CONTENTS

Preface xiRichard I. Whyte

Smoking Cessation: Techniques and Potential Benefits 189Tomasz M. Ziedalski and Stephen J. Ruoss

Tobacco smoking significantly increases the risk of perioperative and postoperative com-plications. Observational evidence suggests that preoperative smoking cessation maydecrease the risk of certain complications. Smoking cessation programs that employbehavioral and cognitive therapy and pharmacotherapy have been used successfully inmany situations and should be used to discourage smoking preoperatively. Further eval-uation of the effectiveness of particular types of interventions is needed to clarify the bestapproach to smoking cessation for surgical patients.

Preoperative Patient Education in Thoracic Surgery 195 Richard I. Whyte and Patricia D. Grant

This article describes the role of preoperative teaching in thoracic surgery. Preoperativepatient teaching may take many forms and is offered to patients across many venues andformats. The goal of patient teaching is to improve patients’ understanding of their dis-ease process and the operation that they are about to experience with the goal of enlist-ing their active participation in the healing process. The additional goal of obtaininginformed consent is not only codified in law, but also has become an ingrained compo-nent to the current physician-patient relationship. The preoperative teaching process isbest approached as a team effort, and multiple modalities often must be used so that thepatient becomes a knowledgeable and willing member of the team.

The Value of Preoperative Pulmonary Rehabilitation 203Shanon T. Takaoka and Ann B. Weinacker

Although pulmonary rehabilitation is potentially beneficial before any surgery, it hasbeen applied and studied primarily in the setting of major thoracic surgical procedures,including lung volume reduction surgery, lung transplantation, and lung resection. Thisarticle defines the essential elements of pulmonary rehabilitation, outlines the prerequi-sites for enrollment, and discusses its current role in the setting of anticipated thoracicsurgery. Pulmonary rehabilitation seems to be a cost-effective, benign intervention withno adverse effects and should remain an essential component of patient managementbefore lung transplantation, lung volume reduction surgery, lung resection, and poten-tially any other elective thoracic surgical procedure.

PREOPERATIVE PREPARATION OF PATIENTS FOR THORACIC SURGERY

VOLUME 15 • NUMBER 2 • MAY 2005 v

Informed Consent: Ethical and Legal Aspects 213Carole A. Klove, Sarah J. DiBoise, Betty Pang, and William C. Yarbrough

The doctrine of informed consent serves the dual function of promoting the beneficence,benevolence, and nonmalfeasance of the physician and the autonomy, bodily integrity,and self-determination of the patient. Conflict arises when a patient’s individual libertyrights clash with a physician’s medical conclusions formed in the patient’s perceivedbest interest. This article explores the ethical and legal nuances of the doctrine ofinformed consent in an attempt to empower the provider with a deeper understandingof the physician’s rights and responsibilities in obtaining a true informed consent.

Fast-Tracking: Eliminating Roadblocks to Successful Early Discharge 221Jules Lin and Mark D. Iannettoni

This article describes common obstacles to successful early discharge that face many thoracic surgeons despite technically successful procedures; these obstacles includeinadequate pain control, prolonged air leaks, and social issues. With continually increas-ing health care costs and limited resources, identifying the factors that affect length ofstay has taken on new importance. Potential solutions that also maintain the quality ofpatient care are discussed and include the use of minimally invasive techniques, opti-mizing pain control, early mobilization, discharge planning, patient education, and thedevelopment of clinical pathways.

Perioperative Antibiotics: When, Why? 229Mark S. Allen

The use of prophylactic antibiotics in general thoracic surgery is well established. Thisarticle explains the rationale for modern-day surgical wound infection prophylaxis, thewhy and the when. Various arguments about the use of antibiotics to prevent empyemaand pneumonia after a thoracic operation also are presented.

Pulmonary Embolism Prophylaxis: Evidence for Utility in Thoracic Surgery 237Dean M. Donahue

Patients requiring thoracotomy for the treatment of malignancy are at risk for develop-ing a pulmonary embolism. Few data exist on effective prophylaxis techniques in thisspecific patient population, yet effective strategies can be inferred from other major sur-gical procedures to reduce the risk of this potentially life-threatening complication.

Management of the Anticoagulated Patient 243Mark H. Meissner and Riyad Karmy-Jones

Patients who are to undergo surgery may be anticoagulated for therapeutic reasons(eg, deep venous thrombosis, valve replacement, lytic therapy) or because of comorbidconditions (eg, renal or hepatic failure). In addition, the proposed operative interventionmay be elective or urgent. The approach to managing the coagulation status is criticallyaffected by the circumstances and requires a basic understanding of the risks involved ofbleeding and correcting the underlying pathophysiology. This article reviews the indica-tions, pharmacology, and complications of common anticoagulation therapies (includinglaboratory and clinical assessment) in the surgical patient.

vi CONTENTS

Preoperative Cardiac Evaluation: Mechanisms, Assessment, and Reduction of Risk 263Euan A. Ashley and Randall H. Vagelos

Considerable uncertainty exists as to when it is appropriate to investigate cardiac disease ina preoperative thoracic patient and which tools are best suited to the task. Common diseaseorigins, commonality of symptoms, and coexistent disease all serve to make accurate diag-nosis and effective risk prediction difficult. Interventions known to reduce risk and savelives are few. This article explores the basis for anesthetic risk in cardiovascular and pul-monary disease. Common disease mechanisms and the utility of tools available to assess riskare discussed. Risk reduction also is discussed, and recommendations specific to the pre-operative cardiac evaluation of the thoracic surgery patient are offered.

Preoperative Preparation for Esophageal Surgery 277Jessica Scott Donington

Esophageal surgeries can be placed into two broad categories: anatomic modificationsfor benign esophageal disorders and resections for carcinomas. The clinical setting andscope of intervention are different for these two groups, as is the preoperative prepara-tion. The goal of preoperative evaluation for benign esophageal disease is to make anaccurate and complete diagnosis; the tools for this include barium esophagogram,endoscopy, pH monitoring, and manometry. The preoperative concerns for esophagealresection for cancer involve accurate staging of the cancer, using CT, positron emissiontomography, and endoscopic ultrasound, and complete physiologic evaluation of thepatient to determine his or her ability to withstand a large operation.

Preoperative Preparation of the Patient with Myasthenia Gravis 287Kemp H. Kernstine

The morbidity and mortality of patients with myasthenia gravis undergoing thymectomycan be substantial. The surgeon must have a thorough knowledge of the evaluation andtests necessary to confirm a diagnosis and should not rely totally on the neurologist’sassessment. Through partnership with the neurologist, the ideal means of medical andsurgical management can be achieved.

Preoperative Pulmonary Evaluation of the Thoracic Surgical Patient 297Aditya K. Kaza and John D. Mitchell

Surgery remains the mainstay of therapy for early-stage non-small lung cancer. Manypatients have poor underlying pulmonary function, in large part resulting from long-termtobacco abuse. It is the responsibility of the thoracic surgeon to assess accurately the pul-monary function of a potentially operable patient at the time of the preoperative evaluation.This assessment provides an objective risk profile associated with the planned pulmonaryresection for the patient and family, minimizes morbidity and mortality, and in some casesleads the surgeon to recommend alternative therapies. This article provides a systematicapproach to the pulmonary evaluation of the thoracic surgical patient.

The Preoperative Anesthesia Evaluation 305Clifford A. Schmiesing and Jay B. Brodsky

Timely and thorough preoperative assessment is a cornerstone of excellent patientoutcomes and efficient use of medical resources. This article focuses on the importantelements of the preoperative anesthetic assessment of a patient presenting for thoracic

CONTENTS vii

surgery. Areas of shared concern between the surgeon and anesthesiologist areemphasized. Cardiovascular risk assessment and preoperative management are high-lighted because cardiorespiratory complications are the major causes of morbidityafter thoracic surgery. Practical and simple strategies for common preoperative issues,including medications and diagnostic testing, are provided, and the benefits of a com-prehensive anesthesia preoperative assessment are discussed.

Index 317

viii CONTENTS

FORTHCOMING ISSUES

August 2005

New Treatments for Gastroesophageal Reflux DiseaseClaude Deschamps, MD, Guest Editor

November 2005

Ethics in Thoracic SurgeryRobert M. Sade, MD, Guest Editor

RECENT ISSUES

February 2005

Advances in Anesthesia and Pain ManagementJerome M. Klafta, MD, Guest Editor

November 2004

MesotheliomaDavid J. Sugarbaker, MD, andMichael Y. Chang, MD, Guest Editors

August 2004

Quality of Life After Thoracic SurgeryAnthony P.C. Yim, MD, Guest Editor

May 2004

Aggressive Surgery for Lung Cancer Valerie W. Rusch, MD, Guest Editor

THE CLINICS ARE NOW AVAILABLE ONLINE!

Access your subscription at:http://www.theclinics.com

Thorac Surg

Preface

Preoperative Preparation of Patients for Thoracic Surgery

Richard I. Whyte, MD

Guest Editor

The preoperative preparation of patients for tho-

racic surgery is complex and involves individuals

from diverse subspecialties within the field of

medicine. This issue of the Thoracic Surgery Clinics

focuses on these interrelationships through contri-

butions from the fields of nursing, law, pulmonary

medicine, cardiology, and anesthesia, in addition to

thoracic surgery. Although several of the authors

are from Stanford University, I have attempted to

provide some diversity in both geographical location

and specialty training in the selection of authors for

this issue.

Because thoracic surgery encompasses a wide

range of pathologic entities, I have attempted to cover

ground that is common to many patients and disease

processes (anesthetic concerns, preoperative teaching,

legal issues of informed consent, smoking cessation,

preoperative cardiac evaluation, antibiotic and deep

venous thrombosis prophylaxis), as well as more

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.03.008

specific issues such as pulmonary rehabilitation, my-

asthenia gravis, esophageal surgery, and fast-tracking

in lung surgery.

I would like to thank the authors who contri-

buted to this issue, because they contributed consider-

able amounts of time in preparing these manuscripts.

I would also like to thank Dr. Mark Ferguson

for giving me the opportunity to put this piece

of collaborative work together. I hope that the

readers find it interesting and valuable, and I

would be happy to receive any feedback on any

of the contributions.

Richard I. Whyte, MD

Department of Cardiothoracic Surgery

Stanford University Medical Center

300 Pasteur Dr, CVRB 205

Stanford, CA 94305, USA

E-mail address: riwhyte@stanford.edu

Clin 15 (2005) xi

reserved.

thoracic.theclinics.com

Thorac Surg Clin

Smoking Cessation: Techniques and Potential Benefits

Tomasz M. Ziedalski, MD, Stephen J. Ruoss, MD*

Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, 300 Pasteur Drive,

H3143, Stanford, CA 94305, USA

Cigarette smoking is the leading preventable

cause of death in the United States and is responsible

for 20% of all deaths, or more than 400,000 deaths

annually [1]. The potential health benefits of smoking

cessation are substantial. Smoking cessation reduces

the risk and slows the progression of already estab-

lished smoking-related lung disease and increases life

expectancy, even when smokers stop smoking after

age 65 years or after the development of a tobacco-

related disease [2].

Each year, 10% of the general population may

undergo surgery with general anesthesia. Although

complications rates vary with the type of surgery per-

formed and the patient’s underlying health status,

pulmonary and cardiovascular complications occur in

10% of the cases [3]. Because smokers have a sixfold

increase in intraoperative and postoperative complica-

tions, efforts directed at reducing smoking prevalence

in prospective surgical patients might be beneficial

in reducing perioperative medical problems [4].

Effects of cigarette smoke

Smoking has multiple effects on the pulmonary

and cardiovascular systems and on wound healing.

In a large retrospective study, specific respiratory

events, such as reintubation, laryngospasm, broncho-

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.003

The authors have no relationship with any commercial

company that has a direct financial interest in the subject

matter of this article. No funding support was received for

this article.

* Corresponding author.

E-mail address: ruoss@stanford.edu (S.J. Ruoss).

spasm, aspiration, hypoventilation, and hypoxemia,

were significantly increased among smokers, with

the relative risks of 1.8 in all smokers, 2.3 in young

(16–39 years old) smokers, and 6.3 in obese young

smokers [5]. The relative risk of perioperative bron-

chospasm was 25.7 in young smokers with chronic

bronchitis [5].

Smoking causes increased mucus production and

damage to the tracheal cilia, leading to decreased

mucus clearance [6]. The combination of decreased

mucus clearance and tobacco smoke–induced im-

pairment of immune function may lead to an in-

creased risk of pulmonary infections [7,8].

Surgery itself is associated with reduced pul-

monary function. This reduced function is observed

predominantly in thoracic and abdominal surgery,

in which atelectasis and diaphragmatic dysfunction

lead to significant reduction in vital capacity and

functional residual capacity [9]. Pulmonary function

impairment is further accentuated among smokers.

Smoking cessation can result in improvement in

maximal expiratory flow rates and closing volumes

[10,11].

Smoking has many effects on cardiac and vascular

function. Short-term effects of smoking are secondary

to increased amounts of carbon monoxide and nico-

tine in the serum. The binding of carbon monoxide to

hemoglobin can reduce the oxygen availability to

peripheral tissues by 12% [7]. It changes the structure

of the hemoglobin molecules, shifting the oxygen-

hemoglobin curve to the left, further reducing oxygen

availability. Carboxyhemoglobin levels of 6% have

been shown to increase significantly the risk of ven-

tricular arrhythmias among patients with coronary

artery disease [12]. By stimulating the stress re-

sponse to surgery, nicotine together with carbon mon-

15 (2005) 189 – 194

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thoracic.theclinics.com

ziedalski & ruoss190

oxide creates an oxygen availability and consump-

tion imbalance.

Nicotine affects coronary vascular resistance and

blood flow. The effects of nicotine on coronary blood

flow include indirect vasodilatory effects by mecha-

nisms related to the increased cardiac work and direct

coronary vasoconstrictor effects [13,14]. The effects

of nicotine replacement therapy on oxygen consump-

tion are not well understood [15].

The association between cigarette smoking and

delayed wound healing is well recognized in clinical

practice, but controlled studies are limited [16–18].

Although the mechanisms are not established, the

effects of the toxic constituents of cigarette smoke,

such as nicotine, carbon monoxide, and hydrogen

cyanide, are potential mechanisms by which smoking

may impair wound repair. Nicotine’s vasoconstrictor

properties may reduce nutritional blood flow to the

skin, resulting in tissue ischemia and impaired

healing of injured tissue. Nicotine increases plate-

let adhesiveness, potentially increasing the risk of

thrombotic microvascular occlusion and tissue ische-

mia. Carbon monoxide and hydrogen cyanide can

contribute further to tissue hypoxemia and inadequate

healing [17]. In addition, the synthesis of subcuta-

neous collagen in smokers is impeded, indicating an

impaired wound healing process [19].

Smoking cessation in the preoperative period

The potential dangers of operative complications

resulting from smoking have been recognized since

the 1940s. In 1944, Morton [20] stated: ‘‘. . . the

morbidity rate for smokers taking more than 10 ciga-

rettes a day is 6 times that for non-smokers . . . it isadvisable for smokers to stop or reduce their smoking

as a precaution against pulmonary complications.’’

Whether preoperative smoking cessation can

reduce the incidence of perioperative and postop-

erative complications is not established. In an un-

controlled observational study of 200 consecutive

patients undergoing elective coronary artery bypass

graft surgery, an association between preoperative

smoking cessation and postoperative pulmonary

morbidity was examined [21]. Postoperative pulmo-

nary complications occurred in one third of the ac-

tive smokers. Patients who had stopped smoking for

2 months or less had a pulmonary complication rate

almost four times that of patients who had stopped for

more than 2 months (57.1% versus 14.5%). Patients

who had stopped smoking for more than 6 months

had rates similar to patients who had never smoked

(11.1% and 11.9%). Preoperative pulmonary dys-

function, increased pack-years of smoking, and

prolonged surgical time were independently and sta-

tistically significantly associated with postoperative

pulmonary morbidity.

This landmark study suggests that smoking ces-

sation should occur at least 8 weeks before surgery

to maximize the reduction of postoperative respira-

tory complications [21]. In addition, because smok-

ing-induced reduction in lung function and the

impairment of immune function may be significantly

reversed by 6 to 8 weeks of abstinence, smoking

cessation interventions are likely to be more benefi-

cial when offered at least 6 weeks before surgery

rather than in the immediate preoperative period

[11,22]. Such timely interventions may be difficult

to achieve unless there is a partnership between sur-

geons and referring physicians. Currently, no ran-

domized trials have assessed the role of preoperative

smoking cessation on perioperative and postoperative

outcomes. A Cochrane review assessed the evidence

for an effect of preoperative smoking intervention on

smoking cessation in the postoperative period and

longer term and on the incidence of postoperative

complications [23]. Although no randomized, con-

trolled data exist for the role of preoperative smoking

cessation, some limited studies have attempted to

answer this question.

A prospective nonrandomized trial designed to

evaluate the effectiveness of written preoperative

advice to stop smoking before admission for elective

surgery showed that such advice was ineffective in

persuading patients to stop smoking. Fifteen percent

of all patients continued to smoke within 1 hour of

surgery, but there was a reduction in the amount of

tobacco consumed [24].

Another small study evaluated a smoking cessa-

tion program, implemented by a nurse in surgical

preadmission clinics [25]. Sixty smokers were ran-

domized into two groups. When attending the pre-

operative clinic, patients in the treatment group

received educational interventions and self-assess-

ment questionnaires relating to smoking cessation,

whereas patients in the control group received routine

information. There was a significant increase in posi-

tive behavior on admission to the hospital in the

treatment group (80% stopped or reduced smoking)

compared with the control group (50% stopped or

reduced smoking), particularly in patients who did

not intend to reduce or stop before admission. Pa-

tients described the approach of the nurse and a leaf-

let devised for the study as the most helpful aspects

of the program. The lack of blinding in this study

limits the applicability of the data, but the approach

to smoking cessation warrants more investigation.

smoking cessation 191

Although it is desirable that smoking cessation

should occur in the preoperative period, it is unclear

if this is the most suitable time for most patients.

Patients may be more likely to comply with smoking

cessation advice during the time of an acute illness

because the possibility of reducing perceived vulnera-

bility to postoperative complications could promote

patient motivation to quit or reduce smoking before

operation. Interventions such as consulting and phar-

macotherapy help patients to stop smoking in mul-

tiple settings and should work in the perioperative

period. Although some patients tend to be more ner-

vous about smoking cessation before surgery because

they might feel that they need to smoke to deal with

the stress of impending surgery, a successful preop-

erative smoking intervention potentially could reduce

perioperative complications and lead to long-term

health gains.

Smoking cessation during the perioperative period

In a prospective, randomized trial of patients

with a diagnosis of cancer who were hospitalized

for a surgical procedure, a one-time, inpatient, nurse-

managed, minimal smoking cessation intervention

was assessed for effectiveness on smoking cessation

[26]. On hospital admission, 64% of the intervention

group and 71% of the usual care group reported their

intention to quit smoking. At 6 weeks postinterven-

tion, only 21% of the intervention group and 14% of

the usual care group were abstinent from smoking.

More than 90% of the intervention group members

who resumed smoking did so within the first week

of discharge. Additional contact before discharge or

within the first few days after discharge may be

necessary to reinforce strategies for remaining absti-

nent [26].

A Veterans Affairs Medical Center randomized,

controlled trial of 324 patients hospitalized for non-

cardiac surgery assessed the effectiveness of an in-

tervention during that hospitalization. Of patients,

52% were randomized into an intervention group

consisting of a multicomponent intervention designed

to increase self-efficacy and coping skills that in-

cluded face-to-face in-hospital counseling, viewing

a smoking cessation videotape, self-help literature,

nicotine replacement therapy, and 3 months of tele-

phone follow-up. The remaining 48% of patients

received self-help literature and brief counseling

lasting 10 minutes. Serum or saliva cotinine levels

were measured to confirm self-reported smoking ces-

sation. At 12 months of follow-up, the self-reported

quit rate was 27% among the intervention group and

13% among the comparison group (relative risk 2.1;

95% confidence interval 1.2–3.5; P < .01). Based on

biochemical confirmation, 15% of the intervention

group compared with 8% of the comparison group

were not smoking at 12 months (relative risk 2; 95%

confidence interval 1–3.9; P = .04) [27].

In another study designed to examine the effect of

a nurse-delivered smoking cessation intervention on

short-term smoking abstinence among hospitalized

postoperative patients, 80 patients were prospectively

randomized. The intervention consisted of three

structured smoking cessation sessions during hos-

pitalization, followed by phone calls once a week

for 5 weeks after discharge. Of the experimental

group, 37.8% of patients were abstinent compared

with 25.6% in the usual care group. Abstinence rates

of experimental group patients from cardiovascular

(40%) and oncology (64.3%) units were higher than

that of general surgery (13.3%) patients. Regardless

of group assignment, 100% of cardiovascular and

oncology patients abstained during hospitalization

compared with only 10.7% of general surgery pa-

tients [28].

A systematic review of all trials of behavioral,

pharmacologic, or multicomponent interventions de-

signed to help hospitalized patients with smoking

cessation showed that intensive intervention con-

sisting of inpatient contact with at least 1 month of

follow-up was associated with significantly higher

cessation rates (odds ratio 1.82; 95% confidence in-

terval, 1.49–2.22) [29]. Any contact during hospitali-

zation with a minimal follow-up failed to show any

significant effect on abstinence.

Therapeutic approaches to smoking cessation

Currently, more than 23% of United States adults

smoke cigarettes, and 70% of smokers report a desire

to quit [30]. Smoking should be viewed as a chronic

disease that requires a long-term management strat-

egy, rather than a quick and easy treatment [31].

Fewer than 10% of smokers who attempt to quit on

their own are successful over the long-term. Smokers

who seek professional help are more successful

[2,31]. The main obstacle to quitting is the addictive

nature of nicotine.

Counseling and pharmacotherapy are effective in

smoking cessation, but the combination of the two

achieves the best results [31,32]. Randomized, con-

trolled trials have shown that a physician’s advice to

stop tobacco smoking increased the rates of cessation

by 30% [32]. Formal counseling sessions, even brief

ones lasting less than 3 minutes, are more effective

ziedalski & ruoss192

than simple advice. Counseling can be performed in a

group setting and usually employs cognitive behav-

ioral methods with which smokers learn to identify

behavioral clues and learn how to cope with stress

and manage symptoms of nicotine withdrawal. Pa-

tients also develop the skills necessary to prevent

relapse [2].

Many pharmacologic approaches are available for

smoking cessation. Nicotine replacement with gum, a

transdermal patch, a nasal spray, and a vapor inhaler

all have shown efficacy in randomized, double-blind

placebo trials and are associated with a doubling

of the long-term (1-year) rates of abstinence [32,33].

The pharmacokinetic properties of the available

nicotine formulations differ, with the patch providing

a stable, fixed dose of nicotine over 16 or 24 hours,

whereas the other formulations have a more rapid

onset and a shorter duration of action.

The goal of nicotine replacement therapy is to

relieve the craving for nicotine and the symptoms of

nicotine withdrawal. One randomized, controlled trial

directly compared the four nicotine replacement

products [34]. Although the efficacy of each product

was similar at week 12 of follow-up, the rates of

compliance varied, being highest for the patch, inter-

mediate for the gum, and lowest for the vapor inhaler

and the nasal spray. Different nicotine replacement

products can be combined safely, and combining the

nicotine patch with gum, inhaler, or nasal spray was

more efficacious than the use of any of these products

alone [32,35]. Nicotine replacement therapy is gen-

erally safe in patients with cardiovascular disease

[36,37]. Although it has not been studied in patients

with unstable angina or recent myocardial infarction,

the risks of nicotine replacement should be lower than

in cigarette smoking [2,15]. In smokers with high

Table 1

Pharmacologic therapy for smoking cessation

Nicotine replacement therapy Product name

Transdermal patch Nicoderm

Nicotrol

Nicotine gum Nicorette

Nasal spray Nicotrol NS

Inhaler Nicotrol Inhaler

Nonnicotine therapy

Bupropion Zyban

Wellbutrin SR

Nortriptyline Aventyl

Pamelor

Clonidine Catapres

nicotine dependence, higher levels of nicotine

replacement may be necessary. This replacement

can be achieved by multiple patches and sometimes

additional amounts of polacrilex gum, nasal spray, or

nicotine inhaler [38,39]. Although specific nicotine

receptor antagonists are not yet available commer-

cially, the role of these agents is under investigation

[40,41].

Besides nicotine replacement therapy, other phar-

macotherapy has been explored (Table 1). The best-

studied and most widely used agent is bupropion.

This antidepressant with dopaminergic and norad-

renergic activity is an effective agent for smoking

cessation and is related to a doubling of smoking ces-

sation rates compared with placebo treatment [32,33].

A randomized, placebo-controlled trial directly com-

pared bupropion alone or in combination with the

nicotine patch [42]. Bupropion produced a signifi-

cantly higher rate of abstinence at 1 year than ei-

ther the nicotine patch or placebo. Treatment with

bupropion and the nicotine patch did not lead to sig-

nificantly higher cessation rates compared with treat-

ment with bupropion alone. The role of combination

therapy warrants further investigation.

Nortriptyline, an antidepressant with noradrener-

gic activity, 75 to 100 mg daily given for 3 months,

starting 10 to 28 days before quitting, was shown to

be efficacious in small trials [43,44]. Several other

antidepressants have been used in smoking cessation,

including doxepin, imipramine, fluoxetine, and ven-

lafaxine. These agents warrant further investigation.

Clonidine, an a-noradrenergic agonist that sup-

presses sympathetic activity, is used most frequently

as an antihypertensive agent. It has been shown to

decrease the symptoms of nicotine withdrawal and

has been effective for smoking cessation [32]. Meca-

Dose Duration of therapy

7, 14, 21 mg patch for 24 h 8 wk

15 mg patch for 16 h 8 wk

2- and 4-mg pieces 8–12 wk

1 piece per hour

0.5 mg per spray 3–6 mo

1–2 doses per hour

4 mg per cartridge 3–6 mo

6–16 cartridges per day

150 mg per for 3 days, then 7–12 wk

150 mg twice a day

75–100 mg/d 12 wk

0.1–0.3 mg twice a day 3–10 wk

smoking cessation 193

mylamine (Inversine), an antihypertensive drug with

nicotine receptor antagonist activity, suppresses

nicotine withdrawal syndrome and increases smoking

cessation rates when administered with a nicotine

replacement therapy [45,46].

Because many smokers report missing the sensory

aspect of smoking, sensory replacement therapy

has been used. Inhalers containing ascorbic or citric

acid had modest increased rates of short-term cessa-

tion [47,48].

Summary

Smokers have a significantly greater risk of

complications during and after operations. Cigarette

smoke has significant effects on cardiac function, cir-

culation, and respiratory function. Preliminary studies

suggest that smoking cessation for a minimum of 6 to

8 weeks before surgery is required to reduce the peri-

operative and postoperative risks of smoking. Smok-

ing cessation programs that employ advice, support

groups, nicotine replacement therapy, or some anti-

depressants have been used successfully in many

situations and should be used to discourage smoking

preoperatively. Further research is needed, however,

to clarify the best approach to smoking cessation for

surgical patients.

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Thorac Surg Clin

Preoperative Patient Education in Thoracic Surgery

Richard I. Whyte, MDa,*, Patricia D. Grant, RNb

aDepartment of Cardiothoracic Surgery, Stanford University Medical Center, CVRB 205, 300 Pasteur Drive,

Stanford, CA 94305, USAbThoracic Surgery Service, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA

Optimal outcome after thoracic surgery, as with

any type of surgery, involves the coordinated activity

of many individuals, including the patient, surgeon,

anesthesiologist, nurses, resident physicians, respira-

tory therapists, and a host of other participants. The

phrase coordinated activity implies that each partici-

pant has knowledge of his or her role and expecta-

tions. For the patient, who is generally uneducated

in the course of the surgical process, this learning

process involves the preoperative and postoperative

period. Through the process of preoperative teaching,

the patient understands his or her role in the overall

process and how he (or she) can facilitate or delay

recovery. This article describes the role of preopera-

tive teaching in thoracic surgery. The focus is not on

the surgeon’s role, but rather the role of the greater

surgical team, which frequently involves nurses,

medical assistants, resident physicians, nurse practi-

tioners, and anesthesiologists.

Because most patients are new to the thoracic

surgical process, the amount of information may be

overwhelming—particularly when patients are con-

fronted with a new diagnosis of malignancy or when

they have no advance knowledge of the magnitude or

risks of the planned surgery. As such, important

concepts often are presented more than once or in

more than one way. Material that the surgeon covers

in the initial consultation often needs to be reinforced

at a subsequent preoperative visit or even again on

the day of surgery.

In the authors’ practice, a recommendation for

surgery often is given at the time of the initial

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.002

* Corresponding author.

E-mail address: riwhyte@stanford.edu (R.I. Whyte).

consultation. Sufficient time is allocated for the sur-

geon to describe the operation and its risks, benefits,

and alternatives. Questions are encouraged, but often

the patient cannot assimilate all of the information

and formulate appropriate questions. Questions often

arise in the following days, as the patient has had time

to digest the information, process it, and assimilate it

on intellectual and emotional levels. If a recommen-

dation for surgery is offered at the initial consultation,

the clinical nurse specialist spends additional time

with the patient interpreting and reinforcing what the

surgeon said, answering questions, and providing a

contact telephone number for subsequent questions.

Patients often have a separate visit a few days be-

fore surgery. At that time, the planned operation is

reviewed again with the patient, and additional ques-

tions are answered. Patients also are seen in a pre-

operative anesthesia clinic by a physician or an

anesthetic nurse practitioner. In this setting, informa-

tion flows two ways: The anesthesia service performs

a preoperative anesthesia assessment, and the patient

has an opportunity to learn more about the planned

anesthesia and postoperative pain issues. The final

opportunity for preoperative teaching is by the

perioperative nurses who, in doing their own pre-

operative patient assessment, answer any remaining

questions and deal with remaining concerns.

Content of preoperative teaching

The content of preoperative teaching should

include all significant issues related to a particular

patient’s operation. For the purposes of discussion,

the content can be separated into two groups: issues

15 (2005) 195 – 201

reserved.

thoracic.theclinics.com

whyte & grant196

related to surgery (or thoracic surgery) in general and

issues related to a specific operation.

General preoperative education

At the initial consultation, the surgeon usually

provides an explanation of the proposed procedure.

Retention of this information is highly variable and

depends on the rapport between the surgeon and

patient; the surgeon’s willingness to provide infor-

mation; and the patient’s curiosity, emotional state of

mind, intelligence, and knowledge base. An intellec-

tually sophisticated patient with a background in the

medical sciences who presents to the office with an

Internet printout of all the latest lung cancer clinical

trials is likely to be handled differently than a poorly

educated patient who has done no background

investigations. Similarly the emotional state of the

patient must be taken into account because it is likely

that an emotionally upset patient hearing the diag-

nosis of ‘‘cancer’’ for the first time may have less

retention than someone who is being provided a sec-

ond opinion or someone who is seeing the surgeon

after a course of preoperative chemotherapy.

At the conclusion of the preoperative process, all

patients need to have some retained understanding of

the planned procedure, why it is being recommended,

what its risks are, whether there are alternatives, and

how their active participation in the surgical process

can make a difference in recovery. Although this

information is generally covered, at some level, by

the surgeon, the surgical nurse often has to review it

with the patient and focus on areas where retention

was inadequate.

Respiratory hygiene

Many of the common complications after tho-

racic surgery—atelectasis, pneumonia, and pulmo-

nary embolism—are pulmonary in nature. Although

pulmonary embolism cannot be prevented through

improvement in pulmonary hygiene, atelectasis and

pneumonia can be prevented through active patient

involvement. Coughing, deep breathing, using an

incentive spirometer, walking, sitting to eat, and

performing other seemingly minor activities all can

contribute to improved pulmonary hygiene and a

decreased incidence of postoperative pneumonia.

Although coughing per se is painful and controver-

sial in terms of its ability to prevent pneumonia,

avoidance of sputum retention is desired. Patients

can be taught to splint the operative side to mini-

mize pain with coughing. Deep breathing can open

collapsed alveoli and prevent overt atelectasis. Walk-

ing and use of an incentive spirometer aim for the

same goals—improved aeration of the lungs and

avoidance of alveolar and segmental collapse. Eat-

ing in bed should be avoided because the often

semirecumbent posture predisposes to aspiration

and regurgitation.

Although all of these respiratory hygiene mea-

sures can be addressed in the postoperative period, it

is best to address these concepts initially in the pre-

operative period. Setting expectations is important,

and in the postoperative period, when the patient’s

sensorium may be clouded by pain and narcotics,

learning is suboptimal. Teaching proper use of an

incentive spirometer is far more effective preopera-

tively than postoperatively when inhalation is com-

promised by pain. When patients are taught how to

use this device preoperatively, they have a relevant

basis from which to compare their postoperative

inspiratory effort and function. Convincing patients

that they can do much better is difficult if they have

never seen the device until the evening after surgery.

Pain

One of the most frightening things for patients

facing surgery is the expectation of pain. Other

frightening concepts include loss of personal control

and death. Because death is usually unlikely, and loss

of control is unavoidable, the expectation of pain

often becomes a major source of anxiety. In the pre-

operative period, the anxiety surrounding pain, rather

than the pain itself, is the problem. Effective pre-

operative teaching can allay these fears, reduce the

anxiety, and provide a framework for realistic expec-

tations regarding postoperative pain [1,2].

A discussion of narcotic analgesics, patient-

controlled analgesia, nonsteroidal analgesics, and epi-

dural anesthesia (continuous, intermittent, and patient

controlled) is appropriate. Side effects, including

nausea, gastrointestinal dysfunction, and the potential

for a lack of efficacy, should be discussed. The goal

of postoperative analgesia also should be discussed.

Patients should not expect to be oblivious to the fact

that they just had surgery, but the goal of post-

operative analgesia should be pain control that pro-

vides patients with an ability to function and interact

with their environment effectively.

Family members should be cautioned that patient-

controlled analgesia is for patients, not family mem-

bers, to control. Family members also should be

cautioned that narcotics may have undesirable side

preoperative patient education 197

effects, such as somnolence, respiratory depression,

dysphoria, disorientation, and even delirium. Family

members should be advised that these side effects

generally resolve quickly after discontinuation of

narcotics, and that the physicians and nurses need

to be made aware if these side effects occur.

Patients should be advised that postoperative early

ambulation is desirable. The upright posture has

many advantages in terms of pulmonary function,

although multiple attachments such as chest tubes,

urinary catheters, epidural catheters, and infusion

pumps often make ambulation difficult. Effective

preoperative counseling sets the expectations, which

can be reinforced in the postoperative period.

Smoking cessation

In thoracic surgical practice, many of the rele-

vant diseases, particularly lung cancer and emphy-

sema, are smoking related. Although many patients

have quit smoking by the time they come to the

thoracic surgeon, others continue to smoke because

the addictive qualities of nicotine outweigh the

intellectual knowledge that smoking is harmful.

Faced with an upcoming operation, the patient may

use smoking as a method of coping with anxiety and

fear. Patients should be counseled vigorously, how-

ever, to stop smoking in preparation for surgery.

Cigarette smoking impairs the mucociliary clearance

mechanisms of the tracheobronchial tree and may

predispose to postoperative pulmonary complications.

The optimal time for smoking cessation is unclear,

and one article even suggested an increase in peri-

operative pulmonary complications when smoking

cessation occurred immediately before surgery [3,4].

Most surgeons encourage patients to stop smoking

in preparation for thoracic surgery. Whether surgery

should be denied to patients who continue to smoke

is controversial. Every effort should be made pre-

operatively to persuade the patient to stop smoking.

Diet and nutrition

Preoperative patient education should cover nu-

tritional issues routinely but is particularly important

in two classes of patients: (1) patients who have

recently experienced a significant weight loss and

(2) patients who are to undergo preoperative chemo-

therapy or radiation therapy. The first group includes

many patients with esophageal cancer in whom

dysphagia or odynophagia have limited their oral

intake and resulted in a long-standing caloric defi-

ciency. Although significant weight loss is common

in patients with metastatic disease, such patients

frequently are identified through preoperative staging

tests and often do not come to the attention of the

surgeon. The second group involves patients who

ideally should be seen by the surgeon before the

neoadjuvant therapy is started. In these patients,

nutritional deficiencies can be expected and conse-

quently preempted. Patient questions regarding nutri-

tional supplementation (including herbal or other

nontraditional forms of treatment) often arise at this

time and can be dealt with appropriately.

Wound care and drains

Although most thoracic surgery patients require

little or no postdischarge wound care, the preopera-

tive visit is a reasonable time to raise this issue. Pa-

tients often have negative expectations about wound

care and often are pleasantly surprised to learn that

care is usually minimal. Occasionally, patients are

discharged home with tubes or drains still in place.

Because percutaneous tubes and drains are an integral

part of modern surgical care and their use has become

ubiquitous, health care providers may become numb

to their invasiveness and the patient’s sense of a loss

of personal image. Patients should be taught about the

uses and benefits of percutaneous tubes and drains as

early as possible. In years past, patients routinely

were kept in the hospital until all drains and tubes

were out: mastectomy patients stayed in the hospital,

on intravenous antibiotics, until the Jackson-Pratt

drains were removed. Now, as a result of ‘‘best prac-

tice’’ analysis, evidence-based medicine, and changes

in reimbursement policies, practices have changed,

and patients are taught that it is acceptable to go

home with a small drain.

Postdischarge social issues

Although it may seem premature to enter into a

discussion of postdischarge psychosocial issues in the

preoperative phase, such a discussion is not inappro-

priate. Postdischarge issues, such as family involve-

ment in postoperative convalescence, job-related

concerns, and expectations regarding physical limi-

tations, including appetite, sleep irregularity, and sex-

ual function, can be broached in the preoperative

period and brought up again in more detail later.

Issues that potentially may delay discharge from the

hospital may become apparent in these discussions

(which are frequently left to the nursing staff), and it

is helpful to address these issues early so that they do

not become problems later. In dealing with the patient

whyte & grant198

and family, cultural sensitivity and family dynamics

may play crucial roles in effecting a smooth post-

operative recovery.

Contact numbers

Part of the preoperative teaching process is to

effect seamless communication between the patient

and the surgeon. Because many surgeons delegate

much of the preoperative teaching to resident phy-

sicians, nurses, and other nonphysician staff, it is

crucial to provide patients with a reliable method of

contacting the surgeon or his or her designee. Pa-

tient satisfaction has an increasing role in deter-

mining where patients go for their care, and one of

the simplest methods for improving patient satisfac-

tion is providing them with a reliable conduit to the

surgeon and his or her staff.

Procedure-specific teaching

In addition to the more general areas discussed

earlier, each patient needs teaching directed toward

the specific operation he or she is to undergo. Infor-

mation that needs to be covered at this stage includes

the size and location of the incision, the general

outline of the operation, the expected postoperative

physiologic state or deterioration from baseline, and

a general overview of the risks of complications or

death. Several common examples are detailed next.

Pulmonary resection (lobectomy/pneumonectomy)

In addition to providing information regarding in-

cision length and position, morbidity, mortality,

and other issues described previously, patients under-

going thoracotomy for pulmonary resection should

receive counseling on postthoracotomy pain and

the potential for decreases in pulmonary reserve.

Thoracotomy incisions are notoriously painful, and

although early postoperative pain can be managed

effectively by modern analgesic techniques, the late

issues of ongoing narcotic use and the incumbent

gastrointestinal side effects should be discussed

proactively. From the standpoint of loss of pulmo-

nary reserve, patients with marginal preoperative

lung function should be advised that they are likely

to have less exercise capacity and that nasal oxygen

therapy may be necessary on a short-term basis. In

the authors’ practice, patients who would be expected

to require supplemental oxygen on a long-term basis

rarely are offered surgery. Patients undergoing

pneumonectomy are at particular risk for symptom-

atic decreases in exercise capacity and should be

counseled accordingly.

Thoracoscopy

Patients scheduled for thoracoscopy, particularly

limited procedures such as lung biopsy, sympathec-

tomy, and pleural biopsy, often can be discharged the

day after surgery. Reports of outpatient thoracoscopy

have appeared in the literature, but the presence of a

chest tube often dictates an overnight stay [5]. Pa-

tients should be advised that the chest tube probably

will be removed on the morning after surgery, and

that issues such as pain, nausea, and general fatigue

will be managed on an outpatient basis.

Esophagectomy patients need to be forewarned

about early satiety and the possibility of dumping

syndrome. The presence of tubes and drains, which

are second nature to the surgeon, are not second na-

ture to the patient. The idea of having a chest tube can

be frightening to some patients. Drains, wound care,

and jejunostomy tubes, all of which are common

to thoracic surgery practice, are foreign to medically

naive patients. Clinicians must be cognizant of pa-

tients’ naivete and address it through good preopera-

tive teaching.

Patients need to have some concept of the risks

of the planned procedure. Although some patients

do not want to face these considerations, the doc-

trine of informed consent is an integral part of the

medical system. The surgeon and members of his or

her team need to balance the patient’s desire for in-

formation (or lack thereof), the need to provide a basis

for informed consent, and the undesirable outcome of

fostering fear and anxiety. In general, at a minimum,

a description of common complications, a qualitative

assessment of morbidity and mortality, and an invi-

tation to go into greater detail should be offered.

Lung volume reduction surgery (and other operations

in patients with severe emphysema)

The major specific issue to address in patients

with severe emphysema is prolonged air leaks. Dis-

cussion of other complications, such as pain control,

risks of pneumonia, and the potential for postopera-

tive mechanical ventilation, should not be omitted,

but prolonged air leaks with the ongoing need for

chest tube drainage specifically should be mentioned.

Techniques such as the use of reinforcing strips for

surgical staplers and surgical glue can be discussed,

although these patients often stay in the hospital for

prolonged periods simply because of the need for

ongoing pleural drainage. Use of one-way valves and

the possibility of being discharged home with a chest

tube in place can be discussed in the preoperative

preoperative patient education 199

phase of care—not as a likely outcome, but so that it

is not such a foreign concept if it needs to come up

again later.

Esophagectomy

Esophagectomy is one of the larger operations

that thoracic surgeons perform regularly. It is asso-

ciated with significant short-term and long term

morbidity and consequently warrants special atten-

tion in a discussion of preoperative teaching. From

the patient’s perspective, esophagectomy generally

is seen in the context of a diagnosis of cancer that

carries an unusually poor long-term outlook. The

operation generally involves two incisions and is as-

sociated with the possibilities of death, a stay in the

ICU, chest tubes, feeding tubes, and other daunting

obstacles. The ‘‘tradeoff’’ is that patients often start

with severe dysphagia (in contrast to lung cancer

patients who are generally asymptomatic) and end

having a much improved quality of swallowing.

For these patients, specific preoperative teaching

issues should include the surgical risks (bleeding,

infection, anastomotic leak, hoarseness [in the case of

a cervical anastomosis], and the risk of perioperative

and operative mortality—1–5% in various series). To

counterbalance these negatives, relief of dysphagia

and the possibility of cure can be raised. The post-

operative issues of early satiety, dumping, and regur-

gitation (the risks of which vary depending on the

planned operative approach) all should be discussed,

although it should be made clear that the degree of

these symptoms and their duration have a wide range.

Photodynamic therapy

Photodynamic therapy is a technique of ablating

obstructing tumors of the major bronchi or esopha-

gus (and now approved for the ablation of columnar-

lined esophageal mucosa) that has the undesirable

side effect of prolonged cutaneous photosensitivity.

The only governmentally approved and commer-

cially available photosensitizing agent in the United

States, Photofrin, is associated with a 6-week period

of photosensitivity, during which time patients

should avoid direct sunlight and wear protective

clothes when outside (eg, gloves, wide-brimmed hat,

long sleeves, long pants). Failure to be compliant

may result in a severe sunburn-like reaction, even to

the point of blistering. It is helpful to council pa-

tients repeatedly on these restrictions and to use a

combination of verbal direction, written material,

and a take-home video. Despite all of these modali-

ties, some patients are noncompliant, but because

the photosensitivity reaction develops quickly, they

rarely repeat their indiscretions.

Transplantation

On review of the literature on preoperative

teaching of patients for thoracic surgery, it is found

that the greatest amount of effort has gone into car-

diac surgery (not a topic of this article) and trans-

plantation [6–8]. One reason is that the preoperative

assessment of patients for transplantation is far

more complicated than it is for most other tho-

racic surgical patients. The other reason is that, for

most transplant patients, the transplant itself is just

the start of a transforming process that results in

lifelong involvement with the transplant center, the

ongoing use of multiple medications, and the need

for periodic physiologic and pathologic assessment

of the outcome (eg, pulmonary function tests, bron-

choscopy with biopsy). The preoperative evaluation

of transplant patients attempts to identify patients with

the greatest chance of benefiting from receiving a

scarce resource (donor organs) and involves a rigor-

ous medical screening and evaluation and a thorough

psychosocial evaluation. Drug or alcohol abuse,

destructive behavior, noncompliance, and lack of

social supports all argue against offering such pa-

tients donor organs. This preoperative assessment

frequently involves psychologists (or psychiatrists)

and social workers in addition to the more ‘‘nuclear’’

team of the surgeon, transplant pulmonologist, and

the rest of the transplant team. Given the complexity

and lifelong duration of the transplant process, it is

not surprising that the preoperative assessment and

teaching processes are more involved.

Research protocols

In addition to providing excellent patient care,

academic medical centers have the added responsi-

bilities of teaching and conducting research. For the

thoracic surgeon, clinical trials provide a mechanism

for improving the outcome of future patients with

lung cancer, esophageal cancer, and end-stage lung

disease. In many academic medical centers, clinical

trial nurses play a vital role in identifying patients for

clinical trials and in educating patients about these

trials. These discussions involve the nature of the

trial, inclusion and exclusion criteria, study design

(randomized/prospective versus open-label/historical

control), and risks and potential benefits associated

with the specific trial in question. Compared with

physician investigators, clinical trial nurses often

have more time to spend with the patients, may be

less perceived as having a vested interest in the out-

come of the trial, and may be more open to questions

than the physician investigator. The downside is that

the nurses may have a less detailed knowledge of

whyte & grant200

the trial (eg, pharmacology, pathophysiology, surgical

anatomy). Consequently, physician backup to these

clinical trial nurses must be available.

Preoperative teaching tools

Verbal instruction

Verbal instruction is the cornerstone tool to pre-

operative teaching, and whoever conveys information

verbally must be cognizant of the recipient’s intellec-

tual level, interest in acquiring the information, at-

tention span, and emotional ability to handle the

information. Multiple factors, such as language bar-

riers, learning disabilities, and cultural barriers, can

impair this knowledge transfer, and other strategies,

including repetition, provision of written material,

interpreters, and drawings, may be necessary. It is

often surprising to find that patients, after what was

thought to be a thorough preoperative discussion,

continue to have basic questions that they are reluc-

tant to discuss with the surgeon and that are asked to

the preoperative nurse or other staff only after the

surgeon has left.

Written material

Complementing verbal instruction and direction is

the dissemination of written material. Nonprofit orga-

nizations have a variety of patient education materials

available at relatively low cost. The American Cancer

Society has a telephone hotline for information that

can be sent to patients free of charge. The information

covers general cancer care and preparation for sur-

gery, including topics such as ‘‘what questions to ask

the doctor’’ and ‘‘what are the risks and side effects

of surgery.’’ The American Lung Association has a

large amount of free and low-cost written material

on smoking cessation and lung health, including pul-

monary function testing, bronchoscopy, lung cancer,

and lung transplantation. Lastly, information packets

for commonly performed operations can be bought

or made ‘‘in house’’; the latter has the advantage

of providing information specific to the institution

and surgeons.

Manufacturers of commercial products often pro-

vide free product-specific patient education packets

or booklets. One example is Axcan Pharmaceuticals,

which supplies patient education material on photo-

dynamic therapy for lung and esophageal cancer and

Barrett’s esophagus. Another example is Denver Bio-

medical, which provides written information and a

patient video on its PleurX pleural catheter. Other

companies, such as Bristol-Myers-Squibb Oncology

and Aventis Pharmaceuticals, supply product-specific

and disease-specific patient information and more

general cancer care information on topics such

as nutrition and exercise in the form of books

and pamphlets.

Web-based material

Much of the information described in this article,

in addition to a wealth of additional information, is

also available online. The American Cancer Society

and the American Lung Association have extensive

websites with large amounts of patient-oriented infor-

mation. In addition, for cancer patients, the National

Cancer Institute provides a detailed and user-friendly

website (www.cancer.gov) with a wealth of material

aimed at the patient level. The University of Pennsyl-

vania (www.oncolink.upenn.edu) also provides an

outstanding patient-centered website that is relatively

free of institutional and commercial bias. Addi-

tional patient-oriented information on clinical trials

is available through the Coalition of National Cancer

Cooperative Groups (www.cancertrialshelp.org).

Numerous pharmaceutical company websites also

offer disease-specific information on disease preven-

tion, diagnosis, causes, and treatment. With the ubiq-

uity of Web access, the authors caution patients that

information obtained on the Web can be highly bi-

ased, poorly referenced, and even self-serving and

promotional in nature, but that reputable sources can

provide valuable insights into their disease and the

treatment options that are available to them.

