Preoperative medical consultation

Med Clin N Am 87 (2003) xv–xvi Preface Preoperative medical consultation Steven L. Cohn, MD, FACP Guest Editor Preo...

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Med Clin N Am 87 (2003) xv–xvi

Preface

Preoperative medical consultation

Steven L. Cohn, MD, FACP Guest Editor

Preoperative medical consultation plays an important role in the practices of both primary care physicians and subspecialists. Despite this fact, many physicians feel inadequately trained to function as consultants in the perioperative period. Prior to 1980, there were essentially no textbooks on the subject, and there were only a few ‘‘landmark’’ papers. The November 1979 issue of the Medical Clinics of North America on ‘‘Medical Evaluation of the Preoperative Patient’’ was essentially the ﬁrst ‘‘book’’ on the subject. Subsequently, numerous articles and textbooks on various aspects of preoperative medical consultation were published. Preoperative medical consultation was covered in the May 1987 issue, select topics in medical consultation in the March 1993 issue, and postoperative medical complications was the topic of the September 2001 issue of the Medical Clinics of North America. The goal of this current issue is to review and update the major topics in preoperative medical consultation. This publication is not intended to be an all-inclusive reference book. It was written by practicing internists with extensive experience in perioperative medicine and expertise in their selected areas. The vast majority of our authors are general internists and members of the Medical Consultation Interest Group of the Society for General Internal Medicine (www.sgim.org). Based on our experience, we have chosen topics we think are the most important or those most commonly encountered in clinical practice. The 15 articles in this issue range from the role of the consultant, preoperative laboratory testing, and perioperative medication management to preoperative risk assessment of patients with diseases

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of the major organ systems and risk reduction strategies to minimize potential postoperative complications. I feel that this information will be useful to all clinicians involved in preoperative medical consultation. I would like to thank my wife Deborah and children Alison and Jeﬀrey for their support, patience, and understanding during this project. Steven L. Cohn, MD, FACP Guest Editor Chief-Division of General Internal Medicine Clinical Professor of Medicine State University of New York, Downstate Medical Center 470 Clarkson Avenue-Box 68 Brooklyn, NY 11203, USA Director-Medical Consultation Service Kings County Hospital 451 Clarkson Avenue Brooklyn, NY 11203, USA

Med Clin N Am 87 (2003) 1–6

The role of the medical consultant Steven L. Cohn, MD, FACP* Division of General Internal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA Medical Consultation Service, Kings County Hospital, Brooklyn, NY, USA

Internists as well as subspecialists are often asked to evaluate a patient prior to surgery. Many primary care physicians, however, feel inadequately trained to function as consultants for preoperative medical evaluations [1]. Additionally, a recent survey of hospitalists found preoperative medical consultation to be an area of importance and one in which the hospitalists felt a need for additional training [2]. Much of the literature on perioperative medicine and medical consultation has been scattered among diﬀerent disciplines, and only recently has this information appeared in medical journals and textbooks typically read by internists. The role of the preoperative medical consultant is to identify and evaluate a patient’s current medical status and provide a clinical risk proﬁle, to decide whether further tests are indicated prior to surgery, and to optimize the patient’s medical condition in an attempt to reduce the risk of complications. Knowledge of medical illnesses that inﬂuence surgical risk, an understanding of the surgical procedure, eﬀective communication and interaction with the other members of the preoperative team, and integration of a management plan are crucial for the medical consultant. This article focuses on the general principles of consultative medicine, techniques to improve compliance, and the concept of risk assessment. Speciﬁc aspects of preoperative risk evaluation and perioperative management as they pertain to individual organ systems are discussed in subsequent articles. General principles of medical consultation The American Medical Association (AMA) noted nine ethical principles pertaining to consultation [3]. Three of these pertain to the referring physician: * Division of General Internal Medicine, State University of New York, Downstate Medical Center, 470 Clarkson Avenue, Box 68, Brooklyn, NY 11203. E-mail address: [email protected] (S.L. Cohn). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 8 - 7

