE4 car-
riers160 and thus a possible increase in cerebral microemboli
during cardiac surgery. Several other genetic polymor-
phisms have recently been found that are associated with
Alzheimer’s disease risk,161–165 and it will be important to
examine whether these Alzheimer’s disease risk polymor-
phisms are also associated with postoperative cognitive dys-
function or delirium risk after surgery.
To investigate further the possible role of inflammation
and possible thrombus formation in POCD, Mathew
et al.166 characterized the PlA2 polymorphism of the plate-
let integrin receptor GP IIb/IIIa, and examined its influence
on cognitive outcome after cardiac surgery. A multivariate
analysis revealed that the PlA2 genotype was significantly
associated with greater decline on the Mini Mental State
Examination (P¼ 0.036). The mechanism may be related
to an increased prothrombotic role, which has been shown
in investigations of coronary artery thrombosis and myocar-
dial infarction.167,168 Overall, the progression of genetic pre-
dictors of perioperative cognitive decline have mimicked the
620 PART IV • Early Postoperative Care
more general progression of genetic studies moving from the
investigation of single candidate genes to multiple candidate
genes and then to genome-wide scans as technology
advances.
Mathew et al. also hypothesized that candidate gene poly-
morphisms in biological pathways regulating inflammation,
cell matrix adhesion/interaction, coagulation-thrombosis,
lipid metabolism, and vascular reactivity are associated with
POCD.169 In a prospective cohort study of 513 patients
(86% European-American) undergoing CABG surgery with
cardiopulmonary bypass, a panel of 37 SNPs was genotyped
by mass spectrometry.169 The association between these
SNPs and cognitive deficit at 6 weeks after surgery was
tested using multiple logistic regression accounting for
age, level of education, baseline cognition, and population
structure. Permutation analysis was used to account
for multiple testing. Mathew found that in European-
Americans (n ¼ 443), minor alleles of the CRP 1059G/C
SNP (OR: 0.37; 95% CI: 0.16–0.78; P¼ 0.013) and the
SELP 1087G/A SNP (OR: 0.51; 95% CI: 0.30–0.85;
P ¼ 0.011) were associated with a reduction in cognitive
deficit. The absolute risk reduction in the observed incidence
of POCD was 20.6% for carriers of the CRP 1059C allele and
15.2% for carriers of the SELP 1087A allele. This compared
with a greater than 40% incidence of decline in those
patients who did not possess either allele (Fig. 42.5).62
Perioperative serum CRP and degree of platelet activation
were also significantly lower in patients with a copy of
the minor alleles, providing biologic support for the observed
allelic association. These results suggest a contribution of
P-selectin and CRP genes in modulating susceptibility to
cognitive decline following cardiac surgery, with potential
implications for identifying populations at risk who might
benefit from targeted perioperative anti-inflammatory strat-
egies. Identifying genetic and mechanistic factors associated
with lower rates of injury and sequelae help us define
50
40
Percent with Cognitive Deficit
30
20
10
0
CRP1059G
SELP1087G
Fig. 42.5 Incidence of postoperative cognitive deficit by CRP 1059G/C and SELP 1087G/A genotypes. The incidence of cognitive deficit was 16.7% in
carriers of minor alleles at both of these loci, compared with 42.9% in patients homozygous for the major allele (n¼386). (Reprinted from Mathew J,
Podgoreanu MD, Grocott GP, et al. Genetic variants in P-selectin and C-reactive protein influence susceptibility to cognitive decline after cardiac surgery. J Am
Coll Cardiol. 2007;49:1934–1942.)
pathways to protection and to provide the opportunity for
preoperative genetic screening to identify patients who
are at risk for cerebral injury and who will most likely benefit
from interventional protective strategies.
ANESTHESIA, SURGERY AND ALZHEIMER’S DISEASE
Cognitive impairment occurring up to 6 weeks after cardiac
surgery has been likened to the cognitive decline seen after
noncardiac surgery by the ISPOCD group and Monk
et al.38,39 The incidence in noncardiac surgery originally
appeared lower than that seen in cardiac surgery, as defined
by our group and others, and is comparable to a group
younger than 60 years old. However, as the noncardiac
population has aged, there has been increased recognition
of the cognitive decline occurring in elderly surgical
patients, suggesting that POCD may be independent of the
type of surgery.149
The association between early POCD and long-term cog-
nitive decline, defined by Newman and colleagues,19 has
increased the evaluation of overlaps between POCD and
Alzheimer’s disease, the most common cause of dementia
in the elderly. Alzheimer’s disease associated with amyloid
β-protein production and accumulation from proteolysis of
amyloid β (Aβ) precursor protein, and the intracellular
accumulation of tangles of the associated protein tau. Sev-
eral lines of evidence suggest that anesthesia and surgery
may increase Alzheimer’s disease risk. Preclinical studies
have shown that anesthetic agents and surgical stress can
promote Aβ and τ pathology in vitro170,171 and in animal
models.172–176 Several investigators have found alterations
in cerebrospinal fluid markers of Alzheimer’s disease
in patients after anesthesia and surgery.177–180 Other
studies181,182 identified that patients who have undergone
anesthesia and surgery have an increased risk of developing
Alzheimer’s disease. As a result of these studies, considerable
CRP1059G CRP1059C CRP1059C
SELP1087A SELP1087G SELP1087A
Presence of Allele
 42 • Postoperative Cognitive Dysfunction and Delirium 621

attention has focused on determining whether POCD repre-

sents a risk factor for the subsequent development of Alzhei-
mer’s disease, and/or whether anesthesia and surgery
increase the risk of developing Alzheimer’s disease are cur-
rently the subject of considerable controversy183 and the
focus of intensive research.184
Despite the cellular evidence, there are few clinical data to
support the claim that repeated exposure to general anes-
thesia is associated with POCD. Furthermore, studies
attempting to find a difference in POCD in patients exposed
to general versus regional anesthesia have been unable to
detect a protective effect from regional anesthesia,185,186
suggesting that the effects of anesthesia may play a lesser
role than that of surgery. These results are limited, though,
by the fact that many patients in the “regional” arms of
these trials received intravenous sedation to a depth similar
to that of general anesthesia.
Although it seems intuitively obvious that larger surgical
procedures (with greater tissue damage and larger ensuing
inflammatory response) would be associated with a higher
risk of POCD, little evidence exists to support this intuition.
Evered compared POCD rates after coronary angiography
with light sedation versus total hip joint replacement under
general anesthesia versus coronary artery bypass surgery
under general anesthesia. Although the incidence of POCD
in the CABG groups was significantly higher than the total
hip group at 7 days, by 3 months they did not find a signif-
icant difference between the three groups, further suggesting
that POCD is probably independent of the type of surgery and
anesthesia.154 Further prospective longitudinal trials needed
to define whether specific anesthetic or surgical techniques
are associated with worsened cognitive outcomes.

Fig. 42.6 Functionally connected networks in the human brain. These

SYSTEMS-LEVEL MECHANISMS OF POSTCARDIAC
SURGERY COGNITIVE DYSFUNCTION
Advances in structural and functional neuroimaging have
been used to examine the neuroanatomic basis of cognitive
dysfunction after surgery. For example, cardiac surgery
patients with structural MRI evidence of increased ventricular
size (a likely neural correlate of cortical atrophy) have
increased odds of developing postoperative delirium.187 Func-
tional MRI measures activity within specific brain regions via
the blood oxygen level, a hemodynamic correlate of neuronal
activity, and can be used to measure postoperative brain activ-
ity changes. A study of 25 patient undergoing cardiac surgery
assessed blood oxygen level dependent functional MRI scans
before and 4 weeks after surgery in on-pump and off-pump
cardiac surgery patients, while they completed a working
memory task.188,37 Patients who underwent on-pump, but
not those who underwent off-pump, cardiac surgery showed
a postoperative decrease in prefrontal cortex activation during
the most demanding attention task, the 3-back condition.188
Future studies will be necessary to determine whether these
changes in prefrontal cortex activity are associated with sub-
jective cognitive complaints after on-pump cardiac surgery.
Functional MRI can also measure activity patterns
between brain regions, known as functional connectivity,
even in regions that are not anatomically connected. Multiple
“functionally connected” human brain networks play impor-
tant roles in specific cognitive processes (Fig. 42.6).189,190
functional brain network region of interest maps were derived from
independent components analysis of low-frequency blood oxygen
dependent signal functional magnetic resonance imaging data from
the Human Connectome Project dataset (n¼497). (A) Default mode
network regions of interest (blue), salience network regions of interest
(red). (B) Dorsal attention network regions of interest (black), fronto-
parietal network regions of interest (light green). (C) Language network
regions of interest (purple), visual network regions of interest (pink).
(D) Cerebellar network regions of interest (yellow), sensorimotor net-
work regions of interest (green). (From Huang H, Tanner J, Parvataneni H,
et al. Impact of total knee arthroplasty with general anesthesia on brain
networks: cognitive efficiency and ventricular volume predict functional
connectivity decline in older adults. J Alzheimers Dis 2018;62:319–333.)
Browndyke recently examined cognitive and functional con-
nectivity changes in 12 patients before and 6 weeks after car-
diac surgery and over the same time interval, in 12
nonsurgical controls with cardiac disease.33 There was a
larger drop in cognition after cardiac surgery than over the
same interval in nonsurgical controls. Furthermore, in car-
diac surgery patients, the degree of postoperative global cog-
nitive dysfunction correlated with the magnitude of
decreased functional connectivity in the posterior cingulate
cortex and the right superior frontal gyrus,33 two key regions
of the brain’s default mode network.191,192 Similar altered
connectivity between the posterior cingulate (a default mode
network hub region) and the prefrontal cortex has been
622 PART IV • Early Postoperative Care
observed in patients with delirium raising the possibility that
default mode network functional connectivity disruptions
may underlie both postoperative delirium and postoperative
cognitive dysfunction.193
FUTURE INTERVENTIONS TO PREVENT OR TREAT
POSTOPERATIVE COGNITIVE DYSFUNCTION
AND/OR DELIRIUM
As we better understand the complexity of POCD and associ-
ated neurologic injuries, a number of novel approaches have
been proposed to improve neurocognitive function in older
adults, ranging from video game-based brain training194 to
vagal nerve stimulation195 to noninvasive transcranial
magnetic196,197 and electrical198 brain stimulation to diet
interventions,199 physical exercise,200,201 and early postoper-
ative ambulation.202–204 Many of these approaches can be tar-
geted and/or titrated in response to specific pathophysiologic
brain activity patterns and/or cognitive deficits present in indi-
vidual patients. These novel approaches have yet to be applied
to prevent or treat POCD or delirium in surgical patients.
Many strategies to protect the brain and to reduce POCD
through targeted areas known to reduce neurologic injury
have been proposed or utilized. As discussed in the previous
sections, programs to reduce inflammation, to avoid hyper-
thermia, to reduce embolization, and to avoid hypoperfusion
have all been part of a clinical strategy to reduce stroke,
POCD, and delirium. Although we have seen evidence of
improvement in focal neurologic injury, it has been more
difficult to show the efficacy of these strategies to reduce
POCD consistently.
Conclusions
The complexity of the brain and its processes are what make
it both the most interesting and the most difficult organ to
understand and predict. Adding to that complexity is the sig-
nificant anatomical and functional differences between the
brains of individual surgery patients.187,33 Optimizing post-
surgery neurocognitive function will probably require an
individualized, patient-centered approach to managing
multiple determinants of brain function ranging from oxy-
gen and glucose delivery, to cerebral perfusion pressure
management, to the careful pharmacologic modulation of
neural network activity, the surgical stress response, and
the ensuing inflammatory response.6 This suggests that
improving cognitive function after anesthesia and surgery
will be complex and challenging. An additional challenge
for future interventional studies will be to track each of
the factors that may influence postoperative cognitive func-
tion and/or delirium, because interventions designed to
reduce postoperative cognitive dysfunction or delirium by
targeting a single risk factor may have counterbalancing
effects if they distract from other intraoperative goals.205
Thus, an important objective will be to develop protocols
designed to optimize simultaneously and practically multi-
ple intraoperative and postoperative variables to support
postoperative cognitive function for older patients. Strate-
gies targeted at perioperative stroke and delirium reduction
will continue to be an aligned portion of the multipronged
plan to improve or reduce POCD.
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siology evidence-based and consensus-based guideline on postopera-
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203. Ely EW. The ABCDEF Bundle: Science and philosophy of how ICU
liberation serves patients and families. Crit Care Med. 2017;45:
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204. Vincent JL, Shehabi Y, Walsh TS, et al. Comfort and patient-centered
care without excessive sedation: the eCASH concept. Intensive Care
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205. Stiegler MP, Tung A. Cognitive processes in anesthesiology decision
making. Anesthesiology. 2014;120:204–217.
 43 Role of Palliative Care
TOBY B. STEINBERG and RACHEL A. HADLER
Defining Palliative Care
Palliative care is defined by the World Health Organization
as “an approach that improves the quality of life of patients
and their families facing the problem associated with life-
threatening illness, through the prevention and relief of suf-
fering by means of early identification and impeccable
assessment and treatment of pain and other problems, phys-
ical, psychosocial and spiritual.”1 The field of palliative med-
icine was developed over the course of the late 20th century
in response to increased awareness of the impact of suffering
on quality of life in a context of care previously divided into
disease-directed therapy or comfort care.2 Dame Cicely
Saunders, one of the founders of the field, described four
broad domains of palliative care: physical, i.e., symptoms;
psychological; social; and spiritual.3 Palliative care can be
delivered across a multitude of care contexts and by a vari-
ety of providers and should be viewed as distinct from hos-
pice, defined later. Palliative care is also referred to in some
contexts as supportive care.
According to some estimates, approximately 75% of pati-
ents approaching end of life would benefit from palliative
care. Estimates of future needs suggest a 40% increase in
these needs by 2040, driven predominantly by dementia
and cancer.4 Illnesses treated by palliative care teams
include heart disease, cancer, stroke, diabetes, renal disease,
Parkinson’s disease, and Alzheimer’s disease.5
The Multidisciplinary Team
One of the focal components of palliative care delivery is the
multidisciplinary team model, which is designed to provide
comprehensive symptom management and to address psy-
chological, social, and spiritual needs. Although the specific
members may vary by institution, a palliative care team
often involves the patient and their supporters, a palliative
physician, other providers on the patient’s care team, a
nurse, social worker, pharmacist, and chaplain as well as
volunteers.6 Physical and occupational therapists and
dietitians are also frequently incorporated onto palliative
care teams.
Palliative Care and Hospice
Whereas palliative care can be implemented at any stage in
care, the term “hospice” specifically describes noncurative,
comfort-targeted care delivered to patients nearing the end
of life.7 Patients referred to hospice have a life expectancy of
6 months or less as assessed by two physicians. Many fea-
tures of hospice care, including a multidisciplinary care
628
team and a focus on comprehensive symptom management,
are shared with palliative care; however, patients enrolled
on hospice care no longer receive disease-directed therapies
targeting their life-limiting illness. Hospice care is tradition-
ally delivered in the home but can also be provided across a
variety of other settings, including inpatient units and nurs-
ing homes. In the United States, hospice care is funded
through a provision in Medicare. A comparison of palliative
care and hospice is seen in Table 43.1.
Primary versus Specialist
Palliative Care
Although palliative medicine is a dedicated medical subspe-
cialty, many of the basic domains of palliative care can be
delivered by all providers. Primary palliative care has been
defined as “the basic [palliative] skills and competencies
required of all physicians and other health-care profes-
sionals.”8 In a seminal 2013 paper, Quill and Abernethy
describe a series of skill sets that all clinicians should be
capable of delivering, including basic management of pain,
depression, anxiety, and other symptoms as well as basic dis-
cussions about prognosis, goals of treatment, suffering, and
code status.9 Specialist consultation is recommended for
guidance regarding management of refractory physical or
complex psychological symptoms as well as for assistance
with management of conflict among stakeholders and in
cases of near-futility (Table 43.2). These recommendations
are congruent with consensus statements from the Center
to Advance Palliative Care (CAPC),10 which further recom-
mend that hospitals should develop screening assessments
to identify unmet palliative needs in patients.
According to a recent study, some 8% of American adults
aged 65 years or older would benefit from primary palliative
care for management of advanced chronic illnesses, pre-
dominantly chronic obstructive pulmonary disease (COPD)
and congestive heart failure (CHF).11 Palliative-focused
organizations such as CAPC, Vitaltalk, and Ariadne Labs
have developed tools designed to inform and improve pri-
mary palliative care delivery by providing a paradigm for
introducing difficult topics and decisions. Two examples of
such tools are depicted in Table 43.3.12,13
Advance Care Planning
Advance care planning describes the engagement of pati-
ents and their family members around decisions that may
need to be made regarding their current and future medi-
cal care. This process frequently includes discussion of cur-
rent and anticipated medical needs with elicitation of the
 43 • Role of Palliative Care 629

Table 43.1 Palliative care versus hospice. Symptom Management

Palliative care Hospice
Patients with life-limiting illnesses frequently experience a
A medical specialty An insurance benefit combination of symptoms, the nature of which may vary
Appropriate at any time during a Appropriate when two or more over the course of their illness. Disease-specific symptomatol-
serious illness, independent of physicians determine likely ogy is addressed later by disease. Table 43.4 describes symp-
goals or prognosis prognosis of 6 months or less toms and management strategies in detail. Table 43.5
Continued curative or life- Goal of comfort-focused care specifically addresses management of cancer pain.
prolonging therapies available
Can follow the patient anywhere Provided at home, in a long-term
care facility, or at an inpatient
End-of-life Care
hospice
Approaches to end-of-life care may vary by patient and dis-
ease, but, broadly, fall under the more general palliative
domains of management of symptoms, spiritual, psycholog-
ical, and social distress. End of life care may involve aggres-
sive symptom control, family counseling, and/or discussion
Table 43.2 Palliative care skill sets. of goals of care depending on the specific clinical context.
Primary palliative care Specialty palliative care Specialist palliative care consultation is recommended for
patients with refractory symptoms, severe existential dis-
Basic pain and symptom Refractory pain and symptoms; tress, complex psychological, social or familial needs.
management (including complex depression, anxiety, grief,
depression and anxiety) existential distress
Routine discussions about:
▪ Prognosis
Conflict between families, staff,
and medical teams related to goals
Impact on Outcomes
▪ Goals of treatment or treatments
▪ Code status Palliative care interventions have been demonstrated to
▪ Advance care planning have a positive impact on a variety of health-care domains,
Delivered by primary provider Ethical challenges or cases of near ranging from quality of life and symptom management to
futility length of stay and costs of care. In a randomized controlled
Delivered by specialized,
trial of standard oncologic care versus oncologic care with
multidisciplinary team integrated palliative care, Temel and colleagues15 demon-
strated that patients receiving palliative care reported
Adapted from Quill TE, Abernethy AP: Generalist plus specialist palliative higher quality of life and reduced depressive symptoms.
care — creating a more sustainable model. N Engl J Med 2013;368:1173–1175. Although patients in the palliative care group were less
likely to elect aggressive end-of-life care, median survival
was longer in this group. Other studies have demonstrated
similar findings with regard to increased life expectancy
Table 43.3 Examples of frameworks for difficult conversa- with early initiation of palliative care in oncology patients.16
tions: SPIKES and REMAP. Proactive palliative care in the medical intensive care unit
Discussing bad news: (ICU) has been demonstrated to reduce ICU length-of-
SPIKES Addressing goals of care: REMAP stay.17 Brumley and colleagues randomized 298 terminally
ill patients to usual care versus in-home palliative care and
▪ S: SET up the interview R: REFRAME the clinical situation looking
▪ P: Assess PERCEPTION: at the big picture demonstrated significant improvements in satisfaction with
Obtain INVITATION E: expect and address EMOTION care as well as increased rates of death at home, reduced
▪ K: Give KNOWLEDGE/ M: MAP out patient goals (ask open-ended emergency room and hospital admission rates, resulting
information questions about goals and values) in reduced costs of care in that population.18 Numerous
▪ E: Address EMOTION A: ALIGN with patient goals
S: SUMMARIZE/ P: PROPOSE a plan
other studies have demonstrated that palliative care can sig-
▪
STRATEGIZE nificantly reduce costs of care and resource utilization across
a variety of inpatient settings.19–22 Further discussion of the
Adapted from Childers JQ et al. REMAP: A framework for goals of care impact of palliative care on outcomes is incorporated into
conversations. J Oncol Practi 2017;13:e844-e850 and Baile WF et al. SPIKES A discussion of disease-specific palliative care in a later section.
six-step protocol for delivering bad news: application to the patient with
cancer. Oncologist 2000; 5:302–311.

Palliative Care for the Surgical

patient’s preferences for utilization of life-sustaining treat-
ments; for example, cardiopulmonary resuscitation, pro-
longed mechanical ventilation, artificial nutrition and
hydration, or comfort care.14 These preferences may be cod-
ified in the form of an advance directive. Palliative care pro-
viders may initiate or assist in advance care planning,
particularly in complex or conflicted situations.
Patient
Successful models for palliative care delivery and quality
improvement in medical ICUs have been described, demon-
strating, among other benefits, shorter medical ICU length
of stay for high-risk groups.23,24 However, the applicability
of these models in the surgical ICU setting has not been fully
addressed.
630 PART IV • Early Postoperative Care

Table 43.4 Symptoms commonly encountered in patients requiring palliative care.

Symptom Pharmacologic therapies Nonpharmacologic therapies
Anorexia Megestrol (may increase risk of thrombus in patients in Patient/family counseling regarding expectations
procoagulant states)
Corticosteroids
Cannabinoids (nabilone and dronabinol)
Mirtazapine
Olanzapine
Melatonin
Anxiety Benzodiazepines, SSRIs, SNRIs, atypical antipsychotics Supportive psychotherapy
(second line) Relaxation
Guided imagery
Hypnosis
Treatment of physical etiology
Discontinuation of anxiety-inducing medications
(e.g. corticosteroids, baclofen, caffeine, methylphenidate)
Constipation Laxatives (emollient stool softeners), bulk-forming agents, High-fiber diet, increase fluid intake, discontinue/reduce doses
osmotic agents, prosecretory drugs, selective opioid-receptor of constipating medications (anticholinergics, opioids)
antagonists (e.g., methylnaltrexone, naloxegol)
Delirium Typical/ atypical antipsychotics, benzodiazepines Reorientation, optimization of sleep–wake cycle, limitation of
(terminal delirium) environmental stimuli
Depression SSRIs Supportive psychotherapy, dignity therapy
SNRIs
Stimulants (in end-of-life patients); mirtazapine; trazodone;
bupropion
Dry mouth Oral swabs and coating agents, discontinuation of triggering
agents (antihistamines, anticholinergics)
Dyspnea Opioids (decrease respiratory drive) Supplemental oxygen (evidence is mixed)
Benzodiazepines (reduce anxiety) Fan
Diuretics (HF) Cognitive therapy
Bronchodilator therapy (COPD)
Corticosteroids (COPD)
Fatigue Methylphenidate Encourage exercise/activity
Steroids (for end-stage/hospice patients only)
Nausea 5HT-3 receptor antagonists, antimuscarinics, antidopaminergics, Gastric decompression, discontinuation/rotation of nausea-
neurokinin-1 receptor antagonists, cannabinoids, corticosteroids, inducing medications (opioids)
benzodiazepines
Pain Opioids, NSAIDs, neuropathic agents Disease-directed therapies (chemotherapy/radiation/surgery/
(see Table 43.5 for more detail) diuresis), physical therapy, complementary therapies
(e.g., music therapy, massage)
Pruritis Antihistamines, opioid antagonists (nalbuphine, naloxone) Treatment of uremia (dialysis)
Discontinuation of stimulating agents/opioid rotation

COPD, Chronic obstructive pulmonary disease; HF, heart failure; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRI, Serotonin-norepinephrine reuptake inhibitors;
SSRI, selective serotonin reuptake inhibitors.

Table 43.5 Common pain syndromes seen in patients with cancer.

Pain type Etiology Description Example Therapeutic options
Visceral Distension/displacement/ Diffuse, cramping, Abdominal pain from Opioids, corticosteroids in some cases,
inflammation of solid and difficult to localize, intraabdominal malignancy treatment of etiology
hollow organs may be referred causing partial/complete bowel
obstruction
Somatic Compression/injury of muscular, Aching, dull, easily Back pain caused by spinal Opioids, NSAIDs/anti-inflammatory
bony and integumentary tissues localized metastases agents (including corticosteroids)
Neuropathic Injury of nerve tissues (related to Radiating, burning, Radiating/ burning upper Neuropathic agents (gabapentinoids,
compression/infiltration by may be associated extremity pain in setting of SSRIs, SNRIs, tricyclic antidepressants),
tumor; often treatment- with paresthesia tumor infiltration of brachial opioids (especially methadone),
induced) plexus ketamine

NSAIDs, Nonsteroidal anti-inflammatory drugs; SNRI, Serotonin-norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors.

Despite intensive research in the past two decades on the
prediction of survival in ICU patients, palliative care has not
been an integral part in caring for postoperative ICU patients.
This is problematic because patients of advanced age and
those with significant comorbidities are increasingly under-
going major surgery and receiving care in surgical ICUs. With
improvement in both intraoperative anesthetic and surgical
care, it is not uncommon for physicians to care for patients
who have had technically successful surgeries, but have
multiple comorbidities, which significantly decrease physio-
logical reserve and increase the likelihood of postoperative
complications.25 Many patients encounter end-of-life issues
in the surgical ICU, but the specific characteristics of patients
with surgical disease, the practice of surgical critical care, and
the practice of surgeons create a specific set of challenges to
the integration of palliative care in the surgical ICU.23
During the perioperative period, patients, families, and
surgical caregivers often have high expectations for recov-
ery, believing that surgical intervention will improve the
patient’s condition. Such expectations make it more difficult
to establish realistic prognoses, treatment goals, and plans
in the event of therapeutic failure.23 Special circumstances
in the surgical ICUs further underscore this issue. Emer-
gency general surgery has a disparate burden of risk from
medical errors, complications, and death compared with
nonemergency general surgery. In fact, emergency general
surgery is an independent risk factor for death and postop-
erative complications.26 In the trauma ICU, the mortality
for critically injured patients averages 10% to 20%, and sur-
vivors often face serious and permanent disabilities. Yet,
because many patients are young and they and their fami-
lies are unprepared for such devastating events, the pro-
viders’ treatment plan is often aggressive resuscitation.
The integration of palliative care in this situation is partic-
ularly challenging.23
The structural organization of the surgical ICU creates
another barrier to integrating palliative care models. Medi-
cal ICUs primarily follow a “closed model” of care, where the
intensivist is the primary provider. However, surgical ICUs
more often utilize an “open or semi-closed model” in which
the primary surgeon retains the primary care responsibility
throughout the critical illness.23 Historically, surgeons had
individual control over patient care; in a typical surgical
team, authority was hierarchical, with major decision-
making concentrated at the highest level. In the open or
semi-closed model of surgical ICUs, the intensivist in the sur-
gical ICU oversees daily critical care issues, but the primary
surgeon determines the overall goals of care. However,
because surgeons spend a great deal of the day in the oper-
ating room, patient care rounds often do not involve the full
interdisciplinary team. This causes a problematic situation
where surgical critical care is occurring at the bedside often
without the attending surgeon, who ultimately will make all
of the major decisions.23
Surgical culture also influences the integration of pallia-
tive care in the surgical ICU. Preoperatively, surgeons often
develop a contractual patient relationship for the perioper-
ative period that has been termed “surgical buy-in.”25
According to Pecanac and group, surgeons “preoperatively
establish the patient’s commitment to an operation as well
as to the ensuring postoperative care, including prolonged
life-supporting treatments.” This buy-in is seen as a commit-
ment made by both the surgeon and the patients to make it
43 • Role of Palliative Care 631
through the operation as well as the postoperative period.27
It has been described as a “covenantal” relationship that is
different from nonsurgical physician-patient’s relationships.
Its emphasis on cure is critically influenced by the surgeons
themselves. The covenant creates a strong sense of obliga-
tion for the surgeon to protect the patient during the periop-
erative period. The patient is seen by the surgeon as
mutually committed to “undertake and endure all sequelae,
including a protracted course with uncertain prospects for
return to an acceptable quality of life.”23
The life-saving attitude of surgery has propagated a view
of intensive care and palliative care as mutually exclusive
methods in the treatment of the critically ill. Thus, palliative
care is often seen as the consequence of failure of surgical
and critical treatments that were meant to prolong life.23
These ideals are grounded in a surgeon’s sense of personal
responsibility for outcomes and “fear of being ‘the agent’
of a patient’s death.”27 This responsibility can lead to emo-
tional distress—especially for elective surgeries, where suc-
cess is expected—which may cause the surgeon to refuse to
consent to withdrawal of life support despite patient and/or
family requests to do so.25 As health-care quality services
increasingly move to use surgical morbidity and mortality
as indicators, the surgeon’s sense of personal failure is rein-
forced.23 For instance, the Society of Thoracic Surgery cre-
ated a national US database with detailed risk-prediction
models for various cardiac surgeries with an aim to improve
quality, to provide feedback on patient care guidelines, and
to standardize performance measures. Some states also pub-
lish surgeon- and institution-specific mortality after cardiac
surgery. Although the intention is for quality improvement,
it also leads to a “shame-and-blame” public reporting. This
affects the acceptance of dying as a phase of life and may fur-
ther negatively impact the integration of palliative care
models into the surgical ICUs.25
For these reasons, improvement in the integration of pal-
liative care with surgical ICU settings requires acknowledge-
ment and sensitivity to the surgeon’s unique role and
finding strategies to strengthen the relationship between
the attending surgeon and the other members of the multi-
disciplinary team. Previous studies have shown that the
success of any effort to improve quality of care in the ICU
depends on active participation and empowerment of criti-
cal care nurses. Especially given the open or semi-closed
nature of the surgical ICU, a nurse practitioner on a surgical
team may be able to help bridge the gap between the sur-
geons and the ICU intensivists.23
Other studies have evaluated the implementation of a
mandatory checklist to improve compliance with a range
of evidence-based critical care practices. Byrnes et al. cre-
ated a checklist that included a review of end-of-life issues,
including plans for family meetings and orders that
addressed appropriate levels of care. They found that a man-
datory verbal review of the checklist at the patient’s bedside
effectively affected practice patterns.28 Other studies
reported similar success with checklist tools demonstrating
that routine reminders can enhance awareness and practice
by providers.23
Many other studies have looked at developing guidelines
to help identify critically ill surgical patients who would ben-
efit from palliative care or “trigger criteria.” In most surgical
ICUs, referral for palliative care consultation depends on
decision-making by individual primary physicians, which,
632 PART IV • Early Postoperative Care
Table 43.6 Barriers to integrating palliative care in surgical
intensive care units.
Characteristics of patients with surgical disease
Belief surgery is curative
Special circumstances (i.e., emergency general surgery, trauma surgery)
Practice of surgical critical care
Open or semi-closed organization
Hierarchical structure
Blocked operating room time
Practice of surgeons
Surgical buy-in
Personal responsibility
Quality measures
as listed previously, is often the attending surgeon. This leads
to a referral process that may be inconsistent and/or ineffi-
cient, and ultimately creates the potential for patients to have
unmet palliative needs. Mosenthal and group suggested that
utilizing specific triggers may help screen patients proactively
and systemically. Screening patients in this way could
increase the “timeliness, consistency, and frequency of refer-
rals for appropriate patients and family members.”23 There
have been numerous efforts at development of trigger criteria
for surgical ICUs, including those by the American College of
Surgeons Surgical Palliative Care Task Force and a consensus
panel of surgical palliative care experts. However, retrospec-
tive studies demonstrated that the intervention did not signif-
icantly change the number of palliative care consultations or
the rate of consultation for surgical ICU patients dying in
the hospital.23,25 Mosenthal also suggests that trigger cri-
teria in the surgical ICU specifically may be more successful
if the criteria are applied to “certain diseases (e.g., cancer
treated with gastrectomy or esophagectomy), surgical ser-
vices (e.g., cardiovascular, transplant, trauma), or complica-
tions (e.g., prolonged respiratory failure.)” They also suggest
that a specific, criteria-based mandatory referral model, as
opposed to deferral to the primary surgeon, may promote
integration of palliative care in the surgical ICU.23,25 The
complexities of palliative care delivery in surgical patients
is further detailed in Table 43.6.
Disease-Specific Palliative Care
CANCER
In spite of ongoing advances in care, cancer is the second lead-
ing cause of death worldwide, accounting for 1 in 6 deaths in
2018.29 Some 1.7 million Americans will be diagnosed with
cancer in 2018, and 600,000 will die of cancer-related
causes.30 Cancer patients frequently suffer a significant symp-
tom burden related both to disease and often to side effects of
treatment,31 particularly at end of life, when by some esti-
mates, up to 54% of patients complain of unendurable symp-
toms.32 Patients with both solid and liquid tumors most
frequently complain of severe fatigue, sleep disturbances, pain,
paresthesia and dry mouth.33,34 In addition to symptom bur-
den, cancer patients also frequently report unmet supportive
care needs in activities of daily living, psychological and psy-
chosocial support, and information.35
Palliative care referral is often delayed in cancer patients,
particularly in patients with hematological malignancies,
with the bulk of referrals occurring within 30–60 days
before death.36–38 As of 2017, the American Society of Clin-
ical Oncologists (ASCO) recommended early initiation of
palliative care, concurrent with disease-directed therapy
and preferably delivered by an interdisciplinary specialty
team, in patients presenting with advanced malignancy.39
Palliative care interventions have been demonstrated to
improve quality of life, mood, and care satisfaction in patients
with solid tumor malignancies.15,40,41 Comprehensive outpa-
tient palliative care clinic services have demonstrated similar
benefits, along with improved symptom management.42
Palliative Care for Non-cancer
Patients
As the field of palliative care has become more established,
care for patients with nonmalignant, life-limiting conditions
differentiated itself from care of cancer patients in several
ways. While trajectories for patients with malignancy
may be relatively clear-cut, prognostication in patients with
life-limiting chronic diseases is often more complex, featur-
ing periods of evident recovery or improvement against a
background of gradual decline.43 This uncertainty, com-
bined with limited access to and knowledge of specialist pal-
liative care, have evolved as barriers to supportive care
delivery in this population.44 Although symptom burdens
by disease are well-differentiated, spiritual, psychological,
and social needs have been less studied in patients with
non-cancer life-threatening diseases.45 Family members of
patients dying of nonmalignant organ failure are more likely
to complain of poor quality care and low levels of support at
the end of life,46 as well as reduced choice in options for
management during the last week in life.47
CONGESTIVE HEART FAILURE (CHF)
CHF affects some 6.5 million Americans over the age of
20 years,48 with incidence approaching 21 per 1000 in adults
over the age of 65 years.49 Patients with CHF suffer from
depression, psychological pain and distress, and symptom
burdens similar to those experienced by cancer patients.50
Over the past two decades, a body of evidence has arisen to
suggest that palliative care consultation in HF reduces read-
mission rates and hospitalization costs.51–54 Randomized con-
trolled trials across multiple care settings have demonstrated
an association between the incorporation of palliative care
into heart failure (HF) care and improved quality of life,
depressive symptoms, spiritual well-being, and symptom con-
trol as well as increased rates of advance care planning.55–57
Both the American Heart Association and the American Col-
lege of Cardiology recommend palliative care consultation for
patients with end-stage HF.58,59
In spite of this body of evidence, palliative care incorpora-
tion into routine HF care is limited. Barriers to routine

