Ebook Surgical review an integrated basic and clinical science study: Part 1

(BQ) Part 1 book Surgical review an integrated basic and clinical science study presents the following contents: Body as a whole, abdomen and gastrointestinal tract, endocrine system and oncology.

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THE SURGICAL REVIEW

An Integrated Basic and Clinical Science

Study Guide

PAIGE M PORRETT, MD, PhD

Resident in Surgery Department of Surgery University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania

JOHN R FREDERICK, MD

ROBERT E ROSES, MD

LARRY R KAISER, MD

President The University of Texas Health Science Center at Houston

Alkek-Williams Distinguished Professor Department of Cardiothoracic and Vascular Surgery University of Texas Houston School of Medicine

Houston, Texas

T H I R D E D I T I O N

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in any form by any means, including photocopying, or utilized by any information storage andretrieval system without written permission from the copyright owner, except for brief quotationsembodied in critical articles and reviews Materials appearing in this book prepared by individuals

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Printed in China

Library of Congress Cataloging-in-Publication Data

The surgical review : an integrated basic and clinical science study guide — 3rd ed / edited by Paige M Porrett [et al.]

1 Surgery—Examinations, questions, etc I Porrett, Paige M

[DNLM: 1 General Surgery 2 Surgical Procedures, Operative—methods WO 100 S9628 2010]RD37.2.S9749 2010

617.0076—dc22

2009019056Care has been taken to confirm the accuracy of the information presented and to describe generallyaccepted practices However, the authors, editors, and publisher are not responsible for errors oromissions or for any consequences from application of the information in this book and make nowarranty, expressed or implied, with respect to the currency, completeness, or accuracy of thecontents of the publication Application of the information in a particular situation remains theprofessional responsibility of the practitioner

The authors, editors, and publisher have exerted every effort to ensure that drug selection anddosage set forth in this text are in accordance with current recommendations and practice at thetime of publication However, in view of ongoing research, changes in government regulations, andthe constant flow of information relating to drug therapy and drug reactions, the reader is urged tocheck the package insert for each drug for any change in indications and dosage and for addedwarnings and precautions This is particularly important when the recommended agent is a new orinfrequently employed drug

Some drugs and medical devices presented in the publication have Food and Drug Administration(FDA) clearance for limited use in restricted research settings It is the responsibility of the healthcare provider to ascertain the FDA status of each drug or device planned for use in their clinicalpractice

To purchase additional copies of this book, call our customer service department at (800) 638-3030

or fax orders to (301) 223-2320 International customers should call (301) 223-2300

Visit Lippincott Williams & Wilkins on the Internet: at LWW.com Lippincott Williams & Wilkinscustomer service representatives are available from 8:30 am to 6 pm, EST

10 9 8 7 6 5 4 3 2 1

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C O N T E N T S

17 Thyroid, Parathyroid, and Adrenal

Glands 233Giorgos C Karakousis, Rachel Rapaport Kelz, and Douglas

L Fraker

18 The Breast 252

Robert E Roses and Brian J Czerniecki

SECTION IV: Cardiovascular and Respiratory

Systems

19 Cardiovascular Disease and Cardiac

Surgery 265Pavan Atluri and Y Joseph Woo

20 Vascular Disease and Vascular Surgery 289

J Raymond Fitzpatrick III and Ronald M Fairman

21 Pulmonary Physiology and Thoracic

Disease 301John R Frederick and Larry R Kaiser

SECTION V: Trauma

22 Trauma Evaluation, Resuscitation, and Surgical

Critical Care 319Ronald F Parsons and Benjamin M Braslow

23 Management of Specific Traumatic

Injuries 334Matthew T Santore and John P Pryor

24 Burn Management 352

David H Stitelman and Patrick K Kim

SECTION VI: Surgical Subspecialties

Benjamin J Herdrich and Kenneth W Liechty

2 Hemostasis and Coagulation 11

Major Kenneth Lee IV and Jeffrey P Carpenter

3 Surgical Infectious Disease 20

Bradley G Leshnower and Babak Sarani

4 Nutrition, Digestion, and Absorption 31

April E Nedeau and John L Rombeau

5 Immunology and Transplantation 47

Hooman Noorchashm, Heidi Yeh, and Ali Naji

6 Statistics and Epidemiology 60

E Carter Paulson and Seema S Sonnad

7 Anesthesia 71

Meghan Lane-Fall and C William Hanson III

SECTION II: Abdomen and Gastrointestinal

Andrew S Newman and Jon B Morris

11 The Small Bowel 121

Jin Hee Ra and Steven E Raper

12 The Colon, Rectum, and Anus 136

Robert T Lewis and Robert D Fry

13 The Hepatobiliary System 159

Paige M Porrett and Kim M Olthoff

14 The Pancreas 176

Joshua Fosnot and Ernest F Rosato

SECTION III: Endocrine System and Oncology

15 Tumor Biology 197

Paul J Foley and Jeffrey A Drebin

16 Melanoma, Sarcoma, Lymphoma, and the

Spleen 216Dale Han, Robert J Canter, and Francis R Spitz

iii

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P R E FAC E

n order to provide our readers with the most rary, concise, yet comprehensive review of surgery, we havemade substantial changes to both the content and format

contempo-of this, the third edition contempo-of The Surgical Review In particular, the

inclusion of key points at the beginning of each chapter will help

surgical residents focus their study time during preparation for the

American Board of Surgery In-Service Training Exam (ABSITE)

For our more advanced readers, a more streamlined text and an

augmentation of figures and tables within the text body will

facili-tate rapid but detailed review of material frequently encountered

during board certification In summary, we are confident that this

edition of The Surgical Review will successfully meet the educational

needs of surgeons at varied levels of training

Two groups of individuals deserve our sincere thanks First, we

thank Lippincott Williams & Wilkins, particularly Brian Brown and

Ryan Shaw, for their patience, editorial expertise, and continued

support of this endeavor Second, we wish to thank our colleaguesand teachers who contributed their extensive knowledge and expe-rience to this book

Finally, we would like to specially acknowledge the tion of Dr John P Pryor to this work Dr Pryor was a gifted educa-tor, physician, and surgeon whose dedication to service was aninspiration to all During the preparation of this edition, he wastragically killed while part of a Forward Surgical Team in Iraq Weare deeply honored to have the opportunity to include one of hislast lessons in this edition, and his participation in future editions

contribu-of The Surgical Review will be sorely missed.

Paige M Porrett, MD, PhD John R Frederick, MD Robert E Roses, MD Larry R Kaiser, MD

v I

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C O N T R I B U TO R S

Ibrahim Abdullah

Resident in Cardiothoracic Surgery,

Division of Cardiac Surgery, Department of Surgery,

Brigham and Women’s Hospital, Harvard Medical School,

Boston, Massachusetts

Pavan Atluri, MD

Resident in Cardiothoracic Surgery,

Division of Cardiovascular Surgery,

Resident in Urology, Division of Urology, Department of Surgery,

University of Pennsylvania School of Medicine,

Professor and Chief, Department of Surgery,

UMDNJ-Robert Wood Johnson Medical School,

Chief of Surgery, Cooper Health System,

Camden, New Jersey

Ara A Chalian, MD, FACS

Associate Professor,

Department of Otorhinolaryngology-Head and Neck Surgery,

Philadelphia, Pennsylvania

Sri Kiran Chennupati, MD

Resident in Otorhinolaryngology,

Department of Otorhinolaryngology-Head and Neck Surgery,

University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania

J Raymond Fitzpatrick III, MD

Resident in Surgery,Department of Surgery,University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania

Paul J Foley, MD

Joshua Fosnot, MD

Douglas L Fraker

Jonathan E Rhoads Associate Professor of Surgical Science,Chief, Division of Endocrine and Oncologic Surgery,Department of Surgery,

John R Frederick, MD

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viii Contributors

Robert D Fry, MD

Emilie & Roland deHellebranth Professor of Surgery,

Chair, Department of Surgery, Pennsylvania Hospital,

Chief, Division of Colon and Rectal Surgery, Department of Surgery,

Philadelphia, Pennnsylvania

Dale Han, MD

Resident in Surgery, Department of Surgery,

C William Hanson, III, MD

Professor of Anesthesia, Surgery and Internal Medicine,

Departments of Anesthesia, Surgery, and Medicine,

Section Chief, Critical Care, Department of Anesthesia,

The University of Texas Health Science Center at Houston,

Alkek-Williams Distinguished Professor,

Department of Cardiothoracic and Vascular Surgery,

University of Texas Houston School of Medicine,

Houston, Texas

Giorgos C Karakousis

Fellow in Surgical Oncology, Department of Surgery,

Memorial Sloan-Kettering Cancer Center,

New York, New York

Rachel Rapaport Kelz

Assistant Professor, Division of Endocrine and Oncologic Surgery,

Department of Surgery,

Patrick K Kim, MD

Assistant Professor of Surgery,

Division of Trauma and Surgical Critical Care,

Resident in Anesthesia, Department of Anesthesia,

Major Kenneth Lee

Bradley C Lega, MD

Resident in Neurosurgery, Department of Neurosurgery,University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania

Bradley G Leshnower, MD

Robert T Lewis, MD

Demetri J Merianos, MD

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Andrew S Resnick, MD, MBA

Assistant Professor, Division of Gastrointestinal Surgery,Department of Surgery,

John L Rombeau, MD

Professor of Surgery, Department of Surgery,Temple University School of Medicine,Philadelphia, Pennsylvania

Matthew R Sanborn, MD

Resident in Neurosurgery, Department of Neurosurgery,University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania

Matthew T Santore, MD

C William Schwab, II, MD

Assistant Professor, Division of Urology, Department of Surgery,University of Pennsylvania School of Medicine,

Contributors ix

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Francis R Spitz, MD

Professor of Surgery, Department of Surgery,

Cooper Hospital University Medical Center,

Camden, New Jersey

Resident in Neurosurgery, Department of Neurosurgery,

x Contributors

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S E C T I O N

Body as a Whole

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• The phases of wound healing include the inflammatory,

proliferative, and remodeling phases

• Platelets are the first responders to a wound, causing

hemostasis and secreting cytokines

• The macrophage is the main cell of the inflammatory phase

• The proliferative phase is composed of granulation tissue

for-mation, neovascularization, fibroplasias, re-epithelialization,and ECM production

• Collagen is secreted as procollagen, which is cleaved and

self-assembled into fibrils and fibers

• Controlling bacterial contamination, maintaining the

proper amount of moisture in the wound, treating edema,

and preventing further injury are the mainstays of localwound care

• Hypoxia and vitamin C deficiency decrease hydroxylation

of proline and lysine residues on collagen molecules,causing destabilization and decreased tensile strength

• Vitamin A administration can attenuate the detrimentaleffect that steroids have on wound healing by stimulatingfibroblast proliferation and collagen synthesis

• Keloids and hypertrophic scars are both examples of anexuberant fibrotic response Keloids, unlike hypertrophicscars, extend beyond the boundaries of the original injury,continue to grow over time, do not regress spontaneously,commonly recur after excision, and are present for mini-mum of 1 year

• Chronic wounds can lead to the development of mous cell carcinoma, which is known as a Marjolin ulcer

squa-INTRODUCTION

The body is well equipped to repair itself following injury The

nor-mal postnatal response to dernor-mal injury is a well-coordinated

process involving many different cell types that progress through

an inflammatory phase, a proliferative phase, and finally a

remodel-ing phase, ultimately resultremodel-ing in rapid wound closure However,

this rapid wound closure is associated with a scar, which is

biome-chanically inferior to the unwounded skin Wound healing

impair-ment is often seen in chronic conditions, such as diabetes mellitus,

peripheral vascular disease (PVD), chronic venous occlusive

dis-ease, immunosuppression, and paralysis These conditions lead to

either a defect in the wound repair mechanism or repeated wound

injury and clinically manifest as nonhealing chronic wounds On

the other end of the spectrum, hypertrophic scars and keloid

for-mation are examples of an exuberant fibrotic response that leads to

excessive scarring and potentially debilitating contractures The

majority of wounds can be treated with basic local wound care,

restoration of perfusion, and maximization of nutrition However,

despite good wound care, a subset of impaired wounds will still fail

to heal It is for these patients that experimental techniques, such as

cellular therapy, aim to restore the wound healing process and

reestablish the skin’s integrity

CATEGORIES OF WOUND HEALING

Wound healing can be divided into three basic categories: primary

intention, secondary intention, and tertiary intention (Fig 1.1)

Healing by primary intention is achieved when wound edges are

reapproximated within hours of initial injury Examples of healing

by primary intention are surgical wounds that are closed at the end of

an operation or lacerations that are sutured closed in the emergencyroom For primary intention to be successful, a wound should be rel-atively clean and recent Wounds that are contaminated or have beenopen for a prolonged period of time should not be closed primarily.Healing by secondary intention occurs when a wound is left openand allowed to close by granulation tissue formation, wound con-tracture, and re-epithelialization This type of healing is epitomized

by an abscess that is drained surgically and treated with daily moistgauze packing until closed Contaminated or infected wounds areoften opened and allowed to heal by secondary intention Infectioncan impair wound healing While an open wound is technicallycontaminated, the body can deal with low levels of contamination aslong as the microbial burden is minimized through drainage ofpurulent material and debridement of necrotic tissue A clean woundwill develop beefy red granulation tissue at the base, progressivelycontract, and re-epithelialize leading to closure The final category ofwound healing is tertiary intention, which is also known as delayedprimary closure Tertiary intention occurs when a wound is left openfor a period of time and treated by local wound care and frequentdressing changes Then, when it appears clean and absent of infec-tion, the wound is closed surgically Lower extremity fasciotomy pro-vides an excellent example of a clinical situation where delayedprimary closure is used Fasciotomy wounds are usually not closedinitially and are treated with dressing changes Then, when the limbswelling recedes, the fasciotomy site is sterilely prepped and suturedclosed This can accelerate healing and reduce scar formation whenperformed in a minimally contaminated wound

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PHASES OF WOUND HEALING

Normal wound healing progresses through three distinct phases

(Fig 1.2) The inflammatory phase begins early with platelet

aggre-gation and hemostasis It continues with the production of

cytokines and growth factors and the recruitment of inflammatory

cells, such as neutrophils, macrophages, and lymphocytes, to the

wound As the inflammation subsides, the proliferative phase, which

consists of granulation tissue formation, neovascularization,

fibroplasia, re-epithelialization, and extracellular matrix (ECM)

production, becomes prominent The major cell type in the

proliferative phase is the fibroblast The remodeling phase is

charac-terized by wound contraction and modification of the ECM,

in-cluding collagen cross-linking

Upon creation of a wound, circulating platelets, which are

de-rived from megakaryocytes in the bone marrow, are exposed to

subendothelial collagen and become activated von Willebrand

fac-tor (vWF), a large multimeric glycoprotein released by endothelial

cells and platelets, mediates initial platelet adherence by binding

both platelet cell surface receptors and subendothelial collagen

Platelets also possess other adhesion molecules such as glycoprotein

IIb/IIIa, which is responsible for binding fibrinogen and mediating

aggregation of platelets at the wound site It is the cross-linking of

platelets by fibrin that forms the platelet plug and causes hemostasis

initially Then, activation of the clotting cascade further stabilizes

the clot Another potent stimulator of platelet aggregation is boxane A2, which is inhibited by aspirin therapy

throm-Activated platelets at the site of a fresh wound also secrete logically active molecules that affect wound healing Platelets havetwo kinds of granules, known as alpha granules and dense granules,which are synthesized and packaged by the megakaryocyte Alphagranules contain growth factors, cytokines, ECM proteins, andclotting factors, such as platelet-derived growth factor (PDGF),transforming growth factor-␤ (TGF-␤), platelet factor-4, throm-

bio-bospondin, fibronectin, fibrinogen, and vWF Dense granules tain vasoactive substances, such as epinephrine, serotonin,adenosine diphosphate, calcium, and histamine Initially, release ofthe dense granules leads to vasoconstriction, which helps to controlhemorrhage Later, these granules promote vasodilation and in-crease capillary permeability, thus promoting the recruitment ofinflammatory cells to the wound Release of PDGF and TGF-␤

con-from alpha granules is an important first step in cell signalingwhich initiates the cellular response PDGF acts through a cell sur-face tyrosine kinase receptor on neutrophils, fibroblasts, smoothmuscle cells, and macrophages exerting chemotactic, activating,and mitogenic effects Similarly, TGF-␤ recruits neutrophils, T cells,

and fibroblasts, activates monocytes, and stimulates collagen duction by fibroblasts It also acts to decrease ECM degradation byinhibiting gene expression of proteases and promoting gene expres-sion of tissue inhibitors of metalloproteinases (TIMP) This results

pro-4 Section I • Body as a Whole

FIGURE 1.2 Phases of wound healing Wound

healing progresses through inflammatory,

pro-liferative, and remodeling phases Cells are

re-cruited to the wound and proliferate in an

organized sequence that results in hemostasis,

granulation tissue formation, ECM production,

neovascularization, re-epithelialization, wound

contraction, collagen production, and collagen

reorganization and cross-linking The end result

is scar formation and wound closure ECM,

ex-tracellular matrix

FIGURE 1.1 Categories of wound healing Wound healing

can progress through primary, secondary, or tertiary intention

The most important factor in determining whether to close a

wound is the level of contamination

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in an increase in collagen formation in the wound Given the