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(1) consultations are indicated on request in doubtful or diﬃcult cases, or when they enhance the quality of medical care; (2) consultations are primarily for the patient’s beneﬁt; and (3) a case summary should be sent to the consulting physician unless a verbal description of the case has already been given. The other six ethical principles of consultation address the responsibilities and role of the consultant: (1) one physician should be in charge of the patient’s care; (2) the attending physician has overall responsibility for the patient’s treatment; (3) the consultant should not assume primary care of the patient without consent of the referring physician; (4) the consultation should be done punctually; (5) discussions during the consultation should be with the referring physician, and with the patient only by prior consent of the referring physician; and (6) conﬂicts of opinion should be resolved by a second consultation or withdrawal of the consultant; however, the consultant has the right to give his or her opinion to the patient in the presence of the referring physician. The concepts for performing eﬀective consultations were described by Goldman’s ‘‘Ten Commandments’’ [4]. These include: (1) determine the question; (2) establish urgency; (3) look for yourself; (4) be as brief as appropriate; (5) be speciﬁc and concise; (6) provide contingency plans; (7) honor thy turf; (8) teach with tact; (9) talk is cheap and eﬀective; and (10) follow-up. Determining the question It is of paramount importance for the consultant to determine precisely why the consultation was actually requested. The manner in which the referring physician phrases the request can inﬂuence the consultant’s response. For example, the consultant is often asked (inappropriately) to ‘‘clear a patient for surgery.’’ Beside the fact that this phrase should never be used because it incorrectly implies that if a patient is ‘‘cleared,’’ he or she will not develop any postoperative complication, it does not specify what the referring physician really wants. The surgeon may be asking for surgical risk assessment, approval to operate, diagnostic or management advice, reassurance, or documentation for medical legal reasons. Without eﬀective communication, the consultant’s response may not answer the question adequately. This need for direct communication in order to minimize the potential for misunderstanding was highlighted by two studies—the ﬁrst study reporting disagreement between the requesting physician and consultant about the primary reason for consultation in 14% of cases [5], and the second study ﬁnding that no speciﬁc question was asked in 24% of consults for diabetic patients, and that consultants ignored explicit questions in another 12% [6]. Answering the question Operative risk is the probability of an adverse outcome or death associated with surgery and anesthesia. It can be divided into four components:

S.L. Cohn / Med Clin N Am 87 (2003) 1–6

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(1) patient-related; (2) procedure-related; (3) provider-related; and (4) anesthetic-related. The consultant, in conjunction with the other members of the team, must ultimately decide, based on the patient’s risk factors, whether the patient is in his or her ‘‘optimal medical condition’’ or ‘‘acceptable’’ condition to undergo the planned surgical procedure. In order to do so, the following questions must be taken into account: (1) what is the status of the patient’s health? (2) if there is evidence of a medical illness, how severe is it, and does it aﬀect or increase operative risk? (3) how urgent is the surgery? (4) if surgery is delayed, will the severity of the medical illness be lessened by treatment? and (5) if there is no reason to delay surgery, what changes need to be made perioperatively in the patient’s management? An estimation of perioperative risk is based on a thorough history, physical examination, review of the available data, and selectively ordered laboratory tests (when indicated). This information should be obtained or conﬁrmed independently, and the consultant should make an extra eﬀort to obtain any additional existing information felt to be necessary to the evaluation. The consultant must also be able to function in the absence of complete data as it may be lacking, unavailable, or irrelevant to the question being asked. The consultant’s advice and recommendations need to be concise and speciﬁc to the question asked by the requesting physician. Whereas a subspecialist who is asked to evaluate a patient’s preoperative cardiac status usually restricts comments to the cardiovascular system, general internists often are more compulsive and try to do more than they were asked. It is important to recognize that the internist’s role as a preoperative medical consultant should focus only on issues relevant to the planned surgical procedure. If other problematic concerns unrelated to the primary reason for consultation are discovered, they can usually be addressed after surgery, but the consultant should ﬁrst discuss them with the referring physician. The disadvantage of making a long list of recommendations that are not really pertinent for surgery is that the other more relevant recommendations may be ignored. Similarly, the consultant should restrict advice to his area of expertise and not make recommendations about the type of anesthesia to be given without having had formal training in anesthesiology. Comments such as ‘‘no absolute contraindication to general anesthesia’’ or ‘‘cleared for spinal anesthesia only’’ are of no value. As noted by Choi [7], ‘‘The prudent medical consultant is wise enough to choose the anesthesiologist rather than the agent or choice of anesthesia.’’ Improving compliance Depending on the setting, referring physicians comply with the consultant’s recommendations 54–95% of the time [8–12]. Factors inﬂuencing compliance are shown in Table 1 [13] and correspond to Goldman’s Ten

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S.L. Cohn / Med Clin N Am 87 (2003) 1–6