utilization of palliative care in patients with HF include lack
of understanding of HF as a terminal disease, uncertain and
variable prognosis, and limited incentive for discussions of
goals of care by providers.60–62 Less than 5% of patients
with HF in the UK and Sweden are seen by specialist palli-
ative care (PC) teams.63,64 Increasingly, researchers are
evaluating primary palliative care interventions in this
population.65,66
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
COPD is a constellation of respiratory disorders affecting
the lower respiratory tract and pulmonary parenchyma
and causing progressive airway obstruction, which may
ultimately lead to death. COPD affects at least 15.7 million
Americans (6.7%),67 and was the third leading cause of
death in the United States in 2014.68 As in patients with
CHF, prognostication in COPD is challenging because of
the disease’s relapsing and remitting course.69 Patients
with COPD frequently experience dyspnea, which is often
associated with comorbid anxiety and depression.70
Patients with severe COPD report lower quality of life
and function in activities of daily living, as well as clini-
cally significant higher levels of anxiety and depression,
than patients with non-small cell lung cancer. They also
report less access to palliative care services than that pop-
ulation.71,72 Prognostication and discussion of advance
care planning, particularly of preferences regarding pro-
longed mechanical ventilation, most commonly occur late
in the disease course, if they happen at all,73 and patients
with COPD are more likely to receive life-sustaining inter-
ventions such as mechanical ventilation, tube feeding,
and cardiopulmonary resuscitation regardless of stated
preferences.74
NEURODEGENERATIVE DISEASE AND DEMENTIA
Patients diagnosed with neurodegenerative disorders,
which include Parkinson’s disease, Huntington’s disease,
motor neuron diseases, and multiple sclerosis, face incurable
diagnoses with often progressive symptom and psychologi-
cal burdens, as well as social isolation and concerns regard-
ing physical dependence.75 Patients with these diagnoses
also face complex challenges with regard to advance care
planning and end-of-life decision-making, as well as existen-
tial concerns related to loss of hope and meaningfulness
with progression of disease.76 Although the palliative care
needs of this population have been explored in some depth,
at this point, studies of interventions are lacking.77
Similarly, evidence for a concrete role of palliative care in
patients with dementia, a spectrum of diagnoses involving
changes in memory and cognition, is weak.78 Qualitative
studies emphasize the value of advance directives, as well
as the lack of benefit of feeding tube placement and intrave-
nous antibiotics in this population. Other palliative care
needs in this population include symptom management,
particularly of pain and agitation, caregiver distress, and
lack of understanding of disease trajectory.79 A 2016
Cochrane Review of studies evaluating palliative care inter-
ventions in adults with advanced dementia demonstrated
43 • Role of Palliative Care 633
an ongoing need for high-quality research in this field.80
At the time of that review, six new studies were underway.
Recently published research on an educational/ supportive
intervention involving integration of hospice care into rou-
tine care of patients with dementia demonstrated encourag-
ing results in terms of palliative care uptake, patient and
family satisfaction.81
END-STAGE RENAL DISEASE (ESRD)
Patients with end-stage renal disease (ESRD), particularly
those patients receiving dialysis, experience a significant
and often under-addressed symptom burden as well as
complex psychosocial needs. Frequently-occurring symp-
toms include fatigue, pruritus, constipation, anorexia,
pain, and sleep disturbances.82 Surveys of patients with
ESRD demonstrate that they are highly dependent upon
their nephrologist for initiation of advance care planning
as well as other facets of palliative care, such as symp-
tom management and psychosocial support. Patients
frequently report a limited understanding of disease tra-
jectory and palliative options prior to initiating hemodial-
ysis; in one study, less than 10% of respondents reported
discussions regarding end-of-life care with their nephro-
logist and 61% regretted starting dialysis.83 Qualitative
research has demonstrated that much of advance care
planning in patients with ESRD is enabled by patient
empowerment and patient-provider relationships, two
key factors that enabled patients to engage in advance
care planning in a hopeful fashion.84
HUMAN IMMUNODEFICIENCY VIRUS (HIV)
The global burden of HIV-associated disease peaked in
2005; however, HIV/AIDs remains among the top 10
causes of death globally.85 As of 2016, 36 million people
worldwide had been diagnosed with HIV (0.8% of the global
population aged 15–29 years). Sub-Saharan Africa is the
region most heavily impacted, with an incidence of HIV
in adults of almost 1 in 25.86 In the United States, the esti-
mated prevalence of HIV in adolescents and adults is
1,122,900, with roughly 50% of this population receiving
continuous HIV care.87
With the widespread availability and efficacy of antiretro-
viral therapy (ART), the course of HIV has evolved signifi-
cantly from the high morbidity and mortality observed in
the 1980s and 1990s; however, patients diagnosed with
HIV, particularly those with AIDS, continue to demonstrate
high levels of palliative care needs. Patients with HIV report
untreated and undertreated symptoms, including pain, but
also must cope with a complex medical course notable for
a high incidence of comorbidities, including malignancy, high
risk of treatment-related side effects and treatment failure,
stigmatization, and uncertain but often terminal prognosis.88
Symptoms frequently observed in patients with advanced dis-
ease include pain, cough, anorexia, malaise, pruritis, and
diarrhea.89 A systematic review of studies evaluating the
impact of palliative care on patient outcomes in this popula-
tion demonstrated that home palliative care and inpatient
hospice significantly improve patient pain and symptom
management, anxiety, insight, and spiritual well-being.90
634 PART IV • Early Postoperative Care
Pediatrics
Some 9300 children aged 1–14 years die in the United
States annually, with leading causes of death including acci-
dents, congenital malformations, cancer, and intentional
injury (homicide/suicide).91 Palliative care has been recom-
mended for children suffering from potentially life-limiting
conditions where curative treatment may fail, intensive
long-term treatment may be required to maintain quality
of life, progressive illnesses when treatment is exclusively
palliative after diagnosis, or extensive long-term disability
with multiple health complications are experienced.92
As the different etiologies of morbidity and mortality
might suggest, children with life-limiting conditions may
have different palliative care needs from adults, and different
frameworks for delivery have been suggested. Palliative care
providers are not only charged with management of phys-
ical and psychological symptoms associated with serious ill-
ness, but also with accommodating varying levels of ability
to communicate care needs and comprehend disease and
prognosis. Complex family and caregiver dynamics, as well
as low reimbursement and limited resources, also make spe-
cialist pediatric palliative care delivery particularly chal-
lenging.93 In 2000, a position paper from the American
Academy of Pediatrics called for an integrated model of care
for terminally ill children incorporating respect of patient
and family dignity, access to palliative care, caregiver sup-
port, and improved professional support and incorporation
of palliative care into pediatrics education.94
Conclusions
Palliative care is a field dedicated to improving quality of life
for seriously ill patients across a variety of domains. Pallia-
tive care can be delivered by a variety of interdisciplinary
providers, including primary providers, who have the ability
to provide components of symptom management and psy-
chosocial support, as well as to elicit values, priorities, and
goals of care. Principles of palliative care are widely utilized
in oncology, as well as for patients with other life-limiting
diseases. More recently, palliative care is being studied in
the perioperative and postoperative intensive care settings,
where it has the potential to enrich and facilitate care of
complex surgical patients.
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 44 Economic Analysis of
Perioperative Optimization
THOMAS L. ARCHER, ERIN MADDY, and ALEX MACARIO
The goal of this chapter is to make the following points:
1. Taxpayers, employers, and employees demand that
medicine deliver better value. Physicians need evidence-
based medicine to establish which interventions are truly
beneficial and modern management techniques to imple-
ment those interventions.
2. Perioperative interventions are investments, each with
its costs and, it is hoped, its benefits. The benefits of peri-
operative interventions are often difficult to quantify in
precise dollar amounts (e.g., pain relief).
3. Three ways of measuring the benefits of health-care
interventions are by improved clinical results (i.e.,
effects), by increased quality-adjusted life-years (QALYs),
or by assigned monetary benefit.
4. Any new intervention being considered must be evalu-
ated in comparison to the best existing alternative. As a
result, the fundamental concept is the incremental cost-
to-effectiveness ratio.
5. Because of the multiplicity of health-care stakeholders
(i.e., patients, providers, payers, and society as a whole),
an economic study in health-care must specify ahead of
time—and be consistent in—its point of view.
6. Costs of perioperative interventions are direct, indirect,
and intangible. Direct costs are the easiest to define
and quantify, but vary depending on the costing
method used. Direct costs decrease over time, because
of competition, the learning curve, technological
progress, work process redesign, and the bundling of
interventions.
7. Much more attention should be directed toward identi-
fying and addressing barriers to implementation of ben-
eficial interventions. These barriers include lack of
awareness (the physician does not know about the
new intervention), of familiarity (knows intervention
exists but not the details), of agreement (physician does
not agree with proposed intervention), of self-efficacy
(does not think they can do it), of outcome expectancy
(does not think it will work), as well as system factors
not allowing successful implementation.
With the aging of the postwar baby boomers and the
explosion of technological options at medicine’s disposal,
health-care systems around the world, whether fee-
for-service or publicly funded, struggle to increase the qual-
ity and to decrease the cost of care. As a result, it is more
important than ever to know what really works and what
does not. The ultimate payers of health-care costs (tax-
payers, employers, and employees) demand that physicians
638
provide better value for the money spent. “Pay-for-perfor-
mance” metrics are one attempt by these payers to reward
systems for attaining the biggest bang for its health-
care buck.
Physicians must first know which perioperative interven-
tions actually benefit patients and then apply those inter-
ventions at the lowest possible cost. This is a moving
target, as the economic attractiveness of perioperative inter-
ventions changes with time, as new interventions are intro-
duced (e.g., new drugs such as oral anticoagulants), old
interventions evolve (e.g., enhanced recovery after surgery),
or as new discoveries are made.
In this chapter, we present the conceptual framework
used for the economic analysis of interventions so that
the reader can critically appraise economic studies of periop-
erative optimization.
Health-Care Interventions as
Investments
Economics describes how people in societies satisfy their
needs and wants in an environment of limited resources.
During the 19th and 20th centuries, economists, political
scientists, and politicians debated the merits of free-market
capitalism, with individual freedom of choice and private
property versus central planning and state ownership of
the means of production. For normal goods, the individual-
istic free market approach is predominant.
In medicine, however, much central planning occurs
because the consumer (the patient) usually does not
directly pay the full cost of the care and is often not able
to judge the quality of the health-care product. In economic
language, physicians are agents for patients, meaning they
are asked to make decisions and “invest” on behalf of their
patients.
COSTS AND (WE HOPE) BENEFITS
Health-care interventions are investments, very similar to
financial investments, in that there is a cost of the interven-
tion, and then there is an outcome—and, one hopes, a benefit.
Unfortunately, many medical practices have not been stud-
ied adequately to find out whether they are really beneficial,
so some of our therapy is of uncertain value. The motivation
of evidence-based medicine is to find out whether our costly
interventions really do, in fact, produce benefits. Once we
know that an intervention actually provides a benefit to

the patient, we have to decide whether the increased benefit
is worth the increased cost.
No medical intervention can be considered cost effective
in isolation but must be compared with an alternative
treatment (usually, the standard therapy). This is hugely
important. For example, if a new analgesic technique
costs $100 and reduces postoperative pain scores by
50%, then its value needs to be compared with the best
current treatment to determine whether it is worthy of
implementation.
In health-care—as in any type of management—we
manage at the margin, constantly analyzing marginal, or
incremental, benefits and comparing them with the marginal,
or incremental, costs. The fundamental analytical concept of
managing at the margin is the incremental cost-effectiveness
ratio, in which the incremental cost of the proposed new
intervention is divided by the increase in effectiveness
achieved by the intervention.
If a new technique achieves a better outcome at lower
cost (e.g., polio vaccination compared with polio treat-
ment), the new cost-saving technique is said to dominate
the old technique, and it should become the new stan-
dard treatment. For example, ultrasound-guided nerve
blocks are superior to nerve stimulator-guided blocks.
The example is imperfect, however, since ultrasound-
guide blocks require initial investments in equipment
and training.1
Health-care interventions differ from financial invest-
ments in one key respect. The primary benefits of health-
care for the patient—such as improved health, improved
function, and pain relief are difficult to quantify in precise
dollar amounts. As an example, if the new postoperative
analgesic reduces pain by 50%, how much is that pain
reduction worth in monetary terms to both the patient
and the payer?
THE AGENCY PROBLEM—PROVIDERS AS
FIDUCIARIES
Doctors are not the primary beneficiaries of the interven-
tions they choose for their patients. Furthermore, doctors
may benefit from the performance of interventions with
unclear patient benefit. For example, knee arthroscopy in
the treatment of knee pain in patients who are middle-aged
or older has “inconsequential” benefit when compared with
conservative therapy.2
Within provider systems, parochial budgetary concerns
may interfere with the simple goal of maximizing benefits
to the patient. For example, a hospital pharmacy committee
may not want to burden the hospital pharmacy budget by
spending extra money on rivaroxaban, despite evidence of
better patient experience and less fatal bleeding with
rivaroxaban than with warfarin.3 This silo problem
whereby each silo worries about their budget more than
the impact on the entire health system is a continuing chal-
lenge that must be recognized.
In summary, health-care suffers from the agency prob-
lem: Will the CEO of a large corporation and other members
of top management (the providers and payers) act in the
interest of the “shareholders” (the patients), or will they
enrich themselves first, and only later think about what is
best for the shareholders?
44 • Economic Analysis of Perioperative Optimization 639
Health-Care Economic Studies
Offer Challenges
THE POINT OF VIEW MUST BE CLEAR AND
CONSISTENT
Because there are multiple actors in health-care, it is essen-
tial that we remain consistent in the point of view of our
analysis. Are we looking at an issue from the point of view
of the patient, the entity paying the bills, the provider
(the physician, hospital, or clinic), or perhaps society as
a whole?
OUR GOAL IS TO KNOW WHAT WORKS AND HOW
MUCH IT COSTS
If we were able to surmount the difficulties involved in
quantifying the monetary and nonmonetary costs and ben-
efits of our perioperative interventions, and if we were able
to specify from whose point of view we were analyzing the
issue, we might be able to construct a chart detailing the
utility and costs of perioperative interventions.
The US Public Health Service Panel on Cost Effectiveness
in Health and Medicine recommends that studies4:
▪ Adopt a societal perspective.
▪ Use community- or patient-derived preference weights
for utilities (as opposed to expert opinion).
▪ Use net costs (cost of intervention minus savings in
future medical costs).
▪ Use appropriate incremental comparisons.
▪ Discount costs and QALYs at the same rate.
Despite the recommendation to approach analysis
from a societal perspective, namely from the point of
view of all involved parties with all outcomes and costs,
the majority of studies do not follow the recommenda-
tion. As of 2005, only 29% of studies involving QALY
included a complete societal perspective (most were
missing key elements such as transportation and care-
giver time).5
The consensus recommendations were updated in 2016 to
include “reference case” and “impact inventory” as a means
to standardize cost-effectiveness analysis to improve compa-
rability between studies. A reference case is a set of recom-
mendations covering components of analysis, methods, and
reporting techniques. Two reference cases should be done,
one from the perspective of the health system and one from
that of society. From the health system perspective, the anal-
ysis should include an incremental cost-effectiveness ratio
and the net benefit (health or monetary). The societal refer-
ence case should include a complete “impact inventory,” a
structured chart of effects and costs, with components includ-
ing patient time, caregiver time, transportation, and effect on
productivity. All analyses should give clear explanations
regarding the perspective being adopted.5
With growing evidence and cost pressure, many
more studies of the costs and benefits of perioperative
interventions have been done to guide physician
behavior.6–8
640 PART V • Conflicting Outcomes Value Based Care
BARRIERS TO DOING THE RIGHT THING
But even if we were able to know exactly what the costs and
benefits of various perioperative interventions were, we
would still find that implementation of known beneficial
interventions lags far behind our awareness of the effectiveness
of the interventions.
There are many possible reasons for the gap between
awareness of beneficial interventions and their implementa-
tion. These include:
Lack of awareness: The physician does not know about
▪ and treat a health impairment. The adjective direct indicates
the new intervention.
Lack of familiarity: The physician knows the intervention
▪ patient. For example, an antibiotic administered to a patient
exists but not the details.
Lack of agreement: The physician does not agree with
▪ attributed to the particular patient who received the
the proposed intervention.
Lack of self-efficacy: The physician does not think they
▪ In economic analyses, direct costs should be estimated on a
can perform the intervention.
Lack of outcome expectancy: The physician does not
▪ vention minus any savings in future medical costs. For exam-
think the intervention will work.
Inertia: The physician does not want to change.
▪ infections, then the cost of the antibiotic for purposes of a
▪ External barriers: The physician wants to change but
cumbersome and inefficient work processes make it diffi-
cult to change.9
It is futile to simply exhort physicians to work harder and
▪ analgesia include nurse and pharmacy labor, pump and dis-
to perform better. Caregivers need work process redesign
as well as concrete positive or negative incentives for
changing their behavior.
The goal then is to build compliance with best practices
into the system, so that the best care is the default option.
For example, best practice for tidal volumes has changed
over time toward a “lung protective ventilation strategy”
with smaller tidal volumes and positive end-expiratory pres-
sure (PEEP). Changing the default setting on the anesthesia
machine is an effective way to change the tidal volumes and
PEEP received by patients.10 The default setting facilitates a
change in practice of physicians without adding additional
hassle. Another example is that placing hand sanitizer in
more convenient and visible locations improves caregiver
compliance with hand hygiene, presumably as a result of
increased ease of performing hand hygiene.11
Costs—What Exactly Do We Mean?
Costs can be analyzed from different points of view—that of
the patient, the provider (physician, hospital, clinic), the
payer, or society as a whole. For example, the cost of a med-
ical service to the payer (e.g., an insurance company)
equals the percentage of charges actually paid by the payer.
However, to the patient, the relevant cost is the out-of-
pocket expense (that portion not covered by insurance) plus
other indirect costs (e.g., inability to work) incurred as a
result of the illness. From society’s point of view, the cost
of a medical service is the total cost of all the different com-
ponents of providing the service, plus the costs of any future
consequences of that service, such as complications or
disability.
To maximize the usefulness of an analysis to different
audiences, the perspective of the analysis needs to be clear
and hopefully relevant to the intended audience. For
example, pharmacists may be more focused on the hospital
or provider perspective. The physician should give greatest
weight to the patient’s perspective, whereas the health
economist is likely to focus on the analysis from society’s
perspective.
Aside from the difficulties presented by differing points of
view, the term costs has many different meanings.
DIRECT COSTS
Direct costs are the value of resources used to prevent, detect,
that there is a clear matching of the expenditure with a
is a direct medical cost because the antibiotic can easily be
medication.
net basis—that is, they are calculated as the cost of the inter-
ple, if an antibiotic can be shown to prevent future wound
cost-utility analysis should be reduced by probable future
savings of medical costs. As another example, the full scope
of costs associated with intravenous (IV) patient-controlled
posables, intangible costs (e.g., adverse events from program-
ming errors), and potential events such as analgesic gaps
from malfunctioning pumps or IV line failures.12
Perioperative clinics reduce laboratory testing, specialty
consultations, and canceled surgeries.13–17 For periopera-
tive clinic cost-utility analysis, the cost of operating the
clinic should be reduced by the future savings (e.g., reduced
laboratory testing). Telephone preoperative clinics have an
additional cost benefit to the patient by decreasing transport
time, caregiver time, and patient time while maintaining the
benefits of an in-person perioperative clinic.18 The net direct
cost of the clinic should be decreased by both the savings of
the perioperative clinic discussed previously and the addi-
tional savings to the patient and their family. A conceptual,
financial, and political problem with this net-cost approach
is that it may be difficult within an institution to spend
money in one area in order to save money in another area.
Proponents of preoperative clinics (and of other efforts to
redesign patient care) need to point out to administration
that investing in a preoperative clinic may produce large
financial returns elsewhere in the hospital, which may more
than pay for the expense of running the clinic. The idea of
investing in the preoperative clinic is being expanded to
include the perioperative setting with a growing trend
toward perioperative surgical homes as a method to reduce
costs and improve outcomes.
INDIRECT COSTS
Indirect costs are the value of production lost to society as a
result of a patient’s absence from work, disability, or death.
Because indirect costs are “opportunity” costs and do not
directly influence expenditures for treating disease, they
are not easily measurable.19 According to the human–cap-
ital approach, indirect costs are estimated as the income lost
while the patient is absent from work.

INTANGIBLE COSTS
Intangible costs represent another category of costs that—
like indirect costs—are difficult to measure. These are
the costs of pain, suffering, grief, and other nonfinancial out-
comes of disease and medical care. They are not usually
included in economic evaluations but are captured indi-
rectly through quality-of-life scales. For example, epidural
analgesia is more expensive than intravenous analgesia
but provides better relief of labor pain. The additional
expected cost to society of epidural analgesia for labor pain
ranges from $259 to $338 per patient (depending on
whether nursing costs are assumed to increase as the
number of epidurals increases).20 Patients, physicians, and
society need to weigh the intangible value of improved pain
relief from epidural analgesia versus the increased cost. For
the treatment of pain in colorectal surgery patients, an algo-
rithm has been proposed.21
COSTS VERSUS CHARGES
Costs are not the same as charges. For example, a hospital’s
cost for giving a medication is usually interpreted to equal
the acquisition cost of the medication, plus the true cost
of delivering it to the patient. In contrast, charge refers to
the amount of money the doctor or the facility bills the
insurance company for the medication. Charges often bear
little or no relation to acquisition cost, as anyone can attest
who has heard about $10 aspirins and $40 plastic bedpans.
COST-ESTIMATION TECHNIQUES
To estimate costs, either a top-down or a bottom-up
approach can be used. One top-down method of estimating
costs uses cost-to-charge ratios, such as those that all US hos-
pitals supply to Medicare. These ratios are used to convert
hospital billing (charge) data to estimated costs. The biggest
advantage of the cost-to-charge ratio method is that charge
data are commonly available and their use is well accepted.
The biggest disadvantage of the cost-to-charge ratio
method is that charge data may not reflect the true cost
to the facility of providing care, particularly when hospitals
markup charges for services in one area to invest in poorly
reimbursed departments (e.g., medical records) or to pay for
the development of new clinical programs. This cost-shifting
is common. For example, areas of the hospital with low cost-
to-charge ratios are used to subsidize areas that have high
costs in relation to their charges.
Another top-down method of estimating costs uses Medi-
care diagnosis-related groups (DRGs) to classify episodes of
care. Although simple and efficient, this method is limited
because it does not account for variations of care within a
DRG, or between hospitals of varying efficiency.
Bottom-up costing is an attempt to measure costs more
precisely, because, in theory, resources are tracked as care
occurs.22 Bottom-up costing separates costs into fixed and
variable components.23 Fixed costs (e.g., rental of the build-
ing that houses the surgery suite) do not change in propor-
tion to the volume of activity, whereas variable costs—such
as the price of a disposable anesthesia circuit—are closely
tied to the volume of production. The majority of the costs
of providing hospital care are related to buildings,
44 • Economic Analysis of Perioperative Optimization 641
equipment, and salaried or full-time hourly labor, all of
which are fixed over the short term.24
A misleading overstatement of costs can occur when a
portion of fixed costs is allocated to what appears to be a var-
iable cost.25 Sometimes one hears operating room (OR) staff
state, “Operating room time costs $40 per minute,” imply-
ing—incorrectly—that if a patient left the operating room
10 minutes sooner, there would be a $400 saving. The truth
is that the mortgage, the administrators, and the nurses all
have to be paid, whether the patient is physically in the OR
or not.
Similar discussion frequently occurs regarding whether
choice of a certain anesthetic (e.g., regional versus general)
can increase patient throughput by decreasing time in
either the operating room or the postanesthesia care unit
(PACU). This would only decrease cost if a marginally
decreased PACU census could be translated into decreased
staffing levels.
SKEWNESS IN COST DATA
A distinctive feature of cost data in health-care is its asym-
metrical distribution (skewed to the right) and large vari-
ance. The three measures of central tendency or
“average” value of a distribution are mode, median, and
mean. High-cost patients (the right-skew) increase the
mean to a greater extent than the median. It is estimated
that the top 5% of patients utilized 50% of health-care
spending, while the lowest 50% only utilized 3% of
health-care spending.26
If information about the costs of alternative treatments is
to be used to guide health-care policy decision making, then
the total budget needed to treat patients with the disease is
relevant. For example, health-care planners may need infor-
mation about the total annual budget involved in providing
a treatment at a particular hospital. An estimate of this total
cost is obtained from data in a trial by multiplying the arith-
metic mean (average) cost in a particular treatment group
by the total number of patients to be treated. It is therefore
the arithmetic mean that is the informative measure for cost
data in pragmatic clinical trials.27
FUTURE COSTS NEED TO BE DISCOUNTED TO
PRESENT VALUES
A cost today is not equivalent to a cost in the future. Even
when inflation is taken into account, a cost or an outcome
today is not equivalent in value to the same cost or outcome
in the future. Because people prefer to have something today
instead of having it in the future, a future value must be dis-
counted to the present, and this can range from 3% to 7%
per year.
GOOD NEWS ABOUT COSTS: MARGINAL COSTS AND
THE LEARNING CURVE
Marginal costs (the cost of the next unit of production) nor-
mally decline over time. Both individuals and institutions
learn and get better at tasks over time. When a technique
becomes routine, people develop ways of performing the
technique easily. For example, an outside clinical laboratory
642 PART V • Conflicting Outcomes Value Based Care
establishes a blood-drawing station right next to the office of
a busy surgeon, thereby saving patient time and travel.
Competition and the freedom to innovate produce process
improvement:
Problem identification ! Invention of a new treatment !
Expensive and difficult implementation ! Skill
acquisition ! Increased volume of treatment ! Increased
competition on the part of suppliers and caregivers ! Drop
in costs ! A new standard of care is established at a lower
marginal cost.
Because of this learning curve, truly beneficial interven-
tions should be performed even if the initial cost seems high,
because we can count on costs coming down over time as a
result of increased volume, experience, and competition.
When curare was proposed as a new intervention to prevent
fractures during electroconvulsive therapy, it might have
been rejected as too expensive. Fortunately, the innovation
was made despite the high initial costs.
Benefits: Clinical Effectiveness
and Utility
Three types of benefits are commonly studied in health-care
economics:
▪ Desirable clinical results (i.e., effect)
▪ Increased utility (quality and duration of life)
▪ Benefit
Desirable clinical effects are desirable outcomes or results
that can be measured such as:
▪ Prolonged survival
▪ Reductions in complication rates
▪ Improved function
▪ Quicker discharge from the hospital
▪ Decreased postoperative nausea and vomiting.
INCREASED UTILITY (QUALITY AND DURATION
OF LIFE)
Health is more than repairing injury, alleviating pain, and
eliminating illness. As long ago as 1948, the World Health
Organization expanded the boundaries of health to include
complete physical, mental, and social well-being. We now
consider the impact of a disease and its treatment on
patients’ daily lives.
For cost-utility analyses, quality of life has to be quanti-
fied—that is, converted into units that can be compared
among different conditions. Utilities are numerical ratings,
or preference weights, of the desirability of health states that
reflect a person’s preferences on a linear scale from 0.00
(death) to 1.00 (perfect health). Preference values for health
states are commonly obtained using valuation techniques
such as the standard gamble, the time trade-off, or the visual
analog scale.28,29
QALYs are now widely used in medical decision-making
and health economics as a useful outcome measure that
reflects both quality of life and duration of survival. This
single-score summary measure is obtained by multiplying
the utility value for a given health condition by its duration.
For example, the QALY score for an individual in perfect
health (with a utility of 1.0) for 1 year (QALY ¼ 1) is con-
sidered equivalent to 2 years in a health state with a utility
of 0.5 (QALY ¼ 1).
BENEFIT
The word benefit is used in a limited sense in the phrase
“cost-benefit analysis” to mean an assigned monetary
equivalent for a nonmonetary benefit.
Types of Economic Analysis
The three major types of economic analysis in health-care
are cost-identification (or cost-minimization) analysis,
cost-effectiveness analysis (which includes cost-utility anal-
ysis), and cost-“benefit” analysis.
COST-IDENTIFICATION (OR COST-MINIMIZATION)
ANALYSIS
Cost-identification analysis simply asks: “What is the cost of
a given intervention?” By calculating the cost of delivering a
drug or by computing the total cost of the medical services
used to treat a condition, the costs of alternative therapies
can be compared. Cost-identification analysis is sometimes
referred to as cost-minimization analysis, because it is
often used to identify which of several therapies has the
lowest cost.
Cost-identification analysis assumes that the outcomes of
the therapies are equivalent, therefore the goal is to find the
least expensive way of achieving a standard outcome. For
example, one study found the pharmacy cost of delivering
postoperative analgesia to patients undergoing joint
replacement surgery represents approximately 3.3% of the
total costs of surgery.30 No statement can be made from that
study about how well the analgesia worked.
COST-EFFECTIVENESS ANALYSIS (WHICH INCLUDES
COST-UTILITY ANALYSIS)
Cost-effectiveness analyses are the most accepted economic
evaluations in health-care because they measure benefits in
patient-oriented terms (clinical effects or quality of life).
They permit comparison between different interventions
by standardizing the denominators (clinical effects or
utility).
Cost-effectiveness analysis, in contrast to cost-
identification analysis, incorporates both cost and effect. It
measures the incremental net cost of performing an inter-
vention (expenditures for the intervention minus savings
in future health-care costs) and compares it with the mar-
ginal, or incremental, benefit obtained. The incremental
cost-effectiveness ratio (ICER) is defined by the equation
ICER ¼ ðC2 C 1 Þ  ðE2 E1 Þ,
where C2 and E2 are the net cost and effectiveness of the new
intervention being evaluated and C1 and E1 are the net cost
and effectiveness of the standard therapy. In cost-utility

analysis, outcomes are reported as $ per QALY. In other
types of cost-effectiveness analysis, results are reported as
$ per desirable clinical effect.
Medical interventions are considered cost effective when
they produce health benefits at a cost comparable to that
of other commonly accepted treatments. A general guide is
that interventions that produce 1 QALY (equivalent to
1 year of perfect health) for under $50,000 are considered
cost effective. With increases in health-care spending,
more studies are using $100,000 per QALY as the
standard.
COST-“BENEFIT” ANALYSIS
Cost-“benefit” analysis, a third type of economic assess-
ment of medical outcomes, forces an explicit decision
about whether the benefit is worth the cost by quantifying
benefit in dollar terms, estimated as the individual’s max-
imal willingness to pay for the benefit. Because translating
the value of health-care benefits (decreased pain and suf-
fering, for example) into monetary terms is tricky, cost-
benefit studies are done less often than cost-effectiveness
studies. For example, if an analgesic provides pain relief
but costs $20, a cost-benefit analysis would have the dif-
ficult methodological challenge of placing a dollar value on
analgesia.
A recent example of cost-benefit analysis found that
maintaining a malignant hyperthermia cart in every
maternity unit in the United States would reduce morbid-
ity and mortality costs by $3,304,641 per year nationally
but would cost $5,927,040 annually.31 These results were
largely driven by the extremely low incidence of general
anesthesia. If cesarean delivery rates in the United States
remained at 32% of all births, the general anesthetic rate
would have to be greater than 11% to achieve cost benefit.
The study concluded that it is not economically rational to
maintain a fully stocked malignant hyperthermia cart
with a full supply of dantrolene within 10 minutes of
maternity units. Rather, the recommendation was that
hospitals institute alternative strategies (e.g., maintain a
small supply of dantrolene on the maternity unit for start-
ing treatment).
DECISION TREES
Decision trees evaluate costs and benefits when outcomes
are uncertain but the probabilities of the outcomes can be
estimated.
Despite their apparent mathematical precision, decision
trees are only as good as their assumptions. For a decision
tree to be meaningful, the following questions are crucial32:
1. Have all relevant interventions to help the patient been
considered?
2. Have all possible benefits and complications that each
intervention might cause been considered?
3. Has what each possible perioperative outcome would
cost the patient, both in monetary and in nonmonetary
terms, been assessed?
4. Have the probabilities of the various outcomes with and
without the contemplated intervention been properly
estimated?
44 • Economic Analysis of Perioperative Optimization 643
SENSITIVITY ANALYSIS
Sensitivity analyses are necessary to evaluate the impact of
changing key determining variables on the final result of the
model.33 When doing an economic modeling study, two dis-
tinct approaches are possible: frequentist and Bayesian. In
the frequentist approach, unknown parameters are
assumed to be fixed and nonrandom (but unknown) quan-
tities that do not have associated probability distributions.
The usual tactic for dealing with this uncertainty is to carry
out a sensitivity analysis by varying the estimate within the
ranges for the parameter reported in clinical trials or pub-
lished literature and observing the effect of this variation
on the result. This is cumbersome because it is difficult to
present the results of varying three or more estimates
simultaneously.
The alternative and now commonly used method is the
Bayesian framework in which the parameters in a model
are random variables, each with its own probability distri-
bution. For example, in a decision tree cost-utility analysis,
the probability, cost, and utility of each outcome and the
duration of survival are all assumed to be variables, each
with a range of possible values in a probability distribution.
A computer program is written to select a value randomly
from the distribution of values of each parameter. In a
Monte Carlo analysis this process is repeated a large number
of times and the mean and the variance of all the final results
from all the runs are computed. This probabilistic sensitivity
analysis normally assumes that the values of the parameters
are independent of one another. The Bayesian framework is
particularly helpful in considering uncertainties in all
parameters simultaneously.34 Importantly, this Bayesian
model may produce results that are different from a simple
analysis based on point estimates of probability and cost.
Conclusion
Economic analysis can help us decide whether beneficial
medical interventions are theoretically “worth the cost.”
But to actually improve medical care—to implement inno-
vations of proven value—it is essential to take human
nature into account. To be successful medical managers,
we have to remember that inertia and habit play large roles
in medical care, that we should make it easy to do the right
thing, that human beings respond to incentives better than
to exhortations, and that competition drives innovation and
improvement. As physicians, also, we should always
remember that our “perspective” should begin with that
of the patient.
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 45 Improving Health-Care Quality
Through Measurement
JASON B. LIU, JILL S. SAGE, and CLIFFORD Y. KO
“Wherever we see systematic measurement of results in health-
care–no matter what the country–we see those results improve.”
MICHAEL E. PORTER, HARVARD BUSINESS REVIEW
(OCTOBER 2013)
Extensive evidence exists demonstrating that health-care
is plagued with overutilization of inappropriate services,
underutilization of appropriate services, and avoidable med-
ical errors. Over the last few decades, the emphasis on
“closing the quality gap” in health-care has escalated and
intensified. Furthermore, measures of quality have become
tools to curb rising and unsustainable health-care costs. To
understand the evolving landscape of health-care quality
and national payment reform initiatives, it is important to
have a fundamental understanding of what quality in
health-care is and how it is most appropriately measured
and used to, ultimately, improve the care of our patients.
In this chapter, we first present an overview of quality in
health-care. Using this background, we then describe how
health-care quality can be measured. Last, we describe four
ways quality measures are commonly used in health-care:
quality improvement, accreditation and verification, public
reporting, and value-based care.
What Is Quality in Health-Care?
Quality can be considered the gap between the care delivered
and the care that should be delivered. As highlighted in the
seminal publication Crossing the Quality Chasm,1 abundant
evidence suggests that health-care falls short in six dimen-
sions: (1) safety, (2) effectiveness, (3) patient-centeredness,
(4) timeliness, (5) efficiency, and (6) equity. These six dimen-
sions comprise the overall concept of health-care quality
(Table 45.1). Improving these six dimensions would therefore
improve health-care quality by ensuring patients receive care
that meets their needs and is based on the best scientific
knowledge. Recognizing that health-care quality is multidi-
mensional is the first step to being able to understand and,
most importantly, to improve it.
In the United States, these six dimensions of quality are
most prominent in the National Strategy for Quality Improve-
ment in Health-care, or simply the National Quality Strategy
(NQS).2 Led by the Agency for Health-care Research and
Quality (AHRQ), the NQS was developed through a transpar-
ent and collaborative process with the goal to align health-
care quality improvement efforts across national, federal,
state, and private-sector stakeholders. Many agencies of the
US Department of Health and Human Services (HHS) have
adopted the NQS, including the Centers for Medicare and
Medicaid Services (CMS), as a framework to improve
health-care quality.
In addition to the inherent multidimensional nature of
quality, there are two additional concepts that should be
understood. First, improving quality along one of these
dimensions does not exclude the ability to improve along
any of the other dimensions of quality. That is, tradeoffs
are not inherent. A corollary to this is that improvement
along one dimension of quality does not necessarily result
in improvement along another dimension. In many
instances, although the dimensions of quality are all inter-
connected to some degree, effort must be spent on simulta-
neously improving all dimensions of quality.
Second, it is important to recognize that although all
dimensions of quality are important, certain dimensions
might be considered more important depending on which
stakeholder is evaluating the health-care system. For
instance, patients have different perspectives of what is
“high quality” compared with what payers, policymakers,
or providers might consider to be of high quality. Patients
might value longer, unhurried face-to-face time during
clinic visits with their health-care provider, whereas
health-care administrators might wish to minimize this
time to maximize the number of patients that can be seen
in a day.
Why Improve Quality?
It is important to understand the motivators for measuring
and improving quality: What drives quality? These motiva-
tions depend on the perspectives of the stakeholders evalu-
ating the care provided and the types of rewards involved.
Rewards can be categorized into those that are intrinsic
or extrinsic.3 Intrinsic rewards represent motivations driven
by philosophy, such as teaching, learning, or healing. Argu-
ably, health-care professionals entered the profession for
intrinsic rewards: to heal patients and to cure them of their
ailments. Extrinsic rewards, in contrast, are material goals,
such as financial gain. The challenge in health-care has
been to figure out when each of these motivations is most
effective as a lever to improve quality. Indeed, there exists
concern that measuring and reporting of health-care qual-
ity might result in punitive action by administrative man-
agers and policymakers, resulting in magnified conflicts
between intrinsic and extrinsic rewards. Quality problems
645
646 PART V • Conflicting Outcomes Value Based Care
Table 45.1 Six dimensions of health-care quality according
to the National Academy of Medicine.
Aim Definition Example
Safety Avoiding injuries to patients Chipped tooth
from the care that is intended during
to help them. intubation
Effectiveness Providing services based on Early removal of
scientific knowledge to all who Foley catheters
could benefit and refraining
from providing services to
those not likely to benefit.
Patient- Providing care that is respective Preoperative
centeredness of and responsive to individual goals of care
patient preferences, needs, and discussion
values and ensuring that
patient values guide all clinical
decisions.
Timely Reducing waits and sometimes Available
harmful delays for both those operating room
who receive and those who for emergencies
give care.
Efficient Avoiding waste, including Unnecessary
waste of equipment, supplies, preoperative
ideas, and energy. echocardiogram
Equity Providing care that does not Care provided to
vary in quality because of patients in rural
personal characteristics such as settings
sex, gender, ethnicity,
geographic location, and
socioeconomic status.
typically occur not because of a failure of goodwill, knowl-
edge, effort, or resources devoted to health-care, but because
of fundamental shortcomings in the ways care is organized,
delivered, or both. Ideally, intrinsic (e.g., curing patients)
and extrinsic (e.g., financial gain) motivators can work in
tandem to improve health-care quality.
Framework for Measuring Quality
Quality measures (performance measures, metrics, indicators,
etc.) are tools used to quantify the care provided to patients.
When used in health-care, quality measures assist in deter-
mining how well care is provided for certain aspects of care,
for certain conditions, or for various populations or communi-
ties. In 1966, Donabedian presented the most commonly used
framework by which to measure quality in health-care today:
structure, process, and outcome (Box 45.1).4
The types of measures used depends on the available sci-
entific knowledge connecting them to the quality gap and
on the resources needed to measure them. Measuring the
totality of care, which often encompasses all types of quality
measures across all six dimensions (Table 45.1), is optimal.
Structural measures are only as good and useful as the
strength of their link to desired processes and outcomes
(Fig. 45.1). Similarly, process and outcome measures must
be related to each other (i.e., causal) in measurable and
reproducible ways to be truly valid and reliable measures
of quality. Because of these concerns, outcomes, which rep-
resent the bottom line, are arguably more attractive to mea-
sure. However, as discussed, without a high level of rigor,
there is the likelihood of misclassifying care, which can have
unintended consequences, such as rewarding poor care or
penalizing optimal care.
In addition to “structure,” “process,” and “outcome,” any
combination of these measures can be combined to form a
composite measure. A composite measure combines the
results of two or more component quality measures, each
of which individually reflect quality of care, combined into
a single quality measure with a single score to provide a
more summative picture. Although attractive because they
can measure care across a continuum and can be easier to
understand by patients, composite measures have their own
share of difficulties. For instance, combining a measure in
which performance is generally poor with a measure in
which performance is generally good results in a composite
measure that may appear average.
As discussed earlier, the perspective of which outcome is
important to measure often varies by stakeholder. For exam-
ple, a patient who did not experience any complications may
be dissatisfied with the surgery she received because she was
not able to return to her usual activities of daily living as she
had hoped, or because her postoperative pain did not resolve
as she might have expected and compromised her quality of
life. In these situations, the patient perspective can be a
more meaningful measure of success. Patient-reported out-
come performance measures (PRO-PMs) are quality mea-
sures based upon aggregated patient-reported outcomes
(PROs) data.7 PROs measure a patient’s health status, qual-
ity of life, health behavior, or experience of care using infor-
mation that comes directly from the patient, family, or
caregiver without interpretation by a health-care provider
or anyone else. PRO-PMs share the same qualities of tradi-
tional outcome measures (i.e., need for risk adjustment)
except they are evaluated from the patient perspective.
Development and Endorsement
of Quality Measures
Numerous stakeholders are involved in improving health-
care quality, including federal (e.g., AHRQ, CMS) and state
government, payers (e.g., Blue Cross Blue Shield), purchasers
(e.g., Pacific Business Group on Health), professional socie-
ties (e.g., American Medical Association), provider organiza-
tions (e.g., American Hospital Association), industries (e.g.,
Pfizer), nonprofit organizations (e.g., National Committee
on Quality Assurance), community health agencies (e.g.,
Wisconsin Collaborative for Health-care Quality), patients
and patient advocates (e.g., National Partnership for Women
and Families), and foundations (e.g., Robert Wood Johnson
Foundation). Accordingly, just as many have developed and
continue to develop quality measures, both broadly across
different health-care settings and specific to their agendas,
specialties, and constituencies’ needs. Although there are
many general principles that should be followed to develop
measures that are meaningful, valid, and reliable, Donabe-
dian astutely condensed them into four basic questions4:
1. Who is being assessed?
2. What are the activities being assessed?
3. How are these activities supposed to be conducted?
4. What are they meant to accomplish?