actions of TGF-␤, it is not surprising that it has been linked to

the development of pathologic fibrosis and hypertrophic scarring

Once hemostasis is achieved, vasodilation and increased

capil-lary permeability, mediated by histamine, serotonin, prostacyclin

(PGI2), nitric oxide (NO), and bradykinin, cause infiltration of

in-flammatory cells to the wound site Neutrophils are the most

im-portant inflammatory cells within the first 24 to 48 hours after

wound creation By 72 hours postwounding, macrophages become

the predominant inflammatory cell type in the wound Together,

neutrophils and macrophages are responsible for decontaminating

the wound of microbes and devitalized tissue and secreting

cytokines and growth factors that coordinate the cellular response

Neutrophils initially migrate to the site of injury driven by cytokine

gradients and cell surface receptor–mediated interactions with the

endothelium and ECM components Once in the wound,

neu-trophils are responsible for phagocytosis of microbes and debris

After 48 hours, the wound is relatively decontaminated and the

number of neutrophils in the wound declines If the wound is not

successfully decontaminated, chemotaxis of neutrophils to the

wound will continue, resulting in persistent inflammation and

de-layed healing Macrophages are also responsible for phagocytosis of

wound debris and microbes They also degrade ECM components,

secrete multiple cytokines and growth factors that drive

recruit-ment of additional cells to the wound, lead to the apoptosis of

neu-trophils, and stimulate fibroblast proliferation

Four to 7 days following injury, lymphocytes arrive at the

wound site in appreciable numbers They secrete cytokines that

have effects on other cells in the wound, including macrophages

and fibroblasts In this way, they likely play a role in mediating the

inflammatory response in chronic wounds While their exact role is

not completely delineated, immunosuppressive regimens that

tar-get T cells, such as corticosteroids, are known to have a negative

ef-fect on wound healing, suggesting that T cells are necessary for

normal wound healing On the other hand, there is research to

sug-gest that T cell suppression can promote regenerative healing, and

corticosteroids have been used to treat and prevent keloid

forma-tion Therefore, the actions of lymphocytes in wound healing are

very complex, and they can either help or hinder optimal wound

healing, depending on the situation

As the inflammatory phase is coming to a close, wound healing

shifts toward the proliferative phase and the processes of granulation

tissue formation, neovascularization, fibroplasias, re-epithelialization,

and ECM production The proliferative phase actually begins several

days after wound formation when the inflammatory phase is

dominant In response to cytokines produced by platelets and

macrophages, fibroblasts migrate to the wound, start to divide, and

begin to produce ECM proteins PDGF and TGF-␤ are two

impor-tant cytokines driving fibroblast chemotaxis and activation; however,

others, such as interleukin-1 (IL-1), interleukin-6 (IL-6), epidermal

growth factor (EGF), fibroblast growth factor (FGF), insulinlike

growth factor-I (IGF-I), and transforming growth factor-␣ (TGF-␣)

all play a role either in a paracrine or an autocrine fashion

Simultaneously, neovascularization is initiated, which can be

divided into the separate processes of angiogenesis and

vasculogen-esis Angiogenesis results in the formation of new blood vessels

from existing blood vessels, while vasculogenesis is the de novo

formation of new blood vessels from bone marrow–derived

progenitor cells known as endothelial progenitor cells (EPC) In

re-sponse to a number of cytokines and growth factors, including

PDGF, FGF, EGF, IGF-I, and vascular endothelial growth factor(VEGF), angiogenesis proceeds as endothelial cells in the woundrelease matrix metalloproteinases (MMP) and other proteases,resulting in degradation of the surrounding ECM and allowingendothelial cells the opportunity to migrate and form immatureblood vessels that later mature into functional capillaries Vasculo-genesis first requires the homing of EPC to the site of the wound.Stromal-derived factor-1␣ (SDF-1␣) and other chemokines con-

trol the recruitment of EPC to the wound EPC are multipotent andhave the ability to differentiate into the various cell types that com-bine to form blood vessels Once in the wound, EPC secrete cy-tokines and growth factors affecting other cells in a paracrinefashion EPC differentiation is likely mediated by many of the samecytokines that control angiogenesis; however, the exact mechanism

is not known This early neovascularization and ECM productionresults in the formation of granulation tissue Importantly, granu-lation tissue can be identified clinically as a clean, beefy red woundbase This is a sign that the inflammatory phase is giving way to theproliferative phase, and wound healing is progressing

The epithelium is an important part of the body’s barrier fense system, and wounding creates a defect in this defense Theprocess of re-epithelialization is initiated very early in the woundhealing process Clot provides a temporary barrier between thewound bed and the outside environment while keratinocytes migrateacross the epithelial gap and proliferate in response to cytokines andinteractions with the ECM The granulation tissue provides a tissuescaffold for the migrating keratinocytes to follow; however, re-epithelialization can occur without significant granulation tissueformation Keratinocyte differentiation follows the migrating edgeuntil the wound is covered with a layer of normal epithelium Gener-ally, a larger wound will take longer to re-epithelialize than a smallerwound Incisional wounds closed primarily will re-epithelializewithin 24 hours

de-While granulation tissue formation, neovascularization, andre-epithelialization are all important components of wound heal-ing, it is the production of collagen that gives the wound itsstrength As these other processes are occurring, fibroblasts arebeing activated and proliferated within the granulation tissue,which has an ECM composed mainly of fibrin, fibrinogen,fibronectin, and vitronectin at this stage in the wound healingprocess This early ECM is degraded at the same time as collagenproduction is occurring, so there is an increase in the woundstrength over time Once the collagen fibers are deposited, remodel-ing and cross-linking continue to improve the wound strength.Collagen is the most abundant structural protein in humanscomprising a major portion of skin, tendon, cartilage, bone, bloodvessels, and cornea There are many types of collagen, but the mostcommon in humans are types I, II, III, IV, and V (Table 1.1) Type I

Chapter 1 • Wound Healing 5

T A B L E 1 1

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collagen is the major type in adult skin with type III comprising a

smaller fraction of the total collagen Collagen is made primarily by

the fibroblast and composed of three polypeptide chains wound

to-gether to form a triple helix Hydroxylation of proline and lysine

amino acids by prolyl hydrolase and lysyl hydrolase leads to

inter-molecular hydrogen bonds, which give collagen its strength and

stability (Table 1.2) These hydroxylation reactions require vitamin

C and oxygen to proceed This explains one mechanism by which

vitamin C deficiency and hypoxia cause impaired wound healing A

triple helix collagen molecule is secreted as procollagen by the

fibroblast into the ECM where it is cleaved by proteases to form

tropocollagen Tropocollagen is cross-linked with other

tropocolla-gen molecules to form fibrils, and then fibrils assemble to form

fibers (Fig 1.3)

There are other components of the ECM that contribute to

wound healing, such as glycosaminoglycans and glycoproteins

Hyaluronic acid is a glycosaminoglycan important in water

reten-tion and cell migrareten-tion within the wound The thrombospondins

and fibronectin are glycoproteins that are found in dermal wounds

Glycoproteins have effects on cell signaling, cell migration, and

function to modulate the actions of biologically active proteins in

the wound The complex interactions between cells and ECM

com-ponents in the wound are not fully known but are currently an

active area of research

As the processes of fibroplasia, neovascularization,

re-epithelialization, and ECM production are occurring, the wound

will start to contract Myofibroblasts and fibroblasts are two of

the major cell types involved in the process of wound

contrac-tion Activated fibroblasts can differentiate into myofibroblasts,

which express ␣-smooth muscle actin and have similarities with

smooth muscle cells Wound contraction occurs as a result of

in-teractions between the cells and the ECM in and around the

wound It not only lessens the time to wound closure but also

reduces the final size of the scar

Once the wound has closed, the healing process continues with

remodeling of the scar to achieve maximum strength Wound

strength increases quickly over the first 6 to 8 weeks and then levels

off Then, the wound continues to slowly gain strength and can

change in appearance over the next year This is a result of the

reor-ganization of the collagen within the wound and an increase in

cross-linking Initially after the wound is closed, the collagen is

dis-organized MMP break down the disorganized collagen, and new

collagen is produced and oriented in line with the tensile forces

present The net amount of collagen in the wound stays roughly

even, but the turnover leads to greater organization, which

im-proves the biomechanical properties of the scar

As described, normal wound healing progresses through a

de-fined series of events that include an inflammatory phase, a

prolif-erative phase, and a remodeling phase When one of these phases is

prolonged or altered, wound healing can be either impaired or berant Both of these are pathologic conditions

exu-IMPAIRED WOUND HEALING

There are many different factors that can alter the course of normalwound healing and thus lead to wound healing impairment Dia-betes mellitus, ischemia, venous insufficiency, pressure ulcers,chronic infection, malnutrition, advanced age, and immunosup-pression are all conditions that can potentiate chronic wounds.Hypoxia, bacterial colonization, ischemia–reperfusion injury, al-tered cellular response to stress, and defects in collagen productionare primary mechanisms of the wound healing impairment present

to varying degrees in these conditions The aim of treatment is tocorrect these defects and thus restore the wound healing process tonormal

Diabetes mellitus is a chronic condition affecting almost

21 million Americans There were approximately 1.4 million newcases of diabetes in 2005, and the incidence has been rising since

1980 The impairment in wound healing seen with diabetes is tifactorial in nature Diabetic wounds have been shown to be defi-cient in growth factor production, including PDGF, KGF, TGF-␤,

mul-HGF, and VEGF These wounds also have a defect in the cellular sponse to growth factors, including decreased cell recruitment, an-giogenesis, re-epithelialization, ECM production, and woundcontracture Other factors contributing to the wound impairment

re-in diabetes are an altered re-inflammatory response, impaired cyte function, and greater susceptibility to soft tissue infection.Diabetes leads to both small and large vessel disease, causing is-chemia and hypoxia Tissue hypoxia in diabetes also preventsnormal reduction–oxidation (redox) reactions in wound healing.Oxygen is required not only for cellular function but also for thehydroxylation of collagen, which gives it the majority of its tensilestrength Large vessel ischemia can often be treated with endovas-cular or open revascularization procedures, but small vessel diseaseand tissue hypoxia still remain In addition to impairment of thewound healing processes, diabetic neuropathy increases the likeli-hood of repeated injury of old wounds Repeated injury not onlyincreases the wound size due to mechanical disruption, but it canalso cause ongoing inflammation and thus healing impairment.Since the diabetic wound healing impairment is multifactorial innature, the treatment of diabetic wounds requires therapies to cor-rect multiple defects in the wound healing process

leuko-Pressure ulcers are a major problem in patients with limited bility Paralysis, stroke, dementia, advanced age, and chronic illnessare just a few of the conditions that can lead to patients being con-fined to bed and thus at risk for pressure ulcer development Pro-longed pressure, usually over a bony prominence such as the sacrum

mo-or greater trochanter, causes tissue ischemia and therefmo-ore necrosisand skin breakdown While frequent repositioning of patients at leastevery 2 hours is helpful and is one of the mainstays of pressure ulcerprevention and treatment, it may result in ischemia–reperfusion in-jury, and the contribution of ischemia–reperfusion injury in thepathogenesis of pressure ulcer development is not known Once apressure ulcer has formed, relieving pressure on the wound with spe-cially designed mattresses and frequent repositioning is essential forhealing Surgical flap closure of pressure ulcers is often contraindi-cated because the same factors that lead to pressure ulcer develop-ment will prevent healing of a surgical flap Contained infection ornecrotic tissue in the wound should be treated aggressively with

6 Section I • Body as a Whole

Enzymes involved in collagen production.

Prolyl hydroxylase Hydroxylation of proline residues

Lysyl hydroxylase Hydroxylation of lysine residues

N- and C-terminal Cleavage of terminal propeptides

propeptidases

Lysine oxidase Linkage of lysine residues

T A B L E 1 2

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drainage or debridement Finally, it is important to maximize

nutri-tion to facilitate healing in patients who have developed pressure

ul-cers since these patients often are malnourished

Ischemic wounds are another type of chronic wound regularly

seen in practice Hyperlipidemia, hypertension, diabetes, smoking,

male sex, old age, and family history are all risk factors for PVD

When the partial pressure of oxygen in tissues drops below 30 mm

Hg, healing will be impaired Hypoxia impairs normal cellular

function and prevents the intermolecular cross-linking of collagen

molecules Ischemic wounds occur most commonly on the distal

portion of the lower extremities Evaluation of chronic wounds of

the lower extremities should include assessment of pulses,

ankle–brachial index, and segmental pressures to assess for thepresence and degree of PVD Smoking is especially harmful towound healing as it is not only a risk factor for PVD but alsocauses hypoxia through increased carbon monoxide levels in theblood and vasoconstriction Cessation of smoking is beneficial towound healing, but can be difficult to achieve due to the highlyaddictive nature of cigarettes In addition to smoking cessation,treatment of ischemic wounds should follow basic wound careprinciples of limiting bacterial contamination, preventing pro-longed pressure on the wound and avoiding repeated injury, aswell as making sure that the necrotic tissue in the wound isdebrided If a chronic wound will not heal in the face of adequate

100,000−200,000 Å

20,000 Å2,000 Å

FIGURE 1.3 A Type I collagen showing triple helix and intramolecular links B Intermolecular

cross-links provide tensile strength.C Assembly of collagen fibrils, fibers, and fiber bundles (From Fine NA, Mustoe TA.

Wound healing In: Greenfield LJ, Mulholland MW, Oldham KT, et al., eds Surgery: Scientific Principles and

Practice 3rd ed Philadelphia: Lippincott Williams & Wilkins; 2001, with permission.)

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wound care, revascularization may help to improve local tissue

oxygenation and allow for wound healing

Chronic venous disease can also lead to persistent nonhealing

wounds Venous hypertension can result from incompetent venous

valves in the lower extremities, chronic deep venous thrombosis, or

vascular trauma It causes extremity edema, vascular congestion,

and local tissue hypoxia Chronic lower extremity edema is

accom-panied by extravasation of fluid and protein, including fibrinogen,

into the ECM Increased ECM fluid and the formation of fibrin

sleeves around capillaries prevent the normal diffusion of oxygen

and nutrients between the ECM and the capillaries and disrupt the

normal mechanisms of wound healing Treatment of chronic

wounds in the face of venous disease requires compression therapy,

which aims to promote healing by limiting the edema Pressure

therapy in conjunction with aggressive local wound care is the

stan-dard treatment of these wounds

Chronic infection can be seen in many different clinical

situa-tions and can prevent normal healing irrespective of etiology In

normal wound healing, the inflammatory phase gives way to the

proliferative phase Bacterial contamination can trap a wound in

the inflammatory phase and prevent healing All open wounds

be-come colonized with bacteria; however, bacterial counts greater

than 105 bacteria/mm3 can stimulate the patient’s immune

re-sponse Increased inflammatory cell recruitment to the wound will

change the cytokine milieu, augment the release of proteases, and

affect the cellular response of other cells in the wound such as

fi-broblasts Wounds with uncontrolled infection require measures to

decrease the bacterial burden Sharp debridement of necrotic

tis-sue, drainage of purulence, antibiotics, and frequent dressing

changes can all help rid the wound of infection and promote

nor-mal healing when used appropriately

Protein–calorie malnutrition and other nutritional deficiencies

are important to assess and correct because they have a detrimental

effect on wound healing Protein–calorie malnutrition can cause

hypoalbuminemia, which can be responsible for wound healing

impairment In addition, specific vitamin or elemental deficiencies

can also lead to wound healing impairment Scurvy is the condition

caused by vitamin C deficiency Posttranslational hydroxylation of

proline and lysine residues, which gives collagen its tensile strength,

is dependent on vitamin C as a cosubstrate Vitamin C deficiency

leads to fragile vessels, bleeding mucous membranes, loss of teeth,

and nonhealing wounds Minerals such as copper and zinc are

im-portant in enzymatic reactions that take place during wound

heal-ing Essential fatty acids are required for synthesis of new cell;

therefore, a healing wound requires adequate supplies The

treat-ment of nutritional deficiencies attempts to replace the deficient

component This is ideally done through an enteral route, but total

parenteral nutrition may be employed if oral feeding is

contraindi-cated Nutritional supplementation above and beyond the required

amount, however, will not further improve wound healing in a

well-nourished patient

Immunosuppression for variable periods of time may be

em-ployed in the treatment of a number of chronic conditions, including

chronic obstructive pulmonary disease, rheumatologic disorders,

in-flammatory bowel disease, and prevention of rejection after

trans-plantation; however, it has negative effects on wound healing The

most commonly used immunosuppressive drugs are corticosteroids,

but chemotherapeutic agents used to attenuate rejection following

organ transplantation such as tacrolimus and rapamycin are also

used frequently Immunosuppressive drugs have a deleterious effect

on the inflammatory phase of wound healing Steroids interferewith prostaglandin synthesis, leukocyte migration, cytokine pro-duction, fibroblast proliferation, and collagen synthesis Vitamin Agiven orally in doses of 25,000 IU/day can attenuate the negativewound healing effects of steroids To improve wound healing insteroid-dependent patients, vitamin A should be given and thedose of steroid reduced to the lowest dose that still produces thedesired effect