Commandments [4]. As noted earlier, the primary reason for the consultation must be determined and addressed [5,9,12]. A timely response is important [14]. Urgent or emergent consultations need to be seen promptly, and elective in-patient consultations should usually be answered the same day as requested but in all cases within 24 hours. The consultant’s report should be informative yet concise. It should include an overall risk assessment, status of the patient for surgery, recommendations for management of the patient’s medications perioperatively, and recommendations to minimize risk of postoperative complications, including prophylaxis for venous thromboembolism, endocarditis, and surgical wound infection. In order to highlight the most important information for the referring physician, we recommend a format where the ﬁrst page of the written consultation report contains the reason for consultation, pertinent medical problems, impression as to whether or not the patient is in optimal medical condition for surgery, and recommendations for perioperative management. The history, physical examination, laboratory and test results, and additional discussion can follow on another page. Deﬁnitive language should be used [5,6,10,14,15], and recommendations should be prioritized, precise, and preferably limited to no more than ﬁve [11,12,16]. Recommendations felt to be ‘‘crucial’’ or ‘‘critical’’ are more likely to be followed [8,11,16], as are therapeutic as opposed to diagnostic recommendations [12,14]. Direct personal communication with the referring physician is preferable to only leaving a note in the chart [5,6,11]. The consultant’s responsibilities rarely end with the initial preoperative consultation. Appropriate follow-up visits with documentation in the chart improve compliance [14,16] and may improve care. The patient’s medical problems and type of surgery will dictate the frequency and duration of follow-up by the consultant. The consultant should sign oﬀ in writing when he or she no longer needs to follow the patient, and arrangements for long-term follow-up after discharge should be noted. Table 1 Factors inﬂuencing or improving compliance with consultant recommendations

Prompt response (within 24 hours) Limit number of recommendations ( 5) Identify crucial or critical recommendations (versus routine) Focus on central issues Make speciﬁc relevant recommendations Use deﬁnitive language Speciﬁed drug dosage, route, frequency, and duration Frequent follow-up including progress notes Direct verbal contact Therapeutic (versus diagnostic) recommendations Severity of illness

(From Cohn SL, Macpherson DS. Overview of the principles of medical consultation. In: Rose BD, editor. Wellesley, MA: UptoDate; 2002; with permission.)

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Comanagement and beneﬁts of medical consultation Whether or not the consultant should write orders depends on the arrangement with the referring physician. In some cases the consultant is being asked only to provide an opinion or advice that the primary attending physician may or may not choose to implement. In other cases, the consultant may actually comanage the case. This latter scenario is being seen more frequently with the proliferation of hospitalists, managed care, and disease management programs. One small study demonstrated a decrease in length of stay when an internist routinely cared for patients after thoracic surgery [17], and comanagement of orthopedic patients with hip fractures and joint replacement surgery is increasing. Other potential beneﬁts provided by preoperative medical consultants include ﬁndings of new diagnoses as well as assessments of pre-existing conditions resulting in changes in patient management, warranting additional work-up or treatment prior to surgery [18–24]. In this regard, they provide added value to the patient and referring physician. Additional outcome measures concerning quality of care should be forthcoming to determine their impact on optimal patient care. Summary The basic concepts of medical consultation have been reviewed. The referring physician and the consultant both have responsibilities to fulﬁll in order to maximize the eﬀectiveness of the consultation in improving patient care. The reasons for and urgency of the consultation need to be communicated to and understood by the consultant. The consultant needs to respond by promptly evaluating the patient, concisely documenting his ﬁndings, and communicating his recommendations to the referring physician. As described by Bates, the ideal medical consultant will ‘‘render a report that informs without patronizing, educates without lecturing, directs without ordering, and solves the problem without making the referring physician appear to be stupid’’ [25]. The consultant should try to support the referring physician and comfort the patient. By following these guidelines, the consultant will be more eﬀective in providing useful, informative advice likely to result in enhanced compliance with the recommendations and improved patient outcome. References [1] Devor M, Renvall M, Ramsdell J. Practice patterns and the adequacy of residency training in consultation medicine. J Gen Intern Med 1993;8:554–60. [2] Plauth III WH, Pantilat SZ, Wachter RM, et al. Hospitalists’ perceptions of their residency training needs: results of a national survey. Am J Med 2001;111:247–54. [3] Opinions and reports of the judicial council. In: Gross RJ, Caputo GM. Kammerer and Gross’ medical consultation: the internist on surgical, obstetric, and psychiatric services. Philadelphia, PA: Lippincott, Williams & Wilkins; 1998. p. 8.