Audiovisual material

Another opportunity for teaching includes provi-

sion of audiovisual material. Axcan Pharmaceuti-

cals, the supplier of Photofrin, has created a video

detailing the risks of photosensitivity and how to

avoid such side effects. Diagrams and models also

may be used. Commercially available lung models

can help the surgeon or clinical nurse specialist ex-

plain the concepts of bronchopulmonary segments,

lobectomy, and wedge resection. Diagrams, which

can be hand-drawn or commercially obtained, can

be used to explain anatomic concepts. Lastly, use of

the patient’s own radiographs can be an excellent

teaching method, and patients generally pay a great

deal of attention to their own radiographs. It takes

preoperative patient education 201

relatively little time to explain the basics of a CT

scan, and patients are often surprised that what

is a ‘‘lung nodule’’ to one physician is a ‘‘worri-

some mass’’ to another. Such teaching methods are

particularly helpful when patients are to be followed

radiographically for an indeterminate pulmonary

nodule. As the saying goes, ‘‘a picture is worth a

thousand words,’’ and 1 or 2 minutes spent with a real

radiograph can take the place of and be more

satisfying than a lengthy description of the films.

Summary

Preoperative patient teaching may take many

forms and is offered to patients across many venues

and formats. The goal of patient teaching is to im-

prove patients’ understanding of their disease process

and the operation that they are about to experience

with the goal of enlisting their active participation in

the healing process. The additional goal of obtaining

informed consent is not only codified in law, but also

has become an ingrained component to the current

physician-patient relationship. The preoperative

teaching process is best approached as a team effort,

and multiple modalities often must be used so that the

patient becomes a knowledgeable and willing mem-

ber of the team.

References

[1] Smeltzer SC, Bare BG. Preoperative nursing manage-

ment. In: Smeltzer SC, Bare BG, editors. Brunner

and Suddarth’s textbook of medical surgical nursing.

10th edition. Philadelphia7 Lippincott Williams &

Wilkins; 2004. p. 399–416.

[2] Miro J, Raich RM. Effects of a brief and economical

intervention in preparing patients for surgery: does

coping style matter? Pain 1999;83:471–5.

[3] Bluman LG, Mosca L, Newman N, Simon DG.

Preoperative smoking habits and postoperative pulmo-

nary complications. Chest 1998;113:883–9.

[4] Ratner PA, Johnson JL, Richardson CG, et al. Efficacy

of a smoking-cessation intervention for elective-surgical

patients. Res Nurs Health 2004;27:148–61.

[5] Chang AC, Yee J, Orringer MB, Iannettoni MD.

Diagnostic thoracoscopic lung biopsy: an outpatient

experience. Ann Thorac Surg 2002;74:1942–6.

[6] Shuldham CM, Fleming S, Goodman H. The impact of

pre-operative education on recovery following coronary

artery bypass surgery: a randomized controlled clinical

trial. Eur Heart J 2002;23:666–74.

[7] Hobbs FD. Does pre-operative education of patients

improve outcomes? The impact of pre-operative educa-

tion on recovery following coronary artery bypass

surgery: a randomized controlled clinical trial. Eur

Heart J 2002;23:600–1.

[8] Bahruth AJ. What every patient should know. . .pretransplantation and posttransplantation. Crit Care

Nurs Q 2004;27:31–60.

Thorac Surg Clin

The Value of Preoperative Pulmonary Rehabilitation

Shanon T. Takaoka, MD, Ann B. Weinacker, MD*

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, 300 Pasteur Drive,

#H3142, Stanford, CA 94305-5236, USA

For many decades, pulmonary rehabilitation has

served as an integral, although relatively unheralded,

component of the medical and surgical manage-

ment of chronic lung diseases. Its value has become

more apparent in recent years with the increasing

prevalence of chronic obstructive pulmonary disease

(COPD) and the renewed interest in lung volume

reduction surgery (LVRS) as a viable surgical option

for selected patients with COPD [1]. Although exist-

ing data primarily support its use in COPD, pulmo-

nary rehabilitation also has been applied with some

success to patients with other chronic lung diseases,

such as cystic fibrosis, interstitial lung disease, and

neuromuscular conditions, and in patients awaiting

lung transplantation or lung resection [2]. Partici-

pation in perioperative pulmonary rehabilitation is

encouraged and often required for patients under-

going such surgeries, with the goals of optimizing

quality of life, functional capacity, and overall sur-

gical outcomes. Although pulmonary rehabilitation

is potentially beneficial before any surgery, it has

been applied and studied primarily in the setting of

major thoracic surgical procedures, including LVRS,

lung transplantation, and lung resection. This article

defines the essential elements of pulmonary rehabili-

tation, outlines the prerequisites for enrollment, and

discusses its current role in the setting of anticipated

thoracic surgery.

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.001

* Corresponding author.

E-mail address: annw@stanford.edu (A.B. Weinacker).

Background

Although the fundamental tenets of pulmonary

rehabilitation were elucidated in the 1970s, they were

not put into widespread practice until more recently.

Subsequently the data from numerous studies have

supported unequivocally the utility of pulmonary re-

habilitation in improving symptoms of underlying

disease, functional capacity, and quality of life, par-

ticularly in patients with COPD [3]. Pulmonary re-

habilitation has been defined as ‘‘a multidimensional

continuum of services directed to persons with pul-

monary disease and their families, usually by an in-

terdisciplinary team of specialists, with the goal of

achieving and maintaining the individual’s maximum

level of independence and functioning in the com-

munity’’ [4]. This definition emphasizes the key

elements of program individualization, family in-

volvement, and a multidisciplinary approach. The

participation of physicians, nurses, respiratory thera-

pists, physical therapists, occupational therapists, die-

titians, and psychologists maximizes surgical benefit

and prepares patients and their families to cope with

the psychosocial stressors of surgery.

Role of preoperative pulmonary rehabilitation

Goals and proposed benefits

The primary goal of pulmonary rehabilitation is

to facilitate the patient’s return to independent func-

tion at the highest possible level (Table 1). To achieve

this goal, concurrent goals are to relieve symptoms

(mainly dyspnea), decrease disability associated with

15 (2005) 203 – 211

reserved.

thoracic.theclinics.com

Table 1

General and surgery-specific goals of pulmonary rehabili-

tation with the anticipated long-term benefits

Goals Benefits

General

Decrease dyspnea

Decrease symptom-related

disability

Optimized functional

status

Enhanced quality

Improve patient compliance of life

Decreased health

care usage

Optimize underlying lung

disease and coexisting

medical conditions

Increase cardiopulmonary

conditioning

Improve nutritional status

Surgery-specific

Improve airway clearance

and diaphragmatic function

Improved tolerance

of surgery

Increase patient tolerance of

symptoms while waiting for

donor organ

Decreased postoperative

complications

Identify compliant patients/

good surgical candidates

takaoka & weinacker204

symptoms, and empower patients to understand and

manage better their disease processes [5]. Likewise,

pulmonary rehabilitation can lead to optimization of

medical therapy, improvement in nutritional status,

and better cardiopulmonary conditioning [6]. Coex-

isting medical conditions, such as infection and

hypoxemia, also should be prevented and managed

in the setting of pulmonary rehabilitation [7]. Ulti-

mately, pulmonary rehabilitation should culminate in

a better overall quality of life, increased participation

in physical and social activities, and decreased health

care use. Data from numerous controlled trials have

shown a decrease in the lengths of hospital stays and

the total number of hospitalizations after rehabilita-

tion and a trend toward fewer visits to the emergency

department or physician’s office [3]. Although pul-

monary rehabilitation has been shown to improve

significantly symptom control, functional status, and

quality of life, most studies have shown no improve-

ment in lung function itself.

In the preoperative setting, the overall goal of

pulmonary rehabilitation is to maximize the advan-

tages derived from the planned surgery. In addition

to the aforementioned benefits, other proposed but

unproven benefits for surgical patients include im-

proved tolerance of the surgical procedure, increased

ability to clear secretions, and decreased work of

breathing as a result of improvement in diaphrag-

matic function [8]. These benefits should decrease

postoperative complication rates; improve postopera-

tive adherence to exercise regimens; and, in the set-

ting of lung transplantation, improve tolerance of the

time spent waiting for an appropriate organ donor.

Some patients may derive so much benefit from re-

habilitation in terms of improved functional status

and quality of life that surgery can be reconsidered or

postponed [2]. Rehabilitation can serve the valuable

purpose of further distinguishing appropriate candi-

dates for surgery. Patients who are too debilitated or

too noncompliant to complete a preoperative rehabili-

tation program are unlikely to have good surgical

outcomes, and consideration of alternative therapeu-

tic options may be indicated [9].

Setting

Pulmonary rehabilitation has been implemented

with remarkable success in the inpatient setting, for-

mal outpatient setting, and home setting. The choice

of setting for an individual patient depends on physi-

cal and psychosocial status, program accessibility, fi-

nancial considerations, and patient preference [3]. For

significantly debilitated patients, home-based reha-

bilitation is preferred, whereas patients with stable

disease, relatively good functional status, and the

ability to travel conveniently are good candidates for

formal outpatient therapy. A study comparing formal

outpatient pulmonary rehabilitation with home-based

therapy in COPD patients indicated that although

improvements in exercise capacity were observed in

both treatment groups compared with controls, the

improvements were sustained for a longer time in the

home-based group. This observed trend was likely

due to the fact that patients participating in home-

based pulmonary rehabilitation tend to continue the

exercise regimens after completion of the prescribed

programs [10].

Benefits related to specific surgical procedures

Lung volume reduction surgery

As the incidence of COPD continues to increase,

LVRS is an increasingly more attractive measure in

the palliation of severe emphysema (Table 2). Given

the established benefit seen in emphysema patients

who participate in pulmonary rehabilitation, it has

become standard practice to require patients awaiting

LVRS to complete a preoperative rehabilitation pro-

gram. In the landmark study by the National Em-

physema Treatment Trial Research Group, all patients

were required to complete 6 to 10 weeks of formal

pulmonary rehabilitation before they could be

randomized to undergo LVRS or continued medical

Table 2

Primary surgical procedures using preoperative pulmonary rehabilitation, proposed benefits based on available studies, and the

strength of the supporting data

Surgery Proposed benefits Data strength

LVRS Improve health-related quality of life, improved

functionality and exercise capacity [11–13,41]

Few or small randomized controlled trials,

many observational studies

Lung transplantation Improved functional status, exercise tolerance,

and quality of life [14–18]

Few or small randomized controlled trials,

many observational studies

Lung resection Increased inspiratory muscle strength and

improved preoperative lung function [19,42]

Few or small randomized controlled or

observational trials

Other high-risk surgery

(ie, CABG,

upper abdominal)

Improved preoperative lung function, decreased

rate of postoperative pulmonary complications,

fewer radiographic abnormalities [20,21]

Few or small randomized controlled or

observational trials

Abbreviations: CABG, coronary artery bypass graft; LVRS, lung volume reduction surgery.

preoperative pulmonary rehabilitation 205

therapy [11]. The combination of pulmonary rehabili-

tation and bilateral LVRS can improve health-related

quality of life significantly. In one study [12], each

intervention contributed differently; the pulmonary

rehabilitation component had the greatest effect

on patients’ perceptions of their physical limitations

secondary to illness, and LVRS more significantly

improved actual physical and social function and

vitality. These findings suggest a complementary

relationship between pulmonary rehabilitation and

LVRS, resulting in greater overall patient benefit

when they are implemented together.

A similar study compared pulmonary rehabilita-

tion with LVRS in 200 patients with severe COPD.

After completing an 8-week rehabilitation course,

patients were randomized to receive either continued

rehabilitation for an additional 3 months or LVRS.

Evaluation of all patients before randomization

showed that the initial rehabilitation program resulted

in a trend toward a longer 6-minute walk distance

(285 ± 96 m versus 269 ± 91 m; P = .14) and a

significant increase in total maximal exercise time

(7.4 ± 2.1 min versus 5.8 ± 1.7 min; P < .001) [13].

Consistent with other studies, however, there was no

improvement in pulmonary function test results after

completion of rehabilitation. The patients who

continued to participate in pulmonary rehabilitation

showed a trend toward higher maximal oxygen con-

sumption and a significant improvement in quality-

of-life indicators. It is unclear, however, whether

these effects have any impact on morbidity and mor-

tality after LVRS. Further studies comparing pulmo-

nary rehabilitation plus LVRS with LVRS alone are

needed to establish definitively the value of preopera-

tive rehabilitation.

Lung transplantation

Enrollment in pulmonary rehabilitation before

lung transplantation is encouraged in many centers

because patients selected for transplantation are often

severely physically deconditioned. Attendance by

lung transplant candidates at pulmonary rehabilitation

programs has been shown to be greater than 80%; this

is likely a reflection of the rate of referral and the

selection of compliant patients [14]. The data sup-

porting the efficacy and benefit of pretransplant re-

habilitation largely comprise uncontrolled studies,

however, which are limited further by small sample

sizes, widely varying program intensities and dura-

tions, and lack of standardized outcome measures.

Four of these studies showed a trend toward im-

provement in functional capacity after rehabilitation,

as represented by improved 6-minute walk distances

in patients with various causes of end-stage lung

disease awaiting either single-lung or double-lung

transplantation [15–18]. The largest of these studies

divided 110 patients into five groups based on the

underlying lung disease and the type of lung trans-

plant planned (single or double). Three of the five

groups experienced significant increases in mean

6-minute walk distances before transplantation, indi-

cating that preoperative pulmonary rehabilitation in

the lung transplant population can result in increased

exercise tolerance. Although the data are limited,

and the effect on surgical outcome has yet to be es-

tablished, pulmonary rehabilitation before lung trans-

plant does seem to improve safely functional status

and patient well-being.

Lung resection

Lung cancer is a major cause of mortality, and

with smoking as the primary risk factor, many

patients undergoing lung resection have associated

COPD. Minimal data exist, however, regarding

pulmonary rehabilitation before lung resection. This

fact may be due in part to the relatively brief time

between cancer diagnosis and surgery, which does

not allow for significant patient participation in

takaoka & weinacker206

rehabilitation. In one of the few existing studies to

date, Weiner et al [19] randomized 32 patients with

COPD undergoing resection for primary lung neo-

plasm to receive either incentive spirometry and in-

spiratory muscle training for 2 weeks before lung

resection or no training at all. The investigators found

that inspiratory muscle strength, as measured by the

maximum inspiratory pressure at residual volume,

increased significantly in the training group, but

remained unchanged in the group that received no

training [19]. The relevance of these data on clinical

outcomes has not yet been established; however, the

data suggest a potential beneficial impact of rehabili-

tation activities on patient lung mechanics.

Other high-risk surgical procedures

Although preoperative pulmonary rehabilitation

has been studied primarily in association with major

lung-related surgeries, two small prospective studies

have shown that patients randomized to undergo 2 to

4 weeks of short-term pulmonary rehabilitation be-

fore coronary artery bypass graft surgery had signifi-

cantly better lung function (ie, peak expiratory flow

rate, inspiratory capacity, gas exchange) postopera-

tively than patients who did not undergo rehabilita-

tion, although the risk of postoperative pulmonary

complications was not consistently reduced [20,21].

These studies were small, however, and have not

been validated.

Another randomized controlled study of 81 pa-

tients examined the efficacy of pulmonary reha-

bilitation in preventing postoperative pulmonary

complications after upper abdominal surgery. Al-

though not clinically significant, the rehabilitation

group had a lower incidence of postoperative pul-

monary complications (7.5% versus 19.5%; P = 0.11)

and significantly fewer radiographic alterations (15%

versus 39%; P = .01) than the control group [22].

Patient selection for pulmonary rehabilitation

Inclusion criteria

Essentially any patient with stable chronic lung

disease who experiences significant symptoms that

diminish functional status or quality of life is an

appropriate candidate to consider for pulmonary re-

habilitation [5]. The magnitude of spirometric abnor-

malities seems to correlate poorly with levels of

dyspnea or functional capacity and is a poor indicator

of eligibility for pulmonary rehabilitation [23]. An

important prerequisite is the patient’s motivation to

participate in the various program elements, which

can be rigorous and demanding. Although advanced

age previously was thought to be a factor prohib-

iting enrollment in pulmonary rehabilitation, it is now

thought that patients of all ages who meet the other

inclusion criteria are eligible to participate. Because

elderly patients often have comorbidities that impair

their musculoskeletal, sensory, and cognitive abilities

(eg, arthritis, decreased visual acuity, dementia), they

are likely to derive considerable benefit from super-

vised exercise programs, nutritional education, and

training in medication administration techniques [24].

It is debated whether smoking cessation should be

a prerequisite or a goal of pulmonary rehabilitation.

Some authors argue that patients who are unable to

quit smoking lack the necessary motivation to be

successful participants in rehabilitation. The educa-

tional and behavioral modification elements of pul-

monary rehabilitation programs have the potential,

however, to be powerful adjuncts to ongoing smoking

cessation efforts. It has been proposed that non-

smokers and smokers who are enrolled in smoking

cessation programs should be deemed good candi-

dates for pulmonary rehabilitation [23].

Exclusion criteria

The only absolute contraindication to enrollment

in pulmonary rehabilitation is a lack of compliance as

shown by prior experience with the patient during the

course of medical treatment or an expressed unwill-

ingness to participate in the program [24]. As men-

tioned previously, active smoking is not a criterion

for exclusion if the patient shows a commitment to

quitting by participating in a smoking cessation pro-

gram in conjunction with pulmonary rehabilitation.

Severe functional disability also is not an absolute

contraindication [23] because patients still may derive

benefit from the exercise program and the adjunctive

educational components. Other comorbidities, par-

ticularly if unstable or symptomatic, that either would

endanger the patient or would interfere with the re-

habilitative process are relative contraindications to

participation; every effort to identify and optimize

treatment of coexisting diseases should be made be-

fore referral for pulmonary rehabilitation. Examples

of these diseases include recent myocardial infarc-

tion, unstable angina, severe pulmonary hyperten-

sion, advanced arthritis, disruptive behaviors, or

significant learning disabilities [3]. Additional exclu-

sion criteria are specific to the individual surgical

procedures, such as age limitations for lung trans-

plantation or specific spirometric parameters for lung

resection. Patients who are denied surgery based on

prohibitive but potentially reversible factors may be-

preoperative pulmonary rehabilitation 207

come better surgical candidates after completion of

a rehabilitation program. Pulmonary rehabilitation

can be an important and efficacious alternative for

patients who are deemed poor operative candidates.

Preoperative pulmonary evaluation

Major pulmonary complications, including pneu-

monia, atelectasis, bronchospasm, and respiratory

failure, are significant causes of postoperative mor-

bidity and mortality. Identification of procedure-

related and patient-related risk factors predisposing

to development of postoperative pulmonary compli-

cations is an essential component of the preoperative

evaluation. Procedure-related risk factors include the

surgical site, with thoracic and upper abdominal sur-

geries incurring the highest risk; duration of surgery;

and type of anesthesia (regional versus general) [25].

Various patient-specific risk factors also have been

identified and are discussed in more detail next. Some

of these risk factors are potentially modifiable with

early identification and initiation of appropriate mea-

sures, including pulmonary rehabilitation.

Patient-related risk factors

The most important risk factor for postoperative

pulmonary complications in the setting of thoracic

surgery is the severity of underlying lung disease.

Historically, specific thresholds for forced expiratory

volume in 1 second (FEV1), forced vital capacity, and

vital capacity were proposed as predictors of high

surgical risk. The literature and clinical experience

have since proven, however, that patients with severe

underlying lung impairment can undergo thoracic

surgery safely, and the previously identified thresh-

olds are not absolute. Currently, marginal surgical

patients are defined as having at least three of the fol-

lowing five pulmonary function abnormalities: FEV1

less than 1.2 L, maximum voluntary ventilation 35%

or less of predicted normal values, mid-expiratory

flow (forced expiratory flow 25–75%) of 0.6 to 1 L/s,

diffusing capacity 35% or less of predicted normal

values, and hypercapnia (Paco2 >45 mm Hg) [26]. In

LVRS, preoperative hypercapnia greater than 45 mm

Hg is strongly predictive of increased postoperative

mortality [27].

Cigarette smoking is an established risk factor for

postoperative complications, especially when the

smoking history exceeds 20 pack-years or if the

patient has smoked within 8 weeks of surgery.

Although the magnitude of this risk has not been

clearly delineated, smokers seem to be at greater risk

for significant postoperative hypoxemia, pneumonia,

delayed extubations, and increased ICU admissions

[28,29]. Additional risk factors for postoperative pul-

monary complications include general health status as

represented by American Society of Anesthesiolo-

gists classification greater than 2 (ie, having more

than mild systemic disease) [30], decreased exercise

capacity as indicated by a maximal oxygen con-

sumption less than 10 mL/kg/min, oxygen desatura-

tion during exercise, inability to climb more than one

flight of stairs, or 6-minute walk distance less than

200 feet before or after rehabilitation [31]. Although

obesity and advanced age have been identified previ-

ously as risk factors, the available data are conflict-

ing, and neither factor is considered independently

to prohibit surgical intervention.

Relevant preoperative testing

After a thorough history and physical examina-

tion, the preoperative pulmonary evaluation before

thoracic surgery usually proceeds in three stages.

Stage I includes measurement of spirometry, diffus-

ing capacity, and arterial blood gases to establish the

baseline severity of underlying lung disease. Stage II

testing uses a quantitative split-function ventilation-

perfusion scan to assess the function of each lung

independently. In patients with marginal lung func-

tion who are anticipating significant lung resec-

tion (primarily pneumonectomy or lobectomy), split

ventilation-perfusion scans facilitate calculation of

the predicted postoperative FEV1. Typically a post-

operative FEV1 less than 0.8 L or less than 35% of

predicted normal values indicates excessive surgical

risk and inoperable disease [26]. Stage III evaluation

is undertaken for patients with a marginal predicted

postoperative FEV1 and comprises primarily various

modes of exercise testing, including stair climbing,

timed walk test, exercise oximetry, and incremental

or submaximal cycle ergometry with the goal of

estimating or measuring maximal oxygen consump-

tion to risk stratify the patient [32]. Generally the

ability to climb higher than 14 m [33], 6-minute walk

distances greater than 700 ft, oxygen saturations 92%

or greater at rest and with exertion on exercise

oximetry, and a maximal oxygen consumption greater

than 15 mL/kg/min are indicators of good surgical

outcome [34]. Conversely, patients who climb less

than 12 m [33], have 6-minute walk distances less

than 500 ft, have oxygen saturations less than 90%

at rest or desaturate by more than 5% with exertion,

and have a maximal oxygen consumption less than

10 mL/kg/min are poor surgical candidates with

increased risk for postoperative pulmonary compli-

Box 1. Prerehabilitation assessment

Complete history and physical examination

Assess dyspnea and health-relatedquality of life

Cognitive evaluation

Mini-Mental Status ExaminationBaseline spirometryPulse oximetry or arterial blood gasCardiopulmonary testing

Determine baseline exercise capacity

Identify cardiac comorbidity orexercise-induced hypoxemia

Formulate exercise prescriptionNutritional assessmentPsychosocial evaluation

Assess support system, coexistingdepression or anxiety, copingand self-care skills

takaoka & weinacker208

cations [33]. Marginal patients are patients with

values intermediate to these criteria.

Table 3

Essential components and associated recommendations for a

multidisciplinary pulmonary rehabilitation program

Intervention Current recommendations

Exercise 20–30 min at least 3–5 times/wk

of muscle group–specific activity,

including aerobic, flexibility, and

strength training, targeting

improvement in dyspnea

Upper and lower

extremity

Ventilatory muscle

training

Use in patients refractory to other

forms of exercise (data conflicting)

Education Medication administration and

compliance, oxygen therapy,

symptom management, breathing

control techniques, nutrition,

energy conservation techniques,

respiratory and chest/airway

clearance methods

Psychosocial/behavior

modification

Smoking cessation, stress

management and coping skills,

end-of-life planning,

sexuality, self-management skills

Outcomes assessment Monitor domains of dyspnea,

health-related quality of life, and

exercise tolerance before, during,

and after rehabilitation

Initial prerehabilitation assessment

Before participation in a pulmonary rehabilitation

program, patients should undergo a formal evaluation

of their physical, mental, emotional, and social status

(Box 1). This assessment is important to ensure a

patient is an appropriate candidate for rehabilitation,

to identify any special areas of need the patient

may have, and to establish a baseline for comparison

with future assessments. An objective measurement

of dyspnea and health-related quality of life using

any one of a variety of rating scales or questionnaires

should be performed. Evaluation of the patient’s

cognitive function (most commonly done with the

Mini-Mental Status Examination) and educational

level also should be included to determine the

patient’s baseline capacities and to identify any

special needs or goals. Nutritional status should be

assessed because patients with severe COPD often

have changes in body weight, body composition, and

eating habits that all can affect exercise performance

negatively and increase mortality, independent of un-

derlying lung function [35]. Finally, patients should

undergo a full psychosocial assessment to evaluate

the level of social and family support, any coexisting

anxiety or depression, and patient coping and self-

care skills [5].

Essential components of pulmonary rehabilitation

Exercise training

Exercise training is a fundamental component

of any pulmonary rehabilitation program (Table 3)

and is the only element with strong support from

the literature. Although there are extensive variations

between programs with respect to exercise mode,

frequency, duration, and intensity, a reasonable ap-

proach uses the patient’s baseline activity level, re-

sults of exercise testing, and unique needs or goals

to determine the initial training regimen. Exercises

in flexibility, aerobic activities, and strength training

should be included. The desired frequency is initially

three to five times per week, increasing to daily, with

a minimum duration of 20 to 30 minutes including

periods of rest as needed. Minimal exercise intensity

is to 50% of maximal oxygen consumption or is

targeted to patient tolerance and gradually increased

[5]. Although heart rate is the traditional target pa-

rameter during exercise, dyspnea ratings are pref-

erable in this setting [36] because most patients with

chronic lung disease are limited by breathlessness,

breathing mechanics, and oxygen desaturation rather

than hemodynamic disturbances. Supplemental oxy-

preoperative pulmonary rehabilitation 209

gen should be used when necessary to maintain an

oxygen saturation 90% or greater during exercise.

Substantial evidence from controlled and uncon-

trolled studies indicates that specific lower extremity

training consistently leads to improvement in exercise

tolerance, particularly in tasks involving those muscle

groups. Typical training modes include walking,

treadmill exercises, stair climbing, and stationary

bicycle. Although the studies are limited by variations

in exercise prescription, there is general agreement

that lower extremity conditioning leads to significant

improvement in various outcome measures, most

notably in timed walk tests [6]. Although the data

for upper extremity exercise are less robust, arm

training usually is included in pulmonary rehabilita-

tion programs for several reasons. First, activities

involving primarily the upper extremities, which in-

clude many essential activities of daily living, seem

to have a higher ventilatory demand and are associ-

ated with more symptoms of dyspnea than are lower

extremity tasks. Second, the shoulder girdle elevates

the rib cage when the arms are anchored and can assist

in ventilation, decreasing the work of breathing during

a particular activity. Third, there is moderate evidence

suggesting that upper extremity exercises decrease

patient dyspnea and increase functional capacity. Up-

per extremity conditioning usually incorporates arm

ergometry or resistance exercises using 1- to 2-kg

weights or gravity [5].

Ventilatory muscle training, including sustained

hyperpnea and inspiratory resistance breathing, has

been proposed as an effective means of improving

respiratory muscle function, decreasing dyspnea and

increasing exercise tolerance. The current data are

largely conflicting, however, and do not support the

routine use of ventilatory muscle training in pul-

monary rehabilitation, although it may be employed

in specific patients who are refractory to optimal

therapy [6].

The benefit obtained with any type of training is

conferred largely to the muscles that undergo targeted

exercise (ie, 6-minute walk distance is improved with

leg but not arm training). Although some cross bene-

fit is seen, training should attempt to parallel the de-

sired outcome as much as possible. Some degree of

training reversibility occurs, and the conditioning

effects are maintained only as long as the activity is

continued [3]. The optimal duration and intensity of

postrehabilitation exercise have not been elucidated.

Chest physiotherapy

Chest physiotherapy, including postural drainage,

chest percussion, and flutter valve use, is applied

primarily to patients with purulent lung disease

(ie, cystic fibrosis, bronchiectasis, chronic bronchi-

tis). The goals of chest physiotherapy are to improve

ventilation and exercise tolerance and to decrease the

work of breathing [37]. Although chest physiotherapy

has been studied mainly in the postoperative setting,

limited data suggest that perioperative chest physio-

therapy may lead to fewer pulmonary complications

after surgery [38].

Education

Although poorly effective when used alone,

educational intervention is an essential component

of pulmonary rehabilitation and encompasses a

wide array of pertinent topics, including the proper

administration of medications (technique, compli-

ance, schedule, and side effects), use of supplemental

oxygen, nutritional support, strategies to relieve

dyspnea, pulmonary anatomy and physiology, and

the pathophysiology of COPD. Patients learn meth-

ods of energy conservation and work simplification,

which ultimately allow them to perform activities of

daily living more easily, and enable them to divert

energy toward other less essential tasks. They also are

taught breathing control techniques, such as pursed-

lip and diaphragmatic breathing [39]. Pursed-lip

breathing is performed by inhaling through the nose

and exhaling against partially closed lips. This

breathing technique theoretically reduces respiratory

rate, arterial carbon dioxide, and minute ventilation,

while increasing arterial oxygen tension, oxygen

saturation, and tidal volume. Diaphragmatic breath-

ing relies on the conscious expansion of the abdomi-

nal wall during inspiration to augment diaphragmatic

mechanical efficiency and reduce dyspnea. Data are

conflicting for both techniques, and some studies

show increased dyspnea using these techniques. In

the case of diaphragmatic breathing, there may be

decreased mechanical efficiency and increased work

of breathing [6].

Psychosocial support

Despite a lack of strong evidence supporting

psychosocial interventions, they are integral to a

multidisciplinary rehabilitation effort. Many patients

with chronic, disabling lung disease have concurrent

mood and thought disturbances, including anxiety,

depression, low self-esteem, poor body image, and

social withdrawal. These problems often are accen-

tuated in the preoperative setting because patients

often are dealing with a recent diagnosis of cancer,

are anxious about an upcoming surgery, or are

takaoka & weinacker210

waiting on the transplant list. As part of a compre-

hensive pulmonary rehabilitation program, patients

learn a variety of relaxation and coping techniques.

They are encouraged to discuss concerns regarding

intimacy and relationships with family and friends

and receive emotional support to do so.

Outcomes assessment

Outcomes monitoring is an essential aspect of

any rehabilitation program to assess patient response

and progress over time. There are three recommended

domains for outcomes monitoring: dyspnea, health-

related quality of life, and exercise tolerance [40].

Dyspnea is classified as either functional (limiting

performance of specific activities) or exertional and

is quantified with a patient-reported severity scale.

Health-related quality of life refers to a patient’s sat-

isfaction or happiness with life in the health domain.

Most rehabilitation programs use disease-specific

questionnaires, such as the Chronic Respiratory

Disease questionnaire or the St. George’s Respiratory

questionnaire, to monitor health-related quality of life

to predict outcomes after pulmonary rehabilitation

[6]. Exercise tolerance typically is monitored by ei-

ther a 6-minute walk or a submaximal or maximal

exercise test. Although less objective and more in-

fluenced by patient effort and motivation than a

submaximal or maximal exercise test, the 6-minute

walk test is a sensitive measure of response to reha-

bilitation and is simple and inexpensive [33]. Other

outcomes to assess include nutritional status, smok-

ing cessation, medication use and compliance, and

changes in anxiety or depression.

Summary

Although data are limited for preoperative pul-

monary rehabilitation, benefit can be inferred largely

from studies done on COPD and pulmonary rehabili-

tation because of the similarity of patient populations.

Although underlying lung function is unchanged, pa-

tients who undergo preoperative pulmonary rehabili-

tation seem to experience an enhanced quality of life

and increased functional capacity. Likewise, multi-

disciplinary rehabilitation programs can result in bet-

ter patient compliance with medications and smoking

cessation and decreased use of various health care re-

sources. Although pulmonary rehabilitation works to

benefit patients anticipating surgery, it also represents

a valuable treatment alternative to patients who are

poor surgical candidates. Pulmonary rehabilitation

seems to be a cost-effective, benign intervention with

no adverse effects and should remain an essential

component of patient management before lung trans-

plantation, LVRS, lung resection, and potentially any

other elective thoracic surgical procedure.

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Thorac Surg Clin

Informed Consent: Ethical and Legal Aspects

Carole A. Klove, RN, JDa,*, Sarah J. DiBoise, JDa, Betty Pang, JDb,

William C. Yarbrough, BAa

aStanford Hospital and Clinics and Lucile Packard Children’s Hospital, 300 Pasteur Drive, Stanford, CA 94305, USAbStanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA

Obtaining informed consent is only one of many

requirements necessary to any medical or surgical

procedure. In contrast to other checkbox items, ob-

taining patient consent, more specifically informed

consent, requires a progressive dialog between the

patient and physician—one in which the patient de-

velops an understanding of the procedure and its

risks and consequences, while the physician learns

about and manages the patient’s expectations.

Informed consent provides an opportunity for both

parties to engage in a meaningful discussion, ulti-

mately leading to a patient’s voluntary and informed

decision. In general, this process fulfills physicians’

ethical responsibilities and their legal duties to inform

patients fully of the diagnosis, prognosis, nature of

the procedure, risks and benefits associated with the

medical intervention, and any alternative treatments

that may exist.

If physicians fail to obtain informed consent,

what legal liability do they have? Originally, failure

to obtain consent was treated in the courts as the

intentional tort of battery [1]. Battery is best defined

as ‘‘an act that was intended to cause, and does cause,

an offensive contact with or unconsented touching of

or trauma upon the body of another’’ [2]. A plaintiff

suing under the theory of battery merely had to prove

that he or she had undergone an unconsented touch-

ing to prevail. The plaintiff needed to prove that

he or she was provided with inaccurate or mislead-

ing information as to the nature of the procedure or

its consequences.

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.005

* Corresponding author.

E-mail address: cklove@stanfordmed.org (C.A. Klove).

Slowly over time, this theory of recovery gave

way to the present-day negligence theory in all

but one state (Pennsylvania) [3,4]. Although battery

still may constitute a theoretical basis for recovery

for medical malpractice, modern health care delivery

lends itself more readily to negligence as a basis of

recovery. To prevail on a theory of negligence, the

plaintiff (injured patient) must establish by a pre-

ponderance of the evidence (>50% likelihood) the

following four elements: (1) the physician owed a

duty to the patient to obtain his or her informed

consent, (2) the physician breached that duty, (3) the

physician’s breach directly and proximately caused

the patient’s injury, and (4) the patient suffered com-

pensable harm. This final element is crucial in that

an inability to show harm in a case of professional

negligence (malpractice) leaves the plaintiff without

the damages portion of his or her complaint and

with no right to recovery. Familiarity with the origins

of the informed consent doctrine and an awareness

of the salient issues surrounding current standards of

informed consent provide physicians with a greater

appreciation of the moral underpinnings and practical

application of this legal doctrine.

Development of the informed consent doctrine

‘‘Law pervades medicine because ethics pervades

medicine’’ [5]. In the health care domain, the law is

often perceived to be a restrictive intrusion on physi-

cian autonomy, and informed consent is yet another

legal doctrine that attempts to shift the focus of

medical decisions from the physician to the ultimate

15 (2005) 213 – 219

reserved.

thoracic.theclinics.com

klove et al214

risk bearer—the patient. The doctrine provides

another source of potential conflict between parties

who traditionally have been in a trusting relationship.

In Schloendorff v Society of New York Hospital,

[6] Justice Cordozo stated: ‘‘Every human being of

adult years and sound mind has a right to determine

what shall be done with his own body; and a surgeon

who performs an operation without his patient’s

consent, commits an assault, for which he is liable

in damages’’ [7]. The physician is bound by a pro-

fessional oath, an ethical code of conduct, and statu-

tory and case law always to act in the best interest of

the patient. In the process, patients receive valuable

input and guidance from a well-educated and knowl-

edgeable advocate and become equipped with the

information necessary to weigh the risks and benefits

for themselves and to proceed with or refuse treat-

ment [8]. The competent rendering of treatment by

physicians and disclosure of information are not the

sole measures of their duty to the patient. Physicians

maintain the additional duty of respecting the

patient’s right to follow or ignore their recommenda-

tions, even if they ultimately disagree with the

patient’s choice.

Physician’s legal duty: materiality

The legal duty of physicians to obtain consent for

treatment has its earliest roots in English law. The

first decision can be traced to the 1767 case of Slater

v Baker and Stapleton [9], in which the court es-

tablished the custom of obtaining consent from the

patient before surgery and assessing legal liability

when that custom was not followed. The Slater court

did not allow, however, for nuances as to whether or

not consent was indeed obtained; consent either

existed or it did not.

This concept of consent did not change until 1914

in Schloendorff v Society of New York Hospital [10].

In this case, the patient consented to an exploratory

surgery that led to the discovery and subsequent

removal of a fibroid tumor. The patient later de-

veloped a gangrenous infection requiring the removal

of several fingers. The court held that the patient

voluntarily consented only to the exploratory surgery

and not to the removal of the tumor and, by violating

the narrow consent given, ‘‘the ministers of healing

whom it [New York Hospital] has selected have

proved unfaithful to their trust’’ [11].

Schloendorff underscored the necessity of volun-

tary approval of a proposed procedure. Despite an

acknowledgment of the need for consent and narrow-

ing the doctrine’s application only to the specific

procedure, the consent doctrine was not fully fleshed

out—to require the physician to inform the patient

fully of relevant, material information that would

guide such a decision. Although far from today’s

model of informed consent, the court in Schloendorff

moved closer toward today’s concept of the patient as

the autonomous decision maker in the process of

electing to undergo a surgical procedure. Consent

given freely but without proper information is mean-

ingless. In 1957, the California Court of Appeals

in Salgo v Leland Stanford Jr. University Board of

Trustees directly addressed this issue.

The Salgo [12] case proved to be the defining

moment in an entirely different doctrine—informed

consent. The case involved the use of translumbar

aortography to determine the degree of blockage in

the descending aorta. The procedure required the

insertion of a large-bore needle into the aorta ap-

proximately 3 to 4 inches away from the patient’s

midline and spinal cord. After the surgery, the patient

was left paralyzed. The appeals court reversed on the

grounds that the trial court had misapplied the res

ipsa loquitur doctrine—a legal doctrine in which

negligence is inferred from injury—in a medical mal-

practice case. Remanding the case, the court stated:

‘‘[a] physician violates his duty to his patient and

subjects himself to liability if he withholds any facts

which are necessary to form the basis of an intelligent

consent by the patient to the proposed treatment’’

[13]. This conditioning of freedom of choice on the

disclosure of ‘‘material’’ information provided the

backbone of the informed consent model today.

Building on the decision in Salgo, two cases

decided in 1960 more clearly defined the affirmative

duty of a physician to disclose by describing the

information that was crucial to impart to the patient.

In Mitchell [14], the patient suffered several fractured

vertebrae while undergoing insulin and electroshock

therapy for schizophrenia. In Natanson [15], the

patient’s radiation therapy for breast cancer inflicted

severe damage to the muscle, skin, and bone beneath

her left arm. Mitchell set forth the simple directive

that risk of collateral damage must be disclosed, and

Natanson established the elements of informed

consent that are fully in force today: disclosure of

the nature of the ailment, nature of the proposed

treatment, consequences of that procedure, probabil-

ity of success, alternative treatments, and the risk of

unfortunate results.

A patient can make an informed decision only

after receiving and assimilating all relevant facts. The

physician must select that information that is ‘‘mate-

rial’’ to the patient. Commonly accepted elements of

a physician’s professional duty of disclosure include

1 Any physician who treats a patient shall inform the

atient about the availability of all alternate, viable medical

odes of treatment and about the benefits and risks of these

eatments. The physician’s duty to inform the patient under

is section does not require disclosure of: (1) Information

eyond what a reasonably well-qualified physician in a

imilar medical classification would know; (2) detailed

chnical information that in all probability a patient would

ot understand; (3) risks apparent or known to the patient;

) extremely remote possibilities that might falsely or

etrimentally alarm the patient; (5) information in emergen-

ies where failure to provide treatment would be more

armful to the patient than treatment; (6) information in

ases where the patient is incapable of consenting.

informed consent 215

diagnosis, prognosis, nature of the procedure, pur-

pose of the procedure, risks and benefits of the prof-

fered treatment, and alternative treatment options

(including nontreatment choices). Rooted in the basic

tenets of bodily integrity and individual autonomy, it

can be confusing to the physician to determine the

level of detail that a particular patient would find

material. Some light may be shed by reviewing what

courts have determined to be material generally and

in specific situations.

The present embodiment of the informed consent

doctrine was enumerated in 1972 [16]. In Canterbury

v Spence, the federal appeals court for the District

of Columbia reviewed a directed verdict in favor of

the physicians against a patient who had agreed to a

surgery to alleviate back pain and, as a consequence

of a postsurgery fall, became paralyzed. According

to the court, the central issue was an inadequate

disclosure by the physicians of risks and alternatives

of the surgical procedure. In deciding Canterbury, the

court provided guidance on the legal disclosure duty

of the physician. Recognizing the great disparity of

knowledge between patients and physicians and the

potential for abuse of patient rights, the court held

that ‘‘[t]o the physician, whose training enables a

self-satisfying evaluation, the answer may seem

clear, but it is the prerogative of the patient, not the

physician, to determine for himself the direction in

which his interests seem to lie’’ [17]. The Canterbury

court made clear that ‘‘[a] physician is under a duty to

treat his patient skillfully but proficiency in diagnosis

and therapy is not the full measure of his responsi-

bility’’ [18]. In determining that the proficient ad-

ministration of experienced care is not the sole gauge

of a physician’s competency, the court found that even

a task completed successfully could constitute mal-

practice if achieved without informed approval from

the patient.

The California Supreme Court also has recognized

this duty and extended it to include providing in-

formation relevant to the prevention of disease [19].

In Truman, the court was reluctant to find that the

patient’s family had no recourse when Truman’s phy-

sician, in failing to recommend annual pap smears,

prevented his patient from receiving a simple di-

agnostic procedure that may have led to earlier

treatment of her cervical cancer and saved her life.

The physician’s negligence in failing to recommend

a procedure that was standard practice within the

medical community negated his patient’s informed

choice. Relying on an earlier California case [20],

the Truman court reiterated the patient’s inherent

right to exercise control over [his or her] own body.

To be effective, the patient’s consent must be self-

determined and informed. In this case, the patient,

never having been empowered with material infor-

mation on which to base an informed decision, ex-

ercised neither element of consent.

Materiality, or relevance of information, is the

crucial factor in determining what facts and informa-

tion the physician must convey to the patient. Neither

the physician who overwhelms the patient with an

exhaustive list of procedures, consequences, benefits,

risks, and alternatives nor the physician who fails to

mention important facts has achieved his or her

purpose. What information is material? That is, what

must a physician include, and what may he or she

omit? The court in Arato [21], relying on the rea-

soning in Salgo and Natanson that ‘‘each patient

presents a separate problem’’ [22], found that mate-

riality is subjectively determined for a given patient

with a specific diagnosis, yet objectively determined

in that the physician must consider what a reasonable

person in the patient’s position would want to know

to make an informed decision. The Arato court held

that the physician is under no duty to disclose infor-

mation material to the patient’s nonmedical interests.

In this case, statistical life expectancy was found to

fall outside of medical interests and outside the pro-

tection of the doctrine of informed consent.

In a case involving a Wisconsin surgeon accused

of failure to obtain informed consent before a pro-

cedure to clip a cerebral aneurysm, the court greatly

expanded the surgeon’s duty of proper disclosure

[23]. In Kokemoor, the court found that in providing

information to the patient, the physician failed to

disclose his experience with the procedure and his

rate of success compared with other physicians and

failed to offer a tertiary care facility with more ex-

perienced physicians. The Wisconsin Supreme Court

extended the doctrine of informed consent and found

that all of these items were material [24].1 As stated

p

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klove et al216

in Canterbury, these material facts are of the sort

‘‘demanding a communication’’ [25] by the physician

and, according to Kokemoor, ‘‘a physician of good

standing would have made the plaintiff aware of the

alternative of lower risk surgery with a different,

more experienced surgeon in a better-equipped

facility’’ [26].

Finally, in Moore [27], the California Supreme

Court held that treating physicians must disclose any

research or economic interests to patients as part of

the informed consent process. The court’s concern

was based in maintaining the integrity of a physi-

cian’s professional judgment in recommending medi-

cal procedures to patients. The court stated, ‘‘. . . aphysician who is seeking a patient’s consent for a

medical procedure must, to satisfy his fiduciary duty

and to obtain the patient’s informed consent, disclose

personal interests unrelated to the patient’s health,

whether research or economic, that may affect his

medical judgment’’ [28].

The above-described cases are a testament to a

variable concept of what constitutes material infor-

mation and what does not. Uniform measures of

materiality, aside from the large concepts in Natanson

or Canterbury, remain largely amorphous. Pragmati-

cally a physician’s duty is measured differently in

different jurisdictions. The standards as to what con-

stitutes material information generally fall into one of

three categories: physician-based disclosure, patient-

based disclosure, and a mixed or hybrid standard.

Although familiarity with the practices of other ju-

risdictions is not strictly required, it is recommended

that physicians have a general knowledge of the

standard set forth in their state of practice.

The physician-based standard is premised on the

notion that physicians encompass certain expert

knowledge that uniquely enables them to determine

what material information to impart to a patient de-

ciding whether or not to undergo a medical proce-

dure. This standard is an objective standard in that the

physician has a legal duty to disclose any information

that a reasonable physician in the same or similar

circumstances would provide to the patient for the

purpose of obtaining consent. This standard is the

most widely adopted and is the rule in roughly half

of all states.2 The primary advantage of a physician-

2 Alabama, Arizona, Arkansas, Colorado, Delaware,

Idaho, Illinois, Indiana, Kansas, Kentucky, Maine, Michi-

gan, Missouri, Montana, Nebraska, Nevada, New Hamp-

shire, New York, North Carolina, North Dakota, South

Carolina, Tennessee, Vermont, Virginia, and Wyoming.

based standard is that it enables the most knowl-

edgeable party to determine the materiality of the

information disclosed; this is also the chief criticism

because the physician’s determinations bear little

‘‘personal’’ responsibility and potentially deprive

the patient of the capability of making a truly in-

formed choice. Other disadvantages include the lack

of established customs in new procedures, discrep-

ancies between patient and physician’s concepts

of materiality, and the exact definition of a ‘‘reason-

able physician.’’

In contrast to the physician-based standard, the

patient-based standard requires the physician to

disclose any information that a reasonable patient

would consider material to a decision concerning his

or her medical treatment [29]. Nineteen states and the

District of Columbia have adopted the reasonable

patient standard.3 The basic premise is that the patient

who ultimately bears the consequences should deter-

mine what information is relevant in making his or

her decision. The patient-based standard is based on a

hypothetical ‘‘reasonable patient,’’ however, and the

physician is left with the problem of subjectively

determining what is important to a particular patient.

The physician-based standard affords the physician a

more objective standard shaped by formal education,

professional custom, and experience.

Finally, states adopting standards with elements

of patient-based and physician-based standards are

described as applying a hybrid standard. Six states

fall into this category: four by statute and two by case

law [30]. In states applying this standard, the

physician may be held to the standard of what the

reasonable physician would disclose in combination

with what the reasonable patient would desire to

know in making an autonomous choice.

Causation

In addition to showing that the physician owed a

duty to the patient and the physician breached that

duty, the plaintiff must prove that he or she was

injured and that the negligence of the practitioner was

a direct and proximate cause of the injury. The issue

of causation is a combination of two issues. First,

3 Alaska, Connecticut, Georgia, Hawaii, Iowa, Louisi-

ana, Maryland, Massachusetts, Minnesota, Mississippi, New

Jersey, Ohio, Oklahoma, Pennsylvania, Rhode Island, South

Dakota, Washington, West Virginia, and Wisconsin.

informed consent 217

decision causation [31] stipulates that had the physi-

cian completely disclosed all of the material infor-

mation, the patient would have chosen differently,

and injury would not have occurred. Second, treat-

ment or injury causation [31] is framed with respect

to the treatment rendered: The injury would have

never occurred but for the physician failing to ex-

ercise reasonable care. The latter concept does not

depend on hindsight and lends itself more readily

to proof and the judicial process.

Damages

Patients must show that they suffered actual

damages from the injury directly caused by the

physician’s failure to disclose material information.

Even if the patient suffered an injury, if that injury

caused no harm that could be remedied by a court

of law, the patient cannot recover under the negli-

gence theory.

Practical aspects

Aside from ethical and legal aspects, several prac-

tical aspects deserve attention. Patient competence to

comprehend a material disclosure is of great concern

to the physician in evaluating the patient’s decision-

making capacity. The determination that a patient is

incompetent to render a legally and medically cog-

nizable decision alters the health care dynamic.