Box 45.1 Donabedian Framework for Measuring Quality.
▪ “Structure” refers to the characteristics of the setting in which care
is provided. The validity of structure as a measure of quality is
predicated on the idea that appropriate resources are needed to
deliver care of high quality. Without certain fundamental struc-
tural resources, high-quality care could not be provided. Examples
include the number of ICU beds, nurse staffing levels, level of
trauma services, or availability of an adverse event reporting
mechanism. Structural measures of quality are typically the easiest
to measure. They have been the motivation for many accredita-
tion programs, such as those of the Joint Commission, to denote a
facility provides high-quality care or, more precisely, has the
capacity to provide high-quality care.
▪ “Process” reflects how the care was delivered. A process measure
seeks to determine whether high-quality clinical care was prop-
erly practiced or delivered. The administration of appropriate
antimicrobial surgical prophylaxis within 60 minutes of surgical
incision is a quintessential process measure in perioperative
medicine. Performing this process leads to higher quality care
because patients are less likely to develop a postoperative sur-
gical site infection; that is, the higher the compliance with this
process measure, the better the outcome. The validity of a process
Structure
Outcome
Process
Fig. 45.1 Relationship between structure, process, and outcome
measures.
Overall, it is most important to answer the last question
and to define the purpose of the quality measure: what is
the gap that, when addressed, will improve quality? In gen-
eral, this involves compiling the evidence base to identify the
current practice and what is the “best practice” as supported
by current scientific knowledge. The difference between
what is done and what should be done is the quality gap.1
Once these questions are answered, then the technical
details of the measure, such as inclusion/exclusion criteria,
risk adjustment variables, validity, reliability, can be speci-
fied, tested, and implemented (Box 45.2).
Endorsement by the National Quality Forum (NQF) is
considered by many to be an essential stamp of approval
for quality measures. Founded on recommendation of
the 1998 President’s Advisory Commission on Consumer
Protection and Quality in the Health-care Industry, the
NQF is an independent organization that brings together
public- and private-sector stakeholders from across the
health-care system to determine high-value measures for
improving the nation’s health and health-care. The NQF
measure endorsement process, also referred to as the Con-
sensus Development Process, provides the nation with a
centralized portfolio of quality measures that meet rigorous
evaluation criteria and could be implemented in both
45 • Improving Health-Care Quality Through Measurement 647
measure, therefore, depends entirely on the existence of a causal
relationship between the process and the outcome. According to
Donabedian, process also “includes the patient’s activities in
seeking care and carrying it out.” Thus, whether a patient dis-
continued their anticoagulation medication within the appropri-
ate timeframe before their operation is another example of a
process measure.
▪ “Outcome” refers to the effects of the care delivered on the health
status of the patient or population receiving that care. Classically,
these are stated in terms of recovery, restoration or improvement
of function, and survival. Many stakeholders want to measure
outcomes because they are concrete and represent the end-
product of the care delivered. However, outcomes are challenging
to measure compared with other types of quality measures. An
appropriate outcome measure must consider several factors:
appropriate time horizon, consistency of data collection methods
for tracking outcomes,5 attribution of members of the surgical
team, the need for a large sample size to detect a statically sig-
nificant outcome,6 cost for the infrastructure required to measure
and collect data, consistent analysis methods, and risk
adjustment.
accountability and quality improvement programs. Exam-
ples of NQF-endorsed perioperative measures are shown in
Table 45.2. In addition to endorsement, the NQF aims to
accelerate development of needed measures, to identify
high-priority measures, to harmonize measures, to drive
more effective implementation of priority measures, and
to understand better what does and does not work in qual-
ity measurement.
Although NQF endorsement is important and a recog-
nizable achievement, quality measure endorsement is
not always necessary. The process of NQF endorsement
takes considerable time, which must be weighed against
the need for improvement. NQF endorsement is often
sought for “high stakes” measures used for purposes of
national, large-scale accountability programs (i.e., public
reporting or pay-for-performance), such as the CMS Qual-
ity Payment Program (QPP) or CMS Hospital Value-based
Purchasing Program. The need for quality measure
endorsement thus depends on how the quality measure
will be used.
NQF MEASURE APPLICATIONS PARTNERSHIP
The NQF also convenes the Measure Applications Partner-
ship (MAP),9 which provides pre-rulemaking guidance to
the HHS for the inclusion of certain quality measures in
public reporting and performance-based payment pro-
grams. The MAP was mandated in the Affordable Care
Act (ACA) to make way for significant enhancements to
the traditional federal rulemaking process by providing a
forum for public and private partnerships to provide feed-
back on quality measures before they are proposed for use
in federal regulations. HHS selected the NQF to provide this
pre-rulemaking input guided by the three-part aim of the
NQS: better care, better health, and lower cost. The MAP is
charged with providing a coordinated look across federal
648 PART V • Conflicting Outcomes Value Based Care

Box 45.2 Calculating quality measures.

Quality measures can be expressed in three common ways,
depending on how the intended data are to be calculated:
(1) proportion, (2) continuous, (3) and ratio.8
1. A proportion measure is a score derived by dividing the number
of cases that meet a criterion for quality (the numerator) by the
number of eligible cases within a given time frame (the
denominator) where the numerator cases are a subset of the
denominator cases (e.g., percentage of eligible women with a
mammogram performed in the last year). Fig. 45.2 depicts a
proportion measure.
2. A continuous variable measure is a measure score in which each
individual value for the measure can fall anywhere along a
continuous scale and can be aggregated using a variety of
methods, such as the calculation of a mean or median (e.g., mean
number of minutes between presentation of chest pain to the
time of administration of thrombolytics).
3. A ratio measure is a score that is derived by dividing a count of
one type of data by a count of another type of data (e.g., the
number of patients with central lines who develop infection
divided by the number of central line days).

Table 45.2 Selected National Quality Forum (NQF)-endorsed perioperative quality measures.
Measure Developer/
Measure title (NQF measure number) Description type steward
Preoperative beta blockade (0127) Percentage of patients aged 18 years and older undergoing isolated Process The Society of
CABG who received beta blockers within 24 hours preceding Thoracic Surgeons
surgery.
Perioperative antiplatelet therapy for Percentage of patients undergoing CEA who are taking an Process Society for Vascular
patients undergoing carotid antiplatelet agent (aspirin or clopidogrel or equivalent such as Surgery
endarterectomy (0465) Aggrenox/Tiglacor, etc.) within 48 hours prior to surgery and are
prescribed this medication at hospital discharge following surgery.
Prevention of CVC-related bloodstream Percentage of patients, regardless of age, who undergo CVC Process American Society of
infections (2726) insertion for whom CVC was inserted with all elements of maximal Anesthesiologists
sterile barrier technique, hand hygiene, skin preparation and, if
ultrasound is used, sterile ultrasound techniques followed.
Postoperative respiratory failure rate Postoperative respiratory failure (secondary diagnosis), mechanical Outcome Agency for
(PSI 11) (0533) ventilation, or reintubation cases per 1000 elective surgical Health-care
discharges for patients ages 18 years and older. Research and
Quality
Perioperative temperature management Percentage of patients, regardless of age, who undergo surgical or Outcome American Society of
(2681) therapeutic procedures under general or neuraxial anesthesia of Anesthesiologists
60 minutes duration or longer for whom at least one body
temperature greater than or equal to 35.5°C (or 95.9°F) was achieved
within the 30 minutes immediately before or the 15 minutes
immediately after anesthesia end time.
Risk-adjusted, case mix-adjusted elderly Hospital-based, risk-adjusted, case-mix adjusted elderly surgery Outcome American College of
surgery outcomes measure (0697) aggregate clinical outcomes measure of adults 65 years of age and Surgeons
older.

CABG, Coronary artery bypass graft; CEA, carotid endarterectomy; CVC, central venous catheter.

programs. It identifies measure gaps and recommends
measures for use in approximately 20 federal quality pro-
grams, including the CMS QPP.
Uses of Quality Measures
Quality measures, once developed, specified, and poten-
tially NQF-endorsed, are commonly used in four ways:
(1) improving care services and delivery, (2) accreditation
and verification, (3) public reporting, and (4) incentive
payments or value-based care. All uses share the same goal
of improving the quality of health-care delivered but do so
with different means depending on the perspective of the
stakeholder and the motivation for reward. For instance,
clinicians, motivated by intrinsic rewards, use quality
measures to assess clinical practices better and to track their
implementation. Payers and insurers, motivated by extrin-
sic rewards, use quality measures to reward success fin-
ancially and penalize failure. Public reporting of quality
measures increases transparency, allowing patients to make
more informed choices about providers and facilities.
Quality Improvement
Quality measures have been traditionally used for internal
monitoring and quality and improvement (QI/PI) activities.

Denominator
exclusions
Denominator
Fig. 45.2 Anatomy of a proportion quality measure. exceptions
Using quality measures in this way helps providers and
institutions track ways to improve care and is related to
professional and personal commitments to care as well as
institutional expectations. Although quality measures have
long been used for internal monitoring and reporting, pro-
viders have not been able to compare themselves easily
with others because the data elements and collection
instruments have not been synchronized. Collecting and
Box 45.3 Diminishing variation in perioperative outcomes: the American College of Surgeons’ National
Surgical Quality Improvement Program (ACS NSQIP).
Gaps in care quality can be considered as unwarranted variation in the
care delivered. The presence of variation in medical practice has been
described since 1938 when Dr. James Alison Glover published his
classic study on the incidence of tonsillectomy in school children in
England and Wales, uncovering geographic variation that defied any
explanation other than variation in medical opinion on the indications
for surgery. Today, there are countless studies in the literature that
have revealed similar variation across myriad medical conditions and
procedures. Measuring unwarranted variation in care is a funda-
mental step to improving it. The American College of Surgeons
National Surgical Quality Improvement Program (ACS NSQIP) is one
well-established tool that has been shown to improve surgical quality
by accurately measuring variation in postoperative outcomes and
feeding these data back to hospitals to drive improvement.10–12
In the 1980s, it was insinuated that the operative mortality at
Veterans Affairs (VA) hospitals varied in comparison with the national
average. In response, the National VA Surgical Risk Study (NVASRS)
was formed in 1991, which established a data collection program
that systematically abstracted surgical outcomes and comorbidity
data from the clinical record and found that risk-adjusted mortality
statistics in the VA were not different than those outside the VA.13
The success of the NVASRS gave rise to the VA National Surgical
Quality Improvement Program (NSQIP), which quantified variation in
perioperative outcomes among VA hospitals and fed the results back
to frontline providers. The program demonstrated a 43% reduction
in 30-day postoperative morbidity, 47% reduction in mortality, and a
decrease in median length of stay from 9 to 4 days between 1991
and 2006.14 Encouraged, the VA NSQIP partnered with the ACS to
develop the Patient Safety in Surgery (PSS) Study with financial
support from the AHRQ to scale and spread these successes into the
private sector. Results demonstrated that implementing the NSQIP
framework in the private sector was also associated with significant
reductions in surgical complications. In October 2004, this seminal
study established the ACS NSQIP as it is recognized today, and
45 • Improving Health-Care Quality Through Measurement 649
Initial population
Denominator
Numerator
Numerator
exclusions
reporting the same data using the same specifications helps
organizations and providers understand how they perform
compared with other organizations. It also enables them to
identify opportunities for focused quality improvement
efforts (Box 45.3). With the rise of national quality pro-
grams, registries, and “big data,” groups of hospitals can
network with each other and learn which interventions
worked or failed at everyone’s respective institutions.
improvements continue to be seen. For instance, Cohen et al.15
demonstrated that for hospitals currently in the ACS NSQIP for at
least 3 years, 69%, 79%, and 71% showed improvement in mortality,
morbidity, and surgical site infections, respectively. They estimated,
for every 10,000 surgical procedures, the improving hospital would
have avoided seven deaths, converted 150 patients from having one
or more complications to having none, and converted 66 patients
from having one or more SSI to having none. Placed into the context
of the more than 30 million operations performed in the United
States annually, these improvements are substantial.
Today, more than 700 hospitals in the United States and inter-
nationally participate (Fig. 45.3), accruing more than 1,000,000
operations annually. Built upon a foundation of high-quality clinical
data with the help of data abstractors collecting data following
standardized definitions directly from the medical record, the ACS
NSQIP recognizes that data are necessary but not sufficient to
achieve quality improvement. Decreasing practice variability
through local standardization has been identified as one approach
to improve quality. Often, hospitals are presented with clinical
guidelines that might not be wholly implementable at the local level.
However, hospitals typically will start with the guidelines as a “straw
man,” and then, with certain tweaks or modifications, are better able
to implement them locally. As a corollary to this principle of
standardization, it is important that hospitals continually perform
surveillance of their data to elucidate whether further modifications
to their standardized processes are needed—a cycle of continuous
quality improvement. Case studies have been developed to help
novice hospitals gain insight into how they might improve their care.
Successful hospitals of different sizes and types (for example, rural or
urban, teaching or nonteaching) were identified to share informa-
tion, such as which problems were targeted and which strategy was
adopted, how a team was assembled and who it included, which
barriers were faced and how they were overcome, and which
“pearls” could be shared with others working in the same areas.
650 PART V • Conflicting Outcomes Value Based Care
QUALITY IMPROVEMENT METHODOLOGIES
There are numerous tools and strategies, mostly process
improvement tools adopted from industry, to improve qual-
ity in health-care. Each approach relies on collecting data
using quality measures to identify areas in need of improve-
ment and to test potential solutions. The most common
process improvement tools are (1) Institute for Health-care
Improvement’s Model for Improvement, (2) Six Sigma, (3)
Lean, and (4) Lean Six Sigma.16
The Model for Improvement17 relies on three key ques-
tions and the Plan-Do-Study-Act (PDSA) cycle to structure
continual improvement of a given process. The three key
questions are:
1. What are we trying to accomplish?
2. How will we know that change is an improvement?
3. What change can we make that will result in an
improvement?
After addressing these three questions, the PDSA cycle is
used as the framework for an efficient trial and learning
methodology—an iterative, step-wise process to achieve
improvement. In the “Plan” stage, objectives are set, a plan
is defined, and a hypothesized outcome is articulated. In
“Do,” the team implements the plan, documents any prob-
lems or unexpected findings, and begin their data analysis.
In “Study,” data analysis is completed, and the results are
compared to the predicted outcomes. In “Act,” the team
Fig. 45.3 Hospitals participating in the ACS NSQIP
in 2018.
identifies further changes that need to be made and decides
whether another PDSA cycle will be necessary.
In the 1980s, Motorola declared that it would achieve a
defect rate of no more than 3.4 parts per million within
5 years, which represented defect rates outside of six stan-
dard deviations (sigma) from the mean. Six Sigma thus
refers to a process of improving quality by eliminating var-
iation. Six Sigma depends upon the Define-Measure-Ana-
lyze-Improve-Control (DMAIC) framework, which has
been shown effective in reducing length of stay after hip
replacement surgery, decreasing discharge time, increasing
efficiency in radiology suites, increasing hand hygiene
compliance, and improving operating room recovery room
processes.
Lean is an approach that considers any resources that are
not allocated to the goal of creating value for the customer
wasteful, and thus should be eliminated. Developed in the
1950s by Toyota, waste (muda) in health-care can take many
forms, such as redrawing a blood sample that was previously
drawn but lost by the laboratory. Lean tools are like those of
DMAIC, including process mapping, work and process obser-
vation, standardizing processes, use of checklists, and error
proofing. Value-stream mapping is a technique that is more
specific to Lean management. In these maps, processes are
mapped along with information and material flows. By map-
ping current states, value-added and nonvalue-added steps
can be identified and properly addressed. In comparison to
Six Sigma, where waste results from variation, Lean aims
to identify wasteful steps in a process.

Both Six Sigma and Lean approaches have individual
benefits that in practice complement each other. Quality
improvement projects can either have a Lean-focused
approach, which apply best practices and focus on imple-
menting standard solutions to increase speed and reduce
lead and process time, or a Six Sigma-focused approach,
which is often used in more complex problems that
involve data-based analytic methods and stress control
mechanisms. The DMAIC framework can be used in
either case.
Accreditation and Verification
Accreditation, or verification, refers to an approval process
conducted by independent (nongovernmental) bodies to
certify that an institution or individual has met certain stan-
dards. Although there are multiple types of accrediting bod-
ies, such as educational (e.g., Accreditation Council for
Graduate Medical Education) and professional societies
(e.g., ACS Metabolic and Bariatric Surgery Accreditation
and Quality Improvement Program), the most well-known
accrediting bodies are the Joint Commission for hospitals
and the National Committee for Quality Assurance (NCQA)
for health plans.
HOSPITAL ACCREDITATION: THE JOINT
COMMISSION
The Joint Commission is an independent not-for-profit orga-
nization that certifies and accredits health-care institutions
and programs in the United States. Accreditation by the
Commission recognizes an organization’s commitment to
meeting certain performance standards related to the pro-
vision of safe and effective care. Accreditation also satisfies
CMS’ Conditions of Participation, which must be met for
hospitals to receive payments from federal sources. The
Commission’s approach to accreditation includes setting
standards developed by either its Board of Commissioners
or by external sources. Once drafted, vetted, and estab-
lished, surveyors are trained in the standards. Surveyors
conduct on-site surveys, typically by randomly selecting
active medical records at the start of a survey and trace
the patients’ progress from unit or department to the next
level of care in exact sequence. The Commission also
reviews an organization’s response to sentinel events,
including any process variation carrying a significant risk
of a serious adverse outcome to a patient. In response to
these events, accredited organizations are expected to con-
duct timely, thorough, and credible root-cause analyses
and to develop action plans to reduce risk, to improve pro-
cess of care, and to monitor the effectiveness of those
improvements. More recently, The Joint Commission devel-
oped the ORYX initiative, which integrates outcomes and
other performance measure data into the accreditation pro-
cess using a set of core measures for hospital quality. The
ORYX initiative became operational in March 1999, when
performance measurement systems began transmitting
data to the Joint Commission on behalf of accredited hospi-
tals. ORYX measurement requirements are intended to
45 • Improving Health-Care Quality Through Measurement 651
support Joint Commission accredited organizations in their
quality improvement efforts.
HEALTH PLAN ACCREDITATION: THE NATIONAL
COMMITTEE FOR QUALITY ASSURANCE (NCQA)
The NCQA is an independent not-for-profit organization
that works to improve health-care quality through the
administration of evidence-based standards, measures,
programs, and accreditation. The NCQA’s accreditation
of health plans and managed care organizations tracks
the quality of care that US health-care plans deliver.
Accreditation of health-care plans involves a rigorous
set of standards and performance measures in a variety
of areas. Specifically, the NCQA uses the Health Plan
Employer Data and Information Set (HEDIS) measures
for accreditation of health plans. The HEDIS is a set of
standardized performance measures designed to yield com-
parative information about the performance of health
insurance plans. HEDIS is used by more than 90% of
America’s health plans to measure performance on impor-
tant dimensions of care and service. Altogether, HEDIS
consists of 94 measures across seven domains of care,
including access issues, patients’ satisfaction with care,
preventative services, utilization, finance, and health plan
management. Because so many plans collect HEDIS data
and because the measures are so specifically defined,
HEDIS makes it possible to compare the performance of
health plans on an "apples-to-apples" basis. The NCQA
also collects data on patient-reported experience via the
Consumer Assessment of Health-care Providers and Sys-
tems (CAHPS) family of surveys.
SURGICAL SPECIALTY VERIFICATION: TRAUMA CARE
The ACS has a long history of activities directed toward
the improvement of trauma care. The ACS Committee on
Trauma (COT) developed the Verification, Review, and
Consultation Program (VRC) in 1987 to help hospitals
evaluate and improve their trauma care through a process
of external review. The ACS does not designate trauma
centers; instead, it verifies the presence of the resources,
structures, and processes listed in Resources for Optimal
Care of the Injured Patient.18 The ACS VRC is designed
to assist hospitals in the evaluation and improvement
of trauma care and to provide objective, external review
of institutional capabilities and performance. This process
is accomplished by an on-site review of the hospital by
a team of experts in trauma care. The team assesses
commitment, readiness, resources, policies, patient care,
performance improvement, and other relevant features
of the program as outlined in Resources for Optimal Care
of the Injured Patient. Trauma centers must focus attention
on the core measures for quality and patient safety
in trauma programs addressing topics such as mortality
review, provider response expectations, trauma team
activation, and monitoring delays in operating room
availability. This program verifies that the resources
needed for high-quality care are available at trauma
centers.
652 PART V • Conflicting Outcomes Value Based Care
Public Reporting and
Transparency
The United States experience with public reporting dates to
1986 and the Health-Care Financing Administration’s
(HCFA, now known as CMS) efforts to report risk-adjusted
hospital mortality rates. With this report, the performance
of more than 5000 hospitals was analyzed and reported
in terms of risk-adjusted mortality. Initially, these analyses
were conducted confidentially to stimulate quality improve-
ment. Under the Freedom of Information Act, however, the
information entered the public domain. These reports, based
upon inaccurate and unreliable data, generated pointed
criticism in the press and among the research community.
The reports came to be known as the HCFA “death lists.” As
a result of the negative public response, the HFCA reports
ceased after 3 years of publication.
In the early 1990s, several states began publicly report-
ing mortality statistics for hospitals and surgeons perfor-
ming open heart surgery. New York State embarked on
a groundbreaking reporting of risk-adjusted mortality
for coronary artery bypass graft (CABG) surgery by hos-
pital and surgeon. In 1992, Pennsylvania began reporting
CABG mortality and by 1998 the state was reporting
risk-adjusted CABG mortality for Pennsylvania cardiac
surgeons, hospitals, and 34 health insurance plans. Fast
forward to today, public reporting continues prominently
through myriad avenues.
Public reporting entails the public release of valid and
reliable data by provider type (e.g., hospitals, physicians),
thereby allowing consumers to compare institutions (or
physicians) based on the same data. The proliferation of
health-care public reporting (“report cards”) over the past
10 to 15 years is a direct response to widespread and grow-
ing concerns about the quality of care. When quality prob-
lems arise in other industries (such as automobile safety),
the solution typically involves a multitude of strategies,
including regulatory reforms, financial incentives, indepen-
dent oversight, and consumer education. Although this last
tactic is only one piece of a much larger puzzle, providing
people with useful information can play an important role
in effecting change.
Advocates for public reporting argue that public reporting
could improve health-care quality by helping patients make
informed choices about their care. Consumers and pur-
chasers will presumably select the highest quality health
plans and providers and avoid those that perform inade-
quately if given the right information and the ability to
use it. By disclosing information on quality, patient decisions
will enable the “health-care market” to work as it should
(i.e., mitigate information asymmetry).
Public reporting can also improve health-care quality by
simply being transparent. Health-care organizations, faced
with public information that reveals differences in perfor-
mance, will improve the quality of care they offer to compete
effectively. Public reports shine a light on the performance of
health-care organizations and compel them to acknowledge
that patients and purchasers have a “right to know” what
they are getting. If not used by consumers of health-care,
some argue that simply reporting on quality measures
may result in a Hawthorne effect to improve performance.
Extensive studies have been undertaken to evaluate the
effectiveness of public reporting on patient care outcomes.
Five systematic reviews synthesized the findings of these
studies but failed to reach a definitive conclusion. Despite
this, organizations such as CMS, The Joint Commission,
the Leapfrog Group, and NCQA provide the public with
information obtained from their quality measures. The
CMS Hospital Compare, Physician Compare, and Nursing
Home Compare websites are examples of this use. The
NCQA Health Plan Report Card is another example. Find-
ings from The Joint Commission accreditation results are
also available online.
Although an admirable endeavor, it is important that the
quality measures used to evaluate provider and hospital per-
formance are supported by evidence and are truly suitable
for reporting to the public. The misuse of quality measures
could lead to misclassification of care and yield misinforma-
tion for patients seeking to be better informed. Several pro-
fessional societies, including the Surgical Quality Alliance
(SQA), have published guidelines for public reporting of
quality measure data (Box 45.4).
Value-Based Health-Care
and Paying for Performance
Historically, US health-care has operated on a fee-for-service
model that incentivizes providers to deliver a volume of ser-
vices for an established payment.20 There has been ongoing
concern that this business model incents physicians to
increase the volume of services, which leads to escalated
costs, resulting in overutilization of services and contribut-
ing to quantifiable increases in health-care costs. The United
States spent 17.8% of its gross domestic product on health-
care in 2016, nearly twice as much as 10 high-income
countries on medical care and performed less well on many
population health outcomes.21 In response, the US Congress
has passed legislation incentivizing health-care models that
deliver care based on the value of care, as opposed to the vol-
ume of care delivered, where value is defined as a measure of
quality of care for the expended cost.
REDEFINING QUALITY AND COST TO TRANSITION
TO VALUE
The shift from volume-based care to value-based care
requires stakeholders to redefine the measurement of qual-
ity of care alongside cost. The first step in the transition
toward value-based care is to define and to measure quality.
In the fee-for-service framework, quality has traditionally
been defined as key process, outcomes, and structural mea-
sures, measuring a single moment in time. Mandated in the
Patient Protection and Affordable Care Act (ACA), the
AHRQ developed the NQS in collaboration with key stake-
holders to create a blueprint for the development of high-
value health-care (Table 45.3).2,22
The NQS initially provided the construct for the transi-
tion toward value-based care. However, as the nation
evolves in learning how to define value, it has become
clear that a value-based framework also calls for measuring
quality longitudinally across an episode of care with shared

Box 45.4 Principles for public reporting of provider performance in health-care according to the Surgical
Quality Alliance.
With representation from more than 20 surgical and anesthesia
specialty societies and organizations, the Surgical Quality Alliance
aims to define the principles of perioperative quality measures,
collaborate in the development of meaningful tools for quality
improvement, and provide a forum for shared and coordinated
effort among the specialties to monitor and respond to federal and
private sector initiatives. In 2014, the SQA outlined the following
guiding principles for public reporting of surgical care19:
1. All reports should make their methodology publicly available
and should include a detailed description of any data used to
estimate performance (i.e., data source), use of statistical risk-
adjustment techniques, the selection of performance measures,
and how clinical performance was categorized. Reporting
bodies should not use “black box” proprietary measures, which
make it impossible to audit the report results.
2. Each report should be independently deemed reliable and valid
prior to release.
3. Reports must be transparent about the observation period for a
given quality measure, including the differentiation between
long-term follow-up and short-term outcomes.
Table 45.3 National Quality Strategy aims and priorities.
Major aims of the National Quality Strategy:
1. Better care
2. Healthy people/healthy communities
3. Affordable care
Major priorities of the National Quality Strategy:
1. Making care safer by reducing harm caused in the delivery of care.
2. Ensuring that each person and family is engaged as partners in their
care.
3. Promoting effective communication and coordination of care.
4. Promoting the most effective prevention and treatment practices
for the leading causes of mortality, starting with cardiovascular
disease.
5. Working with communities to promote wide use of best practices to
enable healthy living.
6. Making quality care more affordable for individuals, families,
employers, and governments by developing and spreading new
health-care delivery models.
accountability. This concept goes beyond the specific priori-
ties of the NQS and requires providers to think of a patient’s
entire health-care journey, thereby moving away from mea-
surement silos. It requires episodic measurement including a
mix of risk-adjusted clinical outcome measures (e.g., surgical
site infection or unplanned readmission), communication
(e.g., shared decision making), PROs (e.g., change in func-
tion status after total knee arthroplasty) alongside meaning-
ful process, outcome, and structural measures.
The next step in defining value in health-care is to deter-
mine how to assess affordable care or cost. An important dis-
tinction to make regarding cost in a value-based framework
is that it is defined as cost to the payer and patient (not the
45 • Improving Health-Care Quality Through Measurement 653
4. Include a statute of limitations within the public report. Out-
dated reports must be removed from circulation.
5. Use proper risk adjustment, as determined by the appropriate
specialty society, to ensure ongoing access for patients who are
at higher risk of complications and poor outcomes.
6. Ensure that specialty societies have an opportunity to provide
input regarding recommended quality measures chosen for
public reporting and participate on the workgroup or panel
selecting measures for the reports.
7. Standardize reporting formats to be easily understood by
patients and their families.
8. Provide opportunity for provider review and feedback before
public reporting. Ensure a proper appeals process, including the
process for managing contested reports.
9. Conduct pilot tests to determine usefulness and effectiveness of
reports.
10. Evaluate the extent to which the report fulfills its stated purpose
and identify any unintended consequences with special focus
on addressing misclassification.
11. Public reports should not be used to establish the standard of
care or duty of care owed by a health-care provider.
cost of services). There has been difficulty in specifying cost
because the measurement system is still largely in a fee-for-
service model and most quality measures only look at a sin-
gle event. Initially, cost measures reported total cost or total
spending per patient based on claims data, such as Medicare
Spending Per Beneficiary measure.23 In more recent years,
the CMS has tried to develop and to implement episode-
based cost measures in their hospital quality programs with
limited success because the cost measures were not tied to
clinical quality measures and, therefore, they are not able
to assess value. Episode-based cost measures are currently
being developed for clinician quality reporting programs
but have not been implemented. Therefore, the “total cost”
measures are still being used across physician and hospital
quality fee-for-service programs. However, true value-based
measurement will require the development of measures that
span the phases of patient care that can be aligned with the
appropriate cost data for those specific episodes.
FROM PAY-FOR-REPORTING TO PAY-FOR-
PERFORMANCE
Along with the shift toward value-based care, federal quality
incentive programs have transitioned from a pay-for-
reporting model to a pay-for-performance model with public
reporting. Pay-for-reporting programs provide bonuses for
reporting and/or penalties for not reporting. Hospitals and
providers are simply incentivized to report on quality of care
and have payment adjusted based on participation, regard-
less of how they performed on the quality measure. In con-
trast, pay-for-performance requires providers and hospitals
to report and then receive payment adjustments based on
their performance on measures—reductions in payment
for poor quality and increases or bonuses in payment for
high quality. Select measures in pay-for-performance pro-
grams are also publicly reported to help consumers choose
654 PART V • Conflicting Outcomes Value Based Care
a physician or hospital. This shift from pay-for-reporting to
pay-for-performance has created a “higher stakes” in qual-
ity reporting. Because pay-for-performance impacts pay-
ment and displays public reports of care, many hospitals
and providers have started to invest a lot of time and
resources into quality improvement.24
CLINICAL CARE MODEL REDESIGN AND HEALTH
INFORMATION TECHNOLOGY
The clinical care model redesign required for health-care
reform has created compounding complexity through efforts
to track, report, and improve care to determine value. To
support this redesign, capturing patient data is a critical com-
ponent, which calls for health information technology (HIT)
that can follow a patient’s care longitudinally, including data
found in claims, clinical data captured in various registries
and other sources, and data reported by the patient. The goal
is to use claims, registry data, and other data sources to mea-
sure the patient in real time at the point of care, creating
knowledge helpful to the patient and care teams.
Congress has recognized the critical importance of the
use of HIT in driving value to bring patient records together,
and therefore included HIT adoption as part the CMS quality
programs through legislation. Hospitals are incentivized to
participate in the CMS Promoting Interoperability (PI) pro-
gram, previously known as the EHR Incentive Program or
“Meaningful Use.” Clinicians are also incentivized to use cer-
tified electronic health record technology (CEHRT) through
the Promoting Interoperability Performance Category that
is embedded in the Merit-based Incentive Payment System
(MIPS). The PI program promotes the use of the electronic
exchange of information using CEHRT.25
Although intended to foster health-care reform, the
requirements of the PI program are another substantial cost
to hospitals and providers because it requires the purchasing
of CEHRT and associated upgrades. This program has also
received a lot of criticism that it cannot keep up with the
pace of technology growth and has slowed the attainment
of widespread health data interoperability, not only between
meaningful users of CEHRT, but more broadly throughout
the wider clinical data ecosystem. An unintended result of
the “Meaningful Use” program is that much of the data is
kept in EHRs, which does not allow for easy exchange to/
from different data sources, including even EHRs to EHRs.
This has largely added to provider burden. Patient data
exchange requires standard data definitions, open source
interfaces, open source clouds and applications in order to
provide analyzed information in a usable format for pro-
viders, hospitals, patients, payers, or other end users.
LEGISLATION TO PROMOTE VALUE-BASED CARE
The passage of several laws in the last decade demonstrate
the US Congress’ commitment toward the shift to value-
based health-care.26–28 Once a law is passed by Congress
it is then interpreted and implemented by the regulatory
body responsible for implementing the new law. The CMS
is primarily responsible for implementing health-care laws
related to hospital and physician payment and is one of
the federal agencies within the US HHS. It is the largest
payer in the United States and because CMS is legally man-
dated to regulate health-care laws, it is often the first payer
to implement new large-scale quality incentive programs.
Often other third-party payers follow suit.
The ACA and the Medicare Access and CHIP Reauthori-
zation Act of 2015 (MACRA) are the two largest recent
pieces of legislation to influence value-based care. There
have also been many smaller legislative changes that fur-
ther define the transition toward value, each reflecting
updates along the way.
PATIENT PROTECTION AND AFFORDABLE CARE
ACT (ACA)
The ACA was designed to improve access, affordability, and
quality of health-care in the United States.28 To meet part of
this intent, the law created several programs aimed at fur-
ther promoting payment incentives based on value, includ-
ing: The Center for Medicare and Medicaid Innovation
(CMMI) with the goal to test, evaluate, and implement
new payment models; the Hospital Value-based Purchasing
program, which incentivizes acute care hospitals with
increased payments for higher quality (not the quantity of
services); and, Medicare Shared Savings Program Account-
able Care Organizations (ACOs), which focus on coordi-
nated, high quality, patient-centered care.
THE QUALITY PAYMENT PROGRAM (QPP)
More recently, MACRA repealed the highly criticized 1997
Sustainable Growth Rate (SGR) Physician Fee Schedule
update (each year the SGR threatened large cuts to phy-
sician Medicare payment but usually resulted in Congress
passing a “doc fix” to prevent these substantial cuts).
The intent of MACRA is to reward clinicians for value
over volume, streamline its quality programs into one sys-
tem, and incentivize participation in eligible alternative
payment models through bonus payments.27 It requires
CMS to implement the QPP, which offers two participation
tracks: The Merit-based Incentive Payment System (MIPS)
and Advanced-Alternative Payment Models (A-APMs)
(Fig. 45.4). Clinicians eligible for this program include
physicians, physician assistants, nurse practitioners, clin-
ical nurse specialists, and certified registered nurse anes-
thetists. Implementation of the QPP began in 2017.
MIPS
Providers who report through MIPS largely still operate in
the fee-for-service model but are incentivized to improve
value by reporting on quality, cost, performance improve-
ment, and the use of EHR technology.29 MIPS took the
CMS legacy quality programs including the Physician Qual-
ity Reporting System (PQRS), the Value-Based Modifier
(VM), and the EHR Incentive Program (commonly referred
to as “Meaningful Use” [MU]), added the new component
Improvement Activities, and combined them to derive a
composite MIPS Final Score. The components of the MIPS
Final Score are now known as Quality (formerly PQRS), Cost
(formerly VM), Promoting Interoperability (formerly MU as
a stand-alone program and Advancing Care Information as
a component of MIPS), and Improvement Activities.