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[4] Goldman L, Lee T, Rudd P. Ten commandments for eﬀective consultations. Arch Intern Med 1983;143:1753–5. [5] Lee T, Pappius EM, Goldman L. Impact of inter-physician communication on the eﬀectiveness of medical consultations. Am J Med 1983;74:106–12. [6] Rudd P, Siegler M, Byyny RL. Perioperative diabetic consultation: a plead for improved training. J Med Educ 1978;53:590–6. [7] Choi JJ. An anesthesiologist’s philosophy on Ômedical clearanceÕ for surgical patients. Arch Intern Med 1987;147:2090–2. [8] Ballard WP, Gold JP, Charlson ME. Compliance with the recommendations of medical consultants. J Gen Intern Med 1986;1:220–4. [9] Ferguson RP, Rubinstien E. Preoperative medical consultations in a community hospital. J Gen Intern Med 1987;2:89–92. [10] Klein LE, Moore RD, Levine DM, et al. Eﬀectiveness of medical consultation. J Med Educ 1983;58:149–51. [11] Pupa Jr LE, Coventry JA, Hanley JF, et al. Factors aﬀecting compliance for general medicine consultations to non-internists. Am J Med 1986;81:508–14. [12] Sears CL, Charlson ME. The eﬀectiveness of a consultation. Compliance with initial recommendations. Am J Med 1983;74:870–6. [13] Cohn SL, Macpherson DS. Overview of the principles of medical consultation. In: UptoDate, Rose, BD (Ed), UptoDate, Wellesley, MA, 2002. [14] Horwitz RI, Henes CG, Horwitz SM. Developing strategies for improving the diagnostic and management eﬃcacy of medical consultations. J Chronic Dis 1983;36:213–8. [15] Klein LE, Levine DM, Moore RD, et al. The preoperative consultation. Response to internists’ recommendations. Arch Intern Med 1983;143:743–4. [16] Mackenzie TB, Popkin MK, Callies AL, et al. The eﬀectiveness of cardiology consultation. Concordance with diagnostic and drug recommendations. Chest 1981;79:16–22. [17] Macpherson DS, Parenti C, Nee J, et al. An internist joins the surgery service: does comanagement make a diﬀerence? J Gen Intern Med 1994;9:440–4. [18] Charlson ME, Cohen RP, Sears CL. General medicine consultation. Lessons from a clinical service. Am J Med 1983;75:121–8. [19] Clelland C, Worland RL, Jessup DE, et al. Preoperative medical evaluation in patients having joint replacement surgery: added beneﬁts. South Med J 1996;89:958–60. [20] Devereaux PJ, Ghali WA, Gibson NE, et al. Physicians’ recommendations for patients who undergo noncardiac surgery. Clin Invest Med 2000;23:116–23. [21] Jainkittivong A, Yeh CK, Guest GF, et al. Evaluation of medical consultations in a predoctoral dental clinic. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80(4): 409–13. [22] Levinson W. Preoperative evaluations by an internist—are they worthwhile? West J Med 1984;141:395–8. [23] Mollema R, Berger P, Girbes AR. The value of peri-operative consultation on a general surgical ward by the internist. Neth J Med 2000;56:7–11. [24] Robie PW. The service and educational contributions of a general medicine consultation service. J Gen Intern Med 1986;1:225–7. [25] Bates RC. The two sides of every successful consultation. Med Econ 1979;7:173–80.

Med Clin N Am 87 (2003) 7–40

The case against routine preoperative laboratory testing Gerald W. Smetana, MD, FACPa,*, David S. Macpherson, MD, MPHb a

Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA b Department of Medicine, University of Pittsburgh, VA Pittsburgh Healthcare System, 130-U/University Drive C, Pittsburgh, PA 15240, USA

Most physicians order a battery of tests before surgery. This practice is widespread and is often based on policy or procedure at the facility where the physician practices. A practice of extensive testing of all patients before surgery is expensive—both in terms of direct costs of the tests and the need for follow-up of unanticipated minor abnormalities, many of which are normal on repeat testing or have no clinical relevance. Since the last review of this topic in 1993 in the Medical Clinics of North America [1], several new studies have been published including a large randomized trial for patients being considered for cataract surgery [2]. We write this article to guide physicians and facility policy makers regarding rational testing before surgery. We focus on adults being considered for elective surgical procedures and consider only preoperative blood tests, urinalyses, electrocardiograms, and chest radiographs—tests that are considered routine by institutions, physicians, and many patients. The reader is referred elsewhere for reviews of preoperative cardiac stress testing and pulmonary function testing. Normal and abnormal test results It is important for physicians to understand how laboratories deﬁne normal and abnormal test results. For many blood test results, a continuous distribution of results is possible. For example, a hemoglobin level may theoretically be measured from 0 through inﬁnity with any value in between. Other tests may have only ordinal results. For example, the degree of proteinuria reported on a dipstick determination may be reported only in * Corresponding author. 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 7 - 5