Advanced age is another factor that prevents normal woundhealing Older patients are more likely to have comorbidities lead-ing to wound healing impairment, such as diabetes, malnutrition,

or PVD However, advanced age alone can impair the body’s sponse to stress Aged fibroblasts respond differently to oxidativestress and ischemia than fibroblasts from young adults Age has alsobeen shown to decrease collagen synthesis, growth factor produc-tion, angiogenesis, and re-epithelialization While currently there is

re-no treatment to reverse the wound healing impairment seen withadvanced age, good basic wound care is very important to maxi-mize the chance of healing

HYPERTROPHIC SCARS AND KELOIDS

Hypertrophic scarring and keloid formation result from an ant wound healing response leading to excessive ECM productionand disfiguring scar formation Hypertrophic scars remain withinthe boundary of the original injury, regress spontaneously, andrarely recur after surgical excision Keloids, unlike hypertrophicscars, extend beyond the boundaries of the original injury, continue

exuber-to grow over time, commonly recur after excision, and are presentfor a minimum of 1 year Both hypertrophic scars and keloids occurmore commonly in dark-skinned patients, and keloids have afamilial predisposition

The pathophysiology of keloid formation involves ongoinginflammation and excessive accumulation of ECM Keloids oftenhave a reddish border, which is an inflammatory zone with a highvessel density and many inflammatory cells There is also increasedproduction of multiple cytokines, including TGF-␤, IGF-1, PDGF,

interleukins, and EGF

The best treatment for keloids is prevention, that is, avoidance

of incisions in patients known to form keloids whenever possible.Multiple treatments have been tried including silicone sheeting,pressure therapy, radiotherapy, steroid injections, verapamil injec-tions, and 5-fluorouracil injections The absence of a single therapyspeaks to the difficulty of treating keloids

WOUND CARE

The majority of wounds can be treated by diligently utilizing basicwound care methods aimed at controlling bacterial contamination,maintaining the proper amount of moisture in the wound, treatingedema, and preventing further injury

Bacterial contamination can usually be controlled by ment of any necrotic or grossly infected tissue, drainage of puru-lence, and frequent dressing changes It keeps the wound in a state

debride-of inflammation and prevents progression into the later stages debride-ofwound healing Debridement effectively removes inflamed tissueand converts the wound from a chronic one to an acute one Allwounds produce fluid and exudates to some degree Frequent

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dressing changes help to control the wound exudate, which can act

as a culture medium for bacterial growth Classic wet-to-dry gauze

dressing changes also cause some mild debridement of dead tissue

when the packing is removed This type of dressing contrasts with

a wet-to-wet dressing, which promotes wound healing instead of

debridement Sometimes wounds produce a large amount of

fibri-nous exudate that collects on the wound surface This should be

debrided either mechanically or enzymatically, as it can act as a

biofilm harboring bacteria There are several commercially

avail-able products that enzymatically remove exudates that collect in

the wound bed Finally, there is also the option of using antibiotics

either topically or systemically to control infection If the wound is

associated with surrounding cellulitis, treatment with systemic

antibiotics should be instituted Antibiotics should be used

selec-tively, as inappropriate use can lead to resistant organisms and

complications such as pseudomembranous colitis

Controlling the level of moisture in the wound is important

not only to limit bacterial growth but also to promote healing and

prevent skin breakdown As stated earlier, all wounds produce

fluid and exudates to varying degrees, and we know that wound

moisture can be beneficial because dry wounds do not

re-epithe-lialize as well as wounds that have been covered with an occlusive

dressing If a wound has a clean base, a dressing that retains

mois-ture is the best choice to promote wound healing However, if a

wound has a large bacterial colonization or produces a large

amount of exudate, an absorptive dressing is needed to prevent

further excess moisture from leading to maceration of the skin at

the wound edges

Edema also can lead to chronic wounds, as it promotes tissue

hy-poxia and prevents diffusion of nutrients from the capillaries

There-fore, compression dressings that lessen edema can be helpful in

treating wounds where edema is a complicating factor Chronic

ve-nous stasis ulcers are the most common wounds where compression

therapy is beneficial Compression therapy should not be used in

those with severe PVD, as it can limit blood flow to the extremity and

have negative effects on wound healing in this setting Also,

compres-sive bandages need to be applied carefully because they themselves

can lead to pressure ulcers When used appropriately, compressive

therapy can be very helpful in the treatment of chronic wounds

Chronic wounds are usually very friable at the base and thus

susceptible to injury with only minor trauma Preventive measures

such as orthotic devices, special pressure off-loading mattresses,

frequent turning, and other manipulations may be required to

pre-vent pressure on the wound In addition, care needs to be taken

when transferring and ambulating a patient with a chronic wound

to avoid any additional trauma to the wound Chronic wounds are

slow to heal already, and any trauma will only enlarge the wound,

delaying and complicating the healing process

There are several relatively new wound care options that have

shown significant promise Growth factors play an important part

in wound healing from the very beginning of the process Treating

wounds with beneficial growth factors has been an area of intense

research Currently, PDGF (i.e., becaplermin topical gel

[Re-granex]) is the lone FDA-approved topical growth factor used in

the treatment of chronic wounds It is a homodimeric protein

pro-duced by recombinant DNA technology, which is applied once

daily to the wound While it has shown some efficacy, good basic

wound care is still required Topical growth factor therapy does

have some limitations There are many growth factors involved in

normal wound healing, which require the proper concentration livered to the right place with optimal timing of delivery Whiletopically delivered single growth factor therapy can replace defi-cient growth factors, it does not address the issues of timing, con-centration, or the complex milieu of biologically active molecules

de-in the wound healde-ing process Gene therapy is an active area of search aimed at delivering deficient growth factors to wounds Thehalf-life of topically applied growth factors is likely short, and genetherapy offers the opportunity to have constant production at thedesired site The safety of gene therapy has not been fully evaluatedand is still in experimental stages

re-Vacuum-assisted closure (VAC) is a negative pressure ing that has gained great popularity in the treatment of chronicwounds It has many potential benefits, including controlling ex-udates, promoting granulation tissue formation, improvingblood supply to the wound, maintaining moisture, lesseningedema, and protecting the wound from trauma VAC dressingsshould be used with caution on abdominal wounds with defects

dress-in the fascia, as bowel fistula formation is a theoretical tion Although randomized clinical trials demonstrating a bene-fit over basic wound care are lacking, VAC dressings have beenreported to be helpful in the treatment of chronic wounds of dif-ferent etiologies, especially when there is a need to controlwound secretions In recent years, VAC dressings have becomeincreasingly more popular in the treatment of difficult woundproblems

complica-Hyperbaric oxygen therapy is a strategy to combat the problem

of hypoxia in chronic wounds By increasing the atmospheric sure and delivering 100% inspired oxygen, the partial pressure ofoxygen in the wound can be increased This can promote angiogen-esis, fibroblast proliferation, leukocyte oxidative killing, and toxininhibition Clinically it has shown to be of benefit in the treatment

pres-of chronic wounds, especially those associated with diabetes Itdoes not replace traditional wound care, but rather is an adjunctivetherapy that may provide benefit in the treatment of impairedwounds

Another area of active research is cellular therapy Cellulartherapy research has focused on determining which cells to useand how to administer them Whole bone marrow, mesenchymalstromal cells (MSC), and EPC are all actively being researched.Bone marrow is a good source of multipotent adult progenitorcells (MAPC) MSC and EPC are both bone marrow–derivedMAPC MSC have the ability to differentiate into mesenchymalcell lines, and EPC can differentiate into the cellular components

of blood vessels Treatment of wounds with MAPC has the tial to augment wound healing via a variety of mechanisms, in-cluding production of cytokines and growth factors, recruitment

poten-of cells to the wound, differentiation into the cellular components

of skin and vessels, modulation of inflammation, and beneficialparacrine effects on other cells in the wound In addition, cellshave the ability to dynamically respond to the wound environ-ment and effect healing Potential delivery techniques includelocal injection, use of a matrix impregnated with desired cells,and recruitment of endogenous cells With cellular therapy, theissues dealing with obtaining of cells and cell banking remainpotential problems Therefore, using autologous cells or recruit-ing endogenous cells are attractive options Cellular therapy hasmany potential benefits, but there are many unanswered ques-tions that require further investigation

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CANCER AND WOUNDS

Cancer should be considered in the differential diagnosis when

there is a chronic wound that has not responded to adequate

ther-apy Chronic wounds can lead to the development of squamous cell

carcinoma at the site of the wound known as a Marjolin ulcer, and

the diagnosis relies on a biopsy of the wound

Pseudoepithelioma-tous hyperplasia or pseudocarcinomaPseudoepithelioma-tous hyperplasia is the

pre-malignant finding prior to formation of a Marjolin ulcer, and with

this finding there should be a high index of suspicion for associated

malignancy in other parts of the wound Marjolin ulcers are treated

with wide local excision and usually require lymph node excision to

adequately stage these lesions

CONCLUSIONS

Wound healing requires a complex coordinated series of events

involving multiple cell types for there to be progress from an acute

wound to a well-healed scar Normal healing progresses through

inflammatory, proliferative, and remodeling phases Failure to

progress through this normal sequence leads to pathologic wound

healing, which can include wound healing impairment or excessive

scar formation Identifying the reason why a wound fails to

progress through the normal phases of healing may allow for

iden-tification and correction of the specific impairment

Revasculariza-tion of limbs, treatment of nutriRevasculariza-tional deficiencies, and

minimization of pressure on chronic wounds are all examples of

modifying treatment to fit the specific etiology of wound healing

impairment In addition, basic wound care that controls bacterialcontamination, maintains the proper moisture at the wound, treatsedema, and prevents further injury is usually successful in achiev-ing closure New therapies such as growth factor therapy, hyper-baric oxygen, and VAC have helped in the treatment of chronicwounds, and emerging therapies such as cellular therapy and genetherapy are in the process of being developed The complex biologybehind chronic wounds and the comorbidities inherent in patientswith these wounds will continue to make chronic wounds a signifi-cant health care problem for many patients Diligence in utilizingestablished methods and continued research to develop new treat-ment strategies provide hope to minimize the effects of thisproblem

Ethridge RT, Leong M, Phillips LG Wound healing In: Townsend

CM, Beauchamp RD, Evers BM, et al., eds Sabiston Textbook of

Surgery: The Biologic Basis of Modern Surgical Practice 18th ed.

Philadelphia: Saunders; 2008

Fine NA, Mustoe TA Wound healing In: Greenfield LJ, Mullholland

MW, Oldham KT, et al., eds Surgery: Scientific Principles and

Practice 3rd ed Philadelphia: Lippincott Williams & Wilkins;

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2

C H A P T E R

Hemostasis and Coagulation

MAJOR KENNETH LEE IV AND JEFFREY P CARPENTER

K E Y P O I N T S

• Platelet function entails adhesion, activation, and granule

release Platelet disorders are characterized by defects in

at least one of these three functions, and antiplateletagents act to inhibit at least one of these steps

• The coagulation cascade features sequential activation of

a number of protein factors, eventually leading to tion of cross-linked fibrin

deposi-• Hemostasis is routinely evaluated with several tests The

bleeding time assesses platelet function, PT/INR evaluates

the extrinsic limb of the coagulation cascade, and the aPTTevaluates the intrinsic limb

• Heparin acts by potentiating the anticoagulant effects ofantithrombin Warfarin inhibits the vitamin K–dependentcarboxylation of factors II, VII, IX, and X

• DIC occurs in the setting of severe disease and causeswidespread deposition of fibrin It causes thrombocytope-nia and depletes coagulation factors, thus prolonging the

PT and aPTT

INTRODUCTION

Understanding the management of bleeding is a prerequisite to

current surgical practice Many surgical procedures involve

large-volume blood loss; treatment intraoperatively and postoperatively

in these instances requires awareness of the mechanisms involved

in hemostasis and coagulation Furthermore, in appreciating these

mechanisms, the surgeon is better equipped to manage patients

with disorders that predispose to hypercoagulability

In this chapter, normal hemostatic mechanisms are

dis-cussed as well as the presentation, evaluation, and treatment of

patients with disorders of hemostasis We also review the variety

of pharmacologic agents available in the management of

bleed-ing and clottbleed-ing disorders Finally, because many disorders are

best managed with product replacement, we briefly recap

com-monly used blood products and adverse events associated with

their use

HEMOSTASIS

When injury to a vessel occurs, a number of sophisticated and

inte-grated processes are activated to minimize blood loss These events

begin at the level of the vascular endothelium and extend to the

re-cruitment and activation of platelets and the formation of

hemo-static clots via the coagulation cascade The multitude of steps

required to achieve hemostasis are themselves controlled;

dysregu-lation of these processes predisposes to hemorrhage and/or

throm-bosis and end-organ injury

Hemostasis occurs in two phases First phase is the rapid

for-mation of a platelet plug at the site of injury This limits bleeding

and develops a scaffold upon which the second phase is initiated

The second phase is the development of an intricate network of

polymerized fibrin protein It occurs through a series of sequential

events termed “the coagulation cascade.” The combination of

cross-linked platelets and fibrin forms a barrier effective in terminatingongoing bleeding from injured vasculature

Blood Vessels and the Endothelium

A principal characteristic of the vascular endothelium is its ability

to maintain a surface that opposes clot formation This is plished in part by elaboration of a number of factors (prostacyclin,nitric oxide, tissue plasminogen activator [t-PA], antithrombin)that inhibit both platelet aggregation/activation and factors in-volved in the coagulation cascade In addition, the endothelium

accom-expresses surface receptors such as thrombomodulin that bind to

and remove circulating procoagulant proteins

When the integrity of the vasculature is violated, several dothelial proteins are exposed that facilitate platelet adhesion andactivation Most notable are tissue factor and collagen, each ofwhich binds to specific platelet receptors to initiate the chain ofhemostatic events The endothelium maintains an active role inhemostasis by downregulating anticoagulant proteins and upregu-lating expression of factors favoring clot formation Cytokinesgenerated in the context of ongoing inflammation (including inter-leukin-1, interleukin-6, and tumor necrosis factor ␣) help to medi-

suben-ate such changes In concert, these events foster initiation ofhemostasis by shifting the local environment from one opposingthrombus to one in which platelets and coagulation factors aresequestered, and clot formation is favored

Platelets

As discussed earlier, the formation of the platelet plug constitutes asignificant event in the hemostatic pathway Platelets are produced

in the bone marrow as fragments of larger progenitor cells termed

“megakaryocytes.” Blood normally contains approximately 150,000

to 400,000 platelets/μL Approximately one-third of platelets are

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sequestered in the spleen Platelet function involves three processes:

adherence, activation, and granule release

As mentioned earlier, injury to the vasculature results in

expo-sure of a variety of subendothelial proteins including several types

of collagen Circulating platelets quickly adhere to collagen fibrils at

the site via the GpIa/IIa and GpVI glycoprotein surface receptors

Associated proteins such as von Willebrand factor (vWF) and

fibrinogen help to stabilize these connections

In addition to localizing platelets to the injury site, binding of

platelet receptors to exposed subendothelial collagen initiates a

sig-nal transduction cascade resulting in platelet activation (Fig 2.1)

Activation induces conformational changes in platelet morphology

that enhance adhesion and aggregation Furthermore, platelet

acti-vation leads to secretion of granule contents including adenosine

diphosphate (ADP), thromboxane A2, platelet-derived growth

fac-tor (PDGF), and serotonin These facfac-tors recruit a variety of cell

types to the site of injury to augment hemostasis and vessel repair

They also promote vasoconstriction to minimize blood loss and

fa-cilitate formation of the hemostatic platelet plug Activation also

entails maturation of the GpIIb/IIIa receptor via a conformational

change This is required for fibrinogen binding, which is central in

the formation of the cross-linked platelet plug

The Coagulation Cascade

To best minimize blood loss from damaged vessels, the platelet plug

acts in concert with the secondary phase of hemostasis—the

coagulation cascade (Fig 2.2) The coagulation cascade consists of anumber of circulating proteins that are normally inactive but be-come serine proteases or cofactors when activated (denoted with alowercase “a”) The liver synthesizes all coagulation factors exceptfactor VIII, which is produced by endothelial cells Synthesis of fac-tors II, VII, IX, and X is vitamin K dependent, as formation of activeprotein requires a posttranslational modification catalyzed by a vita-min K–dependent carboxylase The end result of the coagulation cas-cade is the cross-linked fibrin clot It is reached through theconvergence of two pathways—the extrinsic pathway and the intrin-sic pathway These cascades converge to a set of reactions common toboth, referred to as the common pathway

The intrinsic coagulation pathway originates in the binding ofthree plasma proteins (Factor XII [Hageman factor], high molecu-lar weight kininogen, and prekallikrein) to subendothelial collagen.This series of binding events results in the activation of factor XII,which then activates factor XI Factor XIa then activates factor IX.Factor IXa forms an aggregate with activated factor VIII, calcium

ion, and phospholipids known as the tenase complex (X-ase) that

cleaves factor X to factor Xa, a member of the common pathway

In the extrinsic pathway, tissue factor exposed following dothelial injury is bound in a complex with factor VII and calciumion The tissue factor–factor VII complex then activates factor X, acomponent of the common pathway The combination of tissuefactor, factor VIIa, and calcium ion also activates factor IX, leading

en-to formation of the tenase complex Thus, activation of facen-tor IXrepresents a link between the intrinsic and extrinsic pathways

FIGURE 2.1 Overview of platelet function (see

text for details) (From Coleman RW, Hirsh J,

Marder VJ, et al Hemostasis and

Throm-bosis: Basic Principles and Clinical Practice.