The patient, traditionally a partner in the decision-

making process, may have his or her decision-making

capacity greatly limited. Medical decisions, previ-

ously the sole province of the patient, move to a third

party—a relative, a guardian, or a court appointed

guardian ad litem. The doctrine of informed consent

and all of its requirements still apply, however; the

decision normally reserved for the patient to make

simply is shifted to a surrogate with the mental ca-

pacity to make that determination.

Competence, as it relates to medical decision

making in informed consent, depends on a patient’s

individual capacity. Capacity, as defined by North-

ern, is the ‘‘mental ability to make a rational decision,

which includes the ability to perceive, appreciate all

relevant facts and to reach a rational judgment upon

such facts’’ [32]. Determinations of capacity have

been made in cases involving sexual consent [33],

entrance into contract [34], right to marry [35], exe-

cution of a will [36], ability to donate organs [37],

right to vote [38], and ability to stand trial [39].

Capacity in one context may be insufficient in an-

other, however. The manner in which competence is

evaluated, be it in a judicial hearing, a statutory pro-

vision, or a medical determination, is as varied as the

fields in which it is applied.

In most situations, a minor child is deemed to lack

sufficient capacity to arrive at a medical decision. Yet,

depending on the level of independence and maturity,

age, and the nature of the procedure, certain minors

have a statutory right to consent to the medical

intervention themselves; this generally does not apply

to a minor’s consent to surgery. A parent or guardian

would then act in the role of the child to determine

an appropriate and acceptable decision and give a

substituted informed consent.

The form in which patients receive informa-

tion and the complexity of the information used in

obtaining consent greatly influence a patient’s com-

prehension. Studies of patients’ recollection of infor-

mation gathered in the early stages of the consent

process indicate that patients receiving written infor-

mation, as opposed to verbal information, had greater

recall and recognition after surgery [40,41]. Com-

plexity of information within the consent form and

the patient’s reading ability or language proficiency

seem to have a further impact on comprehension [42].

Some researchers have suggested preconsent testing

of comprehension capacity in cases in which there are

questions as to the involvedness of the subject matter

or the mental ability of the patient [43].

Exceptions to obtaining informed consent

Informed consent is not required in all situations.

As with all rights, in certain situations, a patient’s

right to make a medical decision may be overridden.

In cases of emergency and patient waiver, the deci-

sion rests with the physician. In rare cases, a patient’s

decision may be overridden by the physician’s thera-

peutic privilege.

In cases of emergency, in which informed consent

cannot function properly because of the immediacy of

the situation, informed consent is excused. Where

time is of the essence, death or serious bodily injury

may result from inaction, and the treating physician

has no prior knowledge of the patient’s desire to

refuse the specific treatment administered, informed

consent is presumed, and medical intervention may

be undertaken without liability. In addition, a com-

petent patient holding the right to consent may waive

such rights and defer to the medical decision-making

klove et al218

power of the physician. In each circumstance, the

physician is acting as a surrogate for the patient.

Finally, the doctrine of therapeutic privilege al-

lows the physician to determine that disclosure of

information, although material, would actually harm

the patient. Owing to a strong paternalistic flavor,

therapeutic privilege often finds itself at odds with

informed consent and likewise has fallen out of favor.

Regardless of sound judgment or good intentions,

therapeutic privilege carries with it a measurable

cautionary note: Use sparingly and always document.

If any doubt exists as to whether or not to disclose

certain information, physicians should always err on

the conservative side and disclose.

Summary

The legal doctrine of informed consent looms

large over the medical profession with many interest

groups trying to expand and narrow the doctrine,

including patient rights advocates, managed care or-

ganizations, government agencies, and accreditation

organizations. The legal profession itself has taken no

small part in defining the doctrine. No physician

today is practicing without the daily influence of law

on his or her practice of medicine. The doctrine of

informed consent, with all of its ambiguities and

difficulties, has established a medical duty on the

physician to make a reasonable attempt to unite the

goals of the patient and the physician. Ultimately,

physicians gain from the knowledge that their

wisdom and skill has fostered a decision that is ame-

nable to the patient. The patient gains from a fa-

cilitated decision that truly reflects that individual’s

self-determined will. As a result, both parties enjoy

a newly formed partnership and the return of some-

thing that has long been taken for granted—trust in

the physician-patient relationship.

References

[1] Mohr v Williams, 95 Minn 261 (1905).

[2] Proffitt v Ricci, 463 A.2d 514, 517 (1983).

[3] Warren BJ. Pennsylvania medical informed con-

sent law: a call to protect patient autonomy rights by

abandoning the battery approach. 38 Duq L. Rev

917 (2000).

[4] Kottkamp NA. Finding clarity in a gray opinion:

a critique of Pennsylvania informed consent doctrine.

61 U. Pitt. L. Rev 241 (1999).

[5] Scott C. Why law pervades medicine: an essay on the

ethics in health care. 14 ND J.L. Ethics & Pub Pol’y

245, 245 (2000).

[6] Schloendorff v Society of New York Hospital, 105

N.E. 92 (1914).

[7] Schloendorff v Society of New York Hospital, 105

N.E. 93 (1914).

[8] Washington v Harper, 494 US 210 (1990).

[9] Berg JW, Appelbaum PS, Lidz CW, et al. The legal

requirements for disclosure and consent: history

and current status. In: Berg JW, Appelbaum PS, Lidz

CW, et al, editors. Informed consent: legal theory and

clinical practice. New York7 Oxford University Press;

2001. p. 42.

[10] Schloendorff, 105 N.E. 92 (1914).

[11] Schloendorff, 105 N.E. 95 (1914).

[12] Salgo v Leland Stanford Jr. University Board of

Trustees, 317 P.2d 170 (1957).

[13] Salgo v Leland Stanford Jr. University Board of

Trustees, 317 P.2d 181 (1957).

[14] Mitchell v Robinson, 334 S.W.2d 11 (1960).

[15] Natanson v Kline, 350 P.2d 1093 (1960).

[16] Canterbury v Spence, 464 F.2d 772 (D.C. Cir. 1972).

[17] Canterbury v Spence, 464 F.2d 781 (D.C. Cir. 1972).

[18] Canterbury v Spence, 464 F.2d 781 (D.C. Cir. 1972).

[19] Truman v Thomas, 611 P.2d 902 (1980).

[20] Cobbs v Grant, 8 Cal.3d 229 (1972).

[21] Arato v Avedon, 858 P.2d 598 (1993).

[22] Salgo v Leland Stanford Jr. University Board of

Trustees, 317 P.2d 170, 181 (1957), Natanson v Kline,

350 P.2d 1093, 1104 (1960).

[23] Johson v Kokemoor, 545 N.W. 2d 495 (1996).

[24] Wis. Stat. x 448.30.

[25] Canterbury v Spence, 464 F.2d 772, 787 (D.C.

Cir. 1972).

[26] Johson v Kokemoor, 545 N.W. 2d 495, 510 (1996).

[27] Moore v Regents of University of California, 51 Cal.

3d 120 (1990).

[28] Moore v Regents of University of California, 51 Cal.3d

120, 131–132(1990).

[29] Alaska Stat x 09.55.556.

[30] California (Cobbs v Grant, 8 Cal.3d 229 (1972)),

Florida (Fla Stat Ann x766.103), New Mexico (Gerety

v Demers, 589 P.2d 180 (1978)), Oregon (Ore Rev Stat

x 677.097), Texas (Tex. Civ Prac. & Rem. Code x74.101), and Utah (Utah Code Ann x 78–14–5).

[31] Berg JW, Appelbaum PS, Lidz CW, et al. Legal rules

for recovery. In: Berg JW, Appelbaum PS, Lidz CW,

et al, editors. Informed consent: legal theory and

clinical practice. New York7 Oxford University Press;

2001. p. 137–40.

[32] State of Tennessee, Dept. of Human Services v North-

ern, 563 S.W.2d 197, 209 (1978).

[33] Propes v State, 68 Ga. App. 418 (1942).

[34] Equipto Div Aurora Equip. Co. v Yarmouth, 1996

Wash. App. LEXIS 569 (1997).

[35] Johnson v Johnson, 214 Minn. 462 (1943).

[36] Estate of McKasson v Hamric, 70 Ark. App. 507 (2000).

[37] Curran v Bosze, 141 Ill. 2d 473 (1990).

[38] Pitts v Black, 608 F. Supp. 696 (1984).

informed consent 219

[39] Virgin Islands v Gumbs, 42 V.I. 79 (2000).

[40] Layton S. Informed consent in oral and maxillofacial

surgery: a study of the value of written warnings.

Br J Oral Maxillofac Surg 1994;32:34–6.

[41] Askew G. Informed consent: can we educate patients?

J R Coll Edinb 1990;35:308–10.

[42] Philipson SJ. Informed consent for research: a study

to evaluate readability and processability to affect

change. J Invest Med 1995;43:459–67.

[43] Mayberry MK. Towards better informed consent in

endoscopy: a study of information and consent pro-

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Eur J Gastroenterol Hepatol 2001;13:1467–76.

Thorac Surg Clin

Fast-Tracking: Eliminating Roadblocks to Successful

Early Discharge

Jules Lin, MDa, Mark D. Iannettoni, MD, MBAb,*

aDepartment of Surgery, Section of Thoracic Surgery, Office of Surgery Education, University of Michigan Medical Center,

TC 2207/0342, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USAbDepartment of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Room 1602-JCP,

Iowa City, IA 52242, USA

Ever-increasing health care costs and limited

medical resources have driven health care organiza-

tions to focus on key components of these costs, such

as the hospital length of stay (LOS). This article

summarizes some common obstacles to successful

early discharge that affect thoracic surgical patients.

Some authors also have identified criteria to predict

which patients are more likely to have a prolonged

LOS to anticipate better the needs of these high-risk

patients. Potential solutions to overcome these

obstacles are discussed in hopes of increasing the

rate of successful early discharge. The involvement

of thoracic surgeons in this process is essential to en-

sure that the quality of patient care is maintained and

perhaps even improved.

Although there are multiple reports on the deter-

minants for delayed discharge after chest surgery,

most describe series of cardiac surgical patients.

Several more recent series describe factors involved

in general thoracic surgery, however. In a prospective

study of 130 patients undergoing major pulmonary

resection, Irshad et al [1] identified factors associated

with a hospital stay greater than 6 days (Box 1). The

most frequent medical reasons for a delayed dis-

charge were persistent air leaks (12.3% of patients),

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.007

This article was supported by NIH T32 Surgical

Oncology Research Training Program CA009672-13.

* Corresponding author.

E-mail address: mark-iannettoni@uiowa.edu

(M.D. Iannettoni).

pulmonary infections (6.1%), and atrial fibrillation

(5.1%), which increased the LOS by 13.1, 9.6, and

2.4 days. Cardinale, et al [2] found a 12% incidence

of atrial fibrillation after pulmonary resection for

lung cancer, but found no difference in LOS. Wright

et al [3] reported the most common reasons for failure

of early discharge were inadequate pain control and

persistent air leaks. Discharge delays after esopha-

gectomy also are due to pain control and respiratory

issues, in addition to concerns regarding anastomotic

healing and an enteral diet [4].

Although the mean medically required LOS was

6.9 days in the series reported by Irshad et al [1], the

average LOS was 7.35 days, suggesting additional

social obstacles to early discharge. The most common

cause was inadequate home support, which was found

in 10.2% of patients. Convalescent facilities were

unavailable in 7.1% of cases. Social factors resulted

in an increase of 44 hospital days per 100 patients.

Nonmedical factors were associated with age older

than 75, female gender, and a cancer diagnosis.

Preoperative interventions

Smoking cessation

Many patients presenting with lung cancer con-

tinue to smoke at the time of initial assessment for

pulmonary resection and are at an increased risk for

postoperative complications. Warner et al [5] showed

that smoking cessation more than 8 weeks before

15 (2005) 221 – 228

reserved.

thoracic.theclinics.com

Box 1. Common reasons for failure ofearly discharge

Medical factors

Inadequate pain controlPersistent air leakPulmonary infectionsAtrial arrhythmiaSevere nauseaFever

Social factors

Inadequate home supportUnavailability of convalescent facilities

lin & iannettoni222

coronary artery bypass decreased the risk of pulmo-

nary complications to that of nonsmokers, whereas

patients who quit less than 8 weeks preoperatively

showed no advantage. Studies have shown that even

1 to 2 minutes of advice results in 5% of pa-

tients quitting smoking, which increases with the

use of supplemental pamphlets [6]. Nicotine replace-

ment doubles cessation rates and can be combined

with bupropion.

Preoperative education

Patients should be instructed on the use of the

incentive spirometer and an exercise program if

appropriate. Thorens [7] reported that therapy ini-

tiated before surgery was more effective in reducing

pulmonary complications than therapy begun post-

operatively (47% compared with 27%). The expected

hospital course and discharge plans also should be

outlined clearly for patients and their families along

with a discussion of possible complications. In a pa-

tient satisfaction survey, Wright et al [3] found that

after proper education and instruction, most patients

were comfortable with an earlier discharge.

Intraoperative techniques

Muscle-sparing thoracotomy

Owing to the morbidity associated with a standard

posterolateral thoracotomy incision, alternative ap-

proaches have been developed. A muscle-sparing

thoracotomy preserves the latissimus dorsi and

serratus anterior muscles. Alkcali et al [8] performed

a prospective, randomized trial of 60 patients and

found that there was significantly less postoperative

pain in the muscle-sparing group, but that pulmonary

function and LOS were not significantly different. A

more recent report by de Lima and Carvalho [9]

found, however, that using a muscle-sparing thora-

cotomy contributed to a decrease in hospital stay. The

vertical axillary thoracotomy is another alternative

approach and may offer improved cosmesis and pre-

servation of shoulder girdle function.

Video-assisted thoracic surgery

Compared with thoracotomy, video-assisted tho-

racic surgery (VATS) decreases the amount of chest

wall trauma and postoperative pain. Although a

standard posterolateral thoracotomy may require an

incision 30 to 40 cm long, biopsies can be performed

through three 1-cm ports, and a VATS lobectomy is

performed using a 5- to 8-cm incision. The forced

expiratory volume at 1 second (FEV1), a measure of

pulmonary function, decreases approximately 30%

after a thoracotomy versus 15% in patients under-

going VATS [10]. There also is indirect evidence that

VATS may improve postoperative immune function

by reducing the body’s inflammatory response [11].

VATS is associated with a decreased LOS and an

earlier return to normal activities [12].

Thoracoscopic lung biopsy was evaluated as an

outpatient procedure in 62 patients at the University

of Michigan [13]. Chest tubes were removed in the

recovery room as long as there were no air leaks

and the chest radiograph did not reveal a pneumo-

thorax. Using these criteria, 72.5% of patients were

discharged on the same day of their operation with

an oral analgesic, and only 5% were admitted for

longer than 3 days. There was no operative mortality;

one patient required readmission for a pneumothorax.

Preventza et al [14] found that VATS wedge resection

could be performed with an overnight admission in

87% of patients in a retrospective review of 37 cases,

and that hospital charges were nearly half of that for

a thoracotomy.

Minimally invasive surgical techniques also can

be applied to pulmonary lobectomy and esophagec-

tomy. DePaula et al [15] performed laparoscopic

transhiatal esophagectomy in a series of 11 patients,

although there were no clear decreases in morbidity

or mortality. Nguyen et al [16] used a combined

laparoscopic and thoracoscopic approach for im-

proved visibility. Comparing a minimally invasive

series with historical open transthoracic and trans-

hiatal controls, these authors reported decreased use

of the ICU, blood loss, operating times, and LOS.

fast-tracking 223

Postoperative care

Pain control

Wright et al [3] identified inadequate pain control

as the most frequent reason for not being discharged

by the target date. Postoperative pain also is an

important factor affecting pulmonary function after

thoracotomy, and effective analgesia is crucial in

minimizing pulmonary complications. Intermittent

dosing of narcotics leads to widely varying levels

with inadequate pain control at the trough and depres-

sion of respiratory drive and the patient’s sensorium

at peak levels and can contribute to inactivity, nausea,

and hypotension. Patients with chronic obstructive

pulmonary disease also may be more susceptible to

the respiratory effects of narcotics. Modern analgesic

methods including patient-controlled analgesia, epi-

dural catheters, and regional intercostal nerve blocks

can improve patient comfort greatly and consequently

may lead to better pulmonary function in the post-

operative period.

Thoracic epidural analgesia has been used increas-

ingly in thoracic surgery and has been found to im-

prove vital capacity and functional residual capacity

by decreasing pain, leading to a reduced risk of pul-

monary complications [17]. de Lima and Carvalho

[9] reported that the use of epidural analgesia also

contributed to a decrease in the LOS. Berrisford et al

[18] found that intercostal nerve block with bupiva-

caine resulted in a postoperative FEV1 40% higher

than placebo, and Richardson et al [19] reported

similar results with preservation of postoperative

pulmonary function in patients treated with preinci-

sional pain prophylaxis and postoperative, continuous

intercostal nerve block. In a comparison of lumbar

epidural analgesia and a continuous intercostal

nerve block in 20 patients, no significant differences

were found in pain relief, oxygen saturation, or

pulmonary function [20]. Nausea was less frequent

in the intercostal block group, however, and vomit-

ing, pruritus, and urinary retention occurred only in

the patients with epidural analgesia. Other alterna-

tives include perioperative ketorolac, infiltration of

the incision with local anesthetic, and intercostal

nerve cryoanalgesia.

Persistent air leaks

Prolonged air leaks are a major determinant of

LOS and were identified by Wright et al [3] as the

second most common reason for failure to be dis-

charged by the target date. Rice and Kirby [21] found

that air leaks contributed an average of 5.6 extra days

to the hospital stay. Air leaks tend to occur at suture

lines, in areas of extensive dissection, and especially

in emphysematous lungs. The risk can be decreased

with meticulous operative technique. Patients at

high risk have been treated with various procedures

in the hopes of decreasing the incidence of air leaks,

such as buttressing the staple line with bovine peri-

cardium, pleural tenting, pneumoperitoneum, pleural

decortication, crushing the phrenic nerve, pleural

partition, and muscle flap transposition with varying

degrees of success.

Robinson and Preksto [22] described a series of

48 patients in which pleural tenting was performed

in 20 cases. They found a shorter duration of air leak

of 1.6 days versus 3.9 days, a shorter chest tube du-

ration of 4 days versus 6.6 days, less drainage, and

a decreased LOS of 6.4 days versus 8.6 days.

When an air leak has developed, some surgeons

believe that placing chest tubes to water seal may be

more effective than continuous suction. Cerfolio et al

[23] randomized 140 patients to water seal or suction

on postoperative day (POD) 2. Air leaks resolved in

67% of patients on water seal by POD 3. All of the

patients who did not resolve had leaks greater than

4/7 on an air leak meter. Only 1 of 15 patients (7%)

on suction sealed their air leak by POD 3. Based on

these results, air leaks greater than 4/7 are unlikely to

resolve on water seal, may lead to pneumothorax,

and should be treated with a Heimlich valve as an

outpatient. Cerfolio et al [23] concluded that water

seal is more effective than continuous suction in re-

solving air leaks, although the issue is controversial.

Wain et al [24] described using a bioresorbable

polyethylene glycol–based sealant in 172 random-

ized patients to prevent postoperative air leaks. A

significantly higher percentage of treated patients

were found to be free of air leaks, and there was a

trend toward earlier chest tube removal and decreased

LOS. Porte et al [25] also applied a prophylactic

synthetic sealant and found the percentage of pa-

tients free from air leaks on POD 3 and POD 4 was

higher; however, LOS was not significantly differ-

ent, and four patients developed empyema from in-

fected sealant.

Some authors have advocated outpatient treatment

of air leaks. Use of the Heimlich valve, a small-

caliber tube with a flutter valve, has been shown to

shorten the average LOS after various procedures

[26]. Careful monitoring and follow-up through a

well-coordinated clinic are required. Ponn et al [27]

described a series of 176 patients in which chest

tubes were managed on an outpatient basis, saving

1263 hospital days. The failure rate was 2% for

lin & iannettoni224

postresection air leaks with no mortality or life-

threatening events. McKenna et al [26] also described

the ambulatory management of prolonged air leaks in

25 patients using the Heimlich valve. Chest tubes

were removed an average of 7.7 days after discharge,

decreasing the mean hospital LOS by 46%.

Pulmonary infections

Patients undergoing pulmonary resection are at an

increased risk for respiratory complications because

of a higher incidence of chronic pulmonary disease;

postoperative diaphragmatic dysfunction; decreased

lung volumes; and impaired cough, mucociliary func-

tion, and gas exchange. Respiratory complications

often lead to a prolonged hospital LOS, increased

mortality, and higher costs. Long-term smoking is

the most important risk factor for lung carcinoma, and

Garibaldi et al [28] found that a smoking history was

a significant risk factor for postoperative pneumonia,

highlighting the importance of smoking cessation.

Postoperatively, pulmonary function is affected by

pain, diaphragmatic dysfunction, decreased respira-

tory effort, and lying supine for prolonged periods—

all of which can cause atelectasis and predispose to

pneumonia. In addition to aggressive pain control

and minimally invasive approaches, techniques have

been developed to improve atelectasis postopera-

tively, including cough and deep breathing exercises,

incentive spirometry, intermittent positive-pressure

breathing, and constant positive airway pressure.

Although these methods have not been assessed in

patients specifically undergoing lung resection, pro-

spective studies have been performed after upper

abdominal surgery. Morran et al [29] studied 102 pa-

tients in a randomized trial and found that pneumonia

was significantly reduced after routine postoperative

chest physiotherapy. Celli et al [30] prospectively

evaluated 172 randomized patients and found that

prophylactic regimens significantly reduced pulmo-

nary complications. In addition, a trend was seen

toward a decreased LOS, which was significant in the

incentive spirometry group.

Patients who are intubated in the ICU are at

the highest risk for nosocomial pneumonia. London

et al [31] noted a significant decrease in the incidence

of pneumonia using a prospective protocol that in-

cluded early extubation, and Tovar et al [32] recom-

mended extubation in the operating room when

possible. Early ambulation improves pulmonary

function, and Kamel et al [33] found that time to

ambulation was an independent predictor of the

development of pneumonia and a prolonged LOS.

Social factors

Although medical complications had the most

significant effect on delayed discharge, social factors

also were significant according to Irshad et al [1].

Extensive preoperative education is essential so that

patients and their families clearly understand the

expected postoperative course and possible compli-

cations. Early and proactive discharge planning also

should be initiated during preoperative planning.

Clinic nurses should identify high-risk individuals

who require referral to a case manager. Home support

and caregivers should be identified early, and if the

expected need for a convalescent facility is high,

arrangements should be made to assist in the efficient

transfer of care for the patient’s rehabilitation and

recovery. Postoperatively, restoration of the patient’s

mobility allows a return to independence and self-

sufficiency. At each step, the patient should be given

verbal and written instructions. In addition, a crucial

but often overlooked aspect of successful early

discharge is close, active follow-up with either phone

calls or office visits.

Clinical pathways

Although many of the above-described strategies

are being used individually, there is a large amount

of variation depending on the surgeon and the medi-

cal center. Rosen et al [34] reported that 75% of all

variability in LOS across hospitals is unexplained by

complications and mortality, and that a major reason

for this variability is differences in efficiency. Clinical

pathways (Table 1) have been devised to optimize

care and to help standardize clinical practice by

making all caregivers aware of the expected sequence

of events as patients proceed from a state of illness to

one of wellness. Patient progress in terms of pain

control, diet, and activity level is tracked and

documented, allowing earlier recognition of compli-

cations and intervention. Standard order sheets and

protocols help to reduce errors, and pathways should

be designed with variance codes to identify factors

leading to a prolonged hospital stay to improve future

efficiency. In addition, in academic medical centers,

pathways can help new residents quickly learn the

pattern of care as they rotate from month to month on

different clinical services. Clinical pathways have

been found to improve outcomes in the treatment of

a variety of diseases and have been reported to re-

duce LOS and hospital costs in cardiac surgery [35].

Although numerous studies have evaluated the

use of clinical pathways in thoracic surgery, most

Table 1

Sample clinical pathway for elective pulmonary resection*

Preop Day of operation POD 1 POD 2 POD 3–4

Education Expected course,

possible complications

Review pathway Review pathway,

discharge plans

Review pathway,

discharge plans

Discharge instructions

Interventions Smoking cessation Muscle-sparing

thoracotomy or

VATS, extubate

in OR, transfer to

floor if stable

d/c central line,

wean O2, place

chest tube to

water seal

d/c epidural,

Foley 8 h later,

1st chest tube if

no air leak

d/c 2nd chest tube if

no air leak and output

< 400 mL/d, if air leak

use Heimlich valve

Assessment History and physical Monitor chest

tube output,

cardiac rhythm

O2 saturation O2 saturation Adequate oxygenation,

pain control

Tests Preop labs, PFTs Labs prn, CXR Labs prn, CXR Labs prn, CXR Labs prn, CXR

Activity Exercise program

if appropriate

Ambulate with

assistance

Ambulate, PT

consult prn

Ambulate Ambulate

Medications Nicotine patch prn Preop antibiotics,

epidural, incentive

spirometer

Inhalers, chest PT,

antiemetics prn, d/c

antibiotics

Oral pain

medication prn

Oral pain

medication prn

Nutrition NPO after midnight Evening after OR

full liquids

Resume preop diet

Discharge

planning

Identify patients

for case manager

Confirm home

support

Identify the need

for rehabilitation or

home O2

Set up close follow-up

Abbreviations: CXR, chest x-ray; d/c, discontinue; labs, laboratory tests; NPO, nothing per mouth; OR, operating room;

PFTs, pulmonary function tests; POD, postoperative day; preop, preoperative; prn, as needed; PT, physical therapy; VATS,

video-assisted thoracic surgery.

* Clinical pathways are general guidelines, and variances in individual patient needs and responses are to be expected.

fast-tracking 225

have used historical controls, and the results of these

studies must be considered with caution until pro-

spectively controlled trials are performed. Although

Pearson et al [36] found that LOS decreased 7% for

thoracic procedures after the institution of a clinical

pathway, similar decreases were seen in neighboring

centers without clinical pathways. These authors

believed that the decrease in LOS seen may be due

to competitive pressures or patient selection bias.

Wright et al [3] evaluated the course of 284 pa-

tients undergoing lobectomy and found a decrease in

the LOS from 10.6 to 7.5 days and hospital costs

from $16,063 to $14,792 after the implementation

of a clinical pathway encouraging early discontinua-

tion of antibiotics, removal of chest tubes and epi-

dural catheters, and an aggressive protocol to treat

nausea. Of patients, 68% were discharged by the

target LOS of 7 days. Readmissions and mortality

were not significantly different.

Cerfolio et al [37] evaluated 500 patients who

underwent pulmonary resection using a clinical path-

way. Of patients, 96% were extubated in the operating

room, and 76% did not require admission to the ICU.

Patients with significant comorbidities or instability

were admitted to the ICU for an average of 1 day.

Epidural catheters and chest tubes were removed on

POD 2 if there was no air leak, and drainage was less

than 400 mL/d. The median day of discharge was

POD 4, and patient satisfaction was 91%.

Tovar et al [32] evaluated 10 patients who under-

went major lung resections with cryolysis of the

intercostal nerves and followed a clinical pathway

including extubation in the operating room, dis-

continuation of the Foley catheter and intravenous

fluids on discharge from the recovery room, and

transfer to an intermediate care unit where oxygen

was weaned and an oral diet and ambulation were

started. Chest tubes were removed when there was no

air leak the evening after the operation. Patients were

discharged when they were ambulating indepen-

dently, oxygenation was adequate, and pain was con-

trolled on oral medication. Eight patients were

discharged on the morning of POD 1 and two pa-

tients on POD 2. There were no readmissions, and

the investigators concluded that most patients can

be managed with a 1-day hospital stay after a major

pulmonary resection. In a second study, Tovar [38]

found that 70- and 80-year-old patients also could be

treated with a similar accelerated recovery program

with an average LOS of 1 day.

Fig. 1. The rate of postoperative recovery is significantly

associated (P = .0013) with the overall number of identified

risk factors. OP, day of operation. (From Ueda K, Kaneda Y,

Sakano H, Tanaka T, Li T, Hamano K. Obstacles for short-

ening hospitalization after video-assisted pulmonary resec-

tion for lung cancer. Ann Thorac Surg 2003;76:1816–20;

with permission from the Society of Thoracic Surgeons.)

lin & iannettoni226

Zehr et al [4] described the use of clinical path-

ways for esophagectomy and pulmonary resection. In

the esophagectomy pathway, patients were managed

in the ICU for 24 to 36 hours with overnight in-

tubation. Pain was controlled with epidural analgesia,

and central lines, cervical drains, and Foley catheters

were discontinued on POD 2. Enteral feedings were

started on POD 3 and advanced to 30 mL/h over

2 days. A video esophagram was performed on POD

5 or 6. Under the pathway, LOS decreased from

13.6 to 9.5 days. In the pulmonary resection pathway,

patients were extubated in the operating room with a

12- to 24-hour ICU stay. Pain was controlled with an

epidural catheter, and chest tubes were removed on

POD 3 or 4. The LOS decreased from 8 to 6.4 days.

Nomori et al [39] advocated the early removal

of chest tubes and oxygen support and found in

130 lung cancer patients that earlier removal resulted

in significantly less impairment of the 6-minute walk

distance 1 week postoperatively at 88.8% versus

81.5% of baseline. The clinical pathway encouraged

chest tube removal on POD 1 if there was no air leak

and output was less than 400 mL/d and discontinua-

tion of oxygen support if saturations were greater

than 90%. Only one patient required thoracentesis

after discharge. These authors concluded that chest

tubes and oxygen support restrict mobility and in-

crease patient discomfort and that removal allows

earlier ambulation and recovery of respiratory func-

tion and muscle strength.

Ueda et al [40] described the use of a clinical

pathway to manage patients after video-assisted pul-

monary resections in 40 patients with suspected lung

cancer in a prospective series. Recovery was consid-

ered complete when patients progressed through the

seven steps of the pathway, and the mean recovery

time was 3.7 days. Ueda et al [40] identified six

factors related to a prolonged hospital recovery, in-

cluding age greater than 65, breathlessness, radio-

graphic evidence of emphysema, poor performance

status, preoperative partial pressure of oxygen less

than 80 mm Hg, and a predicted postoperative FEV1

less than 60%. The number of risk factors was

significantly associated with the length of recovery,

and 100% of patients with no risk factors, 68% with

one to three risk factors, and 22% with four to six

risk factors recovered by POD 3 (Fig. 1).

For practitioners contemplating implementation of

clinical pathways, the pathways must be developed

with input from all members of the patient care team,

including surgeons, anesthesiologists, nurses, physi-

cal therapists, and social workers. Involving the care

team in the development process serves to educate the

hospital staff and encourages interest in improving

patient care and efficiency. A thorough review of the

literature should be performed to ensure that path-

ways are based on the best evidence available, with

the understanding that these guidelines can evolve as

more evidence becomes available. If equally valid

alternatives are presented, both can be included as

options in the pathway. Postdischarge patient satis-

faction surveys also are important as the pathways are

continually refined. In addition, it is important to

recognize that standardized clinical pathways are

guidelines intended to streamline patient care, while

improving quality and reducing errors, rather than

rigid protocols; many patients have unique needs

that cannot be managed by a uniform pathway.

Summary

With continually increasing health care costs and

limited medical resources, there has been increasing

focus on shortening hospital stays. Many medical and

nonmedical reasons can lead to a delay in hospital

discharge after thoracic surgery despite technically

successful procedures; common obstacles include

inadequate pain control, prolonged air leaks, and

social issues. Preoperative patient education, mini-

mally invasive surgical techniques, aggressive pain

control, and early resumption of physical activity and

discontinuation of chest tubes and catheters are im-

portant in successful early discharge. Although many

fast-tracking 227

of these components can be combined in clinical

pathways to optimize care with the input of various

members of the patient care team, the thoracic sur-

geon must reassess outcomes constantly to ensure the

maintenance of the quality of care.

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Thorac Surg Clin

Perioperative Antibiotics: When, Why?

Mark S. Allen, MDa,b,*

aDivision of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USAbDepartment of Surgery, Mayo Medical School, Rochester, MN 55905, USA

Before Joseph Lister’s principle of antisepsis,

surgery commonly led to postoperative fevers, com-

monly known as ‘‘irrative fever,’’ followed by infec-

tion, drainage, ‘‘laudable pus,’’ sepsis, and death.

Since the introduction of antisepsis, surgery has pro-

gressed to an endeavor that prolongs and improves

life. About 27 million operations are performed each

year in the United States. Surgical site infections (SSI)

are the third most common nosocomial infection [1].

About two thirds of SSI develop in the surgical inci-

sion. In 1980, Cruse and Foord [2] estimated that

SSI increased hospital stay by 10 days and increased

costs by $2000, and a 1992 analysis revealed each

SSI increased costs more than $3000 and hospital

stay by 7.3 days [3]. Prevention of life-threatening

and costly SSI is important.

A variety of techniques should be considered to

decrease SSI, including recommendations for preop-

erative, intraoperative, and postoperative practices

that may reduce the risk of an infection. Careful sur-

gical technique with avoidance of unnecessary tissue

destruction is probably the most important factor in

decreasing the incidence of postoperative infections.

The use of perioperative antibiotics should be seen as

an adjunct to meticulous technique and proper

procedures. Perioperative antibiotics are thought to

decrease wound infections and may decrease other

SSI in general thoracic surgery, such as empyema and

postoperative pneumonias.

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.005

* Division of General Thoracic Surgery, Mayo Clinic,

200 First Street, SW Rochester, MN 55905.

E-mail address: allen.mark@mayo.edu

The use of prophylactic antibiotics in general

thoracic surgery is well established. This article ex-

plains the rationale for modern-day surgical wound

infection prophylaxis, the why and the when. Various

arguments about the use of antibiotics to prevent

empyema and pneumonia after a thoracic operation

also are presented. The evidence supporting the use

of antibiotic prophylaxis for general thoracic surgical

procedures is overwhelming; however, despite nu-

merous well-done randomized trials, controversy still

exists as to when to stop the antibiotics, which agent

to use, and whether or not the use of antibiotics de-

creases wound infections only or wound infections

and deeper infections, such as pneumonia or em-

pyema (Table 1).

Prophylactic antibiotics were proposed by Eriksen

et al [4,5] in 1954, before any randomized study

had proven their efficacy. Kvale et al [6] reported the

first randomized study to examine the question in

1977. At that time, there was disagreement between

surgeons, who believed perioperative antibiotics

decreased infectious complications, and internists,

who believed perioperative antibiotics did not de-

crease infectious complications but increased resis-

tant organisms. The study by Kvale et al [6] was

the first randomized study on perioperative anti-

biotics for lung surgery since the introduction of

perioperative antibiotics. At Kvale’s institution, the

infection rate was 25% for all thoracic surgery

procedures, which the authors found unacceptable.

They conducted a randomized, prospective, double-

blind study from March 1974 to December 1975.

They gave cefazolin (Kefzol), 500 mg intramuscu-

larly on call and every 6 hours postoperatively until

orally tolerated, then cephalexin (Keflex), 500 mg

15 (2005) 229 – 235

reserved.

thoracic.theclinics.com

Table 1

Randomized studies concerning prophylactic antibiotics

Primary author Year Type of trial Agent(s) used

No.

patients

Wound

infection Pneumonia Empyema

Kvale [6] 1977 Prospective,

randomized,

double-blind

Cefazolin vs placebo 77 Significant

reduction

Significant

reduction

Significant

reduction

Truesdale [7] 1979 Prospective,

randomized,

double-blind

Cefazolin vs placebo 57 NSD NSD NSD

Cameron [8] 1981 Prospective,

randomized

Cephalothin vs placebo 171 NSD NSD NSD

Ilves [9] 1981 Prospective,

randomized,

double-blind

Cephalothin vs placebo 211 Significant

reduction

NSD NSD

Frimodt-

Moller [10]

1982 Prospective,

randomized,

double-blind

Penicillin G vs placebo 101 Significant

reduction

NSD NSD

Tarkka [13] 1987 Prospective,

randomized

Doxycycline

vs cefuroxime

120 NSD NSD NSD

Aznar [14] 1991 Prospective,

randomized,

double-blind

Cefazolin vs placebo 127 Significant

reduction

NSD Significant

reduction

Olak [11] 1991 Prospective,

randomized,

double-blind

Cefazolin 1 vs 6 doses 199 NSD NSD NSD

Krasnik [15] 1991 Prospective,

randomized,

double-blind

Penicillin G

vs Cefuroxime

94 NSD NSD NSD

Wertzel [12] 1992 Prospective,

randomized,

double-blind

Ampicillin/sulbactam

1 vs 3 doses

60 NSD NSD NSD

Frey [16] 1993 Prospective,

randomized

Cefuroxime vs placebo 200 NSD NSD NSD

Bernard [17] 1994 Prospective,

randomized,

double-blind

Cefuroxime vs placebo 203 NSD Chest x-ray

more often

normal

Significant

reduction

Boldt [18] 1999 Prospective,

randomized

Ampicillin/sulbactam

vs cefazolin

120 Not stated Significant

reduction

Not stated

Turna [19] 2003 Prospective,

randomized,

double-blind

Cefuroxime vs cefepime 102 NSD NSD NSD

Abbreviation: NSD, no significant difference.

allen230

orally every 6 hours for a total of 5 days, or placebo.

The vials were identical, so neither the staff nor the

patient knew who received antibiotics versus placebo.

Patients with prior chest infections, patients with

known allergies, patients who had received anti-

biotics within 1 week of surgery, and patients who

had refused informed consent were not eligible.

Specific protocols for postoperative management

and definitions of wound infection, pneumonia, and

empyema were established prospectively. The inves-

tigators randomized 77 patients undergoing pulmo-

nary surgery. Of the control group, 17 of 34 (50%)

developed ‘‘infection,’’ although 50% of these re-

ceived no further treatment. Only 8 of 43 (19%) of

the treated group developed infection (P = .005).

Kvale et al [6] concluded that ‘‘the routine use of

perioperative antibiotics is indicated to prevent post-

operative infections in pulmonary resection.’’

The results of the Kvale trial were challenged by

a subsequent randomized, prospective, double-blind

trial by Truesdale et al [7] in 1979. This group

randomized 57 patients undergoing pulmonary resec-

perioperative antibiotics 231

tion. They used cefazolin, 1 g intramuscularly on

admittance to the operating room, followed by cepha-

lothin (Keflin), 2 g intravenously every 6 hours for

48 hours, starting immediately after surgery, versus

placebo. The vials of antibiotic and placebo were

identical so that patients and physicians did not

know which patients were receiving antibiotics and

which were receiving placebo. In this study, 5 of

29 (17.2%) placebo patients and 5 of 28 (17.8%)

treated patients developed a postoperative infection

(P = not significant). Complications of prophylaxis

occurred in 17.2% (31 of 57) of placebo patients and

64.4% of treated patients and included hypersensi-

tivity reactions in 2, drug fever in 9, phlebitis in 14,

and increased blood urea nitrogen and liver function

tests in 8. Truesdale et al [7] concluded that pro-

phylactic antibiotics for pulmonary resection did not

outweigh the benefits and should not be employed.

This view was supported further by a larger

randomized trial by Cameron et al [8] from Johns

Hopkins Medical Center. They randomized 171 pa-

tients undergoing pulmonary resection to cephalo-

thin, 2 g intravenously the evening before surgery,

at 6:00 a.m. the morning of surgery, during the

operation, and 6 hours after surgery, or placebo (no

antibiotics). The hospital stay was 15.5 days for the

antibiotic group and 15.7 days for the placebo group.

There was no difference in the number of post-

operative fevers. The number of ‘‘septic complica-

tions’’ in the antibiotic group was 22 versus 26 in the

nonantibiotic group. Even when infections were

broken down into pneumonia, empyema, and wound

infection, there were no differences. The authors did

not give the actual numbers of wound infections, so it

is unknown if a trend was evident. They did find that

when postoperative infections occurred in the anti-

biotic group, they were often from gram-negative

organisms that were resistant to cephalothin. They

recommended that patients not receive prophylactic

antibiotics before pulmonary surgery.

Several months after Cameron’s study, the results

from an even larger study from the Toronto general

thoracic surgical group was published [9]. Ilves et al

[9] randomized 211 patients undergoing a pulmonary

or esophageal operation to receive either placebo or

cephalothin, 2 g intravenously at the induction of

anesthesia and 2 g intravenously 4 hours later. During

the study, neither the patients nor the staff knew

which group the patients were in. The surgical prepa-

ration, procedure, and postoperative care were stan-

dardized. The investigators found that 7 patients of

118 (5.9%) in the treatment group developed a wound

infection versus 22 of 93 (23.7%) in the placebo

group (P < .05). There also was a reduction in the

incidence of postoperative pulmonary infections and

empyemas, but the difference did not reach statistical

significance. The investigators were unable to detect

a difference in the bacteriology of the infections

between the two groups. Ilves et al [9] stated their

policy is to ‘‘employ prophylactic perioperative

antibiotic coverage in clean-contaminated major

thoracic cases.’’

A similar result was reported from Denmark by

Frimodt-Moller et al [10] in1982.Theycomparedpeni-

cillin G prophylaxis with placebo in a randomized,

double-blind, controlled prospective trial. The inves-

tigators used penicillin G at a dose of 5 million IU

intravenously immediately before surgery and every

6 hours after surgery for five doses. They random-

ized 94 patients: 45 in the penicillin G group and 47

in the placebo group. There were nine (19.1%)

wound infections in the placebo group versus two

(4.4%) in the prophylactic group (P = .03). There

was no difference in the number of empyemas or

lower respiratory tract infections between the two

groups. Frimodt-Moller et al [10] also showed a sig-

nificant reduction in the length of hospitalization

(3 days) with penicillin G prophylaxis, a highly cost-

efficient finding.

These two major positive studies seem to contra-

dict the study done by Cameron et al [8]. Perhaps the

wound infection rate was already so low at Johns

Hopkins that the study was underpowered to show a

significant difference. Whatever the reason, most

surgeons believed the positive findings of the Ilves

and Frimoldt-Moller studies and discounted the

negative findings of the Cameron study. Even though

most surgeons had been using prophylactic anti-

biotics for general thoracic surgical operations before

the publication of these studies, these findings con-

firmed what they empirically thought to be fact.

The question of whether to give a single dose or

prolonged postoperative prophylaxis was examined

in a randomized study by Olak et al [11], in which

they randomized 208 patients to one dose of cefazolin

(1 g intravenously at the induction of anesthesia) or

the induction dose of cefazolin plus five doses every

8 hours after surgery. They found no difference in the

number of wound infections, pneumonias, or empy-

emas between the two groups and concluded that

there was no benefit to prolonging the antibiotic

prophylaxis after the operation concluded.

Additional confirmation for use of only a single

dose comes from a randomized study done in Ger-

many by Wertzel et al [12]. This group randomized

60 patients undergoing pulmonary resection to re-

ceive ampicillin/sulbactam (Unasyn), either 3 g at

induction or 3 g at induction and two further doses at

allen232

8-hour intervals. They found no difference in the

incidence of wound infection or any other infections.

They did report about a 30% incidence of bronchitis

and pneumonia, but stated that, ‘‘whether PX

[prophylactic antibiotics] is reducing these complica-

tions cannot be answered by our study’’ [12].

With confirmation that prophylactic antibiotics

reduce wound infection rates and that a short course

is effective, interest was turned to studying ways of

decreasing the rate of pneumonia and empyema after

general thoracic surgical operations by employing

prophylactic antibiotics directed at respiratory flora.

In 1987, Tarkka et al [13] published a prospective,

randomized trial from Finland to determine if cefu-

roxime (Zinacef), an agent effective against the

common skin flora Staphylococcus aureus and the

respiratory pathogen Haemophilus influenzae, would

reduce the rates of wound infection and pneumonia

and empyema. They randomized 120 patients to

receive either their usual prophylactic antibiotic,

doximycin, 200 mg orally the day before surgery,

100 mg intravenously during the operation, and

100 mg orally every day for 3 days, or cefuroxime,

1.5 g during anesthesia induction and 0.75 g every

8 hours times three after surgery. The two groups

were comparable in all categories. They found a

significantly lower rate of minor lower respiratory

tract infections in the cefuroxime group, but no dif-

ference in the rate of pneumonia or empyema. Tarkka

et al [13] hypothesized that the bactericidal effects

of cefuroxime may account for the difference.

Aznar et al [14] tried to determine if cefazolin

alone would decrease the rates of empyema and

pneumonia. They randomized 143 patients and, after

excluding 16 patients, were left with 127 patients

(57 in the placebo group and 70 in the cefazolin group).

Cefazolin, 1 g intravenously one half hour before

surgery, was used. There was no significant differ-

ence in the demographics or operations performed

between the two groups. A marked difference in

wound infection (14% versus 1.5%) was shown, but

no statistically significant benefit for empyema (14%

versus 7%) or pneumonia (8.8% versus 4.3%) in the

placebo versus cefazolin group. Aznar et al [14] con-

cluded, as others had, that a preoperative dose of

prophylactic antibiotics decreased wound infection

rates but not the risk of pneumonia or empyema.

In the same year as Aznar’s study, 1991, Krasnik

et al [15] reported a randomized double-blind study

to examine if cefuroxime was better than penicillin G

in preventing empyema and pneumonia as the study

by Tarkka et al [13] had done. The medications were

started just before surgery and repeated every 8 hours

after surgery. Krasnik et al [15] analyzed 94 patients

(48 in the penicillin G group and 46 in the cefuroxime

group). They also found no difference in the rate of

pneumonia or empyema between the two groups and

concluded they still prefer penicillin G for prophy-

lactic antibiotics for pulmonary surgery.

A positive finding from the use of cefuroxime was

reported in a German trial [16]. Frey et al [16] com-

pared no antibiotics with one dose of cefuroxime,

1.5 g intravenously at the induction of anesthesia.

They found fewer wound infections and fewer pa-

tients with ‘‘pronounced infiltration’’ on daily chest

x-rays in the cefuroxime group. Also, the number of

patients requiring additional antibiotics was less in

the treated group compared with the placebo group.

The use of a control group with no antibiotics makes

interpretation of this study difficult.

Another positive study using cefuroxime was

published in 1994 [17]. Bernard et al [17] randomized

203 patients undergoing a general thoracic surgical

procedure. All patients received an induction dose of

cefuroxime, 1.5 g intravenously, and a second dose

2 hours later. Patients were then randomized to

cefuroxime, 1.5 g intravenously every 6 hours for

48 hours, or placebo. The investigators found a

marked reduction in the incidence of empyema: 6%

in the treatment group versus 15.6% in the placebo

group (P = .03). This finding is undoubtedly related

to the fact that seven patients in the placebo group

developed bronchial fistulas, whereas only two in the

treatment group developed fistulas. The development

of fistulas is thought to be unrelated to an infection,

but rather related to local factors at the bronchial

closure. Postoperative chest x-rays were more often

normal in the treatment group, but there was no

difference in the number of patients who developed

purulent expectorations and atelectasis associated

with a temperature greater than 38�C. No information

is given about length of stay for these patients.

Bernard et al [17] concluded, perhaps mistakenly, that

‘‘48-hour antibiotic prophylaxis regime decreases the

rate of deep infectious complications.’’

In another randomized trial that showed effective-

ness in reducing pneumonia, Boldt et al [18]

compared a single injection of cefazolin, 2 g intrave-

nously, with ampicillin/sulbactam, 1.5 g intrave-

nously. They also studied the microbiologic tracheal

aspirates of the two groups and found all the bacteria

were susceptible to the prophylaxis in the ampicillin/

sulbactam group, whereas 8 of 25 patients in the

cefazolin-only group had resistant organisms. They

found fewer bronchopulmonary infections in the

ampicillin/sulbactam group. The group given cefazo-

lin stayed in the ICU longer and incurred higher costs

than the ampicillin/sulbactam group.