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a small number of discrete values (1þ, 2þ, etc.). Finally, some tests have only categorical results, normal or abnormal. The chest radiograph and electrocardiogram are examples. For test results that are continuous, the cut points for determining abnormally high or low values are set by the ‘‘reference range.’’ The reference range is determined as follows. For many test results, the distribution of values within a population of patients without disease is assumed to be normal. That is, if the distribution were plotted, a bell-shape curve would exist. The typical cut point for an abnormally high result is 2 standard deviations from the mean or the top 2.5% of results from a population without known disease. Likewise, an abnormally low result is reported in the bottom 2.5% of results in the population. Thus, in a population of patients without known disease, 5% would be found to have an abnormal test result. The reference range for many continuous tests results simply represents the middle 95% of the population. From the above, one can see that the probability of discovering an abnormal test result is 5% when a single test is ordered. When multiple tests with continuous results are ordered, the probability that at least one result will be abnormal quickly increases. For example, the likelihood of at least one abnormal test result from a chemistry panel of 20 tests is 64%, even in a patient with no disease. Thus, an institutional practice pattern of ordering multiple blood tests routinely before surgery will result in a large number of spuriously abnormal ﬁndings.

Rationale for preoperative testing There are several theoretic reasons why clinicians might order routine preoperative tests. These include: (1) to detect unsuspected abnormalities that might inﬂuence the risk of perioperative morbidity or mortality; (2) to establish a baseline value for a test that has a high likelihood of being monitored and changing after the surgical procedure is complete; and (3) for medical-legal reasons. For the ﬁrst rationale, three actions are possible regarding an abnormal test result. First, clinicians may take action to correct the abnormality before surgery with the hope that correction will decrease the risk of perioperative complications. Second, a serious abnormality might result in the clinician recommending that the surgery be canceled or the nature of the surgery be modiﬁed to a less intensive procedure. Third, the abnormality simply may be ignored. This is discussed further below. In the sections that follow about speciﬁc preoperative tests, we have framed our discussion around the ﬁrst rationale, as little literature exists regarding the use of preoperative tests to serve as a baseline for postoperative values or for medicallegal reasons. Some physicians and institutions may believe that routine screening tests before surgery protect them from legal liability. This is probably not true for

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the following reason. The existing literature suggests that clinicians ignore 30–60% of abnormalities discovered on routine preoperative tests [3]. Thus, in about half the patients in whom an abnormality is discovered, no notation exists in the medical record to reﬂect the physician’s thinking about the abnormality. Should the patient suﬀer a poor outcome, the lack of any documentation before the procedure about the abnormality would increase the probability of a judgment against the physician, should a suit be brought. For this reason, a strategy of routine preoperative screening in the absence of a careful system of documentation regarding even minor abnormalities may expose the physician to more risk than selective screening. Our review of the literature focuses on investigations of preoperative testing in patients for whom abnormal results were unsuspected. In many of these investigations, it was not possible to separate tests that may have been ordered because of ﬁndings on the history and physical exam from those that were ordered for routine reasons. Thus, estimates of the proportion of results that are abnormal probably overestimate the true prevalence of unsuspected abnormalities. We believe this limitation strengthens our overall conclusion that routine testing in patients without signs and symptoms suggesting a signiﬁcant likelihood of abnormal results is unwise. By contrast, investigations of preoperative testing in patients suspected to have abnormal results [4] or in patients whose recent previous results were abnormal [5] show a high prevalence of abnormal results. Normal test results obtained within 4 months before surgery may be safely used as preoperative tests if there has been no change in the clinical status of the patient during the interval. In one report, only 0.4% of such tests repeated at the time of surgery were abnormal; most could have been predicted by the patient’s history [5]. Screening implies that a patient has no known conditions that would increase the likelihood of an abnormal test result. A preoperative test must meet several characteristics to be valuable as a screening test for patients without known disease [6,7]. The disease must be common and contribute to perioperative morbidity. The screening test should be inexpensive and carry little risk to the patient. The test must be highly sensitive and have an acceptably high speciﬁcity so as to minimize false-positive results. A long interval of time must exist between the onset of an abnormal screening test and the development of clinically apparent disease (the detectable preclinical phase). Eﬀective and safe interventions must be available to reduce risk when clinicians identify patients during this phase. We will show in this article that most potential preoperative tests do not meet these criteria. Hemoglobin Blood loss as a result of surgery is common and, in many types of surgery, perioperative transfusion is necessary. Severe anemia during surgery risks tissue hypoxia from impaired oxygen delivery. Thus, unsuspected severe anemia theoretically may predispose the patient to tissue hypoxia