Philadelphia: JB Lippincott Co.; 1994, with

permission.)

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The intrinsic and extrinsic pathways converge at the activation

of factor X to Xa Factor Xa then converts prothrombin (factor II)

to thrombin (IIa) in the presence of factor V, calcium ion, and

phospholipids Prothrombin conversion is accelerated on the

sur-face of activated platelets, demonstrating synergy between the

pri-mary and secondary phases of hemostasis Thrombin amplifies

coagulation by activating platelets and multiple factors within the

coagulation cascade (V, VII, VIII) However, its principal role is the

cleavage of fibrinopeptides A and B from fibrinogen (factor I) to

form “fibrin monomers” that polymerize to form firm clot Factor

XIII, which is also activated by thrombin, cross-links adjacent

fibrin molecules Mature thrombus at sites of injury is generated

from the combination of this polymerized fibrin network and

hemostatic platelet plugs assembled in the primary phase

Fibrinolysis

Unregulated activation of the coagulation system would result in

widespread thrombosis with significant clinical consequence Thus, a

set of mechanisms exists that restricts clot formation to sites of injury

and breaks down thrombus following hemostasis to restore vessel

pa-tency These reactions are termed “the fibrinolytic pathway.”

Central to this regulatory function is the proteolytic enzyme

plasmin Plasmin is generated from its inactive precursor

plasmino-gen by the action of several activators including t-PA and urinary

plasminogen activator (u-PA, urokinase) Streptokinase is a related

bacterial product used therapeutically to activate plasminogen Once

formed, plasmin digests fibrin as well as factor V, factor VIII, factor

XII, and prothrombin (factor II) and therefore plays an integral role

in both the dissolution of clot and the deactivation of coagulation

pathways The reaction remains localized because plasminogen

acti-vation occurs more effectively in the presence of fibrin

Major inhibitors of the fibrinolytic system include

␣2-antiplas-min, which binds and neutralizes plas␣2-antiplas-min, and plasminogen

activator inhibitor (PAI-1), which inhibits both t-PA and u-PA.Pharmacologic inhibitors of fibrinolysis include aprotinin (Trasy-lol) and ⑀-aminocaproic acid (Amicar) Aprotinin is a naturally oc-

curring plasmin inhibitor derived from bovine lung that is usedmost frequently to minimize blood loss in patients post—cardiopulmonary bypass However, its unfavorable side-effectprofile (renal dysfunction, anaphylaxis) has limited its use

⑀-Aminocaproic acid competitively inhibits plasminogen

activa-tion and has secondary direct effects on plasminogen and plasmin

EVALUATING HEMOSTASIS

Diagnosis of inherited or acquired bleeding disorders requiresknowledge of the history, physical examination, risk factors forbleeding disorders, and pattern of ongoing bleeding In many cases,these data alone clearly suggest the diagnosis, and laboratory evalu-ation is simply confirmatory Since hemostasis involves both thedevelopment of the platelet plug and the formation of cross-linkedfibrin networks, screening tests for bleeding must evaluate bothplatelet function and the coagulation cascade

Platelet function is routinely assessed using the platelet countand the bleeding time The normal platelet count is 150,000 to4,000,000/␮L of blood Patients with counts below 50,000/␮L aresubject to easy bruising and bleeding, but spontaneous bleedingdoes not typically occur unless counts are below 20,000/␮L.The platelet count is a normal component of the complete bloodcount (CBC)

The bleeding time detects deficiencies in platelet function thatpromote bleeding despite sufficient platelet quantities It is mostoften measured by making a superficial skin incision on the fore-arm, inflating a blood pressure cuff on the upper arm to 40 mm Hg,and timing the duration of blood flow from the area (the Ivymethod) A bleeding time of 2 to 10 minutes is considered normal.Times between 10 and 15 minutes are associated with increased

Chapter 2 • Hemostasis and Coagulation 13

FIGURE 2.2 The coagulation

cascade (From Lab Tests Online

[www.labtestsonline.org],

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Associ-bleeding, while a bleeding time exceeding 15 minutes indicates risk

for severe/spontaneous bleeding Although the incision is generally

made using automated devices, the test remains somewhat difficult

to standardize across technicians

Plasma coagulation is routinely assessed using the

pro-thrombin time (PT) and the activated partial thromboplastin

time (aPTT) The PT screens the extrinsic, tissue factor–dependent

pathway Prolongation of the PT generally occurs when factor

levels fall below 30% to 50% of normal PT varies across

laboratories because of differences in reagents and detectors

Thus, the international normalized ratio (INR) has been

devel-oped to allow standardized measurements The INR is a

calcu-lated value that compensates for differences in laboratory

instrumentation and in the variety of PT reagents A normal INR

is 1.0 The aPTT screens the intrinsic coagulation pathway

in-volving factors VIII to XII, high molecular weight kininogen, and

prekallikrein Factor levels less than approximately 30% of

nor-mal prolong the aPTT Clinically significant deficits in common

pathway proteins (factors I, II, V, and X) prolong both the

PT/INR and the aPTT

A number of rare coagulation disorders are not detected by

these tests and may therefore be missed in the initial assessment of

a bleeding diathesis Thus, a more extensive workup is warranted

once more common etiologies that do alter these measures have

been excluded

COAGULATION PHARMACOLOGY

Antiplatelet agents and anticoagulants are used in the prevention

and management of a wide variety of cardiovascular diseases As

de-tailed earlier, platelet function involves three processes: adherence,

activation, and granule release Thus, each of the variety of tiplatelet agents achieves its desired effect by interfering with at leastone of these processes Anticoagulants function by inhibiting thesynthesis/activity of coagulation cascade components or by ampli-fying the effects of endogenous anticoagulants The major pharma-cologic antiplatelet agents and anticoagulants are discussed in detailbelow and are summarized in Table 2.1

an-Antiplatelet Agents

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) blockthe enzyme cyclooxygenase that mediates synthesis of thrombox-anes and prostaglandins Thromboxane A2is a powerful mediator ofvasoconstriction, platelet aggregation, and platelet activation, andthe antiplatelet effects of aspirin are primarily due to its absence Theeffects of NSAIDs on the cyclooxygenase enzyme are reversible, butaspirin blocks the enzyme irreversibly Because platelets do not syn-thesize new enzyme, the effects of aspirin extend through the lifetime

of the platelet Ideally, aspirin is to be discontinued at least 1 weekprior to elective surgery to ensure that a sufficient fraction of theplatelet population retains cyclooxygenase activity

The thienopyridines (ticlodipine [Ticlid] and clopidogrel[Plavix]) inhibit platelet aggregation by blocking binding of severalmolecules to their platelet receptor Most significant is their effect

on the binding of ADP to its platelet receptor Irreversible cation of the ADP receptor by these agents blocks ADP-induced ac-tivation and aggregation These agents are primarily used inpatients with established cardiovascular atherosclerotic disease, in-cluding those who have undergone percutaneous stenting of coro-nary and/or peripheral vessels Biotransformation of these agents

modifi-is required for their effects, but active metabolites have yet to be

Antiplatelet and anticoagulant therapies: mechanism, evaluation, and side-effect profile.

Drug/class Mechanism of action Test(s) affected Notable side effects

Aspirin/NSAIDs Block cyclooxygenase activity Bleeding time Bleeding; to be discontinued

inhibiting production of ⬎1 wk prior to surgerythromboxanes

Thienopyridines Block the binding of ADP to its Bleeding time Bleeding; to be discontinued(Ticlid, Plavix) platelet receptor to inhibit platelet ⬎5 d prior to surgery

aggregation and activationGpIIb/IIIa inhibitors Block Gp receptor and inhibit None —

(abciximab) platelet aggregation

Unfractionated heparin Binds to and potentiates the aPTT Heparin-induced

effects of antithrombin thrombocytopeniaLow molecular weight Binds to and potentiates None; can measure —

heparin (Lovenox) the effects of antithrombin factor X activity

Warfarin (Coumadin) Inhibits the vitamin K–dependent PT/INR Warfarin-induced

carboxylation of factors II, VII, skin necrosis

IX, and XDirect thrombin Bind to the catalytic site of PT/INR, aPTT —

inhibitors (lepirudin, thrombin and inhibit its activity

argatroban)

NSAIDs, nonsteroidal anti-inflammatory drugs; ADP, adenosine diphosphate; aPTT, activated partial thromboplastin time; PT, prothrombin time; INR,international normalized ratio

T A B L E 2 1

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isolated The primary side effect of thienopyridines is bleeding.

Clinically significant bleeding occurs at a frequency similar to that

observed with aspirin therapy (approximately 3% to 4% incidence

of major bleeding) Platelet aggregation and bleeding time return

to normal approximately 5 days after discontinuation of Plavix, and

it is therefore recommended that the agent be discontinued at least

5 days prior to surgery, although the reason that the patient is on

this agent must be taken into account before making the decision to

discontinue the drug In a number of situations, the risk of

bleed-ing if the patient continues on Plavix is less than the consequences

of a thrombotic event occurring when the patient is not protected

by its antiplatelet effect

Dipyridamole inhibits the activity of adenosine deaminase and

phosphodiesterase, which causes accumulation of adenosine,

ade-nine nucleotides, and cyclic AMP These mediators inhibit platelet

aggregation and promote vasodilation In the treatment of

cardio-vascular disease, dipyridamole is more commonly employed in

combination with aspirin as Aggrenox

The GpIIb/IIIa receptor is an integrin family member that

plays a central role in platelet aggregation GpIIb/IIIa inhibitors

bind to the receptor to inhibit its effects Several GpIIb/IIIa

in-hibitors are currently available, including the monoclonal antibody

abciximab (ReoPro) Abciximab is a monocolonal antibody

di-rected against the Gp receptor that is most commonly employed as

an adjunct therapy just prior to or immediately following

percuta-neous coronary intervention

Anticoagulants

Antithrombin serves as a potent inhibitor of coagulation in vivo by

inactivating thrombin primarily as well as several other factors in

the coagulation cascade (IXa, Xa, XIa, XIIa) The heparins

(includ-ing unfractionated heparin and low molecular weight heparin

[LMWH]) complex with antithrombin and induce a

conforma-tional change that significantly accelerates its activity Since heparin

primarily affects members of the intrinsic and common pathways,

its dosing is titrated by monitoring prolongation of the aPTT The

target PTT with heparin therapy is generally 1.5 to 2.5 times the

patient’s baseline PTT Primary side effects of unfractionated heparin

are bleeding and thrombocytopenia (discussed later in the chapter)

LMWH (Lovenox) inactivates factor Xa but has less of an effect on

thrombin Dosing is weight adjusted, and the anticoagulant effect is

more predictable than with unfractionated heparin There is also a

lower incidence of clinically significant thrombocytopenia in

pa-tients anticoagulated with LMWH Monitoring is generally not

per-formed but can be followed using anti-Xa activity assays

Warfarin (Coumadin) is by far the most utilized oral

anticoag-ulant It inhibits the vitamin K–dependent ␥-carboxylation of

fac-tors II, VII, IX, and X These facfac-tors are still produced but are

hypofunctional Because warfarin affects factor production, its

ef-fects are not manifested until active factors are cleared from the

cir-culation (36 to 48 hours) Since warfarin principally affects

members of the extrinsic and common pathways, the extent of

co-agulation is followed using the INR The principal side effect is

bleeding, especially in patients who are not compliant with their

medication regimen or its monitoring Far less common but

fre-quently discussed is the phenomenon of warfarin-induced skin

necrosis This occurs because warfarin also inhibits ␥-carboxylation

of the anticoagulant proteins C and S Because proteins C/S have

shorter half-lives than the affected procoagulant factors, a transient

state of hypercoagulability is induced that rarely leads to sis and skin necrosis

thrombo-Direct thrombin inhibitors (lepirudin, bivalirudin, argatroban)inactivate thrombin by binding directly to its catalytic site At thispoint, these agents are primarily utilized in patients in whom he-parins are contraindicated (e.g., in the setting of heparin-inducedthrombocytopenia [HIT] [discussed later in the chapter]) Orallyactive direct thrombin inhibitors are currently in the developmentstages Ximelagatran (Exanta) was submitted to the U.S Food andDrug Administration for approval but was recently withdrawnamid concerns over hepatotoxicity However, the pursuit of an ef-fective oral thrombin inhibitor continues in the form of dabigatran(Pradaxa), which is currently under investigation for clinical use

In addition to the direct thrombin inhibitors, other direct tor inhibitors may soon come into therapeutic use that likely willhave an impact on management strategies Closest to beingapproved for routine clinical use are the direct factor Xa inhibitorsincluding fondaparinux, idraparinux, razaxaban, and rivaroxaban.Orally administered direct factor Xa inhibitors are a potentiallyattractive alternative to both unfractionated heparin (morepredictable anticoagulation and potentially improved side-effectprofile) and Lovenox (oral administration) Both the safety of theseagents and their efficacy with respect to LMWH have yet to be fullyevaluated

fac-Topical Hemostatic Agents

Topical hemostatic agents are frequently employed during surgicalprocedures to minimize minor bleeding Oxidized regenerated cel-lulose (ORC) (Surgicel Nu-Knit, Surgicel Fibrillar) is one of themost commonly employed agents When saturated with blood,ORC greatly expands in volume and provides a gelatinous scaffoldfor the endogenous mechanisms of anticoagulation Gelatinsponges (Surgifoam, Gelfoam) contain collagen and therefore bindand activate platelets to stimulate hemostasis Topical thrombin isalso used in cessation of minor bleeding As discussed earlier,thrombin both activates platelets and plays a central role in the co-agulation cascade by catalyzing conversion of fibrinogen to fibrin

PLATELET DISORDERS

Patients with platelet disorders generally bleed into superficial sitesand often present with petechiae, epistaxis, or gingival bleeding.Bleeding attributable to platelet disorders can be separated undertwo headings: (a) quantitative platelet disorders and (b) disorders

of platelet function Figure 2.3 is a classification scheme organizingmany of the variety of platelet disorders that cause bleeding.Quantitative platelet disorders result from one of threemechanisms—decreased production, increased destruction, orsplenic sequestration Disorders of production are generally charac-terized by primary bone marrow failure or marrow infiltration andare therefore at times accompanied by decreased numbers of othercell lineages (i.e., anemia, neutropenia) Thus, the pattern is oftenrecognizable before diagnosis is confirmed Platelet destruction oftenhas an immunologic basis in the binding of autoantibodies or cross-reactive antibodies to the platelet surface and clearance of immunecomplex–bound platelets in the reticuloendothelial system Seques-tration of platelets in the spleen is normal but can become pathologic

in the setting of splenomegaly This often occurs secondary to liverdisease or splenic infiltration with malignant cells

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Functional platelet disorders result from one of the three

as-pects of platelet function (adhesion, activation, granule release) In

each case, these may be inherited (e.g., von Willebrand disease

[vWD], Glanzmann thrombasthenia) or acquired (e.g.,

drug-induced platelet dysfunction, uremia) These disorders often have

no effect on platelet number and therefore are detectable only with

functional measures such as bleeding time, platelet aggregometry,

or assays that evaluate the contents of platelet granules

von Willebrand Disease

vWD is the most common congenital bleeding disorder; it affects

up to 1% of the population The disorder is characterized by

muta-tions that impair either the synthesis or action of vWF vWF is a

large multimeric glycoprotein that normally has two functions: (a)

linking collagen fibrils and platelets in the early stages of

hemosta-sis and (b) serving as the major carrier protein for circulating

factor VIII

There are three types of inherited vWDs Each is precipitated

by genetic mutations causing qualitative or quantitative

deficien-cies in vWF Type 1, the most common form, is inherited in

autoso-mal dominant fashion and is characterized by a mild to moderate

quantitative deficiency in vWF Type 2 has four subtypes, each of

which is characterized by a normal level of vWF with a particular

functional deficit Type 3 is the most severe form in that vWF is

es-sentially absent Because vWF is the major carrier protein for factor

VIII, these patients may also have factor VIII levels so low as to

cause bleeding similar to that seen in hemophiliacs Type 3 vWD is

inherited in an autosomal recessive fashion and is therefore theleast common form

Because quantitative/qualitative deficits in vWF can affectboth platelet function and circulating factor VIII levels, thedisorder may prolong both the bleeding time and the aPTT(Table 2.2) The platelet count and PT are usually normal Whenclinical suspicion for vWD arises, the diagnosis can usually beconfirmed by demonstrating a reduction in plasma vWF concen-tration and/or a reduction in activity as measured with the risto-cetin cofactor assay The latter is a functional assay that tests thecapacity of vWF to aggregate platelets when stimulated by theantibiotic ristocetin

Mild to moderate cases of vWD can often be treated with thevasopressin analogue D-deoxy desmopressin arginine vasopressin(desmopressin, DDAVP) DDAVP indirectly promotes release ofvWF from the endothelium and therefore increases plasma levels ofvWF and factor VIII However, patients with more severe bleedingoften have an insufficient response These patients require vWF re-placement using purified vWF concentrates Alternatively, factorVIII concentrates mandated in the setting of severely decreasedfactor VIII levels (i.e., type 3 vWD) also contain vWF in highconcentration

Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is thought to be anautoimmune disorder and has a phenotype that often differs inthe pediatric and adult populations It occurs most commonly in

FIGURE 2.3 Classification of platelet

disorders

Derangement of laboratory values in hemostatic disorders.