MIPS
OR
The Merit-based incentive
Payment System (MIPS)
If you decide to participate in MIPS, you will earn
a performace-based payment adjustment
through MIPS
Fig. 45.4 Tracks of the CMS Quality Payment Program.
MIPS is a budget neutral program that benchmarks pro-
viders’ performance against the mean or median based on their
performance across these four categories. Because of the budget
neutrality of MIPS, providers below the mean or median incur
penalties to their Medicare payments to pay the incentive pay-
ments or “bonuses” to those above the mean or median. Unless
meeting particular exclusion criteria, most providers are
expected to be in the MIPS program in the early years of
MACRA with the goal of transition to APMs and thus value-
based care. To incent providers to transition from MIPS, pay-
ment adjustment gradually increases in the early years of MIPS.
The shortcoming of the MIPS program is that it has been
designed around the fee-for-service model, making it nearly
impossible to make a value statement based on care reported
through these programs. To make a value statement on
patient care, it is critical to measure the quality the patient
receives for that specific episode’s cost—instead, the MIPS
program measures care a provider delivers at a single point
in time for total Medicare cost of a patient. While MIPS also
engages in quality measurement, the cases on which quality
is evaluated might or might not be the cases on which cost
in evaluated.
APMs
CMS describes APMs as payment models that create incen-
tives for clinicians to provide high-quality, cost-efficient care
for a specific clinical condition, episode of care, or popula-
tion.30 MACRA created additional incentives for APM par-
ticipation, including a pathway for physicians to move from
fee-for-service in MIPS to value-based care in APMs. The
45 • Improving Health-Care Quality Through Measurement 655
Advanced
APMs
Advanced Alternative Payment
Payment System (MIPS)
If you decide to take part in Advanced APM, you
may earn a Medicare incentive payment for
sufficiently participating in an innovative payment
model.
goal of APMs is to improve the value of care provided, reduce
growth in health-care spending, or both.
Advanced Alternative Payment Models (A-APMs), as
defined in MACRA, have additional criteria that require
the A-APM to take on “more than a nominal amount of
financial risk for monetary losses,” or to be a medical home
model, to utilize CEHRT, and to adjust payment based on
quality measures, equivalent to those in MIPS. There are
a wide variety of APM models—some may be beneficial
by providing tools for improving clinical patient care for
increased efficiency and may have reduced administrative
burden when compared with MIPS. Depending on the pay-
ment model, shared savings or other financial incentives for
participation may also be available. Clinicians who partici-
pate in Advanced APMs that meet the required thresholds
for the percentage of payments or patients included in the
model are considered “qualified” A-APM participants and
are exempt from the MIPS program. For the first 6 years
of the QPP (payment years 2019–24 based on participation
in 2017–22), qualified A-APM participants also receive a
lump sum incentive payment of 5% of their prior year’s
Medicare Part B charges as an incentive to transition from
fee-for-service.
Most CMS innovative payment models fall into three
categories: ACOs, bundled care/episode-based payment,
and patient-centered medical homes. Different examples
of these types of models were determined to meet the
A-APM requirements and approved by CMS for use in the
QPP. Some examples include: Comprehensive Care for
Joint Replacement Payment Model Track 1 with CEHRT
656 PART V • Conflicting Outcomes Value Based Care
requirements (bundled care), Medicare Shared Savings Pro-
gram ACO Tracks 2 and 3, Comprehensive Primary Care
Plus (patient-center medical home). One criticism of the
models approved as A-APMs is they fail to recognize the
team-based nature of modern health-care thereby limiting
A-APM choices for perioperative care teams.31
CHALLENGES IN IMPLEMENTING VALUE-BASED
CARE AND THE PATH FORWARD
Value Is Defined by Payers
A fundamental challenge of value-based care is that value is
judged by payers, instead of patients or other key stake-
holders. This has resulted in a fragmented system where
measurement is kept in payer silos, across disparate pro-
grams based largely on health-care insurance claims, mak-
ing it difficult for providers to redesign care in a way that is
recognized similarly across different payers or across differ-
ent programs even with the same payer (e.g., Medicare pro-
gram directed at clinicians with a separate program directed
at inpatient hospitals). This fee-for-service model measures
the care delivered by multiple providers or different facilities
based on how they are paid, without truly focusing on the
journey of the patient. There has also been a difference in
provider behaviors when quality measurement shifted from
pay-for-reporting to pay-for-performance. Because of the
high stakes nature of payment based on performance, many
providers have expressed concern regarding the reliability
and validity of measures and lack confidence that quality
measures used by payers truthfully reflect their care. This
has resulted in fears that providers may game the system
and “cherry pick” patients, meaning they may only accept
the healthiest patients while rejecting those more likely to
have complications or higher than average cost.3
Excessive Burden With Lack of Valid and Meaningful
Measures
The MIPS program has been criticized for being overly com-
plex, burdensome, reliant on measures that are not mean-
ingful to providers and patients, thereby contributing to
provider burnout. The QPP also includes measures that
do not have the level of statistical rigor needed to determine
payment, with very few opportunities for surgical teams to
participate in APMs and A-APMs. Many critics of MIPS
argue that measurement science must advance to inform
patients and providers accurately to include more reliable
and valid information with appropriate clinical and social
risk adjustment to benchmark physicians accurately.
Open-source infrastructure to capture data, standard meth-
odology to define, obtain and aggregate data is critically
needed to improve quality measurement to make a value
proposition. CMS and other quality organizations such as
NQF have made investments in how to account for social
and community factors but they are in the preliminary
stages of research.32 The effort to standardize and improve
measure science is slow moving.
Challenges in Measuring Cost Alongside Quality
To date, CMS has not been able to measure cost measures
that correlate with quality measures included in the HVBP
and QPP program, making it difficult to measure value in a
patient-centric way. For example, quality and cost measures
in the MIPS program look at different silos of care instead of
the larger episode. It is not possible to make a value state-
ment when quality and cost are measured separately. Some
of the APM models have made progress in getting more
granular data to measure value. To measure cost in a mean-
ingful way all services must be considered and the episode
defined, then the cost of the episode should be determined.
CMS and other payers have been working to create software
to include specific services and define cost, but they have not
been able to accomplish this to date. But truly measuring
value will continue to be elusive because payers continue
to measure quality by tracking the provider instead of the
patient.
Lack of Interoperable Meaningful Data
There is an argument that it is impossible to give the safest,
best care in medicine without improved data integrity,
reduced burden of data aggregation, and the promotion of
larger data exchanges. The complexity of modern medicine
has exceeded the ability of a single physician to provide
all the care a patient requires because there are limits to
the amount of information one can process.33 Fig. 45.5
Fig. 45.5 Example of health-care complexity in the
neonatal ICU.

illustrates just how complex a care environment can be.34
The picture of an infant in the NICU shows there are often
hundreds of parameters needed to monitor and treat a
patient. In an environment with hundreds of parameters,
providers are also bombarded with interruptions and dis-
tractions, which is a formula for overload and failure. Lon-
gitudinally mapping patients’ needs when they suffer from
multiple chronic diseases and acute exacerbations is equally
complex. Medical errors are the third leading cause of death
in the United States—it is estimated that 250,000 people die
each year because of a medical error.35 Many of these errors
can probably be prevented if providers are given data to
inform care and thereby prevent the error. Physicians,
nurses, and other members of the care team would benefit
from machine readable and analyzed information repre-
sented to them in a useful format. This would allow them
to predict adverse events and prevent them with Clinical
Decision Support. However, because HIT incentive pro-
grams have been EHR-focused, they lack focus on the
patient and therefore have limited utility for a care team.
Conclusions
Health-care quality is multidimensional, comprised of six key
dimensions that need improvement. The first step to improv-
ing health-care quality is by measuring the quality gaps using
quality or performance measures. These quality measures
can then be used in four key ways to monitor improvements
in health-care: (1) internal quality improvement, (2) accred-
itation and verification, (3) public reporting, and (4) value-
based care. There remains a tremendous amount of work
ahead for the US health-care system to be in the position to
make a value statement based on quality and cost measure-
ment. To move toward a value-based care system, the appro-
priate data and interoperable infrastructure must be readily
available to track and to measure the episodic journey of
the patient. Critical to the success of a value-based model is
to leverage data that are patient-centered, allowing for value
to be defined by the patient and not simply measuring the pro-
vider with fee-for-service incentives. However, the nation
must build this framework based on a coordinated care model
because fee-for-service payment models inherently promote
silos of care and add to provider burden. With the successful
use of tools made available in APMs, it may be possible to
make a value statement on the care patients receive. APMs
provide opportunity for providers to get out of the fee-for-
service framework, but there must be more opportunities in
APMs to acknowledge the team-based nature of surgical care.
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media/files/advocacy/sqa/2014sqa_publicreportingdocument.ashx;
2014.
20. Sethi MK, Frist WH. An introduction to health policy: A primer for physi-
cians and medical students. New York, NY: Springer; 2013.
21. Papanicolas I, Woskie LR, Jha AK. Health care spending in the
United States and other high-income countries. JAMA. 2018;319(10):
1024–1039.
22. National Quality Forum (NQF). Multistakeholder Input on Priority
Setting for Health Care Performance Measurement: Getting to
Measures that Matter. http://www.qualityforum.org/prioritizing_
measures/; 2018.
23. QualityNet. Medicare Spending Per Beneficiary (MSPB) Measure Over-
view. Available at http://qualitynet.org/dcs/ContentServer?c¼Page&
pagename¼QnetPublic%2FPage%2FQnetTier2&cid¼12287720
53996; 2018.
24. Casalino LP, Gans D, Weber R, et al. US physician practices spend
more than $15.4 billion annually to report quality measures. Health
Aff (Millwood). 2016;35(3):401–406.
25. Centers for Medicare and Medicaid Services. The Quality Payment Pro-
gram Promoting Interoperability. Available at https://qpp.cms.gov/
mips/promoting-interoperability; 2018.
26. Marjoua Y, Bozic KJ. Brief history of quality movement in US health-
care. Curr Rev Musculoskelet Med. 2012;5(4):265–273.
27. Hussey PS, Liu JL, White C. The medicare access and CHIP reauthor-
ization act: Effects on medicare payment policy and spending. Health
Aff (Millwood). 2017;36(4):697–705.
28. Obama B. United States health care reform: Progress to date and next
steps. JAMA. 2016;316(5):525–532.
29. Centers for Medicare and Medicaid Services. CMS Quality Payment
Program. Available at: MIPS Overview; 2018. https://qpp.cms.gov/
mips/overview.
658 PART V • Conflicting Outcomes Value Based Care
30. Centers for Medicare and Medicaid Services. CMS Quality Payment Pro-
gram APMs Overview. 2018; https://qpp.cms.gov/apms/overview.
31. Opelka F, Sage J, Coffron M. Development of alternative payment
models for surgical care. Semin Colon Rectal Surg. 2018;29(2):84–88.
32. National Quality Forum (NQF): Evaluation of the NQF Trial Period for
Risk Adjustment for Social Risk Factors, 2017. Available at http://
www.qualityforum.org/Publications/2017/07/Social_Risk_Trial_
Final_Report.aspx. Accessed 04/20/2018.
33. Obermeyer Z, Lee TH. Lost in thought - the limits of the human
mind and the future of medicine. N Engl J Med. 2017;377(13):
1209–1211.
34. Howe S. Raising an early warning in the ICU: T3. Vector. https://
vector.childrenshospital.org/2013/03/raising-an-early-warning-in-
the-icu-t3/; 2013.
35. Makary MA, Daniel M. Medical error-the third leading cause of death
in the US. BMJ. 2016;353:i2139.
 46 Delivering Value Based Care:
The UK Perspective
ALEXANDER I.R. JACKSON and MICHAEL P.W. GROCOTT
Introduction: Rising Demand and
Resource Constraint
One of the few constants throughout health-care is an inex-
orable rise in demand. This rise has been ongoing for many
years and is driven by several factors. Across the decades, as
health-care has advanced, demand has been generated by
new life-saving and life-enhancing treatments, which reach
patients and conditions previously untreated. For example,
the total knee replacement (TKR) was first developed in the
1970s, yet more than 700,000 are now performed each
year in the United States.1 The positive effect of such tech-
nical health-care advances, combined with changes in soci-
ety and public health, significantly increases life expectancy
in many developed countries (see Fig. 46.1). However, this
increased life expectancy is now, in turn, providing a demo-
graphic driver of demand. The sharpest rise in demand is
now occurring as the post-war “baby boom” generation
reach old age, with a longer life expectancy than their fore-
bears. The ultimate outcome of this is a progressively aging
population. The global population aged over 60 years dou-
bled between 1980 and 2017 and over the next 25 years
the proportion of the population aged over 85 years will
double in the UK.2 An aging population, with higher levels
of morbidity and disability,3 drives increased health-care
demand.4 How this rising demand will be met poses a signif-
icant challenge for all areas of health-care.
Historically, rising demand has been met through
increased spending. Over the last 50 years, health-care
spending has been on a steady upward trajectory both in
raw currency terms and as a percentage of GDP (see
Fig. 46.2). Such an inexorable rise cannot be a sustainable
long-term solution. A 2007 report by the Congressional
Budget Office of the United States suggested that if spend-
ing patterns increased at historical rates, health-care
spending would approach 100% of GDP after 75 years,
and even when some limits to excess spending are intro-
duced, health-care could still account for almost half
(49%) of GDP by 2082.5 It seems likely that figures of this
magnitude will be deemed unacceptable by wider society. If
demand continues to increase, yet spending cannot keep
pace, there must be some constraint in health-care
resources. In order to achieve the best health-care out-
comes in a resource constrained environment value must
be sought wherever possible. Perioperative medicine offers
a means to deliver surgical care in a more cost-efficient
manner. Interventions, pathways, and systems that aim
to reduce complications and improve patient outcomes
have a byproduct of reduced resource utilization and this
chapter will explore how this may be delivered and its
importance in what are set to be increasingly resource-
constrained times.
The Cost and Value of Surgery
Surgery is, by its very nature, a resource-intensive undertak-
ing. In the UK’s National Health Service (NHS) an operating
theater is estimated to cost £1200/hour (approximately
$1500/hour) or £20/minute.6 Even the most straightforward
procedures, therefore, have significant cost attached. How-
ever, as the complexity escalates, so too do the costs of the
procedure. A surgical implant, an inpatient hospital stay, a
planned critical care admission all add to the total cost. What
is important to recognize, however, is that the total cost is not
dictated by the procedure alone. The same procedure per-
formed on two different patients, or even the same patient
under different circumstances, may yield an entirely different
final sum. For example, the cost of an emergency procedure is
higher than the equivalent procedure performed electively.7
These cost variations arise in a number of ways. The
duration of inpatient stay is a major influencer of final cost.
NHS reference costs suggest an average figure of £431
(approx. $475) per excess bed day for elective care.8 Of
course, extended inpatient stay is often dictated by clinical
need, but reductions in length of stay (LoS) over the years
suggest altered practice plays a role.9 Widespread variation
in LoS, unexplained by clinical differences, continues to
exist,10 suggesting scope for improvement remains.
The single biggest driver of increased costs, however, may
be complications or morbidity. These can lead to prolonged
length of hospital stay, additional investigations, reinterven-
tions and additional critical care stays, each with associated
costs.10,11 A study in the Netherlands suggested that
although only 20.8% of colectomy patients develop major
complications, these patients account for 53% of all costs.11
Studies in Europe and the United States replicate this
marked cost increase in cases where postoperative morbid-
ity occurs.12,13 Just as for prolonged LoS, complications will
never be entirely preventable. Variation is found both
within and between health-care systems.14,15 This suggests
scope for improvement exists and a number of national pro-
jects, such as the American College of Surgeons’ National
Surgical Quality Improvement Program (ACS NSQIP) in
the United States16 and the Perioperative Quality
659
660 PART V • Conflicting Outcomes Value Based Care
Life expectancy over time (1951−2019)
Country
85
80
Life expectancy (Years)
75
70
65
1960
Fig. 46.1 Life expectancy over time (1951–2019). (From OECD (2020), Life expectancy at birth (indicator). https://doi.org/10.1787/27e0fc9d-en (Accessed on
(8/3/2020)). With permission.)
Improvement Programme (PQIP) in the UK,17,18 seek to
measure this and to promote quality improvement through
reduction in unwarranted variation.
In summary, in settings where inpatient hospital stay and
complications can be minimized significant monetary sav-
ings may be made, while performing the same procedure.
Enhanced recovery after surgery (ERAS) offers some evi-
dence of this occurring in practice.19,20 However, when
considering cost reduction and factors that influence it, it
is also key to consider another concept closely related to cost
but importantly different, value.
Value is a complex concept that economists have debated
for centuries. The most important part of this concept for our
purposes, which most modern economists would agree
with, is that value is related to the benefit, or utility, that
the consumer gains,21 as well as the costs associated with
Australia France Japan UK USA
1980 2000 2020
year
it for the provider. In traditional free market economics,
the consumer makes their own judgement on the benefit
they will gain and decides upon a value. If this value is
acceptable to the provider or seller, for example if it exceeds
the cost, then a transaction or sale will take place. In reality
there is more complexity but at its heart this is how trade
works in most economic sectors.
In health-care, several factors distort this seemingly sim-
ple calculation. Government intervention is a feature in
most health-care markets, although the level of involve-
ment varies greatly and will modify or entirely remove
the cost aspect of an individual consumers calculation. Even
private insurance-based models distort choice on an individ-
ual procedure basis as the full cost of a single intervention
may not be realized.22 Regardless of this economic distor-
tion, the decision-making process for an individual is
 46 • Delivering Value Based Care: The UK Perspective 661

Health-care spending 1970−2018 (% GDP and per capita)

Country UK USA

20.0% $10000

15.0% $7500

Health-care spend (US Dollars/capita)

GDP spent on health-care (%)

10.0% $5000

5.0% $2500

0.0% $0

1970 1980 1990 2000 2010 2020 1970 1980 1990 2000 2010 2020
Year Year

Fig. 46.2 Health-care spending over time (1970–2018). (From OECD (2020), Life expectancy at birth (indicator). https://doi.org/10.1787/27e0fc9d-en
(Accessed on (8/3/2020)). With permission.)

profoundly different where health-care is concerned. There
is a high level of complexity in understanding the options
available, and a significant knowledge imbalance between
the provider and consumer.23 Even where symmetry of
knowledge exists uncertainty remains: we are not yet able
to predict with certainty the outcome of health-care inter-
ventions on an individual basis. The decisions can also be
very high stakes, with life and death discussions not uncom-
mon. There may often be limited time to make such deci-
sions. All these factors combine to mean that patients
cannot be expected to behave as the perfect, rational
decision-maker of economic theory.23 Therefore, patients
will, typically, and to differing extents, rely upon advice from
health-care professionals. To protect patients and to ensure
the impartiality of this advice, professional standards exist to
govern the behavior of providers; further divorcing health-
care from a typical free market scenario.23 Fortunately,
health-care professionals continue to enjoy, comparatively,
high levels of trust24 and play a vital role in guiding their
patients through health-care decisions.
Returning to value, if we accept it is related to the benefit
to the consumer (or in this case the patient) and combine
this with the role of the health-care practitioner in guiding
the patient, then the concept of value to the health-care pro-
vider should be inherently patient centered.25 A surgical
intervention, which delivers no benefit or utility to a patient,
no matter how low its cost, will offer extremely poor value,
while conversely an expensive intervention that offers great
benefit may offer good value. In essence minimizing the cost,
both financial and personal, while maximizing benefit offers
increased value. The challenge for health-care does not arise
from understanding this concept or appreciating the impor-
tance of value, but instead from quantifying it.
Perhaps the simplest and most intuitive expression of this is26:
Value ¼ Benefit Cost
662 PART V • Conflicting Outcomes Value Based Care
An alternative expression, which has been advocated spe-
cifically for health-care is25:
Value ¼ Benefit=Cost
However, for both of these there is a fundamental limita-
tion. Both require accurate and consistent measurement of
both benefit and cost. Cost initially appears to be the simpler
of the two. As discussed previously, while those issues are
highly relevant, it is important to note when considering
value we should assess not only the cost of the surgical inter-
vention but also examine the full cycle of care for a
patient.25 For example, it has been suggested that bariatric
surgery may significantly reduce health-care costs in the
long-term by reducing the severity and costs of managing
chronic conditions such as sleep apnea, diabetes, and
asthma,27 while other surgeries such as transplants may
require additional lifelong medical costs.28
The measurement of benefit is more complex still. The
challenge here is twofold. First, how to predict and subse-
quently measure the benefit of any intervention and second,
how this measured benefit can then be quantified in a uni-
form fashion to allow a meaningful cost benefit analysis.
Considering the latter: one option is to place a monetary
value on health-care outcomes, however, this approach is
fraught with challenges and no perfect solution exists. A
number of approaches have been advocated including:
cost-effectiveness analysis, cost-utility analysis, and incre-
mental cost-effectiveness ratios (ICERs).26 None of these is
without controversy. ICERs, for example, are widely used
in the UK by the National Institute for Health and Care
Excellence (NICE) to define thresholds for providing a treat-
ment.29 In the United States, however, the Patient Protec-
tion and Affordable Care Act (2010) prohibited the use of
cost-effectiveness thresholds by Medicare, although their
ongoing use in research was not affected.30
Each approach discussed previously has potential advan-
tages and pitfalls. Yet conceptually they all encourage a
drive toward the same endpoint. Value in health-care
should be about delivering the maximal patient benefit for
the minimal unit cost. This should be measured with the
patient at the center, examining the entire health journey,
not siloed to individual elements. This will be increasingly
important as resource constraints becomes a more pervasive
feature of global health-care. The remainder of this chapter
will focus on the role of perioperative medicine in
delivering this.
Shared Decision Making
Having discussed value and the traditional economic model
of relating it to consumer/patient benefit it would seem log-
ical to seek to replicate this as closely as possible within
health-care. A number of the challenges discussed (relating
to complexity, knowledge imbalance, uncertainty of out-
come and benefit, and time to make decisions) are all factors
that can be potentially ameliorated.
Shared (or collaborative) decision making (SDM) is an
approach to surgical decision making, which focuses on
the patient, their individual circumstances, health and
views and helps them to decide between treatment options,
including no treatment at all.31 The model allows clinicians,
ideally working in a multidisciplinary team, the time and
resources to meet with patients and families and overcome
many of the barriers to patients making their own value
judgment as has been discussed earlier. Complex decisions
can be broken down, additional information provided, time
given and, although uncertainty of outcome and benefit are
unavoidable, we are able to provide individualized risk
estimates.32
The consequence of SDM on value is likely to be positive.
Although there are resource implications for operating a
SDM service33 these may be outweighed by patients making
alternative health-care choices. During SDM, patients who
are at high risk of complications and poor outcomes will
have this explained to them. A proportion of these patients
are likely to weigh this against the potential benefits of sur-
gery and opt for either no surgery or alternative less high-
risk interventions. This is in line with the earlier discussion
about consumer value judgments. The choice for alterna-
tive, or no, treatment is most likely to be made by those
at highest risk and as we have discussed postoperative com-
plications dramatically increase health-care costs, while
these high-risk patients may also receive less benefit as peri-
operative morbidity is associated with poorer long-term
health outcomes.34,35 As such, through SDM we are able
to empower patients to make the appropriate decisions for
themselves, while simultaneously reducing some of the
highest risk procedures, all whilst avoiding paternalistic
rationing of care. Indeed, a recent study explored the asso-
ciation between SDM, resource utilization and patient-
reported outcome measures (PROMs) and suggested that
poor SDM was associated with increased resource utilization
and worse PROMs.36
The value challenge for SDM is likely to be related to how
it is delivered. Although the principles of SDM should be
applied in all cases, a dedicated multidisciplinary discus-
sion or clinic may only deliver value for higher risk
groups.37 For example, the cost of delivering this to gener-
ally healthy individuals undergoing minor procedures is
unlikely to yield significant reductions in resource utiliza-
tion as few will opt for alternative, less resource intensive,
options. At present insufficient data exist to provide a clear
level of risk or complexity at which a formalized SDM pro-
cess will improve value, although there is an argument for
a clinical and ethical imperative of SDM for all.37 Further
study will hopefully yield more information on cost effec-
tiveness at different levels of risk; but at present clinicians
should focus on applying the principles at all patient con-
sultations and ensuring those at highest risk are prioritized
for formal SDM.
Preoperative Optimization
The majority of patients, particularly in the context of an
aging population, are likely to have some kind of modifiable
factors, which contribute to their risk and subsequent out-
come (physical fitness, anemia, smoking, etc.). As the name
suggests, these are modifiable and with suitable interven-
tions risk may be reduced and outcomes improved. How-
ever, many of these interventions require, or benefit from,
time. At present, surgical pathways tend to focus on evalu-
ation of the primary pathology and deciding upon the opti-
mal treatment. There is often no, or extremely limited,
 46 • Delivering Value Based Care: The UK Perspective 663

Up to ~50 days 2−14 days

First formal
GP referral
physiological
assessment

Low risk
Diagnostic
Hospital tests/ Surgical Preassessment
MDT Medium risk Surgery
clinic tumor clinic clinic
staging
Fig. 46.3 Current typical pathway to sur- +/- postoperative
gery. MDT, Multidisciplinary team. (From High risk critical care
Grocott, Michael P. W., James O. M. Plumb,
Mark Edwards, Imogen Fecher-Jones, and Contemplation
Denny Z. H. Levett. Re-designing the path- of surgery +/- delay for
way to surgery: better care and added value. investigations,
optimization, decision
Perioperative Medicine 2017;6(1) 1–7.) making

Up to 62 days

GP referral

Preassessment
Diagnostic clinic: Stratified
Hospital tests/ Surgical
MDT final preparations perioperative
clinic tumor clinic
staging (face-to-face or package
remote)

Contemplation
of surgery

“Patient staging”: Low risk

Surgery school:
Simple online patient education / exercise
risk screening Medium risk intervention / smoking
+/- CPET cessation / group support
High risk

High risk clinic:
collaborative decision
making with MDT / tailored
medical interventions
Trigered add-ons:
anemia management /
comprehensive geriatric
assessment / renal, cardiac,
respiratory optimization

Fig. 46.4 Redesigned pathway to allow much earlier preassessment and risk stratification with more time for optimization. CPET, Cardiopulmonary
exercise testing; MDT, multidisciplinary team. (Reproduced with permission from Grocott, Michael P. W., James O. M. Plumb, Mark Edwards, Imogen Fecher-
Jones, and Denny Z. H. Levett. Re-designing the pathway to surgery: better care and added value. Perioperative Medicine 2017;6(1)1–7.)

evaluation of overall physiology and modifiable risk factors,
while surgery is being contemplated38 (see Fig. 46.3). It is
only after the final decision to operate is taken that these
are considered, by which point time is often limited. An
alternative pathway has been proposed38 (see Fig. 46.4),
which emphasizes that this “patient staging” at the point
of contemplation greatly increases the time available for
addressing modifiable risk factors, as well as informing the
multidisciplinary team about overall patient physical status
for any proposed interventions. This pathway also offers var-
iable levels of assessment and intervention based on risk,
addressing some of the issues discussed previously regarding
SDM, which also apply to other preoperative measures.
Such pathway reengineering is in keeping with the desire
to deliver value. Simply changing the point at which
assessments and interventions take place will not radically
alter costs but can greatly increase effectiveness of certain
interventions.39 Delivering greater benefit for similar cost
will yield a clear increase in overall value. This section
will look at a number of potential modifiable factors and
how these can improve value by improving patient
outcomes.
COMORBIDITY
We have already addressed the increasing burden of comor-
bidity on the surgical population. Comorbidity, typically,
increases perioperative risk and may affect recovery. How-
ever, in most cases, this effect is modifiable and perioperative
medicine seeks to optimize their management, reducing
664 PART V • Conflicting Outcomes Value Based Care
their overall effect on patient risk. Two of the most prominent
examples in perioperative medicine are diabetes and anemia.
Anemia can be found in up to 39% of patients,40 with
higher rates in colorectal cancer,41 or patients with menor-
rhagia.42 Anemic patients have three times the rate of blood
transfusions of nonanemic patients, exposing them to the
risks of transfusion, as well as increased overall mortality.40
The most common form of anemia, iron deficiency anemia,
is often amenable to intervention with both oral and intra-
venous (IV) iron being efficacious.43,44
There has been a recent focus on perioperative anemia as
a target for preoperative intervention. Pathways for screen-
ing, diagnosis, and treatment have been developed.45 Ran-
domized controlled trials (RCTs) have shown IV iron to be
effective at treating anemia, reducing transfusion rates,
and reducing LoS.46 The cost-effectiveness of this has been
explored and there is growing evidence that the reduction
in transfusion more than offsets the cost of delivering a peri-
operative anemia service.47,48 This matches well our previ-
ously outlined criteria for value. Similar or better outcomes
are being delivered, while the overall cost of patient care is
reduced. This example also demonstrates the importance of
considering the entire care journey. If only the preoperative
period is considered, treating anemia will increase overall
cost but as soon as the remainder of the perioperative period
is considered, overall cost savings as well as increased ben-
efits are observed, cementing treatment of anemia as a
treatment delivering value.
Diabetes offers a model for other long-term comorbidities. It
is a multisystem disorder of glucose homeostasis and has a
profound impact on surgical outcomes, with increased LoS,
complications, and mortality.49,50 However, as a risk factor
diabetes is, to a degree, modifiable.51 Given that both hypogly-
cemia and hyperglycemia are associated with worse out-
comes.50,52 Interventions to maintain glucose homeostasis
are advised, but attempts at extremely tight blood glucose
control (4.5–6.0 mmol/L) in the critical care setting have
demonstrated potential harm to this approach,53 as such most
bodies advocate more liberal targets of approximately 6.0–
10.0 mmol/L.54–56 This may be achieved through modifica-
tion of existing medication, advice for fasting perioperatively,
and institution of a plan for preoperative and postoperative
glucose control, such as variable rate insulin infusions.
The value gain may come from reduction of postoperative
complications. The most notable area is the reduction of sur-
gical site infections (SSI), which are 1.5 times more likely in
diabetic patients.57 SSIs add an average of almost 10 days to
LoS and increase cost by $20,842 per admission in the
United States.58 As such, a reduction in SSIs may yield sig-
nificant cost savings and the interventions to aid blood glu-
cose control should be comparatively low cost. However,
because of the multifactorial nature of SSI and other compli-
cations, as well as variable cost implications, demonstrating
cost effectiveness is less straightforward than for anemia.
However, there may be other ways in which value can be
added. The perioperative period can provide an impetus for
longer term improvement. The optimization of medications,
additional education, and the raising of patient awareness
about diabetes management may all contribute to sustained
improvements in diabetic control. This holds true for other
comorbidities but for all of them proving this experimentally
can be challenging. From a value perspective this is an
intriguing proposition. There are immediate benefits for sur-
gical outcomes, which offset some of the initial cost, while
longer term benefits may then be simply adding value to
the intervention.
Finally, surgery offers an opportunity to identify diabetes
in the undiagnosed diabetic, although agreement is not uni-
versal on the value of testing all at-risk individuals there
may be benefit.59 In patients who are found to be hypergly-
cemic in the perioperative period, complications rates are
most increased in those without a diagnosis of diabetes,50
with other studies also finding that this state of impaired glu-
cose homeostasis without a diagnosis of diabetes has an
association with poor outcomes.60,61 This suggests there
may be benefit to screening high-risk individuals, not only
to improve their perioperative wellbeing but potentially
longer term health through optimal management of undiag-
nosed diabetes or a prediabetic state. The value proposition
for this is as yet unproven but particularly when potential
long-term benefits are fully accounted for, given the
lifelong morbidity diabetes drives, this may make for a
compelling case.
As alluded to, much of what has been discussed for diabe-
tes, regarding diagnosis, optimization, and long-term
change may hold true for other comorbidities. Heart failure,
COPD, sleep apnea, pain, cardiac ischemia, cardiac devices,
and chronic pain are all areas where potential for optimiza-
tion exists39 and the value case for these may develop as ser-
vices mature.
PREHABILITATION AND BEHAVIORAL CHANGE
In addition to the formal medical diagnoses or comorbidities
already discussed, most surgical patients can improve
other modifiable factors to improve their overall risk profile.
Physical fitness, smoking cessation, reducing alcohol intake,
psychological preparation, and nutritional optimization are
all areas where changes in patient behavior and interven-
tions by health-care professionals, even in the absence of
pathology, can alter risk and outcome.
Prehabilitation is a comparatively recent innovation in
perioperative care. Initially focusing on exercise interven-
tions to improve functional capacity,62 it has progressed
to become multimodal encompassing behavioral, psycho-
logical, and nutritional interventions.63 Although precise
components, interventions, and protocols vary between ser-
vices, the overall aim is similar. All aim to target and
improve modifiable risk factors to prepare patients for sur-
gery physiologically and psychologically. Early evidence is
encouraging,64,65 with further trials ongoing.66,67 A recent
RCT showed a significant reduction in complications follow-
ing an exercise-focused prehabilitation program,64 while a
cost-consequence analysis performed as secondary analysis
of the same trial suggested this intervention may be cost
effective.68 This analysis was not without limitations, but
remains encouraging.69
As larger trials are completed, further cost-effectiveness
data relating to prehabilitation may be expected. However,
there is substantial variation in the characteristics of differ-
ent prehabilitation approaches. The components, interven-
tions, setting, and intensity vary between prehabilitation
protocols. It may be that some are more effective, while
others have lower costs. This variation may highlight some

of the challenges around delivering value in health-care. No
single solution is the panacea, with multiple approaches
potentially having merit and, on occasions, different solu-
tions may be more effective in different contexts. Nonethe-
less, prehabilitation may offer an important opportunity to
deliver value in perioperative care.
More broadly there is also potential value in using the
perioperative time period as a “teachable moment” to affect
behavioral change. The concept of a teachable moment
(TM) as a health event that motivates individuals to change
their behavior is established for smoking cessation, with par-
ticular life events such as pregnancy and smoking-related
cancer diagnoses as powerful TMs.70 The perioperative
period has been suggested as another potential TM38 with
smoking,71 alcohol consumption,72 physical activity,65,73
and diet65 all suggested as potential targets. These match
the same areas targeted by many prehabilitation proto-
cols.63 This is logical because behaviors that can be altered
to improve perioperative risk may also, if sustained, modify
long-term risk. Equally, if new behaviors can be adopted
during a prehabilitation phase, they may become easier to
sustain in the long-term. Estimating the benefit of this can
be challenging because lengthy follow-up and responder
bias can make research problematic. However, if the initial
intervention (prehabilitation) can demonstrate cost-
effectiveness in the short term any long-term behavior
change could be described simply as value-added, but none-
theless should be considered when the value of these inter-
ventions is being considered.
Intraoperative Care
The focus of anesthetists has traditionally been the deliver-
ing intraoperative care within the operating theater.39
Despite this long history and many decades of research there
remains potential scope for enhancing value. As the avail-
ability and quality of monitoring, and thus data about a
patient, has increased there has been a move toward more
individualized intraoperative care, particularly for high-risk
patients.74 As such we might expect a degree of variability in
clinical practice, driven by individualized patient care. How-
ever, a study of fluid therapy in the United States suggested
that the strongest predictor of fluid therapy received was not
any patient variable, but rather the identity of the care
provider.75 We see variability in multiple aspects of intra-
operative care including: oxygen therapy,76 ventilation,77
and transfusion.78 Observational data also suggest that this
variation can be linked to increased LoS and increased
cost—a clear loss of value.79 As such, if through standard-
ization of care we are able to reduce interoperator variabi-
lity while maintaining individualized care, we may be able
to deliver better value for patients and health services.
Postoperative Care and Recovery
ERAS, first described by Professor Henrik Kehlet in the
1990s,80–82 has significantly changed postoperative care
with a focus on returning patients to normal function as
quickly as able. Key features include patient education, min-
imally invasive surgery, optimizing fluid therapy and
46 • Delivering Value Based Care: The UK Perspective 665
analgesia, early mobilization, and restarting oral nutrition.
ERAS implementation is associated with improved outcomes
and reduced cost, demonstrating an excellent example of
improved value in health-care.82 Achieving and sustaining
high levels of compliance with such protocols remains a chal-
lenge83 and opportunities for adding value remain by improv-
ing reliability of ERAS delivery,84 with novel techniques such
as mobile applications (“apps”) under investigation.85
A challenge persists in delivering value through appropri-
ate individualized care. Some patients require additional
monitoring, care, and support in the perioperative period,
with elective critical care admissions an important compo-
nent of this.86 Critical care is an expensive resource8 and
there is no universal consensus regarding thresholds for
admission. It is a field where many parts of the world already
experience the resource constraints discussed at the start of
this chapter.87 Widespread variation in practice exists and
may be related to resource availability.88 To optimize value
in this area patient selection is likely to be key.89 Perioper-
ative medicine has a key role to play in risk prediction with
the aim of ensuring that the patients who may benefit most
are admitted to critical care beds, while unnecessary costs
are not accrued on those who will derive limited or no ben-
efit. Indeed, critical care may not be the ideal environment
for enhanced recovery, which in low-risk patients may be
better achieved on a surgical ward.39 Studies of planning
postoperative care based on risk suggest possible advan-
tages,90 as well as efficient resource utilization. There is also
likely to be scope for intermediate care settings that offer
augmentation over traditional ward care but without the
full expense of a critical care admission.39
Conclusions
Throughout the patient journey opportunities for enhancing
value can be found. From shared decision making before any
surgery has been agreed, through postoperative recovery and
beyond to patients’ long-term health behaviors, benefits, cost
savings, and overall value gain may be achieved. A number of
overall principles override. The patient journey should be the
key focus, examining the entirety of their care and health
experience. Siloed thinking to particular aspects limits poten-
tial long-term value gain. Individualized care ensures that
unnecessary resources are not used while the optimal patient
care is delivered. Looking at health-care systems, unexplained
and unnecessary variation can be targeted with incremental
gains in efficiency possible. At the heart of it, the delivery of
value is patient centered, seeking to maximize patient benefit
while reducing unnecessary cost. Value is both essential and
desirable and perioperative medicine is central to its delivery
in surgical care.
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 47 Transitions From Hospital
to Home
RACHEL E. THOMPSON and AMIR K. JAFFER
Worldwide more than 200 million surgeries are performed
each year; in the United States more than 50 million inpa-
tient procedures occur annually. In 2009, the World Health
Organization demonstrated that implementation of a rela-
tively simple day-of-surgery checklist was associated with
decreased rates of postoperative complications and death.1
Since that time, numerous evaluations of perioperative
checklists and coordinated care efforts have demonstrated
significant improvements for patients. In a review of
10 years of Enhanced Recovery programs, length of stay
consistently decreased by more than one day moreover,
complication rates in these studies on average decreased
by 30%.2
The focus on perioperative care programs has gained sig-
nificant attention in the last decade. Enhanced Recovery,
The Surgical Home, and Strong for Surgery are among
some of the better-known programs. These programs have
in common the goal of improving surgical outcomes by
preparing for surgery, engaging patients, standardizing
interventions, and speeding recovery. As a result, postop-
eratively patients are going directly from the hospital to
home more often and more quickly than ever before. When
building perioperative programs, together with focusing on
speeding recovery, shortening time to ambulation and
return of bowel function, health systems need to be pre-
pared for the next step—the transition from hospital
to home.
Paths from Hospital to Home
There are varied paths to home from the hospital (Fig. 47.1).
Some patients require continued rehabilitation whether
more intensive as found in acute rehabilitation centers, or
lower acuity provided in nursing facilities skilled in post-
acute care. Some patients may be ready to return home with
home-based services; others may be able to return to inde-
pendent living directly (Table 47.1).
A major driver of postacute expense in the United States is
whether the patient is discharged to a postacute facility
compared to home.3 Postacute facilities have not histori-
cally been incentivized to reduce utilization in order to max-
imize value. However, this pressure is emerging as bundled
payment programs become more prevalent.
Currently, the decision to discharge to a postacute facility
is widely variable from one institution to another,3 under-
scoring a need for improved understanding and coordina-
tion of care. For certain populations, discharge to home
directly has been demonstrated to be more cost-effective
and equally safe when compared with postacute facilities.4
668
Factors Associated with Nonhome
Discharge
Studies of discharge location have identified factors associ-
ated with nonhome discharge to include higher baseline
comorbidity, older age, frailty, non-white race, Medicare
recipient, cognitive impairment, poor nutrition, length of
stay, and postoperative complications.5–11 These factors
can be grouped into:
1. baseline level of physical function (i.e., frailty, ability to
perform activities of daily living [ADLs]),
2. baseline cognitive function,
3. degree of social support,
4. surgical invasiveness, and
5. degree of deconditioning that occurs in the acute setting.
Predictive models for nonhome discharge have been devel-
oped and several found that preoperative factors alone were
adequately predictive (C-statistics 0.87 to 0.88) to merit pre-
operative initiation of discharge planning.10,12 In addition,
the American College of Surgeons National Surgical Quality
Improvement Program (ACS NSQIP) Risk Model, which
incorporates 22 preoperative variables and was based on
an analysis of 1.4 million Americans, also estimates risk of
nonhome discharge, among other outcomes.13,14
Planning for Transitions
Identifying the need for postoperative nonhome discharge
or the need for home-based services prior to surgery will
allow both adequate time to initiate arrangements and to
provide better insight into the recovery required as the sur-
gical team and patient discuss care options. Using a predic-
tive model, be it ACS NSQIP or one of the cardiac specific
published models, can help identify patients who can begin
postdischarge planning prior to surgery.
Discharge planning should begin at the time of the deci-
sion to undertake surgery. Multidisciplinary assessments
should include: frailty, ability to perform ADLs, cognitive
function assessment (i.e., MiniCog assessment), potential
home-based social and family-based support. These baseline
assessments should be considered along with surgical inva-
siveness and risk of postoperative complications to inform
planning for postoperative postdischarge needs. As a best
practice, these assessments could be shared via an electronic
medical record with the Case Management or Care Coordi-
nation department to assist with discharge planning.
Depending on the degree of immobility from the surgical