Box 1. Centers for Disease Control andPrevention recommendations to reducesurgical site infections

Preoperative

1. When possible, identify and treatall existing infections

2. Do not remove hair preoperativelyat or around the incision, unless itinterferes with the operation

3. If hair is removed, remove it imme-diately before the operation, pref-erably with electric clippers

4. Control serum blood glucose levelsin all diabetic patients

5. Encourage tobacco cessation6. Do not withhold necessary blood

products7. Require patients to shower or

bathe with an antiseptic agent onat least the night before surgery

8. Thoroughly wash and clean at andaround the incision site to removegross contamination before per-forming antiseptic skin preparation

9. Use an appropriate antiseptic agentfor skin preparation

10. Apply preoperative antiseptic skinpreparation in concentric circlesmoving toward the periphery

11. Keep preoperative hospital stay asshort as possible

12. No recommendation to wean ste-roids, enhancenutrition, applymupi-rocin to nares, or enhance woundspace oxygenation

Intraoperative

Surgical team1. Keep nails short and do not wear

artificial nails2. Perform preoperative surgical scrub

for 2–5 minutes3. Obtain appropriate cultures from, and

exclude from duty, surgical personnelwho have draining skin lesions untilinfection has been ruled out or per-sonnel have received adequate ther-apy and infection has resolved

4. Wear a surgical mask that coversthe mouth and nose

5. Wear a cap or hood to cover fullyhair on the head and face

6. Use surgical gowns and drapes thatare effective barriers when wet

Ventilation1. Maintain positive-pressure ventila-

tion in the operating room with re-spect to the corridors and adjacentareas

2. Maintain a minimum of 15 airchanges per hour, of which at least3 should be fresh air

3. Filter all air through the appropriatefilters

4. Introduce all air at the ceiling andexhaust near the floor

5. Do not use UV radiation in the op-erating room to prevent SSI

6. Keep operating doors closed exceptas needed

7. Limit the number of personnel enter-ing the operating room to necessarypersonnel

Postoperative

1. Protect incision with a sterile dress-ing for 24–48 hours

2. Wash hands before and after dress-ing changes and any contact withthe surgical site

3. When an incision’s dressing must bechanged, use sterile technique

4. Educate the patient and family re-garding proper incision care, symp-toms of SSI, and the need to reportsuch symptoms

5. No recommendation on the need tokeep incision covered after 48 hoursor on the appropriate time to showeror bathe with an uncovered incision

Adapted from Mangram A, Horan T,Peason M, Silver L, Jarvis W. Guidelinefor prevention of surgical site infection,1999. Infect Control Hosp Epidemiol1999;20:247–78; with permission.

perioperative antibiotics 233

allen234

A more recent randomized trial comes from Tur-

key, where Turna et al [19] hypothesized that using a

third-generation cephalosporin may have greater

activity against gram-negative pathogens and reduce

the rate of postoperative pneumonias. They random-

ized 104 patients to receive either cephalexin, 1.5 g

intravenously 1 hour before surgery and every

12 hours for 48 hours postoperatively, or cefepime

(Maxipime), 1 g intravenously for 24 hours after sur-

gery. The study was powered to find a 30% difference

in the 40% infection rate in the investigators’ de-

partment. In contrast to the prior studies, these inves-

tigators found no difference in the infection rates

between the two groups, and the third-generation

cephalosporin was more expensive.

Even with these well-done randomized, double-

blind control trials, the use of prophylactic antibi-

otics to reduce the rate of pneumonia or empyema

remains controversial. At present, there are con-

flicting results in the literature, and the use of pro-

phylactic antibiotics is nonuniform throughout

thoracic surgery.

Highlighting the consequence of these conflicting

data is a 1990 study by LoCicero [20], in which he

surveyed 408 thoracic surgeons about their practice

of prophylactic antibiotic usage. A quarter of the

surgeons were from a university practice, and almost

three quarters were in a private practice. About half of

the respondents had been in practice for 5 to 15 years.

Prophylactic antibiotics were given in only 80.9%

of patients undergoing pulmonary resection, despite

the overwhelming evidence of effectiveness presented

earlier in this article. The percentage of use was

worse for esophageal operations (77.7%), open lung

biopsies (51%), or other thoracic procedures (52%).

The most commonly used drugs were cephalosporin

(54.4%) and late-generation cephalosporin (30.1%).

Almost all surgeons who gave prophylactic anti-

biotics gave them before the skin incision. The length

of administration also varied. In pulmonary resec-

tions, antibiotics were given for 1 day in 17%, 2 days

in 40.3%, 3 days in 21%, and greater than 3 days in

15.9%. For esophageal operations, the use tended to

be longer—for 2 days in 30%, 3 days in 18.9%, and

greater than 3 days in 38.3%.

The current guidelines for prevention of SSI are

available online (http://www.cdc.gov/ncidod/hip/ssi/

ssi.pdf). This document is a comprehensive descrip-

tion of procedures and techniques to minimize SSI.

Included is an excellent description about antimicro-

bial prophylaxis for all surgical procedures. It

emphasizes that prophylactic antibiotics are not an

attempt to sterilize tissues, but rather to reduce the

burden ‘‘to a level that cannot overwhelm host de-

fenses.’’ Four principles are outlined to maximize the

effectiveness of antimicrobial prophylaxis:

1. Use prophylaxis based on clinical trials.

2. Use a safe, inexpensive agent that is bacteri-

cidal for most contaminants (S. aureus for gen-

eral thoracic surgery).

3. Establish serum levels at the time of incision

(give on call to operating room).

4. Maintain levels during operation, and discon-

tinue ‘‘at most’’ a few hours after inci-

sion closure.

Also included in this document is a variety of

procedures and techniques related to skin preparation,

operating room environment, and medical personnel

hygiene to reduce SSI (Box 1). Given all the

recommendations, the best method of reducing

infection remains meticulous technique and attention

to detail.

References

[1] Mangram A, Horan T, Peason M, Silver L, Jarvis W.

Guideline for prevention of surgical site infection,

1999. Infect Control Hosp Epidemiol 1999;20:247–78.

[2] Cruse P, Foord R. The epidemiology of wound infec-

tion: a 10-year prospective study of 62,939 wounds.

Surg Clin North Am 1980;60:27–40.

[3] Poulsen KB, Bremmelgaard A, Sorenson AI, et al.

Estimated costs of postoperative wound infections. A

case-control study marginal hospital and social security

costs. Epidemiol Infect 1994;113:283–95.

[4] Eriksen K, Hansen J, Lund F. Postoperative infection

in surgery of the lung: prophylaxis with high level

systemic penicillin therapy. Acta Chir Scand 1954;107:

460–5.

[5] Eriksen K, Hansen J. Prophylactic use of antibiotics in

surgery of the lung. Acta Chir Scand 1964;128:651–8.

[6] Kvale P, Ranga V, Kopacz M, Cox F, Magalligan D,

Davila J. Pulmonary resection. South Med J 1977;

70(Suppl 1):64–9.

[7] Truesdale R, D’Alessandri R, Manuel V, Diacoff G,

Kluge R. Antimicrobial vs placebo prophylaxis in

noncardiac thoracic surgery. JAMA 1979;241:1254–6.

[8] Cameron J, Imbembo A, Keiffer R, Spray S, Baker R.

Prospective clinical trial of antibiotics for pulmonary

resection. Surg Gynecol Obstet 1981;152:156–8.

[9] Ilves R, Cooper J, Todd T, Pearson F. Prospective,

randomized, double-blind study using prophylactic

cephalothin for major, elective, general thoracic op-

erations. J Thorac Cardiovasc Surg 1981;81:813–7.

[10] Frimodt-Moller N, Ostri P, Pedersen I, Poulsen S.

Antibiotic prophylaxis in pulmonary surgery: a double-

blind study of penicillin versus placebo. Ann Surg

1982;195:444–50.

perioperative antibiotics 235

[11] Olak J, Jeyasingham K, Forrester-Wood C, Hutter J,

Al-Seerah M, Brown E. Randomized trial of one-dose

versus six-dose cefazolin prophylaxis in elective gen-

eral thoracic surgery. Ann Thorac Surg 1991;51:956–8.

[12] Wertzel H, Swoboda L, Joos-Wurtemberger A, Frank

U, Hasse J. Perioperative antibiotic prophylaxis in gen-

eral thoracic surgery. Thorac Cardiovasc Surg 1992;40:

326–9.

[13] Tarkka M, Pokela R, Lepojarvi M, Nissinen J, Karkola

P. Infection prophylaxis in pulmonary surgery: a ran-

domized prospective study. Ann Thorac Surg 1987;44:

508–13.

[14] Aznar R, Mateu M, Miro J, et al. Antibiotic prophy-

laxis in non-cardiac thoracic surgery: cefazolin versus

placebo. Eur J Cardiothorac Surg 1991;5:515–8.

[15] Krasnik M, Thiss J, Frimodt-Moller N. Antibiotic

prophylaxis in non-cardiac thoracic surgery: a double

blind study of penicillin vs. cefuroxime. Scand J Thorac

Cardiovasc Surg 1991;25:73–6.

[16] Frey D, Reichmann A-K, Mauch H, Kaiser D. ‘‘Single-

shot’’ antibiotikaprophylaxe in der thoraxchirurgie:

Senkung der postopertiven infektionstrate. Infection

1993;21(Suppl):35–44.

[17] Bernard A, Pillett M, Goudet P, Viard H. Antibiotic

prophylaxis in pulmonary surgery a prospective

randomized double-blind trial of flash cefuroxime

versus forty-eight-hour cefuroxime. J Thorac Cardio-

vasc Surg 1994;107:896–900.

[18] Bolt J, Piper S, Uphus D, Fussle R, Hempelmann G.

Preoperative microbiologic screening and antibiotic

prophylaxis in pulmonary resection operations. Ann

Thorac Surg 1999;68:208–11.

[19] Turna A, Kutlu C, Ozalp T, Karamustafaoglu A,

Mulazimoglu L, Bedirhan M. Antibiotic prophylaxis

in elective thoracic surgery: cefuroxime versus cefe-

pime. Thorac Cardiovasc Surg 2003;51:84–8.

[20] LoCicero J. Prophylactic antibiotic usage in cardio-

thoracic surgery. Chest 1990;98:719–23.

Thorac Surg Clin

Pulmonary Embolism Prophylaxis: Evidence for Utility in

Thoracic Surgery

Dean M. Donahue, MDa,b,*

aDivision of Thoracic Surgery, Harvard Medical School, Boston, MA 02114, USAbDivision of Thoracic Surgery, BLK1570, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA

The clinical presentation of pulmonary embolism

(PE) is a spectrum that ranges from asymptomatic

small emboli to a life-threatening condition with

profound cardiogenic shock. Most patients with PE

have deep vein thrombosis (DVT) that is clinically

not apparent. In a study by Girard et al [1], 82% of

venography-proven pulmonary emboli had ultra-

sound evidence of DVT; however, only 42% of these

patients had clinical signs or symptoms suggesting

DVT. Because most patients at risk for PE have

no clinical warning signs, an effective prophylaxis

against PE must be targeted at preventing DVT.

Despite the widespread concern for postoperative

PE, there has been little written regarding the in-

cidence of PE in patients undergoing thoracotomy

for lung resection. To date, there has been only

one prospective study of thoracic surgical patients

examining the incidence of PE [2]. In this study,

postoperative thromboembolism occurred in 19%

of patients (including 5% with pulmonary emboli).

Guidelines from the Seventh American College of

Chest Physicians Conference on Antithrombotic and

Thrombotic Therapy were published in 2004, but

these did not address prophylaxis recommendations

specific to thoracic surgical procedures [3]. Patients

undergoing major thoracic surgical procedures fre-

quently have several risk factors for developing

DVT, including older age, malignancy, and smoking

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.003

* Division of Thoracic Surgery, BLK1570, Massachu-

setts General Hospital, 55 Fruit Street, Boston, MA 02114.

E-mail address: ddonahue@partners.org

(Box 1). Because these risk factors are thought to be

cumulative [4], an effective strategy for thrombopro-

phylaxis is an important component of postopera-

tive care.

Risk factors in thoracic surgical patients

Possibly the greatest risk factor for developing

PE is the necessity of undergoing a major surgical

procedure. Patients undergoing major surgery have an

approximately sixfold increase in risk of PE [3]. The

risk varies depending on the type of procedure per-

formed; most series identify a neurosurgical proce-

dure involving the brain or meninges as having the

highest incidence of symptomatic PE (approximately

6%) [5]. Orthopedic surgical procedures involving

hip or knee arthroplasty have an approximately 3%

incidence of PE, but there are few published data on

PE in patients undergoing thoracotomy. In a series of

337 patients undergoing pulmonary resection without

any prophylaxis against DVT, there was a 2.1% inci-

dence of clinically apparent PE [6]. When pneumatic

compression devices were used in the next 362 pa-

tients, the incidence of PE fell to zero.

The presence of cancer increases the risk of PE

by sixfold [7]. Cancer patients undergoing surgery

have twice the risk of developing DVT and a three-

fold increase in risk of a fatal PE compared with

patients without cancer [8,9]. The presence of malig-

nancy also is associated with a diminished response

to thromboprophylaxis [9]. A retrospective review of

autopsies performed in major US teaching hospitals

showed that 25% of patients dying with lung cancer

15 (2005) 237 – 242

reserved.

thoracic.theclinics.com

Box 1. Risk factors for venousthromboembolism

Acquired

Surgery or hospitalization with immobilityTraumaMalignancyPrevious or family history of PE or DVTAgePregnancy, oral contraceptive use,

or hormone replacement therapyCongestive heart failureChronic renal diseaseHypertensionLupus anticoagulant (antiphospholipid

antibody syndrome)ObesitySmokingImmobility, including prolonged air travelIndwelling venous foreign bodiesThoracic outlet obstruction

(Paget-Schroetter syndrome)Hyperhomocysteinemia

Inherited

Factor V Leiden mutationProthrombin gene mutationAntithrombin III deficiencyProtein C deficiencyProtein S deficiency

0

200

400

600

800

1000

1200

0-14

20-2

430

-34

40-4

450

-54

60-6

4

age (years)

Inci

den

ce (

per

100

,000

)

Fig. 1. Increasing risk of pulmonary thromboembolic events wit

Petterson TM, O’Fallon WM, Melton 3rd LJ. Trends in the inc

a 25-year population-based study. Arch Intern Med 1998;158:585

donahue238

had PE. In half of these patients, PE was the cause of

death [10].

Other features common to thoracic surgical pa-

tients, such as advancing age and smoking, increase

the risk of PE. Advancing age has been well estab-

lished as a risk factor for PE, including patients

undergoing surgical procedures. The risk has been

shown to rise exponentially with age (Fig. 1) be-

ginning at age 40 [11–13].

Although there have been several case reports

of PE after thoracic surgical procedures, there are

only three large published series. Ziomek et al [2]

published the only prospective series. They per-

formed preoperative venous duplex scanning of the

lower extremities and ventilation-perfusion scans in

77 patients, including 65 patients with cancer. Neither

subcutaneous heparin nor compression devices were

routinely employed; early ambulation/mobilization

was the only routine DVT prophylaxis. In this series,

there were four cases of DVT and one PE identified

preoperatively—all in patients who had prior surgery

within 1 year. After thoracotomy and pulmonary

resection, there was a 14% incidence of DVT and a

6% incidence of PE. The PE was identified at a mean

4.5 days after surgery (range 2–6 days). In 27% of

patients developing DVT, PE also was identified. The

one postoperative death in the series was due to PE.

Risk factors for the development of DVT included

cancer (compared with patients with benign pulmo-

nary disease), primary lung cancer (compared with

metastatic disease to the lung), adenocarcinoma

(compared with other cell types), and advancing age.

Kalweit et al [14] reported a series of 1735 patients

undergoing pulmonary resection for malignancy.

Prophylaxis against PE included intravenous heparin

70-7

480

-84

males

females

h age. (Adapted from Silverstein MD, Heit JA, Mohr DN,

idence of deep vein thrombosis and pulmonary embolism:

–93; with permission.)

Box 2. Options for thromboprophylaxis

Mechanical

Early ambulationGraduated compression stockingsIntermittent pneumatic compression

deviceInferior vena cava filter

Pharmacologic

Heparin

Unfractionated

Low-molecular-weightEnoxaparinDalteparinTinzaparin

Warfarin

pulmonary embolism prophylaxis 239

beginning on the first postoperative day. When

ambulatory, patients were changed to subcutaneous

heparin injections three times a day. Compression

stockings were placed on patients with varicose veins

or a prior history of DVT. In this series, the incidence

of massive PE was 1.6%, with 23 confirmed and

4 clinically suspected cases. Twenty-five of these

patients died, resulting in an overall PE-related

mortality of 1.4%. The postoperative mortality in

the series was 7.2%, with PE accounting for 20% of

the deaths. No data were provided on the over-

all incidence of DVT or nonlethal PE. Autopsies

performed on 20 of these cases revealed 19 patients

with a central embolism and 1 patient with peripheral

emboli. In half of the cases, DVT was found at

autopsy. Nearly all of the patients dying from PE had

their event occur between 13 hours and 4 days after

their operation. In half of these patients, the lethal PE

occurred within the first 48 hours after surgery; this

may reflect the delay in initiating thromboprophy-

laxis until the first postoperative day.

Direct thrombin inhibitors

Lepirudin

Bivalirudin

Argatroban

Desirudin

MelagatranDirect factor Xa inhibitors

FondaparinuxActivated protein CTissue factor pathway inhibitorNematode anticoagulant peptide c2

Prophylaxis against pulmonary embolism

The methods available to reduce the risk of DVT

and PE are outlined in Box 2. Options for thrombo-

prophylaxis can be divided into mechanical and

pharmacologic methods.

Mechanical thromboprophylaxis

Mechanical means of reducing the risk of PE

include early ambulation, graduated compression

stockings, intermittent pneumatic compression (IPC)

devices, and inferior vena cava filters. These modali-

ties are particularly useful in patients in whom

the risk of bleeding reduces or prevents the use

of anticoagulants.

Early ambulation has reduced significantly the

incidence of ultrasound-documented and symptom-

atic PE in patients undergoing total hip arthroplasty

[15]. After a minor surgical procedure, early ambu-

lation is adequate prophylaxis for patients younger

than 40 years old with no additional risk factors. It is

useful only as an adjunct in prophylaxis for post-

operative thoracic surgical patients.

Elastic stockings or graduated compression stock-

ings were first shown to be effective in PE prevention

in 1952 [16]. Properly fitting stockings are estimated

to produce a 60% reduction in the relative risk of PE

in general surgical patients [17]. Improperly applied

or fitted stockings may result in a tourniquet effect

that reduces venous flow and increases the risk of PE

[18]. Properly fitted stockings should be placed

before the induction of anesthesia and worn through-

out the hospitalization. Although there are no con-

trolled studies of postoperative outpatient use, it is

reasonable to continue use of the stockings in patients

with limited mobility. Caution also needs to be taken

in patients with peripheral arterial disease to avoid

soft tissue injury [19,20]. If stockings are used, the

underlying skin should be checked frequently.

It is assumed that IPC devices reduce the risk of

PE by improving venous blood flow and reducing

stasis, although there is debate regarding the role of

IPC devices in activating local plasminogen and

subsequent fibrinolysis [21,22]. The reduction in

PE risk has been shown to be most pronounced in

individuals with a body mass index of less than

25 kg/m2 [23]. These devices are safe and have few

drawbacks; however, their efficacy depends on near-

continuous use in nonambulatory patients. IPC de-

Fig. 2. Radiograph of inferior vena caval filter placed just

below renal vein.

donahue240

vices have shown equivalent PE prophylaxis com-

pared with low-molecular-weight heparin (LMWH)

in patients undergoing hip arthroplasty [24]. These

mechanical methods of prophylaxis can reduce the

risk of DVT, but there are no randomized trials that

show a reduction in the risk of death or PE.

Placement of filters in the inferior vena cava

(Fig. 2) can reduce the incidence of PE (but not DVT)

to 0.3% to 3.8% in patients who cannot be given

anticoagulation [25]. These filters typically are used

in patients at high risk for PE who have a contra-

indication to anticoagulation, patients who have de-

veloped PE despite appropriate anticoagulation, or

patients who have had a major hemorrhage while

on anticoagulation. Complications related to inferior

vena cava filters include filter migration, thrombosis

of the inferior vena cava, and recurrent DVT with

postphlebitic syndrome. In the only controlled trial to

date of inferior vena cava filter placement in acute

DVT patients, there was a trend toward reduced fatal

PE; however, there were significantly more episodes

of recurrent DVT [26]. Temporary or retrievable fil-

ters have been designed potentially to reduce the

long-term sequelae of these devices. Several models

are currently available, but they have yet to gain

widespread acceptance.

Pharmacologic thromboprophylaxis

Unfractionated heparin (UFH) is a heterogeneous

substance composed of branched glycosamino-

glycans. Individual heparin molecules range from

3000 to 30,000 D with varying anticoagulant activity,

with only one third of the dose of UFH binding to

antithrombin III [27,28]. UFH can be given in low

doses subcutaneously or administered intravenously.

Subcutaneous UFH at a dose of 5000 U begun pre-

operatively and continued two or three times a day

is a common prophylaxis regimen used in thoracic

surgical patients. A meta-analysis of 70 randomized

trials including 16,000 patients undergoing general,

urologic, or orthopedic surgical procedures showed

that subcutaneous UFH reduced the risk of fatal PE

by nearly two thirds [29].

By depolymerizing UFH, LMWH is produced with

superior pharmacokinetics. LMWH has a more pre-

dictable dose-response curve and an increased plasma

half-life [30]. Reduced binding of LMWH to platelets

likely results in the lower incidence of heparin-induced

thrombocytopenia seen compared with UFH [31].

Trials comparing UFH with LMWH show supe-

rior DVT prophylaxis and a reduced bleeding risk

for LMWH. The risk of bleeding related to heparin

is dose dependent. A meta-analysis of subcutaneous

UFH versus LMWH showed the incidence of bleed-

ing after hip arthroplasty was 2.6% for UFH, 1.8%

for LMWH, and 0.3% for placebo [32].

Other anticoagulants, including aspirin and war-

farin, have little use in PE prophylaxis in thoracic

surgical patients. The antithrombotic statement from

the Seventh American College of Chest Physicians

Conference on Antithrombotic and Thrombotic Ther-

apy does not recommend aspirin alone as prophylaxis

against DVT or PE [3]. The use of warfarin typically

is limited to very-high-risk patients undergoing neu-

rosurgery or lower extremity orthopedic procedures.

Newer agents, such as direct thrombin inhibitors,

direct factor Xa inhibitors, and others (see Box 2)

target specific components of the coagulation system.

These agents have generated considerable interest in

thromboprophylaxis. Direct thrombin inhibitors are

used frequently in the treatment of heparin-induced

thrombocytopenia. Desirudin, a recombinant hiru-

din, was shown to be more effective than LMWH in

preventing PE without an increased risk of bleeding

[33]. The direct factor Xa inhibitor fondaparinux

reduced the risk of thromboembolism by 55% over

LMWH with no clinical difference in bleeding [34].

Prophylaxis recommendations in thoracic surgical

patients

Few data are available in thoracic surgical patients

to support a specific prophylaxis regimen. A strategy

pulmonary embolism prophylaxis 241

can be developed based on data inferred from nu-

merous trials of patients undergoing other major

surgical procedures. These recommendations are

outlined in Table 1.

For prophylaxis against PE to be effective, it must

be initiated as soon as the risk of DVT begins. There

is little risk to applying properly fitted graduated

compression stockings. These stockings should be

placed preoperatively and continued until the patient

is consistently ambulating. IPC devices should be

placed and activated before the induction of anes-

thesia, when the period of immobility begins.

Pharmacologic prophylaxis should be used in

addition to mechanical measures in patients under-

going thoracotomy. Patients age 40 to 60 with no

additional risk factors undergoing surgery for benign

disease can receive subcutaneous UFH twice daily

or LMWH daily. A higher risk group includes any

patient older than 60 and any patient with cancer or a

prior DVT. This group should receive UFH three

times a day or LMWH at a dose of 3400 U or more

Table 1

Risk stratification for thromboembolism

Risk group % Fatal PE Prophylaxis

Low risk < 0.01 Early ambulation

Minor surgery, age < 40

Moderate risk 0.1–0.4 Subcutaneous

UFH bid

Minor surgery,

risk factors present

LMWH �3400 U qd

Major surgery, age < 60,

no risk factors

IPC or GCS

High risk 0.4–1 Subcutaneous

UFH tid

Major surgery, age > 60,

no risk factors

LMWH >

3400 U qd

Major surgery, age < 60,

single risk factor

IPC

Highest risk 0.2–5 LMWH >

3400 U qd

Patients with multiple

risk factors

Fondaparinux

Major trauma patients UFH or

LMWH plus

Spinal cord injury IPC and GCS

Abbreviations: GCS, graduated compression stockings; IPC,

intermittent pneumatic compression (device); LMWH, low-

molecular-weight heparin; UFH, unfractionated heparin.

Modified from Geerts WH, Pineo GF, Heit JA, et al.

Prevention of venous thromboembolism: the Seventh ACCP

Conference on Antithrombotic and Thrombolytic Therapy.

Chest 2004;126(3 Suppl):338S–400S.

daily. The highest risk group—anyone with more

than one risk factor—would receive this regimen plus

an IPC device and compression stockings.

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Shimizu N. Intermittent pneumatic compression is

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Thorac Surg Clin

Management of the Anticoagulated Patient

Mark H. Meissner, MDa,b, Riyad Karmy-Jones, MDb,c,*

aDepartment of Vascular Surgery, University of Washington School of Medicine, Harborview Medical Center,

325 9th Avenue, Seattle, WA, 98195, USAbDepartment of Interventional Radiology, University of Washington School of Medicine, Harborview Medical Center,

325 9th Avenue, Seattle, WA, 98195, USAcDepartment of Cardiothoracic Surgery, University of Washington School of Medicine, Harborview Medical Center,

325 9th Avenue, Seattle, WA, 98195, USA

Patients who are to undergo surgery may be anti-

coagulated for therapeutic reasons (eg, deep venous

thrombosis [DVT], valve replacement, lytic therapy)

or because of comorbid conditions (eg, renal or he-

patic failure). In addition, the proposed operative in-

tervention may be elective or urgent. The approach to

managing the coagulation status is critically affected

by the circumstances and requires a basic understand-

ing of the risks involved of bleeding and correcting

the underlying pathophysiology. This article reviews

the indications, pharmacology, and complications of

common anticoagulation therapies (including labora-

tory and clinical assessment) in the surgical patient.

Coagulation system

Normal hemostasis requires the complex inter-

action of platelets; the endothelium; and more than

100 procoagulant, inhibitory, and fibrinolytic proteins

(Fig. 1). Primary hemostasis results in the immediate

formation of a platelet plug at the site of vascular

injury. The generation of thrombin (factor IIa), the

key effector enzyme of coagulation, and the conver-

sion of soluble fibrinogen to insoluble fibrin result

in the stabilization of the platelet plug by a secondary

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.006

* Corresponding author. Department of Surgery, Box

359796, Harborview Medical Center, 325 9th Avenue,

Seattle, WA 98195.

E-mail address: karmy@u.washington.edu (R. Karmy-Jones).

organized fibrin thrombus on the surface of acti-

vated platelets.

Coagulation is initiated either by mechanical in-

jury or cytokine-induced activation of endothelial

cells and monocytes. In either case, tissue factor, a

single-chain receptor for factor VII, is exposed as a

membrane protein. This pathway, also known as the

extrinsic pathway, is the most important physiologic

pathway for initiation of coagulation in response to

injury. Exposed tissue factor binds inactive factor VII

and activated factor VIIa, a small amount of which

circulates in blood. The tissue factor:VIIa complex

autoactivates factor VII and activates factors IX and X

[1,2]. Feedback amplification occurs as factor VII

bound to tissue factor is activated by factors VIIa,

IXa, and Xa.

Subsequent formation of the prothrombinase

complex, composed of phospholipid bound pro-

thrombin (factor II), factor Xa, and its factor Va

cofactor, results in the generation of thrombin from

prothrombin. There seems to be a threshold response

in which a certain level of initiating procoagulant

stimulus (VIIa– tissue factor) is required to produce

effective thrombin generation [3,4]. When this thresh-

old is reached, the amount of thrombin generated is

independent of the initiating stimulus. Thrombin

activates factors V, VIII, and XI, which cause feed-

back amplification through further activation of

factor IX. The thrombin-mediated conversion of

pro-cofactors V and VIII is particularly important

because the active cofactors serve to assemble the

prothrombinase and tenase complexes. Thrombin-

15 (2005) 243 – 262

reserved.

thoracic.theclinics.com

aPTT

INR

TT

Intrinsic SystemNon-endothelial Surface

XII

IX

VIII

Xa+V, Ca++(IV),VI

Prothrombim (II) Thrombin

Fibrinogen Fibrin

Thrombus

PlateletAggregation

Granulerelease

vWFThrombin

Platelet adhesion

collagen vWF Fibrinogen

Platelet receptorsIa Ib IIa IIIb

Collagen ShearInjury

Extrinsic SystemInjury

Tissue Thromboplastin(III)+

VII

ACT

↑ ↑ ↑

↑ ↑

Fig. 1. The coagulation system. Schematic of normal hemostasis.

meissner & karmy-jones244

mediated activation of factor V may be the rate-

limiting step in coagulation [5].

Phospholipid membranes are crucial to the for-

mation of the procoagulant tissue factor:VIIa, pro-

thrombinase, and tenase complexes. Platelets are the

primary source of these phospholipids and, through

amplifying the process by several orders of magni-

tude, play a crucial role in propagating coagulation.

When activated, either through their interaction with

collagen or by binding to fibrin in coagulating

plasma, negatively charged phosphatidylserine resi-

dues are translocated to the outer platelet membrane

[6]. The coagulation factors involved in formation of

these complexes depend on 9 to 12 amino-terminal

g-carboxyglutamic acid residues for interaction with

the phospholipid surface [7]. These residues, formed

posttranslationally in a vitamin K–dependent pro-

cess, are required for calcium binding and correct

folding for interaction with the phospholipid mem-

brane [1].

Various models suggest that the tissue factor

pathway of coagulation can be functionally divided

Table 1

Antithrombotic agents

Mechanism

of action

Currently

approved agents

Anticoagulants IIa / Xa inhibitors Unfractionated

heparin

Xa > IIa inhibitors Low-molecular-

weight heparins

Xa inhibitors Fondaparinux

IIa inhibitors Lepirudin

Bivalirudin

Argatroban

Tissue factor

pathway inhibitors

IXa inhibitors

Vitamin K

antagonists

Warfarin

Antiplatelet

agents

Cyclooxygenase

inhibitors

Aspirin

Phosphodiesterase

inhibitors

Dipyridamole

ADP antagonists Ticlopidine

Clopidogrel

GP IIb/IIIa

antagonists

Abciximab

Tirofiban

Eptifibatide

management of the anticoagulated patient 245

into two phases. During the initiation phase, nano-

molar amounts of thrombin and femtomolar to

picomolar quantities of factors VIIa, IXa, Xa, and

XIa are generated [8]. Most importantly, this phase

leads to quantitative activation of the Va and VIIIa

cofactors. The prothrombin time (PT) and activated

partial thromboplastin time (aPTT) measure only

the initiation phase of coagulation. The propagation

phase is characterized by explosive prothrombin acti-

vation and thrombin generation. This phase is largely

driven by the tenase complex–mediated activation

of factor X [8]. Most of the major congenital

deficiencies and clinically effective anticoagulants

have their major effect during the propagation phase.

The efficacy of most anticoagulants depends on their

ability to inhibit thrombin after formation of the

initial fibrin-platelet clot.

The physiologic importance of the intrinsic co-

agulation pathway, through which coagulation is

initiated by a combination of factor XII, high-

molecular-weight kininogen, prekallikrein, and fac-

tor XI, is unclear. The less important role of the

intrinsic pathway is suggested by the observation that

few deficiencies of the intrinsic pathway are asso-

ciated with bleeding. Thrombin-induced activation of

factor XIa is likely important in the propagation of

coagulation, however, generating sufficient factor IXa

to prevent severe bleeding, after the tissue factor

pathway has been terminated by its natural inhibitors

[2,4,6,7].

Negative regulators of coagulation include tissue

factor pathway inhibitor, which regulates the initia-

tion phase of coagulation, and the antithrombin (AT)

and the protein C systems, which regulate the propa-

gation phase. A tissue factor pathway inhibitor:Xa

complex binds VIIa– tissue factor to form an inactive

complex, limiting the initiation phase but allowing

sustained activation through factors VIIIa, IXa, and

XIa [3,4,7,9]. The protein C system is initiated by

the interaction of thrombin with endothelial bound

thrombomodulin. Undergoing a conformational

change, the thrombomodulin-bound thrombin loses

its activity toward fibrinogen and factors V, VIII, and

XIII and activates the vitamin K–dependent zy-

mogen protein C [7]. Activated protein C, together

with its protein S cofactor, cleaves phospholipid

bound factors VIIIa and Va. AT, a serine protease

inhibitor, is present in significant molar excess to its

target proteases and inhibits factors IIa, VIIa, IXa,

Xa, XIa, and XIIa. In contrast to the protein C

pathway, AT acts as a scavenger and preferentially

inhibits circulating, rather than membrane bound,

factors IIa and Xa. Thrombin bound to fibrin clot is

relatively protected from the action of AT. These

pathways function synergistically to limit more

effectively the response to tissue factor than any

single mechanism alone. The combination of tissue

factor pathway inhibitor and AT is 70-fold more

potent than either inhibitor alone.

Therapeutic anticoagulation

A variety of anticoagulation agents are currently

available, each with unique and at times comple-

mentary mechanisms depending on which part of the

coagulation cascade they primarily affect (Table 1).

Antiplatelet agents

Platelets play a significant role in many cardio-

vascular disorders and are an attractive target for

reducing long-term morbidity and mortality. Cur-

rently approved antiplatelet agents, used either as an

adjunct to vascular interventions or to reduce car-

diovascular morbidity, include aspirin; the adenosine

diphosphate (ADP) antagonists clopidogrel and ticlo-

pidine; and the glycoprotein (GP) IIb/IIIa antagonists

abciximab, eptifibatide, and tirofiban. Numerous trials

meissner & karmy-jones246

have established that antiplatelet therapy reduces the

risk of myocardial infarction (MI) and stroke by one

third and vascular death by one sixth among patients

with ischemic coronary or cerebrovascular disease

[10,11]. A meta-analysis of several randomized trials

including patients with vascular disease suggests a

25% reduction in the odds of sustaining an important

vascular event (stroke, MI, or vascular death) with the

use of antiplatelet agents [12]. The widespread use

of antiplatelet agents may account partially for the

reduction in mortality in patients with peripheral vas-

cular disease.

Aspirin has been the most widely studied anti-

platelet agent. It acts to inactivate permanently the

cyclooxygenase (COX) activity of prostaglandin H

synthase-1 and synthase 2 (COX-1 and COX-2) by

acetylation of the COX site in the enzymatic domain.

These isozymes catalyze the first step leading from

arachidonic acid to thromboxane A2, which induces

platelet aggregation and vasoconstriction, and pros-

taglandin I2, which inhibits platelet aggregation and

causes vasodilation. Aspirin undergoes extensive

first-pass hepatic metabolism to salicylate, a weak

reversible COX inhibitor. Despite its short half-life

(15–20 minutes), once-daily dosing is able to in-

hibit platelet thromboxane A2 production completely

through irreversible inhibition of COX-1 and has

proved equally effective in low (50–100 mg/d) and

high (900–1500 mg/d) doses [11]. In contrast, endo-

thelial prostaglandin I2 production is derived from

COX-1 and COX-2 activity, COX-2-dependent syn-

thesis being relatively aspirin resistant [13]. Never-

theless, even low doses of aspirin given over the

long-term reduce basal and stimulated prostacyclin

production [14]. Although the clinical relevance of

reduced prostacyclin production is controversial, use

of the lowest effective dose may maximize efficacy

and minimize toxicity. Aspirin has other effects at

high doses, including an anti-inflammatory action

and suppression of plasma coagulation, but it is

doubtful that these effects are as clinically relevant as

suppression of platelet thromboxane A2 production.

Because the mean life span of circulating platelets is

10 days, approximately 50% of platelets remain

functional 5 to 6 days after treatment.

The clinical role of dipyridamole, an inhibitor of

cyclic nucleotide phosphodiesterase that increases

cyclic adenosine monophosphate levels within plate-

lets, is controversial [15]. Although its efficacy

remains in doubt, more recent studies have suggested

a benefit in patients with prior stroke or transient

ischemic attacks compared with aspirin alone [13].

Ticlopidine and clopidogrel are thienopyridine

derivatives that selectively inhibit ADP-induced

platelet aggregation through permanent alteration of

a postulated ADP receptor. Both can be considered

prodrugs, being hepatically metabolized to an active

transient metabolite, and are considered to act through

similar mechanisms [15,16]. Both drugs increase the

bleeding time, with a maximal effect after 5 to 6 days

of oral administration. At least some trials have

suggested that the antiplatelet effect of ticlopidine

may delayed for 2 weeks, making ticlopidine a sub-

optimal agent when immediate antiplatelet effects

are required.

Clopidogrel is six times more potent and has a

better safety profile than ticlopidine and may be more

effective than aspirin among patients with symp-

tomatic peripheral arterial disease. Clopidogrel is

rapidly hepatically metabolized to an active platelet

inhibitor with a short half-life. Similar to aspirin, the

active metabolite of clopidogrel is thought to alter

platelet function permanently, with cumulative inhi-

bition on repeated daily dosing. At doses of 50 to

100 mg, clopidogrel requires 4 to 7 days to reach a

steady state of 50% to 60% inhibition of ADP-

induced platelet aggregation. Loading doses of the

drug (300 mg) result in much more rapid inhibition,

however [13]. Approximately 7 days are required for

platelet function to return to normal after cumulative

doses are stopped. The bleeding risk associated with

clopidogrel is approximately equivalent to that of

aspirin, although aspirin is more likely to cause gas-

trointestinal bleeding [17].

Aspirin and the thienopyridines target only

thromboxane A2 and ADP-mediated platelet aggre-

gation, leaving the action of other agonists intact.

It is now recognized that the integrin aIIbb3 (GPIIb/

IIIa) is the final common pathway of platelet ag-

gregation and that receptor antagonists are potent

inhibitors of platelet aggregation [13]. Expression

of the GPIIb/IIIa integrin mediates fibrinogen bind-

ing to platelets through the Arg-Gly-Asp (RGD)

and Arg-Gly-Asp-Ser (RGDS) amino acid sequences

of fibrinogen, von Willebrand factor, and fibronec-

tin [15]. Many GPIIb/IIIa inhibitors have been

developed, including monoclonal antibodies, pep-

tides containing the RGD sequence, and RGD

mimetics. The monoclonal antibodies, such as ab-

ciximab (ReoPro,) are noncompetitive antagonists,

whereas the peptides and peptidomimetics are com-

petitive inhibitors [18]. In addition to their anti-

platelet effects, these agents diminish thrombin

generation through reduced phosphatidylserine

exposure and factor V binding [6]. For unclear

reasons, antibody antagonists of GPIIb/IIIa are better

inhibitors of thrombin generation than are the pep-

tide inhibitors.

management of the anticoagulated patient 247

Indirect thrombin inhibitors

Unfractionated heparin

Compounds that inhibit thrombin by potentiat-

ing the action of AT, such as unfractionated heparin

(UFH) and low-molecular-weight heparin (LMWH),

are known as indirect thrombin inhibitors. Although

the use of bovine products has declined with the ap-

pearance of bovine spongiform encephalopathy, UFH

is prepared from tissue extracts of porcine intestine

or bovine lung [19]. Commercially available products

are a heterogeneous mixture of glycosaminoglycans.

Pharmacology and mechanism of action. Heparin

acts primarily to catalyze the antithrombin (AT)-

mediated inhibition of thrombin (factor IIa) and

factors IXa, Xa, IXa, and XIIa; the greatest clinical

effect is on factors IIa and Xa. In the absence of a

catalyst, either endothelial heparan sulfates or exoge-

nous heparin, AT inactivates thrombin and factor

Xa at a low basal rate. Heparin binding to AT causes

a 9000-fold and 17,000-fold increase in inhibi-

tory activity against thrombin and factor Xa [20].

Neither UFH nor LMWH is able to inactivate

phospholipid-bound factor Xa or fibrin-bound throm-

bin. Fibrin-bound thrombin is protected from the

action of AT by formation of heparin/thrombin/

fibrin complexes that render it inaccessible to AT-

bound heparin.

The structure and size of the individual heparin

chains determine their ability to catalyze inhibition of

thrombin and factor Xa. The catalytic effect of

heparin depends on the binding of a unique penta-

saccharide sequence to a specific site on AT, pro-

ducing a conformational change that exposes its

reactive center. This pentasaccharide sequence is

present in only 20% to 50% of UFH chains and even

fewer LMWH chains [19]. AT-mediated inactivation

of factor Xa requires only the presence of the appro-

priate pentasaccharide sequence, whereas binding

to factor IIa further requires a flanking chain 15 to

16 saccharide units in length and containing a second

domain that electrostatically attracts the AT reactive

site [19,21]. Heparin chains must have a minimum

molecular weight of approximately 5400 D for

thrombin binding [22,23]. Anti–factor IIa activity

increases with the size of the heparin molecule, while

anti– factor Xa activity remains stable [5]. The anti–

factor Xa and anti– factor IIa activity of UFH is

approximately equal. The effect of heparin on the

aPTT primarily reflects its anti– factor IIa, rather than

anti– factor Xa, activity. Oligosaccharide chain length

also is an important determinant of clearance; longer

chains—chains with greater anti–factor IIa activity

and influencing the aPTT—are cleared more rapidly

than shorter chains [24].

UFH and LMWH also have anticoagulant proper-

ties independent of AT. Both agents cause the release

of tissue factor pathway inhibitor from the vascular

endothelium, leading to inhibition of factor X acti-

vation and subsequent thrombin generation. These

drugs also enhance activated protein C inactivation of

factor V, but not factor Va, in an AT-independent

manner. Such an effect could downregulate thrombin

production by decreasing the amount of membrane-

bound factor V capable of conversion to factor Va

and blocking the factor V/Va site with inactive fac-

tor V [25]. UFH also causes the release of platelet

factor 4 from activated platelets. Finally, heparin has

several biologic effects unrelated to its anticoagulant

action, including osteoblast suppression/osteoclast

activation associated with osteopenia, inhibition of

vascular smooth muscle cell proliferation, and

increased vascular permeability. Heparin also binds,

stabilizes, and potentiates the activities of several

growth factors and cell adhesion glycoproteins [26].

In addition to its specific binding to AT, heparin

also binds nonspecifically to several plasma proteins,

endothelial cells, and macrophages [24]. Many

heparin-binding proteins, such as vitronectin and

fibronectin, are acute-phase reactants, contributing

to the variable anticoagulant effect of heparin [27].

Binding to platelet factor 4 and multimers of von

Willebrand factor may be particularly important

because this clears higher molecular weight chains

from the circulation, renders them ineffective as anti-

coagulants, and lowers the effective heparin concen-

tration at sites of vascular injury [28,29]. The platelet

factor 4/heparin complexes are also one of the

antigens responsible for heparin-induced thrombocy-

topenia (HIT). Nonspecific protein binding signifi-

cantly affects the clearance of heparin, resulting in

a bioavailability of only about 30% and causing

variability in dose response and heparin resistance

in some patients [22,30].

UFH is cleared from the plasma in two phases—

a rapid, saturable phase secondary to endothelial and

macrophage binding and slower, unsaturable renal

clearance. The clearance of therapeutic doses of

heparin is dose related. The half-life of heparin in-

creases from 30 minutes after an intravenous bolus

of 25 U/kg to 60 minutes after a dose of 100 U/kg.

At therapeutic doses, the half-life of plasma heparin

activity is 63 ± 19 minutes, whereas that of the

heparin-induced change in aPTT is 84 ± 71.5 minutes

[31]. It is now realized, however, that heparin also has

some postdrug effects, such as the release of tissue

meissner & karmy-jones248

factor pathway inhibitor, whic may not follow the

pharmacokinetics of the drug.

Dose and administration. Heparin may be admin-

istered by continuous intravenous, intermittent intra-

venous, or intermittent subcutaneous injection.

Continuous intravenous administration is most com-

monly used; trials evaluating the safety and efficacy

of intermittent subcutaneous injection often have

been contradictory [32]. Although heparin is a large,

highly anionic molecule that is poorly absorbed from

the gastrointestinal tract, carrier molecules that

increase passive intestinal absorption and enable oral

administration also have been developed [33,34].

Heparin is measured in terms of the US Pharma-

copoeia unit, defined as the amount of heparin

causing 1 mL of sheep blood to half-clot when kept

at 20�C for 1 hour. Because UFH is a heterogeneous

mixture of compounds with variable biologic activity,

however, absolute dosages are irrelevant to its toxic

and therapeutic effects. The anticoagulant response

varies among patients, and the use of UFH requires

laboratory monitoring, most often using the aPTT.

Differences in anticoagulant response are due to

individual differences in the clearance of heparin

and in the aPTT response to a given amount of hepa-

rin. For the treatment of venous thromboembolism

(VTE), a therapeutic aPTT range of 1.5 to 2.5 times

the control value was previously recommended.

Ratios near the lower end of this target range are

associated with subtherapeutic heparin levels, how-

ever [35]. The responsiveness of different aPTT

reagents to heparin varies, and there is no equivalent

to the international normalized ratio (INR) used to

adjust for variability in PT reagents. The use of a

fixed therapeutic range for the aPTT is no longer

acceptable, and current recommendations are that

heparin dose be adjusted to achieve an aPTT

equivalent to a heparin level of 0.2 to 0.4 U/mL

measured by protamine titration [35,36]. Although at

least some data suggest that the aPTT response is

poorly related to the therapeutic outcome in VTE and

MI [24], the aPTT should be checked 6 hours after an

intravenous bolus dose and approximately 3 hours

after a subcutaneous dose of UFH. Heparin can be a

difficult drug to titrate, and failure to achieve a

therapeutic aPTT is among the most common errors

associated with use of the drug. Although some

authors have suggested that failure to achieve a thera-

peutic aPTT within the first 24 hours is associated

with a substantially higher risk of recurrent VTE,

others have found no difference in 3-month recur-

rence rates among patients achieving (5.3–7%) or

not achieving (6.3–7.8%) a therapeutic aPTT within

24 hours if initial heparin doses exceed 30,000 U/24 h

[36,37]. Monitoring anti– factor Xa levels is an

alternative in patients with lupus anticoagulant or

factor XII deficiency, in whom the aPTT may be

unreliable [22].

For the treatment of VTE, most more recent

studies have used an initial heparin bolus dose of

5000 U followed by a starting infusion rate of

30,000 to 35,000 U/24 h [36]. Weight-based nomo-

grams have been shown to outperform other

approaches to UFH administration, however, increas-

ing the aPTT above the therapeutic threshold more

rapidly, better estimating eventual heparin require-

ments, and requiring fewer dosage adjustments [38].

Current consensus recommendations for VTE include

initial treatment with 80 U/kg of heparin intra-

venously followed by a maintenance infusion of

18 U/kg with subsequent dosage adjustment to

maintain an aPTT in the therapeutic range [24,28].

Nomograms for VTE have incorporated a higher

dose than for unstable angina because the bleeding

risk is higher among patients receiving thrombolytic

therapy or GP IIb/IIIa antagonists. Variability in labo-

ratory reagents requires, however, that the appro-

priate therapeutic range and dosage adjustments be

locally determined.

Because of their rapid onset of action, UFH and

LMWH are currently the anticoagulants of choice

when immediate anticoagulation is required. Estab-

lished indications for UFH include the prevention and

treatment of VTE; periprocedural use in cardiac

surgery, vascular surgery, and coronary angioplasty;

as an adjunct to coronary stents; and in the treatment

of disseminated intravascular coagulation. The only

randomized trial comparing initial anticoagulation

with heparin versus no anticoagulation in the treat-

ment of VTE was stopped after enrolling only

35 patients because of the high mortality and recur-

rence rate in the untreated group [39]. Among the

19 patients randomized to no treatment, 5 died, and

5 others had nonfatal recurrent pulmonary embolism,

compared with 1 death and no recurrences in the

16 treated patients. A 5-day course of intravenous

UFH, when followed by oral anticoagulation, has

been shown to be sufficient for the treatment of VTE.

The incidence of recurrent thromboembolism during

or within 1 week of heparin therapy is 1.4% [40].

UFH administered in a dose of 5000 U subcutane-

ously every 8 to 12 hours also has been shown to be

effective in the prevention of VTE in general surgery

patients and seriously ill medical patients [24]. UFH

usually is combined with antiplatelet agents (aspirin

or GPIIb/IIIa inhibitors) or thrombolytic agents in

the treatment of acute coronary syndromes.

management of the anticoagulated patient 249

Complications. Bleeding is the most common

complication associated with anticoagulant therapy.

The risk of major bleeding associated with UFH and

LMWH has been reported to be 0% to 7% and 0%

to 3% [41]. Others have noted major bleeding in 4%

to 6% of patients treated with UFH [32,40], with fatal

bleeding in 1% to 2% of patients with major bleeding

[42]. Although approximately half of patients with a

major bleeding event have a supratherapeutic aPTT

within 24 hours of hemorrhage [40], the aPTT is

poorly predictive of bleeding complications. In con-

trast, 24-hour heparin dose per m2 body surface

area is significantly related to bleeding. The aPTT

independent bleeding risk associated with heparin

may be due to its other effects, such as those on

platelet function. Most major bleeding episodes

during treatment for VTE have been noted to occur

near the end of initial heparin treatment when the INR

is approaching the therapeutic range [40]. A body

surface area 2 m2 or less (odds ratio 2.3, confidence

interval 1.2–4.4) and malignancy (odds ratio 2.4,

confidence interval 1.1–4.9) are independent risk

factors for bleeding while receiving parenteral anti-

coagulants [42].

Other risks associated with UFH include elevated

liver function tests, HIT, and osteopenia with long-

term administration. Increased plasma levels of liver

enzymes have been reported in 18% to 89% of

patients receiving heparin and are seen in association

with LMWH [43].