Disorder Platelet count Bleeding time PT/INR aPTT

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childhood and is generally characterized by acute onset of often

profound thrombocytopenia following recovery from a viral

ill-ness This form (designated acute ITP) is the most common cause

of immune, pediatric thrombocytopenia and is generally

self-lim-ited More than half of children recover within 6 weeks and ⬎75%

of cases resolve within 6 months Acute ITP is caused by antibodies

possibly generated in response to viral antigens that react with

platelet peptides resulting in immune complex formation and

clearance in the reticuloendothelial system Most adults present

with a less severe, indolent version of ITP, denoted chronic ITP The

etiology is again autoimmune

ITP is generally regarded as a diagnosis of exclusion The

differ-ential diagnosis includes primary hematologic disorders (leukemia,

aplastic anemia), marrow infiltrative disorders (metastatic tumor,

myelofibrosis), other autoimmune disorders (SLE [systemic

lupus erythematosus]), and infectious etiologies (HIV [human

im-munodeficiency virus], CMV [cytomegalovirus], EBV [Epstein-Barr

virus]) The diagnostic evaluation must be tailored to clinical

suspi-cion and may include serologies and bone marrow biopsy ITP affects

platelet number alone; other coagulation studies are unaffected

(Table 2.2)

Treatment of ITP differs on the basis of the clinical scenario

As most diseases in children are self-limited, treatment is often

unnecessary unless spontaneous bleeding occurs or the platelet

count places the patient at risk for spontaneous bleeding Some

advocate conservative management in the pediatric population

even in the face of profoundly low platelet counts (⬍20,000/␮L)

because the condition generally resolves By contrast, ITP in the

adult population is less likely to remit without intervention In

either case, platelet counts typically respond to a course of

gluco-corticoids and/or intravenous immunoglobulin (IVIG) IVIG

in-creases platelet counts more rapidly than corticosteroids but is

more costly Platelet transfusions are rare and are restricted to

patients with life-threatening bleeding Persistent bleeding that is

not controlled with medical measures or requires repeated

inter-vention is sometimes managed with splenectomy Patients

gener-ally respond well to surgery as ⬎60% experience remission after

splenectomy

Heparin-Induced Thrombocytopenia

A decrease in the platelet count is observed in as many as 20% of

patients treated with heparin However, this trend must be followed

carefully to rule out the potentially catastrophic process commonly

referred to as HIT It is caused by antibodies that recognize the

complex of heparin bound to the heparin-neutralizing protein

platelet factor 4 (PF4) Binding of antibody to the heparin–PF4

complex has two effects Initially it results in platelet aggregation

and activation via the Fc portion of the immunoglobulin with the

resultant platelet aggregates cleared by the reticuloendothelial

system, leading to the characteristic thrombocytopenia Platelet

aggregation/activation predispose to thrombosis, while aggregate

clearance and the resultant thrombocytopenia predispose to

hemorrhage

Diagnosis of HIT requires a high level of clinical suspicion In

contrast to benign thrombocytopenia, which normally occurs

within several days of heparin treatment, immune-mediated HIT

generally begins later, usually 4 to 10 days after institution of

he-parin therapy The platelet count often falls below 100,000 but

gen-erally does not reach nadirs associated with spontaneous bleeding

If the clinical picture leads to a suspicion of HIT, the diagnosis isconfirmed using a variety of tests The 14C serotonin release assay

is performed by radiolabeling platelets with 14C and then mixingthem with patient serum and two concentrations of heparin Re-lease of 14C reflects platelet activation and suggests the diagnosiswhen observed at a therapeutic heparin concentration Theheparin-induced platelet aggregation assay is performed by mixingdonor platelets with patient serum again in the presence of twoconcentrations of heparin Aggregation seen in the presence of atherapeutic heparin concentration is considered a positive test.Finally, ELISA-based assays that demonstrate binding of patientantibodies to heparin-PF4 complexes are sometimes utilized indiagnosis These are best interpreted in conjunction with the afore-mentioned functional assays, because many patients have ELISA-detectable antibodies that do not aggregate/activate platelets andare therefore of no clinical significance

Once a diagnosis of HIT is confirmed or even before when theclinical suspicion is high, the heparin infusion must be discontin-ued Whether additional therapy is required depends upon the clin-ical scenario In the setting of thrombosis, anticoagulation isrequired and can be achieved using the direct thrombin inhibitorsdiscussed earlier (argatroban, lepirudin) Anticoagulation is alsouseful in preventing thrombosis in patients with new diagnoses ofHIT, but this is not practiced universally If platelet counts remainsufficient and there is no evidence of thrombosis, the process can

be managed conservatively

COAGULATION DISORDERS

Disorders of the coagulation cascade can result in either agulability or bleeding Venous thrombosis and pulmonary em-bolism are frequent clinical manifestations of the hypercoagulablestate Although many different conditions predispose to throm-boembolism, their common theme is a shift in the balance be-tween endogenous procoagulant and anticoagulant mechanisms.When inherited, these disorders involve mutations that preventinactivation of clotting factors or inhibit intrinsic mechanisms ofanticoagulation Bleeding disorders are often the result of quanti-tative factor deficiencies In contrast to the mucosal bleedingpresent with quantitative/qualitative platelet disorders, bleedinginto the joints is most common in patients with significant factordeficits Bleeding into soft tissues and the GI tract is also fre-quently noted

hyperco-Hemophilia

Hemophilia A is an X-linked recessive deficiency in factor VIII thataffects males almost exclusively The extent of bleeding in patientswith hemophilia A depends on the factor level—levels ⬎5% of nor-mal are generally associated with disease characterized by mildbleeding in instances of trauma, while levels ⬍1% cause severebleeding that often occurs spontaneously Majority of patients withhemophilia A have severe disease Hemophilia B is also X-linked re-cessive but is less common than hemophilia A It is caused by quan-titative deficits in factor IX The extent of bleeding is againdependent on the level of circulating factor, but fewer patients withhemophilia B have factor levels ⬍1% of normal

Approximately 70% of hemophiliacs have a diagnosis lished prior to a clinically significant bleeding event usually aided

estab-by family history and genetic studies In the undiagnosed patientChapter 2 • Hemostasis and Coagulation 17

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with a clinical picture suggesting hemophilia (i.e., hemarthroses),

initial studies should include a CBC, INR, and aPTT Patients with

hemophilia A and B have normal platelet number and function and

thus a normal bleeding time The INR is normal, but the PTT is

prolonged The diagnosis is confirmed by demonstrating decreased

circulating levels of factor VIII and factor IX

Hemophilia is treated by factor replacement Factor VIII and

factor IX concentrates are now common; the use of

cryoprecipi-tate and fresh frozen plasma (FFP) in treating hemophiliacs is

now restricted to increasingly rare settings in which factor

con-centrates are unavailable Factor IX deficiency was traditionally

treated with prothrombin complex concentrate, which contains all

of the vitamin K–dependent coagulation factors However, these

concentrates contained trace quantities of activated coagulation

factors and sometimes resulted in thromboembolism Dosing of

factor replacements is based on weight, volume of distribution,

and the level of factor required Generally, factor levels must be

raised above approximately 20% of normal in the case of an

uncomplicated bleed More extensive bleeding may necessitate

maintaining the level above 50% and as high as 80% to 100% for

several days or weeks

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is characterized by a

series of events leading to widespread coagulation, which depletes

both platelets and clotting factors, paradoxically resulting in

bleed-ing This condition can occur in response to a variety of triggers but

is frequently associated with overwhelming infection, malignancy,

severe trauma, obstetrical complications, massive transfusion, or

exposure to toxins Factors elaborated in these settings can activate

the coagulation cascade, diffusely resulting in deposition of fibrin

throughout the microvasculature These local coagulation depots

deplete circulating levels of both coagulation factors and platelets

predisposing the patient to bleeding Although typically regarded as

a bleeding disorder because of the severe bleeding that can

occa-sionally occur, death in this setting is frequently the result of

end-organ failure secondary to microthrombosis

The quantitative deficit in both platelets and clotting factors in

the setting of DIC is reflected in a prolonged PT, PTT, and bleeding

time However, what distinguishes DIC from other coagulopathies is

the presence of products signifying increased thrombin/fibrin

pro-duction and degradation This is reflected in decreased levels of

fib-rinogen with increased fibrin degradation products and in an elevated

D-dimer The D-dimer assay detects cross-linked fibrin derivatives

Because DIC manifests in various ways, the treatment approach

is multifaceted In the setting of severe bleeding, DIC is managed by

supporting hemodynamics and replacement of platelets and

coagu-lation factors through transfusion with platelet concentrates and

FFP Cryoprecipitate is also used to maintain the fibrinogen level

When thrombosis is the predominant presentation, treatment with

intravenous heparin can be instituted in patients that remain

candi-dates for anticoagulation However, heparin has not been definitively

shown to be beneficial, and the desired level of anticoagulation can

be difficult to determine in these patients in whom severe bleeding is

of concern and the aPTT is often already prolonged Heparin is

therefore not frequently utilized in the acute setting Ultimately, the

consumptive coagulopathy is best managed by treating the

underly-ing pathologic process Mortality remains high because of difficulties

in treating the primary disorder

Factor V Leiden

The most common inherited procoagulant disorder is the factor VLeiden mutation It accounts for approximately 40% to 50% of pa-tients with inherited thrombophilia The frequency of heterozygos-ity for the factor V Leiden mutation among American whites isapproximately 5%; it is lower among other races Homozygosity ismuch less common (approximately 0.1%), but these patients aredisproportionately represented clinically because of their greatlyincreased risk of thromboembolism Factor V is ordinarily inacti-vated by cleavage at multiple sites This is catalyzed by activatedprotein C (aPC) In the factor V Leiden disorder, mutation of argi-nine to glutamine in position 506 of factor V prolongs its activity

by rendering it impervious to cleavage by aPC

Clinically, patients with the factor V Leiden mutation generallypresent with venous thrombosis Patients with thrombosis found tohave the factor V Leiden mutation should be treated with intravenousheparin and transitioned to oral anticoagulation There is not yet aconsensus on whether patients who suffer one thrombotic eventshould be subjected to lifelong anticoagulation Many clinicians favor

a shorter course of 3 months to 1 year, as the risk of recurrence isthought to be low Recurrent thromboembolism in the setting of thefactor V Leiden mutation is an indication for lifelong treatment

Protein C/S Deficiency

aPC and protein S act in conjunction to inhibit factors Va andVIIIa Protein C and protein S deficiencies are most commonlycaused by heterozygous mutations inherited in autosomal domi-nant fashion In their absence, persistent activity of factors V andVIII promotes recurrent venous thrombosis The diagnosis of pro-tein C/S deficiency is most commonly made by the combination ofimmunoassays that detect serum levels and functional assays How-ever, the correlation between serum level and symptoms is not pre-cise since some asymptomatic patients have levels lower than thosewith recurrent thrombosis Similar to other thrombotic syndromes,the treatment of symptomatic patients with protein C/S deficiencytypically consists of heparin and oral anticoagulation Neonateswith homozygous mutations for protein C deficiency can presentwith a severe consumptive coagulopathy that is refractory toheparin and must be treated with exogenous protein C

As detailed earlier, the heparins complex with antithrombin andpotentiate its activity Thus, patients with a mild quantitative defi-ciency in antithrombin can be treated with intravenous heparinacutely, provided that the level of antithrombin is sufficient forheparin activity Higher heparin doses are often required sinceantithrombin is present in reduced quantities After institution of in-travenous therapy, patients need to be transitioned to oral anticoagu-lation The risk of recurrence is higher in the setting of antithrombindeficiency than in other thrombophilias, and lifelong anticoagulation

is therefore recommended Antithrombin concentrate has been used

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effectively in patients with severe thrombosis or in whom adequate

anticoagulation cannot be achieved with heparin alone

TRANSFUSION MEDICINE

Despite the variety of agents available in managing patients with

bleeding and clotting disorders, factor replacement remains a

criti-cal aspect of therapy As our understanding of the function

of particular blood components and our ability to isolate these

components have progressed, the standard of care in management

of the blood supply has shifted to component therapy This trend

currently persists, as noted earlier, in the increasing prevalence of

recombinant/purified factors as treatment options

Both the decision to transfuse and the therapeutic approach

depend on the clinical status Packed red blood cells (PRBCs) are

used in the setting of symptomatic anemia or to keep the

hemoglo-bin level above that mandated by the clinical scenario (the so-called

transfusion trigger) Each unit of PRBC raises the hematocrit 2% to

4% in a 70-kg person Platelet transfusions are used in patients

with thrombocytopenia or qualitative platelet deficits After platelet

transfusion, the platelet count should increase at least 5,000/mL for

each unit of platelets transfused FFP is best utilized in the setting of

multiple factor deficiencies or to reverse pharmacologic

anticoagu-lation A unit of plasma contains near-normal levels of all

coagula-tion factors and increases factor levels by about 3% A dose of 10 to

15 mL/kg of FFP should replete coagulation factors to levels requisite

for hemostasis Whether prophylactic preoperative use of FFP is of

benefit in patients with a minimally elevated INR (⬍2.0) is currently

the focus of an National Institutes of Health (NIH)-sponsored

ran-domized trial

Adverse reactions occur in approximately 1% to 5% of all

transfusions The most common transfusion reaction is the febrile,

nonhemolytic reaction Clinically, this appears as an isolated fever

occurring approximately 1 to 6 hours after transfusion As fever is

often the initial symptom in more severe transfusion reactions, an

appropriate diagnostic workup is mandated Hemolytic reactions

are caused by complement-mediated destruction of transfused cell

components by preexisting antibodies Fever is the most common

initial manifestation, but these reactions can result in DIC and

car-diovascular collapse if complement activation and cytokine release

are considerable When a transfusion reaction is suspected,

transfu-sion should be stopped immediately, and the donor unit should besent to the blood bank with blood samples drawn from a remotesite for crossmatching Treatment of the patient is supportive Fluidadministration should commence immediately if there are anysigns or symptoms of a hemolytic reaction (flank pain, red/brownurine) to prevent the complication of renal failure

Acute-onset dyspnea, hypoxia, and pulmonary edema during orshortly after transfusion should raise concern for transfusion-relatedacute lung injury (TRALI) This syndrome is caused by donor anti-bodies that attack recipient leukocytes localized to the pulmonaryvasculature, leading to fluid exudation and pulmonary edema Theincidence of TRALI is thought to be approximately 1 per 1,000 to5,000 units transfused The treatment also is supportive Mechanicalventilation with high positive end-expiratory pressure is often re-quired, but ventilatory requirements decrease as the acute lung injuryresolves Glucocorticoids have been used in management, but there

is insufficient evidence for efficacy of these agents

With improvements in screening donor blood components,risk of viral transmission has decreased substantially The risk oftransfusion-associated HBV infection is approximately 1:60,000

to 1:250,000 per unit The risk of HCV infection is approximately1:1,000,000 to 1:2,000,000 HIV transmission risk is approximately1:1,000,000 to 1:2,000,000

Baldwin ZK, Spitzer AL, Ng VL, et al Contemporary standards forthe diagnosis and treatment of heparin-induced thrombocy-

topenia (HIT) Surgery 2008; 143:305–312.

Calaitges, JG, Silver D Principles of hemostasis In: Rutherford RB,

Cronenwett JL, Gloviczki P, et al., eds Vascular Surgery,

Philadelphia: WB Sunders; 2000

Cesarman-Maus G, Hajjar KA Molecular mechanisms of

fibrinoly-sis Br J Haematol 2005; 129:307–321.

Hoffman R, Blanz EJ Jr, Shattil SJ, eds Hematology: Basic Principles

and Practice 3rd ed New York: Churchill Livingstone; 2000.

Lane DA, Philippou H, Huntington JA, et al Directing thrombin

Blood 2005; 106:2605–2612.