Postacute rehab
Hospitalized Postacute skilled
surgical patient facility
Long-term acute
care
Fig. 47.1 Paths from hospital to home. The path to home postdischarge is not always direct or even linear.
Table 47.1 Discharge disposition options. At the time of
discharge, a patient’s current level of function will determine
his/her immediate postdischarge needs. Several of these are
time limited and would not be available long term.
Short-term postacute options Long-term living options
Home independently Home independently
Home with family/friend support Home with family/friend support
Home with home health Home with home health
Postacute skilled nursing Assisted living facility
Long-term acute care Long-term care facility
Acute rehabilitation
procedure itself, repeat assessment of functional status will
probably be essential following surgery to best define the
needed resources.
Costs of Failed Transitions
It has been estimated that preventable readmissions cost
Medicare $12 billion in 2011.15 Readmissions are the most
notorious measure of transition failure. As a result, increas-
ingly payors are targeting readmission reduction programs
across the United States.
When planning for discharge, the team should assess for
and mitigate risk of readmission. A look at readmissions
among orthopedic patients found that older age, longer
length of stay, discharge to skilled nursing facility, higher
BMI and ASA greater than 4 were all associated with
increased risk.16 In this analysis, nearly half of readmissions
were associated with wound issues, another quarter with
medical complications. A multicenter study of 90-day read-
missions following major cancer surgeries found type of sur-
gery, number of comorbidities, type of hospital, and
discharge to skilled nursing facility all associated with
increased risk for readmission.17 Among patients undergo-
ing vascular surgery, investigators found that preoperative
risk factors were not associated with readmission, but open
procedures and postoperative pneumonia were.18 This
47 • Transitions From Hospital to Home 669
Home with home Home
services independently
Assisted living
Long-term care
literature is highly variable and thus provides us general
rather than specific guidance; nonetheless, awareness of
these factors when planning for discharge could help miti-
gate readmissions.
Ensuring the Transition
Key components to ensure a smooth transition include a
solid communication strategy and patient engagement. In
2003, Eric Coleman published “Falling through the cracks,”
calling for systems improvements in transitions of care.19
Subsequently, Coleman developed and tested a model for
improving transitions that reduced readmissions and overall
costs.20,21 Cornerstones of these interventions include:
“1) tools to promote cross-site communication, 2) encourage-
ment to take a more active role in their care and to assert their
preferences, and 3) continuity across settings and guidance from
a transition coach.”
Another successful transitions program has been the Society
of Hospital Medicine’s BOOST program, which has been imple-
mented in 180 hospitals nationwide. BOOST provides an imple-
mentation framework designed to help health systems identify
areas of need and offers guidance and tools to address these
needs. The key components of BOOST include mentored
implementation, data analysis, and the BOOST Toolkit.22
The Institute for Health-care Improvement has also
designed an implementation toolkit.23 Key design elements
in this work include patient engagement, collaboration, and
communication of shared care plans. Foci for interventions
include partnering with patients and families to determine
needs, effectively educating patients and families, develop-
ing appropriate postdischarge follow-up, and providing
real-time handoff communication at discharge.
These and other transition programs have two common
themes: effective communication and patient and family
engagement.
Essentials of effective clinical communication. Standardizing
communication to responsible providers in facilities or
clinics is as complex as the variation of needs in post-
discharge care. Yet, communication failure is the leading
670 PART V • Conflicting Outcomes Value Based Care
Awareness of postdischarge options
Assess patient needs prior to surgery
Develop
understanding of
Assess baseline
local resources
physical, cognitive,
and emotional needs
Use calculator to
determine likelihood
of nonhome
discharge
Assess social support
Fig. 47.2 Care transition planning for postoperative transition from the hospital.
cause of medical errors. Programs that commit to ensuring
communication between providers at time of a transition
have demonstrated superior results. Methods to ensure
communication range from utilizing standardized forms,
to educating patients, to hiring transition coaches, and to
employing care providers who transect clinical locations.
In this unique and more recent version of closing the com-
munication chasm, hospitals employ providers to check on
their recently discharged patients at postacute facilities, cre-
ating a “connected care model.”24 Many organizations have
partnered with longer term skilled facilities to create a pre-
ferred care network based on readmission rate performance.
Patient and family engagement. Engaging patients and their
families in postdischarge care can be tremendously helpful
in ensuring the transition. In the BOOST program, patients
are provided with a clear and concise written summary of
their hospital care to carry information to their next stage
called the Patient PASS. Several programs recommend
implementing the technique of TeachBack in discharge
counseling to ensure patient and family understanding.
Putting it all Together
In order to develop truly comprehensive and collaborative
perioperative care programs, health systems should evalu-
ate the current state of transitions and identify improve-
ments and opportunities in their procedures. Key concepts
highlighted in this review include the need to be aware of
discharge options, to assess patient needs prior to surgery,
to incorporate an assessment of risk for readmission, and
to build a process that bridges the inpatient world with
the next location through patient engagement and solid
communication (Fig. 47.2).
As the population in the United States ages and numbers
of surgical interventions continue to rise, formalized periop-
erative care programs will be created and existing programs
will expand. In these programs, it is essential to attend to the
transition from hospital to home. The path home varies and
will increasingly be visualized through the lens of value to
the patient and the system. Important research in this area
Assess readmission risk
Build a bridge
Identify specific risks
Plan for close follow-
Educate and engage
up and other
patients and families
interventions to
mitigate risks
Develop to standard,
clear, and concise
communication links
is anticipated in the coming decade that will inform and
improve our clinical practices. In the meantime, careful
and consistent attention to ensuring solid communication
and engaging our patients and their families is imperative.
References
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 Index

Note: Page numbers followed by f indicate figures, t indicate tables and b indicate boxes.

A Acute ischemic stroke (AIS), endovascular therapy, anesthesia for

Abdominal aortic aneurysm (AAA), 73–74, 74t. See also Aortic (Continued)
aneurysm(s) fluid and glucose management, 395
Abdominal compartment syndrome (ACS), 251–252, 255, 546–547 oxygenation and ventilation, 395
and cardiac dysfunction, 256–257 planning, 394–395
Abdominal surgery type, 395, 395t
major Acute kidney injury (AKI), 68b, 224–226, 252
fluid management, 514–515, 515f based on urine output and serum creatinine, 253b
nutrition, 516–517 biomarkers, 255
perioperative care, 514–515 consensus diagnostic criteria, 224–225, 224t
postoperative ileus, 515–516 definition of, 570
postoperative nausea and vomiting (PONV), 515–516 vs. functional oliguria, 254–256
surgical site infections, 517 future (early) AKI biomarkers, 225–226, 225f
surgical wound classification, 517t management of, 571
pulmonary complications of oliguria secondary to, 257
reducing, 511–513 postoperative
risk of, 90, 281 in cardiac surgical patient, 497–498
pulmonary management, 511–514 cardiopulmonary bypass, 71–72, 71t
surgical site infection, risk for, 446–447 patient characteristics and, 68–71
Abiomed BVS 5000, for ventricular failure after cardiac surgery, 172f post–cardiopulmonary bypass, 72–73
Absorptive atelectasis, 577 renal testing, 74t, 75–76, 75b
ACC. See American College of Cardiology risk scoring algorithms for, 76–78, 76b, 77f, 77–78t
Accelerated fibrinolysis, 436 with vascular surgery, 73–75, 74t
Acetaminophen, 525 sepsis-induced, 571
Acetazolamide, for hyperphosphatemia, 602 Acute normovolemic hemodilution (ANH), 440–441
Acetylsalicylic acid. See Aspirin preoperative, 103–104, 103f, 103b
Acid–base balance, myocardial, in cardiac surgery, 126 Acute rejection (AR), in intestinal transplantation, 535
Acid–base imbalance, postoperative, in cardiac surgical patient, 168 Acute renal failure score, 76, 77f, 77t
Acidosis, 546 Acute respiratory distress syndrome (ARDS), 523, 570, 576,
hyperchloremic, 603 582–583
myocardial, 126 aspiration-induced, 415
Acquired immunodeficiency syndrome (AIDS), 435 Acute spinal cord injury, perioperative management of adults
ACS. See Abdominal compartment syndrome anesthetic management and considerations, 391–393
Activated partial thromboplastin time (aPTT), 18, 104, 104f, airway evaluation, 391
108–110, 109f airway management, 391–392, 392f
Activated protein C (APC), 17–18, 20 hemodynamic management, 392–393, 394t
Acupoint stimulation, for postoperative nausea and vomiting, 418 induction of anesthesia, 391
Acupuncture, for postoperative nausea and vomiting, 418 monitors, 391–393
Acute central nervous system injury, perioperative management of, cardiovascular complications, 390
355–409 endovascular therapy in AIS, anesthesia for, 393–395
airway evaluation and management, 372–383 blood pressure goals, 395
evaluation, 372 fluid and glucose management, 395
hyperventilation, 378–379 oxygenation and ventilation, 395
oxygenation, 375–378 planning, 394–395
temperature, 379–382 type, 395, 395t
therapeutic options, 372–375 miscellaneous, 390–391
ventilation, 378 pulmonary complications, 390
cranial nerves, 355–357 spinal shock, 390, 391t
mental status, 355–357 Acute tubular necrosis (ATN), 252
motor and sensorial function, 355–357 and intrarenal oliguria, 254, 254b
muscle strength and reflex grading scale, 356t ischemic, 252
neurologic examination, 355 in liver transplantation recipient, 533
reflexes, 355–357 nephrotoxic, 252, 257
waveform analysis, 361–362 obstructive oliguria, 252
Acute Dialysis Quality Initiative (ADQI), definition of oliguria, 251 in renal transplant recipient, 534
Acute ischemic stroke (AIS), endovascular therapy, anesthesia for, Acute vision loss, spine surgery, unique issues after, 526
393–395 Adenosine-induced transient circulatory flow arrest, 304
blood pressure goals, 395 Adrenal glands, physiology of, 593

672
 Index 673

Adrenal insufficiency Alzheimer’s disease, 618–619

chronic steroid supplementation and, 593 and postoperative cognitive dysfunction, 620–621
diagnosis of, 593 AMA. See American Medical Association
incidence of, 593–594 Ambulation, 429
management of, 593 postoperative, for prevention of postoperative ileus, 421
myxedema coma and, 596 American College of Cardiology/American Heart Association
primary, 593 (ACC/AHA), 36–37, 41–42
secondary, 593 American College of Chest Physicians (ACCP), 114–115, 114t
tertiary, 593 American College of Surgeons National Surgical Quality Improvement
diagnosis of, 593 Program (ACS NSQIP), 279, 659–660
incidence of, 593 American College of Surgery, 33
Adrenocorticotropic hormone (ACTH). See also Corticotropin American Society of Anesthesiology (ASA), 28, 33, 88–89
stimulation testing American Society of Regional Anesthesia and Pain Medicine, 115,
secretion of, in stress, 593 116–117t
Advanced-alternative payment models (A-APMs), 654–655 American Spinal Injury Association, neurologic assessment for spinal
Advanced Cardiac Life Support algorithm cord injury, 338, 339f
for bradycardia, 191, 193f Aminocaproic acid, 438–439
for cardiac arrest, 191, 194f for intraoperative blood loss, 526
for pulseless electrical activity and asystole, 191, 194f Aminoglycosides
for tachycardia, 191, 192f nephrotoxicity, 67
Affordable Care Act (ACA), 647–648 and perioperative renal injury, 227
Afibrinogenemia, 106 Amiodarone prophylaxis, 507
Afterload, in postoperative low cardiac output state, 169 Amrinone
management of, 170 for perioperative right ventricular dysfunction, 176
Age for ventricular failure after cardiac surgery, 170, 170t
cardiac surgery, 51 Analgesia
creatinine, and ejection fraction (ACEF), 48–49, 49f inflammatory response, perioperative modulation of, 13–14
and renal function, 68–69 pharmacology of, in obesity, 591
Agency for Health-care Research and Quality (AHRQ), 645 postoperative
AHA. See American Heart Association mode of, and coagulation function, 20–21
AHI. See Apnea-hypopnea index for rib fractures, 549–550
Air embolism, coronary, 164 Andexanet alfa, 438
Airway assessment, postoperative, in neurosurgical patient, Anemia, 389, 435, 508
555–556 and cerebral ischemia, 558–559
Airway complications, 539–540 in chronic renal failure, 263
Airway management for comorbidities, 664
in acute CNS injury, 372–383 neurophysiologic effects of, 389–390
acute spinal cord injury, perioperative management of adults with, Anesthesia. See also General anesthesia; Regional anesthesia
391–392, 392f cardiac, 124–125
in cervical spine injury, 372–375 agents for, 125
in obesity, 589–590 depth of, in management of intracranial hypertension, 306–307
in obstetric anesthesia, 469 duration of, and risk of pulmonary complications,
postoperative, in neurosurgical patient, 555–556 90–91
in spinal cord injury, 335–336 induction of, for major abdominal surgery, 511
Airway obstruction, atelectasis in, 577 inflammatory response, perioperative modulation of, 13–14
Airway patency, loss of, 280 maternal, fetal effects of, 476–478, 477t
AKI. See Acute kidney injury mode of, and coagulation function, 19–20
Alarmins. See Danger-associated molecular patterns (DAMPs) in morbidly obese, percentages of, 513f
Albumin, 10t and neurologic outcomes, in cardiac surgery,
intraoperative therapy with, in kidney transplant recipient, 270 318–319
in resuscitation, 543–544, 557 obstetric, 470f
Alcohol-based solutions, for prevention of surgical site disinfection, airway management in, 469
448 planning for, 469–470
Alfentanil, for sedation of neurosurgical patient during respiratory for preeclamptic patients, 463
support, 556 and renal perfusion, 67–68
ALI. See Acute lung injury surgical training and, 28–29
Alkalosis in valvular heart disease, 184–185
chloride-resistant, 603 Anesthetic(s)
chloride-responsive, 603 in cardiac anesthesia, 125
hypochloremic, 603 inhaled, renal failure and, 264–266
Allograft, definition of, 268 Aneurysm(s). See also Aortic aneurysm(s)
Allopurinol, 132 cerebral, 298–306
Alpha-2-adrenergic agonists clipping
perioperative therapy with, 147 anesthetic management for, 302–304
in valvular heart disease, 184 cerebral protection during, 298–306
Alpha-2-antiplasmin, 436 emergence, 304
Alternative payment models (APMs), 655–656 induction, 303, 305
Alvimopan therapy, for postoperative ileus, 422 maintenance, 303–305
674 Index

Aneurysm(s) (Continued) Antihypertensive therapy

monitoring, 302–303 in acute CNS injury, 386, 387t
premedication, 302 in pregnancy, 463
embolization, 305–306 Anti-inflammatory drug, 616–617
complications of, 306 Antimetabolites, for organ transplant recipient, 531
thromboembolism in, 306 Antimicrobial prophylaxis
feeding vessels, temporary occlusion of, 304 postoperative, for thoracic surgical patient, 517
preoperative management of, 298–302 and prevention of surgical site infections, 449
rupture optimal dosing of, 449
during embolization procedure, 306 systemic antibiotics, 449
intraoperative, 304–305 timing of, 449
Angiography in valvular heart disease, 182
in cardiac surgical patient Antimicrobial therapy. See also Antibiotics
with graft failure, 162 in valvular heart disease, perioperative management
postoperative, 161–162f, 164–165 of, 186
cerebral, 303, 305 Antioxidant(s)
postoperative, in neurosurgical patient, 554 endogenous, 132
Angiotensin-converting enzyme (ACE), 2–3 exogenous, in cardiopulmonary bypass, 132
Angiotensin-converting enzyme inhibitors (ACEI), Antiplatelet agents, 147–148
557 Antiplatelet therapy, perioperative management of, 107
nephrotoxicity, 67 Antiretroviral therapy (ART), for HIV, 633
perioperative therapy with, 146–147 Antiseptic agents, for prevention of surgical site disinfection, 448
and renal outcomes, 231–232 Antithrombin III, 17, 19
Angiotensin, inflammatory response, 10–12 deficiency of, and venous thromboembolism, 428
Angiotensin receptor blockers, 146–147 in hemodilution, 19
ANH. See Acute normovolemic hemodilution Antithrombotic therapy, for venous thromboembolic
ANP. See Atrial natriuretic peptide disease, 523t
Antacid(s) Antithymocyte globulin, 531
nonparticulate, 413 Anxiolytics, premedication with, in cardiac anesthesia, 125
phosphate-binding, for hyperpho, 602 Aorta, assessment of, 316
Antiarrhythmic drugs, in valvular heart disease, perioperative Aortic aneurysm(s)
management of, 184 descending thoracic, classification of, 341, 342f
Antibiotic prophylaxis, postoperative, for thoracic surgical patient, repair
517 paraplegia after, 341–347, 349f
Antibiotics. See also Antimicrobial prophylaxis; Antimicrobial therapy and renal outcome, 228, 230
for patients who have aspirated, 414–415 spinal cord ischemia in, 341–347
for sepsis, 569 prevention of, 342–343, 343t
Antibiotic sutures, and prevention of surgical site infections, 450 treatment of, 342–343, 343t
Anticholinergics, for postoperative nausea and vomiting, 418 thoracic repair, paraplegia after, 341–347
Anticoagulants thoracoabdominal
coagulation cascade and site of action of, 432f Crawford classification of, 342, 343f
protein(s), 16 repair, paraplegia after, 341–347, 349f
Anticoagulation, 433 Aortic arch repair, 321–322
perioperative management, in valvular heart disease, 183–184 intraoperative electroencephalographic monitoring, 324
in pregnancy, 184 neuroprotection, 322–325
reversal of, 433, 438 Aortic atheroma, 314
in valvular heart disease, perioperative management of, 183–184 Aortic cross-clamp, placement, and postoperative renal outcomes,
for venous thromboembolism, 431–432 73–74, 74t, 234
with ventricular assist devices for ventricular failure after cardiac Aortic dissection
surgery, 174 in pregnancy
Anticoagulation therapy anesthetic considerations in, 466
ACCP guidelines, 114–115, 114t management of, 466
arrhythmia, prevention of, 508 maternal mortality due to, 464
direct oral anticoagulants, 113–115, 115t signs and symptoms of, 466
indications, 112 Aortic manipulation, in cardiac surgery, and emboli, 316
neuraxial blockade, 115–117, 116–117t Aortic plaque disruption, 618
unfractionated heparin, 113 Aortic regurgitation, perioperative management of, 187–188
warfarin, 113 hemodynamic principles for, 185t
Anticonvulsants, and muscle relaxants, 293–294, 296 Aortic stenosis, perioperative management of, 186
Antidiuretic hormone (ADH). See also Vasopressin hemodynamic principles for, 185t
Antidiuretic hormone, action of, 598 Aortic surgery, renal outcomes with, 73–75, 74t
Antiepileptic drug (AED) therapy, 61–62 Aortic valve repair or replacement (AVR), 49–51, 441
Antifibrinolytics, 471 Aortocaval compression, 475–476
intraoperative use of, and renal outcome, Apixaban (Eliquis), 430–431t
234–235 Apnea. See Obstructive sleep apnea/hypopnea syndrome
Antifibrinolytic therapy, 438–439 Apnea–hypopnea index, 88
Antihistaminergics, for postoperative nausea and vomiting, 418 Apneic oxygenation, 511–512
Antihistamines, 418 Apolipoprotein E hypothesis, 619
 Index 675

Aprotinin Aspiration (Continued)

intraoperative use of, and renal outcome, 234–235 prevention, 580f
nephrotoxicity, 67 risk factors for, 579t
AQA. See Ambulatory Care Quality Alliance treatment for, 579–581, 580f, 580t
ARDS. See Acute respiratory distress syndrome Aspiration pneumonitis, definition, 85t
ARF (acute renal failure). See Renal failure, acute Aspirin, 349, 429, 522
Argatroban, 430–431t and perioperative renal injury, 238–239
ARI (acute renal injury). See Renal injury(ies), acute perioperative therapy with, 147–148
ARISCAT score, 279, 279b for venous thromboembolism, 430–431t
Arrhythmia(s). See also specific arrhythmia Assessment of Blood Consumption (ABC), in trauma, 543
anesthetic medications, 191–193, 195f Assessment, preoperative. See Preoperative assessment
of automaticity, 191 Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT)
diagnosis and medical therapy, 201–202 risk score model, 88
electrolyte disturbances, 193 Asystole, 199, 200f
hemodynamic and physiologic causes, 194 Atelectasis, 280, 511, 577–579
hyperkalemia, 193 absorptive, 577
hypokalemia, 193 clinical manifestations of, 577–578
hypomagnesemia, 193 definition, 85t
in hypomagnesemia, 600 diagnosis of, 578
management of, 191 mechanical ventilation in, 577
mechanism of, 191 passive, 577
abnormal automaticity, 191 postoperative, epidemiology, 280
reentrant pathways, 191 preoxygenation for prevention of, 512f
triggered, 191 prevention for, 578f
postoperative, in cardiac surgical patient, 496 risk factors for, 577, 577b
prevention of, 507–508 treatment for, 578–579, 578f
agent for treatment, 507–508 Atenolol
anticoagulation therapy, 508 effect on postoperative ileus, 422t
rate control, 507–508 pharmacology, 146
rhythm control, 508 Atherosclerosis, aortic. See Aortic atherosclerosis
reentrant pathways, 191 Atrial dysrhythmias, 495–496
with subarachnoid hemorrhage, 290 Atrial fibrillation (AF), 196–197, 197f, 202, 507
Arterial blood gas analysis catheter ablation, 203
in cardiac surgery, 126 paroxysmal, 196
preoperative, 92 postoperative, 166
Arterial pressure augmentation, 344 in cardiac surgical patients, 495–496, 496b
Artifacts, recognition of, 201–202 surgical ablation, 203
Artificial liver support, 530 in thoracic surgical patient, postoperative
ASA. See Acetylsalicylic acid; American Society of Anesthesiologists management of, 507
Aschner reflex, 195 onset of, 507
Ascorbic acid. See Vitamin C prevention of, 507
Asepsis treatment of, 507
definition of, 447 Atrial flutter, 196–197, 196f
and prevention of surgical site infections, 447–449 Atrial natriuretic peptide (ANP), 73
principles of, 447 and renal preservation, 237–238
ASIA. See American Spinal Injury Association Atrial tachycardia, multifocal, 196
Aspiration, 579–581 Atrioventricular (AV) junctional rhythms, 199
clinical manifestations of, 579 Atrioventricular nodal reentrant tachycardia (AVNRT),
diagnosis of, 579 196, 196f
of gastric contents, 411–415 Atrioventricular (AV) synchrony, and cardiac output after cardiac
etiology of, 411–412 surgery, 165–166f, 166
incidence of, 411–412 Automaticity, arrhythmia of, 191
management of, 414–415, 415f Autonomic dysreflexia, 352, 390
morbidity with, 411 Autonomic hyperreflexia, 352
NPO guidelines, 413–414 Awake craniotomy, 297–306, 299–301t
obesity and, 412 Awake endotracheal intubation, 373
pathogenesis of, 411–412 Awake fiberoptic intubation, 373t
risk factors for, 412, 412b Axillary artery cannulation, 323
risk reduction, 412–413 Azathioprine, for organ transplant recipient, 531
incidence, 579 α-Tocopherol. See Vitamin E
obesity and, 591
of oropharyngeal secretions, and pulmonary complications, 86 B
outcome with, 579 Babinski reflexes, 356
pathophysiology of, 579 Bag valve mask ventilation (BVM), 373
pneumonitis caused by, 411, 480 Balanced resuscitation, 543
treatment of, 415 Barbiturates
by pregnant patient, 414 adverse effects and side effects of, 370
during nonobstetric surgery, 480 therapy with, for intracranial hypertension, 370
676 Index

Bariatric surgery, 516 Blood pressure

and pregnancy, 469 arterial
pulmonary management after, 513–514 augmentation, in aortic aneurysm repair, 344
Bayesian framework, 643 postoperative, in neurosurgical patient, 556
BBB. See Blood–brain barrier dysfunction in CNS injury
Benzodiazepines determination of optimum, 383–385
in cardiac anesthesia, 125 on ICP-plateau waves, 383–385
for sedation of neurosurgical patient during respiratory support, 556 during intracranial surgery, management of, 295
therapy with, for postoperative nausea and vomiting, management of, 232
418 in acute CNS injury, 385–389
Beriplex P/N (CSL Behring), 438 during cardiopulmonary bypass, 315
Beta-blockers during intracranial surgery, 295
adverse effects and side effects of, 144 postoperative, in cardiac surgical patient, 491–492
cardiac injury, 2–3 in spinal cord injury, 336
neurologic injury, 3–4 with subarachnoid hemorrhage, 302
perioperative therapy with, 262 Blood-sparing strategies, 103, 103b
recommendations for, 146 Blood transfusion(s), 14, 216. See also Transfusion therapy
premedication with, in cardiac anesthesia, 125 Blood urea nitrogen
therapy with as marker of renal function, 222
for cardiac surgical patient, 163 nonrenal factors affecting, 76, 76b
in valvular heart disease, perioperative management Blood volume, 102
of, 184 B-Lynch suturing, 471
Beta-receptor blocker, 196 BMI. See Body mass index
Betrixaban (Bevyxxa), 430–431t BNP. See B-type natriuretic peptide
Bilateral positive airway pressure (BiPAP), 590 Body mass index (BMI), 468
Biomarkers, 569 in obesity, 588
pain and outcomes in perioperative setting, 609 Body temperature. See Temperature
BiPAP. See Bilevel positive airway pressure Body weight. See also Body mass index; Obesity; Overweight
Biphasic positive airway pressure (BiPAP), 513–514 and pulmonary complications, 283f
Bisoprolol, pharmacology, 146 BOOST program, 669–670
Bispectral index (BIS), 369 Bottom-up costing, 641
BIS-guided anesthetics, 57 Bovine spongiform encephalopathy (BSE), 452
Bivalirudin, 430–431t, 437 Bradyarrhythmias, 199–201
Biventricular pacing, 198–199, 199f pacemakers, 204
Bleeding. See also Hemorrhage postoperative, in cardiac surgical patient, 495
after cardiopulmonary bypass, 436 Bradycardia, beta-blocker–induced, 144–146
clotting factor deficiencies and, 436 Brain, hypoperfusion of, global, 322
common disease states associated with, 435–438 Brain injury
clotting factor deficiency, 436 acute, cerebrovascular reserve and, 371–372
heparin-induced thrombocytopenia, 437–438 hypercarbia in, 555
hepatic insufficiency, 435–436 hypertension and, in postoperative neurosurgical patient, 556–557
platelet deficiency, 436–437 hypoxia in, 555
renal failure, 436 management of patient with, 547–548
complications, risk for postoperative, 57–66
history-taking about, 105–106 traumatic, neuroprotective effects of hypothermia in, 379–382
preoperative assessment of, 105–106, 105f, 106t, 106b Brain natriuretic peptide (BNP), 41
questionnaire for detection of, 105, 106b Brainstem lesions, airway assessment and management with,
liver failure and, 436 555–556
magnesium and, 601 Brief Pain Inventory (BPI), 607
postoperative, in cardiac surgical patient, 494–495 British Thoracic Society (BTS), 505
renal failure and, 436 Bronchospasm, definition, 85t
risk of, preoperative assessment of, 435–438 Budd–Chiari syndrome, 532–533
Bleeding diathesis, 263 Bundle branch blocks, 200, 200–201f
Bleeding disorders Burn injury, and renal toxicity, 70–71
acquired, characteristics of, 106
history-taking in, 105–106, 106t, 106b C
Bleeding time, in chronic renal failure, 265–266 CABG. See Coronary artery bypass grafting
Blood. See also Transfusion therapy CAD. See Coronary artery disease
as cardioplegia solution, 128 Calcineurin inhibitors, for organ transplant recipient, 531
from cardiotomy suction, reinfusion, 130–131 Calciphylaxis, in chronic renal failure, 262
intraoperative management of, 439 Calcitonin, action of, 603
leukocyte depletion, in cardiopulmonary bypass, 131 Calcium
Blood–brain barrier dysfunction, 312, 616–617 distribution of, in body, 602
Blood gas management, during cardiopulmonary bypass, homeostasis, in chronic renal failure, 262–263
324–325 ionized, concentration of
Blood loss factors affecting, 602
after acute normovolemic hemodilution, 102 normal, 602
maximum allowable, 102t, 103f physiologic functions of, 602
 Index 677

Calcium channel antagonist drugs, 386 Cardiac risk assessment

Calcium channel blockers, 73, 239 in cardiac surgery
therapy with ACEF score, 48–49, 49f
intraoperative, in kidney transplant recipient, the congenital heart surgery, 51–52
perioperative, 164–165 EuroSCORE, 48
Calcium chloride, for hyperkalemia, 600 extracorporeal mechanical support, 52, 53t
Canadian Cardiovascular Society (CCS) guidelines, 41–42 frailty vs. age, 51
Canadian C-Spine Rule for Radiography (CCSRR), 337, 337f mortality, 53–54
Cancer outcome measurement, 46
pain syndromes, in patients with, 630t Parsonnet score, 47–48
and venous thromboembolism, 433 perioperative development of, 46–47
Candida infections, 444–445 risk adjustment, 46
Cannulation of axillary artery, 323 risk calculators, 47, 48t
Caprini Score, 428 risk stratification models, 47, 47t
Carbohydrate drinks, preoperative administration, algorithm, 211, Society of Thoracic Surgery, 49–51, 50t
212f ventricular assist devices, 53, 54t
Carbon dioxide (CO2) noncardiac surgery, perioperative
arterial partial pressure of coronary artery bypass grafting, 43
and cerebral blood flow, 378–379, 379f coronary revascularization, 42
physiology of, 378 ECG abnormalities, 36
elimination of, 378 evaluation algorithm, 37–38
maternal–fetal gradient of, 481 functional capacity, 37–38
production of, 378 history, 36, 37t
increased, 378 metabolic equivalents, 37, 39t
Cardiac arrest, for cardiac surgery, and myocardial protection, 130 percutaneous coronary intervention, 43
Cardiac arrhythmias physical examination, 36, 37t
anesthetic medications, 191–193, 195f risk models, 40–42, 40–41t
of automaticity, 191 surgical risk factor chart, 37, 39–40t
diagnosis and medical therapy, 201–202 Cardiac surgery
electrolyte disturbances, 193 after acute myocardial infarction, optimal timing of, 124
hemodynamic and physiologic causes, 194 anesthesia for, 124–125
hyperkalemia, 193 arrhythmias, 203
hypokalemia, 193 cardiovascular risk assessment in
hypomagnesemia, 193 ACEF score, 48–49, 49f
management of, 191 congenital heart surgery, 51–52
mechanism of, 191 EuroSCORE, 48
abnormal automaticity, 191 extracorporeal mechanical support, 52, 53t
reentrant pathways, 191 frailty vs. age, 51
triggered, 191 mortality, 53–54
reentrant pathways, 191 outcome measurement, 46
Cardiac catheterization, in valvular heart disease, 181–182, 188 Parsonnet score, 47–48
Cardiac death, with valvular heart disease, 181 perioperative development of, 46–47
Cardiac dysfunction, and ACS, 256–257 risk adjustment, 46
Cardiac dysrhythmia, postoperative, in cardiac surgical patient, risk calculators, 47, 48t
495–496 risk stratification models, 47, 47t
Cardiac enzymes Society of Thoracic Surgery, 49–51, 50t
elevation, with surgery, 154, 155f ventricular assist devices, 53, 54t
in perioperative myocardial infarction, 155–156, 159f central nervous system protection during, 311–334
in perioperative myocardial ischemia, 155–156 cerebral injury after, 311–316
Cardiac failure, 537 incidence of, 311
Cardiac index, in cardiac surgical patient, and hospital death rate, risk factors for, 311, 312t
165–166, 165f significance of, 311
Cardiac injury complications of
perioperative, and outcomes, 2–3 gastrointestinal, 499
with subarachnoid hemorrhage, 298 neurologic, 498–499
Cardiac output. See also Low cardiac output state, postoperative postoperative, 494–499
in cardiac surgical patient, and hospital death rate, 165–166, 165f depression in, 619
postoperative ECG abnormalities after, 154, 156t
in cardiac surgical patient, 492–493 embolic events, 311
measurement of, 168 endocarditis prophylaxis for, 183b
reduced etiologic factors, 311–312
and renal reserve, 68–69 glucose homeostasis during, 619
signs and symptoms, 68–69 glycemic control for, 588
Cardiac rate, optimization, in postoperative low cardiac output state, hemostatic agents in, 132
169–170 inflammation in, 616–617
Cardiac resynchronization therapy, 204 intraoperative postprocedural phase, management of, 164
Cardiac rhythm, optimization, in postoperative low cardiac output intraoperative preprocedural phase, management of, 163–164
state, 169–170 ischemic injury in, prevention of, 122–142
678 Index

Cardiac surgery (Continued) Cardiopulmonary bypass (Continued)

metabolic considerations in, 125–128 pharmacologic protection against, 131–132
monitoring during, 124–125 institution, for unstable cardiac surgical patient, 164
myocardial pH in, 126 ischemia-reperfusion injury in
myocardial protection during, 128–132 pathophysiology of, 130
perioperative myocardial ischemia and/or infarction with pharmacologic protection against, 131–132
definition of, 154–157 management of, and renal outcomes, 233
diagnostic criteria for, 154–157 normothermic versus hypothermic, 315
postoperative cognitive dysfunction in, 613–614 pulsatile, 131
postoperative phase, 486–504 pulsatile perfusion, 315
assessment in, 487–488 pump for
blood pressure in, 491–492 centrifugal, 131
cardiac output in, 492–493 roller, 131
complications in, 494–499 types of, 131
fast tracking in, 499–500 renal ischemia during, 71–72, 71t
ICU admission in, 487–488 rewarming after, temperature control during, and neurologic
management of, 164–165 outcomes
mechanical cardiac support in, 493–494 vasoplegic syndrome after, 169
perfusion pressure in, 490–491 weaning from
respiratory management in, 488–490 evaluation for, 166
stabilization phase, 490–494 failure of, 165–166f, 166
transport in, 487–488 Cardiopulmonary dysfunction, spine surgery, unique issues after,
steroid use in, 132 524–527
temperature management during, 618–619 Cardiopulmonary exercise testing (CPET), 37, 505
thyroid hormone and, 596–597 Cardiothoracic surgery-intensive care unit, 487
transfusion therapy in, 127–128 Cardiotomy suction, blood from, reinfusion, 130–131
valvular and myocardial ischemia, 163 Cardiovascular disease
Cardiac surgery-associated AKI, 223–224 in chronic renal failure, 267–268
Cardiac tamponade, 169 obesity and, 591
postoperative, in cardiac surgical patient, 497 Cardiovascular Health Study, 51
Cardiogenic shock, with subarachnoid hemorrhage, 298 Cardiovascular (CVS) monitoring, 212–213
Cardiomyopathy Cardiovascular Risk Index (CVRI), 41
peripartum Cardiovascular risk, with valvular heart disease, 181
anesthetic considerations in, 465–466 Cardiovascular system, preoperative assessment of, for carotid
diagnosis of, 465 endarterectomy, 290
diagnostic criteria for, 465b Cariporide, 165
etiology of, 465 Carotid endarterectomy
incidence of, 465 anesthetic management in, 290
management of, 465 cerebral monitoring, ischemia, 292–293, 292b
onset of, 465 general anesthesia for, 292
risk factors for, 465 indications for, 292
signs and symptoms of, 465 physiologic management in, 291–292
therapy for, 465 postoperative care for, 293
in pregnancy, maternal mortality due to, 465 preoperative assessment for, 290–291
Cardioplegia regional anesthesia for, 292
blood, 128, 158–159 Carotid stenosis, and stroke risk, 314
composition, 128 Carotid stump pressure, 293
crystalloid, 128 CARP trial. See Coronary Artery
and myocardial protection, 128–132 Catalase, 132
potassium-based depolarizing chemical, 128, 130 Catecholamines, 388
retrograde delivery, advantages and disadvantages of, 129–130 Catechol-Omethyltransferase (COMT), 609
route of delivery, 129–130, 158–159 Cauda equina syndrome, 350
temperature for, 126, 129, 158–159 CBF. See Cerebral blood flow
Cardiopulmonary bypass Cefazolin, postoperative, for thoracic surgical patient, 517
for acute normovolemic hemodilution, 440–441 Cell-mediated AR, 535
and acute renal ischemia-reperfusion injury, 226 Cell salvage, 439–440
blood filtration in, 131 and retransfusion, 103, 103b
blood flow in, pulsatile versus nonpulsatile, 131 Cell savers, 130
blood gas management, 314–315 Center for Medicare and Medicaid Innovation (CMMI), 654
blood pressure management during, 315 Centers for Medicare and Medicaid Services (CMS), 29, 32. See also
cannulation techniques, and myocardial protection, 130 National Voluntary Hospital Reporting Initiative
circuit for Center to Advance Palliative Care (CAPC), 628
heparin-bonded, 130 Central nervous system. See also Neurologic injury(ies)
modifications, 130–131 acute injury
open versus closed, 131 airway evaluation and management in, 372–383
inflammatory response to cardiovascular, 383–390
and neurologic outcomes, 315–316 neuroprotective effects of hypothermia in, 378–379
pathophysiology of, 130 oxygenation in, 375–378, 375–378f
 Index 679