Based on etiology and the risk of complications,

HIT often is divided into types I and II [44]. Type I

HIT derives from the intrinsic proaggregatory ef-

fect of heparin and is generally asymptomatic,

characterized by a decrease in platelet count within

the first 3 days of therapy and rarely associated

with platelet counts less than 100,000/mL [44]. The

platelet count often returns to the normal range

despite continued heparin therapy. Type II HIT is

the most common drug-induced, immune-mediated

thrombocytopenia, occurring in 1% to 3% of patients

receiving heparin for more than 5 days [45,46].

Thrombocytopenia results from antibodies directed

against multimolecular complexes of platelet fac-

tor 4 and heparin chains longer than 12 to 14 sac-

charide units. The heparin/platelet factor 4/IgG

complex binds to platelet Fc receptors, causing

antibody-mediated platelet activation and inducing

platelet-derived procoagulant microparticles. The

antibody also may bind similar epitopes on endothe-

lial cells, potentially resulting in immune-mediated

endothelial injury [44,46]. Heparin antibodies have

been noted in 40% of patients undergoing cardiac

surgery [47].

Early manifestations of type II HIT include a

decrease in platelet count of greater than 50%,

often to less than 100,000/mL, and skin lesions at

injection sites. Thrombocytopenia is usually first

seen after 5 to 10 days of heparin therapy, but can

be seen within hours in previously exposed pa-

tients. Manifestations can occur after heparin is

administered in any dose by any route, but are ob-

served most frequently in patients receiving hepa-

rin as postoperative prophylaxis. In one series of

127 patients with HIT, 73.2% were receiving hepa-

rin for prophylactic indications [45]. Several labo-

ratory tests for HIT have been developed. Platelet-

associated IgG is almost always elevated but has low

specificity. The 14C-serotonin platelet release assay to

detect heparin-dependent IgG antibodies is sensitive

and specific (>90%) for HIT, but results are not

immediately available. Commonly accepted diagnos-

tic criteria for HIT include (1) a decline in platelet

count to less than 150,000/mL 5 or more days after

beginning heparin and (2) a positive platelet14C-

serotonin release assay.

In contrast to other immune-mediated thrombo-

cytopenias, type II HIT is associated with a high risk

of thrombosis. Arterial or venous thrombosis may

develop in 50% to 75% of patients, and the mortality

rate is 25% to 30% [24,48]. HIT is recognized before

the occurrence of a thrombotic event in only half

of patients [45]. Although some investigators have

reported arterial events to be more common, others

have reported a 4.3:1 ratio of venous to arterial events

[45]. Arterial thrombi usually consist primarily

of platelets, giving rise to the description ‘‘white

clot syndrome.’’

If platelet counts fall precipitously or reach levels

of less than 100,000/mL, heparin should be stopped

and alternative anticoagulants, such as lepirudin or

argatroban, used until the patient is therapeutic on

warfarin. For patients with asymptomatic HIT, the

30-day cumulative thrombosis rate is 52.8% [45].

Because thrombosis may occur even after withdrawal

of heparin, even asymptomatic patients should be

therapeutically anticoagulated with alternative agents

until the platelet count has normalized [24]. Other

authors have suggested that asymptomatic patients be

treated until the HIT antibody can no longer be

detected [48]. Because there is a high incidence of

cross-reactivity with heparin-dependent antibodies,

LMWH should not be used in patients with type II

HIT. Occasional reports of venous gangrene associ-

ated with decreased protein C levels suggest that

warfarin, without an alternative parenteral anticoagu-

lant, should not be used as initial monotherapy for

acute HIT [22,24,44].

meissner & karmy-jones250

Low-molecular-weight heparin

LMWH was specifically developed to provide an

agent that was more specific than heparin, separating

its anti– factor IIa and anti–factor Xa activity, with

the potential benefit of reducing the hemorrhagic side

effects [19]. LMWH is derived from the chemical or

enzymatic depolymerization of UFH to produce a

heterogeneous mixture of species with mean molecu-

lar weights of 4500 to 5000 D. The methods of

depolymerization and species produced differ sub-

stantially between LMWH preparations. By defini-

tion, LMWH has a mean molecular weight of less

than 8000 D with at least 60% of all molecules

having a molecular weight of less than 8000 D. In

contrast, 30% of the components of UFH are low-

molecular-weight chains.

The biologic difference between UFH and the

LMWH arises from their predominant inactivation of

factor Xa and reduced cellular and protein binding.

Because of their shorter chain length, most LMWH

species are unable to form the ternary complex

required for the inactivation of thrombin, although

they retain their ability to inactivate factor Xa.

Among the eight LMWH species approved for use

in the world (four in the United States), the anti–

factor Xa–to–anti– factor IIa ratio varies between

1.5 and 4 compared with 1 for UFH [19,24]. Because

the affinity of heparin for plasma proteins depends on

chain length, LMWH has substantially reduced pro-

tein binding. Because of reduced binding to cells and

plasma proteins, LMWH is primarily renally cleared

and has less interaction with macrophages, platelets,

and osteoblasts. Corresponding clinical advantages

of LMWH include 90% to 100% bioavailability, al-

lowing once-daily or twice-daily subcutaneous injec-

tion; a more predictable dose-response, which permits

weight-based dosing without the need for laboratory

monitoring; a longer half-life; and less risk of

osteopenia and HIT. Because of the high incidence

of cross-reactivity, however, LMWH should not be

substituted for UFH in patients with HIT. Although

early animal studies suggested LMWH may have a

wider therapeutic window and lower risk of bleeding,

this has not been confirmed clinically, and there are

no significant differences in bleeding rates between

UFH and LMWH [5,49].

Because the aPTT primarily reflects anti–factor

IIa activity, it is not useful for monitoring the anti-

coagulant activity of LMWH. Monitoring is unneces-

sary in most patients, however, and usually is

considered only in clinical situations in which the

dosage is poorly defined or difficult to predict. The

potency of LMWH is measured most often by chro-

mogenic assays for anti– factor Xa activity. For

twice-daily administration in the treatment of DVT,

anti– factor Xa levels of 0.6 to 1 IU/mL measured

4 hours after a subcutaneous dose seem to be

adequate. Monitoring of anti–factor Xa levels may

be appropriate in children and pregnant women,

obese patients (>110 kg), and patients with renal

failure. Possibly because plasma assays measure only

the ability to inactive free factor Xa rather than that

within the prothrombinase complex, the relationship

between anti– factor Xa activity and in vivo efficacy

or complications is poor. In the treatment of DVT,

the degree of thrombus regression after 10 days of

LMWH seems weakly related to anti– factor Xa

levels, however.

Depending on the preparation and indication,

LMWH can be administered subcutaneously once

or twice daily based on total body weight. Established

indications for LMWH include the prophylaxis and

treatment of VTE and the early treatment of unstable

angina. Compared with UFH, the use of LMWH in

the treatment of unstable angina or non–Q wave MI

is associated with a 15% to 20% relative risk re-

duction in MI or death during the first 7 to 14 days,

although this benefit is not sustained in the long-term

[24]. Other benefits of LMWH are either unclear

(in combination with thrombolysis in the treatment

of Q wave MI) or doubtful (prevention of restenosis

after coronary angioplasty).

Factor Xa inhibitors

Factor Xa may be a particularly suitable target for

directed anticoagulants because it is located at the

convergence of the intrinsic and extrinsic pathways

and is higher in the coagulation cascade than other

potential targets. Specific inhibitors of factor Xa

that are currently available or in clinical trials include

various pentasaccharide derivatives. In contrast to

heparin and LMWH, these drugs are homogeneous

synthetic agents with isolated pharmacologic targets,

selectively inhibiting factor Xa without a correspond-

ing effect on factor IIa. The pentasaccharide sequence

corresponds to the minimal binding sequence on the

heparin chain required for interaction with AT. These

agents indirectly inhibit the activity of factor Xa

through AT and, in contrast to heparin, do not prolong

the aPTT.

Fondaparinux (Arixtra) is a synthetic pentasac-

charide that reversibly binds the heparin-binding site

of AT, increasing its anti– factor Xa activity more

than 270-fold [50]. Because it interacts only with the

heparin-binding site, the drug is ineffective against

thrombin but has high anti– factor Xa activity. Free

management of the anticoagulated patient 251

factor Xa rather than factor Xa bound in the

prothrombinase complex seems to be the primary

target of the drug [29]. Because the agent inhibits

thrombin generation, but not thrombin itself, the

thrombin-mediated amplification loops are preserved,

and these agents do not compromise thrombin or

ADP-induced platelet aggregation. There is, however,

some experimental evidence that in the presence of

fondaparinux, AT also is able to inhibit factor VIIa

bound to tissue factor [51].

A terminal methyl group prevents nonspecific

binding to plasma proteins, giving fondaparinux

a predictable pharmacologic response [52,53]. No

changes in the pharmacokinetic properties of the drug

have been noted with concomitant administration

of aspirin, warfarin, and some nonsteroidal anti-

inflammatory drugs. In contrast to UFH, fondapa-

rinux is relatively insensitive to platelet-derived

heparin neutralizing proteins. Limited data suggest

that fondaparinux does not form complexes with

platelet factor 4 and does not cross-react with

antibodies from patients with type II HIT [54]. The

drug is 100% available after subcutaneous injection

with an elimination half-life of about 17 hours,

allowing once-daily subcutaneous administration in

a fixed dose without monitoring. Because the drug

is not metabolized and is primarily renally excreted,

precautions may be necessary in patients with re-

nal dysfunction.

Fondaparinux currently is approved for major

orthopedic prophylaxis. In a meta-analysis of

7344 patients undergoing hip replacement, major

knee surgery, or surgery for hip fracture, fondapa-

rinux, 2.5 mg once daily started postoperatively,

reduced the odds of VTE by 55.2% compared with

enoxaparin (6.8% versus 13.7%) [55]. Major bleed-

ing events were more common among patients

receiving fondaparinux (2.7% versus 1.7%), however.

Compared with placebo after an initial 7-day course

of fondaparinux in patients undergoing hip fracture

surgery, extended prophylaxis for 21 days reduced

the incidence of VTE at 4 weeks from 35% to 1.4%

[53]. In the treatment of acute DVT, early results of

phase II and III trials suggest that fondaparinux at a

dose of 7.5 mg once daily is comparable in safety and

efficacy to initial treatment with LMWH [50,53].

Early phase II studies also have shown fondaparinux

to be at least equal to UFH as an adjunct to coronary

thrombolysis and angioplasty [52,53].

The half-lives of pentasaccharide derivatives

depend on their binding affinity for AT, the concen-

tration of AT, and the elimination half-life of AT.

Pentasaccharide analogues differing in their binding

affinity to AT and half-life have been developed.

These include an O-methylated, O-sulfated pentasac-

charide with an affinity for AT 34-fold times higher

than that of fondaparinux [56]. The half-life of

this drug is prolonged to 61.9 hours in nonhuman

primates and 80 hours in humans. Idraparinux is

a long-acting anti– factor Xa pentasaccharide in

phase III clinical trials for the treatment of VTE.

The drug can be administered as a weekly subcuta-

neous dose. Phase III studies evaluating the efficacy

of idraparinux in VTE and atrial fibrillation are in

progress or planned [53].

Warfarin

Pharmacology and mechanism of action

The vitamin K antagonists are currently the

most widely used oral anticoagulants. Vitamin K–

dependent coagulation proteins include factors II,

VII, IX, and X and proteins C and S. All except

protein S are synthesized exclusively in the liver. In

all cases, the g-carboxyglutamate residues function

to accelerate thrombin formation by binding calcium

ions, causing the protein to undergo a conformational

change that exposes the platelet phospholipid-binding

domain. Vitamin K–dependent proteins also are in-

volved in other regulatory processes, including bone

metabolism and vascular wall homeostasis, and the

vitamin K antagonists interfere with physiologic pro-

cesses other than the processes related to coagulation.

The vitamin K antagonists are derived from

4-hydroxycoumarin and include warfarin, phenpro-

coumon, and acenocoumarol. All act through the

enzyme, KO reductase, which is responsible for gen-

eration of the active form of vitamin K, the hydro-

quinone KH2. A deficiency of KH2 causes production

of partially carboxylated and decarboxylated proteins

with decreased procoagulant activity. Warfarin is the

most widely used vitamin K antagonist and is the

11th most frequently prescribed drug in the United

States [57]. It is a racemic mixture of R and S enan-

tiomers that are differentially metabolized; S-warfarin

is approximately three times more potent. Warfarin

circulates bound to plasma proteins and has a half-life

of 36 to 42 hours.

The anticoagulant effect of warfarin is notoriously

variable and is influenced by factors affecting the

metabolism of warfarin; dietary and gastrointestinal

factors influencing the availability and absorption

of vitamin K1; and factors, such as acute illness,

that alter the synthesis and metabolism of vitamin K–

dependent procoagulants. A reduced response to

warfarin may occur in patients with a diet high in

green vegetables or receiving vitamin K supplements,

meissner & karmy-jones252

whereas the effect may be potentiated in patients

receiving intravenous antibiotics or with fat mal-

absorption. Given the diversity of drug interactions,

more frequent monitoring of the INR is warranted

when new medications are added or withdrawn.

Genetic factors also may play a role in the anti-

coagulant response to warfarin. Hereditary resistance

to warfarin has been reported, with affected patients

requiring 2.6 mg/kg/d of warfarin [58]. These patients

require high plasma levels of warfarin for adequate

anticoagulation, but have otherwise normal warfarin

pharmacokinetics. Conversely, genetic heterogeneity

for cytochrome P-450 CYP2C9, the enzyme respon-

sible for converting S-warfarin to its inactive

hydroxyl forms, is associated with decreased dose

requirements. Patients with a low warfarin dose

requirement (<1.5 mg/day) are six times more likely

to have a variant CYP2C9 allele associated with

impaired S-warfarin metabolism [59]. These individ-

uals have been noted to have more problems on in-

duction of warfarin therapy and a 3.7-fold higher rate

of major bleeding complications.

The anticoagulant effect of warfarin most com-

monly is measured using the PT, which is sensitive to

reductions in three of the four vitamin K–dependent

procoagulants (factors II, VII, and X). Thromboplas-

tin reagents used in the PT assay vary in their

responsiveness to the anticoagulant effects of war-

farin, which in the past led to clinically important

differences in recommended oral anticoagulant doses;

this has largely been rectified by standardizing

thromboplastins according to their international sen-

sitivity index (ISI), which measures the responsive-

ness of a given thromboplastin to a reduction in

vitamin K–dependent factors in comparison to a

reference standard. The effect of warfarin-induced

anticoagulation is now standardized by converting the

PT measured with local thromboplastin reagents to an

INR, calculated as [24]:

INR ¼ patient PT=mean normal PTð ÞISI

Some evidence suggests that the anticoagulant effects

of warfarin, as measured by the PT, are disassociated

from the antithrombotic effects during the induction

of treatment. This observation arises from the fact

that prolongation of the PT early after initiating

warfarin primarily reflects reductions in factor VII,

which has the shortest half-life. The antithrombotic

effect is more closely related to the level of

prothrombin, however, which has a half-life of

96 hours compared with 6 to 24 hours for factors

VII and IX. The delayed reduction in prothrombin

levels is the basis for overlapping heparin and

warfarin treatment.

Dose and administration

Randomized clinical trials have established the

effectiveness of warfarin for the primary and sec-

ondary prevention of VTE; for the prevention of

embolism in patients with prosthetic heart valves

or atrial fibrillation; for the prevention of stroke,

recurrent MI, and death in patients with anterior MI;

for the prevention of anterior MI in patients with

peripheral vascular disease; and for the prevention of

MI in high-risk men [24]. Other commonly recog-

nized indications include rheumatic mitral valve

disease, mitral valve prolapse, mitral annular calcifi-

cation, nonrheumatic mitral regurgitation, mobile

aortic atheromas or plaques greater than 4 mm in

size, and systemic thromboembolism of unknown

etiology. One large randomized trial has shown oral

anticoagulants to be more effective than aspirin in

preventing thrombosis of infrainguinal vein, but not

prosthetic, grafts [60].

Although there is limited evidence that an INR of

1.3 to 2.0 may reduce myocardial ischemic events

when used as primary prevention in men without

ischemic heart disease, the therapeutic effect of war-

farin is significantly reduced at INR values less than

2 [24]. A moderate intensity of anticoagulation (INR

2.0–3.0) is appropriate for most indications. Excep-

tions requiring more intense anticoagulation include

some types of mechanical prosthetic heart valves and

some patients with antiphospholipid antibody syn-

drome. Limited evidence suggests an improved out-

come in patients with antiphospholipid antibodies

who are anticoagulated to an INR of 2.5 to 3.5.

The appropriate initial warfarin dose is contro-

versial, although initiating warfarin at a dose of 5 mg,

rather than with a loading dose of 10 mg, is often

recommended. As noted earlier, the antithrombotic

effect of warfarin is most closely related to pro-

thrombin levels, which are equivalently reduced by

a 5- or 10-mg dose [24]. A therapeutic INR usually

can be achieved within 4 to 5 days after initiating

warfarin at 5 mg/d. Adverse effects of loading doses

of warfarin include a more rapid reduction in

protein C and a higher risk of overanticoagulation.

Higher initial doses should be avoided in patients at

risk of bleeding or with a known deficiency of

protein C or S, in whom the risk of skin necrosis is

higher [61]. Although parenteral anticoagulants can

be avoided when instituting anticoagulation for

chronic atrial fibrillation, heparin should be adminis-

tered simultaneously for 4 to 5 days, until the INR is

in the therapeutic range on two measurements at least

management of the anticoagulated patient 253

24 hours apart, if urgent anticoagulation is required

for the treatment of thromboembolic disease. Simul-

taneous initiation of heparin and warfarin is safe

and not associated with more frequent recurrence or

hemorrhage [61]. Several studies have shown that

the use of adjuvants such as computer-driven pro-

tocols and nomograms can improve the initiation

and maintenance of anticoagulation with vitamin K

antagonists [61].

Complications

Although effective in preventing thrombosis,

warfarin has a narrow therapeutic window. Several

factors, including widespread adoption of the INR,

decreased intensity of anticoagulation, and the orga-

nization of anticoagulation clinics, have increased the

safety of long-term oral anticoagulation; however,

bleeding remains the most important associated

complication and is closely related to the intensity

of anticoagulation. Clinical trials have established

that the bleeding risk increases as the INR is in-

creased from 2.0 to 3.0 to 3.0 to 4.5 and rises expo-

nentially as the INR increases to greater than 5.0 [24].

Total time in the therapeutic range also is an

important determinant of bleeding risk and anti-

coagulant efficacy. Risk factors for bleeding include

a history of hemorrhage, previous stroke, and

comorbid conditions such as renal insufficiency or

hypertension. The independent risk of bleeding

associated with age is controversial, but at least some

data suggest that elderly patients can be anticoagu-

lated safely if closely monitored in the setting of

an anticoagulation clinic. The overall rate of major

bleeding during a 3-month course of warfarin to

maintain an INR of 2.0 to 3.0 is 3% or less [41].

Various clinical trials have reported major bleeding

rates between 0.5 and 4.2 per 100 patients; cohort

studies have reported higher rates of 1.2 to 7 episodes

per 100 patients [61]. The risk of bleeding is

increased when high-intensity warfarin (INR 3.0–

4.5) is used in combination with aspirin [24].

Increased rates of minor bleeding also have been

reported with lower intensity regimens, however.

Nonhemorrhagic adverse effects of warfarin

include an associated embryopathy and warfarin-

induced skin necrosis. Oral anticoagulants cross

the placenta and are associated with a characteristic

embryopathy, CNS deficits, and increased rates of

fetal death. The coumarin derivatives interfere with

calcium deposition, causing irregular deposition in

areas that are not normally calcified, and approxi-

mately 30% of infants born to mothers taking these

drugs have serious bone defects. Although the

incidence of embryopathy is highest during the first

6 to 12 weeks of gestation, fetal bleeding and

death may occur throughout pregnancy. Although

warfarin is contraindicated during pregnancy, it can

be administered safely to nursing mothers [24].

Warfarin-induced skin necrosis is a rare complication

associated with large loading doses of warfarin and

presumably occurs when the introduction of warfarin

causes a more rapid reduction in protein C levels than

in the other vitamin K–dependent procoagulants. The

incidence is estimated to be between 1:100 and

1:10,000, and it is more common in women with a

predilection for the breast, thighs, and buttocks [62].

Patients with deficiencies of the protein C pathway

may be particularly susceptible to skin necrosis,

although this complication also may occur in non-

deficient individuals. Introducing warfarin gradually

while the patient is receiving therapeutic doses of

parenteral anticoagulants can minimize the potential

for this complication.

Direct thrombin inhibitors

Thrombin has multiple roles in coagulation,

including conversion of fibrinogen to fibrin, ampli-

fication of the coagulation cascade, and activation of

platelets. Given its central role in coagulation and

cardiovascular disease, the treatment of many throm-

botic disorders is directed toward blocking the action

of thrombin. Heparin historically has been used as a

primary treatment of such disorders, although it has

several limitations, including extensive protein bind-

ing and an inability to inactivate platelet-bound factor

Xa and fibrin-bound thrombin.

This last consideration may be particularly impor-

tant. The thrombin molecule contains three binding

sites, including the catalytic site responsible for

the cleavage of substrates (active site), a substrate

recognition site that also functions as the binding site

for the AT component of the heparin-AT complex

(exosite 1), and a heparin binding domain (exosite 2)

[27,30]. Heparin bound to exosite 2 bridges more

fibrin onto thrombin and renders the heparin/fibrin/

thrombin complex inaccessible to inhibition by AT

[27]. Such fibrin-bound thrombin serves as a reser-

voir of thrombogenic activity capable of converting

factors V and VIII to their active form, generating

fibrin from fibrinogen, activating factor XIII, and

attenuating fibrinolysis [23]. Bound thrombin also

continues to activate platelets through thromboxane

A2–independent mechanisms that are not inhibited

by aspirin [63]. Platelet-bound factor Xa is similarly

resistant to inactivation by the heparin/AT complex,

meissner & karmy-jones254

serving as a source of further thrombin generation

[23]. Drugs such as heparin incompletely attenuate

the thrombotic process, a potentially important con-

cern at sites of arterial injury.

The direct thrombin inhibitors offer several poten-

tial advantages over heparin. These agents act inde-

pendently of AT, either blocking the active site or

preventing interaction with its substrates. Several

direct thrombin inhibitors have been developed and

can be classified as being natural substrate analogues,

recombinant derivatives, or synthetic inhibitors; as

being directed against the active site or exosites; and

as being reversible or irreversible inhibitors. Three

parenteral direct thrombin inhibitors—lepirudin,

bivalirudin, and argatroban—are currently available,

and oral direct thrombin inhibitors, such as ximela-

gatran, are on the immediate horizon. Lepirudin and

argatroban are approved for the treatment of HIT,

and bivalirudin is approved as an adjunct to coronary

angioplasty. These agents typically can be monitored

with the aPTT.

Fibrin binding does not compromise agents

directed against the active site. Although inhibitors

that also bind exosite 1 compete with fibrin, the

fibrin-thrombin interaction is of low affinity in the

absence of heparin. The lower molecular weight

thrombin inhibitors are more effective against fibrin-

bound thrombin, presumably because of better

diffusion into the thrombus. In addition to inhibiting

the action of thrombin on fibrinogen, the direct

thrombin inhibitors block amplification of coagula-

tion through activation of factors V and VIII and

fibrin stabilization by factor XIII [48]. These agents

do not bind plasma proteins and result in a more

predictable dose-response than heparin. Additionally,

in contrast to heparin, these drugs are not neutralized

by platelet factor 4 and multimers of von Willebrand

factor, large quantities of which may be present at

sites of arterial plaque rupture. Finally, the direct

thrombin inhibitors do not promote the platelet

release reactions and inactivate thrombin-induced

platelet activation [64]. The combined ability to in-

hibit fibrin-bound thrombin without inducing platelet

aggregation may be particularly important in the

management of acute coronary syndromes. In a meta-

analysis including 35,970 patients, the use of direct

thrombin inhibitors in the setting of acute coronary

syndromes was associated with 15% reduction in

death or MI compared with heparin [63]. It was

estimated that 125 patients would need to be treated

with a direct thrombin inhibitor to avoid one event.

Although not currently supported by any data, simi-

lar concerns may exist in a patient with peripheral

vascular disease.

Despite similar advantages, there are potentially

important differences in the anticoagulant profiles

of the direct thrombin inhibitors, and they should

not be regarded as pharmacologically equivalent.

These agents vary in their specificity, and at least

some are capable of inhibiting other serine prote-

ases. Additionally, the theoretical observation that

some of these drugs, particularly the tripeptide deri-

vatives, may interfere with fibrinolysis is of un-

known significance.

Hirudin derivatives

Hirudin, a 65–amino acid polypeptide derived

from salivary extracts of the medicinal leech (Hirudo

medicinalis), is the prototype direct thrombin inhibi-

tor. Various recombinant derivatives of hirudin have

been developed. Lepirudin is a recombinant deriva-

tive of hirudin lacking a sulfated tyrosine at residue

63 and is known as a desulfatohirudin or deshirudin.

A long-acting polyethylene glycol–complexed hi-

rudin derivative (PEG-hirudin) also has been devel-

oped and evaluated in phase II trials [63]. Native

and recombinant hirudins form an essentially irre-

versible 1:1 complex with the active site and exo-

site, although the deshirudins have a 10-fold lower

affinity for thrombin [23,27]. Although most direct

thrombin inhibitors have a predictable anticoagulant

response, hirudin’s narrow therapeutic window man-

dates monitoring.

Lepirudin has a half-life of 1.3 hours, is renally

excreted, and can be monitored using the aPTT.

An initial bolus infusion of 0.4 mg/kg followed by a

continuous infusion of 0.15 mg/kg/h with subsequent

adjustments to maintain the aPTT between 1.5 and

2.5 times baseline has been recommended [22].

Because it is renally cleared, strict dosage adjustment

in renal failure is required. Lepirudin is approved for

the treatment of HIT. Clinical trials also have shown

hirudin to be at least as safe and effective as heparin

in the management of unstable angina, as an adjunct

to thrombolytic therapy, and in the prophylaxis and

treatment of VTE [27]. Concern remains, however,

that hirudin’s narrow therapeutic window may limit

its application in acute coronary syndromes, where

high doses are often required, and bleeding rates may

be higher [23,63,65].

Hirulogs

The hirulogs inhibit thrombin by binding to the

catalytic site and the anion binding exosite. Bivali-

rudin (Angiomax), currently approved for the man-

agement of acute coronary syndromes, is a 20–amino

management of the anticoagulated patient 255

acid synthetic analogue of hirudin. In contrast to

hirudin, inhibition by bivalirudin is reversed by

cleavage of the amino terminus by thrombin, freeing

the active site and leaving only the low-affinity inter-

action between the carboxyterminus and exosite 1.

Because it is a reversible inhibitor, bivalirudin may

have a wider therapeutic window than hirudin.

Bivalirudin has a half-life of 25 minutes and is elimi-

nated by renal clearance and proteolytic cleavage.

Clearance is reduced in patients with renal insuffi-

ciency. Although bivalirudin causes dose-dependent

increases in the activated clotting time, aPTT, INR,

and thrombin time, point-of-care monitoring with the

activated clotting time is the most often used. For

percutaneous coronary intervention, dose adjustment

to maintain an activated clotting time of 350 seconds

or greater has been recommended [30].

Small molecule direct thrombin inhibitors

Small molecule direct thrombin inhibitors also

have been developed. These include many tripeptide

derivatives or peptidomimetic compounds, such as

argatroban, melagatran, efegatran, inogatran, and

napsagatran. Most small molecule direct thrombin

inhibitors are characterized by a strongly basic group

interacting with the active site of thrombin, have low

oral bioavailability, have short plasma half-lives and

are hepatically metabolized. All produce predictable

anticoagulation measurable by common coagulation

assays with minimal drug interactions. Plasma levels

and anticoagulant response tend to be linearly related

to dose with little intraindividual variation. Because

of interactions, however, the PT/INR cannot be used

to monitor the introduction of oral vitamin K

antagonists while receiving parenteral direct thrombin

inhibitors. Similar to UFH, a coagulation rebound

phenomenon has been observed with parenteral direct

thrombin inhibitors. Compared with other direct

thrombin inhibitors used in the treatment of acute

coronary syndromes, the univalent inhibitors are

associated with a borderline increased risk of MI

and lower rates of major bleeding [63].

Of the parenteral small molecule direct thrombin

inhibitors, argatroban (Acova) is the only agent that

is currently approved by the US Food and Drug

Administration. Argatroban is an arginine derivative

that functions as a reversible, competitive inhibitor at

the catalytic site of thrombin. In contrast to heparin,

argatroban does not cause release of tissue factor

pathway inhibitor, a factor that may contribute to its

predictability and relatively low incidence of bleed-

ing. It has a half-life of 30 to 45 minutes and is

hepatically metabolized by hydroxylation and aroma-

tization of the 3-methyltetrahydroquinolone ring with

subsequent biliary excretion [22,27,66]. Hepatic

insufficiency is associated with a fourfold decrease

in the total clearance of argatroban and a twofold to

threefold increase in half-life [66,67]. In contrast to

the other available direct thrombin inhibitors, the

clearance and half-life of argatroban are independent

of renal function. The anticoagulant effect of arga-

troban is predictable with a low coefficient of

variability between healthy subjects. The response

is dose dependent, however, and requires monitoring

with either the aPTT or activated clotting time.

Ximelagatran (H 376/95) is the orally available

prodrug of melagatran, a dipeptide direct thrombin

inhibitor. The prodrug is 170 times more lipophilic

than melagatran, allowing oral administration and

absorption [68]. In contrast to other small molecule

inhibitors, ximelagatran has an oral bioavailability of

18% to 24% with minimal protein binding and low

variability in plasma levels [67,68]. Ximelagatran is

biotransformed to melagatran after oral administra-

tion and competitively and reversibly binds to the

active site of thrombin. Active melagatran is cleared

by the kidneys with a half-life of 3 hours. It can

be administered twice daily and has a predictable

pharmacokinetic effect that is not influenced by age,

gender, or weight, requiring no monitoring. The drug

has no relevant interactions with food or drugs

metabolized by cytochrome P-450.

Several clinical trials evaluating the safety and

efficacy of ximelagatran in VTE and atrial fibrillation

are currently under way or have been reported. Com-

pared with dalteparin (5000 IU once daily), the com-

bination of subcutaneous melagatran (3 mg twice

daily) started preoperatively and oral ximelagatran

(24 mg twice daily) postoperatively reduced the fre-

quency of VTE in orthopedic patients from 28.2% to

15.1%, although the frequency of excessive bleeding

was higher (5% versus 2.4%) [69]. Ximelagatran in a

dose of 24 mg twice daily also has shown efficacy

comparable to that of enoxaparin in preventing

VTE after total knee replacement [70]. In contrast,

ximelagatran at a dose of 36 mg twice daily was

significantly more effective than warfarin in reducing

the incidence of VTE and death (20.3% versus

27.6%) in patients undergoing total knee replacement

[71]. No increased bleeding was observed in patients

receiving 36 mg of ximelagatran twice daily.

Ximelagatran also has shown promise in the

extended treatment of a first episode of VTE. After

completion of a 6-month course of anticoagulation,

ximelagatran (24 mg twice daily) reduced the inci-

dence of recurrent thromboembolism from 12.6% to

2.8% at 18 months [61]. There was no increased

meissner & karmy-jones256

bleeding among patients receiving ximelagatran,

although increased transaminase levels were more

frequent (6.4% versus 1.2%) than in patients receiv-

ing placebo. Ximelagatran also has shown promise in

the prevention of stroke in patients with nonvalvular

atrial fibrillation, and clinical trials evaluating the

utility of this approach are in progress [72]. Com-

pared with aspirin alone in patients with acute

coronary syndromes, ximelagatran and aspirin for

6 months significantly reduced the incidence of

death, nonfatal MI, and severe recurrent ischemia

from 16.3% to 12.7% [73]. Such extended treatment

may provide effective secondary prophylaxis and

protect against rebound events after UFH or LMWH

is discontinued. The incidence of major bleeding did

not differ between groups, although elevated trans-

aminase levels were more common among patients

receiving ximelagatran. Transaminase elevation seems

to be dose related, to occur within 2 to 6 months of

treatment, and to be asymptomatic. Other phase II

trials have noted a 4.3% incidence of self-limited

transaminase elevation [72]. Given the limitations of

warfarin, it is anticipated that these drugs will replace

vitamin K antagonists in the long-term treatment of

atrial fibrillation and VTE.

Reversing the action of anticoagulants

Heparin and low-molecular-weight heparin

The anticoagulant effect of UFH can be reversed

by the administration of protamine, a cationic heparin

binding protein. Protamine is administered in a

neutralizing dose of 1 mg per 100 U of UFH. The

60-minute half-life of heparin must be considered in

calculating the protamine dose. Risks of protamine

administration include bradycardia and hypotension,

which can be reduced by slow administration, and

allergic reactions associated with previous exposure,

including protamine-containing insulin, vasectomy,

and fish allergies. Although protamine is effective in

reversing heparin’s anti – factor IIa activity and

reducing the aPTT, it binds less well to shorter

heparin chains and only partially neutralizes anti–

factor Xa activity. Protamine sulfate can be used in

patients with clinical bleeding while receiving

LMWH, but is less effective than with UFH. Standard

doses of protamine have been shown to reverse

acutely only 42% of the factor Xa activity and 92%

of the anti– factor IIa activity after a subcutaneous

dose of tinzaparin [74]. As a result of the subcuta-

neous depot, however, there is a gradual return of

anti– factor IIa and anti– factor Xa activities.

Warfarin

There are three approaches to correcting a supra-

therapeutic INR: discontinuation of warfarin, admin-

istration of vitamin K1, and infusion of fresh frozen

plasma (FFP) or prothrombin concentrate. All of

these approaches have disadvantages, including

slow reversal and transient warfarin resistance for

vitamin K and the risk of viral transmission for the

plasma-derived products. The appropriate approach

to an individual patient depends on the INR, the

presence of bleeding, and the need for invasive

procedures. The risk of bleeding is significantly

increased at an INR greater than 4.0 to 5.0, and in

a nonbleeding patient, the INR optimally should be

corrected below this range but not into the subthera-

peutic range. Oral vitamin K significantly reduces

the INR within 24 hours. Low-dose (0.5–2.5 mg)

intravenous vitamin K also is effective, although

higher doses (� 10 mg) are associated with temporary

warfarin resistance on reintroducing oral anticoagu-

lants [75]. Although occasionally associated with

anaphylaxis, intravenous administration of small

doses (0.5 mg) of vitamin K1 to excessively anti-

coagulated patients reduces the INR to less than

5.5 within 24 hours without causing excessive delay

when reinstituting anticoagulation [76].

Current recommendations include lowering or

omitting a dose in patients with an INR less than

5.0 and no bleeding. For nonbleeding patients with

an INR greater than 5.0 but less than 9.0, with-

holding one or two doses with or without adminis-

tering 1 to 2.5 mg of oral vitamin K is acceptable.

For patients with an INR greater than 9.0, 3 to 5 mg

of oral vitamin K1 reduces the INR within 24 to

48 hours. For patients with serious bleeding, FFP or

prothrombin concentrate should be administered in

conjunction with 10 mg of vitamin K1 by slow

intravenous infusion.

Management of a patient undergoing surgery or

other invasive procedure requires special attention.

The anticoagulant effects of warfarin require sev-

eral days to recede after the drug is stopped and

several days to become therapeutic after restarting

the drug. Most patients require about 4 days to

reach an INR less than 1.5 after warfarin is stopped.

For patients at low risk for bleeding, reducing

the INR to 1.3 to 1.5 before invasive procedures is

acceptable. Postoperative intravenous heparin ther-

apy has been estimated to cause major bleeding in

3% of patients; approximately 3% of these epi-

sodes are fatal or disabling [77]. It is currently

recommended that the management of antico-

agulated patients undergoing invasive procedures

management of the anticoagulated patient 257

be guided by the underlying risks of thrombosis

and bleeding.

For VTE, preoperative therapeutic UFH or LMWH

is warranted when the INR is less than 2.0 in patients

with an event within 1 month of surgery, whereas

postoperative therapeutic anticoagulation is appro-

priate for patients with an event within the preceding

3 months. For arterial thromboembolism, preopera-

tive therapeutic anticoagulation with UFH or LMWH

is recommended only for patients undergoing surgery

within 1 month of an event. Postoperative heparin

anticoagulation should be considered in such patients

only if the risk of bleeding is low. Bridging therapy

has not been recommended for patients with me-

chanical heart valves or nonvalvular atrial fibrillation

without a history of arterial embolism. For patients

with a low risk of thrombosis, such as patients with a

remote (>3 months) history of DVT or atrial fibril-

lation without stroke, warfarin can be discontinued

preoperatively, the procedure performed with ap-

propriate postoperative prophylaxis when the INR

has returned to normal, and warfarin restarted.

For intermediate-risk patients, warfarin should be

discontinued approximately 4 days preoperatively,

the procedure performed when the INR normalizes,

and the patient covered perioperatively beginning

2 days before surgery with low-dose UFH or LMWH.

For patients with a high risk of thrombosis, such

as patients with recent DVT, prosthetic mitral valves,

or older mechanical valves, warfarin should be

discontinued approximately 4 days preoperatively

and the patient bridged with full-dose UFH or

LMWH as the INR falls below the therapeutic range

approximately 2 days preoperatively. The risk of

thromboembolism exceeds that of bleeding in pa-

tients undergoing dental procedures, and warfarin

need not be discontinued in patients at low risk

for bleeding.

Table 2

Typical laboratory patterns of coagulopathy

Platelets Bleeding time aP

Warfarin N N N

Heparin N N "Thrombocytopenia # N–" N

vWD N " N

Liver failure N Variable "Hemophilia N N "Fibrinolysis N N "Abbreviations: aPTT, activated partial thromboplastin time; FDP, fib

N, normal; TT, thrombin time; vWD, von Willebrand disease.

Newer anticoagulants

No effective reversal agents exist for many of

the newer anticoagulants. There is no specific

antidote for the pentasaccharide derivative factor Xa

inhibitors, although limited data suggest that recom-

binant factor VIIa normalizes the thrombin generation

time in healthy volunteers [53]. Protamine does not

reverse the effects of the direct thrombin inhibitors.

Potential thrombin inhibitor antagonists, including

desmopressin, factor VIIa, factor VIII, and activated

prothrombin complex (Feiba), have been suggested

[48]. Most of the direct thrombin inhibitors have a

half-life of only 30 to 45 minutes in normal indi-

viduals. Although lepirudin should not be used in

patients with renal insufficiency, accidental over-

dosage in these patients can be managed with dialysis

using a polymethylmethylacrylate membrane [27].

Bivalirudin is also approximately 25% cleared by

hemodialysis [30].

Assessment of bleeding potential

One single test rarely can truly assess the risk

of bleeding or define the etiology of a coagulopathy.

A comprehensive approach, combining clinical sce-

nario and laboratory tests, is required and can be com-

plex and confusing (Table 2). Owings and Gosselin

[78] provided a comprehensive review of this topic.

The approach varies depending on whether in the

preoperative or postoperative phase and whether or

not there is active bleeding.

Clinical assessment

The primary assessment should begin with

the history and physical examination. Simple ques-

TT INR TT Fibrinogen FDP

–" " N N 0

N–" " N 0

N N N 0

N N N 0

" N–" " 0

N N N 0

" " N–# "rin degradation product; INR, international normalized ratio;

meissner & karmy-jones258

tions about bleeding history, such as easy bruising,

frequent nosebleeds, family history of bleeding

disorders, and medications, may direct a specific

evaluation. Physical assessment includes observing

bruising, telangiectasias, conjunctival hemorrhages,

or purpura. Attention to temperature is important,

particularly in the ICU or trauma setting. Patients

with body temperatures 35�C or lower should be

actively rewarmed. In some settings, such as major

trauma, operative intervention may have to be

stopped to allow time for resuscitation and rewarm-

ing, correcting diffuse bleeding. Hypothermic co-

agulopathy may not be associated with abnormal

aPTT or INR because these tests usually are per-

formed at 37�C, correcting the inhibition of coagu-

lation. Hemodilution can occur if greater than 10 U

of packed red blood cells are given in a short time

without plasma replacement.

Laboratory assessment

Normal activated partial thromboplastin time and

normal international normalized ratio

Patients who exhibit persistent bleeding despite

having normal aPTT and INR often have disordered

platelet activity, owing to either low numbers or

function. A platelet disorder may be suspected by a

prolonged bleeding time, reduced platelet count, or

tests of platelet function. Patients who are to undergo

major surgery require at least a platelet count greater

than 20,000/mm3 [78]. In general, the authors prefer

to maintain counts greater than 50,000/mm3 before

lung resection thoracotomy for at least 48 hours or

until chest drains are discontinued. This preference is

not based on any solid evidence, however, and varies

significantly from case to base, depending on the

sense of the risk of bleeding. Decreased platelet count

can be secondary to immune disorders (eg, HIT,

thrombocytopenia purpuras, antibiotic reactions) or

acquired conditions (eg, disseminated intravascular

coagulopathy [DIC], dilutional coagulopathy, myelo-

dysplastic syndromes). Clinically significant bleeding

can occur when platelet counts decrease to less than

10,000/mm3, and patients in whom even minor

bleeding would be catastrophic (eg, following neuro-

surgical procedures) should have platelet counts

maintained at greater than 20,000/mm3. Other tests

of platelet number or function are available. The

bleeding time is considered inaccurate because nor-

mal results are seen in half of patients with congenital

thrombocytopenia [79]. Other rapid tests, such as the

Sonoclot or Thromboelastogram, are available and

can be useful in studying platelet function and

number separately.

Platelet dysfunction may be anticipated by a his-

tory of medication. Aspirin, as noted earlier, causes

an irreversible dysfunction that lasts the lifetime of

the platelet, or approximately 10 days. Patients who

are to undergo elective surgery should stop aspirin at

least 7 days before surgery; patients requiring urgent

operation, depending on the complexity of the

procedure, can be treated by platelet transfusion.

Acquired disorders include renal failure, which can

be managed by desmopressin. Hereditary conditions,

of which von Willebrand disease is the most

common, also should be considered. von Willebrand

disease has three forms: type I (reduced concen-

tration), type II (dysfunctional), and type III (absent).

Desmopressin also can be used, although in some

forms (type IIb) it is contraindicated. Cryoprecipitate

can be helpful. Deficits in von Willebrand factor

function also are seen in patients with renal failure.

Preoperatively, in elective surgery patients, manage-

ment can include dialysis (to reduce the level of

uremia) and an infusion of 0.3 to 0.4 mg/kg of

desmopressin 1 hour before surgery. Desmopressin

has a half-life of 55 minutes and can be repeated

every 12 hours, although after two doses resistance

can be seen in some cases [80]. Probably the most

common scenario in which platelet dysfunction is

encountered in thoracic surgery is after cardiopulmo-

nary bypass. Minimizing pump suction, the return of

salvaged blood using heparin-bonded circuits seems

to be beneficial in reducing the risk of bleeding,

thrombotic complications, and inflammatory cascade–

mediated complications.

Prolonged activated partial thromboplastin time and

normal international normalized ratio

The most common cause of a prolonged aPTT is

heparin administration. Management, as discussed

earlier, can include simply withholding heparin or

administering (carefully) protamine sulfate. FFP does

not correct the effect of heparin, and because heparin

acts by potentiating AT, which is present in FFP, this

may accentuate the anticoagulation activity of hepa-

rin. In some thrombotic states, FFP is administered

with heparin specifically for this purpose. FFP, by

binding the agent, reverses the effect of direct

thrombin inhibitors. Hereditory deficiencies of factors

VIII, IX, and XI (hemophilia A, B, and C) usually

do not manifest with abnormal coagulation parame-

ters until factor activity levels decrease to less than

40%. Management includes transfusion of FFP, cryo-

precipitate, or specific factor replenishment. FFP

contains 1 U/mL of factor VIII; cryoprecipitate, 5 to

10 U/mL; and factor VIII concentrate, 25 U/mL. The

half-life is 8 to 12 hours. One recommended approach

management of the anticoagulated patient 259

has been to transfuse to levels as close to 100% as

possible immediately before operation, then maintain

levels greater than 40% until sutures and drains are

removed [81]. Recombinant factor VII (rVIIa) also

has been used for factor VIII and factor IX deficiency.

von Willebrand disease also may be associated

with prolonged aPTT and can be confirmed by

studies of platelet function or measurement of cir-

culating levels. Management has been discussed in

the previous section.

Increased international normalized ratio and normal

activated partial thromboplastin time

The two most common etiologies of increased

INR and normal aPTT are liver failure and warfarin

administration. Correction of the latter has been

discussed. In the former, FFP administration is the

mainstay of treatment, unless the disease is so far

advanced that a DIC state exists, in which case

cryoprecipitate is often required, as is desmopressin

and platelet transfusion.

Increased international normalized ratio and

increased activated partial thromboplastin time

The causes of increased INR and increased

aPTT are often multifactorial. It is important, par-

ticularly in patients without bleeding or who have no

reason to have a bleeding tendency, to ensure that the

laboratory tests were done correctly (eg, inadequate

volume of blood). Hemodilution and nephrotic syn-

drome result in a loss of coagulation factors. DIC

represents a consumption of factors, and D-dimer

levels greater than 2000 ng/mL support the diagnosis.

DIC can be mild, moderate, or severe (Table 3). At

the most advanced stage, DIC bleeding is a result

of consumption of factors and excessive fibrinolysis.

Initial management includes addressing the under-

Table 3

Phases of disseminated intravascular coagulation

Phase 1 No obvious clinical manifestations

Routine laboratory screening normal

Directed tests (eg, prothrombin fragments)

may reveal thrombin generation

Phase 2 Bleeding from wounds, IV sites

aPTT, INR", fibrinogen#, FDP +

Phase 3 Multiple organ dysfunction syndrome

Diffuse bleeding

aPTT, INR"", fibrinogen, FDP##Abbreviations: aPTT, activated partial thromboplastin time;

FDP, fibrin degradation product; INR, international normal-

ized ratio.

lying cause and correcting hypothermia. Subsequent

treatment is administration of FFP, cryoprecipitate,

calcium, and platelets, until bleeding stops, and

aPTT and INR normalize [78]. If fibrinogen is less

than 100 mg/dL, cryoprecipitate is probably the

more effective vehicle for replenishment. Alternative

approaches have attempted to use heparin to inhibit

clotting, allowing restoration of clotting factors, or

antifribrinolytics, such as aminocaproic acid. In

trauma patients, with uncontrollable nonsurgical

bleeding, with or without hypothermia, rVIIa has

been studied with some success [82].

Hypercoagulable states and venous

thromboembolism

The bulk of this article has addressed issues

relating primarily to hypocoagulable states. Hyper-

coagulability states are important to recognize, if only

because of the risk of VTE and graft occlusion. In

addition, the inflammatory response to surgery may

increase the risk of thrombosis. Acquired conditions

that predispose to VTE in particular are trauma,

cancer, and immobility. Other acquired conditions

include diverse syndromes, such as the previously

discussed HIT and lupus anticoagulant. Congenital

deficiencies in coagulation include AT III, plas-

minogen, proteins C and S, and overall such defects

may be present in 20% of cases of recurrent VTE

[80]. Acute VTE associated in the setting of con-

genital protein C or protein S deficiency should be

treated with heparin. Long-term therapy can be based

on warfarin, with the aforementioned caution re-

garding slow institution of therapy in patients with

protein C deficiency.

Summary

Excessive bleeding or thrombosis is a preeminent

concern for all surgeons. Patients may be at risk

because of medical therapy, underlying disease, or

complications related to both. An understanding of

the coagulation cascade—mechanisms and tests of

function—permits a rational, if not always complete,

basis for a plan of therapy. Newer anticoagulation

medications are changing how thrombotic complica-

tions, such a VTE or graft occlusion, are treated or

prevented. This entire area is undergoing rapid

evolution, and the approaches that have been standard

for decades soon will be supplanted. Ultimately,

however, the most important assessment is made at

the bedside by the clinician.

meissner & karmy-jones260

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Thorac Surg Clin

Preoperative Cardiac Evaluation: Mechanisms, Assessment,

and Reduction of Risk

Euan A. Ashley, MRCP, DPhil*, Randall H. Vagelos, MD*

Division of Cardiology, Stanford University School of Medicine, Falk CVRB, 300 Pasteur Drive, Stanford, CA 94305, USA

In the management of cardiovascular and pulmo-

nary disease, the paths of cardiologists and thoracic

surgeons inevitably cross. Interdependence of blood

oxygenation and tissue perfusion means that rarely

does a disease of one system exist in isolation. Al-

though widely acknowledged, however, considerable

uncertainty exists as to when it is appropriate to in-

vestigate cardiac disease in a preoperative thoracic

patient and which tools are best suited to the task.

Common disease origins, commonality of symptoms,

and coexistent disease all serve to make accurate

diagnosis and effective risk prediction difficult. In

addition, interventions known to reduce risk and

save lives are few. This article explores the basis for

anesthetic risk in cardiovascular and pulmonary

disease. Common disease mechanisms and the utility

of tools available to assess risk are discussed. Risk

reduction also is discussed, and recommendations

specific to the preoperative cardiac evaluation of the

thoracic surgery patient are offered.