Sadler JE, Mannucci PM, Berntorp E Impact, diagnosis, and

treatment of von Willebrand’s disease Thromb Haemost 2000;

84:160–174

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3

C H A P T E R

Surgical Infectious Disease

BRADLEY G LESHNOWER AND BABAK SARANI

K E Y P O I N T S

• The toxic properties of Gram-negative bacterial endotoxin

rest in the lipid A moiety of the LPS molecule The toxin stimulates the hypothalamus to produce fever andstimulates macrophages to release TNF-␣, which can

endo-result in septic shock

• Necrotizing fasciitis is a polymicrobial infection requiring

radical operative debridement and a broad-spectrumantibiotic regimen that includes high-dose penicillin to

cover Clostridium sp and vancomycin to cover MRSA (methicillin- or oxacillin-resistant S aureus).

• Bacterial inoculation of the peritoneal cavity results in

(a) phagocytosis of the bacteria by macrophages, (b)

clear-ance of the bacteria via translymphatic absorption, and

(c) sequestration of the remaining intraperitoneal bacteria

by inflammatory exudates

• The most common cause of a wound infection in a cleancase is a break in sterile technique

INTRODUCTION

Joseph Lister dramatically changed the practice of surgery with his

1867 landmark document On the Antiseptic Principle in the Practice

of Surgery The incorporation of antiseptic techniques immediately

impacted morbidity and mortality, reducing postoperative

infec-tions from 90% to 10% Surgical infectious diseases include

infections that require surgical intervention and infections that

re-sult from surgical intervention An understanding of host defenses,

microbiology, antimicrobial therapies, and proper antiseptic

tech-nique is required of all practicing surgeons

HOST DEFENSE MECHANISMS

Barriers

The body has many natural barriers that serve important roles in

preventing infection The skin is the first line of defense against

infectious disease It functions as a mechanical barrier against

mi-crobial invasion and provides an unfavorable environment for

microbial growth with its acidic pH (5 to 6) and relative lack of

water Its constant epithelial cell proliferation allows daily cell

turnover and sloughing of both dead cells and resident flora

Throughout the epithelial surface of the respiratory tract lies a

mucous blanket that contains immunoglobulin A The mucociliary

mechanism captures inhaled particulates within the superficial

mu-cous blanket resting on the ciliated respiratory epithelium from thelarynx to the terminal bronchioles The mucus is steadily rolledtoward the mouth by the motion of the cilia The regularly beatingcilia convey particles and alveolar macrophages embedded in themucous blanket from the distal airways toward the pharynx wherethey are expelled by coughing This process efficiently clears particles

by the mucociliary mechanism every 14 minutes Secretory munoglobulin A (IgA) (S-IgA), produced by the lymphoid tissuethroughout the respiratory tract, offers additional protection to thehost by preventing bacterial adherence to the respiratory epithelium

im-The acidic pH of gastric secretions prevents the growth of most

bacteria in the stomach, keeping it essentially sterile The tion of antacids into the stomach compromises this natural barrier,and the stomach becomes vulnerable to bacterial and/or fungal col-onization Aspiration in the setting of gastric pH neutralizationposes an increased risk of developing pneumonia

introduc-The small and large intestines are colonized with abundantbacterial flora, and there is an increasing gradient in the concentra-tion of bacteria proceeding from the small to the large bowel

Antibiotic Action Mechanisms of Resistance

␤-Lactams Inhibit cell wall synthesis Bacterial ␤-lactamase

Reduced penetrationVancomycin Inhibits cell wall synthesis Reduced penetrationTetracyclines Bind to ribosomes and Downregulation of transport Aminoglycosides inhibit RNA transcription mechanisms

MacrolidesChloramphenicolFluoroquinolones Inhibit DNA helicase Alteration of target binding sites

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Peristalsis and a normal motility pattern keep the bacterial

popula-tion of the small bowel constant Bacterial content increases

signif-icantly in the colon

The urinary tract is normally sterile except at the urethral

ori-fice Urine also contains IgA, which prevents bacterial adherence to

the urothelium The most important natural defense of the bladder

in males is the long urethra, which is quite distant and thus

pro-tected from the anus The incidence of urinary tract infections

(UTIs) is increased in women because the urethra is short and in

close proximity to the fecal stream

Microbial Flora

Microbes themselves contribute to host defense, particularly in the

gastrointestinal (GI) tract The gut, which is sterile in utero, is

initially exposed to microbes during birth and during the initial

feedings Thereafter, the GI tract becomes colonized The

composi-tion of the resident flora changes as the host diet changes The

nor-mal microflora of the GI tract add to host defense by occupying

potential epithelial binding sites, which limits pathologic microbial

penetration This is known as colonization resistance or tropism The

resident microflora also function as a physical mucobacterial

bar-rier, which is constantly maintained by rapid cell turnover, the

shedding of enterocytes, mucus production, and bacterial growth

The presence of microflora in the GI tract also promotes the

devel-opment of gut-associated lymphoid tissue

The distal small intestine and colon harbor the largest

concen-trations of microorganisms in the GI tract Bacterial anaerobes

(Bacteroides fragilis, Fusobacterium, Peptostreptococcus) outnumber

aerobes (Escherichia coli, Enterococcus faecalis) in the colon by a ratio

of 300:1 The total concentration of bacteria in stool is 1012CFU/g,

which represents approximately 30% of the dry weight of feces

Immunology

Phagocytic leukocytes, in concert with the cellular adaptive and

humoral immune systems, constitute the host’s most formidable

defense mechanism against infection Phagocytes in the circulating

blood are monocytes and granulocytes (neutrophils, eosinophils,

and basophils) Macrophages are differentiated monocytes that

re-side in all living tissues of the body but are heavily concentrated in

the lungs, liver, and spleen These noncirculating cells are referred

to as the reticuloendothelial system Macrophages, monocytes, and

granulocytes initiate the eradication of bacteria and fungi by

in-gesting these pathogens in a process known as phagocytosis This is

the single most important process in the control of infection While

phagocytes can eliminate microbes independently, they also play

an important role in the host’s immune response by serving as

antigen-presenting cells to T lymphocytes Circulating phagocytes

migrate to areas of inflammation by following a gradient of

chemoattractant molecules in a highly efficient process known as

chemotaxis At the site of inflammation, opsonization facilitates

phagocytic recognition of the pathogenic species Opsonization is

the process by which opsonins (immunoglobulins and

comple-ment) bound to the surface of microbes, interact with receptors on

the phagocyte, and promote ingestion Disorders in opsonization

result in a failure to clear the offending microbe and place the host

at a high risk of bacterial infection, especially from encapsulated

bacteria Opsonization and subsequent phagocytosis are the host’s

primary method of eliminating extracellular pathogens

Microbes that live inside cells (primarily viruses) are cleared

by the host’s cellular immune system Cellular immunity consists

of an afferent limb that is responsible for recognizing foreign gen and an efferent limb that destroys the infected cell Upon in-duction of an immune response, macrophages, as well as otherprofessional antigen-presenting cells such as B cells and dendriticcells, process and then present antigen on their cell surface in con-junction with major histocompatibility complex (MHC) mole-cules MHC molecules are transmembrane proteins, subdividedinto class I and class II, which are critical in stimulating T cell re-sponses (see Chapter 5) The antigen–MHC class II complex binds

anti-to T lymphocytes that express the CD4 molecule and are known as

helper T cells Helper T cells interact with the antigen-presenting

macrophages and proliferate into a subpopulation of T cell clonesthat recognize the specific antigen(s) and amplify the immune re-sponse These cells produce specific lymphokines that promote

B cell differentiation into antibody-generating plasma cells and

coordinate the effector arm of the immune response Effector cells

consist of monocytes, macrophages, granulocytes, and cytotoxic Tcells that express the CD8 molecule Cytotoxic CD8 T cells can killvirally infected cells by direct contact Although the contributions

of the cytotoxic T cells are significant, the majority of antigenelimination is handled by the monocytes, macrophages, and gran-ulocytes In this manner, a small number of sensitized T lympho-cytes can respond to a microbial invasion, stimulate a largeimmune response, and eliminate infection from the host

Humoral responses to infection are dependent on

im-munoglobulins and complement Imim-munoglobulins are primarily

directed against extracellular pathogens They protect the hostfrom infection by (a) neutralizing viruses and bacterial toxins,(b) inhibiting microbial attachment to host cells, (c) opsonizingpathogens for elimination by phagocytes, and (d) activating thecomplement cascade Five classes of immunoglobulins are pro-duced by B cell–derived plasma cells: IgG, IgA, IgM, IgD, and IgE.IgM, IgG, and IgA are most directly involved in microbial defense.IgM is the first immunoglobulin produced in the initial response

to antigen and is a potent activator of complement IgG is ported across the placenta from mother to fetus and protects thenewborn until the fourth month of life and is also the predomi-nant immunoglobulin produced and circulating during amnesticresponses IgA is a monomer in the circulating blood and com-bines with a secretory component and an amino acid chain (J chain) to form the polymeric S-IgA S-IgA acts as a first line ofdefense against pathogens by preventing bacterial adherence tothe mucosal epithelium of the respiratory, GI, and genitourinary(GU) tracts IgA deficiency is the most common immunoglobu-lin deficiency Patients with IgA deficiency can present with re-current mucosal infections resulting in bronchitis, allergies, or GImalabsorption

trans-The complement system is a nonspecific defense system

designed to allow for an immediate response to invading isms It is an efficient and self-regulated cascade that requires thebinding of only a few molecules of antibody to activate largeamounts of complement The proteins that constitute the comple-ment system are inactive by themselves, but interaction withantigen–antibody complexes or microbial cell surfaces activatesthese substances and initiates a cascade of reactions, whichultimately results in cell lysis The complement cascade can beactivated through two separate pathways, which converge into acommon final pathway (Fig 3.1)

organ-Chapter 3 • Surgical Infectious Disease 21

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The majority of microbial elimination is carried out by the

phagocytic leukocytes These effector cells are attracted to the area

of inflammation by chemokines released during mast cell

degranu-lation and engulf the opsonized pathogens Patients with recurrent

infections should be screened for complement deficiencies The

most serious is C3 deficiency, which results in recurrent infections

with Gram-negative and encapsulated organisms

SURGICAL MICROBIOLOGY

AND PATHOGENICITY

Viruses

Viruses are obligate intracellular pathogens composed of a central

core of genetic material (DNA or RNA) surrounded by a protein

coat (the capsid), which protects the nucleic acid and serves as a

ve-hicle of transmission from one cell to another Some viruses have

an outer membrane (the envelope) that comprises lipids acquired

from the host’s nuclear membrane Viruses do not contain any cell

machinery and therefore depend entirely upon the host cell to

pro-vide the energy and the biosynthetic organelles for viral replication

As the virus replicates, the process continues until the host cell lyses

or the virus buds off to infect another cell Viruses cause disease by

cell lysis or by interfering with normal cell machinery to cause

cel-lular dysfunction One concern during viral infection is the

associ-ated risk of bacterial superinfection This may occur in part due to

the impaired phagocytic capacity of virally infected macrophages

or polymorphonuclear leukocytes (PMNs) rendering the host

more vulnerable to bacterial infection Viral infections can cause

congenital malformations (TORCH viruses), chromosomal

dam-age (herpes), altered immune function (human immunodeficiency

virus [HIV]), and increased cellular proliferation and oncogenesis

(HTLV-I) Viruses have been implicated in surgical diseases such as

appendicitis (enterovirus), ulcerative colitis (cytomegalovirus[CMV]), and intussusception (adenovirus) Viral illnesses rarely re-quire surgical intervention One exception is hepatitis B or C infec-tion causing cirrhosis and end-stage liver disease that may requireliver transplantation (see Chapter 13)

Bacteria

Bacteria generate their own energy and contain all the biosyntheticmachinery necessary for self-replication Their structure includes asingle circular molecule of DNA, ribosomes, a cytoplasmic mem-brane, and a cell wall Some bacteria carry plasmids, which areautonomously replicating strands of DNA that may carry genesconferring resistance to antibiotics Bacteria are prokaryotes andhave no nuclear membrane They have three general shapes: rods,spheres, and spirals Differences in cell wall structure determinewhether bacteria stain Gram-positive or -negative (Fig 3.2).The initial step in bacterial pathogenicity is adherence to an ep-ithelial surface Once attached to the host, bacteria cause disease byinvading tissues, producing toxins or inciting pathologic immune

responses Streptococcus pneumoniae is an example of a bacterial

species that invades tissue Other bacteria produce toxins that can

be subdivided into two classes: exotoxins and endotoxins Protein

exotoxins cause hemolysis of red blood cells, white blood cell death,necrosis of tissues, degradation of intercellular substances, andclotting of plasma Important surgical diseases resulting from bac-

terial exotoxins include necrotizing fasciitis caused by Clostridium

perfringens, Streptococcus pyogenes (Group A Strep), and coccus aureus, and toxic megacolon caused by Clostridium difficile.

Staphylo-Endotoxins are macromolecular complexes of phospholipids, saccharide, and protein, which form the outer layer of the cell wall

poly-of Gram-negative bacteria Lipopolysaccharide (LPS or endotoxin)

is composed of a “core” polysaccharide region and a unique

Classical pathway

of activationRecognition of antigen−

antibodycomplexesC1qrs

C4C2

Rapid andefficient

Alternative pathway

of activationRecognition of bacteria and

other activatingsurfacesD

C3B

Slow andinefficient

Mast cell degranulationOpsonizationRecruitment of the alternative pathwayInitiation of the membrane attack complex

Membrane attack complexC5

C6C7C8

FIGURE 3.1 Pathways of complement activation (From

O’Leary JP, ed The Physiologic Basis of Surgery 3rd ed.

Philadelphia: Lippincott Williams & Wilkins; 2002:179,

with permission.)

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“O antigen” polysaccharide region, which are covalently bound to

the “lipid A” region (Fig 3.3) The toxic properties of LPS largely

rest with the lipid A moiety of the molecule LPS induces fever by

direct action on the hypothalamus and by stimulating the release of

pyrogens like IL-1, IL-6, and tumor necrosis factor (TNF) It can

cause septic shock by activating the complement system, causing

the release of vasoactive substances like prostaglandins,

collage-nases, and serotonin and inducing disseminated intravascular

co-agulation, platelet aggregation, and thrombocytopenia

Fungi

Fungi are primitive eukaryotes, which contain DNA in their

nu-cleus and organelles capable of biosynthesis and energy generation

in their cytoplasm External to their plasma membrane lies a rigid

cell wall that protects the cell from osmotic rupture Most medically

important fungi are molds Molds are multicellular fungi that form

long filaments called hyphae and reproduce by forming spores

Yeasts are unicellular fungi that reproduce by budding Many fungi

are dimorphic and grow as either form depending on their ronment An immunocompetent host rarely develops invasive fun-gal infections However, there are three main mechanisms by whichfungi can gain access to human tissues and cause disease: (a) in-halation, (b) inoculation of the subcutaneous tissues, and (c) colo-nization of mucosal surfaces Histoplasmosis, blastomycosis, andcoccidioidmycosis are examples of fungal diseases caused by in-halation of spores into the lung Inoculation of the subcutaneoustissues by spores occurs in sporotrichosis In this uncommon occu-pational disease, gardeners who injure their skin with contami-nated thorns or branches present with nodules and ulcers on theirhands and feet that may require surgical drainage Fungal coloniza-tion of mucosal surfaces in a normal host rarely causes infection.However, in the immunocompromised patient, opportunisticinfections like esophageal candidiasis or pulmonary aspergillosiscan occur Fungal disease must always be considered when treatinginfections in immunocompromised groups such as diabetics

envi-or transplant patients Other risk factenvi-ors fenvi-or the development offungal disease include prolonged hospitalization, intravenous can-nulae, prolonged or broad-spectrum antibiotic administration,hyperalimentation, immunosuppressive drugs, burns, trauma, andmalnutrition

ANTIMICROBIAL THERAPY

Proper selection of antimicrobial therapy requires the knowledge of(a) the most common pathogens causing the specific infection,(b) the mechanism of action of the selected agent, (c) the mecha-nisms of resistance to the selected agent, (d) potential side effects ofthe selected agent, and finally (e) sensitivity patterns of the mostcommon microbes in the environment (e.g., hospital) in whichthey are being prescribed The following is a brief overview of themost common classes of antibiotics Table 3.1 offers a comprehen-sive list of antimicrobial agents and their spectrum of activityagainst common bacterial pathogens

Inhibitors of Cell Wall Synthesis

The majority of antimicrobial agents that inhibit cell wall synthesisshare a common structural element, a ␤-lactam ring The ␤-lactam ring binds to division plate proteins on the bacteria and inhibits cell

Chapter 3 • Surgical Infectious Disease 23

FIGURE 3.2 The wall of the Gram-positive organism (A) contains a

much larger cell wall, while the Gram-negative bacteria (B) has both an

inner and an outer membrane around the relatively thin cell wall

(From Fry DE Surgical infections In: O’Leary JP, ed The Physiologic

Basis of Surgery 2nd ed Philadelphia: Lippincott Williams & Wilkins;

1996:185, with permission.)

Capsule

Cell wall

Plasma membraneCytoplasm

CapsuleEndotoxinOuter membraneCell wallPeriplasmic spaceInner membrane

Cytoplasm

A

B

(NH2)(NH2)GlcFa

GlcFa

PEtNH

polysaccharide

O-AntigenpolysaccharideFa

P

PEtNH

KDOFa

FIGURE 3.3 The chemical structure of

lipopolysaccharide (endotoxin) includeslipid A, the O-antigen side chain, and thecore polysaccharide Lipid A is the toxicmoiety of endotoxin and interacts withvarious cells to induce the septic response

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wall peptidoglycan synthesis, thus inducing autolytic bacteriolysis.