Central nervous system (Continued) Chest radiograph(s)

perioperative management of, 355–409 emergency, in postoperative patient, 168, 168f
ventilation in, 378 preoperative, 92
postoperative imaging of, 552–553 in trauma, 544–545
preoperative assessment of, for carotid endarterectomy, 298 in valvular heart disease, 181–182
protection (see also Cerebral protection; Neuroprotection) Chlorhexidine gluconate, for surgical site disinfection,
during cardiac surgery, 311–334 448
risk assessment, 57–66 Chloride
Central nervous system (CNS) dysfunction, postoperative, 613, 614f homeostasis, abnormalities of, 603
Central venous pressure, monitoring, in trauma patient, 545 physiologic functions of, 603
CentriMag system, 174, 175t Cholecystokinin, effect on postoperative ileus, 422t
Cerebral autoregulation, during cardiac surgery, 311–312 Cholinesterase inhibitors, therapy with, for postoperative ileus, 422,
Cerebral blood flow (CBF), 376f 422t
autoregulation of, heterogeneous, 384, 385f, 556 Chronic daytime hypoxemia, 591
heterogeneous, 556 Chronic kidney disease (CKD), inflammatory response, 12–13
hyperventilation and, 364, 364–365f Chronic obstructive pulmonary disease (COPD), 71, 628
and intracranial pressure, relationship of, 384, 386f palliative care for, 633
PaO2 and, 375, 375–376f pathophysiology of, 86
and postoperative cognitive dysfunction, 618 and pulmonary complications, 87
Cerebral blood volume pulmonary hypertension in, preoperative detection, 92–93
blood pressure and, 383–384, 384f Chronic opioid use, 608
reduction, in treatment of intracranial hypertension, 363 Chronic pain, 608
regional, and ventricular fluid pressure, 383–384, 384f Brief Pain Inventory (BPI), 607
Cerebral cortical oxygenation, 547 inflammatory cytokines in, 609
Cerebral embolization, 311 McGill Pain Questionnaire, 607
Cerebral herniation, treatment algorithm, 362–363 Chronic renal disease, 433
Cerebral hypoperfusion, 378–379, 379f Chronic right heart failure, 537
global, 311–312 Chvostek’s sign, 602
Cerebral ischemia Circulatory assist devices, mechanical, for ventricular failure after
anemia and, 558–559 cardiac surgery, 175, 175t
antihypertensive therapy and, 387, 387t Cisapride, effect on postoperative ileus, 422t
hyperglycemia and, 559 Cisatracurium
Cerebral metabolic rate of oxygen (CMRO2), 618–619 in chronic renal failure, 269
Cerebral metabolism, reduction of, in management of intracranial renal failure and, 269
hypertension, 307 CJD. See Creutzfeldt-Jakob disease
Cerebral oximetry, 315 Clamp and sew technique, 342–343
Cerebral perfusion pressure (CPP), 556 Clonidine, 557
and blood flow, 293 for hypertension in pregnancy, 463
and cerebral blood flow, 357–358, 386f neuroprotective effects of, 387t
and cerebrovascular resistance, 384, 386f perioperative therapy with, 147
and control of intracranial pressure, 303 and renal outcomes, post–cardiopulmonary bypass,
hypovolemia and, 557 73
increased intracranial pressure and, 358f sympatholytic effects of, 387t
in trauma patient, 547 Clopidogrel. See Aspirin, + clopidogrel
Cerebral protection. See also Central nervous system, protection; Closed model of care, 631
Neuroprotection Clotting factor(s), 16, 17f
during cerebral aneurysm clipping, 298–306 deficiencies, 109, 109f
Cerebral vasospasm, with subarachnoid hemorrhage, 302 and bleeding, 436
Cerebrospinal fluid, drainage, 369 congenital, 109
Cerebrospinal fluid drainage, 326 II, deficiency of, 109f
lumbar, in aortic aneurysm repair, 344 V, deficiency of, 109f
in trauma patient, 547 VII, deficiency of, 109, 109f
ventricular VIIa, recombinant, in cardiac surgery, 132
and control of intracranial pressure, 303 VIII, deficiency of, 109, 109f (see also Hemophilia A)
for intracranial hypertension, 360, 361f IX, deficiency of, 109f, 110 (see also Hemophilia B)
Cerebrovascular reserve, 371–372 X, deficiency of, 109f, 110
Cerebrovascular resistance, and cerebral blood flow, relationship of, XI, deficiency of, 109f, 110
384, 386f XII, deficiency of, 109f, 110
Certified electronic health record technology (CEHRT), 654 Cluster analysis, pain and outcomes in perioperative setting, 608–609
Cervical spine CMS. See Centers for Medicare and Medicaid Services
injury CMS Hospital Value-based Purchasing Program, 647
intubation in, 372–375 CMS Quality Payment Program (QPP), 647
radiographic evaluation of, 337, 338f CNS. See Central nervous system
manual in-line immobilization of, 336 Coagulation
Cervical spine distraction, during airway instrumentation, 373–375 dysregulation (see Coagulopathy)
Cesarean delivery, 465–466 extrinsic, 16–17, 17f, 19, 104, 109
and subsequent placenta accreta, 465–466, 470, 471f proteins of, and inflammatory signaling pathways, 21
Charlson comorbidity index, and pulmonary complications, 90 inflammation, 17–18
680 Index

Coagulation (Continued) Compound A, 68, 265

intrinsic, 16–17, 17f, 104, 109 Computed tomography
pathways, 104, 104f, 109 of cervical spine injury, 337–338, 338f
perioperative changes in, 18–20 chest, in anesthetized patient, 83–84, 86f
perioperative monitoring of, 18 cranial, in trauma patient, 547
tests of, 104, 104f, 108–110, 109f postoperative, in neurosurgical patient, 553–554
Coagulation cascade Concussion, 62, 63t
activation, 16–17, 17f, 104 Conduction defects, 200–201, 201f
anesthesia and, 19–20 Congenital heart disease, pregnancy in women with, 466, 467f
body temperature and, 20 Congenital heart surgery, 51–52
intraoperative, 19–20 Congestive heart failure (CHF)
intravenous fluid management and, 20 obesity and, 590–591
postoperative, 20–21 palliative care for, 632–633
site of surgery and, 19 with valvular heart disease, 181
trauma coagulopathy, 20 Consumer assessment of health-care providers and systems
physiology of, 16 (CAHPS), 651
proteins of, 16, 18f Continuous positive airway pressure (CPAP), 3, 283, 513–514, 579
Coagulation factors. See Clotting factor(s) for obstructive sleep apnea/hypopnea syndrome, 589–590
Coagulopathy, 546 postoperative, in obese patient, 589–591
laboratory testing for, 107–111, 107b, 108–109f, Continuous venovenous hemodiafiltration, and renal outcomes in
110b, 111f post-cardiopulmonary bypass, 73
perioperative Cooling blanket bath, 380–381
management of, 107–111, 107b, 108–109f, COPD. See Chronic obstructive pulmonary disease
110b, 111f Coronary artery(ies)
pathophysiology of, 18–20 right, spasm, after CABG, 161f
proinflammatory effects, 21 spasm
risk factors for, 18–20 after CABG, 160–161, 161–162f
pregnancy in women with, 464 in cardiac surgical patients, risk factors for, 160–161
and venous thromboembolism, 433 in perioperative myocardial ischemia/infarction, 160–162,
Cockcroft-Gault equation, 75–76 161–162f
Cognitive decline, 60 Coronary artery bypass graft (CABG), 441, 613–614, 652
Cognitive domains, 59 after acute myocardial infarction, optimal timing of, 124
Cognitive dysfunction bleeding in, 494
after cardiac surgery cardiac mortality after, 156, 158f
etiology of, 315 ECG abnormalities and, 156, 157t
risk factors for, 311, 315 cardiac surgery, perioperative, 51
postoperative, 614f fast tracking after, 500
and Alzheimer’s disease, 620–621 glucose control during, 126–127
anesthesia in, 613, 620–621 graft compression after, 160, 162f
in autoregulation, 618 graft failure, 162
in cardiac surgery, 613–614 mechanical ventilation, 490
in cerebral blood flow, 618 minimally invasive direct, 133
depression in, 619 monitoring during, 124–125
embolic load, 618 myocardial pH in, 126
genetic factors in, 619–620 neurologic injury in, 311–316
incidence of, 614–615, 615f off-pump, 133
mean arterial pressure (MAP) management for, 618 fast tracking after, 500
modifiable factors, 616t neurologic outcomes with, 316–317
neuroinflammation in, 616–617 and renal outcome, 228–229
with noncardiac surgery, 614–615, 615f on-pump, and renal outcome, 228–229
nonmodifiable factors, 616t perioperative cardiac risk assessment, 43
in oxygen delivery, 618 stroke risk with, 314
partly modifiable factors, 616t and thyroid hormone, 597
pathophysiologic mechanisms, 613, 617f Coronary artery disease (CAD), 36–38, 38f, 43
pathophysiology of, 616 in chronic renal failure, 260, 262
prevention and treatment, future interventions for, 622 Coronary artery revascularization prophylaxis (CARP), 43
Cognitive function, perioperative decline, 4 Coronary revascularization, 42
cardiac surgery and, 4 after acute myocardial infarction, optimal timing of, 124
and mortality rate, 4 Cortical mapping, 297–298, 299–301t. See also Speech mapping
noncardiac surgery and, 3–4 Corticosteroids (dexamethasone), 238, 363
Cognitive impairment, 31 in cardiopulmonary bypass, 131–132
Colloid(s), 418, 424 and sepsis, 595
hemostatic effects, 20 for sepsis, 571–572
intraoperative infusion, 103b, 104 supplementation of, 591–595
in resuscitation, 557 effect on hypothalamic-pituitary-adrenal axis, 593
Colonic pseudo-obstruction, 526 in myxedema coma, 596
Compartment syndrome(s), in trauma patient, 547 patient at risk with, identification of, 594
Complex regional pain syndrome (CRPS), 609 perioperative management of, 594
 Index 681

Corticosteroids (dexamethasone) (Continued) D

therapy with Dabigatran (Pradaxa), 429, 430–431t, 521–522
for organ transplant recipient, 531 Dalteparin (Fragmin), 430–431, 430–431t
in spinal cord injury, 338–341 Damage-associated molecular patterns (DAMPs), 566
Corticotrophin-releasing factor (CRF), 420 Damage control, in trauma, 545–546, 545f
Cortisol, secretion of Danger-associated molecular patterns (DAMPs), 10
normal, 593 Danger hypothesis, 9–10
in stress, 593 Darbopoetin alpha, and treatment of anemia in renal
Cost-benefit analysis, 643 failure, 263
Cost-effectiveness analysis, 642–643 D-dimer assays, 18, 581
methodological problems in, 639 in diagnosis of deep venous thrombosis, 429
Cost-identification analysis, 642 Deceased donor kidney (DDK), 269
Cost-minimization analysis, 642 Decision tree analysis, 643
Cost-utility analysis, 642–643 Decompressive craniectomy, 370–372
Cosyntropin stimulation testing. See Corticotropin stimulation testing physiologic issues, 371–372
Cough test, positive, and risk of postoperative pulmonary cerebrovascular reserve, 371–372
complications, 89, 89t and TBI, 371
Coumarin therapy, bleeding disorder with, 109f Deep incisional surgical site infection, 444, 445b
COX-2 inhibitors, 422 Deep sternal wound infections (DSWI), 499
CPAP. See Continuous positive airway pressure Deep vein thrombosis (DVT), 581
CPB. See Cardiopulmonary bypass diagnosis, 429
CPP. See Cerebral perfusion pressure management of, 427–434
CPT. See Current Procedural Terminology medications in prophylaxis and treatment of, 430–431t
CP-122,721 therapy, for postoperative nausea and obesity and, 591
vomiting, 418 in orthopedic surgery, 521
Craniotomy, 297–306, 299–301t. See also Intracranial surgery pathophysiology, 428
decompressive, 370–372 postoperative, in neurosurgical patient, 559
C-reactive protein, 10t in postoperative total joint arthroplasty patients
Creatine kinase (CK), MB isoenzyme asymptomatic, 522
elevation, with surgery, 154–155, 155f incidence of, 521
in perioperative myocardial ischemia/infarction, 154–156, symptoms of, 521
158–159f prevention of, 428–429, 559
Creatinine clearance (CrCl) risk factors for, 559
as measure of renal reserve, 68–69 site of surgery and, 19
perioperative evaluation of, 235–236 in trauma patient, 548
postoperative Define-Measure-Analyze-Improve-Control (DMAIC)
in heart transplant patients, 5, 5f framework, 650
prognostic significance of, 75–76 Delirium, 498–499
Creatinine, serum definition of, 572
as measure of renal reserve, 68 postoperative, 57–59, 58f, 63t, 613, 614f
nonrenal factors affecting, 76, 76b anesthesia, 613
perioperative evaluation of, 224 definition, 57, 58f
postoperative, prognostic significance of, 5, 75, 597 emergence delirium, 59
Creutzfeldt-Jakob disease (CJD), 452–453 inflammation in, 616–617
variant, transfusion-transmitted, 435 intraoperative management, 57–59
CRF (chronic renal failure). See Renal failure, chronic modifiable factors, 616t
Cricoid pressure, 373 nonmodifiable factors, 616t
Cricopharyngeus, 411–412 partly modifiable factors, 616t
Cricothyroidotomy, emergency, 336 pathophysiologic mechanisms, 613, 617f
Crystalloid(s), 418, 424 prevention and treatment, future interventions for, 622
as cardioplegia solution, 128 risk factors, 57, 58t
hemostatic effects, 20 treatment of, 59
intraoperative infusion, 103b, 104 preoperative, 31
in resuscitation, 557 Dementia, palliative care for, 633
CSF. See Cerebrospinal fluid, drainage Dental procedures, endocarditis prophylaxis for, 182
CT. See Computed tomography Depression
CT-ICU. See Cardiothoracic surgery-intensive care unit in cardiac surgery, 619
CT pulmonary angiogram (CTPA), of pulmonary embolism, 430 in postoperative cognitive dysfunction, 619
CT scans, for pulmonary embolism, 581–582 Descending neurogenic-evoked potentials (DNEPs), 350–351
CVR. See Cerebrovascular resistance Desirudin, 430–431t
Cyclooxygenase (COX), 422 Desmopressin (DDAVP), 436
Cyclosporine, for organ transplant recipient, 531 in cardiopulmonary bypass, 132
Cystatin C for hypernatremia, 598
as marker of renal function, 226 Detsky modified risk index, 41
serum, measurement, 76 Dexamethasone, 363, 593
Cysteine-rich protein (CYP 61), 76 inflammatory response, perioperative modulation of, 14
Cytokine profiling, in pain, 609 for postoperative nausea and vomiting, 418
Cytomegalovirus (CMV), in organ transplant recipient, 540 and renal preservation, 238
682 Index

Dexmedetomidine, 381, 477, 498–500, 616–617 DVT. See Deep venous thrombosis
postoperative delirium, 57–58 Dysfibrinogenemia, 109, 109f
for sedation of neurosurgical patient during respiratory support, 556 Dyspnea, preoperative, and pulmonary complications, 88
Diabetes insipidus Dysrhythmia(s). See Arrhythmia(s)
central, 598
diagnosis of, 558, 598 E
etiology of, 598 Eagle criteria, 41
management of, 558 Early Goal-Directed Therapy (EGDT), 569–570
nephrogenic, 598 EAU. See Epiaortic ultrasound
Diabetes mellitus, 587–588. See also Gestational diabetes EBM. See Evidence-based medicine
cardiac surgery in, glycemic control for, 588 ECG. See Electrocardiography
for comorbidities, 664 Echocardiography
and infection, 587–588 perioperative, 36
inflammatory response, 13 in peripartum cardiomyopathy, 465
management of, 587 in postoperative low cardiac output state, 168–169
perioperative, 126–127, 260 preoperative, 92–93
and outcomes, 588 in pulmonary hypertension, 466–467
management of, in neurosurgical patient, 559 in valvular heart disease, 181–182
noncardiac surgery in, glycemic control for, 588 Eclampsia, 463
pathophysiology of, 587 ECMO. See Extracorporeal membrane oxygenation
and renal function, 68–69, 260–261 Economic analysis, types of, 642–643
type I, definition of, 587 Economics, of perioperative optimization, 638–644
type II, definition of, 587 Edema
and wound healing, 587 postoperative, in neurosurgical patient, 557–558
Diaphragm, respiratory excursion pulmonary (see Pulmonary edema)
in mechanical ventilation, 83–84, 87f Edoxaban (Savaysa), 430–431t
in spontaneous breathing, 83–84, 87f EEG. See Electroencephalography
DIC. See Disseminated intravascular coagulation Effector-cell protease receptor-1 (EPR-1), and inflammatory signaling
Digoxin, 507 pathways, 21
Dihydroergotamine, effect on postoperative ileus, 422t EGDT. See Resuscitation, early goal-directed therapy
Dilitiazem prophylaxis, 507 Eisenmenger syndrome, 466
and renal outcomes, 239 Elastic compression stockings, 429
Direct costs, 640 Electrocardiogram (ECG), for pulmonary embolism, 581
Direct oral anticoagulants (DOACs) therapy, 113–115, 115t, 441 Electrocardiography
Disease-directed therapies, 628 abnormalities, with subarachnoid hemorrhage, 298–302
Disease-specific palliative care, 632 in cardiac surgical patients, 154, 156t
cancer, 632 intraoperative postprocedural monitoring with, 164
Disseminated intravascular coagulation (DIC), 109, 109f, 436, in evaluation of arrhythmias, 201
566–567 hypercalcemia, 603
Diuretics hyperkalemia, 600
and hypokalemia, 599 hypermagnesemia, 601
loop hypocalcemia, 602
and renal outcomes in cardiopulmonary bypass, 72 hypokalemia, 599
and renal preservation, 237 intraoperative, 124
therapy with ST-segment changes, conditions leading to, 154, 156t
for hypomagnesemia, 600 in valvular heart disease, 181–182
intraoperative, in kidney transplant recipient, 271 Electroconvulsive therapy, 195–196
in valvular heart disease, perioperative management of, 184 Electroencephalography, during barbiturate therapy for intracranial
Dobutamine, for ventricular failure after cardiac surgery, 170t hypertension, 370
Dolasetron, for postoperative nausea and vomiting, 417 Electrolyte balance. See also specific electrolyte
Dopamine disturbances of, 587–606
and renal outcomes in cardiopulmonary bypass, 72 Electrolyte imbalance, postoperative, in cardiac surgical patient, 168
therapy with, intraoperative, in kidney transplant recipient, 272 ELPQUIC Emergency Laparotomy Quality Improvement Bundle,
for ventricular failure after cardiac surgery, 170, 170t 217–218, 218f
Dopamine receptor antagonists, for postoperative nausea and Embolic load, 618
vomiting, 417–418 Emboli, prevention/reduction of, in cardiac surgery, 311
Dopexamine hydrochloride, 236 Embolization
Downstream providers, documentation and transmission, 33 cerebral, in cardiac surgery, 311
Dripps–American Surgical Association (ASA), 40–41 gaseous, with carbon dioxide, 314
Droperidol, fatal arrhythmias, 192 related to aortic atherosclerosis
Droperidol, for postoperative nausea and vomiting, 417–418 prevention of, 234
Drug(s). See also Medication(s) and renal outcomes, 234
cerebral blood volume-reducing, for treatment of intracranial and renal outcomes, 252
hypertension, 369–370 Embol-X intra-aortic filtration system, 234, 313–314, 313f
metabolites, renal excretion of, 263–264, 265t Emergency general surgery, 217–218, 219f
nephrotoxicity, 67 Enalapril
renal excretion of, 265, 265t and intracranial pressure, 387t
Duke Activity Status Index (DASI), 37 neuroprotective effects of, 387t
 Index 683

Enalapril (Continued) Extracorporeal membrane oxygenation, 166

sympatholytic effects of, 387t for ventricular failure after cardiac surgery, 171–172, 175t
Encephalopathy, uremic, 263 Extracorporeal membrane oxygenation (ECMO) support, 52, 53t,
Endocarditis 570
and embolic renal injury, 227, 227f Extubation, postoperative, for cardiac surgical patient, 488–489, 489t,
prevention of, in valvular heart disease, 182, 183b 500
Endocrine disorders, 587–603
End-of-life care, 629 F
Endogenous opioids, 420 Factor V Leiden, and venous thromboembolism, 428
Endovascular carotid artery angioplasty, and stenting for carotid FAST. See Focused abdominal sonography for trauma
stenosis, 293 Fasting, preoperative, 411, 413
Endovascular therapy in AIS, anesthesia for, 393–395 Fat embolism syndrome (FES), 523–524
blood pressure goals, 395 biochemical theory states for, 523
fluid and glucose management, 395 characterization, 523
oxygenation and ventilation, 395 management, 524
planning, 394–395 mechanical theory for, 523
type, 395, 395t mortality, 523
End stage renal disease (ESRD), 533. See also Renal failure, chronic scoring systems, 523–524
causes of, 259 signs and symptoms, 523
palliative care for, 633 treatment of, 524
Enflurane, and renal function, 68 Fenoldopam, renal outcomes in cardiopulmonary bypass, 73, 236
Enhanced recovery after surgery (ERAS), 31–32, 508, 511, 660, 665 Fentanyl
intravenous fluid infusion, 208 in cardiac anesthesia, 125
principles of modern fluid therapy, 208, 209f renal failure and, 265
pulmonary inflammation, 285, 285t for sedation of neurosurgical patient during respiratory
versus traditional, 208–209, 210f support, 556
eNOS. See Nitric oxide synthase (NOS), endothelial Fetal heart rate, monitoring, during nonobstetric surgery, 479–480,
Enoxaparin (Lovenox), 430–431, 430–431t 480f
in prevention of venous thromboembolism, 559 FEV1. See Forced expiratory volume at 1 minute
Enteral nutrition, 549 Fever, 363, 381–382
early postoperative for prevention of postoperative ileus, 421 management of, 382
Enteric feeding, postoperative, for thoracic surgical patient, 516–517 postoperative, in cardiac surgical patient, 499
Ephedrine, 468 in stroke patient, 382
for maternal hypotension during regional block, 467–468 Fibrin
for maternal hypotension in regional block, 478 formation, 16
Epiaortic ultrasound, 314, 327 and inflammatory signaling pathways, 21
Epidural analgesia, and prevention of postoperative ileus, 423 Fibrinogen, 16, 104f
Epilepsy, 61–62, 63t Fibrinolysis
Epinephrine physiology of, 16
for septic shock, 570 proteins of, 17, 17f
for ventricular failure after cardiac surgery, 170, 170t site of surgery and, 19
EPR-1. See Effector-cell protease receptor-1 First-degree atrioventricular block, 200–201, 201f
Epsilon-aminocaproic acid Flash sterilization, 452
in cardiopulmonary bypass, 132 Flecainide, 507
intraoperative use, and renal outcome, 234–235 Fluid boluses, 211, 212f
Ergot alkaloids, contraindications to, in pregnancy, 466 Fluid management
Erythromycin, effect on postoperative ileus, 422t in chronic renal failure, 261–263
Erythropoietin, 103, 103b, 239 to decrease maternal hypotension during regional block, 464
therapy with, for anemia in renal failure, 263 and electrolyte balance, 261–263
Esmolol, 596 goal-directed, and gastrointestinal outcome, 423–424
effect on postoperative ileus, 422t during intracranial surgery, 295
neuroprotective effects of, 387t intraoperative
sympatholytic effects of, 387t and postoperative nausea and vomiting, 418
ESRD. See End-stage renal disease and postoperative outcomes, 423
Etomidate therapy, for intracranial hypertension, 369 and renal outcomes, 232
European Respiratory Society (ERS), 505 postoperative
European Society for Anaesthesiology and the European Society of in neurosurgical patient, 558
Intensive Care Medicine (ESA-ESICM) joint taskforce, 277 for prevention of postoperative ileus, 421
European Society of Cardiology/European Society of Anaesthesiology in preeclamptic patient, 464
(ESC/ESA), 36, 41–42 preload versus coload, 468
European Society of Thoracic Surgeons (ESTS), 505 Fluid overload, 256
EuroSCORE, cardiovascular risk assessment, 48 Fluid responsiveness, 211, 215–216, 218–220
Evidence-based medicine, 638–639 Fluid resuscitation, 570
Exercise testing Fluoride exposure, and renal function, 68
in pneumonectomy candidate, 97 Focused abdominal sonography for trauma, 544–545
preoperative, 92 Foley catheters, 390–391
Expiratory reserve volume, in obesity, 591 Folic acid, preoperative therapy with, 103b
External ventricular drainage system, 360, 361f Fondaparinux (Arixtra), 429, 430–431t
684 Index

Forced expiratory volume at 1 minute (FEV1) Glucose

predicted postoperative, in pneumonectomy candidate, 97 blood levels (see also Glycemic control; Hyperglycemia;
preoperative, in pneumonectomy candidate, 97 Hypoglycemia)
and risk of postoperative pulmonary complications, 89t intraoperative, and renal outcomes, 234
4-factor Kcentra, 438 and myocardial protection, 126–127
Fracture, rib, pain control for, 549–550 perioperative management of, 126–127
Frailty, cardiac surgery in, 51 and cerebral injury, 559
FRC. See Functional residual capacity for hyperkalemia, 600
Freedom of Information Act, 652 management, 238
Free-water deficit Glucose control in cardiac and noncardiac surgery, 589f
estimation of, 598 Glucose homeostasis, during cardiac surgery, 619
management of, 598 Glycemic control
Fresh frozen plasma (FFP), 435–436, 438, 495 for cardiac surgery, 588
Functional capacity, preoperative assessment of, 37–38, 42 and neurologic outcomes, 382–383
Functional connectivity, functional MRI measures, 621–622 in neurosurgical patient, 559
Functional MRI, 621–622 for noncardiac surgery, 588
Functional oliguria vs. acute kidney injury, 254–256 in prevention of infection, 587–588
Functional residual capacity and prevention of surgical site infections, perioperative, 450–451
in obesity, 591 in trauma patient, 549
postoperative, 84–86 Goal-directed fluid therapy (GDFT), 211–212, 212f, 232
Furosemide Goal directed hemodynamic therapy (GDHT), 208, 209f
intraoperative therapy with, in kidney transplant Goal-directed volume resuscitation, and gastrointestinal outcome,
recipient, 271 423–424
and renal outcomes in cardiopulmonary bypass, 72 Goiter, 596
Goldman cardiac risk index, 41
G GPIIb/IIIa receptor antagonists. See Glycoprotein IIb/IIIa inhibitors
Gaseous emboli, 311, 312t Granisetron, for postoperative nausea and vomiting, 417
Gaseous microemboli, 618 Graves’ disease, 596
Gastric decompression, for postoperative ileus, 421 Growth factors (IGF-I, EGF, HGF), 240
Gastric emptying
factors affecting, 412
in pregnancy, 480 H
Gastric feeding, risk factor for pulmonary aspiration, 580–581 Haloperidol, 498–499
Gastrointestinal abnormalities, in chronic renal failure, 263 Halo system, 392
Gastrointestinal complications, postoperative Hashimoto thyroiditis, 595
in cardiac surgical patient, 499 Hb. See Hemoglobin
prevention and treatment of, 410–426 HbMIN. See Hemoglobin, lowest tolerable
Gastrointestinal surgery, endocarditis prophylaxis for, 182 HCPCS. See Health-care Common Procedure Coding System
GCS. See Glasgow Coma Scale HDR. See Health Disease Research
General anesthesia, 463, 465–466 Head
for carotid endarterectomy, 292 manual in-line immobilization of, 336
for cesarean delivery, 469 positioning of, and control of intracranial pressure, 306
in chronic renal failure, 264 Head injury. See Brain injury; Central nervous system
for cortical mapping, 297–298, 299–301t Health-Care Financing Administration (HCFA), 652
obstetric, maternal morbidity and mortality in, 469 Health-care quality measurement
and postoperative ileus, 421 anatomy of proportion, 649f
in pregnant patient, 477–478 calculation, 648b
General endotracheal anesthesia (GETA), 395 clinical care model redesign, 654
Genitourinary procedures, endocarditis prophylaxis for, 182 concepts, 645
Genomic factors, CPB-associated, and neurologic development of, 646–648
outcomes, 312 dimensions of, 645, 646t
Geriatrics and renal function, 223 Donabedian framework for, 647b
Gestational diabetes, 587 endorsement of, 646–648
complications of, 587 extrinsic rewards, 645–646
definition of, 587 framework for, 646
treatment of, 587 health information technology (HIT), 654
GFR. See Glomerular filtration rate health plan accreditation, 651
GIK. See Glucose-insulin-potassium hospital accreditation, 651
Glasgow Coma Scale (GCS), 356, 547, 552, 553b intrinsic rewards, 645–646
Glomerular filtration rate, 251 legislation to promote value-based care, 654
estimation, 70, 74t, 75, 75b National Quality Forum (NQF), 648t
evaluation of, 70 measure applications partnership, 647–648
postoperative, prognostic significance of, 75 National Quality Strategy aims and priorities, 653t
Glucocorticoid(s) Patient Protection and Affordable Care Act (ACA), 654
physiologic functions of, 593 from pay-for-reporting to pay-for-performance, 653–654
secretion of paying for performance, 652–657
normal, 593 public reporting and transparency, 652, 653b
in stress, 593 quality improvement, 648–651
 Index 685

Health-care quality measurement (Continued) Hemodynamics, intraoperative, in kidney transplant recipient, 270
American College of Surgeons’ National Surgical Quality Hemoglobin
Improvement Program (ACS NSQIP), 649b, 650f acute renal injury related to, 227
methodologies, 650–651 harvest during acute normovolemic hemodilution, 103–104
Quality Payment Program (QPP), 654–656, 655f lowest tolerable, 103–104
redefining quality and cost to transition to value, 652–653 acceptable levels, 103b
structure, process, and outcome, 646, 647b, 647f lowering, 104
surgical specialty verification, 651 optimal level, in acute CNS injury, 389–390
uses of, 648 preoperative concentration, 102
value-based care and path forward, 656–657 Hemoglobin, optimal, 216
cost measurement, challenges in, 656 Hemoglobinuria, 227
excessive burden with lack of valid, 656 Hemophilia
interoperable meaningful data, lack of, 656–657, 656f hemophilia A, 110, 436
payers, defined by, 656 hemophilia B, 110, 436
value-based health-care, 652–657 Hemophilia A, 110, 436
Health information technology (HIT), 654 Hemophilia B, 110, 436
Health Plan Employer Data and Information Set (HEDIS), 651 Hemorrhage, 70–71. See also Bleeding
Heart. See Cardiac entries maternal, in childbirth
Heart block, 194–195, 200 California Maternal Quality Care Collaborative Obstetric
Heart disease Hemorrhage toolkit, 471, 471f
chronic, and pregnancy, 466 peripartum, 470–471
clinical predictors, 36, 37t postpartum, 470–471
ischemic (see Myocardial ischemia) risk factors for, 470
in pregnancy, 464–466 Hemostasis, 104–105, 104f
Cardiac Disease in Pregnancy (CARPREG II) score, 465f primary tests of, 107–108, 107b, 108f
maternal mortality due to, 464 secondary tests of, 108–110, 109f
predictors of adverse events in, 464f Hemostatic agents, in cardiopulmonary bypass, 132
signs and symptoms, 36, 37t Heparin
valvular (see Valvular heart disease) prophylaxis
Heart failure (HF) for deep venous thrombosis, 548
palliative care in, 632 for venous thromboembolism, 548
with valvular heart disease, 181 therapy with
Heart manipulation, 316 low-molecular-weight, perioperative management of, 183
Heartmate, 172–174, 175t perioperative management of, 186
Heart murmur(s), evaluation of, 181–182 unfractionated, anticoagulation therapy, 112–113
Heart rate, postoperative, in cardiac surgical patient, 168 in valvular heart disease, perioperative management of, 186
Heart transplantation for venous thromboembolism, 430
cardiac allograft rejection, 537 Heparin-bonded CPB circuit, 130
donor, 536 Heparin-induced thrombocytopenia (HIT), 582.
hyperacute rejection, 537–538 See also Thrombocytopenia, heparin-induced
postoperative management for, 536–538 4Ts scoring system for, 437
recipient, 536 management of, 437–438
rejection of, 537 Hepatic artery thrombosis (HAT), 532–533
renal injury in, 5 Hepatic encephalopathy, 530
HEDIS. See Health Plan Employer Data and Information Set Hepatitis C virus (HCV), in organ transplant recipient, 540
HELLP syndrome, 107, 469 Hepatorenal syndrome, 533
Hematocrit, management of, during cardiopulmonary bypass, 233 Herniation syndromes, 359, 360t
Hematologic abnormalities, in chronic renal failure, 263 Herniorrhaphy, 511
Hematologic risk assessment, 101–120 Hexamethonium, and neurologic outcomes, in acute CNS injury, 386,
indications for, 101, 102b 387f, 388
Hematoma(s) High-efficiency particulate air (HEPA) filters, 451
epidural, 370 High-flow nasal oxygen (HFNO2), 283–285
after neurosurgery, 554–555 High-quality shared decision-making, 27–29, 28f
subdural High-value interventions, 26
after neurosurgery, 554–555 Hip surgery. See Total hip arthroplasty
development of, 361f Histamine (H2) antagonists, 413
management of, 371 HIT. See Thrombocytopenia, heparin-induced
Hemodialysis HOCM. See Hypertrophic cardiomyopathy
and hepatitis C, 267 Hormonal manipulation, in sepsis, 571–572
and hypercalcemia, 603 Hospice, and palliative care, 628, 629t
new-onset postoperative renal failure requiring, 225, 238 Hospice care, 628
and pulmonary hypertension, 261, 264 Hospital-acquired infections (HAIs), 444
Hemodilution. See also Acute normovolemic hemodilution Hospital anxiety and depression scale (HADS), 607
during cardiopulmonary bypass, 233 Hospital to home, transitions from, 668
and coagulation function, 20–21 care transition planning for, 670, 670f
Hemodynamic instability, with valvular heart disease, 181 costs of failed transitions, 669
Hemodynamic measurement, in postoperative low cardiac output ensuring, 669–670
state, 168–169 effective clinical communication, 669–670
686 Index

Hospital to home, transitions from (Continued) Hyperphosphatemia, 601–602

patient and family engagement, 670 in chronic renal failure, 260t
nonhome discharge, factors associated with, 668 clinical manifestations of, 601
paths from, 668, 669f, 669t first-line therapy, 602
planning for, 668–669 Hypertension
HPA. See Hypothalamic-pituitary adrenocortical axis in autonomic dysreflexia, 352
HQA. See Hospital Quality Alliance and brain injury, in postoperative neurosurgical patient, 556–557
5-HT3 receptor antagonists, for postoperative nausea and vomiting, in chronic renal failure, 261–262
417 gestational, 464, 468
Human brain, functionally connected networks in, 621f induced, in acute CNS injury, 380
Human immunodeficiency virus (HIV), palliative care for, 633 intra-abdominal, in trauma patient, 546–547
Hunt and Hess grading system, modified, 298, 302t and intracranial pressure, 384, 385f
Hydralazine, 557 management of
for hypertension in pregnancy, 463 in acute CNS injury, 386–388, 387t, 387f
and intracranial pressure, 387, 387t in pregnancy, 462–464
Hydrocortisone, perioperative supplementation with, 594, 594t obesity and, 590–591
Hydroxyethyl starch, intraoperative use of, and renal in pregnancy, 461–464, 462f
outcomes, 232 anesthetic considerations in, 463
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase management of, 462–464
inhibitors. See Statins maternal mortality with, 461–462
Hyperalimentation, 571 risk factors for, 461
Hypercalcemia, 602–603 and renal function, 71, 260
anesthetic considerations in, 603 with subarachnoid hemorrhage, 302
clinical manifestations of, 602–603 Hyperthermia, 618–619
hemodialysis and bisphosphonate therapy, 603 neurologic effects of, 315, 381–382
treatment for, 603 prevention of, in cardiac surgery, 315
Hypercapnic respiratory failure, 576 Hyperthyroidism, 596
causes of, 576 Hypertonic saline (HTS), 366–368, 367f
mechanisms, 576 adverse effects and side effects of, 368
Hypercarbia, 481 infusion, 369
in brain injury, 555 for intracranial hypertension, reduction of, 367f, 368–369
maternal and fetal, 481 intracranial complications, 368
Hyperchloremia, 603 systemic complications, 369
Hypercoagulability, 18 and renal failure, 368–369
perioperative, 18–20 Hypertrophic cardiomyopathy, perioperative management of,
and venous thromboembolism, 428 hemodynamic principles for, 185t
Hyperfibrinolysis, 543 Hyperventilation
Hyperglycemia, 263, 549, 587–588, 619 cerebral and systemic effects of, 364–365, 364–365f
during cardiopulmonary bypass, and renal outcomes, 234, 238 and cerebral perfusion, 378–379, 379f
and cardiovascular outcome, 126–127 and control of intracranial pressure, 306–307
and cerebral injury, 382–383, 559 for management of intracranial pressure, 363–366, 554
and infectious complications, 588 pregnancy, nonobstetric surgery in, 481–482, 481b
management of, 381–383 in TBI, 365
and neurologic outcomes, 383 Hypervolemia, in chronic renal failure, 261–262
Hyperkalemia, 599–600 Hypoalbuminemia, 433, 447–448
acute, 600 Hypocalcemia
in chronic renal failure, 262 in chronic renal failure, 260t
definition of, 599 clinical manifestations of, 602
ECG abnormalities, 600 definition of, 602
manifestations of, 599 management of, 602
potassium balance, 262 Hypocapnia, 364
Hyperlactatemia, 567–568 Hypochloremia, 603
Hypermagnesemia, 601 Hypocoagulability, 18
in chronic renal failure, 262 Hypoglycemia, 619
definition of, 601 Hypokalemia, 599
electrocardiographic changes in, 601 in chronic renal failure, 262
treatment of, 601 definition of, 599
Hypernatremia outcomes with, 599
definition of, 598 treatment, 599
management of, 598 Hypomagnesemia, 600–601
outcomes with, 598 causes of, 600
signs and symptoms of, 598 in chronic renal failure, 262
Hyperosmolar therapy, 366–368, 366t treatment of, 600
hypertonic saline, 366–368, 367f Hyponatremia, 390–391, 596–598
for intracranial hypertension, 366–368 definition of, 597
mannitol, 366 hypervolemic, 597
Hyperosmotic therapy, and control of intracranial pressure, 307 hypovolemic, 597
Hyperoxia, 489, 570 isovolemic, 597
 Index 687