Procedures

In the United States, and for the purposes of

this article, thoracic surgery is distinguished from

cardiac surgery by the exclusion of procedures in-

volving the heart and proximal vascular tree, includ-

ing the coronary arteries and thoracic aorta, but

excluding the pericardium. The most common pro-

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.004

* Corresponding authors.

E-mail addresses: euan@stanford.edu (E.A. Ashley),

rvagelos@cvmed.stanford.edu (R.H. Vagelos).

cedure in the database of the Society for Thoracic

Surgeons is wedge resection, representing 16% of all

submitted procedures (Table 1) [1]. During the data

collection period, lobectomy constituted 14.5% of

procedures, and esophagectomy constituted 4.5%;

pleurodesis and decortication constituted 5% of pro-

cedures. Endoscopic procedures made up 13%, of

which mediastinoscopy accounted for 7.4%, flexible

bronchoscopy accounted for 4.5%, and esophagos-

copy accounted for 1.2%. The 30-day mortality of

the patients in this database was around 5%, a figure

that emphasizes the high risk of thoracic surgery and

the comorbidity of the patients.

Noncardiac surgery and the cardiovascular

system

To understand fully the value of preoperative car-

diac evaluation, it is helpful to define what exactly it

is about surgery that increases the risk of cardiac

morbidity (Box 1).

Effects of surgery on the cardiovascular system

Although anesthesiologists have many tools at

their disposal with which to control pain, a degree of

nociception and associated autonomic reflex is inevi-

table in response to surgical ‘‘injury.’’ Pain fibers

relay in the brainstem, where reflex sympathetic out-

flow results in augmentation of circulating catechol-

amines and the classic ‘‘fight-or-flight’’ response:

tachycardia, hypertension, cardiac inotropy, vasodila-

tion of skin and skeletal muscle, and vasoconstriction

of intestinal arterioles. These stressors are com-

15 (2005) 263 – 275

reserved.

thoracic.theclinics.com

Table 1

Thoracic surgery procedures*

Procedure %

Lobectomy 14.5

Wedge resection, single 9.5

Mediastinoscopy 7.4

Wedge resection, multiple 6.5

Esophagectomy 4.8

Pleurodesis 2.7

Decortication 2.3

Segmentectomy 1.9

Tracheostomy 1.8

Mediastinal mass resection 1.7

Pericardial window 1.6

Chest wall repair 1.5

Chest wall resection 1.5

Open pleural drainage 1.4

Thymectomy 1.1

* Thoracic surgery procedures submitted to the General

Thoracic Surgery Database; January 2002–June 2003. The

Society of Thoracic Surgeons, 6633 North Saint Clair Street,

Suite 2320, Chicago, IL, USA 60611–3658.

Box 1. Sources of cardiac risk

Nociception and stress increaseendogenous sympathetic nervoussystem activity.

Death of cells leads to release ofintracellular contents—increasedserum potassium and circulatingprotein load.

Death of cells leads to increases incirculating inflammatory mediators.

Anesthetic induction can be associatedwith vasodilation and negativeinotropy.

Succinylcholine can increase serumpotassium.

Narcotic agents inhibit sympatheticreflexes in patients dependent onsympathetic tone.

Volatile agents are cardiodepressantand vasodilatory.

Volatile agents cause coronary dilation,which may lead to coronary steal.

Some volatile agents (halothane)sensitize the myocardium tocatecholamines.

Some volatile agents (desflurane) in-crease myocardial oxygen demand.

ashley & vagelos264

pounded further by blood loss, fluid shift, and meta-

bolic compromise. The ‘‘surgical’’ death of cells

leads to release of intracellular contents and increases

in the plasma levels of intracellular proteins and ions

with a negative transmembrane gradient (eg, potas-

sium). Easily tolerated by a healthy heart, these

metabolic and energetic derangements challenge the

diseased heart and may precipitate ischemia or

decompensated function.

Although sympathetic outflow can be largely

controlled during the procedure, patients with pre-

existing heart failure, who are dependent on sym-

pathetic tone, represent an important exception.

Reducing endogenous sympathetic drive in a popu-

lation with chronic remodeling of the adrenergic

system could lead to decompensation for lack of

circulating catecholamines.

Cardiac effects of general anesthesia

In addition to effects specific to the surgery it-

self, additional cardiovascular challenge is associated

with general anesthesia. Most agents are negative ino-

tropes and vasodilators.

Induction agents

Agents for anesthetic induction, such as propofol,

decrease arterial pressure mainly through vasodila-

tion, whereas barbiturates, such as thiopental, are

negatively inotropic [2]. In contrast, etomidate and

ketamine are minimally cardiodepressant, and the

latter can increase heart rate and blood pressure

through activation of the sympathetic nervous sys-

tem [3].

Neuromuscular blockade

Newer neuromuscular blocking drugs generally

have few cardiovascular side effects. Succinylcho-

line, commonly used because of its rapid onset, can

produce unpredictable changes in heart rate and

increases serum potassium concentration by approx-

imately 0.5 mEq/L. Pancuronium increases blood

pressure and heart rate by blocking muscarinic ace-

tylcholine receptors in the sinoatrial node, increases

sympathetic activity via antimuscarinic actions, and

inhibits reuptake of catecholamines.

Narcotic-based anesthetics

Narcotic-based anesthetics have little direct effect

on myocardial contractility or vasomotor tone, but

attenuate sympathetically mediated cardiovascular

reflexes in response to pain. Although this feature

makes them highly attractive agents for anesthesia in

cardiac patients, narcotic-based anesthetics are less

suitable for patients chronically dependent on en-

preoperative cardiac evaluation 265

dogenous sympathetic tone, in whom the withdrawal

of these reflexes may cause profound hemodynamic

change. In addition, synthetic narcotics are po-

tently vagotonic.

Volatile anesthetics

Volatile anesthetics, such as isoflurane, are used

for maintenance of general anesthesia and produce

varying degrees of vasodilation and negative ino-

tropy, a result of sympathetic nervous system in-

hibition. The negative inotropy includes impaired

diastolic relaxation, which may cause increased end-

diastolic pressures. One volatile agent, desflurane,

has a biphasic effect on sympathetic tone, increasing

activity at lower doses and inhibiting activity at

higher doses [4]. In relation to the coronary circu-

lation, effects of volatile agents are varied. Some

vasodilate coronary arteries, contributing, at least in

theory, to coronary ‘‘steal’’ (vasodilation in the pres-

ence of hemodynamically significant stenoses causes

ischemia by decreasing the coronary perfusion pres-

sure through the distal collateral network). Some

agents, such as halothane, sensitize the myocardium

to catecholamine-induced dysrhythmias, an effect

compounded by hypercapnia.

Manifestations

The combined effects of surgery and anesthesia

are complex, but relate mostly to a balance between

sympathetic nervous system activity (positive ino-

tropy, net increase in vascular resistance) and the

abrogation of these effects directly or indirectly by

anesthesia. These phenomena increase risk in three

ways. First, the negative inotropy of anesthesia may

contribute to decompensated ventricular function and

pulmonary edema, which increases sympathetic

drive. Second, increasing the workload of the heart

may induce ischemia through stable obstructive

coronary disease (low flow but no acute syndrome,

analogous to stable angina). This ischemia amplifies

the risk of arrhythmia already provided by increased

circulating catecholamines and the increased sensi-

tivity to them caused by some anesthetics. Third,

surgery is associated with unstable coronary syn-

dromes and myocardial infarction (MI), most of

which occur in the postoperative, rather than intra-

operative, period.

Non–Q wave, troponin-positive MI and ST

elevation MI occur early in the postoperative period

(8–24 hours) [5–8]. In one study of 185 patients

undergoing major vascular surgery, non–ST eleva-

tion infarction followed periods of prolonged silent

ischemia (50% of perioperative MIs were silent in

another study [8]). This silent ischemia was preceded

by periods of modest tachycardia (typically 90–

100 beats/min) providing a potential early warning

sign and, possibly, a mechanism [7,9]. The presence

of a spectrum of acute syndromes was confirmed

in a postmortem study, in which postoperative MIs

clustered into two groups: patients with no plaque

rupture who tended to present early in days 1 to 3 and

patients with plaque rupture who presented in an even

distribution from days 1 to 12 [10]. Some authors

have suggested different mechanisms are implied in

these two groups [5], although the evidence for this

implication is sparse.

The pathophysiologic basis of postoperative acute

coronary syndromes is not clear. One hypothesis is

that prolonged intraoperative sympathetic overactiva-

tion with hypercontractility and increased blood pres-

sure causes greater intracoronary mechanical forces,

which makes coronary plaques more likely to rupture

(‘‘mechanical’’ hypothesis). Another is that circulat-

ing inflammatory factors released in response to inci-

sion and cautery ‘‘sensitize’’ plaques from the

intraluminal side (‘‘inflammatory’’ hypothesis). Sup-

port for the latter hypothesis comes from the growing

consensus that acute coronary syndromes reflect

activation of at least one branch of, and perhaps the

whole, coronary tree [11,12]. In addition, because

most ischemia is silent and occurs 8 to 24 hours after

the procedure, either the effect takes some time to

build (consistent with the inflammatory hypothesis),

or there is another effect relating to anesthetic re-

covery, for which the most likely candidate is un-

controlled pain causing sympathetic activation and

increased blood pressure (consistent with the

mechanical hypothesis). The reality almost certainly

lies in between with contributions from both of these

mechanisms. There is increasing interest in measur-

ing (and abrogating) inflammatory mediators in

cardiovascular disease generally, although this has

not met with universal success [13].

Risk of cardiac disease in the pulmonary patient

It has been known for some time that chronic

obstructive pulmonary disease (COPD) is an impor-

tant risk marker for atherosclerosis. Even modest

reductions in forced expiratory volume in 1 second

(FEV1) result in large increases in hazard ratios for

ischemic heart disease independent of age, cigarette

smoking, diastolic blood pressure, cholesterol con-

centration, body mass index, and social class [14].

These authors found that FEV1 was equivalent to

cholesterol in predicting ischemic risk. In another

ashley & vagelos266

study [15], severe airflow obstruction almost doubled

the chances of ECG evidence of MI. Although classic

mechanisms of pulmonary hypertension and right

ventricular failure (cor pulmonale) provide a link with

severe pulmonary disease, a relationship with earlier

stage COPD has been less explored. Such early

disease can affect the heart, however, at least in the

form of right axis deviation on the 12-lead ECG [16].

In relation to pathogenesis, Sin and Man [15]

suggested that low-level inflammation originating in

the airways can become systemic and trigger parallel

inflammatory changes in coronary arteries. These

authors showed that patients with highly elevated

C-reactive protein and moderate or severe airflow

obstruction had an infarction injury score higher than

groups without airflow obstruction or groups with

low C-reactive protein, suggesting an additive effect

of these factors on the severity of cardiac injury

after MI. A link with systemic inflammation also is

supported by studies discussing the importance of

systemic inflammation in the prediction [17] and

pathogenesis [18] of heart disease and human [19]

and animal studies [20] showing that particulate air

pollution contributes to the progression of athero-

sclerosis and vulnerability of plaques to rupture.

A second link between pulmonary and cardiovas-

cular disease is provided by the use of inhaled

b-agonist drugs, such as albuterol. In one case-controlstudy [21], compared with subjects who did not fill a

b-agonist prescription, subjects who had filled one

b-agonist prescription in the 3 months before their

index date had an elevated estimated risk of MI,

suggesting a direct effect of inhaled b-agonists on the

processes of plaque erosion and rupture. There was no

dose-response relationship between b-agonist use andrisk. Not all investigators have found such a connec-

tion, however. Ferguson et al [22] performed a pooled

analysis of cardiovascular safety data from salmeterol

use and found no increased risk of cardiovascular

adverse events compared with placebo. There were no

clinically significant differences in heart rate, ectopy,

or 24-hour ECG monitoring between the salmeterol

group and the placebo group [22].

Regardless of the effect of inhaled b-agonists,there is evidence of abnormal endogenous sympa-

thetic tone in COPD patients. Volterrani et al [23]

studied heart rate variability in patients with COPD

and age-matched controls at rest and during vagal and

sympathetic maneuvers. Patients with COPD showed

a depressed global heart rate variability and in par-

ticular a depressed heart rate variability response to

sympathetic and vagal stimuli. More recently, Heindl

et al [24] found that microneurography of the pero-

neal nerve, a surrogate for sympathetic system acti-

vation, was higher in COPD patients with hypoxemia

compared with healthy subjects. On administration

of oxygen, activation decreased only in the COPD

patients, providing direct evidence of baseline sym-

pathetic activation in patients with chronic respiratory

failure. Other authors have found similar results [25].

Assessment of perioperative risk

Surgical risk comprises a combination of factors

relating to the procedure and the patient. The

American Heart Association rates thoracic surgery

as intermediate risk, defined as an estimated risk rate

of less than 5% (consistent with an estimated overall

mortality of approximately 5% [1]). Data relating

specifically to the cardiovascular risk of thoracic sur-

gery are limited, however; most investigators assess-

ing cardiac risk in noncardiac surgery have studied

patients undergoing major vascular surgery.

Risk relating to the surgical patient has been

studied by many investigators and considered by

consensus panels [26]. One problem, already men-

tioned earlier, is that there is currently no test, im-

aging or otherwise, which adequately identifies

‘‘rupture-prone’’ plaques or individuals. It is chal-

lenging to attempt to predict which patients are likely

to have an acute coronary syndrome and which are

likely to have only ischemia with stable obstruction.

Traditional two-dimensional coronary catheterization

is an excellent technique to measure luminal diame-

ter, but vascular remodeling means that encroachment

is a late phenomenon, and studies have shown that

luminal diameter bears little relation [27] (or perhaps

even an inverse relation [28,29]) to likelihood of

plaque rupture. Although some authors have hypothe-

sized that patients might fall into a rupture-prone and

a rupture-resistant group, direct evidence for this is

currently lacking.

Despite this uncertainty and the emerging para-

digm shift, the approach to predicting risk is clear:

measure relevant factors to the best of current ability,

document outcome, and enter the results into a multi-

variate risk prediction model. The issue of workup

bias always is confounding (patients who are judged

by current local criteria to have increased risk have

some intervention, altering that risk); however, the

analysis is still informative.

Guidelines

There have been at least 10 multivariate models

published analyzing risk in noncardiac surgery.

STEP 1 Need fornoncardiac surgery

Coronary revascularizationwithin 5 yr?

Operatingroom

Recurrentsymptomsor signs?

Recent coronary angiogramor stress test?

Intermediate clinicalpredictors†

Intermediate clinical predictors† Intermediate Clinical Predictors†

Major Clinical Predictors**

Minor Clinical Predictors ‡

Minor or noclinical predictors ‡

Minor or no clinical predictors ‡

Operatingroom

Operatingroom

Operatingroom

Postoperative riskstratification and risk

factor reduction

Postoperative riskstratification and risk

factor reduction

Postoperative riskstratification and

risk factor management

Go tostep 6

Go tostep 7

Unstable coronarysyndromes

Decompensated CHF

SignificantarrhythmiasSevere valvulardisease

Renal insufficiency

Diabetes mellitus

Prior MIMild angina pectoris

Compensated orprior CHF

Consider coronaryangiography

Subsequent caredictated by findings and

treatment results

Subsequent care*dictated by findings and treatment results

Subsequent care*dictated by findings and treatment results

Consider delayor cancel noncardiac

surgery

Medical managementand risk factormodification

Clinical predictors

Major clinical predictors**

Clinical predictors

Functional capacity

Surgical risk

Noninvasive testing

Invasive testing

Clinical predictors

Functional capacity

Surgical risk

Noninvasive testing

Invasive testing

Recent coronaryevaluation

Low risk

Low risk

High risk

High risk

Emergencysurgery

Favorable result andno change in

symptoms

STEP 2

STEP 3

STEP 4

STEP 6

STEP 8

STEP 8

STEP 7

Yes

Yes

•

•

•

•

••

•

•

•

Abnormal ECGAdvanced age•

•

History of stroke•

Low functionalcapacity

Rhythm otherthan sinus

•

•

Uncontrolled systemichypertension

•

Poor

(<4 METs)

Poor

(<4 METs)

Moderateor

excellent(<4 METs)

Moderateor

excellent(>4 METs)

Lowsurgical riskprocedure

Highsurgical riskprocedure

High surgical risk

procedure

Considercoronary

angiography

Considercoronary

angiography

Noninvasivetesting

Noninvasivetesting

Intermediatesurgical riskprocedure

Intermediateor low

surgical riskprocedure

Yes

No

No

No

Urgent or electivesurgery

Unfavorable result orchange in symptoms

STEP 5

Fig. 1. The American Heart Association/American College of Cardiology algorithm for preoperative screening. CHF, congestive

heart failure; MI, myocardial infarction. (From Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for

perioperative cardiovascular evaluation for noncardiac surgery—executive summary: a report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on

Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002;105:1257–67; with permission.)

preoperative cardiac evaluation 267

Box 2. Clinical predictors of increasedperioperative cardiovascular risk

Major

Unstable coronary syndromes

Acute or recent MI* with evidence ofimportant ischemic risk by clinicalsymptoms or noninvasive study

Unstable or severe angina (Canadianclass III or IV)y

Decompensated heart failureSignificant arrhythmias

High-grade atrioventricular block

Symptomatic ventricular arrhythmiasin the presence of underlying heartdisease

Supraventricular arrhythmias with un-controlled ventricular rate

Severe valvular disease

Intermediate

Mild angina pectoris (Canadian class Ior II)z

Previous MI by history or pathologicQ waves

Compensated or prior heart failureDiabetes mellitus (particularly insulin-

dependent)Renal insufficiency

Minor

Advanced ageAbnormal ECG (left ventricular hyper-

trophy, left bundle-branch block,ST-T abnormalities)

Rhythm other than sinus (e.g., atrialfibrillation)

Low functional capacity (e.g., inabilityto climb one flight of stairs with abag of groceries)

History of strokeUncontrolled systemic hypertension

* The American College of CardiologyNational Database Library defines recentMI as >7 days but �1 month (30 days);acute MI is within 7 days.

y May include stable angina in patientswho are unusually sedentary.

z Campeau L. Grading of angina pecto-ris. Circulation 1976;54:522–3.From Eagle KA, Berger PB, Calkins H, et al.ACC/AHA guideline update for periopera-tive cardiovascular evaluation for noncar-diac surgery—executive summary: a reportof the American College of Cardiology/American Heart Association Task Force onPractice Guidelines (Committee to Updatethe 1996 Guidelines on Perioperative Car-diovascular Evaluation for Noncardiac Sur-gery). Circulation 2002;105:1257–67;with permission.

ashley & vagelos268

Goldman’s cardiac risk index was first proposed in

1977 and was used extensively [30]. Underestimation

of risk in abdominal aortic procedures [31] led to

modifications of this index [32] and the use of imag-

ing to add to the risk profile [33]. The publication of

several other systems [34,35] led to the formation of a

consensus panel of the American Heart Association

and the American College of Cardiology in 1996.

This committee collated the evidence into a set of

guidelines [36], which are reviewed annually and

which were updated more recently [26].

The consensus panel offered a stepwise algo-

rithm for the management of preoperative cardiac risk

(Fig. 1). It begins with the assessment of prior

coronary evaluations and incorporates clinical pre-

dictors derived from multivariate analyses, estimated

functional capacity, and surgery-specific risk (Boxes 2

and 3). One author suggested a simplified score based

on these guidelines, which may be more readily

recalled (Tables 2,3).

The key question that the guidelines attempt to

address is whether further invasive or noninvasive

testing would be helpful in assessing preoperative

risk. As with nonsurgical cardiac patients, pretest

probability derived from clinical predictors accounts

for most of the risk. Further testing generally adds

little except in the intermediate probability patients.

In addition, common cardiovascular tests, such as the

12-lead ECG or echocardiographic estimation of

resting left ventricular function, offer little beyond

preprobability [37]. In contrast, during exercise or

pharmacologic stress, echocardiography allows ear-

lier detection of ischemia and localization of the

ischemic region not afforded by ECG ST depression

alone. Thallium scintigraphy also offers localization.

Although it could be argued that pharmacologic stress

Table 2

Abbreviated algorithm for assessment of cardiac risk*

Clinical predictors Functional capacity Surgical risk

Major 4 Poor 2 High 2

Intermediate 2 Moderate or 0 Intermediate 1

preoperative cardiac evaluation 269

with a sympathetic agonist, such as dobutamine,

might better mimic the actual stress of surgery, func-

tional capacity has been shown repeatedly to be a

potent predictor of risk in perioperative and general

populations [38–41].

Box 3. Surgery-specific risk* fornoncardiac surgical procedures

High (reported cardiac risk often >5%)

Emergent major operations,particularly in the elderly

Aortic and other major vascular surgeryPeripheral vascular surgeryAnticipated prolonged surgical

procedures associated with largefluid shifts or blood loss or both

Intermediate (reported cardiac riskgenerally <5%)

Carotid endarterectomyHead and neck surgeryIntraperitoneal and intrathoracic surgeryOrthopedic surgeryProstate surgery

Low (reported cardiac risk generally<1%)y

Endoscopic proceduresSuperficial proceduresCataract surgeryBreast surgery

* Combined incidence of cardiac deathand nonfatal MI.

y Do not generally require further pre-operative cardiac testing.From Eagle KA, Berger PB, Calkins H, et al.ACC/AHA guideline update for periopera-tive cardiovascular evaluation for noncar-diac surgery—executive summary: a reportof the American College of Cardiology/American Heart Association Task Force onPractice Guidelines (Committee to Updatethe 1996 Guidelines on Perioperative Car-diovascular Evaluation for Noncardiac Sur-gery). Circulation 2002;105:1257–67;with permission.

better

Minor 0 Low 0

* Each patient gets a point score from each of the three

columns. The total score for the three columns is added. A

point score of �4 suggests the need for further cardiac

evaluation. A patient with �3 points could proceed safely to

the operating room.

From Stinson DK. An abbreviation of the ACC/AHA algo-

rithm for perioperative cardiovascular evaluation for noncar-

diac surgery. Anesth Analg 2003;97:295–6; with permission.

These observations were confirmed by Kertai

et al [42], who performed a meta-analysis of the

prognostic accuracy of different diagnostic tests for

predicting perioperative cardiac risk. They compared

ambulatory ECG, exercise ECG, radionuclide ven-

triculography, myocardial perfusion scintigraphy,

dobutamine stress echocardiography, and dipyrida-

mole stress echocardiography and found that dobuta-

mine stress echocardiography had the optimal

combination of sensitivity (85%) and specificity

(70%) for predicting postprocedure events. In the

statistical model, significant differences were found,

however, only between dobutamine stress echocar-

diography and perfusion scintigraphy (odds ratio 5.5).

Assessing risk in thoracic surgery populations

Although none of the major risk prediction studies

were performed in a thoracic surgery population,

several issues specific to this population warrant

discussion. Although echocardiography offers advan-

tages over ECG in the detection of ischemia and

the assessment of valvular and ventricular function,

chronic lung disease can make quality images dif-

ficult to acquire. One solution is dobutamine stress

MR imaging [43]. Dobutamine stress MR imaging

has not been studied in a perioperative population,

but MR imaging has advantages in accuracy and

reliability over echocardiography [44] and is particu-

larly advantageous in patients with suboptimal

echocardiographic image quality (Fig. 2) [45].

Exercise intolerance is nonspecific, and in patients

with chronic lung disease, it can be unclear whether

reduced functional capacity relates to a modifiable

cardiovascular cause or a less modifiable pulmonary

cause. To approach this problem, there has been

Table 3

Noninvasive tools for evaluation of cardiac risk*

Type of test

No.

studies

No.

patients

Mean

age (y)

Proportion

of men (%)

History of

CAD (%)

Proportion

of DM (%)

Sensitivity

(%; 95% CI)

Specificity

(%; 95% CI)

Radionuclide

ventriculography

8 532 67.0 83 45 25 50 (32–69) 91 (87–96)

Ambulatory ECG 8 893 68.0 72 55 32 52 (21–84) 70 (57–83)

Exercise ECG 7 685 64.5 72 36 28 74 (60–88) 69 (60–78)

Dipyridamole stress

echocardiography

4 850 66.8 78 28 33 74 (53–94) 86 (80–93)

Myocardial perfusion

scintigraphy

23 3119 65.5 78 40 30 83 (77–89) 49 (41–57)

Dobutamine stress

echocardiography

8 1877 67.3 76 37 16 85 (74–97) 70 (62–79)

Abbreviations: CAD, coronary artery disease; CI, confidence interval; DM, diabetes mellitus.

* Tests are sorted according to ascending sensitivities.

From Kertai MD, Boersma E, Bax JJ, et al. A meta-analysis comparing the prognostic accuracy of six diagnostic tests for

predicting perioperative cardiac risk in patients undergoing major vascular surgery. Heart 2003;89:1327–34; with permission.

ashley & vagelos270

interest in using exercise testing with gas analysis

[46–48]. Wasserman [49] first defined an index to

help distinguish pulmonary and cardiovascular dis-

ease: the breathing reserve index. This index is the

ratio of maximal minute ventilation during exercise to

maximal voluntary ventilation at rest. Although most

healthy subjects achieve a maximal ventilation of

only 60% to 70% of maximal voluntary ventilation at

peak exercise, maximal ventilation in patients with

COPD approaches or equals the maximal voluntary

ventilation. These patients reach a ventilatory limit

during exercise, whereas normal subjects and patients

with cardiovascular disease generally have a sub-

stantial ventilatory reserve (20–40%) at peak exer-

cise. Medoff et al [46] extended this concept to

Fig. 2. Sensitivity and specificity of dobutamine echocar-

diography and MR imaging divided according to image

quality. Dobutamine MR imaging may be particularly useful

in thoracic surgery patients with chronic lung disease. (From

Pujadas S, Reddy GP, Weber O, et al. MR imaging

assessment of cardiac function. J Magn Reson Imaging

2004;19:789–99; with permission.)

submaximal exercise, comparing patients with COPD

with cardiac patients and normal controls. For all

patients, the breathing reserve index at lactate thresh-

old correlated with the breathing reserve index at

maximal oxygen consumption and was higher for

pulmonary patients than for cardiac patients and

controls (Fig. 3). The optimal cutoff (breathing

reserve index at lactate threshold �0.42) predicted

pulmonary limitation with a sensitivity of 96.9%

and a specificity of 95.1%, confirming the utility of

this index in separating pulmonary and cardiac causes

of disease.

Fig. 3. The breathing reserve index. Mean values are

represented by horizontal lines. CVL, cardiovascular; NL,

normal; PML, pulmonary. (From Medoff BD, Oelberg DA,

Kanarek DJ, et al. Breathing reserve at the lactate threshold

to differentiate a pulmonary mechanical from cardiovascular

limit to exercise. Chest 1998;113:913–8; with permission.)

preoperative cardiac evaluation 271

Risk reduction

Revascularization

Implicit in the determination of preoperative risk

is the assumption that this risk can be attenuated

by appropriately targeted intervention. There are few

data to support this idea, however. Studies from

nonsurgical patients attest to the long-term risk re-

duction of bypass grafting, but preoperative status

does not alter the indication (left main stem and or

multivessel disease), and the significant risk associ-

ated with the procedure means that bypass grafting is

not indicated simply to reduce perioperative risk. A

more gray area is represented by percutaneous coro-

nary intervention (PCI), which is relatively lower

risk. In the setting of an MI or an acute coronary

syndrome, the efficacy of PCI is clear [50]. Trials of

long-term clinical outcomes of patients with stable

coronary artery disease randomized to PCI versus

medical therapy found no impact on mortality,

hinting at potential limited efficacy of preoperative

PCI on postoperative risk. It has been argued, how-

ever, that because such studies were performed in an

era before stents, glycoprotein IIb/IIIa inhibitors, and

widespread statin use, their results are of debatable

value in evaluating current practice. Although stents

undoubtedly are associated with better outcome and

less restenosis than balloon angioplasty, the wide-

spread use of statins may counterbalance this benefit

through their effect on plaque stabilization [51,52].

For stable patients, the principal benefit of PCI may

be the alleviation of symptoms and a renewed ability

to exercise unhindered by angina.

Despite these theoretical discussions, there is

widespread acceptance that inducible ischemia in

Fig. 4. (A and B) Effect of acute b-blockade on perioperative risk.

atenolol on mortality and cardiovascular morbidity after noncar

Research Group. N Engl J Med 1996;335:1713–20; and B from Pol

on perioperative mortality and myocardial infarction in high-risk pa

Cardiac Risk Evaluation Applying Stress Echocardiography Study

an artery with angiographically significant steno-

sis should be treated before elective surgery. The

choice of intervention is a further dilemma, however.

Although healing after balloon angioplasty is rela-

tively short (perhaps 1 week), implantation of a bare

metal stent must be accompanied by 4 weeks of

potent antiplatelet therapy to allow endothelialization

of the implant. Implantation of a drug eluting stent

now warrants 3 to 6 months of such treatment. The

benefit of converting a stable flow-limiting lesion

into a disrupted non– flow-limiting lesion with

implanted thrombogenic material should be discussed

[53], and this obligatory delay should be incorporated

into the preoperative discussion. If surgery is more

urgent than this time frame allows, one study

suggested a 2-week delay would avoid most compli-

cations [54], although individual case reports confirm

that risk is increased even at 6 weeks [53].

Medical therapy

There are two randomized placebo-controlled

trials examining the impact of perioperative b-block-ade on patients with cardiac risk factors (Fig. 4)

[55,56]. In the first trial (Fig. 4A), Mangano et al [55]

randomized 200 patients undergoing noncardiac

surgery to atenolol or placebo. Overall mortality after

discharge was significantly lower among the ateno-

lol-treated patients than among patients who were

given placebo, and this effect was maintained over

2 years of follow-up (10% versus 21%; P = .019). In

the second study (Fig. 4B), Poldermans et al [56]

randomized 173 patients with positive dobutamine

echocardiography to bisoprolol or standard care. Two

patients in the bisoprolol group died of cardiac causes

(3.4%) compared with nine patients in the standard

(A from Mangano DT, Layug EL, Wallace A, et al. Effect of

diac surgery. Multicenter Study of Perioperative Ischemia

dermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol

tients undergoing vascular surgery. Dutch Echocardiographic

Group. N Engl J Med 1999;341:1789–94; with permission.)

ashley & vagelos272

care group (17%; P = .02). This pattern also was seen

in nonfatal MI, which occurred in nine patients in the

standard care group (17%) and in no patients in

the bisoprolol group (P < .001). The fact that these

trials achieved statistical significance with only a

few patients suggests a potent protective effect for

b-blockade in postoperative cardiac risk, something

that may have been predicted from the earlier dis-

cussion of pathophysiology.

Although these trials represent the best current

evidence for effective intervention, they say nothing

about the risk of the increasing number of cardiac

patients who are already on b-blockers. Foex et al

reviewed the literature to identify studies examining

the relationship between long-term b-blockade and

adverse perioperative outcome [57]. Of 18 studies

identified, none showed a protective effect of long-

term b-blockade. Cumulative odds ratios calculated

for the likelihood of MI, cardiac death, and major

cardiac complications showed that patients receiving

long-term b-blocker therapy were more likely to have

an MI. Although it seems logical that this finding

relates to the use of b-blockers in a higher risk group

(patients with known hypertension or coronary artery

disease), the populations in the acute studies also

were at high risk, which may have accentuated the

benefits of acute b-blockade. Matching patients for

risk to test this hypothesis would not be ethical,

but the upregulation of b-receptors in long-term

b-blockade provides one explanation and suggests

there may be benefit from additional b-blockade in

the perioperative period.

It could be argued that the applicability of

b-blocker studies to thoracic surgery patients is

limited by the presence of COPD, which traditionally

is held to preclude the use of these medications. More

recent studies have shown that there is little or no

downside to the use of cardioselective b-blockade in

COPD patients [58]. Cardioselective b-blockersproduced no significant change in FEV1 or respira-

tory symptoms compared with placebo and did not

significantly affect the FEV1 treatment response to

b2-agonists in the meta-analysis by Salpeter et al [59].

Even nonselective b-blockers, such as carvedilol,

have been shown to be tolerated well by COPD

patients who have no significant reversible airflow

limitation (patients with asthma tolerated carvedilol

poorly). Finally, Gottlieb et al showed that overall

risk is similarly reduced in COPD patients as in the

general population: Mortality was 40% lower in the

COPD subgroup with b-blockade [60].

For patients with known intolerance of b-blockers,alternative possibilities exist. Four studies have

suggested beneficial effects of the centrally acting

a2-agonists clonidine or mivazerol in reducing post-

operative cardiac events. The mechanism seems to

relate to central sympatholysis, although the inhibi-

tion does not extend to the hypothalamic-pituitary-

adrenal axis [61].

The effects of calcium channel blockers on

perioperative cardiac risk were assessed in a meta-

analysis by Wijeysundera and Beattie [62]. Eleven

studies encompassing 1007 patients were included in

an analysis showing that calcium channel blockers

significantly reduced ischemia and supraventricular

tachycardia and exhibited a trend toward reduction

in death and MI. Most of the benefit seemed to relate

to the use of diltiazem, emphasizing the role of con-

trolling heart rate in postoperative risk (the mechani-

cal hypothesis). In a meta-analysis, Stevens et al [63]

did not corroborate these positive effects of calcium

channel blockers. The earlier study suggests, how-

ever, that a tighter focus on rate-limiting calcium

blockers might yield clearer results.

Two studies have shed light on the protective role

of HMG-CoA reductase inhibitors (statins) in post-

operative risk. Poldermans et al [64] conducted a

case-control study among 2816 patients who under-

went major vascular surgery and found that statin

therapy was significantly less common in cases than

in controls (8% versus 25%; P < .001). Lindenauer

et al [65] performed a retrospective cohort study of

780,591 patients and found that treatment with lipid-

lowering agents was associated with lower crude

mortality (2.13% versus 3.05%; P < .001), and that

this effect remained after adjustment for propensity.

Although clearly arguing for a randomized controlled

trial, reports such as the Heart Protection Study [66]

mean that patients with demonstrable risk increas-

ingly will be on these lifesaving medications.

Summary

The changing paradigm in cardiovascular disease

in which atherosclerotic lesions exist in a spectrum of

stable to unstable, the lack of a perfect prediction

tool, and the paucity of randomized controlled data

on appropriate intervention make protection of car-

diac patients undergoing thoracic surgery challeng-

ing. Nociception-related sympathetic drive combines

with inflammatory stimuli and the cardiodepressant

effects of anesthesia to create a window of maximum

risk in the early postoperative period (8–24 hours),

and although multivariate models have shown that a

combination of surgery-specific risk, patient-specific

cardiovascular history, and estimated functional

capacity best determine the need for further inves-

preoperative cardiac evaluation 273

tigation, the optimal choice of investigation is

unclear. Exercise or dobutamine stress echocardiog-

raphy provide the best validated investigations, and in

the case of poor images, dobutamine MR imaging is

increasingly used. When disease is found, medical

and interventional options are available. PCI is often

used, but the risk of converting a stable flow-limiting

lesion into a less stable non–flow-limiting lesion

must be considered, along with a delay for anti-

platelet therapy and endothelialization of the stent.

Alternatively, medical protection with acute b-block-ade or a2-agonists reduces risk (although b-blockadeoften is avoided in chronic lung disease, even

nonselective agents are safe in patients with non–

airways reactive COPD). In addition, it is likely

that statin use reduces risk, probably by stabilizing

plaques, but patients with cardiac risk are increas-

ingly likely to be taking this medication already.

The assessment and management of cardiac risk in

the perioperative thoracic surgery patient is challeng-

ing. With focused, rational, and individually tailored

management; tight monitoring of postoperative pain;

and a close working relationship between the surgeon,

anesthesiologist, and cardiologist, patient care can be

optimized, and risk can be effectively controlled.

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2005–16.

Thorac Surg Clin

Preoperative Preparation for Esophageal Surgery

Jessica Scott Donington, MD

Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk CVRB,

300 Pasteur Drive, Stanford, CA 94305, USA

Esophageal surgery requires careful attention to

detail to avoid complications and ensure operative

success. Careful preoperative assessment and prepa-

ration is as important as meticulous surgical tech-

nique in ensuring a successful outcome. Most elective

esophageal surgeries can be placed into two broad

groups: resections for cancer and interventions for

benign esophageal conditions, such as gastroesopha-

geal reflux disease (GERD) and esophageal motility

disorders. Although proper preoperative diagnosis

and evaluation are vital to the operative success of

both groups, the patient population, risk factors,

scope of procedure, anticipated outcome, and pre-

operative preparation are different, and they are

addressed separately here.

Preoperative evaluation for benign esophageal

disease

The surgical treatment of benign esophageal

disorders is challenging because it attempts to alter

esophageal anatomy with the goal of improving func-

tion. A successful outcome is assessed by the ability

to provide symptom relief without complication. The

introduction of laparoscopic and thoracoscopic tech-

niques in the 1980s and 1990s has had a significant

impact on the use of surgery for the control of be-

nign esophageal conditions. Less invasive approaches

have altered the attitude of patients and physicians

toward surgical intervention for functional disease of

the esophagus. With the increased use of surgery

comes an increased risk of improper patient selection.

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.001

E-mail address: jsd@stanford.edu

Symptoms of esophageal disease, such as dysphagia,

epigastric pain, heartburn, regurgitation, and belch-

ing, are nonspecific and can occur in a variety of

esophageal, gastric, and duodenal disorders [1]. A

precise diagnosis is vital before any surgical inter-

vention for benign esophageal disease.

GERD is the most common benign disorder of the

esophagus and accounts for 75% of benign esopha-

geal disease [2]. Although many of the symptoms

of GERD can be controlled with medication, such an

approach is inadequate to control all symptoms and

prevent complications in many patients. Achalasia is

the most common primary motility disorder of the

esophagus, and similar to GERD, surgical treatment

now is most commonly laparoscopic. Patients with

typical and atypical symptoms of disease should un-

dergo a full battery of clinical tests to confirm the

diagnosis and exclude other causes of symptoms.

Other motility disorders that need to be recognized

or ruled out preoperatively include diffuse esopha-

geal spasm, nutcracker esophagus, hypertensive lower

esophageal sphincter (LES), and nonspecific motility

disorders. An extensive workup also is necessary to

rule out secondary motility disorders of the esopha-

gus, which develop from long-standing disease and

greatly hamper the success of surgery if not identified

before intervention.

Most patients undergoing procedures for benign

esophageal disease are relatively healthy and ambu-

latory. Malnutrition is not a major preoperative con-

cern because most of these patients still can swallow.

Most of these operations now are performed lapa-

roscopically with short hospitalizations and rapid

return to oral intake. The procedures are relatively

well tolerated with low rates of morbidity and mor-

tality. The successful relief of symptoms after these

15 (2005) 277 – 285

reserved.

thoracic.theclinics.com

donington278

operations depends on a precise diagnosis and iden-

tification of patients who are most likely to benefit

from the procedure. The focus of the preoperative

evaluation is on an accurate and precise diagnosis,

rather than cardiopulmonary status of the patient.

Barium esophagogram

Radiographic study of the esophagus is a fun-

damental part of the comprehensive evaluation of

patients with esophageal dysfunction. A barium eso-

phagogram defines esophageal anatomy and provides

some functional assessment of the esophagus. Esopha-

gogram should include examination of the esopha-

geal body and the upper and lower sphincters.

Videotaped swallows can be analyzed in slow motion

for better delineation of functional disorders. Barium

esophagogram should be one of the first diagnostic

tests in patients with dysphagia. It can contribute to

the diagnosis with typical findings such as the ‘‘bird-

beak’’ tapering of the distal esophagus in achalasia

and can exclude quickly anatomic diseases, such as

diverticulum or neoplasm (Fig. 1). The role of radio-

graphic studies in GERD is also to identify anatomic

complications of the disease, such as stricture. Con-

trast esophagography provides information that is

vital in the planning of an antireflux operation, in-

cluding the location of the gastroesophageal junction,

the presence and size of a hiatal hernia, the presence

of an intrathoracic stomach, or the presence of a

shortened esophagus. Any one of these findings may

Fig. 1. Contrast (barium) esophagograms showing achalasia (A),

esophagus (C).

cause the surgeon to alter his or her approach and

consider an open versus a laparoscopic approach or a

thoracic versus an abdominal approach.

Endoscopy with biopsy

Endoscopy should be performed in all patients

with benign esophageal disorders, including GERD,

to exclude or identify esophageal complications. It is

useful to grade the severity of esophagitis, rule out

infectious agents, identify strictures and diverticula,

and establish the size of hiatal hernia. Biopsy speci-

mens should be obtained of any mucosal abnormali-

ties to exclude the presence of Barrett’s esophagus or

malignancy; cultures also should be sent so that yeast

and other infectious agents can be treated preopera-

tively, and strictures can be dilated.

Esophageal manometry

Esophageal manometry is an essential preopera-

tive test in patients undergoing procedures for GERD

or another motility disorder. It is the gold standard for

the assessment of the function of the LES and body

of the esophagus. It allows for the diagnosis of pri-

mary esophageal motility disorders, such as achala-

sia, diffuse esophageal spasm, nutcracker esophagus,

and hypertensive LES. Esophageal manometry can

identify the effects of systemic disorders, such as

scleroderma and diabetes. At manometry, the LES

is described in terms of its position relative to the

diaphragm, length, resting pressure, and relaxation in

esophageal diverticulum (B), and adenocarcinoma of distal

preoperative preparation for esophageal surgery 279

response to swallowing. Esophageal body motility is

described by the amplitude and progression of con-

tractions in response to wet and dry swallows. Im-

paired esophageal motility can lead to delayed

esophageal emptying and prolonged acid exposure

of the esophageal mucosa. Poor esophageal body mo-

tility also has been shown to affect the development

and persistence of reflux-associated respiratory symp-

toms. If esophageal body motility disorders are recog-

nized preoperatively, adjustments to the operative

procedure can be made, including a looser or partial

wrap. Missed motility disorders have a significant

impact on the success of antireflux procedures.

Twenty-four-hour pH monitoring

Twenty-four-hour pH monitoring is probably

the most important test to confirm the diagnosis of

GERD. This test, which has 90% sensitivity in the

diagnosis of GERD, is performed as an outpatient

procedure and requires that proton-pump inhibitors

be stopped for at least 7 days and H2-blockers be

stopped 2 days before testing [3]. Patients are in-

structed to attend to their normal activities and restrict

their diets to foods with pH between 5.0 and 6.0. The

patients keep a careful record of any reflux symptoms

during the study period. The pH monitor measures

the amount of time the esophagus pH is below a

given threshold over a 24-hour period. Most centers

use a pH of 4 as the threshold. If the esophageal

Fig. 2. The primary tumor is defined by the depth of invasion thr

mucosa and submucosa. T2 invades into, but not through, the mu

invades adjacent structures. Lymph nodes are defined by the prese

TW. Clinical staging of esophageal carcinoma: CT, EUS, PET. Ch

mucosa is exposed to a pH of less than 4 for more

than 5% of the testing time, pathologic acid reflux is

present [4]. A positive test is determined by the

amount of time that the distal esophagus is exposed to

a pH less than 4, the number of reflux episodes with

pH less than 4, the number of episodes lasting more

than 5 minutes, and the length of the longest episode

[4]. Patients with alkaline reflux also can have

damage to the esophageal mucosa despite a negative

pH test. In these cases, an intraluminal bile salt probe

can be placed in the esophagus to confirm a diag-

nosis. Although pH studies classically are used to

confirm the diagnosis of GERD, they also have a

distinct pattern in achalasia and other motility

disorders in which there is stasis and fermentation

in the esophagus that leads to lactic acid production

and a consistently low pH through the day.

Summary

Careful preoperative evaluation of esophageal

anatomy and function is key to the successful out-

come of surgical intervention for benign esophageal

disease. The expectation for symptom relief without

complication is high in this patient population. It

is imperative that the anatomy and function of the

esophagus are thoroughly delineated preoperatively

so that the correct diagnosis can be made, and the

correct operation can be performed. Endoscopy, pH

monitoring, manometry, and radiographic studies are

ough the layers of the esophageal wall. T1 is limited to the

scularis propria. T3 extends through the muscularis, and T4

nce (N1) or absence (N0) of metastatic spread. (From Rice

est Surg Clin N Am 2000;10:473; with permission.)

Table 1

TNM staging of esophageal carcinoma

donington280

used together to provide the most complete picture of

esophageal pathology.

T: Primary tumor

TX Tumor cannot be assessed

T0 No evidence of tumor

Tis High-grade dysplasia

T1 Tumor invades the lamina propria, muscularis

mucosa, or submucosa. It does not breach the

submucosa

T2 Tumor invades into and not beyond the

muscularis propria

T3 Tumor invades the paraesophageal tissue but

does not invade adjacent structures

T4 Tumor invades adjacent structures

N: Regional lymph nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastases

N1 Regional lymph node metastases

M: Distant metastasis

MX Distant metastases cannot be assessed

M1a Upper thoracic esophagus metastatic to

cervical lymph nodes

Lower thoracic esophagus metastatic to celiac

lymph nodes

M1b Upper thoracic esophagus metastatic to other

nonregional lymph nodes or other distant sites

Midthoracic esophagus metastatic to either

Preoperative evaluation for esophagectomy for

carcinoma

The preferred treatment for localized esophageal

carcinoma is resection. The morbidity and mortality

associated with esophagectomy are significant, and

this has made resection prohibitive for many patients

and oncologists. Improved anesthetic care, improved

postoperative care, and meticulous surgical technique

have reduced the rate of perioperative complications,

but even at the busiest centers mortality ranges from

3% to 5%, and morbidity can be 60% [5]. Preopera-

tive selection and patient preparation are crucial for

esophageal resection. In preparation for an esopha-

gectomy, the clinician must perform adequate staging

of the disease, evaluate the general medical condition

of the patient, consider the mode of resection and

reconstruction, and educate the patient to the antici-

pated postoperative course and long-term changes

that may affect diet and lifestyle.

nonregional lymph nodes or other distant sites

Lower thoracic esophagus metastatic to other

nonregional lymph nodes or other distant sites

Stage grouping

Stage 0 Tis N0 M0

Stage I T1 N0 M0

Stage IIA T2 N0 M0

T3 N0 M0

Stage IIIB T1 N1 M0

T2 N1 M0

Stage III T3 N1 M0

T4 Any N M0

Stage IVA Any T Any N M1a

Stage IVB Any T Any N M1b

From Rice TW. Clinical staging of esophageal carcinoma:

CT, EUS, PET. Chest Surg Clin N Am 2000;10:472;

with permission.

Staging esophageal cancer

Preoperative staging is crucial to proper alloca-

tion of treatment and determination of prognosis in

esophageal cancer. Accurate presurgical staging has

been elusive. No one test addresses all aspects of

disease staging, and multiple tests must be used

together to provide an accurate preoperative stage.

The American Joint Commission on Cancer Staging

[6] developed the current staging system, which

uses the TNM system. T characterizes the primary

tumor and is graded by depth of invasion through the

esophageal wall (Fig. 2). N describes nodal involve-

ment. M characterizes metastatic spread. The TNM

subsets are organized into staging groups 0 through

IV (Table 1).

The current noninvasive staging recommenda-

tions from the American Joint Commission on Cancer

Staging include evaluation with CT, endoscopic

ultrasound (EUS), and positron emission tomography

(PET) [6]. More invasive modalities, such as laparos-

copy and thoracoscopy, have been investigated as a

way to provide more accurate staging and have been

found to be highly accurate in the staging of lymph

nodes [7]. These techniques require the use of a

general anesthetic and a longer hospital stay and in

general are considered by many clinicians to be too

invasive for routine use.

Computed tomography

CT has long been the essential tool for staging

esophageal cancer and remains a valuable initial tool

(Fig. 3). CT can detect metastatic disease or obvious

unresectable locoregional disease. It is widely avail-

able, inexpensive, noninvasive, and a cost-effective

first step in the staging of esophageal cancer [8]. CT

has limited value for T and N staging. The normal

Fig. 3. CT scans showing extensive involvement of the gastric cardia (A), malignant adenopathy along the left gastric artery (B),

and loss of definition of the mediastinal planes (C) in a patient with a large mid-third squamous cell carcinoma of the esophagus.

preoperative preparation for esophageal surgery 281

esophagus is 3 mm thick, and anything greater than

5 mm on CT is considered abnormal [9]. Current CT

technology does not allow detailed visualization of

the esophageal wall and is unable to determine depth

of invasion and cannot distinguish between T1, T2, or

T3 disease. CT has some value in the identification

and exclusion of T4 tumors, particularly when the

clinician can identify a fat plane surrounding the

tumor. CT criteria for invasion of adjacent structures

includes displacement or indentation into the airway

and greater than 90� arc interface with the aorta [10].

CT easily visualizes abnormal lymph nodes in the

paraesophageal and retroperitoneal fat. Lymph nodes

greater than 1 cm in short axis are considered abnor-

mal [6]. The sensitivity of CT for mediastinal lymph-

adenopathy is 34% to 61%, and the sensitivity of CT

in the abdomen is 50% to 76% [11].