Side chains of the ␤-lactam ring distinguish the agents of this class

from one another and are responsible for the variance in their

ac-tivity The major mechanism of resistance against this class of

an-tibiotics is bacterial production of the enzyme ␤-lactamase, which

disrupts the ␤-lactam ring.

Penicillin G, the prototypical ␤-lactam, has excellent

bacteri-cidal activity against most Gram-positive and anaerobic organisms

The broad-spectrum penicillins (e.g., ampicillin, piperacillin) add

coverage against Gram-negative organisms ␤-Lactamase activity

can be overcome by the addition of enzymatic inhibitors, such

as sulbactam or tazobactam, to the parent antibiotic The most

common adverse effect of the penicillins is the development of anallergic reaction that can range from a benign rash to, on rare occa-sions, anaphylactic shock

The cephalosporins are also broad-spectrum ␤-lactams, which

are classified by generations on the basis of their antimicrobial ity First-generation cephalosporins have strong Gram-positive, mod-est Gram-negative, and poor anaerobic coverage Second-generationcephalosporins have increased Gram-negative and anaerobic activitybut weaker Gram-positive activity Third-generation cephalosporinstarget Gram-negative enteric organisms, and fourth-generation

activ-cephalosporins have extended activity against Pseudomonal species.

Despite their broad spectrum of activity, all cephalosporins are

General spectrum of activity of commonly used antimicrobial agents.

MicroorganismGram-positive Gram-negative AnaerobicAntimicrobial

Agent Streptococci Staphylococci Enterococci Enterics Pseudomonas Cocci BacteroidesPenicillins

NOTE: Higher numbers correspond to higher sensitivity of the organism to the antibiotic

aDifferent specific agents within the same general class vary markedly with respect to spectrum of activity

From Dunn DL, Rotstein OD Diagnosis, prevention, and treatment of infection in surgical patients In: Greenfield LJ, Mulholland MW, Oldham KT,

et al., eds Surgery: Scientific Principles and Practice 3rd ed Philadelphia: Lippincott Williams & Wilkins, 2001, with permission.

T A B L E 3 1

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ineffective against enterococcal infections There is a 1% incidence

of cross-allergic reaction between cephalosporins and penicillins,

with the majority of reactions occurring with early-generation

cephalosporins (e.g., cefazolin)

Other synthetic ␤-lactams include imipenem and meropenem,

which offer the broadest range of activity (positive,

Gram-negative, Pseudomonas, and anaerobes) of all antibiotics

Aztre-onam provides good Gram-negative and pseudomonal coverage

and is unique in that it does not pose a danger in patients with an

allergy to either penicillin or cephalosporins Vancomycin does not

contain a ␤-lactam ring in its structure, but it inhibits cell wall

syn-thesis by preventing glycopeptide polymerization It is effective

against the majority of Gram-positive organisms and is the

treat-ment of choice for MRSA and Staphylococcus epidermidis

infec-tions However, it has poor tissue penetration and may not be an

optimal antibiotic for severe pneumonia or soft tissue infection

Inhibitors of Ribosomal Protein Synthesis

Aminoglycosides, macrolides, tetracyclines, and chloramphenicol

in-hibit bacterial protein synthesis by interfering with ribosomal

ac-tivity All of these agents are considered bacteriostatic except for the

aminoglycosides, which are bactericidal The aminoglycosides bind

irreversibly to the 30S subunit of bacterial ribosomes and are

espe-cially active against aerobic Gram-negative bacilli, Pseudomonas sp.,

and S aureus They are ineffective against anaerobes The most

common mechanism of resistance is plasmid-induced

modifica-tion of the aminoglycoside, which decreases its ability to penetrate

the bacteria and reduces its binding affinity for the ribosome Other

less common mechanisms include modified bacterial enzymes that

reduce aminoglycoside transport into the bacteria and the

evolu-tion of bacteria deficient in aminoglycoside binding sites The two

most common adverse effects of the aminoglycosides are

nephro-toxicity and otonephro-toxicity, although these effects are seen mostly with

prolonged exposure to high trough levels of the medication

The macrolides (erythromycin, clindamycin) bind to the 50S

ri-bosomal subunit to prevent protein synthesis This class of agents

has a broad spectrum of activity against Gram-positive bacteria

and cover Mycoplasma well Erythromycin is commonly combined

with neomycin orally to prepare the bowel for surgery because both

medications (especially neomycin) are poorly absorbed and pose

little risk from systemic exposure Clindamycin is also effective

against anaerobes and Gram-negative bacteria Resistance to this

class of agents is usually due to decreased permeability of the cell

wall or alteration of the ribosomal subunit

Tetracyclines bind to the 30S ribosomal subunit and have a

broad spectrum of activity against positive and

Gram-negative aerobes and anaerobes Gonococci, meningococci,

pneu-mococci, and many Hemophilus influenza organisms are highly

susceptible to the tetracyclines, and they are the treatment of choice

for chlamydia, syphilis, and Lyme disease The predominant

mech-anism of resistance manifests as decreased transport of the drug

into the bacteria Adverse reactions include nausea, vomiting,

esophageal ulcerations, vertigo (minocycline), and permanent

dis-coloration of the teeth in children (tetracycline)

Chloramphenicol is a broad-spectrum bactericidal agent with

excellent penetration through the blood–brain barrier, but its use is

limited to critically ill patients or for highly resistant organisms

because of its potential side effects of bone marrow suppression

and irreversible aplastic anemia Like the macrolides, phenicol binds to the 50S ribosomal subunit and is active againstvirtually all Gram-positive and Gram-negative bacteria, spiro-chetes, rickettsiae, chlamydiae, and mycoplasmas The notable

chloram-exceptions are methicillin-resistant S aureus, Pseudomonas

aerugi-nosa, Serratia marcescens, and many of the Enterobacter species.

Resistance to chloramphenicol can occur and is due to alteration ofthe bacterial cell membrane permeability

Inhibitors of Folic Acid Synthesis

Sulfonamides and trimethoprim are bacteriostatic antimicrobial

agents, which inhibit bacterial DNA replication by interfering with

the folic acid synthetic pathway Sulfonamides are structurally lar to para-aminobenzoic acid (PABA) and are readily incorporated into the folic acid biosynthetic pathway Trimethoprim inhibits di-

simi-hydrofolate reductase, a vital enzyme in the pathway These agentswork synergistically to inhibit the production of folic acid Withoutfolic acid, bacteria are unable to synthesize the purine bases which,along with the pyrimidines, are necessary to form the backbone ofDNA strands (humans get folic acid through their diet, and there-fore host purine synthesis is unaffected) Bacteria are unable toreplicate, and the pathogen is eliminated A sulfonamide andtrimethoprim are typically administered together and are com-

monly used for the treatment of UTIs, and infections with MRSA They are effective prophylactics against Pneumocystis carinii infec-

tion in immunocompromised patients Adverse reactions are ally due to the sulfonamide portion of the molecule and includenausea, vomiting, diarrhea, rash, acute hemolytic anemia, aplasticanemia, agranulocytosis, and thrombocytopenia Organisms de-velop resistance by overproduction of PABA or decreased affinityfor the sulfonamide

usu-Inhibitors of DNA Synthesis

The fluoroquinolones inhibit DNA synthesis by binding to DNA

helicase proteins, which are vital to unwinding the double helixduring replication They have a broad spectrum of activity againstboth Gram-positive and Gram-negative pathogens including

Pseudomonal species and MRSA They are ineffective against

anaer-obes The mechanisms of resistance are decreased bacterial ability and alteration of the target DNA helicase proteins The mostcommon reported adverse effects of fluoroquinolones are nausea,vomiting, and abdominal discomfort Fluoroquinolones are fre-quently used in the treatment of respiratory, GI, and GU infectionsbecause of their broad spectrum of activity and the ability toachieve high serum and tissue drug levels with oral administration.However, prolonged or recurrent exposure to fluoroquinolones isassociated with rapid development of resistance

perme-Metronidazole’s mechanism of action is poorly understood,but it is believed to cause DNA strand breakage and fatal DNAhelicase destabilization It is the most effective antimicrobial agent

against anaerobes, including all Bacteroides species Because of its

rapid oral absorption and low cost, metronidazole is the treatment

of choice for C difficile enterocolitis Adverse effects include nausea

and diarrhea, and it has disulfiram-like properties when mixedwith alcohol, resulting in severe abdominal cramping, flushing, andvomiting Despite its frequent use, resistance to metronidazole byanaerobes is extremely rare

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Antifungal Therapy

Amphotericin B, fluconazole, and caspofungin are the most

com-monly prescribed antifungal agents in surgical patients

Ampho-tericin B has a broad spectrum of activity against fungi and can be

used for the majority of fungal infections It is a polyene macrolide

that binds to fungal membrane sterols to cause cell lysis and is

con-sidered the definitive treatment for all systemic fungal infections It

is a potent drug, but it is also toxic and its side effects can limit its

use Frequent adverse effects at the onset of therapy include fever,

chills, nausea, vomiting, and hypotension Nephrotoxicity is the

most common serious side effect associated with amphotericin B

and develops in up to 80% of patients Amphotericin B can also

cause anaphylaxis, reversible normocytic anemia,

thrombocytope-nia, leukopethrombocytope-nia, severe electrolyte disturbances, and

throm-bophlebitis at the injection site It is also available in a liposomal

form (AmbiSome), which is associated with a lower toxicity profile

but is more expensive Resistance to amphotericin B is very rare

Fluconazole is a safer alternative to amphotericin B in the

treat-ment of many fungal diseases Its mechanism of action is the

disrup-tion of fungal membrane sterol synthesis It is most commonly used

for infections caused by the Candida species except Candida

glabrata (Torulopsis) Increasingly, Candida albicans is also

becom-ing resistant to this agent It is highly effective in the treatment of

mucosal candidiasis and candiduria and is administered as lifelong

maintenance therapy (after induction therapy with amphotericin B)

for HIV-infected patients with cryptococcal meningitis

Life-threatening infection by any of these fungi usually requires

ampho-tericin B or caspofungin treatment Nausea, vomiting, and diarrhea

are the most commonly reported side effects of fluconazole

Caspofungin, an echinocandin, is also a safer alternative to

am-photericin B and differs from fluconazole in that it has broader

an-tifungal activity As with the other anan-tifungal agents, its mechanism

of action involves disruption of fungal cell wall synthesis Because

of its broad spectrum and low toxicity, caspofungin is the preferred

agent for empiric fungal coverage in patients with severe sepsis or

septic shock The spectra of coverage for the commonly used

anti-fungal agents are listed in Table 3.2

SURGICAL PROPHYLAXIS

Surgical wound infections are the most common nosocomial

infec-tions among surgical patients Up to 5% of all patients undergoing

an operation develop wound infections that result in prolonged

hospitalizations, increased costs, and significant morbidity The jority of wound infections can be attributed to endogenous contam-ination from the host’s resident microflora (e.g., skin and GI tract) orexogenous contamination from a break in sterile technique Carefulmaintenance of sterile technique is sometimes overlooked duringprolonged or emergent operations Endogenous contamination ofthe surgical site is a persistent threat starting from the time of inci-sion until the sterile incision re-epithelializes Proper preparation ofthe surgical site begins with hair removal using clippers as opposed

ma-to razors just prior ma-to the time of procedure Shaving the surgical sitethe night before surgery actually increases the infection rate by100% Shaving promotes bacterial growth in the razor nicks on theskin The operative site should be scrubbed with a germicidal deter-gent and then painted with an antimicrobial solution of iodine, povi-done–iodine, or chlorhexidine Both iodine and chlorhexidine arebactericidal but chlorhexidine may provide a longer period of bacte-ricidal activity after its application This significantly reduces thequantity of skin microflora present at the time of the incision If therespiratory, GI, or GU tracts are entered during the procedure, a sep-arate set of instruments should be used and then removed from thefield, and the surgeons should change their gloves, after the “dirty”portion of the procedure is complete These easily applied principlescan have a dramatic impact on reducing the incidence of wound in-fections from endogenous contamination

Preoperative intravenous antibiotic administration has proven

to reduce the risk of postoperative wound infection in contaminated and contaminated cases (see Table 3.3) Patientsundergoing “clean case” surgery do not require prophylactic anti-biotics because the infection rate is low (1.5%) and not significantlylowered by prophylaxis Alternatively, when prosthetic materials areimplanted in clean cases, especially during cardiac surgery through

clean-a mediclean-an sternotomy, clean-and for clean-all neurosurgicclean-al procedures, phylactic antibiotics do significantly reduce the rate of infection.The optimal time of antibiotic administration is 30 to 60 minutesprior to skin incision so that therapeutic blood levels are achieved

pro-at the time of skin incision Prolonged operpro-ations or operpro-ationsassociated with large blood loss require an additional dose; how-ever, postoperative dosing does not significantly alter the rate ofinfection and may lead to the development of resistant organismsand an increased risk of adverse reactions

Cefazolin, a first-generation broad-spectrum cephalosporin, iscommonly used as the prophylactic agent for the majority of sur-gical procedures If Gram-negative bacteria and anaerobes are

General spectrum of activity of commonly used antifungal agents.

Organism Amphotericin Fluconazole Caspofungin Voriconazole

T A B L E 3 2

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anticipated in the operative site (e.g., during bowel surgery), the

second-generation cephalosporins cefotetan or cefoxitin may be

superior For patients allergic to cephalosporins, vancomycin is a

good alternative, but it lacks Gram-negative and anaerobic activity

Certain operative sites have higher risks of infections and require

additional prophylaxis Historically, patients undergoing colorectal

surgery have benefited from mechanical cleansing of the bowel and

oral administration of erythromycin and neomycin to reduce the

bacterial concentration within the colon Recently, there are new

data suggesting that mechanical bowel preparation may not

signifi-cantly alter wound infection rate but may increase morbidity by

causing the patient to be dehydrated prior to surgery, although this

remains controversial

Tenets of surgery that are known to decrease the incidence of

wound infection include: obliteration of dead space, removal of

devitalized tissue, wound closure without tension, and hemostasis

without compromise of the vascular supply to the wound The

presence of hematoma, seroma, and dead tissue supplies sufficient

adjuvant and media for bacterial growth Although drains were

originally designed to evacuate hematoma and reduce the risk of

infection, open drains (e.g., Penrose) have been shown to increase

infection rates by serving as an entry portal for bacteria Closed

suction drains (e.g., Jackson-Pratt bulb suction) enable the drain

tip to remain sterile and have proven effective in reducing infection

rates in certain settings Generally, the presence of any foreign body,

including drains, increases the risk of infection, and therefore

drains should only be used when the accumulation of blood or

fluid is anticipated

Immunotherapy is rarely used to prevent surgical infections, but

it is very successful in preventing tetanus The tetanus toxin is

pro-duced by the organism Clostridium tetanii and inhibits

neurotrans-mitter release leading to spastic paralysis After a full course of active

immunization (full childhood series or three doses in adults), passiveimmunization with a booster injection of the toxoid protects adultsfor as long as 10 years Patients with dirty wounds should receive abooster injection of the toxoid if their last booster was more than

5 years prior to the current event It is imperative to ask all patientswith wounds about their tetanus immunization history Patients withunclear or incomplete immunization histories and those who havenever received immunization should receive the tetanus immunoglob-ulin and toxoid booster at the same time in different injection sites

SPECIFIC INFECTIONS Intra-abdominal Infections

Peritonitis is a surgical disease that can be rapidly fatal if untreated

Primary peritonitis occurs in patients with impaired host defenses Secondary peritonitis results from contamination of the peritoneal

cavity by a perforated viscus or external trauma Tertiary peritonitis is

the result of a change in the host microbial flora following antibiotictreatment of secondary peritonitis so that normally low-virulence mi-crobes become pathogenic Prosthetic device–associated peritonitisoccurs in patients with indwelling intraperitoneal prosthetic devicessuch as peritoneal dialysis catheters or ventriculoperitoneal shunts.The induction of secondary peritonitis requires the presence ofboth bacteria and an adjuvant like blood, stool, or debris The host re-sponse to microbial invasion of the peritoneal cavity occurs by threedifferent mechanisms: phagocytosis, clearance, and sequestration.Following a bacterial inoculation of the peritoneal cavity, bacteria

undergo phagocytosis by resident macrophages These activated

macrophages release cytokines, which attract additional phagocyticleukocytes (e.g., PMNs) to assist them in engulfing the invadingorganisms and eliminating them from the peritoneal cavity The

Classification of operative wounds and risk of infection.