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in the perioperative period if not corrected preoperatively. For this reason, a case can be made on the basis of physiology for routine hemoglobin (or hematocrit) measurements for patients in whom signiﬁcant blood loss is anticipated. The prevalence of anemia discovered on routine screening varies depending on the study population. In our review of 8 studies (Table 1), the overall incidence of hemoglobin abnormalities was 1.8%. Studies of older patients [8,9] show a prevalence of anemia ranging from 4–9%. The positive likelihood ratio for abnormal hemoglobin, derived from only 2 studies that allowed such calculation, was 3.3. A baseline hemoglobin determination has been shown to predict the need for subsequent transfusion in patients undergoing surgical procedures associated with signiﬁcant blood loss [10]. Thus, a rationale can be made for a baseline hemoglobin to aide in planning for transfusions perioperatively. We recommend that patients have preoperative hemoglobin or hematocrit determination only if the planned surgical procedure is likely to result in signiﬁcant blood loss. Patients undergoing surgery not anticipated to result in signiﬁcant blood loss should be screened only if a history and physical examination suggest severe anemia. A medical history of profound fatigue, past history of anemia, malignancy, or renal insuﬃciency or physical examination ﬁndings suggesting anemia (resting tachycardia or conjunctival pallor) should prompt a hemoglobin determination even in patients undergoing minor surgery. White blood cell count The prevalence of unanticipated elevations of white blood cell counts is very low. In 4 of the 5 available studies, the prevalence was less than 1% (Table 2). In the two studies in which authors assessed management changes related to abnormal white blood cell counts, no patient underwent a management change [11,12]. In the two studies that allow the calculation of likelihood ratios for abnormal white blood cell counts, the ﬁndings suggest that an unanticipated elevated white blood cell count is unrelated to perioperative morbidity [11,12]. For this reason, we believe that routine screening white blood cell determinations should not be obtained before surgery. Clinicians should obtain preoperative white blood cell counts in patients with symptoms suggesting infection, those in whom a myeloproliferative disease is known or suspected (on the basis of splenomegaly or diﬀuse lymphadenopathy) or in those patients at high risk for leukopenia related to drugs or other known diseases. Platelet count Ten investigations have been published regarding the usefulness of platelet counts (Table 3). The incidence of abnormalities of platelet counts is

Ambulatory surgery Total hip arthroplasty for osteoarthritis Elective ASA class 1

1988 Prospective 1989 Retrospective

1991 Retrospective

1995 Retrospective

2001 Prospective

McKee and Scott [65] Johnson et al [48] Sanders et al [9]

Narr et al [29]

Perez et al [49]

Dzankic et al [8]

Noncardiac

Elective

Cholecystectomy

193 100

397

ASA class 1 or 2 70 years of age Hemoglobin or older > 10.0 g/dL

9363

1402

526

Hemoglobin 3782 >10.0 g/dL Reference range 3068

Reference range Reference range

Reference range

Hemoglobin 292 >10.0 g/dL or 18 g/dL Reference range 1005

Deﬁnition of normal test

1.8

10.5

1.4

0.8

9.8 4.0

3.3

0.7

0.3

0.1

0.1

0.2

0.0

3.3

0.6

20.4

0.9

1.1

0.7

Percent of Total Percent of all tests number tests that that inﬂuence LRþ LR of patients are abnormal management (CI) (CI)

Abbreviations: ASA, American Society of Anesthesiologists; CI, Conﬁdence Interval; LR, likelihood ratio.