CT is useful for the detection of metastatic dis-

ease. The most common sites of metastatic spread

from esophageal cancer are the liver, lung, bone, and

adrenal glands. A CT scan of the chest and upper

abdomen encompasses most of those sites. CT has a

sensitivity of 70% to 80% for detection of liver me-

tastases 2 cm or larger [12]. Its sensitivity decreases

significantly in subcentimeter lesions.

Positron emission tomography

PET uses a radioactively labeled glucose molecule

fluorodeoxyglucose F 18 (FDG) to image tumor tis-

sue. FDG becomes trapped in the glycogen pathway

and accumulates in cells that are metabolically active.

FDG is reported to accumulate in 97% of esophageal

cancers [13]. The availability of PET is becoming

more widespread, and at present its role in the staging

of esophageal cancer is being evaluated in a coop-

erative group setting by the American College of

Surgeons Oncology Group (AOSOG Z0060).

The sensitivity of PET for detecting primary

esophageal tumors is high [13]. The technique is

not able to distinguish esophageal wall layers or

paraesophageal tissue, therefore it has no value

in determining T status. PET also is poor at differ-

entiating regional lymph nodes from the primary

tumor because the uptake from the primary tumor

frequently overwhelms uptake in regional nodes. The

donington282

sensitivity, specificity, and accuracy of PET for loco-

regional lymph nodes are 52%, 94%, and 84% com-

pared with 15%, 97%, and 77% for CT [13]. The

most important role for PET is in screening for distant

metastatic disease. Most studies indicate that PET is

superior to CT in detecting metastases. Sensitivity of

PET is 70% to 75%, and specificity is 90% to 93%

[14]. PET is able to detect metastatic disease that is

occult on CT in 15% to 20% of patients [15].

Endoscopic ultrasound

EUS is a significant advancement in the preopera-

tive evaluation of esophageal cancer. It is currently

the most accurate mode of determining T and N status

of esophageal tumors. EUS combines flexible endos-

copy with high-frequency ultrasound and provides

360� visualization of the layers of the esophageal

wall. The esophageal wall is visualized in five dis-

crete alternating hypoechoic and hyperechoic layers

surrounded by paraesophageal tissues (Fig. 4). The

fourth layer represents the muscularis propria, which

is crucial in differentiating early-stage tumors from

T3 tumors. The accuracy of determination of T status

by EUS is 84% [16], which is far superior to that of

CT. The accuracy of T status determination seems to

vary with the depth of invasion. EUS is most accurate

for T4 tumors (88–100%) and least accurate at

predicting T1 tumors (75–82%) [11]. Frequently the

standard EUS probe cannot be passed through a

malignant stricture, and this significantly impairs the

accuracy of the examination. The inability to pass the

probe is in itself an accurate predictor of a T3 or T4

tumor in 90% of patients [17], but does not allow for

Fig. 4. Esophageal ultrasound of a T3N1 esophageal can-

cer. Arrows indicate penetration of the tumor into the mus-

cularis propria. Arrowhead indicates an enlarged nearby

lymph node.

the evaluation of celiac lymph nodes. Small probes

and safer dilating techniques allow for more complete

studies [18].

EUS also is an excellent tool for the evaluation

of regional lymph nodes in esophageal cancer. Fea-

tures that indicate malignant involvement include size

greater than 1cm, round shape, sharp edges, and a

hypoechoic center [16]. Accuracy of predicting nodal

involvement is nearly 100% when all four character-

istics are present [19]. EUS seems to be more accu-

rate for the diagnosis of celiac nodal involvement

than mediastinal node involvement [20]. The ability

to combine fine-needle aspiration with EUS offers

even greater precision in staging by providing his-

tologic verification of suspicious lymph nodes. The

sensitivity, specificity, and accuracy of EUS and fine-

needle aspiration in detecting celiac lymph node in-

volvement are 98%, 100%, and 98% [21].

EUS does not allow evaluation of distant sites

and has a limited role in the assessment of metastatic

disease. EUS can detect metastatic spread to organs

adjacent to the stomach and esophagus. Metastases

to the left lateral segment of the liver and the retro-

peritoneum can be detected by EUS, and biopsy

specimens can be obtained [12].

Bronchoscopy

Bronchoscopy is an important tool in the evalua-

tion of patients with carcinoma involving the

proximal esophagus and mid-esophagus. Direct

tracheobronchial involvement renders the patient T4

and unresectable. Brushings, washings, and biopsy

samples increase the rate of detection of invasion

compared with visual inspection alone [22].

Patient evaluation

An esophageal resection results in a significant

physiologic insult to the patient, and a patient’s gen-

eral medical condition is a major factor when de-

ciding whether a patient with esophageal cancer can

undergo resection. The mortality from esopha-

gectomy at major centers in the United States has

declined from of 12% in the 1970s to 3% to 7% in the

1990s [23]. Adequate preoperative patient selection

is an important part of that reduction in mortality,

by identifying high-risk patients in whom resection

would be hazardous. Factors to consider in preopera-

tive risk analysis include age, pulmonary function,

cardiac function, and nutritional status.

preoperative preparation for esophageal surgery 283

Age

Age older than 70 has been identified by some

authors as a risk factor for poor outcome after esopha-

gectomy, with cardiopulmonary causes accounting

for most deaths in this age group [24]. More recent

series have not seen an increase in complication rates

in the elderly when properly selected [25], even in

patients who receive induction chemoradiotherapy

[26]. Age is recognized as an independent risk factor

for the development of pulmonary complications

[27], and older patients need a full cardiopulmonary

evaluation preoperatively.

Pulmonary evaluation

Pulmonary complications are among the most

frequent complications after esophagectomy. They

also are among the most devastating complications,

resulting in prolonged hospital stay, increased costs,

and increased hospital mortality. Respiratory failure

is a significant risk factor for death after esophagec-

tomy [28]. The rate of pulmonary complications after

esophagectomy is 29% to 35%, higher than after any

common operation, including a major lung resection

[27]. Reasons cited for this increase include surgery

in two cavities, disruption of lymphatics, disruption

of respiratory muscles, placement of conduit in the

chest, and recurrent laryngeal nerve injury [27]. Pa-

tient factors, including preexisting lung disease,

tobacco and alcohol abuse, and poor performance

status, also contribute to pulmonary complications.

Attempts have been made to identify patients who are

at increased risk for postoperative pulmonary com-

plications after esophagectomy. Aside from age,

overall performance status (Eastern Cooperative

Oncology Group scale) and percent forced expiratory

vital capacity in 1 second have been recognized as

risk factors for pulmonary complications [27]. Be-

cause outcome after esophagectomy is influenced

heavily by pulmonary status, careful preoperative

pulmonary assessment with pulmonary function tests

is mandatory. In addition, high-risk patients may re-

quire arterial blood gas or expired gas analysis during

exercise for appropriate evaluation.

Nutritional evaluation

The most common presenting symptom in pa-

tients with esophageal cancer is dysphagia, a symp-

tom often associated with significant weight loss.

There is a correlation between preoperative values of

prognostic nutritional index and the incidence of

postoperative complications [29]. In addition, there is

a decrease in the rate of resectability in patients with

anorexia [30]. Nutritional supplementation should

be considered in any patient with a greater than

10%weight loss or an abnormally low serum albumin

level [31]. Patients receiving preoperative radiation

and chemotherapy are at increased risk for preopera-

tive malnutrition. For these patients, preopera-

tive nutritional supplementation, through either an

operatively placed jejunal feeding tube or a naso-

enteric tube, should be considered before the start of

therapy to help improve nutritional status before sur-

gical resection.

Cardiac evaluation

After esophagectomy, death resulting from iso-

lated cardiac cause is uncommon, but cardiac events

are recognized as a common cause of morbidity, with

atrial arrhythmias being the most common cardiac

complication [28]. A cardiac history, physical exami-

nation, and ECG are required in all patients. The need

for a more extensive evaluation with echocardio-

graphy or stress evaluation is based on the patient’s

coronary disease risk factors, including advanced age,

tobacco use, diabetes, hypertension, elevated choles-

terol, and presence of peripheral vascular disease.

Mode of resection and reconstruction

Numerous accepted surgical approaches to esopha-

geal resection and reconstruction exist. The most com-

monly used procedures in the United States are the

transthoracic (Ivor Lewis) and transhiatal approaches.

The approach used is individualized based on the

tumor characteristics and location, the surgeon’s pref-

erence, and the patient’s medical needs. A careful

history of previous operations or diseases is needed

before making a decision regarding the approach for

resection and the conduit for reconstruction. Severe

chronic obstructive pulmonary disease or history of

previous thoracotomy or empyema may preclude a

transthoracic approach.

The stomach is the conduit of choice for recon-

struction for most surgeons. The stomach has an

extensive vascular supply, large size (it can reach to

the base of the tongue in most cases), and recon-

struction requires only one anastomosis. In patients

with a history of previous gastric surgery or extensive

tumor extension into the stomach, a secondary plan

donington284

for reconstruction needs to be considered. The colon

is the next most commonly used replacement. If a

colon interposition is anticipated, angiographic and

colonoscopic (or radiographic) evaluation should be

done preoperatively, and the colon should be pre-

pared before surgery. Either right or left colon can be

used. Esophageal reconstruction with the colon

requires three anastomoses, but functional results

are good.

Summary

Careful preoperative assessment is crucial in pa-

tients undergoing esophagectomy. The procedure

carries significant morbidity and mortality, and care-

ful evaluation is vital to minimizing risks. Tumor

stage and the patient’s general medical condition play

equally important roles in determining operability.

Patients with impaired pulmonary, cardiac, or nutri-

tional function need to be identified, and reversible

impairments need to be treated preoperatively. Pre-

operative tumor staging is done with a combination

of tests, which should include CT, PET, and EUS

for best noninvasive staging and more invasive tech-

niques used on an individual basis.

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Thorac Surg Clin

Preoperative Preparation of the Patient with

Myasthenia Gravis

Kemp H. Kernstine, MD, PhD

Department of Thoracic Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Suite 2001,

Duarte, CA 91010-3000, USA

The combination of symptoms of myasthenia

gravis (MG) was first described in the latter part of

the 19th century [1]. The role of the thymus in the

pathogenesis of MG was theoretical until the work

of Sauerbruch and Blalock [2]. In 1939, Blalock et al

[3] reported performing a thymectomy in a myas-

thenic woman who had dramatic postoperative symp-

tom improvement. Blalock et al [4] reported their first

myasthenic thymectomy series 2 years later. Several

features, including the timing of surgery from the

time of diagnosis, the age of the patient, and the de-

gree of symptoms and the extent of the thymic resec-

tion, seem to correlate with remission [5]. Residual

tissue (2 g) after thymectomy may perpetuate the

symptoms [6].

The role of thymectomy in the treatment of MG

is not well defined. Identification of an appropriate

patient depends on a variety of characteristics. First,

does the patient have MG? A thorough evaluation of

the classic symptoms of the disease and others that

are in the differential diagnosis should be performed.

Provocative tests may assist in modifying the diag-

nosis; disease classification by symptoms and treating

drugs helps to determine the likelihood of surgical

resection success. Are there comorbid diseases that

might pose a significant obstacle to surgery? Would

thymectomy benefit the patient? These are a few of

the questions that are addressed in this article.

MG is the fatigue of voluntary muscles that

worsens with repetitive or continuous use and im-

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.01.002

E-mail address: kkernstine@coh.org

proves with rest. The symptoms worsen as the day

progresses. The proximal muscle groups are pre-

dominantly affected and usually symmetrically. The

shoulders and upper extremities are more commonly

involved than the lower extremities. Sudden or grad-

ual weakness of the skeletal musculature, even with

minimal exertion, is the classic presentation. Ptosis,

diploplia, and blurring are the presenting symptoms

in nearly 50% of patients, and in 15%, they are the

sole symptoms. Of patients, 85% develop generalized

muscle weakness. In 20%, the bulbar muscles alone

are affected.

The physical examination may show a loss of

smile, facial weakness, and nasal speech. Patients

frequently may sit slumped forward, unable to hold

their head erect. Patients may be febrile and have

rhonchi, rales, and wheezing from the recurrent as-

piration. The gag reflex may be absent. In contrast

to other potential diseases, the pupils in MG should

react to light and accommodation, and the corneal

reflex should be preserved. Placing an ice pack over

the eyelids of myasthenic patients with ptosis tem-

porarily improves the lagging lid. Signs of exoph-

thalmos may represent coexistent thyroid disease.

Limitation of neck flexion and extension may be a

sign of coexistent rheumatoid arthritis. Myasthenic

patients may have associated atrial fibrillation and

signs of heart failure. Provocative testing during the

examination to show weakness with repetitive ac-

tion includes hand grip strength with a dynamometer,

head raising, and arm and leg raising. Stepping up

and down on a footstool may prove difficult as the

exercise is repeated. Patients may have an elevated

white blood cell count, fever, and chest x-ray findings

15 (2005) 287 – 295

reserved.

thoracic.theclinics.com

kernstine288

consistent with pneumonia. A thorough history and

physical examination by the MG surgeon often

provides sufficient information to make the diagnosis

and determine the appropriate test to confirm it. To

assist in grading the disease and following the course

of therapy, Barohn et al [7] developed a quantitative

MG score that has been adopted by the Myasthenia

Gravis Foundation (Table 1).

MG is an autoimmune disease. Nearly 90% of

MG patients test positive for acetylcholine receptor

(ACh-R) antibodies [8]. The serum from affected

patients may be transferred experimentally to and

induces symptoms in test animals. Plasmapheresis

reduces or relieves the symptoms. A complex inter-

action of the thymic myoid cells with the local cyto-

Table 1

Quantitative myasthenia gravis score for disease severity

Test item None Mild

Grade 0 1

Double vision on lateral

gaze right or left

(circle one), seconds

61 11–60

Ptosis

(upward gaze), seconds

61 11–60

Facial muscles Normal lid

closure

Complete, weak,

some resistance

Swallowing 4 oz water

(1⁄2 cup)

Normal Minimal coughing

or throat clearing

Speech after counting aloud

from 1 to 50 (onset

of dysarthria)

None at 50 Dysarthria at 30–4

Right arm outstretched

(90� sitting), seconds240 90–239

Left arm outstretched

(90� sitting), seconds240 90–239

Vital capacity, % predicted �80 65–79

Right-hand grip, kgW

Men �45 15–44

Women �30 10–29

Left-hand grip, kgW

Men �35 15–34

Women �25 10–24

Head lifted

(45� supine), seconds120 30–119

Right leg outstretched

(45� supine), seconds100 31–99

Left leg outstretched

(45� supine), seconds100 31–99

From Barohn RJ, McIntire D, Herbelin L, et al. Reliability test

Acad Sci 1998;841:769–72; with permission.

kine and complement pathways is believed to initiate

and perpetuate the disease [9]. Neither ACh-R anti-

body concentration nor antibody binding seems to

correlate with the severity of the disease or the prog-

nosis. Ultimately, there is a gradual destruction of the

nicotinic postsynaptic motor end plate ACh-R. The

decrease in the number of receptors seems to corre-

late with the severity of disease [10]. Symptoms usu-

ally occur when the amount of receptors is less than

30% of normal [11]. Other abnormalities identified in

the synaptic cleft include a reduction in the end plate

folds and an increase in the distance of the synaptic

cleft. The result is less ACh released with repetitive

stimulation, in essence a ‘‘rundown’’ phenomenon,

and less effect from the ACh released [12]. Drugs,

Moderate Severe Score

2 3

1–10 Spontaneous

1–10 Spontaneous

Complete, without

resistance

Incomplete

Severe coughing/

chocking or nasal

regurgitation

Cannot swallow

(test not attempted)

9 Dysarthria at 10–29 Dysarthria at 9

10–89 0–9

10–89 0–9

50–64 <50

5–14 0–4

5–9 0–4

5–14 0–4

5–9 0–4

1–29 0

1–30 0

1–30 0

Total quantitative

myasthenia gravis

score (range, 0–39)

ing of the quantitative myasthenia gravis score. Ann N Y

Box 1. Myasthenia Gravis Foundationclassification*

I—May have weakness of eye closure

All other muscle strength is normalII—Mild weakness affecting other

than ocular muscles

Alsomay have ocular muscle weak-ness of any severityIIa—Predominantly affecting limb

or axial muscles or bothAlsomay have lesser involve-

ment of oropharyngeal orrespiratorymusclesorboth

III—Moderate weakness affecting otherthan ocular muscles

Alsomay have ocular muscleweak-ness of any severity

IIIa—Predominantly affectinglimb or axial muscles or bothAlso may have lesser

involvement of oropha-ryngeal muscles

IIIb—Predominantly affectingoropharyngeal or respira-tory muscles or both

IV—Severe weakness affecting otherthan ocular muscles

Also may have ocular muscle weak-ness of any severity

IVa—Predominantly affecting limbor axial muscles or bothAlso may have lesser

involvement of oropha-ryngeal muscles

IVb—Predominantly affectingoropharyngeal or respira-tory muscles or both

V—Defined by intubation, with or with-out mechanical ventilation exceptwhen employed in routine postop-erative management. The use of afeeding tube without intubationplaces the patient in class IVb

* It is recommended that the most se-verely affected muscles be employed todefine the patient’s class. The maximumseverity—the most severe pretreatmentstatus determined by this classification—is recommended as a permanent pointof reference.

Data from Appendix: Myasthenia GravisFoundation of America Recommendationsfor Clinical Research Standards. In:Kaminski HJ, editor. Myasthenia Gravisand related disorders. Totowa (NJ): Hu-mana Press; 2003. p. 373–80.

preoperative preparation of mg patient 289

body temperature, and emotions may worsen the

neuromuscular transmission.

The age of presentation is bimodal. The most

typical patients are young women in their 20s and 30s

(mean 26 years). The male-to-female ratio is 1:4, and

for patients younger than 30, it is 1:5. Among older

patients, men are more common. The symptom onset

may be slow or rapid. The prevalence is 1 to 14 per

100,000 [13]. Since the 1980s, the mortality asso-

ciated with MG has decreased. As a result, the num-

ber of living patients has increased. Ten percent of

patients have an additional associated autoimmune

disorder; 4% have thyroid abnormalities, more com-

monly hypothyroidism.

The Myasthenia Gravis Foundation has made

numerous modifications to the Osserman Classifica-

tion (Box 1). The classification provides a means

to evaluate the natural history, assist in developing

a treatment plan, and assist in determining a prog-

nosis. It is not a linear grading system. The examiner

simply determines whether there is presence of

ocular, bulbar, generalized, or proximal muscle weak-

ness and makes a rough subjective assessment of

the severity.

A general understanding of the diagnostic tests

assists in confirming the diagnosis. Before surgery, it

is helpful to have a neurologist who is experienced

in the disease examine the potential surgical patient.

Electromyography (EMG) has been used since 1895.

The ‘‘jolly test’’ repetitively stimulates a peripheral

motor nerve at 2 to 3 Hz while recording the muscle

action potential from two surface electrodes. The test

is considered diagnostic when the height of the mea-

sured action potential decreases by 15% or more

with the repetitive stimulation. Accuracy is optimized

when the symptomatic muscle groups are tested. Fifty

percent of MG patients have false-negative EMG,

especially patients with mild generalized symptoms

or ocular symptoms only. The test is simple to per-

form, but interpretation varies by observer.

Single-fiber EMG or ‘‘jitter test’’ requires an

experienced neurophysiologist and is expensive to

perform. Fine-needle electrodes are placed between

two muscle fibers innervated by a single motor neu-

ron. The variation and the action potential between

Box 2. Differential diagnosis of patientswith myasthenia gravis

Congenital myasthenic syndromesDrug-induced myasthenic syndromes

Penicillamine, organophosphates

Curare

Procainamide

Quinines

Aminoglycosides

MetoclopramideEaton-Lambert syndromeAmyotrophic lateral sclerosisMuscular atrophyHyperthyroidismGraves’ diseaseBotulismProgressive external ophthalmoplegia

(Kearns-Sayre syndrome)Intercranial mass compressing

cranial nervesPsychoneurosis

kernstine290

the two muscle fibers are measured. The test is 95%

sensitive and is best done in patients with generalized

MG. The specificity is 50% because other nerve dis-

orders may produce a false-positive result. This test

typically is used to assess response to therapy.

The Tensilon (edrophonium) test is fairly simple

to perform: 0.1 to 0.2 mg of Tensilon is given in-

travenously initially to determine if symptoms im-

prove. If there is no response, an additional 2 mg of

the drug is administered. If there is no symptom

improvement, 9 mg is given. The onset of action is

usually within 30 seconds and lasts approximately

5 minutes. The gradual increase in edrophonium dose

is meant to avoid a cholinergic crisis. This test is least

sensitive in patients with ocular symptoms only, but

is 95% sensitive in the general MG population.

Observer variability occurs. A test has its maximum

sensitivity when the patient is at his or her weakest.

To evaluate better equivocal or weak test results,

neostigmine (Prostigmin), a cholinesterase inhibitor,

may be given to prolong the response.

The binding, blocking, and modulating antibody

test is a radioimmunoassay using radioactive iodine–

tagged a-bungarotoxin, which binds specifically and

irreversibly to the ACh-R antibody. The test is 80%

to 90% sensitive. The modulating or blocking anti-

bodies are positive in 5% of patients who are binding

antibody negative [14]. The 10% to 20% who are

antibody negative still have a circulating immune

complex that affects the motor nerve end plate and

can cause symptoms on passive transfer of serum

[15]. Among patients with ocular symptoms, 50% are

antibody positive. The test is the most specific of the

tests used, although patients with amyotrophic lateral

sclerosis, biliary cirrhosis, tardive dyskinesia, thyroid-

itis, thymoma without MG, and lupus erythematosus

can have false-positive antibody tests [16]. The

antibody levels do not correlate with the symptoms

or the effectiveness of therapy [17,18]. Anti–striated

muscle antibodies are associated with patients who

have a thymoma [19]. Seronegative patients are more

likely female and more frequently have either ocular

and bulbar symptoms only or severe bulbar, neck,

and respiratory symptoms. As a group, these patients

are less likely to respond to thymectomy [20]. A

relatively rare group of ACh-R antibody–negative

MG patients express antibodies against the muscle

receptor tyrosine kinase [21]. These patients are much

less likely to benefit from thymectomy because they

are less likely to have thymic pathology.

Box 2 lists the other potential diseases that may be

confused with myasthenia gravis. The first, congeni-

tal myasthenic syndrome, is not a single disease, but

rather a group of several rare congenital myasthenic

syndromes associated with weakness in neonates and

infants [22]. Typically, there is a family history of the

abnormality, there is no ACh-R antibody present, and

the Tensilon test is negative. These syndromes

represent a host of synaptic abnormalities that result

in weakness [23].

MG syndrome can develop in a small percentage

(<1%) of patients treated with penicillamine. Fre-

quently the syndrome begins with ocular symptoms

and can progress to generalized myasthenia. The

Tensilon test, EMG, and the ACh-R antibody tests are

positive. Organophosphates, procainamide, quinines,

aminoglycosides, and metoclopramide all can cause

MG-type symptoms. The symptoms usually improve

with discontinuation of the drugs.

Botulism also can result in ocular and bulbar

weakness. In botulism, the pupils do not respond to

light or accommodation. With repeated nerve stimu-

lation, EMG shows an increased response, rather

than the decrease seen with MG.

Brainstem pathology, such as tumors or aneu-

rysms, can cause dysfunction in the cranial nerves.

On physical examination, evaluation of cranial

nerves III through VI may prove beneficial. The loss

of a corneal reflex is not a finding in MG, whereas

it is in brainstem lesions. MRI of the brain and skull

base may be beneficial to differentiate these lesions

preoperative preparation of mg patient 291

from MG. Generalized symptoms of myasthenia re-

duce the likelihood of brainstem pathology.

Kearns-Sayre syndrome is a mitochondrial disor-

der that presents in children as ptosis and ophthalmo-

plegia and may continue to progress to generalized

muscle weakness. There is associated retinal degen-

eration and progressive cerebellar disease. Muscle

biopsy specimens also may help to differentiate this

disease from MG.

Thyroid disease may coexist with MG and may be

difficult to differentiate from it. When exophthalmos

is present, the eye disease is more likely due to

Graves’ disease than MG. The presence of MG

warrants performing thyroid function studies.

Amyotrophic lateral sclerosis can cause progres-

sive muscular weakness, including the bulbar mus-

cles. The peripheral nature of the weakness and the

associated hyperreflexia and Babinski sign can help

to differentiate this disease from MG. Amyotrophic

lateral sclerosis can have a positive Tensilon test and

ACh-R antibody.

Psychoneuroses and depression may simulate or

may appear similar to MG. With psychoneuroses and

depression, the fatigue is greater in the morning, in

contrast to the worsening fatigue through the day with

MG. Provocative testing also may help to differentiate

MG from psychoneuroses and depression.

Eaton-Lambert syndrome may have similar char-

acteristics to MG and is associated with small cell

lung cancer and Hodgkin’s disease in 85% of cases.

Pelvic muscle and truncal weakness is more fre-

quently an early symptom, making it difficult for

patients to stand up out of a chair. Bulbar and ocular

symptoms are rare; however, ptosis may be seen. The

shoulders are less frequently involved with Eaton-

Lambert syndrome. Eaton-Lambert symptoms are

more pronounced in the morning and seem to

improve through the day; there also may be asso-

ciated autonomic abnormalities, such as dry mouth.

EMG shows an increased response rather than the

decreased response in MG. Autoantibodies to the

P/Q-type calcium channels are found in more than

95% of patients with Eaton-Lambert syndrome.

These autoantibodies also may be found in patients

with MG, but are relatively rare (<5% of patients).

After reviewing the history and physical exami-

nation findings and the provocative testing results,

excluding other potential diseases, the degree of dis-

ease or the Myasthenia Gravis Foundation Associa-

tion classification is determined (see Box 2). The

neurologist chooses medication that minimizes the

symptoms with minimal side effects. Cholinesterase

inhibitors or anticholinesterases increase the synaptic

cleft ACh. Prolonged use may enhance the destruc-

tive effect of MG [24,25]. Medications include

neostigmine and pyridostigmine (Mestinon). Pyrido-

stigmine has a longer half-life and usually is started at

60 mg three times per day; it may be increased to

1500 mg/d. After the drug is initiated, most patients

experience symptomatic improvement. The improve-

ment is short-lived, and it is beneficial to have a

second agent to treat the patient in preparation for

surgery. The side effects are diarrhea, rhinorrhea,

nausea, increased salivation and tears, bronchorrhea,

and abdominal pain. Excessive dosing may result in a

cholinergic crisis, which is characterized by myosis,

paralysis, salivation, tearing, bronchorrhea, diaphore-

sis, and wheezing. Progressive weakness associated

with anticholinesterases may be difficult to differen-

tiate from undertreatment or overtreatment of MG in

the postoperative period.

Corticosteroids are used at doses of 50 to 100 mg/d

of prednisone (1–2 mg/kg/d for children). Symp-

toms may worsen significantly 4 to 8 days after

corticosteroids are started, prompting some physi-

cians to admit patients for steroid initiation. Approxi-

mately 3 to 6 weeks are required for symptoms to

improve. When symptom management is optimized

(usually 3–6 months), the dose may be adjusted for

lifelong use. Side effects of steroid use include

cataracts, cushingoid features, aseptic necrosis of the

femoral heads, obesity, psychosis, hypertension, glu-

cose intolerance, osteoporosis, and gastrointestinal

ulceration. Prednisone doses of less than 10 mg/d

may reduce the likelihood of complications before a

median sternotomy is performed, although the pres-

ence of steroids may serve to reduce poststernotomy

complications [26].

Immunosuppressive medications also may be

beneficial and are used in a significant percentage

of patients. Azathioprine (Imuran) is used frequently

to decrease steroid doses or to benefit patients who

are incompletely treated with steroids or unable to

tolerate steroids. More specifically, immunosuppres-

sive therapy attempts to target the T cells. Azathio-

prine most frequently is used lifelong, and its onset

effect takes approximately 3 to 12 months. The dose

is started at 50 mg/d for the first week, then increased

2 to 3 mg/kg/d until the desired effect is achieved.

Nearly half of patients show some improvement.

Approximately 10% of patients have flulike reaction,

and there is associated bone marrow suppression,

nausea, vomiting, and biliary stasis.

Cyclosporine is an alternative immunosuppressive

agent that inhibits interleukin-2 by helper T cell. Cy-

closporine seems to have a more rapid response than

azathioprine; the dose is 5 mg/kg/d. Side effects in-

clude hypertension, hirsutism, and renal dysfunction.

Fig. 1. CT scan of patient who presented with myasthenia

and was found to have a large, malignant thymoma.

kernstine292

Intravenous immunoglobulin improves symptoms

for periods of weeks to months. Patients are given a

daily dose of 400 mg/kg/d intravenously over a 5-day

period. It is generally well tolerated. This medication

may be useful in controlling symptoms in children

with more advanced disease before thymectomy.

Plasmapheresis may be performed removing 1 to

3 L of plasma each session every other day for three

to five sessions. The goal is to achieve the desired

effect after the plasmapheresis has been performed.

The improvement may last several weeks and may

occur in antibody-positive or antibody-negative pa-

tients. Plasmapheresis seems to be significantly effec-

tive in patients with respiratory dysfunction (with

vital capacity <2 L) and patients who may be on a

ventilator [27,28] and is superior to anticholines-

terase medication [29,30]. Patients with advanced

disease who receive preoperative plasma exchange

required less long-term ventilation and shorter ICU

stays [31]. Plasmapheresis may allow the discon-

tinuation of anticholinesterase drugs preoperatively,

reducing the bronchorrhea that is associated with

anticholinesterase drugs.

Other diseases may coexist with MG and should

be screened preoperatively. Associated thyroid dis-

ease may exist in 5% to 10% of MG patients. Pa-

tients may be hypothyroid or hyperthyroid, and the

associated thyroid disease may worsen the symp-

toms of myasthenia. It is recommended that thyroid

function tests be performed routinely before surgi-

cally treating patients with MG. Other autoimmune

diseases include rheumatoid arthritis and systemic

lupus erythematosus; measuring a screening serum

antinuclear antibody and rheumatoid factor may be

beneficial as well.

Thymic hyperplasia is found in 70% and thymic

atrophy in 20% of surgically resected patients [32].

Thymomas are found in approximately 10% to 20%

of patients with MG. These tumors are rare in patients

younger than age 20; the incidence is greatest in older

men. Patients with thymomas are less likely to bene-

fit from thymectomy. In the initial evaluation and

preoperatively, patients should have a screening chest

CT scan for thymoma (Fig. 1), which is approxi-

mately 88% sensitive [33]. There is no evidence that

MRI is superior to CT in screening for thymomas.

Before surgery, assessing the areas of potential

organ dysfunction may be of significant benefit. In-

spiratory and expiratory muscles may be dysfunc-

tional [34,35]. Spirometry may show a normal total

lung capacity, but a low vital capacity with a normal-

to-high residual volume [36]. Patients who are at risk

for prolonged ventilatory support include patients

with advanced disease; a Myasthenia Gravis Founda-

tion classification II or higher (see Box 2); duration of

MG for more than 6 years; history of steroid require-

ment; and a prior history of MG-induced respiratory

insufficiency, vital capacity less than 2.9 L, pyrido-

stigmine dose greater than 750 mg/d 48 hours before

surgery, or maximal expiratory force less than 40 to

50 cm H2O [37–40]. The upper airway may be af-

fected or obstructed by bulbar muscular dysfunction

or potential mediastinal thymic compression from an

anterior thymic mass [41]. There may be a risk of

airway obstruction at the time of intubation. A flow-

volume loop may be beneficial in evaluating these

patients. If this is present, the patient may need to be

intubated using an awake intubation technique of lo-

cal anesthesia and mild sedation.

Patients with MG also may have associated car-

diac dysfunction [42]. They may have conduction de-

fects and arrhythmias, including sinus bradycardia,

premature ventricular contractions, and atrial fibrilla-

tion. There also may be some primary left ventricular

filling dysfunction—a condition that seems to be

more frequent in patients with thymoma [43,44]. A

preoperative ECG and possibly an echocardiogram

may be warranted, particularly if symptoms and signs

of cardiac dysfunction are present.

In preparing a patient for surgery, the goals are

to suppress the immune response, decrease the cir-

culating antibodies, and optimize the neuromuscu-

lar transmission. The anticholinesterase medication

should be minimized over several weeks before sur-

gery to reduce the likelihood for postoperative bron-

chorrhea and rhinorrhea, while maintaining symptom

control. On the morning of surgery, a half dose of

anticholinesterase inhibitor should be given to pa-

tients with mild symptoms, and a full dose should be

given to patients with moderate-to-severe symptoms

preoperative preparation of mg patient 293

[45]. Steroids should be minimized to reduce the

likelihood of postoperative wound healing problems,

infection, and pulmonary complications.

From the anesthetic standpoint, some inhalation

agents should be avoided in MG patients [46,47].

Propofol has been used and does not seem to affect

neuromuscular transmission [48]. Depolarizing mus-

cle relaxants, such as succinylcholine, are less likely

to be effective. Preoperative plasmapheresis may de-

lay significantly the reversal of succinylcholine. The

nondepolarizing agents, such as atracurium, are not

dependent on plasmacholinesterases and are better

agents [49].

The role of thymectomy in the management of

MG is controversial. Although there is long-standing

evidence that the procedure is beneficial, the timing

of surgery and the surgical approach are controver-

sial. Some authors believe that thymectomy is valu-

able as an initial form of therapy because it reduces

the likelihood for long-term sequelae of MG. Other

authors believe that thymectomy should be reserved

for patients who fail medical management or have

excessive medication-related side effects. Thymec-

tomy is rarely, if ever, an emergent procedure. The

procedure has a mortality of less than 1%, although

morbidity may be substantial in the most severely

affected patients; 22% of patients with preoperative

respiratory insufficiency may require long-term me-

chanical ventilation [50].

In a meta-analysis of 21 nonthymomatous MG

cohorts from 1953 to 1998, patients who received

thymectomy were 2.1 times more likely to develop

treatment-free remission, 1.6 times more likely to

become asymptomatic, and 1.7 times more likely to

have improved symptoms compared with patients

who did not undergo surgery [51]. Median sterno-

tomy is the most frequently used approach, but other

techniques, including the transcervical thoracoscopic

and robotic approaches, have been described. The

patient selection for each of these approaches has not

been completely elucidated.

Summary

All patients who are to undergo a thymectomy

should be evaluated thoroughly by a neurologist—

ideally one with special training and interest in the

diagnosis and management of MG. Confirmatory

tests to diagnose MG and other potential diseases

should be reviewed. The antibody test seems to be

most specific, but there are rare cases of other dis-

eases that are ACh-R antibody positive. In 10% of

MG patients, serology is negative, and other tests are

necessary to confirm the diagnosis. All patients

should undergo a contrast-enhanced high-resolution

CT scan with 5- to 8-mm slices because thymoma or

thymic carcinoma may be present. Pulmonary func-

tion tests, including vital capacity, forced expiratory

volume, maximal expiratory force, arterial blood gas,

and a flow-volume loop, should be performed. Exer-

cise testing to evaluate for hypoxia and hypotension

with exercise and ambulation also may be appro-

priate. A thorough assessment for cardiac dysfunc-

tion, including echocardiography, nuclear medicine

studies, or a formal cardiology evaluation, may be

beneficial. Because MG is a complex autoimmune

disease, preoperative blood tests should include thy-

roid function testing, antinuclear antibody, and rheu-

matoid factor in addition to routine preoperative

studies. Plasmapheresis or intravenous immuno-

globulin should be considered for patients with

advanced disease, bulbar symptoms, or poor pulmo-

nary function. Given these guidelines, careful selec-

tion of candidates for surgery should optimize the

long-term results for patients with MG.

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Thorac Surg Clin

Preoperative Pulmonary Evaluation of the

Thoracic Surgical Patient

Aditya K. Kaza, MD, John D. Mitchell, MD*

Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center,

4200 East 9th Avenue, C-310, Denver, CO 80262, USA

Surgery remains the mainstay of therapy for early-

stage non–small lung cancer, with approximately

45,000 cases of early-stage disease (stages I, II, and

select IIIA) diagnosed annually. Many of these pa-

tients have poor underlying pulmonary function, in

large part resulting from long-term tobacco abuse.

It is the responsibility of the thoracic surgeon to as-

sess accurately the pulmonary function of a poten-

tially operable patient at the time of the preoperative

evaluation. This assessment provides an objective risk

profile associated with the planned pulmonary resec-

tion for the patient and family, minimizes morbidity

and mortality, and in some cases leads the surgeon to

recommend alternative therapies.

General considerations

Several questions should be asked in the general

pulmonary assessment of a patient being considered

for lung resection surgery. Careful appraisal of prior

history and pertinent review of systems (Box 1) often

can predict the objective results obtained in sub-

sequent pulmonary function testing.

Is the patient currently smoking? Active use of

tobacco at the time of surgery predisposes patients to

a variety of postoperative pulmonary complications

[1,2], usually through increased production and

reduced clearance of sputum in the perioperative

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.004

* Corresponding author.

E-mail address: john.mitchell@uchsc.edu

(J.D. Mitchell).

period. Significant atelectasis, pneumonia, or respi-

ratory insufficiency requiring intubation may result.

Patients should be counseled regarding the benefits

of abstinence from smoking as early as possible

before the procedure. A long prior smoking history

may suggest significant occult parenchymal disease

(chronic obstructive pulmonary disease), but is asso-

ciated with increased risk even in the absence of such

findings [3].

Does the patient have an occupational or travel

history that would predispose him or her to certain

pulmonary disorders? A variety of industrial and

environmental exposures, both organic and inorganic,

can lead to the insidious development of interstitial

lung disease and reduced pulmonary function [4].

Common environmental agents include silica, asbes-

tos, beryllium, and animal/bird products (farmer’s

lung or variants). A history of travel to areas endemic

to certain fungal infections (Coccidioides or Histo-

plasma) also may be relevant.

What is the activity level of the patient? Patients

with suboptimal performance on objective exercise

testing are at increased risk for perioperative cardio-

pulmonary complications [5–8]. In addition, self-

reported poor exercise tolerance has been shown to be

associated reliably with increased postoperative risk

[9]. Pulmonary rehabilitation, although not always

practical, may improve exercise tolerance dramati-

cally and is strongly advocated before lung trans-

plantation or lung volume reduction surgery [10,11].

Does the patient have a history of prior or active

pulmonary infection? A history of recurrent pulmo-

nary infections may suggest impaired mucociliary

clearance, airway obstruction, or localized bronchiec-

15 (2005) 297 – 304

reserved.

thoracic.theclinics.com

Box 1. General considerations in thepulmonary resection candidate

Smoking historyOccupational and travel historyExercise tolerancePrior history of:

Recurrent pulmonary infections

Recognized pulmonary airway/paren-chymal disease

Cardiac disease

Pulmonary or cardiac surgery

kaza & mitchell298

tasis. Successful treatment of active infection before

surgical resection is advised, but not always feasible

in the setting of a postobstructive infectious process.

Is an underlying pulmonary parenchymal disorder

present? The concomitant presence of significant

obstructive, interstitial, or infectious lung disease can

have a major impact on the patient’s functional status

and the conduct of the proposed operation. In addi-

tion, certain pulmonary disorders (particularly inter-

stitial lung disease) may be associated with a poor

prognosis, which may influence the degree of risk a

patient maywish to assume in the perioperative period.

Is cardiac disease present? Many cardiac and

pulmonary disorders have common etiologic factors.

The presence of significant ischemic or valvular heart

disease can have an impact on postoperative pulmo-

nary complications. Preexisting right ventricular

dysfunction has been shown to be a risk factor for

complications after pulmonary resection [12].

Has the patient had prior thoracic surgery? A

prior history of pulmonary resection or significant

intrathoracic procedure can have a significant impact

on the risk profile at the time of subsequent surgery.

Spirometry

Spirometry is a simple, inexpensive, readily

available test and remains the starting point in the

evaluation of a patient for proposed pulmonary

resection. Spirometry should be performed with the

patient in stable condition, with and without the

use of inhaled bronchodilators. A bronchodilator re-

sponse greater than 15% is considered significant and

indicates a component of reactive airways disease.

The forced expiratory volume in 1 second (FEV1)

is the most commonly used parameter from spiro-

metric testing for pulmonary risk assessment. Sev-

eral large studies in the past have suggested FEV1

criteria for safe pulmonary resection, including an

FEV1 greater than 1.5 L for a proposed lobectomy

and greater than 2 L for a pneumonectomy [13–15].

These criteria have been adopted as guidelines by at

least one major thoracic society, with no further

testing needed to ensure operability [16]. The

difficulty with these absolute values is that they do

not take into account size or gender of the particular

patient, producing bias against resection in smaller

individuals. For this reason, most practitioners use

or express measured FEV1 as a percentage of the

predicted value for the patient’s gender, height, and

weight. In this fashion, investigators have suggested

an FEV1 greater than 80% of the predicted value is

associated with a low risk of perioperative complica-

tions after major lung resection, and no further testing

is needed (Fig. 1) [17]. Other parameters investigated

include maximum voluntary ventilation (MVV) and

FEV25–75%, with a MVV less than 40% predicted or

a FEV25–75% of 0.6 to 1 L indicative of a marginal

candidate for lobar resection [18].

Diffusion capacity

The diffusion capacity in the lung for carbon

monoxide (Dlco) was found to be the most

important predictor of mortality and was the sole

predictor of postoperative pulmonary complications

in a retrospective review of 237 patients published by

Ferguson et al [19] in 1988. In this study, a Dlco

less than 60% of predicted was associated with

increased mortality. The importance of Dlco in risk

assessment before lung resection has been substanti-

ated by further reports, with little interplay between

Dlco and either FEV1 or maximum oxygen con-

sumption (Vo2max) [20,21].

Arterial blood gas analysis

The presence of resting hypercapnea, defined as a

Pco2 greater than 45 mm Hg on room air, has long

been described as a relative contraindication to lung

resection [14,18]. Other reports dispute this assertion,

however, and show equivalent outcomes above and

below this value [22–24].

Prediction of postoperative function

Most patients presenting for lung surgery are

likely to have reduced lung function, and it is the

responsibility of the surgeon to ensure adequate

Fig. 1. (A) CT scan of a patient with severe environmental mycobacterial disease involving the left lung. Pneumonectomy

was suggested, with a preoperative FEV1 1.1 L or 53% predicted. (B) Quantitative lung perfusion scan of the same patient, with

5% of total lung perfusion to the affected lung. Postoperative FEV1 values corresponded to calculated values of 1.05 L, or

50% predicted. See text. (Courtesy of Marvin Pomerantz, MD.)

preoperative pulmonary evaluation 299

pulmonary function will remain after the proposed

resection. If preoperative pulmonary function testing

reveals suboptimal function (FEV1 and Dlco < 80%

predicted), additional testing is indicated to estimate

the predicted postoperative (ppo) values. The most

commonly used methods include nuclear medicine

ventilation-perfusion (V/Q) scanning [15,25–28],

quantitative CT [29,30], and segment counting

[31,32]. These methods may be applied to the actual

and the percent predicted spirometry/Dlco values,

although the latter is more common.

Nuclear medicine V/Q scanning provides the

relative contribution of each lung to overall pulmo-

nary function (Fig. 2). For a pneumonectomy,

calculation of the ppoFEV1 (or % predicted ppo-

FEV1) can be accomplished easily using the data

from the perfusion scan and the preoperative spi-

rometry results:

ppoFEV1 ¼ preoperative FEV1

� 1�% perfusion to affected lungð Þ

Although discrepancies may occur when there is

significant V/Q mismatching, numerous studies have

shown good correlation between predicted and actual

measured FEV1 using this formula, with several

studies noting a slight underestimation of the actual

measured postoperative value, providing an element

of safety for a marginal patient [15,25,33]. Use of

the perfusion scintigraphy data also may be applied

to predict ppoDlco and ppoVo2max [26]. Some

investigators have suggested that dynamic perfusion

SpirometryDLCO

FEV1 > 80% predictedDLCO > 80% predicted

Offer Surgery

FEV1 < 80% predictedDLCO < 80% predicted

Estimation ofPostoperative Function

(ppo)* ppoFEV1 >40% predicted ppoDLCO >40-50% predicted

ppoFEV1 <40% predicted ppoDLCO <40-50% predicted

Exercise Study

Defer Surgery

VO2max >15 ml/kg/min

VO2max <15 ml/kg/minppoVO2max >10 ml/kg/min

ppoVO2max <10 ml/kg/min

ProposedLung

Resection

Fig. 2. Algorithm for preoperative pulmonary evaluation. *Estimated with quantitative perfusion scan, CT scan, or seg-

ment counting.

kaza & mitchell300

MR imaging techniques may be a feasible alternative

to V/Q scintigraphy [34].

The perfusion study also may be used to predict

function after lobectomy, as described by Wernly

et al [15]:

ppoFEV1 ¼ preoperative FEV1 � preoperative FEV1

�% perfusion to affected lung

� # resected segments

# segments in affected lung

An alternative method of calculating ppoFEV1 with-

out the use of a quantitative perfusion study involves

simply accounting for the number of resected seg-

ments as a percentage of the total number of segments

in both lungs, as described by Juhl and Frost [31].

With 19 lung segments, each segment accounts for

roughly 5.26% of the overall lung function:

ppoFEV1 ¼ preoperative FEV1

� ð1� ½# segments resected

� 5:26�=100Þ

Simple segment counting obviates the need for

expensive nuclear medicine testing and has been

adopted as the preferred method of calculating

postoperative spirometry values after lobectomy by

at least one major thoracic society [16]. Although

segment counting has been suggested to be as

accurate as V/Q scintigraphy [35], it does not take

into account the functional differences between vary-

ing segments, which may prove important in mar-

preoperative pulmonary evaluation 301

ginal patients with heterogeneous patterns of lung

disease, such as emphysema. Perhaps to account for

this factor, one group suggested adding 250 mL of

volume to the ppoFEV1 calculated by segment count-

ing, to obtain a more reliable estimation of post-

operative function [32].

At least one study has compared scintigraphy,

segment counting, and quantitative CT in predicting

postoperative pulmonary function [36]. In this study,

four parameters were assessed: FEV1, FVC, Dlco,

and Vo2max. Although scintigraphy and CT were

found to be useful, perfusion scintigraphy was noted

to be the most accurate.

Numerous studies have shown ppoFEV1 to be a

predictor of perioperative risk. Historically a cutoff of

ppoFEV1 less than 800 mL was used as a determinant

of unresectability [37]. More recent studies suggest

that morbidity and mortality are significantly in-

creased if the ppoFEV1 is less 40% [22,38–40].

Similarly, ppoDlco has been shown to be strongly

predictive of complications and death when the value

is less than 40% [18,21]. At least one group has

suggested the product of ppoFEV1 and ppoDlco

(predicted postoperative product) less than 1650 may

be an even more sensitive indicator of postoperative

mortality [33].

Exercise testing

Patients considered at high risk for perioperative

complications on the basis of standard spirometry

testing and calculation of postoperative function

should undergo exercise testing. The purpose of ex-

ercise testing is to identify some patients deemed

high risk but still able to tolerate resection with ac-

ceptable morbidity and mortality.

The easiest form of exercise testing is stair

climbing, with the height climbed inversely related

to the frequency of postoperative complications

[41,42]. Investigators have found increased morbid-

ity and mortality when less than 2 flights [43,44],

3 flights [45,46], 12 m [47], or 44 steps [48] are

climbed. One study found the height climbed to be

the sole predictor of morbidity through multivariate

analysis [47]. Others have shown correlation with the

patient’s Vo2max [49].

The 6-minute walk test was modified from the

original 12-minute test and provides objective evi-

dence of the patient’s exercise function [50]. The test,

usually performed in a hallway over a preset distance,

measures the distance a patient can walk quickly on a

hard, flat surface in 6 minutes. The test is self-paced

and does not reflect maximal exercise capacity. Some

investigators believe that because most activities of

daily living are performed in a submaximal exercise

environment, the test is a better assessment of the

patient’s general exercise tolerance. Holden et al [48]

found an achieved distance of greater than 1000 feet

to be associated with improved surgical outcomes

after lung resection. The 6-minute walk test is

commonly used in lung transplantation evaluations

and was used to exclude patients with severely

reduced exercise capacity after pulmonary rehabili-

tation in the National Emphysema Treatment Trial

[10]. A variation of the 6-minute walk test is the

shuttle walk, in which patients ambulate between two

cones placed 10 m apart. The walking speed, paced

by an audio signal, is increased each minute until the

patient is unable to continue. The shuttle walk more

closely correlates with Vo2max, with one study

showing that inability to complete 25 shuttles (250 m

[about 820 ft]) suggested a Vo2max less than 10 mL/

kg/min [51].

Where available, formal cardiopulmonary exer-

cise testing should be pursued when preliminary

spirometry and split function studies suggest the

patient is at increased risk of perioperative compli-

cations. The test usually is performed with incre-

mental work performed on a treadmill or bicycle

ergometer, measuring oxygen saturation and exhaled

gases to determine Vo2, Vo2max, carbon dioxide

output, and minute ventilation. The most commonly

used parameter measured with cardiopulmonary

exercise testing is Vo2max, which denotes a plateau

above which further increases in work do not result in

greater oxygen consumption. This parameter differs

slightly from Vo2peak, which describes the highest

oxygen consumption achieved before symptoms

(fatigue, dyspnea) forced the patient to stop the test.