Clean Elective, not emergency, nontraumatic, primarily ⬍2

closed; no acute inflammation; no break in technique;

respiratory, gastrointestinal, biliary, and genitourinary tracts not entered

Clean-contaminated Urgent or emergency case that is otherwise clean; elective ⬍10

opening of respiratory, gastrointestinal, biliary, or genitourinary tract with minimal spillage (e.g.,appendectomy) not encountering infected urine

or bile; minor technique breakContaminated Nonpurulent inflammation; gross spillage from ⬃20

gastrointestinal tract; entry into biliary or genitourinary tract in the presence of infected bile

or urine; major break in technique; penetratingtrauma ⬍4 hours old; chronic open wounds to begrafted or covered

Dirty Purulent inflammation (e.g., abscess); preoperative ⬃40

perforation of respiratory, gastrointestinal,biliary, or genitourinary tract; penetratingtrauma ⬎4 hours old

From Cruse PJ, Foord R The epidemiology of wound infection A 10-year prospective study of 62,939 wounds

Surg Clin North Am.1980; 60:27–40

T A B L E 3 3

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resident macrophages represent the host’s first line of defense

Clear-ance occurs via translymphatic absorption of bacteria, fluid, and other

particles through specialized structures in the peritoneal mesothelium

on the underside of the diaphragm The bacteria transit through

stomata located between mesothelial cells into lymph vessels, which

drain into the thoracic duct The bacteria gain access to the

blood-stream when the thoracic duct empties into the left subclavian vein

Clearance of the peritoneal cavity is a highly efficient process that

re-sults in bacteremia within minutes of bacterial invasion into the

peri-toneal cavity Pathogens that escape phagocytosis and clearance

undergo sequestration It is hypothesized that once the mesothelial

cells of the peritoneal cavity recognize infection or injury, they

pro-duce an inflammatory exudate rich in opsonins and fibrinogen This

exudative fluid forms fibrin polymers which, along with the

omen-tum and other mobile viscera, wall off contaminated enteric contents,

seal perforations, and prevent further bacterial seeding of the

peri-toneal cavity If the inflammatory fluid and fibrin deposition

com-pletely isolate bacteria from the host’s phagocytic cells, a cavity is

created which promotes bacterial proliferation and results in the

for-mation of an abscess An average of four to five isolates usually occur

in patients with secondary intra-abdominal infections, and 80% to

90% of specimens contain both aerobic and anaerobic bacteria This

can be one method of differentiating secondary bacterial peritonitis

from primary or prosthetic device–associated bacterial peritonitis

The difference is critical because primary peritonitis is treated with

antibiotics alone, whereas secondary peritonitis requires operation to

control and remove the source of infection Commonly encountered

aerobic isolates seen with secondary peritonitis include

Gram-negative bacilli (E coli, Enterobacter sp., Klebsiella sp.), Gram-positive

cocci (streptococci, staphylococci, and enterococci species), and the

Bacteroides species (especially B fragilis) Clostridium and the

anaero-bic cocci are the other common anaerobes isolated

Antibiotic therapy should be initiated as soon as the diagnosis of

peritonitis is established Initial therapy is empiric and must cover a

wide spectrum of microorganisms If the likelihood of resistant

Gram-negative rod infection is small, then ampicillin/sulbactam,

piperacillin/tazobactam, or a second-generation cephalosporin is a

good initial option If the perforated viscus is in the lower rather than

upper GI tract, anaerobic coverage should be included Surgical

in-tervention for peritonitis is aimed at identifying and controlling the

source of the infection, evacuating pus and enteric contents, and

preventing sepsis Antibiotics should be tailored on the basis of the

results of intraoperative cultures and should be continued

postoper-atively General guidelines for the discontinuation of antibiotics

include (a) when the patient is hemodynamically stable, well

appear-ing, and afebrile for 48 hours, (b) when the leukocyte count has

normalized for 48 hours, and (c) the band count is ⬍3%

Postoperative Pneumonia

Postoperative pneumonia is the most common infection in surgical

intensive care units (ICUs) Pneumonia is the leading cause of ICU

mortality and is the result of compromised host defenses

Postoperative pneumonia can be classified into three categories:

ventilator-associated pneumonia (VAP), nonventilator-associated

pneumonia, and aspiration-associated pneumonia VAP is defined

as the development of a pulmonary infection after the initiation of

mechanical ventilation and is classified as early (within 4 days

of the initiation of mechanical ventilation) or late (after 4 days

of mechanical ventilation) Endotracheal intubation allows the

microflora of the oropharynx direct access to the tracheobronchialtree, eliminates the host’s natural defense mechanism of coughing,and disrupts the competency of the glottis The mortality rate ofVAP is 40% to 70% Early VAP tend to be caused by community-

acquired microbes (methicillin-sensitive S aureus, Hemophilus sp.,

Streptococcus sp.), whereas late VAP is frequently due to nosocomial

infection (Pseudomonas, Acinetobacter, MRSA).

Nonventilator-associated pneumonia begins with the ment of atelectasis from reduced tidal volumes Decreased tidal vol-umes in the postoperative patient are secondary to the lingeringeffects of general anesthesia, postoperative pain and splinting, andreduced respiratory drive from narcotics The collapse of airways

develop-in atelectatic lung segments impairs the mucociliary mechanismand prevents clearance of bacteria This leads to local bacterial pro-liferation in an enclosed space, which can progress into a lobarpneumonia

The development of aspiration-associated pneumonia may ormay not be preceded by an obvious aspiration event Gross aspira-tion, commonly due to an altered sensorium and a distended stom-ach, causes a chemical pneumonitis which places the lung at a highrisk of bacterial infection Microaspiration causes pneumonia in amore subtle manner

In healthy patients, microaspiration of normal oropharyngealflora is typically a benign event that stimulates the cough reflex andresults in expectoration of the aspirated microbes Postoperativepatients have an impaired cough reflex and the composition oftheir oropharyngeal flora is altered by gastric acid–reducing med-ications These medications alkalinize the normally acidic milieu ofthe stomach, which results in gastric proliferation of intestinal bac-teria and retrograde colonization of the oropharynx In this cir-cumstance, microaspiration poses an increased risk of pneumonia,

as each occult event exposes the tracheobronchial tree to more ulent Gram-negative enteric pathogens

vir-Restoration of the normal host defenses is the key to ing postoperative pneumonia This includes early extubation,ambulation, coughing, deep breathing, incentive spirometry, andpostural chest physiotherapy Aggressive suctioning of the airwayshelps manage secretions and prevents mucus plugging in both ven-tilated and nonventilated patients Aspiration precautions includegastric decompression and an upright position during oral intake.Treatment of postoperative pneumonia consists of the mainte-nance of the pulmonary toilet by the methods described earlier,and broad-spectrum or culture-directed antibiotics

prevent-Necrotizing Soft Tissue Infections

Necrotizing fasciitis is the most serious of all soft tissue infections

and is associated with a mortality rate of 40% or higher ing these infections can be challenging, and a high index of suspi-cion is critical because the classic signs of a wound infection areoften absent The infection is introduced through a break in the skin (e.g., incision, perineal decubitus ulcer, enterostomy),although the inciting event is not identified in up to 50% of cases.Signs of a necrotizing soft tissue infection include skin discol-oration or necrosis; subcutaneous crepitus; blebs; or a thin, grayishfoul-smelling drainage Often, the overlying skin may have arelatively normal appearance, masking significant infection of theunderlying tissues The presence of gas on x-ray or CT scans of theinvolved soft tissue may aid in the diagnosis; however, the absence

Diagnos-of gas does not rule out the diagnosis A failure to respond to

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conventional nonoperative therapy, rapid progression of any clinical

signs of soft tissue infection, or a significant change in the patient’s

hemodynamic status may be the earliest signs of a necrotizing soft

tissue infection necessitating urgent operative intervention

Primary operative therapy of necrotizing fasciitis is radical

de-bridement of all infected and necrotic tissue so that margins into

grossly normal, bleeding, healthy tissue are achieved Patients

require an average of three surgical debridements, spaced 12 to

36 hours apart, to obtain control of the infection Very rarely,

am-putation of extremities may be required to gain control of this

in-fection Wounds are packed loosely open with a gauze that is

changed frequently These infections tend to be polymicrobial and

synergistic in nature, and both aerobic and anaerobic organisms are

usually present Empiric broad-spectrum antibiotic therapy should

be initiated immediately with high doses of penicillin G included in

the regimen to treat Clostridium sp Because of the recent marked

increase in the prevalence of MRSA, however, vancomycin should

also be given Gram stain and culture data sent from intraoperative

specimens can aid in subsequent direction of the postoperative

antibiotic regimen

Gram-negative Bacterial Sepsis

Gram-negative bacterial sepsis is one of the most lethal disease

processes that occur in the surgical population Factors that

predispose patients to this disease include old age, disability,

mal-nutrition, immunosuppression, prior or concurrent antimicrobial

administration, renal insufficiency, diabetes mellitus, congestive

heart failure, malignancy, the presence of a central line, and

respira-tory or urinary tract intubation Many different organisms can

cause this devastating septic cascade, but E coli is the most

com-mon Fever, abnormal metabolism, activation of the complement

and coagulation cascades, decreased systemic vascular resistance

(hypotension), increased cardiac output, and elevated lactate are

features of this disease Gram-negative sepsis can lead to multiple

system organ dysfunction The mechanisms by which

Gram-negative infections produce these detrimental physiologic host

re-sponses are not fully understood but are related to capillary

endothelial inflammation with microthrombi formation

Blood cultures confirm the diagnosis, but Gram-negative

sep-sis is usually suspected when septic physiology is recognized,

espe-cially in the setting of a known source of infection Empiric

antibiotic administration initiated early in the course of the disease

is beneficial, but the mortality rate of this disease despite antibiotic

therapy remains 20% to 30%

Catheter and Prosthetic Device Infections

Many patients require long-term indwelling intravenous catheters for

chemotherapy or parenteral hyperalimentation Infection is a major

problem with such devices The most common pathogenic organisms

involved are S aureus and S epidermidis, which produce a biofilm that

facilitates adherence to the catheters and prevents antimicrobial

pene-tration Fungal and Gram-negative organisms also infect indwelling

catheters, especially in immunocompromised patients who have been

receiving long-term antibiotic therapy Optimal treatment of these

types of infections consists of device removal and initiation of an

ap-propriate antimicrobial agent In patients receiving long-term

hyper-alimentation without alternative intravenous access sites, the catheter

may be left in place and treated with a prolonged course of antibiotic

therapy However, sepsis, bacteremia, or fungemia necessitatescatheter removal regardless of the circumstances

Urinary Tract Infections

UTIs are the most common cause of Gram-negative bacterial sepsis

in hospitalized patients The presence of 105CFU/mL of urine in apatient is diagnostic of a UTI Many antimicrobial agents concen-trate in the urine facilitating efficient therapies Culture and sensi-tivity reports should be obtained and follow-up specimens should

be sent to the laboratory to confirm eradication Over 80% of UTIs

are due to E coli; other common pathogens include Klebsiella,

Proteus, Pseudomonas, and Enterobacter species.

HIV in the Surgical Patient

The HIV epidemic over the past 25 years has created new infectious

disease challenges for the surgeon This blood-borne virus is mitted by exposure to infected blood or body fluids The virus infects

trans-CD4 lymphocytes and releases RNA and the enzyme reverse

tran-scriptase This enzyme, using the host cell machinery, produces

mul-tiple copies of viral DNA (cDNA) from the template RNA ThiscDNA incorporates itself into the host’s chromosomes and new viri-ons are produced Viral synthesis continues until the capacity of thecell has been exceeded and the T lymphocyte ruptures, releasing mul-tiple copies of the virus into the blood to infect other host CD4 lym-phocytes This ultimately results in depletion of host CD4 cells andimmunosuppression When the CD4 count drops below 200 cells/␮L

or the patient manifests an indicator condition/infection (e.g.,

P carinii pneumonia, Toxoplasmosis, Cryptosporidiosis), the patient

is considered to have acquired immunodeficiency syndrome (AIDS).

Patients with AIDS often present with abdominal pain ing the attention of a surgeon Because of their immunocom-promised state, these patients are susceptible to a variety ofopportunistic infections but more often have uncommon presenta-tions of common diseases A recent study found that only 10% ofHIV-positive patients had an opportunistic infection as the cause

requir-of their abdominal pain The most common surgical causes requir-ofabdominal pain in patients with HIV are bowel perforation, bowelobstruction, appendicitis, and cholecystitis

Acute appendicitis is as common in the HIV-positive tion as it is in the general population, but its presentation may beatypical It may present as right lower quadrant pain and a normalwhite blood cell count Up to 40% of patients with appendicitis andAIDS will not mount a fever In addition to a fecalith, appendicitismay be incited by obstruction of the appendiceal orifice by Kaposisarcoma (KS) or a CMV infection leading to acute appendicitis.Generally, HIV-positive patients tend to present later in the course

popula-of disease and therefore are more likely to have perforated dicitis at the time of operation However, there is no difference inmortality from appendicitis between patients who are HIV positive

appen-or HIV negative

GI tract obstruction may be caused by CMV, non-Hodgkinlymphoma (NHL), KS, and mycobacterial infection CMV infec-tion is the most frequent cause, typically occurring in the terminalileum and colon The infection can progress and cause bowel perfo-ration because of ischemia resulting from CMV-induced vasculitis

As with appendicitis, symptoms may be vague and clinical tis may be absent in late-stage AIDS CMV-induced perforation ofthe GI tract has a poor prognosis and is a marker of advanced-stageChapter 3 • Surgical Infectious Disease 29

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peritoni-AIDS These patients have a high probability of death from

peri-tonitis or another AIDS-related illness

The second most common cause of bowel obstruction in

patients with AIDS is NHL Peripheral lymphadenopathy is usually

absent but bulky central adenopathy is noted on CT scan

Treat-ment is based on chemotherapy and protease inhibitors but the

overall prognosis is dismal The surgical goal is to palliate the

symptoms of obstruction Bowel obstruction due to KS should be

suspected in patients with cutaneous KS Although GI tract KS can

also cause GI hemorrhage, intussusception, appendicitis, or

chole-cystitis, it most commonly causes bowel obstruction The gold

standard for diagnosis is endoscopy and biopsy Treatment is

sup-portive with immune reconstitution using protease inhibitors

Radiation therapy may also be beneficial in some cases

Acalculous cholecystitis is twice as common as calculous

chole-cystitis in patients with AIDS for reasons that remain uncertain but

may be related to the high incidence of viral and other opportunistic

infections Most patients present with right upper quadrant/

epigastric pain and nausea/vomiting, but fever, jaundice, and

ele-vated liver function tests are seen in less than 25% of cases

Leukocy-tosis is also unusual Ultrasound remains the most commonly used

screening study, but hydroxyiminodiacetic acid (HIDA) scan may be

useful in equivocal cases In patients who cannot undergo operation,

percutaneous cholecystostomy remains the treatment of choice

The most common nonsurgical causes of abdominal pain in this

population are pancreatitis, infectious enteritis/gastritis, and NHL

Other less common causes include cholangitis and splenomegaly The

high incidence of pancreatitis is related to the use of protease

in-hibitors Enteritis/gastritis is frequently due to opportunistic infection

with CMV, fungi, or mycobacterial species Treatment is based on

restoring immune competence and antibiotic therapy Cholangitis in

the AIDS patient can be due to stenosis at the ampulla of Vater or

scle-rosis of the biliary epithelium Cryptosporidium is the most

com-monly involved pathogen, and CMV is the second most common

cause Patients frequently present with abdominal pain, nausea/

vomiting, and elevated liver function tests but are rarely jaundiced.Intra- and extrahepatic biliary dilatation is seen on ultrasound Diag-nostic confirmation and treatment are via endoscopic retrogradecholangiopancreatography (ERCP), which can allow sphincterotomyand stent placement The overall prognosis is poor, and there is nosurgical treatment for this problem Splenomegaly can develop most

commonly as a result of CMV, Salmonella, or mycobacterial infection

and is present in up to 70% of patients with AIDS but is usuallyasymptomatic Splenectomy is indicated in cases complicated byrefractory thrombocytopenia (which is not due to bone marrowfailure), splenic abscess, splenic infarct with abdominal pain, orhemorrhage due to rupture

Beauchamp RD, Evers BM, Mattox KL, eds Sabiston Textbook of

Surgery 16th ed Philadelphia: WB Saunders; 2001:171–188.

Dellinger EP Surgical infections and choices of antibiotics In:

Townsend CM Jr, Beauchamp RD, Evers BM, et al., eds Sabiston

Textbook of Surgery 16th ed Philadelphia: WB Saunders;

2001:171–188

Dunn DL, Rotstein OD Diagnosis, prevention, and treatment of fection in surgical patients In: Greenfield LJ, Mulholland MW,

in-Oldham KT, et al., eds Surgery: Scientific Principles and

Pra-ctice 3rd ed Philadelphia: Lippincott Williams & Wilkins;

2001:178–202

Fry DE Surgical infection In: O’Leary JP, ed The Physiologic Basis

of Surgery 3rd ed Philadelphia: Lippincott Williams & Wilkins;

2002:212–258

Fry DE Surgical problems in the immunosuppressed patient In:

Townsend CM Jr, Beauchamp RD, Evers BM, et al., eds Sabiston

Textbook of Surgery 16th ed Philadelphia: WB Saunders;

2001:189–197

Howard RJ, Simmons RL Surgical Infectious Diseases 3rd ed.

Norwalk: Appleton & Lange; 1998

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