Subtotal for studies with outcomes data Total

Elective

1987 Prospective

Turnbull and Buck [12]

No known medical conditions

1987 Retrospective

Kaplan et al [21]

All types

1985 Retrospective

Study

Population characteristics

Study design (prospective or Type of Year retrospective) surgery

Table 1 Hemoglobin abnormalities G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 11

1985 1987

1988 1989

1995 1999

Kaplan et al [21] Turnbull and Buck [12]

Johnson et al [48] Sanders et al [9]

Perez et al [49] Haug and Reifeis [50]

Subtotal for studies with outcomes data Total

Year

Study

Retrospective Prospective

Prospective Retrospective

Retrospective Retrospective

Study design (prospective or retrospective)

Table 2 White blood cell count abnormalities

Ambulatory surgery Total hip arthroplasty for osteoarthritis Elective Oromaxillofacial surgery in oﬃce setting

All types Cholecystectomy

Type of surgery

ASA class 1 or 2 ASA class 1 or 2

No known medical conditions

Population characteristics

5359

1109

3047 380

212 104

611 1005

Total number of patients

0.7

0.9 0.8

0.0 2.9

0.2 0.1

Percent of tests that are abnormal

0.0

0.0 0.0

Percent of all tests that inﬂuence management

0.0

0.00

LRþ (CI)

1.1

1.0

1.0 1.1

LR (CI)

12 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

Elective Ambulatory surgery Total hip arthroplasty for osteoarthritis Elective Elective major surgery Elective Oromaxillofacial surgery in oﬃce setting Noncardiac

1988 Prospective 1988 Prospective

1989 Retrospective

1991 Retrospective 1993 Prospective

Sanders et al [9]

Narr et al [29] Macpherson et al

Subtotal for studies with outcomes data Total

Dzankic et al [8]

2001 Prospective

Perez et al [49] 1995 Retrospective Haug and Reifeis [50] 1999 Prospective

All types Cholecystectomy

1985 Retrospective 1987 Retrospective

Kaplan et al [21] Turnbull and Buck [12] Rohrer et al [11] Johnson et al [48]

Study

Study design (prospective or Year retrospective) Type of surgery

Table 3 Abnormalities of platelet count

70 years of age or older

ASA class 1 Excluded those with bleeding history or on asprin ASA class 1 or 2 ASA class 1 or 2

No known medical conditions

Population characteristics

>115K

Reference range Not stated

9670

1116

520

3068 380

3782 111

63

Reference range

>100K >150K

163 212

Reference range Reference range

>115K and <800K 366 Reference range 1005

Deﬁnition of normal test

0.9

1.9

0.4 0.0

1.2 0.9

0.0

8.0 0.0

0.5 0.0

Percent Total of tests number that are of patients abnormal

0.02

0.0

0.0

0.3 0.0

0.0

0.0

0.0

1.0

1.0

Percent of all tests that inﬂuence LRþ LR management (CI) (CI)

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 13

14

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0.9%. One study reported a yield of 8%, but all patients in this investigation had slightly elevated counts rather than thrombocytopenia [11]. Management changes on the basis of unanticipated abnormalities in platelet count are rare. In our article, only 0.02% of all measurements of platelet count were abnormal and inﬂuenced surgical management. For this reason, we do not recommend routine platelet counts before surgery unless the history and physical exam ﬁndings suggest a high likelihood of thrombocytopenia or thrombocytosis. Patients with a history of bleeding or easy bruising, known myeloproliferative disease, or who have been recently exposed to drugs known to cause thrombocytopenia such as chemotherapeutic agents, should have a platelet count measured before surgery. Many institutions bundle hematocrit, hemoglobin, white blood cell count, and platelet count into a complete blood count. Because we recommend a hemoglobin or hematocrit in any patient anticipated as having signiﬁcant blood loss from surgery, the clinician will probably also receive a white blood count and platelet count. If minor abnormalities in platelet count or white blood cell count are discovered, the clinician should ﬁrst repeat the tests. If the abnormalities remain, the physician should consider a prudent search for diseases that might cause the abnormality. In most cases, however, the surgical procedure can proceed without delay, as the abnormalities are unlikely to inﬂuence the surgical outcome. Coagulation tests Many diﬀerent coagulation tests are available to the clinician. Theoretically, these tests might detect a predisposition to perioperative hemorrhage. In this article, we discuss only the prothrombin time and partial thromboplastin time, as they are the most commonly ordered laboratory tests to screen for coagulation disorders. We have chosen not to discuss the bleeding time as it is infrequently used as a routine screening test before surgery. Furthermore, the studies that have investigated the bleeding time have demonstrated it is a poor predictor of perioperative bleeding, even when used in populations on aspirin or nonsteroidal anti-inﬂammatory drugs (NSAIDs) [13,14]. It therefore is not a recommended routine screening test. Investigation of the prothrombin time shows a low yield of discovering unsuspected disease. Of the 6 investigations reviewed, the yield was 1% or less for 5 of them (Table 4). In the one study in which a likelihood ratio could be calculated, an abnormal test did not predict bleeding and a normal test was not reassuring that bleeding would not occur [9]. Abnormal screening partial thromboplastin times are more common. Of the 7 studies reviewed (Table 5), abnormal test results were found in as high as 16% of patients [15]; the overall incidence was 6.5%. Despite the higher yield, among the four studies in which likelihood ratios could be calculated, the partial thromboplastin time was not predictive of perioperative hemorrhage if abnormal (positive likelihood ratio [LR] 1.7).