Such limitations are common in patients with ad-

vanced lung disease.

Several studies have shown patients to be at low

risk for perioperative complications if the preopera-

tive Vo2max is greater than 20 mL/kg/min [52–54],

whereas others use Vo2maxgreater than 15mL/kg/min

as a cutoff for resection [55,56]. A Vo2max less than

10 mL/kg/min is associated with prohibitive morbid-

ity and mortality [17,52,57,58]. Bolliger et al [58]

found a ppoVo2max less than 10 mL/kg/min to cor-

relate with a 100% postoperative mortality.

Exercise oximetry has been suggested to be

helpful in predicting postoperative complications by

some authors [16,59,60] and not by others [61].

Ninan et al [59] found desaturation with exercise

greater than 4% highly predictive of longer ICU stays

and major morbidity.

kaza & mitchell302

Effect of lung volume reduction surgery

Occasionally a patient with a lung mass and poor

pulmonary function may present with functional and

anatomic factors favorable for lung volume reduction

surgery [10]. Because successful lung volume reduc-

tion surgery results in an improvement in FEV1 and

other pulmonary parameters, a combined operation

has been proposed as a strategy to allow safe resec-

tion. The pulmonary mass may reside in the severely

emphysematous part of the lung or may be resected

separately from the lung volume resection. Several

small studies have validated this approach in selected

patients [62,63].

Summary

Fig. 2 is an algorithm for the preoperative

pulmonary evaluation of the lung resection candidate.

Patients should undergo routine spirometry and

diffusion capacity testing. If the FEV1 and Dlco

are greater than 80% predicted, no further study is

needed. When these parameters are less than 80%,

some estimation of postoperative function is likely

needed, taking into account the proposed resection.

Patients with ppoFEV1 or ppoDlco less than 40%

are at increased risk of perioperative complications or

death and should undergo formal exercise testing. A

Vo2max or ppoVo2max less than 10 mL/kg/min is

associated with prohibitive risk for anatomic lung

resection, and alternative treatment modalities should

be considered.

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Thorac Surg Clin

The Preoperative Anesthesia Evaluation

Clifford A. Schmiesing, MD*, Jay B. Brodsky, MD

Department of Anesthesia, Stanford University Medical Center, 300 Pasteur Drive, H3524, Stanford, CA 94305, USA

Nowhere is the challenge and importance of the

collaboration of surgeons and anesthesiologists

greater than in thoracic surgery. Most patients facing

major chest surgery for advanced malignancy are

elderly and frequently have serious complications of

lifelong tobacco use. Airway management, lung iso-

lation techniques, and multimodal efforts to manage

respiratory complications and control postoperative

pain are just a few examples of the challenges con-

fronting physicians caring for thoracic surgical pa-

tients. Cardiorespiratory complications are the major

causes of morbidity after thoracic surgery [1].

Delivery of efficient, cost-effective medical care

to increasingly knowledgeable patients presents

another layer of complexity to the task facing sur-

geons and anesthesiologists. Most of the millions of

surgical procedures performed annually in the United

States are on an outpatient or same-day admission

basis. Previously, in the era before use review and

preauthorization requirements, preoperative patient

preparation could occur in the hospital without limits

on the number of consultants and diagnostic tests

obtained. Risk assessment, if it was considered at

all, was limited to ‘‘You know, she may not make it

through surgery.’’ Patients today know more and

expect more and often are active participants in

medical decisions affecting their care. It is now un-

usual to cancel a surgical procedure because the

patient is ‘‘too sick.’’

Many goals of the anesthesia and surgical pre-

operative assessment overlap. Shared goals include

obtaining a complete current and past medical history,

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights

doi:10.1016/j.thorsurg.2005.02.006

* Corresponding author.

E-mail address: cschmies@stanford.edu

(C.A. Schmiesing).

performing a thorough physical examination, and

obtaining and evaluating pertinent diagnostic tests to

assess risk and optimize outcome. Problems such as

postoperative respiratory failure, perioperative myo-

cardial infarction, blood pressure control, coagulopa-

thies, inadequate pain control, and end-of-life issues

concern anesthesiologists and surgeons. Other impor-

tant common goals are obtaining informed consent;

addressing a patient’s questions and concerns; and

educating the patient and family members about the

surgical procedure, anesthesia, and recovery period.

Specific anesthetic concerns include preoperative air-

way assessment, intravenous access, suitability of re-

gional anesthetic techniques, and the patient’s likely

response and tolerance to anesthetic agents.

One key element of the preoperative assessment is

timing. Timely preoperative assessment allows early

identification of potential problems and proactive

planning before surgery. Examples of issues that

can benefit from early detection and intervention in-

clude identification and treatment of exacerbations of

chronic obstructive pulmonary disease; the need to

obtain autologous or designated donor blood dona-

tions; control of hypertension; substance abuse; and

evaluation of new symptoms or conditions, such

as chest pain or arrhythmias. Medication adjustment

may require significant lead-time. Conversion or ces-

sation of anticoagulant regimens typically requires

1 week, and initiation of antihypertensive therapy

may take even longer. Simply obtaining relevant out-

side medical records under the new Health Insurance

Portability and Accountability Act mandates, such as

prior anesthetic records documenting a difficult in-

tubation or intraoperative incident, can require sev-

eral days [2].

Early preoperative assessment also is important

because nobody benefits from avoidable last-minute

15 (2005) 305 – 315

reserved.

thoracic.theclinics.com

Box 1. Anesthesia PreoperativeAssessment Clinic positive outcomes

� Decreased rate of surgical delays andcancellations

� Reduction in preoperative testing andspecialty consultations

� Convenient ‘‘one-stop’’ coordinatedpresurgical preparation for admission,laboratory, and preanesthesiaservices

� Development of clinical pathwaysand protocols to improve efficiencyand quality of care

� Enhanced patient education

Table 1

American Society of Anesthesiologists physical status

classification

Class 1 Healthy patient, no medical problems

Class 2 Mild systemic disease

Class 3 Severe systemic disease, but not incapacitating,

or multiple systemic problems

Class 4 Severe systemic disease that is a constant threat

to life

Class 5 Moribund, not expected to survive 24 h

regardless of operation

schmiesing & brodsky306

surgical cancellations [3]. An inadequate preoperative

evaluation that fails to identify a patient on warfarin

or to discover a history of exertional chest pain in the

holding area minutes before surgery results in loss of

time and resources because of delay or cancellation or

may lead to pressure to proceed despite unresolved

medical issues [4]. Patients may be devastated or

angry when their surgery is cancelled at the last

minute for reasons they can barely comprehend,

especially when it is due to miscommunication

or oversight.

Communication is another important element in

the preoperative assessment. Effective collaboration

between the anesthesiologist and the surgeon is en-

hanced when key information is shared in an open

and timely manner. This is a ‘‘two-way’’ street. When

a potential problem or unresolved issue is identified,

especially one with no simple solution, it benefits the

physicians involved to discuss the matter and develop

a management plan before surgery. No one wants to

be surprised by a problem in the operating room

that was identifiable early on. Examples of issues that

benefit from early preoperative planning include a

patient who refuses blood products, a patient who

requires extensive preoperative medical clearance or

testing, an extremely high-risk patient, an impaired

patient, or a patient with complicating social situa-

tions. Preoperative ‘‘team’’ collaboration can enhance

working relationships and create an atmosphere of

respect and trust between the anesthesiologist and the

surgeon. Everyone, but most importantly the patient,

benefits from this team approach.

Anesthesia preoperative assessments are per-

formed in a variety of settings depending on nu-

merous factors, including patient demographics and

acuity levels and institutional factors such as physi-

cian staffing constraints, surgical volume, and avail-

able facilities. The model effectively implemented at

the authors’ institution and at many other academic

and large medical centers is an Anesthesia Preopera-

tive Assessment Clinic (APEC) [5]. The benefits of

an Anesthesia Preoperative Assessment Clinic are

listed in Box 1.

Beyond the American Society of Anesthesiologists

classification system

An important assumption underlying the preop-

erative assessment is that it can improve outcome

by identifying high-risk patients. The well-known

American Society of Anesthesiologists (ASA) Physi-

cal Status Classification has been used routinely for

decades to stratify patient health status and to

estimate risk (Table 1). Although the ASA Physical

Status Classification remains a useful means to

convey quickly an overall impression of a patient’s

status, it is imprecise and has limited utility. First, the

ASA classification allows considerable leeway in

how patients are classified. A young patient with

controlled hypertension would be classified status

ASA class 2. An elderly patient with poorly con-

trolled hypertension, chronic opiate use and toler-

ance, obesity, and long-standing tobacco abuse also

might be classified ASA class 2, especially if he or

she were asymptomatic. The ASA Physical Status

Classification does not take into account the under-

lying risk of the planned surgical procedure. A patient

classified ASA class 4 with advanced coronary artery

disease (CAD) is at low risk for complications after

cataract removal, but at considerably higher risk

when undergoing an esophagectomy. Lastly, the ASA

classification system is not specific enough to be

useful in making management decisions for individ-

ual patients.

A more useful approach to preoperative risk as-

sessment and management is to consider each of the

patient’s diseases or problems individually and in

Box 2. Preoperative medicationconsiderations

1. Patients should provide a completelist or the actual pill bottles so thatmedications can be administered ac-curately during their hospitalization.

2. Most medications should be contin-ued up to, and including, the day ofsurgery (taken with a small sip ofwater). Notable exceptions include:

a. Oral and injectable diabeticmedications

b. Antiplatelet and anticoagulantmedications

c. Diuretics

d. Dietary supplements, herbs, andmegadose vitamin preparations

3. In most instances, patients can con-tinue opiate analgesics on the dayof surgery without ill effect. Manypatients assume they cannot takepain medications on the day of sur-gery, andappreciate being instructedthey can.

4. The frequency of prn opiate analge-sics should be determined preopera-tively to anticipate opiate toleranceor withdrawal.

5. If an analgesic is discontinued be-fore surgery (eg, ibuprofen), con-sider giving the patient a suitablealternative (eg, celecoxib or acet-aminophen/hydrocodone [Vicodin]).

6. Some patients benefit from a pre-operative anxiolytic (eg, alprazolam)

preoperative anesthesia evaluation 307

aggregate and to consider how each medical con-

dition would affect the patient’s response to anes-

thetic and surgical stresses. Each significant medical

condition should be assessed in terms of its severity

and degree of organ impairment, then the condi-

tion should be optimized to the fullest extent pos-

sible given the constraints and the reality of the

clinical situation. A medical problem may or may not

be significant.

Consider a patient with a history of viral hepatitis.

A distant history of hepatitis A holds no relevance to

an upcoming lobectomy for lung cancer. It carries no

anesthetic or surgical risk, does not require detailed

assessment, and cannot be optimized before surgery.

Hepatitis C, on the other hand, is a chronic destruc-

tive liver disease with a large variation in clinical se-

verity from completely asymptomatic to profoundly

debilitating and life-threatening. Hepatitis C may

have marked physiologic consequences during the

perioperative period, including coagulopathy, en-

cephalopathy, pulmonary and cardiac dysfunction,

fluid imbalances, electrolyte abnormalities, malnutri-

tion, and impaired drug metabolism. It is important to

determine the degree of hepatic impairment caused

by hepatitis C through history, physical examination,

and subsequent focused diagnostic testing, including

hepatic, renal, and coagulation function. Many

patients with long-standing hepatitis C have no

significant abnormalities of coagulation and hepatic

function, whereas others are severely impaired. When

the degree of impairment has been determined, risk

assessment and planning for specific problems can

occur. Examples of planning include drainage of

pleural and peritoneal effusions, preparation and

preoperative administration of blood products,

choices of intraoperative invasive monitoring and

postoperative nursing care, suitability of regional

anesthesia, and fluid management. Individual assess-

ment of specific problems guides testing, planning,

and management. It is more useful than simply

assigning an ASA classification based on a history

of ‘‘hepatitis.’’

for preoperative anxiety orinsomnia.

7. Preprinted instructions with explicitinformation regarding preoperativemedications are helpful to ensurecompliance.

8. With the continual flood of newmedications, it is advisable alwaysto look up unfamiliar medications toavoid medication errors and harmfuldrug interactions.

Preoperative assessment of common medical

conditions

Hypertension

Preoperative hypertension is common [6]. Factors

that can exacerbate hypertension before surgery in-

clude pain, anxiety, and patient confusion about

antihypertensive regimens in the immediate preopera-

tive period. Severe preoperative hypertension is as-

schmiesing & brodsky308

sociated with labile intraoperative blood pressure.

This situation can result in significant hypotension,

increasing the risk of myocardial ischemia and

infarction, cerebral and renal dysfunction, and dys-

rhythmias [6–8]. Patients with renal insufficiency

and congestive heart failure secondary to hyper-

tension should be considered at higher operative risk

[9]. Moderate hypertension (diastolic blood pressure

< 110 mm Hg) did not increase risk, however, in one

study of more than 600 patients undergoing sur-

gery [10].

As a general rule, patients presenting with severe

uncontrolled hypertension (systolic blood pressure

> 200mmHgor diastolic blood pressure > 110mmHg)

should be treated before elective surgery. Treatment

of hypertension usually can be accomplished with-

out cancellation of surgery when identified early

(ie, at least 1 week). The b1-selective b-blockers(atenolol and metoprolol) are effective choices when

antihypertensive therapy must be initiated and no

contraindications to b blockade are present. The

combination of atenolol and an anxiolytic, such

as alprazolam, is effective in treating preoperative

hypertension in a previously untreated patient. Key

points regarding initiation of efforts to control

preoperative hypertension include rapid initiation

and titration of therapy coordinated through an Anes-

thesia Preoperative Assessment Clinic and the pri-

mary care physician or surgeon and close monitoring

and follow-up to ensure safety and effectiveness.

Treatment should be reassessed 1 to 2 days before sur-

gery to avoid the need for a last-minute cancellation.

Patients whose hypertension is well controlled

preoperatively should be instructed to continue their

antihypertensive medications up to and including the

day of surgery. Diuretic medications are an excep-

tion; they should be avoided the day of surgery.

General points regarding preoperative medication

use are provided in Box 2.

Box 3. Lee’s revised cardiac risk index

One point is assigned for each of thefollowing when present:

1. High-risk surgical procedure2. History of ischemic heart disease

(excluding previousrevascularization)

3. History of congestive heart failure4. History of stroke or transient ische-

mic attack5. Preoperative insulin therapy6. Preoperative creatinine >2 mg/dL

Ischemic heart disease and cardiac risk

Perioperative myocardial infarction and cardiac

death remain a major problem [11]. Identification,

risk stratification, preoperative testing, and manage-

ment for each individual patient may be difficult and

complex. These issues become more complex in the

setting of surgery for malignancy, where any benefit

of diagnostic testing and therapeutic interventions

to improve cardiac outcomes may require weeks to

months to complete, but must be weighed against the

risk of delaying potentially curative surgery. Numer-

ous guidelines to help identify high-risk patients

have been published [9,12–16]. Detailed comparison

of these guidelines is beyond the scope of this arti-

cle. One simple approach to risk assessment is dis-

cussed, however.

Patients can be stratified into low-risk, intermedi-

ate-risk, and high-risk groups. Analysis of clinical

variables is the first step in stratification. One useful

assessment tool is the revised cardiac risk index by

Lee et al [16], based on six clinical variables listed in

Box 3. The index is simple to apply using readily

available preoperative data. Patients with fewer than

3 points are generally at low risk, whereas patients

with 3 or more points are at high risk for periopera-

tive cardiac events (Fig. 1). Analysis suggests that

routine use of noninvasive diagnostic testing, includ-

ing myocardial perfusion imaging and dobutamine

stress echocardiography, provides little additional in-

formation beyond that obtained from Lee’s revised

cardiac index, especially in low-risk patients [17].

Functional testing is useful in further stratifying

patients with 3 or more points. Testing of these

high-risk patients can identify a group of extremely

high-risk patients with extensive areas of myocardial

ischemia. This small subset of patients seems to be

at very high risk of serious cardiac complications,

with or without protective perioperative b-blockertherapy [18,19].

The question often arises as to whether coronary

revascularization should be performed before non-

cardiac surgery. Several studies have shown that pa-

tients who have had coronary artery bypass graft

(CABG) procedures in the 5 years before a noncar-

diac operation had fewer cardiac deaths and myo-

cardial infarctions than patients receiving medical

therapy alone [12,20,21]. Based on these findings, the

American College of Cardiologists and the American

Heart Association do not recommend preoperative

0.4 0.9

6.6

11

0

2

4

6

8

10

12

14

16

18

20

Car

dia

c E

ven

t Rat

e (%

)

I (0 points) II (1 point) III (2 points) IV (≥ 3 points)

Risk Class Based on Number of Points

Fig. 1. Major cardiac event rates by the revised cardiac risk index. (Data from Lee TH, Marcantonio ER, Mangione CM, et al.

Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation

1999;100:1043–9.)

preoperative anesthesia evaluation 309

stress testing in patients who remain asymptomatic

within 5 years of a CABG procedure [22]. No data

support prophylactic preoperative CABG surgery or

percutaneous coronary interventions in patients who

otherwise would have no indication for these pro-

cedures [23,24]. Revascularization procedures should

be reserved for patients who, independent of surgery,

require it. A CABG operation also should be consid-

ered in the small subset of patients who are discov-

ered to have serious, life-threatening CAD based on

preoperative testing that shows multiple areas of

ischemia consistent with high-grade stenosis [18].

Prophylactic perioperative b-blocker (PPBB) ther-apy is effective in reducing perioperative cardiac

death and myocardial infarction in patients at risk for

or known to have CAD who are undergoing major

noncardiac surgical procedures [25–27]. The prac-

tice of PPBB has received strong endorsement from

numerous organizations, including the American

Heart Association, American College of Cardiolo-

gists, and American College of Physicians. PPBB

was included near the top of a list compiled by the

Agency for Hospital Research and Quality of proven

patient safety practices that merit wider implementa-

tion [26].

The benefit of PPBB seems greater for high-risk

patients with vascular disease and known positive

stress tests undergoing major vascular surgery [26].

Preprinted forms can help clinicians implement

PPBB in appropriate patients. Fig. 2 presents the

general inclusion and exclusion criteria in use at the

authors’ institution for PPBB, based on the work of

Wallace et al [27]. The comparative effectiveness of

the b1-selective blocking agents versus the nonse-

lective agents and the optimal length of therapy have

not been determined. Studies to date have considered

treatment for a minimum of 14 days. PPBB is gen-

erally well tolerated even in patients with a history

of congestive heart failure and chronic obstructive

pulmonary disease, although certain contraindications

must be considered before initiating therapy [26–28].

The preoperative assessment is an opportune time

to identify patients likely to benefit from PPBB and

to initiate it.

Valvular heart disease

Severe valvular heart disease is a high-risk clinical

predictor in patients undergoing noncardiac surgery

[22,29]. It is important to distinguish patients with

severe valvular heart disease from patients who have

milder disease or who simply have a benign flow

murmur. Clinical features of benign murmurs are

listed in Box 4 [30–32]. Preoperative echocardiog-

raphy should be considered for a murmur that does

not meet these criteria. Echocardiography determines

the etiology of the murmur and assesses overall

cardiac function. A resting echocardiogram cannot

identify inducible ischemia and is not a substitute for

a stress echocardiogram.

Even in the absence of severe valvular heart

disease, preoperative identification of patients with

mild-to-moderate valvular heart disease is important

in planning perioperative management. These pa-

tients often require antibiotic prophylaxis to prevent

bacterial endocarditis. Long-term warfarin therapy

may need to be interrupted and possible ‘‘bridging’’

Stanford University Department of Anesthesia

Prophylactic Perioperative Beta Blockade (PPBB) Considerations

All patients scheduled for major elective non-cardiac surgery requiring general anesthesia and a hospital stay qualify. Patients foremergency surgery, hemodynamically unstable patients, and renal transplant patients need to be assessed individually1 . These guidelinesare intended to provide supplemental information for use with the Prophylactic Perioperative Beta Blockade (PPBB) Protocol order form(15-1797).

Consider PPBB for patients within at least one of the following categories:Known coronary artery disease Any two of the following: age > 65 years,Atherosclerotic vascular disease hypertension, current smoker, hyperlipidemiaDiabetes

Patients within any of the following categories should not receive PPBB:Known sensitivity to beta blockers Second or third degree heart blockAcute congestive heart failure Systolic blood pressure (SBP) < 100 mmHgAcute bronchospasm Heart rate < 60 beats per minute (bpm)Acutely hemodynamically unstable patients

Care must be taken with administration to patients with a history of asthma or COPD.

Drug Choice: Atenolol, bisoprolol and metoprolol may all be used. They are all long-acting, Beta-1 selective and have similar efficacy inthe prevention of death after myocardial infarction. Other beta blockers without intrinsic sympathomimetic effect are probably equivalent,so if a patient is on another beta blocker it is unnecessary to change to a Beta-1 selective drug. However, the dosage should be adjustedto keep the HR < 80 bpm.

How should PPBB be initiated?

Preoperatively: If HR > 60 bpm and SBP > 100 mmHg, then oral dosing with twice daily metoprolol (25-50 mg), or once dailyatenolol (50-100 mg) can be started several days before surgery. Target HR is > 50 and < 70 bpm.

In Holding Area prior to surgery: If HR > 60 bpm and SBP > 100 mmHg, metoprolol 2.5-5.0 mg IV can be given while monitoringHR and BP. For maximal beta blockade, consider additional dose(s) every 10 minutes if HR remains > 70 bpm and SBP > 100mmHg. Target HR is > 50 and < 70 bpm.

During Surgery: If HR >60 bpm and SBP >100 mmHg, metoprolol 2.5-5.0 mg IV every 10 minutes may be given 30 minutes priorto emergence. Target HR for maximal beta blockade is < 70 bpm. Alternatively, esmolol infusion may be titrated to maintain HR <70 during emergence.

PACU or ICU after surgery: If HR > 60 bpm, and SBP > 100 mmHg, metoprolol 2.5-5.0 mg IV may be given while monitoringHR and BP. For maximal beta blockade, consider additional dose(s) every 10 minutes if HR remains > 70 bpm and SBP > 100mmHg. Target HR is > 50 and < 70 bpm. Consider use of PPBB Protocol order form (15-1797).

Postoperative Care: If the patient is to be kept NPO, metoprolol 2.5-10 mg IV every 6 hours dosing should be continued withtarget HR > 50 and < 70 bpm while maintaining SBP > 100 mmHg. When patient is able to take oral medications the patient maybe switched to twice daily oral metoprolol (25-50 mg), or once daily atenolol (50-100 mg) with dosage adjusted to keep HR > 50and < 70 bpm and SBP > 100 mmHg. Consider use of PPBB Protocol order form (15-1797).

PPBB should be continued for at least 7 days postoperatively. Patients with a history of coronary artery disease may benefit fromindefinite beta blockade therapy.

1 These guidelines provide basic recommendations. They are not intended as absolute or standard requirements. Practice guidelines should bemodified based on clinical needs and individual practice to ensure the highest quality of patient care.`

References:

1. Mangano DT, Browner WS, Hollenberg M, Li J, Tateo IM. Long-term cardiac prognosis following noncardiac surgery. The study ofPerioperative Ischemia Research Group [see comments] [Journal Article]. Journal of the American Medical Association (JAMA), July 8,1992 268(2);233-9.

2. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM, Association of perioperative myocardial ischemia withcardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group [seecomments] [Journal Article] New England Journal of Medicine, Dec. 17, 1990, 323(26):1781-8.

3. Mangano DT, Layug EL, Wallace A, Tateo IM, McSPI: Effect of atenolol on mortality and cardiovascular morbidity after noncardiacsurgery. New England Journal of Medicine, 1996. 335:1713-1720.

4. Poldermans D, Boersma E, Jeron J, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction inhigh-risk patients undergoing vascular surgery. New England Journal of Medicine, 1999; 341:1789-94.

5. Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, Miller D, Mangano D, Group. MR: Prophylactic atenololreduces postoperative myocardial ischemia. Anesthesiology 1998; 88:7-17.

This form is not intended to be a permanent part of the patient's Medical Record.

Fig. 2. Prophylactic perioperative b-blocker therapy inclusion and exclusion criteria.

schmiesing & brodsky310

Box 4. Clinical features of benign flowmurmurs

Location: left sternal border andnonradiating

Timing: mid or early systolicIntensity: grade 2 or lessNo unexplained cardiac or pulmonary

symptoms (eg, dyspnea, chest pain,orthopnea, syncope)

No additional unexplained cardiac signs(eg, rales, S3, significant peripheraledema)

No ECG or chest radiograph evidenceof ventricular hypertrophy

Box 6. Preoperative diagnostic testingconsiderations

preoperative anesthesia evaluation 311

therapy with low-molecular-weight heparin substi-

tuted when the short-term risk of thromboembolism is

high [33,34]. Anesthetic management also may be

altered. In addition to routine practice, invasive moni-

toring (arterial line, central line, pulmonary artery

catheter, or transesophageal echocardiography), sub-

Box 5. Preoperative diabeticconsiderations

Adequacy of control

1. Assess overall long-term blood glu-cose control

2. Determine preoperative short-termrisk of hyperglycemia andhypoglycemia

Diabetic medication regimen

1. Determine current diabetic regimen(oral and injectable)

2. Develop preoperative managementplan

Associated diabetic complications

1. Consider presence or risk of

a. CAD

b. Peripheral vascular disease

c. Renal insufficiency

d. Autonomic neuropathy2. Perform diagnostic testing to assess

for complications

stitution of anesthetic agents, avoidance of regional

anesthesia, and an increase in the level of postop-

erative monitoring may be required. Rarely is valve

replacement indicated before noncardiac surgery.

In general, patients should be considered for preop-

erative valve replacement only when they otherwise

would meet criteria for valve replacement surgery.

Stenotic valvular lesions generally are more prob-

lematic than regurgitant ones. The presence of aortic

stenosis, even when asymptomatic, has been shown

to increase risk in noncardiac surgery [9,15]. Current

trends suggest that a patient with asymptomatic aortic

stenosis, in the absence of other significant cardiac

problems, can undergo general anesthesia for non-

cardiac surgery with careful anesthetic monitoring

[35–37]. Fifty percent of patients with aortic stenosis

also have CAD. It is important to have a complete

preoperative cardiac assessment. The key point is to

identify and quantify aortic stenosis and to plan for

1. History and physical examinationare the best predictors of clinicalcourse [46].

2. Testing results in considerable ex-pense, inconvenience, and discom-fort for the patient.

3. Repeating tests that were recentlynormal rarely reveals significantchanges [47].

4. Testing when there is low proba-bility of a disease increases thelikelihood of false-positive results,leading to unnecessary and poten-tially harmful workups and delays[48,49].

5. Abnormal tests with medical signifi-cance often are overlooked resultingin medical liability (eg, mild anemiacaused by occult gastrointestinalmalignancy) [50].

6. Abnormal test results, even whenreal, may not change management.

7. Testing is helpful when new orunexpected signs or symptoms arefound before surgery. Workup gen-erally should be the same as ifthe patient were not scheduledfor surgery (eg, chest pain, wheez-ing, syncope).

Table 2

General preoperative testing recommendations for specific disease states

Preoperative diagnosis ECG

Chest

x-ray Hct/Hb CBC Electrolytes Renal Glucose Coagulation LFTs

Drug

levels Ca+

Cardiac disease

Chronic atrial fibrillation X Xy

CHF X ± ±

Hypertension X ± X* X

MI history X ±

PVD X

Stable angina X ±

Vulvular heart disease X ±

CNS disorders

Seizures X X X X X

Stroke X X X X X

Coagulopathies X X

Endocrine disease

Addison’s disease X X X

Cushing’s disease X X X

Diabetes X ± X X

Hyperparathyroidism X X X X

Hyperthyroidism X X X X

Hypoparathyroidism X X X

Hypothyroidism X X X

Hematologic disorders X

Hepatic disease

Alcohol/drug-induced X X

Infectious hepatitis X X

Tumor infiltration X X

Malabsorption/

poor nutrition

X X X X X ±

Morbid obesity X ± X

Pulmonary disease

Asthma

Chronic bronchitis X ± X

Emphysema X ± Xz

Lung cancer X X X X X X

Renal disease X X X

Select drug therapies

Anticoagulants X X

Aspirin/NSAID (No tests)

Chemotherapy X

Digoxin (digitalis) X ± X

Dilantin X

Diuretics X X

Phenobarbital X

Corticosteroids X X

Theophylline X

X = obtain; ± = consider.

Abbreviations: CBC, complete blood count; CHF, congestive heart failure; Hct/Hb, hematocrit/hemoglobin; LFTs, liver function

tests; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; PVD, peripheral vascular disease.

* Patients on diuretics.y Patients on digoxin.z Patients on theophylline.

From Fischer SP. Preoperative Considerations. In: Jaffe AR, Samuels IS, editors. Anesthesiologist’s manual of surgical

procedures. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 2004. p. A–4; with permission.

schmiesing & brodsky312

preoperative anesthesia evaluation 313

potential intraoperative problems. Unrecognized se-

vere aortic stenosis may be the cause of major peri-

operative complications.

Mitral stenosis is more difficult to identify by

auscultation than aortic stenosis. Mitral stenosis

presents as a low-pitched diastolic rumble with or

without an opening snap. Symptomatic patients with

mitral stenosis and pulmonary hypertension are at

high risk [38]. Patients with either aortic or mitral

regurgitation who have preserved left ventricular

function are generally at lower risk from anesthe-

sia [39,40].

Diabetes mellitus

Diabetes is the most common endocrine disorder

in surgical patients, affecting approximately 5% of

the North America population [41,42]. Diabetic

patients present numerous issues to be considered

during the preoperative assessment (Box 5). Asso-

ciated CAD is a significant problem and should

always be considered during the preoperative assess-

ment of a diabetic patient. General goals include

avoidance of hyperglycemia and hypoglycemia.

Surgery should be scheduled early in the day. Fast-

ing patients should be cautioned about symptoms of

hypoglycemia and hyperglycemia and advised to

monitor glucose levels at home. Patients should be

given clear instructions about how and when to ad-

just their diabetic regimen.

In general, fasting type 2 diabetics on diet or oral

therapy alone simply may withhold their medications

on the day of surgery. Type 1 and type 2 diabetics

requiring insulin can be managed with a ‘‘sliding

scale’’ on the day of surgery or with a downward

adjustment in their usual insulin regimen, switching

from long-acting to short-acting or intermediate-

acting insulins. Patients on insulin pumps usually

can continue them at their basal rate.

No single formula or conversion scale fits all

clinical situations. It is helpful to enlist the patient’s

experience when deciding how to adjust insulin-

dosing regimens because patients usually have good

insight into their likely responses to changes in their

oral intake and therapy. Simply instructing a patient

who is coming for surgery early in the morning to

take their morning insulin at 5 a.m. is not appropri-

ate if they normally do not take their insulin until

10 a.m. Changes should be conservative; one should

not aim for tight preoperative glycemic control.

Blood glucose levels of 120 to 200 g/dL are generally

well tolerated and safe. Frequent checks of blood

glucose levels at home and after the patient arrives

at the hospital minimize problems.

Preoperative diagnostic testing

In addition to the cardiovascular screening tests

discussed previously, preoperative evaluation before

thoracic surgery often includes a complete assessment

of pulmonary function and reserve. Detailed discus-

sions of appropriate pulmonary testing strategies

before thoracic surgery are presented elsewhere in

this issue. What is considered ‘‘appropriate’’ routine

preoperative testing continues to evolve, more re-

cently taking a path leading to fewer, not more, tests.

There is little evidence to suggest a clear benefit for

most routine testing and much to argue against it

[43–45]. Some factors to consider regarding diag-

nostic testing are presented in Box 6. Often the type

of operation determines the appropriate tests. General

testing guidelines for specific medical conditions

are provided in Table 2 [51].

Summary

Thorough and timely anesthesia preoperative

evaluation is essential for good patient outcomes.

Perioperative care is becoming more complex and

comprehensive, while older and sicker patients are

being considered for major thoracic surgery. In ad-

dition to pulmonary and wound care, prevention of

cardiac complications with b-blocker therapy, mul-

timodal pain control, tighter glycemic control, nutri-

tional support, and prevention of thromboembolism

are important perioperative goals. Early identification

of significant medical and nonmedical issues allows

for complete evaluation and planning and decreases

the likelihood of delays, cancellations, and compli-

cations. Good communication and preparation benefit

everyone. The implementation of an anesthesia pre-

operative assessment program or clinic can help

achieve these important goals.

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Index

Note: Page numbers of article titles are in boldface type.

A

Acetylcholine receptor antibodies, in myasthenia

gravis, 288–289

Acova, in anticoagulation, after thoracic surgery, 255

Activated partial thromboplastin time, in anticoagu-

lated patients, 258–259

b-Agonists, and risk of cardiac disease, 266

Air leaks, after thoracic surgery, as contraindication

to early discharge, 223

Airway obstruction, myasthenia gravis and, 292

Ampicillin/sulbactam, for surgical site infections,

231–232

Amyotrophic lateral sclerosis, versus myasthenia

gravis, 291

Anesthesia, in thoracic surgery, cardiac assessment

for. See Cardiac assessment.

preoperative assessment for, 305–315

ASA classification in, 306–307

diabetes mellitus in, 313

goals of, 305

hypertension in, 307–308

myasthenia gravis in, 293

physician communication in, 306

setting for, 306

tests in, 313

timing of, 305

valvular heart disease in, 309, 311, 313

Angiomax, in anticoagulation, after thoracic surgery,

254–255

Antibiotics, for surgical site infections, 229–235

ampicillin/sulbactam, 231–232

CDC recommendations for, 233

cefazolin, 229–232

cefuroxime, 232

cephalexin, 234

cephalothin, 231

historical aspects of, 229–232

intraoperative, 233

mechanical ventilation and, 233

penicillin G, 231, 232

postoperative, 233

preoperative, 233

randomized studies of, 230–232, 234

Anticoagulated patients, 240, 241, 243–262

antiplatelet agents in, 245–246

bleeding potential in, assessment of, 257–259

clinical, 257–258

laboratory tests in, 258–259

coagulation system in, 243–245

direct thrombin inhibitors in, 240, 253–256

hirudin derivatives, 254

hirulogs, 254–255

small-molecule, 255–256

factor Xa inhibitors in, 250–251

hypercoagulability in, and venous thromboembo-

lism, 259

indirect thrombin inhibitors in, 247–253

low-molecular-weight heparin, 240, 241, 250

complications of, 249

dose and administration of, 248–249

pharmacology and mechanism of action of,

247–248

reversing action of, 256

unfractionated heparin, 240, 241, 247–249

complications of, 249

dose and administration of, 248

pharmacology and mechanism of action of,

247–248

reversing action of, 256

warfarin in, 251–253

complications of, 253

dose and administration of, 252–253

pharmacology and mechanism of action of,

251–252

reversing action of, 256–257

Antidepressants, in smoking cessation, 192

Antiplatelet agents, in anticoagulation, after thoracic

surgery, 245–246

1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/S1547-4127(05)00051-4 thoracic.theclinics.com

Thorac Surg Clin 15 (2005) 317–322

Aortic stenosis, anesthetic risks of, 311, 313

Argatroban, in anticoagulation, after thoracic

surgery, 255

Arixtra, in anticoagulation, after thoracic surgery,

250–251

Arterial blood gas analysis, before lung resection, 298

Arterial thrombosis, in anticoagulated patients, 249

Aspirin, in anticoagulation, after thoracic surgery,

245–246

Atenolol, to reduce risk of cardiac complications, of

thoracic surgery, 271

Azathioprine, for myasthenia gravis, 291

B

Barium esophagogram, before esophageal

surgery, 278

Biopsy, endoscopic, before esophageal surgery, 278

lung, thoracoscopic, early discharge after, 222

Bisoprodol, to reduce risk of cardiac complications,

of thoracic surgery, 271–272

Bivalirudin, in anticoagulation, after thoracic surgery,

254–255

b-Blockers, to reduce risk of cardiac complications,

of thoracic surgery, 309

Botulism, versus myasthenia gravis, 290

Brainstem disorders, versus myasthenia gravis,

290–291

Bronchoscopy, to stage esophageal cancer, 282

Bupropion, in smoking cessation, 192

C

Calcium channel blockers, to reduce risk of cardiac

complications, of thoracic surgery, 272

Cancer, pre-existing, as risk factor, for pulmonary

embolism, 237–238

Cardiac assessment, before esophageal surgery, 283

before thoracic surgery, 263–275, 308–309

chronic obstructive pulmonary disease and,

265–266

clinical predictors of risk in, 268

effects of anesthesia, 264–265

clinical features of, 265

induction agents, 264

narcotic-based, 264–265

neuromuscular blockade, 264

volatile agents, 265

effects of surgery on cardiovascular system,

263–264

exercise tests in, 270, 301

guidelines for, 266, 268–269

inhaled b-agonists and, 266magnetic resonance imaging in, 269–270

risk reduction in, 271–272

pharmacologic, 271-272

revascularization in, 271

surgery-specific risk in, 269

Cardiac disease, anesthetic risks of, 308–309

myasthenia gravis and, 292

Cardiopulmonary exercise tests, before lung

resection, 301

Cardiovascular function, cigarette smoke and,

189–190

Cephalosporins, for surgical site infections.

See Antibiotics.

Chest physiotherapy, in preoperative pulmonary

rehabilitation, 209

Chronic obstructive pulmonary disease, and risk of

cardiac disease, 265–266

Clonidine, in smoking cessation, 192

Clopidogrel, in anticoagulation, after thoracic

surgery, 246

Computed tomography, to stage esophageal cancer,

280–281

Coronary artery bypass grafts, before non-cardiac

surgery, 308–309

preoperative pulmonary rehabilitation in, 206

Cyclosporine, for myasthenia gravis, 291

D

Deep venous thrombosis, and pulmonary embolism.

See Pulmonary embolism.

Depression, versus myasthenia gravis, 291

Diabetes mellitus, anesthetic risks of, 313

Diet, preoperative patient education on, 197

Diffusion capacity, assessment of, before lung

resection, 298

Dipyridamole, in anticoagulation, after thoracic

surgery, 246

Direct thrombin inhibitors.

See Anticoagulated patients.

INDEX318

E

Eaton-Lambert syndrome, versus myasthenia

gravis, 291

Edrophonium test, for myasthenia gravis, 290

Electromyography, of myasthenia gravis, 289–290

Emphysema, lung volume reduction surgery for,

preoperative assessment for, 302

preoperative patient education on, 198–199

preoperative pulmonary rehabilitation in,

204–205

Empyema, after thoracic surgery, prevention of, 232

Endoscopic biopsy, before esophageal surgery, 278

Endoscopic ultrasonography, to stage esophageal

cancer, 282

Epidural analgesia, after thoracic surgery, 223

Esophageal cancer, staging of. See

Esophageal surgery.

Esophageal surgery, mode of resection and

reconstruction in, 283–284

patient selection for, 282–283

preoperative preparation for, 277–285

barium esophagogram in, 278

endoscopic biopsy in, 278

esophagectomy for cancer, 280

manometry in, 278–279

pH monitoring in, 279

staging esophageal cancer, 280–282

bronchoscopy in, 282

computed tomography in, 280–281

endoscopic ultrasonography in, 282

positron emission tomography in, 281–282

Esophagectomy, preoperative patient education

on, 199

Exercise tests, in cardiac assessment, before lung

resection, 301

before thoracic surgery, 270

Exercise training, in preoperative pulmonary

rehabilitation, 208–209

F

Factor Xa inhibitors, in anticoagulation, after thoracic

surgery, 250–251

Fondaparinux, in anticoagulation, after thoracic

surgery, 250–251

G

Gastroesophageal reflux disease, surgery for, preop-

erative preparation for. See Esophageal surgery.

H

Hemorrhage, in anticoagulated patients, 249

Heparin. See Anticoagulated patients.

Hirudin derivatives, in anticoagulation, after thoracic

surgery, 254

Hirulogs, in anticoagulation, after thoracic surgery,

254–255

Hypertension, anesthetic risks of, 307–308

I

Immunoglobulin, intravenous, for myasthenia

gravis, 292

Immunosuppressive drugs, for myasthenia

gravis, 291

Imuran, for myasthenia gravis, 291

Indirect thrombin inhibitors. See

Anticoagulated patients.

Induction agents, in thoracic surgery, cardiac assess-

ment for, 264

Infections, after thoracic surgery, as contraindication

to early discharge, 224

surgical site, antibiotics for. See Antibiotics.

Intermittent pneumatic compression, to prevent

pulmonary embolism, after thoracic surgery,

239–240

International Normalized Ratio, in anticoagulated

patients, 258–259

Inversine, in smoking cessation, 192–193

J

‘‘Jitter test,’’ for myasthenia gravis, 289–290

‘‘Jolly test,’’ for myasthenia gravis, 289

K

Kearns-Sayre syndrome, versus myasthenia

gravis, 291

Kefzol, for surgical site infections, 229–232

L

Lepirudin, in anticoagulation, after thoracic

surgery, 254

Lobectomy, preoperative patient education on, 198

INDEX 319

Low-molecular-weight heparin. See

Anticoagulated patients.

Lung biopsy, thoracoscopic, early discharge

after, 222

Lung cancer, resection of, preoperative assessment

for. See Lung resection.

Lung resection, preoperative assessment for,

297–304

arterial blood gas analysis in, 298

cardiac disease in, 298

diffusion capacity in, 298

exercise tests in, 301

lung volume reduction surgery, 302

occupational and travel history in, 297

patient’s activity level in, 297

prediction of postoperative function in,

298–301

prior or active infections in, 297–298

prior thoracic surgery in, 298

smoking cessation in, 297

spirometry in, 298

underlying parenchymal disorder in, 298

preoperative patient education on, 198

preoperative pulmonary rehabilitation in,

205–206

Lung volume reduction surgery, preoperative

assessment for, 302

preoperative patient education on, 198–199

preoperative pulmonary rehabilitation in,

204–205

M

Magnetic resonance imaging, in cardiac assessment,

before thoracic surgery, 269

Manometry, before esophageal surgery, 278–279

Mecamylamine, in smoking cessation, 192–193

Mitral stenosis, anesthetic risks of, 313

Muscle-sparing thoracotomy, early discharge

after, 222

Myasthenia gravis, 287–295

acetylcholine receptor antibodies in, 288–289

and anesthesia, 293

cardiac disease with, 292

classification of, 289

clinical features of, 287

diagnosis of, 289–290

electromyography in, 289–290

radioimmunoassays in, 290

Tensilon test in, 290

differential diagnosis of, 290–291

management of, 291–293

immunosuppressive drugs in, 291

intravenous immunoglobulin in, 292

plasmapheresis in, 292

pyridostigmine in, 291

steroids in, 291

thymectomy in, 293

physical examination for, 287–288

upper airway obstruction in, 292

with thyroid disorders, 292

N

Narcotic-based anesthesia, in thoracic surgery,

cardiac assessment for, 264–265

Neuromuscular blockade, in thoracic surgery, cardiac

assessment for, 264

Nicotine replacement therapy, in smoking

cessation, 192

Nortriptyline, in smoking cessation, 192

Nosocomial pneumonia, after thoracic surgery, as

contraindication to early discharge, 224

prevention of, 232

Nutrition, preoperative patient education on, 197, 283

P

Pain management, inadequate, after thoracic surgery,

as contraindication to early discharge, 223

preoperative patient education on, 196–197

Penicillin G, for surgical site infections, 231, 232

Penicillinase, and myasthenia gravis syndrome, 290

pH monitoring, before esophageal surgery, 279

Photodynamic therapy, preoperative patient education

on, 199

Physiotherapy, chest, in preoperative pulmonary

rehabilitation, 209

Plasmapheresis, for myasthenia gravis, 292

Pneumatic compression stockings, to prevent pulmo-

nary embolism, after thoracic surgery, 239

Pneumonectomy, preoperative patient education

on, 198

Pneumonia, after thoracic surgery, as contraindication

to early discharge, 224

prevention of, 232

INDEX320

Positron emission tomography, to stage esophageal

cancer, 281–282

Prednisone, for myasthenia gravis, 291

Protamine, to reverse anticoagulation, after thoracic

surgery, 256–257

Psychoneuroses, versus myasthenia gravis, 291

Pulmonary assessment, before esophageal surgery, 283

Pulmonary embolism, after thoracic surgery, 237–242

prevention of, 239–241

guidelines for, 240–241

mechanical techniques for, 239–240

pharmacologic techniques for.

See Anticoagulated patients.

risk factors for, 237–239

pre-existing cancer, 237–238

Pulmonary function, cigarette smoke and, 189

Pulmonary rehabilitation, before thoracic surgery,

203–211

chest physiotherapy in, 209

coronary artery bypass graft, 206

education in, 209

exercise training in, 208–209

goals and proposed benefits of, 203–204

lung resection, 205–206

lung volume reduction surgery, 204–205

outcomes assessment in, 210

patient selection for, 206–207

psychosocial support in, 209–210

pulmonary evaluation in, 207–208

setting for, 204

smoking cessation in. See Smoking cessation.

transplantation, 205

upper abdominal, 206

Pyridostigmine, for myasthenia gravis, 291

R

Radioimmunoassays, for myasthenia gravis, 290

Respiratory hygiene, preoperative patient education

on, 196

S

Small-molecule direct thrombin inhibitors, in

anticoagulation, after thoracic surgery, 255–256

Smoking cessation, before thoracic surgery,

189–194, 197, 206, 207, 297

and early discharge, 221–222

bupropion in, 192

clonidine in, 192

counseling in, 191–192

effects of cigarette smoke, 189–190

on cardiovascular function, 189–190

on pulmonary function, 189

on wound healing, 190

mecamylamine in, 192–193

nicotine replacement therapy in, 192

nortriptyline in, 192

in perioperative period, 191

Spirometry, before lung resection, 298

Steroids, for myasthenia gravis, 291

Surgical site infections, antibiotics for.

See Antibiotics.

T

Tensilon test, for myasthenia gravis, 290

Thienopyridines, in anticoagulation, after thoracic

surgery, 246

Thoracic surgery, early discharge after, 221–228

clinical pathways in, 224–226

contraindications to, persistent air leaks,

223–224

pulmonary infections, 224

muscle-sparing thoracotomy and, 222

pain management and, 223

preoperative education and, 222

preoperative smoking cessation and, 221–222

social factors in, 224

video-assisted thoracoscopic surgery and, 222

in anticoagulated patients.

See Anticoagulated patients.

informed consent in, 213–219

causation in, 216–217

damages and, 217

exceptions to, 217–218

historical aspects of, 213–214

physician’s legal duty: materiality, 214–216

practical aspects of, 217

patient education before, 195–201

audiovisual materials in, 200–201

for esophagectomy, 199

for lung resection, 198

for lung volume reduction surgery, 198–199

for photodynamic therapy, 199

for research protocols, 199–200

for thoracoscopy, 198

for transplantation, 199

on contact numbers, 198

on diet and nutrition, 197, 283

INDEX 321

on pain management, 196–197

on respiratory hygiene, 196

on smoking cessation. See Smoking cessation.

on wound care and drains, 197

postdischarge social issues, 197–198

verbal instructions in, 200

Web-based materials in, 200

written instructions in, 200

preoperative assessment for, cardiac.

See Cardiac assessment.

lung resection. See Lung resection.

preoperative pulmonary rehabilitation in.

See Pulmonary rehabilitation.

pulmonary embolism after.

See Pulmonary embolism.

smoking cessation before. See Smoking cessation.

surgical site infections after, antibiotics for.

See Antibiotics.

Thoracoscopic lung biopsy, early discharge

after, 222

Thoracoscopy, preoperative patient education

on, 198

Thoracotomy, muscle-sparing, early discharge

after, 222

Thrombocytopenia, in anticoagulated patients, 249

Thymectomy, for myasthenia gravis, 293

Thyroid disease, versus myasthenia gravis, 291

with myasthenia gravis, 292

Ticlopidine, in anticoagulation, after thoracic

surgery, 246

Transplantation, preoperative patient education

on, 199

preoperative pulmonary rehabilitation in, 205

U

Ultrasonography, endoscopic, to stage esophageal

cancer, 282

Unasyn, for surgical site infections, 231–232

Unfractionated heparin. See Anticoagulated patients.

Upper abdominal surgery, preoperative pulmonary

rehabilitation in, 206

V

Valvular heart disease, anesthetic risks of, 309,

311, 313

Vena cava filters, to prevent pulmonary embolism,

after thoracic surgery, 240

Venous thrombosis, in anticoagulated patients, 249

Ventilatory muscle training, in preoperative

pulmonary rehabilitation, 209

Video-assisted thoracoscopic surgery, early discharge

after, 222

Vitamin K, to reverse anticoagulation, after thoracic

surgery, 256

W

Warfarin. See Anticoagulated patients.

Water seal, for persistent air leaks, after thoracic

surgery, 223

Wound care, preoperative patient education on, 197

Wound healing, cigarette smoke and, 190

X

Ximelagatran, in anticoagulation, after thoracic

surgery, 255–256

INDEX322