Hyponatremia (Continued) Idiopathic thrombocytopenic purpura, 436

management of, 597–598 perioperative management of, 107, 108f
outcomes with, 598 IHA. See Integrated Health Association
in postoperative neurosurgical patient, IL-10, 566
557–558 Ileus, postoperative, 420–424, 515–516
treatment of, 597 etiology of, 420–421
type of, 597 general anesthesia, 421
Hypoperfusion during cardiac surgery, 311–312 postoperative opioids, 420–421
Hypophosphatemia nonpharmacologic methods, 421
definition of, 601 pharmacologic therapy for, 421–423, 422t
etiology of, 601 spine surgery, unique issues after, 526
treatment of, 601 treatment of, 421–423
Hypopnea. See Obstructive sleep apnea/hypopnea syndrome Imaging, in spinal cord injury, 337–338, 348–349, 349f
Hypotension Immunoactivation, 567
beta-blocker–induced, 144–146 Immunologic function, in chronic renal failure, 264
during cardiac surgery, 311–312 Immunomodulation, in sepsis, 571
management of, in acute CNS injury, 388–389 Immunonutrition, 517
maternal Immunosuppressive therapy, for organ transplant recipient, 531
fetal effects of, 478 Impella system, 174–175, 174f, 175t
management of, 478–479 Implantable cardioverter-defibrillators (ICDs), 203, 496
in regional anesthesia, 467–468 Implanted neurostimulator devices, 63t, 64
and renal toxicity, 70–71 Incentive spirometry (IS)
in spinal cord injury, 336 for atelectasis, 579
and spinal cord ischemia after aortic aneurysm repair, 344, 345f postoperative, in thoracic surgical patient, 506–507
Hypothalamic-pituitary-adrenocortical axis Incremental cost-effectiveness ratios (ICERs), 639, 662
chronic steroid supplementation and, 593 Indirect costs, 640
response to stress, 593 Indomethacin, and perioperative renal injury, 227
Hypothermia, 370, 379, 450, 618–619 Infection(s), 350. See also Sepsis; Surgical site infection(s)
and hypoxic-ischemic encephalopathy after cardiac arrest, in chronic renal failure, 263
380–381 control, in sepsis, 569
intraoperative in organ transplant recipient, 540
and coagulation function, 20 postoperative
and myocardial protection, 125–126, 128, 130 in cardiac surgical patient, 499
and renal outcomes, 234 diabetes and, 587–588
in management of intracranial hypertension, 307 in neurosurgical patient, 560
neuroprotective effects of, 323–324, 379–380 prevention of, glycemic control and, 587–588
postoperative, in cardiac surgical patient, 168 renal failure and, 264
for rescue ICP therapy, 380 spine surgery, unique issues after, 526
surgical decompression, 370 in trauma patient, 549
and TBI, 380 Inferior vena cava (IVC) filters, 429, 432, 548, 582
in valvular heart disease, 184 Inflammaging, 12
Hypothermia blanket, 382 Inflammation, 566–567
Hypothermic circulatory arrest (HCA), 321–322 in cardiac surgery, 616–617
Hypothermic fibrillatory arrest, 130 in postoperative delirium, 616–617
Hypothyroidism, 595–596 Inflammatory response
clinical manifestations of, 596 CPB-associated
Hypovolemia, 491 and neurologic outcomes, 312
and cerebral perfusion, 557 pathophysiology of, 130
in chronic renal failure, 264 pharmacologic protection against, 131–132
and shock, 256 and renal toxicity, 70–71
Hypoxemia, 511, 524, 579 to surgery
Hypoxemic respiratory failure, 576 aging, 12
causes of, 576 chronic kidney disease, 12–13
Hypoxia definition, 9–10, 10–11t, 11f
acute, treatment algorithm for, 583f diabetes mellitus, 13
in brain injury, 555 pathogen-associated molecular patterns,
definition of, 583 10–12, 13f
renal medullary, 222–223 perioperative modulation, 13–14
in spinal cord injury, 336 Injury(ies). See also Ischemia-reperfusion injury
Hypoxic ischemic brain injury, 63–64, 63t brain (see Brain injury)
Hypoxic-ischemic encephalopathy, after cardiac arrest, 380–381 burn, and renal toxicity, 70–71
cardiac, with subarachnoid hemorrhage, 298
I ischemic, prevention of, in cardiac surgery, 122–142
Ibuprofen, 382 lung (see Acute lung injury)
ICER. See Incremental cost-effectiveness ratio neurologic (see Neurologic injury(ies))
ICP. See Intracranial pressure perioperative
ICU. See Intensive care unit neurologic, and outcomes, 3–4, 4–5t
Idarucizumab, 433, 438 and outcomes, 2–8
688 Index

Injury(ies) (Continued) Intracranial surgery (Continued)

association versus causality in, 6 induction of, 294
renal, and outcomes, 5–6, 5f maintenance of, 294–295
renal (see Renal injury(ies), acute) arterial blood pressure during, management of, 295
spinal cord (see Spinal cord injury) emergence from, management of, 296
iNOS. See Nitric oxide synthase (NOS), inducible fluid management during, 295
Inotropic therapy muscle relaxants for, 295–296
in postoperative low cardiac output state, 170–171 preoperative evaluation for, 294
for postoperative neurosurgical patient, 557 ventilation during, management of, 295
in valvular heart disease, perioperative management of, 184 Intramedullary cement, complications relating to, 524
Instruments, surgical, sterilization of, 451 Intraoperative blood loss, spine surgery, unique issues after, 526
Insulin, 559 Intraoperative neurophysiologic monitoring (IONM), 347f
for hyperkalemia, 600 Intravenous fluid overload, 209–210, 211f
infusion, 381–382 Intubation
Insulin replacement therapy, 530 in acute CNS injury, awake versus asleep, 372–375
Intangible costs, 641 in cervical spine injury, 372–375
Intensive care unit goiter and, 596
cardiac surgical patient in, 487 in spinal cord injury, 336
admission of, 487–488 Invasive mechanical ventilation, 277
assessment of, 487–488 Iodine-based antiseptics, and prevention of surgical site infections, 448
transport of, 487–488 Iodophors, and prevention of surgical site infections, 448
neurologic-neurosurgical, 552 IPC. See Ischemic preconditioning
Intensive insulin therapy, 498 Iron, preoperative therapy with, 103, 103b
Interleukin 1β (IL-1β), 9–10 Ischemia. See Myocardial ischemia
Intermittent positive-pressure breathing (IPPB), 579 Ischemia during CEA, cerebral monitoring, 292–293, 292b
Internal mammary artery Ischemia-reperfusion injury
malperfusion syndrome, 161–162, 165 CPB-associated
stenosis, after CABG, 161f pathophysiology, 130
International Hypothermia Aneurysm Trial (IHAST), 304 pharmacologic protection against, 131–132
International Study of Postoperative Cognitive Dysfunction (ISPOCD), myocardial, prevention of, operative strategies for, 128–134
59–60 Ischemic heart disease. See Myocardial ischemia
Intestinal transplantation, 535 Ischemic injury, prevention of, in cardiac surgery, 122–142
donor, 535 Ischemic preconditioning, 133, 150
postoperative management for, 535 renal, 231
recipient, 535 Isoproterenol, for ventricular failure after cardiac surgery, 170t
Intra-aortic balloon pump, 163–164, 163f, 166 ITP. See Idiopathic thrombocytopenic purpura
postoperative, in cardiac surgical patient, 493
for ventricular failure after cardiac surgery, 171 J
Intracardiac surgical manipulation, 195 JAMA Surgery, 3
Intracranial hypertension Jaw-thrust maneuver, 335–336, 336f
exacerbating factors, 358 JCAHO. See Joint Commission on Accreditation of Health-care
hyperemic, 358–359, 359f Organizations
management of, 306–307 Jehovah’s Witness, 101–102
oligemic, 358–359, 359f Joint Commission, 29, 651
physiology of, 357–358, 357f
positive end-expiratory pressure and, 375–378, 377–378f K
presentation, 359 Kidney(s). See also Renal entries
treatment of, 362, 363f function measures, 226
algorithm for, 362–363 function, postoperative, in cardiac surgical patient, 497
types of, 358–359, 359f immature, 223
Intracranial pressure (ICP), 378f ischemic preconditioning reflex in, 231
blood pressure and, 383–384, 384f during pregnancy, 223
increased (see also Intracranial hypertension) preservation, 269–270
airway assessment and management with, 555 stress measures, 226
compensatory mechanisms for, 357 transplantation of, 267–272
and intracranial volume, relationship of, 357, 357f albumin, 270
management of, 306–307 anesthesia management for, 269
monitoring, 359–361 calcium channel blockers, 271–272
normal, 358 cardiac disease evaluation and management, 268
positive end-expiratory pressure and, 375–378, 377–378f cold storage and, 270
postoperative, in neurosurgical patient complications of, 533
management of, 554 deceased criteria donor, 267
monitoring, 554 deceased-donor, 269
with subarachnoid hemorrhage, 297 delayed graft function after, 534
in trauma patient, 547 diuretics, 271
Intracranial surgery donor, 533
anesthesia for donor criteria, 267
emergence from, management of, 293–296 dopamine, 272
 Index 689

Kidney(s) (Continued) Low molecular weight heparin (LMWH) (Continued)

furosemide, 271–272 for venous thromboembolism, 429–431
hemodynamics and intravascular volume, 270 Lumbar puncture, in children with thrombocytopenia, 108f
immunology of, 268 Lung protective ventilation strategy, 512
intraoperative management, recipient selection, 270–272 Lung resection, candidate for, preoperative evaluation, 97–98, 98f
ischemic preconditioning, 270 Lung transplantation, 538–540
and kidney viability, 269–270 donor, 538
living-donor, 267, 269 infection after, 540
mannitol, 272 postoperative management of, 539–540
postoperative management, 533–534 recipient, 538
post-transplant complications, 268 Lung volume, loss, postoperative, 86
recipient, 533 Lupus anticoagulant, 109f, 110
recipient selection, 267–268 LVAD. See Left ventricular assist devices
resuscitation fluid, 270–271 Lymphocele, in renal transplant recipient, 534
standard criteria donor, 267
tubular damage, 226 M
Kidney donor risk index (KDRI), 267, 533 mABL. See Blood loss, maximum allowable
Kidney Failure, 240–241 Macroemboli, 311, 312t
Kidney Protective Bundle, 240 Magnesium, in cardiac surgery, 600
KIM-1, 76 Magnesium balance
abnormalities of, 600–601 (see also Hypermagnesemia;
L Hypomagnesemia)
Labetalol in chronic renal failure, 262
for hypertension in pregnancy, 463 Magnesium sulfate
neuroprotective effects of, 387t for hypomagnesemia, 600
sympatholytic effects of, 387t therapy with, in preeclampsia/eclampsia, 463
Laminar airflow, 451 Magnetic resonance imaging (MRI)
Laparoscopic and robotic-assisted surgery, 216–217, 217f of cervical spine injury, 337–338, 342f
Laparoscopic surgery, and risk of pulmonary complications, 91 for microemboli, 618
Laryngeal height, and risk of postoperative pulmonary complications, postoperative, in neurosurgical patient, 554
89, 89t Magnetic resonance pulmonary angiography (MRPS), of pulmonary
Laryngeal mask airway (LMA), 374 embolism, 430
Laryngeal reflexes, 411 Major adverse cardiac event (MACE), 38f
Laxative therapy, for postoperative ileus, 422 Malnutrition, 508, 516
Learning curve, 641–642 Mannitol, 236
Lee index, 39f, 40, 40–41t adverse effects and side effects of, 366
Left anterior fascicular block, 200, 200f and renal outcomes in cardiopulmonary bypass, 72
Left atrial appendage occlusion, 203 therapy with
Left bundle branch block, 200, 200f intraoperative, in kidney transplant recipient, 271
Left posterior fascicular block, 200, 201f for postoperative management of intracranial pressure, 554
Left ventricular assist devices MAP. See Mean arterial pressure
cardiovascular risk assessment in, 53 Marginal costs, 641–642
for ventricular failure after cardiac surgery, 172–175, 173f, 175t Mass lesion(s), intracranial, removal of, and control of intracranial
Left ventricular ejection fraction (LVEF), 42 pressure, 306
Left ventricular hypertrophy, obesity and, 590 McGill Pain Questionnaire, 607
Leukocyte depletion, 131 MDCT. See Computed tomography, high-resolution multidetector
Level of consciousness, decreased, airway assessment and Mean arterial pressure, 554, 557
management with, 555 and intracranial pressure, relationship of, 357–358
Liberal versus restrictive fluid therapy, 209–211 Mean arterial pressure (MAP), 213, 214–215f
Lidocaine fixing flow, 213–215
anti-inflammatory effects of, 19 management, 618
therapy with, for intracranial hypertension, 369–370 randomized trials, 213–214
Liver failure and bleeding, 436 Measure applications partnership (MAP), 647–648
Liver impairment and venous thromboembolism, 433 Mechanical bowel preparation (MBP), and prevention of surgical site
Liver, transplantation of, 531–533 infection, 447
donor, 532 Mechanical circulatory support (MCS), 493–494
infection after, 540 Mechanical thromboembolectomy, for venous thromboembolism, 432
postoperative management, 532–533 Mechanical ventilation, 524
recipient, 531–532 in atelectasis, 577
rejection in, 540 postoperative, for cardiac surgical patient, 488–490, 489b, 489t
Local anesthetics, anti-inflammatory effects of, 19 weaning from, for cardiac surgical patient, 490
Low cardiac output state, postoperative Medicare Access and CHIP Reauthorization Act of 2015 (MACRA),
in cardiac surgical patient, 165–175 654
assessment, 167–169 MedPAC. See Medicare Payment Advisory Commission
management of, 169–175 Medullary hypoxia, 222–223, 223f
Lower esophageal sphincter (LES), 411 Memory impairment, 613–614
drugs affecting, 411, 412t Mendelson’s syndrome, 480
Low molecular weight heparin (LMWH), 349–350, 521–523, 582 Meperidine, renal failure and, 265
690 Index

Merit-based Incentive Payment System (MIPS), 654–655 Mycophenolate mofetil, for organ transplant recipient,
Metabolic abnormalities, in chronic renal failure, 263 531
Metabolic acidosis, in chronic renal failure, 262–263 Mycophenolic acid, for organ transplant recipient, 531
Metabolic alkalosis Myocardial conditioning, 133–134
chloride-resistant, 603 Myocardial infarct/infarction, 2, 150–151
chloride-responsive, 603 acute, cardiac surgery after, optimal timing of, 124
Metabolic equivalents (METs), 37, 39t intraoperative management
Metabolic response. See Hypermetabolic response anesthetic selection, 148
Metabolism, in cardiac surgery, 126 ischemic preconditioning, 150
Methicillin-resistant S. aureus (MRSA) management of, 149–150, 151f
prophylaxis, 449–451 monitoring, 148–149
screening and decolonization, 447 perioperative, 19
Methimazole therapy, for thyroid storm, 596 angiotensin-converting enzyme, 146–147
Methylnaltrexone therapy, for postoperative ileus, 422 angiotensin receptor blockers, 146–147
Methylprednisolone definition of, 155–157
for sepsis, 571–572 diagnostic criteria for, 155–157
in spinal cord injury, 341 etiology, 157–163
therapy, in spinal cord injury, 341 medication optimization, 144
Metoclopramide therapy myocardial revascularization, 144
for postoperative ileus, 422, 422t natural history of, 143, 144f
for postoperative nausea and vomiting, 417–418 pathophysiology, 143, 144f
Metoprolol therapy, in thyroid storm, 596 risk factors for, 157–158
Microemboli, 311, 312t, 618 risk stratification, 143–144, 145f
MIDCAB. See Coronary artery bypass grafting, minimally invasive screening, 143–144, 145f
direct postoperative, in cardiac surgical patient, 497
Mild hypothermia, 526 in pregnancy
Milrinone differential diagnosis of, 466
contraindications to, 166 incidence of, 466
for perioperative right ventricular dysfunction, 176 maternal mortality due to, 464
for ventricular failure after cardiac surgery, 170, 170t onset of, 466
MiniCog assessment, 668–669 risk factors for, 466
Mini Mental State Examination, 619–620 signs and symptoms of, 466
Minute ventilation, 481 treatment of, 466
Mitral regurgitation, perioperative management of, 188 with valvular heart disease, 184
hemodynamic principles for, 187t Myocardial injury after noncardiac surgery (MINS), 2–3, 213, 214f
Mitral stenosis, perioperative management of, 187 Myocardial ischemia
hemodynamic principles for, 185t monitoring for, intraoperative, 124–125
Mitral valve prolapse, perioperative obesity and, 591
management of, hemodynamic principles for, 187t perioperative
Mobilization, postoperative, for prevention of postoperative definition of, 154–165
ileus, 421 diagnostic criteria for, 154–165
Model for End-stage Liver Disease (MELD) score, 531–532 etiology, 157–163
Modern fluid therapy, 208 prevention of
MODS. See Multiple organ dysfunction syndrome intraoperative strategies for, 124–134
Monitoring, central, in pregnancy-induced hypertension, 463 in noncardiac surgery, 143–153
Monomorphic sustained ventricular tachycardia, 198, 199f nonoperative strategies for, 124–128
Monte Carlo analysis, 643 operative strategies for, 128–134
Morbidity. See also Injury(ies) perioperative strategies for, 123–124
obese, pulmonary management in, 513–514, 514f Myocardial protection, 122–142
perioperative, and outcomes, 2–8 controversies in, 123
Mortality rate(s), postoperative, neurocognitive decline and, 4 historical perspective on, 123
Motor evoked potentials, intraoperative monitoring of, 344–346 hypothermia in, 125–126
Motor examination, 356 noncardioplegia strategies, 130
MPTP. See Mitochondrial permeability transition pore transfusion strategy for, 127–128
MRI. See Magnetic resonance imaging Myoglobin
MRSA. See Staphylococcus aureus, methicillin-resistant acute renal injury related to, 227
Multidimensional affect and pain survey (MAPS), 607 elevation, with surgery, 154–155, 155f
Multidisciplinary team model, 628 Myoglobinuria, 227
Multifocal atrial tachycardia (MAT), 196–197, 197f Myxedema coma, 596
Multiple organ dysfunction syndrome (MODS) clinical manifestations of, 596
incidence of, 16 common precipitants of, 596
pathogenesis of, 16 definitive management of, 596
Muscle relaxant(s)
anticonvulsants and, 296 N
in chronic renal failure, 265 N-acetylcysteine, 236
for intracranial surgery, 295–296 Nadir hematocrit, 216
Muscle strength, postoperative assessment of, 552 Narrow QRS complex tachycardia, 196
MVO2. See Myocardial oxygen consumption Nasogastric drainage, for postoperative ileus, 421
 Index 691

Nasogastric intubation, postoperative, for thoracic surgical patient, Neurosurgery (Continued)

516 infectious risks and, 560
Nasogastric tube (NGT), postoperative, for thoracic surgical patient, neurologic support, 552–555
516 nutrition in, 559–560
National Committee for Quality Assurance (NCQA), 651 postoperative imaging, 552–554
National Early Warning Score (NEWS), 568–569 respiratory support, 555–556
National Institute for Health and Care Excellence (NICE), 662 postoperative complications of, management of, 554–555
National Quality Forum (NQF), 647–648, 648t Neutrophil gelatinase-associated lipocalcin (NGAL), in renal injury,
Measure Applications Partnership (MAP), 647–648 226
National Quality Strategy (NQS), 645 Neutrophil-lymphocyte ratio (NLR), 10t
aims and priorities, 653t NHS. See British National Health Service
National Surgical Quality Improvement Program (NSQIP), 30, 40–41, Nicardipine, 557
40t, 278–279, 649 for hypertension, in acute CNS injury, 387
Nausea and vomiting, postoperative and intracranial pressure, 387t
established, treatment of, 420 and neurologic outcomes, in acute CNS injury, 386
evidence-rating scales for, 416b neuroprotective effects of, 387t
incidence of, 416 Nicotinamide adenine dinucleotide phosphate. See NADPH
management of, 416–418 Nifedipine
in neurosurgical patient, 560 for hypertension in pregnancy, 463
pharmacologic prophylaxis of, 417–418, 417b and intracranial pressure, 387t
pharmacologic treatment of, 417–418 neuroprotective effects of, 387t
prevention of Nimodipine, and neurologic outcomes, in acute CNS injury, 386
risk factors for, 416, 416b NIPPV. See Positive-pressure ventilation, noninvasive
strategy for, 418–420, 419f Nitric oxide (NO), 420, 567
NCQA. See National Committee on Quality Assurance Nitroglycerin, 557
Neostigmine therapy, for postoperative ileus, 422, 422t contraindications to, 166
Nephrotoxin(s) and intracranial pressure, 387t
acute tubular necrosis caused by, 257 and neurologic outcomes, in acute CNS injury, 387
and perioperative renal injury, 227 therapy with
Nesiritide, 498 intravenous, for cardiac surgical patient, 163
Neuraxial anesthesia, 350 for myocardial infarction in pregnancy, 466
central, spinal cord injury in, 347–350 in pregnancy, 466
Neuraxial devices, infectious risks of, 560 Nitroprusside, 557
Neuraxial techniques, 115–117, 116–117t and intracranial pressure, 387t
Neurocognitive dysfunction, pathophysiology, after surgery, 616 and neurologic outcomes, in acute CNS injury, 387
Neurodegenerative disease, palliative care for, 633 Nitrous oxide, fetal effects of, 476
Neurogenic shock, 390 N-methyl-d-aspartate (NMDA) receptor blockade, 477
spinal cord injury and, 336, 344, 351 NNE. See Northern New England Cardiovascular Disease Study Group
Neuroinflammation, 616–617 nNOS. See Nitric oxide synthase (NOS), neuronal
Neurokinin-1 antagonist therapy, for postoperative nausea and Noncardiac surgery
vomiting, 418 glycemic control for, 588
Neurolept analgesia, for cortical mapping, 297–298, 299–301t perioperative cardiac risk assessment in, 36–45
Neurological Outcome Scale for TBI (NOS-TBI), 356 in pregnancy, and preservation of fetal viability,
Neurologic disturbances, in chronic renal failure, 263 475–484
Neurologic examination Non-steroidal anti-inflammatory drugs (NSAIDs), 349,
focused postoperative, 552, 553b 513, 525
in spinal cord injury, 337–338, 338f aspirin, 238–239
Neurologic injury(ies). See also Central nervous system cyclo-oxygenase-2 inhibitors, 238–239
perioperative, and outcomes, 3–4, 4–5t nephrotoxicity, 67
postoperative, in cardiac surgical patient, 498–499 and perioperative renal injury, 227, 238–239
Neuromuscular blocking agents (NMBA), pulmonary inflammation, for postoperative ileus, 423
282–283 Nonsustained ventricular tachycardia (NSVT), 197–198, 198f
Neuronal necrosis, CPB-associated, and neurologic outcomes, 312 Nonthoracic surgery
Neuropathy(ies), in chronic renal failure, 263 evaluation paradigm for, 95–96t, 96, 96f
Neuroprotection preoperative pulmonary evaluation, 86–87
aortic cannulation strategy, 313–314 Norepinephrine
blood–brain barrier and, 312 for maternal hypotension during regional block, 467–468
in cardiac surgery, 311–334 renal failure and, 265
cardiopulmonary circuit modifications, 312–313 in septic shock, 570, 572
pharmacologic strategies, 325 for ventricular failure after cardiac surgery, 170, 170t
pharmacologic therapies, 315–316 Normocarbia, 481
strategies, 316–317, 317t Normothermia
Neurosurgery, 552–562. See also Intracranial surgery intraoperative, in valvular heart disease, 184
postoperative care for, 552, 553f perioperative, 450
cardiovascular support in, 556–557 Normovolemia, intraoperative, 103b, 104
fluid and electrolyte support in, 557–558 Novel oral anticoagulants (NOACs)
gastrointestinal and endocrine support, 559–560 therapy, 495
hematologic support in, 558–559 for venous thromboembolism, 431–432
692 Index

NovoSeven, 495 Ondansetron, for postoperative nausea and vomiting, 417

NPO. See Fasting OPCAB. See Coronary artery bypass grafting, off-pump
NQF. See National Quality Forum Open/semi-closed model, 631
NSAIDs (non-steroidal anti-inflammatory drugs), 349, 500, 513, 525 Operating room
nephrotoxicity, 67 bovine spongiform encephalopathy (BSE), 452
and perioperative renal injury, 227, 238–239 prion disease, iatrogenic cases of, 452–453
for postoperative ileus, 423 Opioid(s)
NSICU. See Intensive care unit, neurologic-neurosurgical in cardiac anesthesia, 125
N-terminal fragment of proBNP (NT-proBNP), 41 in chronic renal failure, 265
Numeric Rating Scale (NRS), 607 for pain, 609
Nutrition. See also Enteral nutrition, early postoperative; Total postoperative, and ileus, 420–421
parenteral nutrition postoperative, for thoracic surgical patient, 516
in chronic renal failure, 263 for sedation of neurosurgical patient during respiratory support, 556
postoperative, for neurosurgical patient, 559–560 Opioid antagonist therapy, for postoperative ileus, 422
for sepsis, 571–572 Optimization, of patient’s status
support, for trauma patient, 548–549 perioperative, economic analysis of, 638–644
preoperative, 29–31, 30f
O Oral carbohydrate drinks, preoperative administration, algorithm,
Obesity, 468–469 211, 212f
and aspiration, 412 Oral decontamination, 282
cardiovascular complications of, 590–591 Oral procedures, endocarditis prophylaxis for, 182
comorbidities in, 588 Organ dysfunction, in sepsis, 568
and deep venous thrombosis, 591 Organ injury. See Injury(ies)
definition of, 588 Organ/space surgical site infection, 444, 445b
epidemiology of, 468, 588 Organ transplantation, 530–542
extreme candidates for, 530
definition of, 588 donors, types of, 530–531
health consequences of, 588 organs for, 530
intraoperative considerations in, 591 Orthopedic surgery, 521–529
noninvasive ventilation, treatment with, 589–590 morbidity and mortality in, 521
in parturient, anesthetic management of, 468–469 spine surgery, unique issues after, 524–527
perioperative management of, recommendations for, 591 acute vision loss, 526
postoperative considerations in, 591 cardiopulmonary dysfunction, 524–527
in pregnant woman, risks associated with, 468 ileus and colonic pseudo-obstruction, 526
preoperative evaluation and management of, 588–589 infection, 526
prevalence of, 588 intraoperative blood loss, 526
and pulmonary complications, 90 superior mesenteric artery (SMA) syndrome, 527
and pulmonary embolism, 591 syndrome of inappropriate antidiuretic hormone, 526
and venous thromboembolism, 433 total joint arthroplasty, care after, 521–524
Obesity-hypoventilation syndrome (OHS), 589 fat embolism syndrome (FES), 523–524
Obstructive oliguria, 252, 254 intramedullary cement, complications relating to, 524
Obstructive sleep apnea (OSA)/hypopnea syndrome, 3 and venous thromboembolism, 433–434, 521–523
cardiovascular complications of, 590–591 OSA. See Obstructive sleep apnea/hypopnea syndrome
diagnosis of, 589 OSAHS. See Obstructive sleep apnea/hypopnea syndrome
management of, 592f Outcome(s), perioperative morbidity and, 2–8
with noninvasive ventilation, 589–590 Overt hypothyroidism, 595
obesity and, 588–589 Overweight
and perioperative complications, 88 definition of, 588
prevalence of, 588–589 prevalence of, 588
risk factor, 588–589 Oxygen. See also Reactive oxygen species (ROS)
risks and management strategies for, 513–514, 514f arterial partial pressure of, and cerebral blood flow, 375,
Oculocardiac reflex, 195 375–376f
Off-pump coronary artery bypass (OPCAB), 500 consumption. See also Myocardial oxygen consumption
Ogilvie syndrome. See Colonic pseudo-obstruction maximal (VO2max), in pneumonectomy candidate,
Oliguria 97
acute, treatment of, 251–258 in postoperative cognitive dysfunction, 618
causes of, 254b 100%, for pregnant patient, during nonobstetric surgery, 480–481
definition of, 251 supplementation
epidemiology of, 251 for aspiration, 581
evaluation of patient with, 252–256 postoperative, in obese patient, 591
intrarenal, 254, 254b in spinal cord injury, 335–336
postoperative, in cardiac surgical patient, 498 transport, 167–168, 168f
postrenal, 252, 254b Oxygenation in acute CNS injury, 375–378, 375–378f
prerenal, 251–252, 254b Oxygen extraction factor (OEF), 364
renal tubular injury, 252 Oxygen free radicals, formation of, supplemental oxygen and,
secondary to AKI, 257 480–481
secondary to obstruction, 257 Oxygen supplementation, 450
treatment of, 256–257 Oxytocin, 467
 Index 693

P Parathyroid hormone, action of, 602

PABD. See Preoperative autologous blood donation Paresis, 567
Pacemaker dependency, postoperative, in cardiac surgical patient, 495 Parsonnet score, 47–48
Packed red blood cells (PRBCs), 435 Passenger lymphocyte syndrome, 533
transfusion, 101–104, 102t, 103f, 103b, 127 Passive atelectasis, 577
PACs. See Premature atrial contractions Pathogen-associated molecular patterns (PAMPs), 566
PAI. See Plasminogen activator inhibitor autonomic changes, 10–12
Pain, 610. See also Headache features, 10
back (see Back pain) host factors, 12, 13f
cancer (see Cancer pain) neuroendocrine response, 12
cancer patient, syndromes in, 630t systemic processes, 10
and coagulation function, 19 Patient blood management (PBM), 435
and outcomes in perioperative setting, 607–612 Patient-controlled analgesia (PCA), 525, 578–579
assessment tools, growth of unidimensional, 607 Patient PASS, 670
biomarkers of risk, 609 Patient Protection and Affordable Care Act (ACA), 654
chronic, 608 Patient-reported outcome measures (PROMs), 662
clinical phenotyping, cluster analysis, 608–609 Patient-reported outcome performance measures (PRO-PMs), 646
genetic risks predictors, 609 Patient-reported outcomes (PROs), 646
multidimensional assessment, 607 Pattern recognition receptors (PRRs), 566
multidimensional assessment instruments, 608t Pay for performance, 638
optimization, 609–610 PC. See Platelet count
perioperative functional outcomes, 607–608 PCCs. See Prothrombin complex concentrate
personalized pain medicine, 608 PE. See Pulmonary embolism
psychiatric comorbidity assessment instruments, 608t Pediatrics, palliative care for, 634
recommendations to, 610t PEEP. See Positive end-expiratory pressure
risk predictive tools, 608 Pentobarbital therapy, for intracranial hypertension, 370
Pain Catastrophizing Scale (PCS), 607 Percutaneous coronary intervention (PCI), 43
Pain control. See also Analgesia Percutaneous endoscopic gastrostomy (PEG) tubes, 580–581
postoperative, and coagulation function, 20–21 Perfusion pressure, postoperative, in cardiac surgical patient, 490–491
for rib fractures, 549–550 Pericarditis, uremic, 261
Palliative care, 628–636 Perioperative fluid therapy
advance care planning, 628–629 central intravascular volume, 208
barriers to integration, 632t crystalloids versus colloids, 208
definition of, 628 within enhanced recovery pathway, 208, 209f
disease-specific, 632 and hemodynamic plan, 218–220, 219f
cancer, 632 physiological stressors, 208–209, 209f
domains of, 628 and postoperative IV fluid maintenance rate, 215–216
end-of-life care, 629 Perioperative interventions
and hospice, 628, 629t barriers to implementation of, 638
impact on outcomes, 629 benefits of, 638–639
multidisciplinary team model, 628 desirable clinical effects as, 642
for non-cancer patients, 632–633 doing the right thing, 640
chronic obstructive pulmonary disease, 633 increased utility as, 642
congestive heart failure, 632–633 measures for, 638
end-stage renal disease (ESRD), 633 monetary, 638
human immunodeficiency virus, 633 and quality and duration of life, 642
neurodegenerative disease and dementia, 633 costs of, 638–642
for pediatrics, 634 versus charges, 641
primary versus specialist, 628 data for, skewness in, 641
skill sets, 629t direct, 640
SPIKES and REMAP, 629t estimation, techniques for, 641
for surgical patient, 629–632 future, discounted to present values, 641
symptom management, 629 indirect, 640
symptoms encountered in patients, 630t intangible, 641
Pancreas, transplantation of, 534–535 economic analysis of, 638–644
donor, 534 agency problem and, 639
exocrine anastomotic leak in, 535 challenges in, 639–640
postoperative management, 534–535 goal of, 639
recipient, 534 methodological problems in, 639–640
Pancreaticoduodenectomy, 511 point of view in, 639
Pancreatitis, 535 implementation of, versus acceptance of, 640
Pancuronium, contraindications to, 264 as investments, 638–639
PaO2. See Oxygen, arterial partial pressure of marginal costs of, learning curve and, 641–642
PAR-1. See Proteinase-activated receptor-1 (PAR-1) Perioperative ischemic evaluation (POISE) trial, 2–3
Parachlorometaxylenol (PCMX) and prevention of surgical site Perioperative neurocognitive disorders, 613
infections, 448 Perioperative pulmonary complications (PPCs), 3
Paraplegia, after thoracic or thoracoabdominal aortic aneurysm Perioperative quality improvement programme (PQIP), 659–660
repair, 341–347 Peripheral neuropathy, in chronic renal failure, 263
694 Index

Peripheral vascular disease, and risk of postoperative renal Pneumonia (Continued)

dysfunction, 71 ventilator-associated, prevention of, 549
Persisting hyperlactatemia, 570 Pneumothorax, definition, 85t
Personalized pain medicine, 608 POCD. See Postoperative cognitive dysfunction
Pexelizumab, effect on perioperative myocardial morbidity, 165 POD. See Postoperative delirium
PFA-100. See Platelet function analyzer Polygenic risk scoring, 609
PF4-heparin enzyme-linked immunosorbent assay (ELISA) test, 437 Polysomnography, 589
Pharmacodynamics, in chronic renal failure, 264–266, 264t Population management, 31–32, 32f
Pharmacokinetics, in chronic renal failure, 264–265 Positive end expiratory pressure (PEEP), 3, 489, 578, 640
Phenylephrine, 467 hemodynamic effects of, 169
for maternal hypotension during regional block, 467–468, 478 and intracranial pressure, 375–378, 377–378f
postoperative, in cardiac surgical patient, 491–492 Positive-pressure breathing (IPPB), 507
for ventricular failure after cardiac surgery, 170t Positive-pressure ventilation, postoperative, in cardiac surgical patient,
pH, myocardial, 126 491–492
Phosphate, homeostasis Post-conditioning, for myocardial protection, 134
abnormalities of, 601–602 Postoperative cognitive dysfunction (POCD), 63t, 614f
in chronic renal failure, 262–263 and Alzheimer’s disease, 620–621
Phosphodiesterase inhibitor(s). See also Amrinone; Milrinone anesthesia in, 613, 620–621
for perioperative right ventricular dysfunction, 176 pathophysiology and association, 60–61
Phosphorus in autoregulation, 618
distribution of, in body, 601 in cardiac surgery, 613–614
homeostasis, abnormalities of, 601–602 in cerebral blood flow, 618
Phrenic nerve injury, 540 definition, 59–60
Physical examination, findings in, associated with postoperative depression in, 619
pulmonary complications, 89–90 embolic load, 618
Placenta accreta, risk factors for, 470, 471f genetic factors in, 619–620
Placenta previa, and subsequent placenta accreta, 470, 471f incidence, 60, 614–615, 615f
Plain film radiography, of cervical spine injury, 337–338, 338f interventions, 61
Plan-Do-Study-Act (PDSA) cycle, 650 mean arterial pressure (MAP) management for, 618
PlA2 polymorphism, in postoperative cognitive dysfunction, 619–620 modifiable factors, 616t
Plasmin, 105 neuroinflammation in, 616–617
Plasminogen, 17, 105 with noncardiac surgery, 614–615, 615f
Plasminogen activator inhibitor (PAI), 17 nonmodifiable factors, 616t
Plateau waves, 383–385, 384–385f, 387–388 in oxygen delivery, 618
Platelet(s) partly modifiable factors, 616t
activation of, 107b pathophysiologic mechanisms, 613, 617f
dysfunction, 436–437 pathophysiology of, 616
GPIb receptors, 104 prevention and treatment, future interventions for, 622
GPIIb/IIIa receptors, 104 risk factors, 60, 60t
in hemostasis, 104–105 screening tools, 60, 61t
liver failure, 436 surgery for, 620–621
peripheral consumption, causes of, 107b systems-level mechanisms for, 621–622
phospholipids, 104, 104f Postoperative delirium. See Delirium, postoperative
production, impaired, causes of, 107b Postoperative nausea and vomiting (PONV), 515–516, 560
redistribution, causes of, 107b Postoperative pulmonary complications (PPC), 277, 577
Platelet count. See also Thrombocytopenia Centers for Disease Control (CDC) classification, 277
indications for, 105 definition of, 278b, 278t
low, causes of, 107–108, 107b, 108f health-care costs, 278
in pregnancy-induced hypertension, 462 incidence of, 576
preoperative testing of, 107 longer-term outcomes, 278–279
for thrombocytopenia, 464 pathophysiology, 279–281
upper and lower limits, 115–117 perioperative, 280–281
Platelet function analyzer, 18, 108 prediction of, 279
Platelet function testing, indications for, 105 prevention, 281–285
Platelet transfusion, indications for, 107 treatment, 285
Pleural effusion, postoperative, definition, 85t Post-Operative Pulmonary Complications After Use of Muscle
PMNs. See Polymorphonuclear leukocytes Relaxants in Europe (POPULAR) study, 3
Pneumatic compression (IPC) devices, 582 Postoperative respiratory failure (PRF), pulmonary factors, 87
for prevention of venous thromboembolism, 429 Potassium balance
Pneumonia, 277, 280, 572 abnormalities of, 598–600
in lung transplant recipient, 538 in chronic renal failure, 262, 262t
postoperative P4P. See Pay for performance
epidemiology, 83 PPCs (postoperative pulmonary complications). See Pulmonary
risk calculator, 95t, 96 complications, postoperative
risk categories for, 93–94, 94t Praxbind, 433
risk factors for, extrapulmonary, 89–90 Prazosin, for hypertension in pregnancy, 463
risk index for, 93–94, 93t Predicted postoperative (PPO) value, 506
risk factors for, operative, 90–91 Prednisone, 594
 Index 695

Preeclampsia, 461 Propofol, 500

anesthetic considerations in, 463 in cardiac anesthesia, 125
diagnostic criteria for, 462f renal failure and, 264–265
management of, 462–464 for sedation of neurosurgical patient during respiratory support, 556
maternal mortality with, 461–462 therapy with
Pregnancy for intracranial hypertension, 369
anticoagulation in, 184 for postoperative nausea and vomiting, 418
and aspiration, 412 Propofol infusion syndrome (PRIS), 369
gastric emptying in, 480 Propranolol
heart disease in, 464–466 effect on postoperative ileus, 422t
infant mortality rates in, 459, 460f neuroprotective effects of, 387t
maternal death in, causes of, 460f, 464 sympatholytic effects of, 387t
anesthetic, 459, 460f therapy with, in thyroid storm, 596
in developed and developing regions of world, 460f Prostaglandin(s) (PG), 240
direct, 459 and postoperative ileus, 422
indirect, 459 Protease(s), of extrinsic coagulation system, and inflammatory
thromboembolic, 460–461 signaling pathways, 21
maternal morbidity, causes of, 459 Proteinase-activated receptor-1 (PAR-1), and inflammatory signaling
maternal mortality rates in, 459, 460f pathways, 21
noncardiac surgery in, and preservation of fetal viability, 475–484 Protein C, 17–18, 104
nonobstetric surgery in deficiency of, and venous thromboembolism, 428
aspiration during, 480 recombinant human activated (see Drotrecogin-alfa therapy)
fetal heart rate monitoring during, 479–480, 480f Protein S, 17
full stomach, 480 deficiency of, and venous thromboembolism, 428
and hyperventilation, 481–482, 481b Proteinuria, tubular
and miscarriage, 482 as marker of renal function, 223
100% oxygen for, 480–481 in renal injury, 223, 234
patient position on fetal/maternal outcomes, 476t Prothrombin complex concentrate (PCC), 438, 495
and preterm labor, risk of, 482 Prothrombin time (PT), 18, 104, 104f, 108–110, 109f
thrombophilia and, 460–461 indications for, 105
and venous thromboembolism, 428, 433 Proton pump inhibitors (PPIs), 412–413
Pregnancy-induced hypertension, 461–464, 462f P-selectin, 620
anesthetic considerations in, 463 Pseudothrombocytopenia
management of, 462–464 causes of, 107, 107b
maternal mortality with, 461–462 perioperative management of, 107, 108f
risk factors for, 461 PSVT. See Supraventricular tachycardia, paroxysmal
Prehabilitation, value-based care, UK perspective, 664–665 PT. See Prothrombin time
Preload, in postoperative low cardiac output state, management of, PTCP. See Pseudothrombocytopenia
169–170 PTT. See Partial thromboplastin time
Premature atrial contractions, 194–195 PTU. See Propylthiouracil
Premature ventricular contractions (PVCs), 197, 198f Pulmonary angiography, of pulmonary embolism, 430
postoperative, 166 Pulmonary artery catheterization (PAC), 488
in cardiac surgical patient, 496 for cardiac surgical patient, 163
Premedication, in valvular heart disease, 184 hemodynamic measurements using, 168
Preoperative anemia, 216 intraoperative, in valvular heart disease, 186
Preoperative assessment. See also Cardiac risk assessment intraoperative use of, 124–125
appropriateness of care, 27–29 limitations of, 168
appropriate testing, 33 in pregnancy-induced hypertension, 463
cardiac (see also Cardiac risk assessment) in pregnant woman with pulmonary hypertension, 466–467
discharge planning, 33–34 in trauma patient, 545
documentation and transmission, downstream providers, 33 Pulmonary artery pressure, preoperative, 92–93
elements, 26–27, 27t Pulmonary aspiration, 280
high-quality shared decision-making, 27–29, 28f Pulmonary capillary occlusion pressure (PCOP), 491
patient and family education, 33–34 Pulmonary capillary wedge pressure, in postoperative low cardiac
for pneumonectomy candidate, 97–98, 98f output state, 168–169
population management and, 31–32, 32f Pulmonary complications, 390. See also Acute lung injury; Acute
protocols and pathways, 27 respiratory distress syndrome
pulmonary, 91–93 lung resection and, 97–98, 98f
regulatory issues, 32–33 postoperative, 277
risk assessment and optimization, 29–31, 30f Centers for Disease Control classification, 277
value, 26 definition, 83, 85t, 278b, 278t
Preoperative autologous blood donation (PABD), 103, 103b epidemiology, 83
Preoperative fluid management, 210–211 etiology, 83–86, 86–87f
Primary palliative care, 628 health-care costs, 278
Primary pulmonary hypertension, 538 incidence of, 83
PRIMO-CABG trial, 165 longer-term outcomes, 278–279
Procalcitonin, 566b nonthoracic surgery, preoperative pulmonary evaluation, 86–87
Prokinetic agents, for postoperative ileus, 422 pathophysiology, 83–86, 86–87f, 279–281
696 Index

Pulmonary complications (Continued) Pulmonic regurgitation, perioperative

perioperative, 280–281 hemodynamic principles for, 187t
physical findings associated with, 89, 89t Pulmonic stenosis, perioperative management of, hemodynamic
prediction of, 279 principles for, 185t
prevention, 281–285 Pulse pressure variation (PPV), 393
treatment, 285 Pupillary assessment, in acute CNS injury, 356–357
risk factors for, 83, 84t Purpura. See Idiopathic thrombocytopenic purpura; Thrombotic
extrapulmonary factors, 89–90 thrombocytopenic purpura
postoperative pneumonia risk calculator, 95t, 96 PVR. See Pulmonary vascular resistance
preoperative testing, 91–93 PVRP. See Physician Voluntary Reporting Program
pulmonary factors, 87–88 Pyruvate, 567–568
STOP-Bang score, 88, 89t
surgical factors, 90–91, 90t Q
surgical lung injury prediction model, 95–96t, 96 QALYs. See Quality-adjusted life-years
risk prediction scores, 93–95, 93–94t QS/QT. See Shunt fraction (venous admixture)
type of surgery and, 16 Quality-adjusted life-years, 638–639, 642–643
Pulmonary disease. See Chronic obstructive pulmonary disease Quality Payment Program (QPP), 654–656, 655f
(COPD); Restrictive lung disease Quick sequential organ failure assessment score (qSOFA), 569b
Pulmonary edema
definition, 85t R
in pregnancy RCRI. See Revised Cardiac Risk Index
causes of, 464 RDI. See Respiratory disturbance index
incidence of, 464 Reactive oxygen species (ROS), 132
prevention of, 464 Recanalization, in hemostasis, 105
with subarachnoid hemorrhage, 298, 304 Recombinant activated factor VII (rFVIIa), 495
Pulmonary embolism (PE), 581–582 Recombinant angiotensin II, for septic shock, 572
clinical manifestations of, 581 Recombinant human erythropoietin, 239
diagnosis of, 429–430, 581–582 Red blood cell transfusion, 101–104, 102t, 103f, 103b, 127
management of, 427–434 REE. See Resting energy expenditure
medications in prophylaxis and treatment of, 430–431t Reentry, arrhythmias of, 203
obesity and, 591 Reflex(es), postoperative assessment of, 552
in orthopedic surgery, 521 Regional anesthesia
pathophysiology, 428 for carotid endarterectomy, 292
in pregnancy, 466–467 for major abdominal surgery, 513
prevention of, 428–429 obstetric, 459, 467, 477
prophylaxis, 582 maternal hypotension in, 467–468
in trauma patient, 548 renal failure and, 265–266
treatment for, 582 Regulatory agencies, 32–33
Pulmonary Embolism Rule-out Criteria (PERC), 429 Rehabilitation, 572
Pulmonary function assessment Remifentanil, 500
preoperative, in thoracic surgical patient, 505–506 renal failure and, 265
exercise capacity, 505 for sedation of neurosurgical patient during respiratory support, 556
predicted postoperative values, 506 Renal artery stenosis
pulmonary function tests, 505 during cardiopulmonary bypass, 233, 239
in pneumonectomy candidate, 97 and risk of postoperative renal dysfunction, 70
Pulmonary function testing, 86, 505 Renal atheroemboli, 252
assessment of, 505 Renal blood flow
preoperative, 91–93 during cardiopulmonary bypass, 233, 235
in pneumonectomy candidate, 97 distribution of, 67
Pulmonary hypertension, 428, 432 reduction
detection, preoperative, 92–93 pathophysiology of, 67
dialysis and, 261 patient characteristics and, 70
obesity and, 590–591 Renal disease/dysfunction
in pregnancy, 466–467 cardiovascular mortality, 260–261
maternal mortality due to, 464 chronic, 259–261
Pulmonary inflammation, 280, 282 postoperative, 5
Pulmonary injury, perioperative, and outcomes, 3 perioperative, risk assessment for, 67–82
Pulmonary management postoperative
after bariatric surgery, 513–514 with cardiopulmonary bypass, 71–72, 71t
in morbidly obese, 513–514, 514f genetic predisposition to, 73
Pulmonary risk assessment, 83–100 patient characteristics and, 68–71
for pneumonectomy candidate, 97–98, 98f post–cardiopulmonary bypass, 72–73
Pulmonary thromboendarterectomy, 582 predicted probabilities of, preoperative risk factors and, 76–77,
Pulmonary vascular resistance 78t
in heart transplant recipient, 537 risk assessment for, 67–82
intraoperative, in valvular heart disease, 184 risk factors for, 67, 68b
perioperative, 175–176 with vascular surgery, 73–75, 74t
Pulmonary vascular resistance (PVR), 467 staging, 259, 260t
 Index 697

Renal failure Renal toxicity. See also Nephrotoxin(s)

acute preoperative patient variables and, 70–71
oliguria in, 257 Renal vein thrombosis, 252
perioperative, outcomes with, 259 Repetitive monomorphic ventricular tachycardia, 197–198, 198f
postoperative, 5–6 Resistive index, 532–533
risk factors for, 76 Respiratory failure
and bleeding, 436 acute
chronic, 259–261 definition of, 576
anesthetic techniques used, 264–266 in perioperative patient, 576–583
clinical abnormalities in, 260, 260t postoperative
fluid and electrolyte disturbances in, 261–263 causes of, 576
gastrointestinal abnormalities in, 263 factors, 577
hematologic abnormalities in, 263 definition, 85t
immunologic dysfunction in, 264 hypercapnic, 576
metabolic abnormalities in, 263 causes of, 576
neurologic disturbances in, 263 mechanisms, 576
nutritional abnormalities in, 263 hypoxemic, 576
pathophysiology of, 261–264 causes of, 576
pharmacology in, 264–266, 264t postoperative, risk categories for, 93–94, 94t
postoperative, 5–6 principles of management, 583
hypertonic saline therapy and, 368–369 risk factors for
for hypomagnesemia, 600 operative, 90–91
intraoperative considerations in, 266–267 pulmonary, 87
intraoperative monitoring in, 266 type II, causes of, 577b
perioperative management of, 259 Respiratory Failure Risk Index, 93–94, 93t
postoperative Respiratory infection, and pulmonary complications, 87–88
prediction, risk scoring algorithms for, 76–78, 76b, 77f, 77–78t Respiratory support, postoperative, in neurosurgical patient, 555–556
risk assessment for, 67–82 Respiratory tract procedures, endocarditis prophylaxis for, 182
risk factors for, 21 Resuscitation, 543–545. See also Goal-directed volume resuscitation
and risk of postoperative renal dysfunction, 70t assessment of, 544
type of surgery and, 16 balanced, 543
Renal function early goal-directed therapy, in sepsis, 569–570
perioperative, risk stratification for, 223 endpoints of, 544–545
preservation of (see Renal preservation) fluid for, selection of, 543–544
Renal function test(s), 74t, 75–76, 75b postoperative, for neurosurgical patient, 557
Renal impairment, and venous thromboembolism, in spinal cord injury, 336
433 Resuscitative endovascular balloon occlusion of the aorta (REBOA),
Renal injury(ies) 546, 546f
acute, postoperative, 5–6 Revised Cardiac Risk Index (RCRI), 39f, 40, 40–41t
acute, surgery-related, 226 Rheological effect, 366
embolic, 227 Rhythm control, arrhythmia, prevention of, 508
inflammatory, 226–227 RI. See Resistive index
ischemia-reperfusion and, 226 Rib fractures, pain control for, 549–550
mechanisms of, 226–227 Richmond Agitation and Sedation Scale (RASS), 369
nephrotoxins in, 227 Right bundle branch block, 200, 200f
pigments and, 227 Right heart failure, obesity and, 591
perioperative, and outcomes, 5–6, 5f Right ventricular assist device, for ventricular failure after cardiac
renal preservation strategies for, 228–241 surgery, 172–174, 175t
Renal insufficiency. See Renal failure Right ventricular dysfunction, perioperative
Renal medulla, hypoxia, 222–223, 223f diagnosis of, 175–176
Renal oxygen delivery, modifiers of, 233–234 etiology of, 175
Renal oxygen demand, modifiers of, 234 management of, 176
Renal perfusion RIRR. See ROS-induced ROS release
anesthesia and, 67–68, 226, 233 Risk Adjustment for Congenital Heart Surgery (RACHS-1), 51–52
and oliguria, 251–252 Risk assessment. See also Cardiac risk assessment
reduced, patient characteristics and, 70 hematologic, 101–120
surgery and, 67–68 perioperative, 37–40, 39–40t
Renal physiology, 222–224 for pneumonectomy candidate, 97–98, 98f
Renal preservation, 228–241, 259 preoperative, 29–31, 30f
postoperative management and, 236–241 pulmonary, 83–100
preoperative management and, 228–230 renal, 67–82
procedure planning for, 228 algorithm for, 69f
Renal replacement therapy (RRT), 498. See also Hemodialysis Risk prediction score(s)
Renal reserve, reduced pulmonary complications, 93–95, 93–94t
patient characteristics and, 69–70 renal, 76–78, 76b, 77f, 77–78t
and risk of postoperative renal dysfunction, 69–70, 70t Rivaroxaban (Xarelto), 430–431t, 438
Renal risk, perioperative, 228 RNS. See Reactive nitrogen species
Renal risk scoring algorithms, perioperative, 76–78, 76b, 77f, 77–78t Rocuronium, in chronic renal failure, 265
698 Index

ROS. See Reactive oxygen species Serotonin-release assay (SRA), 437

RVAD. See Right ventricular assist device Severe hypoxemic respiratory failure, 277
Sevoflurane
S renal failure and, 265
Saline and renal function, 68
hypertonic Shared decision-making, 27–29, 28f
adverse effects and side effects of, 368 Shared (collaborative) decision making (SDM), 662
dosage and administration of, for hyponatremia, 597 Shock. See Septic shock
infusion, 369 Shuttle walk test, 505
for intracranial hypertension, 367f, 368–369 SIADH. See Syndrome of inappropriate antidiuretic hormone secretion
and renal failure, 368–369 Sinus bradycardia, 199, 200f
in resuscitation, 543–544, 554 Sinus tachycardia, 196, 196f
resuscitation with, for hypercalcemia, 603 Sirolimus, for organ transplant recipient, 531
SCD. See Sequential compression devices SIRS. See Systemic inflammatory response syndrome
SCN9A mutations, in pain, 609 6-minute walk test (6MWT), 505
Scoliosis, 525 Six Sigma, 650–651
Scopolamine, for postoperative nausea and vomiting, 418 Sleep apnea. See also Obstructive sleep apnea/hypopnea syndrome
Second-degree Mobitz type I atrioventricular block (Wenckebach), and perioperative complications, 88, 283
200–201, 201f Sleep-related breathing disorders, 88
Second-degree Mobitz type II atrioventricular block, 200–201, 202f Smoking
Sedation, for neurosurgical patient, 556 and perioperative complications, 88
Segmental spinal artery preservation, 326 and pulmonary complications, 281–282
Seizure(s) Smoking cessation, 3
central nervous system risk assessment, 61–62, 63t optimal timing, postoperative, in thoracic surgical patient, 506
postoperative, in neurosurgical patient, 557–558 therapy, 281–282
SELDI-TOF-MS. See Surface-enhanced laser desorption/ionization Society of Neuroscience in Anesthesiology and Critical Care, 62–63
time-of-flight mass spectrometry Society of Thoracic Surgery (STS), 49–51, 50t
Selective cerebral perfusion, 323–324 Sodium
Sengstaken–Blakemore tube tamponade, 471 dosage and administration of, for hyponatremia, 597
Sensitivity analysis, 643 fractional excretion of, in functional oliguria versus AKI, 255
Sensory examination, 356 homeostasis
Sepsis abnormalities of, 597–598 (see also Hypernatremia;
antibiotics and infection control, 569 Hyponatremia)
circulatory support, 569–570 in chronic renal failure, 261–262
clinical features, 568–572 urinary, in functional oliguria versus AKI, 255
and corticosteroids, 595 Sodium bicarbonate
definition of, 564 for hyperkalemia, 600
epidemiology, 564–566 for prevention of contrast-induced nephropathy,
future directions, 572–573 232
history of, 564 Sodium nitroprusside (SNP), for hypertension in pregnancy, 463
laboratory features, 569 Solid organ transplantation (SOT), 540. See also Organ transplantation
management of, 565f, 569 heart transplantation
and multiple organ dysfunction syndrome, 16 cardiac allograft rejection, 537
nutrition, 571–572 donor, 536
organ support and therapeutic strategies, 571–572 hyperacute rejection, 537–538
pathophysiology, 566–568 postoperative management for, 536–538
cardiovascular function, 567 recipient, 536
hormonal and metabolic changes, 567–568 rejection of, 537
immunoactivation and paresis, 567 intestinal transplantation, 535
inflammation, 566–567 donor, 535
organ dysfunction, 568 postoperative management for, 535
renal support, 570–571 recipient, 535
and renal toxicity, 70–71 kidney transplantation of
respiratory support, 570 complications of, 533
severe, 564 delayed graft function after, 534
Septic complications, postoperative, in cardiac surgical patient, 499 donor, 533
Septic shock, 17–18 postoperative management, 533–534
cardiovascular function in, 567 recipient, 533
definition of, 564 liver transplantation, 531–533
future directions, 572–573 donor, 532
incidence of, 566 infection after, 540
laboratory features, 569 postoperative management, 532–533
management of, 565f, 569 recipient, 531–532
vasoactive agents in, 235 rejection in, 540
vasopressors in, 570b lung transplantation, 538–540
Sequential compression devices (SCDs), 429, 582 donor, 538
in prevention of venous thromboembolism, 548 infection after, 540
Sequential organ failure assessment (SOFA), 10t postoperative management of, 539–540
 Index 699

Solid organ transplantation (SOT) (Continued) Spinal cord injury (Continued)

recipient, 538 secondary injury after, prevention of, 335–336
pancreas transplantation, 534–535 treatment of, advances in (future directions for),
donor, 534 338–341
exocrine anastomotic leak in, 535 Spinal cord ischemia, 341–343, 343t
postoperative management, 534–535 detection and treatment of, 349f
recipient, 534 incidence of, 342
Somatosensory evoked potential (SSEP) monitoring, 292–293 partial left heart bypass for, 343
in cerebral aneurysm clipping, 303 Spinal cord perfusion pressure, 344
intraoperative of, 344–346, 347f, 348t Spinal shock, 351, 390, 391t
Specialist palliative care, 628 Spinal surgery
Speech mapping spinal cord injury in, 350–351
anesthesia for, 297–298, 299–301t unique issues after
intraoperative electrophysiologic and anatomic components of, 297 acute vision loss, 526
need for, determination of, 297 cardiopulmonary dysfunction, 525–526
Spinal anesthesia, 468 ileus and colonic pseudo-obstruction, 526
Spinal cord infection, 526
function intraoperative blood loss, 526
intraoperative assessment of, 342–343, 343t superior mesenteric artery syndrome, 527
postoperative assessment of, 552 syndrome of inappropriate antidiuretic hormone, 526
preservation of, 335–354 Sputum retention, 280
infarction, in aortic aneurysm repair, 341–347 SSEPs. See Somatosensory evoked potentials
ischemia, 325–326 SSIs. See Surgical site infection(s)
after aortic aneurysm repair, hypotension and, 344, Stagnara Wakeup test, 350–351
345–346f Stair climbing test, 505
in aortic aneurysm repair, 341–347 S. aureus, 444–445, 447
detection of, 347, 349f State-Trait Anxiety Inventory, 607
spinal tolerance, 326–327 Statins
time, 326 perioperative therapy with, 146
lesions, airway assessment and management with, 556 recommendations for, 146
perfusion pressure, 326 in valvular heart disease, 184
protection of, 321 Stent grafts, aortic, 75
Spinal cord injury Sterile inflammation, 9–10
acute, perioperative management of adults with Sterilization method, of surgical instruments, for prevention of surgical
anesthetic management and considerations, 391–393 site infections, 451
airway evaluation, 391 Steroids, 616–617
airway management, 391–392, 392f inflammatory response, perioperative modulation of, 14
hemodynamic management, 392–393, 394t and renal preservation, 238
induction of anesthesia, 391 supplementation of, perioperative, 594–595
monitors, 391–393 Stockings, elastic compression, 429
cardiovascular complications, 390 Stress response. See also Inflammatory response
endovascular therapy in AIS, anesthesia for, 393–395 and coagulation function, 19
blood pressure goals, 395 Stress testing, 42
fluid and glucose management, 395 Stress ulcer prophylaxis, in trauma patient, 548
oxygenation and ventilation, 395 Stroke
planning, 394–395 carotid disease and, 290
type, 395, 395t hyperthermia after, 382
miscellaneous, 390–391 incidence of, 290
pulmonary complications, 390 perioperative, 3–4, 5t, 19, 193
spinal shock, 390, 391t risk factors for, 291, 291b
anesthetic considerations in, 351–352 postoperative, in neurosurgical patient, 555–556
Canadian C-Spine Rule for Radiography (CCSRR), prior stroke, 62–63, 63t
337, 337f risk factors for, 62, 63t
in central neuraxial anesthesia and analgesia, 347–350, 349f Stroke volume variation (SVV), 393
immobilization in, 336 STS. See Society of Thoracic Surgery
National Emergency X-Radiography Utilization Study (NEXUS), STS-Congenital Heart Surgery Database (STS-CHSD), 52
337, 337t STS–European Association for Cardio-Thoracic Surgery
neurologic assessment in, 338, 339f (EACTS), 52
pharmacologic therapy in, 338–341 STS predicted risk of mortality and morbidity (STS-PROMM), 51
primary mechanisms of, 335 Subarachnoid hemorrhage (SAH), 386, 387f, 388–389
radiographic evaluation of, 337, 338f and blood pressure management, 388
secondary mechanisms of, 335 cardiopulmonary effects of, 298–302
in spinal surgery, 350–351 complications of, 303
surgery for, 341 epidemiology of, 298
systemic problems caused by, 351–352 neurologic effects of, 298
traumatic, 335–341 neurologic status after, grading scales for, 298, 302t
case-fatality rate for, 335 preoperative management of, 298–302
incidence of, 335 Subcutaneous unfractionated heparin (UFH), 349–350
700 Index

Succinylcholine, 372–373 Surgical site infection(s) (Continued)

in chronic renal failure, 265 procedure-related factors, 447
for craniotomy, 295–296 smoking cessation, 446
Sufentanil prevention of, 445–452
pharmacology of, in obesity, 591 prion disease and operating room, 452–453
renal failure and, 265 risk factors for, 445, 446t
Superficial incisional surgical site infection, 444, 445b Surgical site infections (SSIs), 511
Superior mesenteric artery (SMA) syndrome, spine surgery, unique for comorbidities, 664
issues after, 527 postoperative, for thoracic surgical patient, 517
Superoxide dismutase, 132 Surgical stress
Supraventricular tachycardia with aberrant conduction, 198 classification of, 594, 595b
Surface-enhanced laser desorption/ionization time-of-right mass and steroid supplementation, 594
spectrometry (SELDI-TOF-MS), 76 Surgical wound classification, 444, 517t
Surgery Symmetry aortic connector system, 234
duration of, and risk of pulmonary complications, 91 Sympatholytic therapy, in acute CNS injury, 386
and renal perfusion, 67–68 Syndrome of inappropriate antidiuretic hormone secretion
site of, and coagulation function, 19 in postoperative neurosurgical patient, 557–558
Surgical buy-in, 631 spine surgery, unique issues after, 526
Surgical lung injury prediction model, 95–96t, 96 Systemic hypertension, 537
Surgical Quality Alliance (SQA), 652, 653b Systemic inflammatory response, 16
Surgical site infection(s) aging, 12
classification of, 444, 445b chronic kidney disease, 12–13
costs of, 444 definition, 9–10, 10–11t, 11f
criteria for, 445b diabetes mellitus, 13
distribution of pathogens, 446t pathogen-associated molecular patterns, 10–12, 13f
incidence of, 444 perioperative modulation, 13–14
incisional Systemic inflammatory response syndrome (SIRS) criteria, 10t, 564
deep, 444, 445b
superficial, 444, 445b T
intraoperative setting, 447–452 Tachyarrhythmias, types, 196–199
antibiotic sutures, 450 Tacrolimus, for organ transplant recipient, 531
antimicrobial prophylaxis, 449 Targeted temperature management (TTM), 381
asepsis and surgical technique, 447–449 Tbathmin, 382
cleaning environmental surfaces, 451 TBI. See Traumatic brain injury
facility-related factors, 451–452 TCD. See Transcranial Doppler ultrasound
flash sterilization, 452 TCP. See Thrombocytopenia
gowns and drapes, 449 Teachable moment (TM), 665
hair removal, 447–448 TEG. See Thromboelastography
microbiologic sampling, 451 Temperature. See also Hyperthermia; Hypothermia
MRSA prophylaxis, 449–451 in acute CNS injury, 379–382
perioperative glycemic control, 450–451 monitoring and rewarming, 381
perioperative normothermia, 450 targeted temperature, 381
perioperative supplemental oxygen, 450 timing and duration of, 381–382
procedure-related factors, 447–449 in cardiac surgery, 125–126
skin preparation, 448 cardioplegia and, 126, 129
sterilization of surgical instruments, 451 and neuroprotection, 312
surgical attire, 448–449 hyperthermia, 315
surgical hand scrub, 448 hypothermia, 315
traffic control, 451 intraoperative, and coagulation function, 20
ventilation, 451 management, during cardiac surgery, 618–619
wound closure, 450 and neurologic outcomes, in cardiac surgery, 312
wound protectors, 450 in rewarming after cardiopulmonary bypass, and neurologic
microbiology, 444 outcomes, 325
mortality, 444 Temporary vessel occlusion, 304
organ/space, 444, 445b Terlipressin, for septic shock, 572
pathogenesis of, 444 TFESIs. See Transforaminal epidural steroid injections
pathogens in, sources of, 444–445 Therapeutic hypothermia (TH), 380–381
postoperative and post discharge setting, 452 complications associated with, 381–382
postoperative antibiotics, 452 Thiopental, 556
showering, 452 therapy with, for intracranial hypertension, 370
surveillance, 452 Third-degree complete atrioventricular block, 200–201, 202f
preoperative setting, 445–447 Thirst sensation, 598
bowel preparations, 447 Thoracic aortic disease, neurologic injury, 320–327
diabetes status and control, 445 Thoracic endovascular aortic repair (TEVAR), 327, 343–344
malnutrition, 446–447 Thoracic surgery
MRSA screening and decolonization, 447 arrhythmia, prevention of, 507–508
patient-related factors, 445–447 enhanced recovery after surgery (ERAS), 508
preoperative bathing and showering, 447 pulmonary complications, prevention of, 506–507
 Index 701

Thoracic surgery (Continued) Transcatheter aortic valve replacement (TAVR)

pulmonary function assessment, preoperative, 505–506 etiologies, 317–318
exercise capacity, 505 neurologic injury in, 317–320
predicted postoperative values, 506 Transcranial Doppler ultrasound, in intracranial hypertension, 358,
pulmonary function tests, 505 358f
Thoracoabdominal aortic aneurysms (TAAA), 341–347, Transcranial motor evoked potentials (TcMEPs), 348f, 350–351
342f Transesophageal echocardiography, 314
Thoracoabdominal aortic repair, 322, 322f, 323t in cardiac surgery monitoring, 148–149, 154
neuroprotective strategies, 325–327, 325t intraoperative postprocedural, 164
Thoratec blood pump, for ventricular failure after cardiac surgery, intraoperative, 124
172f, 174, 175t perioperative monitoring with, 154
Thrombin, and inflammatory signaling pathways, 21 in valvular heart disease, 181–182
Thrombocytopenia wall motion abnormalities detected by, 154
congenital, perioperative management of, 107, 108f Transfusion-related immuno-modulation (TRIM), 14
gestational, 107 Transfusion requirements in critical care (TRICC) trial, 101
heparin-induced, 437–438 Transfusion therapy
perioperative management of, 107, 108f autologous pre-donation of blood for, 103–104, 103b
immune, 107 (see also Idiopathic thrombocytopenic purpura) in cardiac surgical patient, 488, 488f
perioperative management of, 107, 108f history of, 435
pregnancy in women with, 464 intraoperative alternatives to, 103b, 104
Thromboelastography (TEG), 18, 544 intraoperative management of, 438–441
in hemodilution, 20 massive, 543
Thromboembolism. See also Venous thromboembolism postoperative, for neurosurgical patient, 559
in cerebral aneurysm embolization procedure, 306 requirements for, in critical care, 544
maternal, in pregnancy, 459–461 triggers for, 544
in pregnancy, risk factors for, 459–460, 461f Transient arrhythmias, 194–195
Thromboembolism-deterrent stockings (TEDS), 582 Transient ischemic attacks, risk factors for, 62
Thrombolysis, 432 Transjugular intrahepatic portosystemic shunt
Thrombophilia (TIPS), 530
epidemiology of, 460–461 Trauma
in pregnancy, 460–461 damage control in, 545–546, 545f
Thrombophlebitis, 559 initial assessment of patient in, 544
Thrombosis, immobilization and, 19 multisystem, 543–551
Thrombotic thrombocytopenic purpura, 436 and renal toxicity, 70–71
Thrombus/thrombi. See Venous thromboembolism spinal cord injury in, 335–341
Thyroid disease, and anesthesia, 595–597 and venous thromboembolism, 433
Thyroid hormone(s) Traumatic brain injury (TBI)
and cardiac surgery, 596–597 and decompressive craniectomy, 371
intravenous administration of, in myxedema coma, 596 hyperventilation in, 365
Thyroid storm, 596 target PACO2 recommendations in, 365–366
Thyrotoxicosis, 596 Trauma care, 651
Tirofiban, 437 Trauma coagulopathy, 20
Tissue factor, 16–17 Trauma exsanguination protocol, 543
in hemostasis, 104, 104f Trendelenburg position, in valvular heart disease, 184
and inflammatory signaling pathways, 21 Tricuspid regurgitation, perioperative
and thrombogenesis, 19 hemodynamic principles for, 187t
Tissue factor pathway inhibitor (TFPI), 16–17 management of, 188
Tissue plasminogen activator (t-PA), 17, 105, 436 Tricuspid stenosis, perioperative management of, 188
Tissue trauma, 616–617 hemodynamic principles for, 185t
Toll-like receptors (TLRs), 9–10 Tricuspid valve disease, perioperative management of,
Top-down method, 641 188
Torsades de pointes (TDP), 191–192, 195f Trigger criteria, 631–632
Total body water, 598 Trimethaphan
Total hip arthroplasty, 521–522 neuroprotective effects of, 387t
Total intravenous anesthesia, renal failure and, 265 sympatholytic effects of, 387t
Total joint arthroplasty, care after, 521–524 Troponin I
fat embolism syndrome (FES), 523–524 elevation, with surgery, 154, 155f
intramedullary cement, complications relating to, in perioperative myocardial ischemia/infarction,
524 156–157, 160f
venous thromboembolic disease, 521–523 Troponin T
Total knee arthroplasty, 522 elevation, with surgery, 154, 155f
Total knee replacement (TKR), 659 in perioperative myocardial ischemia/infarction, 156–157, 160f
Total parental nutrition (TPN), 530 Trousseau’s sign, 602
TPA. See Tissue plasminogen activator TTP. See Thrombotic thrombocytopenic purpura
Tracheobronchitis, definition, 85t Two-person nasotracheal technique, 336
Tranexamic acid (TXA), 438–439, 543 Two-person orotracheal technique, 336
for intraoperative blood loss, 526 Type 2 diabetes mellitus (T2DM), 13
intraoperative use of, and renal outcome, 234 Type II respiratory failure, causes of, 577b
702 Index

U Valvular heart disease (Continued)

UK’s National Health Service (NHS), 659 perioperative management of, 181–190
Ultrasound. See also Focused abdominal sonography for trauma; hemodynamic principles for, 185t
Transcranial Doppler ultrasound nonpharmacologic, 184
carotid, 324 physiologic principles of, 184
Doppler premedication, 184
in cardiac surgical patients, intraoperative postprocedural preoperative assessment of, 181–182
monitoring with, 164 preoperative preparation in, 182–184
of deep venous thrombosis, 429 regurgitant, perioperative management of, 184
uterine, in preeclampsia, 461 stenotic, perioperative management of, 184–185, 185t
epiaortic, 314 Vancomycin, prevention of surgical site disinfection, 449–450
Ultrasound assisted catheter directed thrombolysis (USAT), for venous Vaptans, 598
thromboembolism, 432 Variant Creutzfeldt-Jakob disease (vCJD), 435, 452
Unfractionated heparin (UFH), 521–522 Vascular access, 263
for venous thromboembolism, 429–430, 430–431t Vascular Events in Noncardiac Surgery Patients Cohort Evaluation
UPA. See Urokinase plasminogen activator (VISION) trial, 2
Upper esophageal sphincter (UES), 411 Vascular surgery, renal dysfunction after, 73–75, 74t
Upper respiratory infection, and pulmonary complications, 87–88 Vasoconstriction, in hemostasis, 104
Urea, fractional excretion of, in functional oliguria versus AKI, 255 Vasodilators
Uremia and neurologic outcomes, in acute CNS injury, 386–387
definition of, 260–261 for postoperative neurosurgical patient, 557
pathophysiology of, 261 and renal outcomes in, post–cardiopulmonary bypass, 73
Uremic bleeding, 263, 265–266 Vasoplegic syndrome, after cardiopulmonary bypass, 169
Uremic encephalopathy, 263 Vasopressin
Urinary proteomics, 76 effect on postoperative ileus, 422t
Urine inflammatory response, 10–12
osmolality, 255 in septic shock, 572
sodium level, in functional oliguria versus AKI, 255 for ventricular failure after cardiac surgery, 170t
Urine output. See also Oliguria Vasopressor selection
as marker of renal function, 224, 224t pregnancy in women with, 467–468
Urokinase plasminogen activator, 17, 105 in septic shock, 570b
Uterine blood flow VATS. See Video-assisted thoracoscopic surgery
in preeclampsia, 467 vCJD. See Creutzfeldt-Jakob disease, variant
in pregnancy, 478 VD. See Dead space ventilation
Utility value(s), of health states, 642 VD/VT. See Dead space to tidal volume ratio
VE. See Minute ventilation
V Vecuronium
VA. See Veterans Affairs in chronic renal failure, 264
Value-based care pharmacology of, in obesity, 591
in health-care quality measurement, 656–657 Venoarterial extracorporeal life support (VA ECLS), 493–494
cost measurement, challenges in, 656 Venoarterial extracorporeal membrane oxygenation (VA-ECMO),
excessive burden with lack of valid, 656 171–172, 174f, 175t
interoperable meaningful data, lack of, 656–657, Venous foot pumps (VFP), 582
656f Venous thromboembolic disease (VTED), 521–523
payers, defined by, 656 deep venous thrombosis, 521
legislation to, 654 recommendations for prophylaxis against, 522–523
UK perspective, 659–667 total hip arthroplasty, 521–522
comorbidity, 663–664 total knee arthroplasty, 522
cost and value of surgery, 659–662 Venous thromboembolism (VTE) prophylaxis, 521, 581.
health-care spending over time, 661f See also Thromboembolism
intraoperative care, 665 acquired risk factors for, 428
life expectancy over time, 660f cancer, 433
postoperative care and recovery, 665 complications of treatment, 432–433
prehabilitation and behavioral change, 664–665 critically ill patients, 434
preoperative optimization, 662–665, 663f incidence of, 581
rising demand and resource constraint, 659 and liver impairment/coagulopathy, 433
shared decision making, 662 and obesity, 433
Value-stream mapping, 650 and orthopedic, 433–434
Valvular heart disease. See also specific valve pathophysiology, 428
anesthesia in, 184–185 perioperative, 19
anticoagulation, 183–184 pregnancy, 433
antimicrobial prophylaxis in, 182, 183t, 183b prevention, 428–429, 548
chronic medications, 184 prophylaxis, 582
intraoperative management of, 184–186 and renal impairment, 433
monitoring options, 185–186 risk factors, 548, 581, 581b
physiologic principles, 184 special considerations, 433–434
pathophysiology of, and perioperative management, in trauma patient, 433, 548
184 treatment of, 430–432, 430–431t, 432f
 Index 703

Ventilation Vitamin C, antioxidant effects, 132

in acute CNS injury, 378 Vitamin D
during intracranial surgery, management of, 295 action of, 602
in pregnant patient, management of, 481 supplementation, for sepsis, 572
for prevention of surgical site disinfection, 451 Vitamin E, antioxidant effects, 132
pulmonary inflammation, 282 Vitamin K, 435–436, 438
Ventilation–perfusion (VQ) scans, 506 deficiency, 109, 109f, 436
Ventilatory support Volume expansion, intraoperative, and renal outcomes, 237
pulmonary inflammation, 283, 284t von Willebrand’s disease, 436–437
in respiratory failure, 285 in hemostasis, 104
Ventricular arrhythmias, 195, 203–204 tests of, 108f
postoperative, in cardiac surgical patient, 496 V/Q mismatch. See Ventilation-perfusion mismatch
Ventricular assist devices, 53, 54t, 166, 530 V/Q scan. See Ventilation-perfusion lung scan
after acute myocardial infarction, 124 VT. See Tidal ventilation
axial flow devices, 174, 175t VTE. See Venous thromboembolism
postoperative use of, in cardiac surgical patient, 491–492
for ventricular failure after cardiac surgery, 172–174, 172–174f, W
175t Wada test, 297
Ventricular dysfunction Wakeup test, 350–351
perioperative, in cardiac surgical patient, 165–176 Warfarin, 437, 495
postoperative, risk factors for, 165 Warfarin therapy
Ventricular failure, perioperative, in cardiac surgical patient, 165–176 anticoagulation therapy, 113
management algorithm for, 167f in valvular heart disease, 183
Ventricular fibrillation, 193, 199f for venous thromboembolism, 430–431t, 431
Ventricular paced rhythms, 198–199, 199f Water balance, in chronic renal failure, 261–262
Ventricular tachycardia (VT), 198, 199f, 202 Wells score, 429
catheter ablation, 203 Wheezing, and risk of postoperative pulmonary complications, 89, 89t
implantable cardioverter-defibrillators, 203 Wide association studies (GWAS), 609
neuromodulation therapies, 203–204 Wide QRS complex tachycardia, 197
Verbal rating scales (VRS), 607 Wolff-Parkinson-White syndrome, 199, 199f
Verification, Review, and Consultation Program (VRC), 651 World Federation of Neurological Surgeons (WFNS), grading scale for
Veterans Affairs National Surgical Quality Improvement Program subarachnoid hemorrhage, 298, 302t
(VA NSQIP), 445 Wound healing, diabetes and, 587
VHD. See Valvular heart disease Wound hematoma, 293
Viral infections, in organ transplant recipient, 540
Visual Analog Scale (VAS), 607 X
Vitamin B12, preoperative therapy with, 103b Xenotransplantation, 530