1985 1987

1988

1989

1993

1995

Kaplan et al [21] Turnbull and Buck [12]

Rohrer et al [11]

Sanders et al [9]

Macpherson et al [51]

Perez et al [49]

Retrospective

Prospective

Retrospective

Prospective

Retrospective Retrospective

Abbreviation: PT, Prothrombin time.

Subtotal for studies with outcomes data Total

Year

Study

Study design (prospective or retrospective)

Table 4 Abnormalities of prothrombin time

Elective

Total hip arthroplasty for osteoarthritis Elective major surgery

Elective

All types Cholecystectomy

Type of surgery

Excluded those with bleeding history or on asprin ASA class 1 or 2

No known medical conditions

Population characteristics

Reference range

Reference range Reference range

PT <13 Reference range

Deﬁnition of normal test

3786

207

3043

0.3

0.2

0.0

1.1

95

111

0.8

1.0 0.0

123

201 213

Total number of patients

Percent of tests that are abnormal

0.0

0.0

Percent of all tests that inﬂuence management

0.00

0.00

LRþ (CI)

1.01

1.01

LR (CI)

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 15

1993 Prospective

1995 Retrospective

Perez et al [49] Subtotal for studies with outcomes data Total

1988 Prospective 1989 Retrospective

Macpherson et al [51]

Elective Total hip arthroplasty for osteoarthritis Elective major Excluded those surgery with bleeding history or on asprin Elective ASA class 1 and 2

1987 Retrospective

Turnbull and Buck [12] Rohrer et al [11] Sanders et al [9]

No known medical conditions

All types All invasive tests or procedures Cholecystectomy

1985 Retrospective 1986 Retrospective

Population characteristics

Kaplan et al [21] Suchman and Mushin [15]

Study

Study design (prospective or Type of Year retrospective) surgery

Table 5 Abnormalities of partial thromboplastin time (PTT)

111

PTT < 32 sec

Reference range 2955

123 63

210

199 2134

Reference range Reference range

Reference range

PTT < 40 sec PTT < 26.5 sec

Deﬁnition of normal test

6.5

0.3

7.2

2.4 7.9

1.4

0.5 16.3

Percent of tests Total that are number of patients abnormal

0.1

2.4

0.0

1.7

0.0

0.0

0.00

1.5

0.86

1.00

1.02

1.07

0.88

Percent of all tests that inﬂuence LRþ LR management (CI) (CI)

16 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

17

The prothrombin time and partial thromboplastin time should not be used as routine screening tests before surgery. Patients who have a history of bleeding disorders are a reasonable subgroup to screen. Clinicians should also order a prothrombin time in patients with chronic liver disease or malnutrition, and in those taking chronic antibiotics that might lead to clotting factor deﬁciencies. We refer the reader elsewhere for examples of screening questionnaires that may be used better to select patients for testing [16–18]. An extensively validated questionnaire has not been published to our knowledge, however. Electrolytes A theoretic rationale for measuring serum electrolytes routinely before surgery would be to identify patients at risk for adverse postoperative events including arrhythmia. Previous studies have primarily evaluated abnormalities of serum sodium and potassium. Clinical lore suggests that hypokalemia would be the most clinically important preoperative electrolyte abnormality to detect. The evidence does not, however, suggest a relationship between this laboratory abnormality and postoperative adverse events. For example, in the study of Hirsch et al, there was no association between preoperative potassium levels and the incidence of intraoperative arrhythmias among a cohort of 447 patients undergoing major vascular or cardiac surgery [19]. This held true even among the subset of patients with congestive heart failure. Similarly, in a case control study of patients with supraventricular tachycardia after coronary bypass surgery who were matched to controls, no diﬀerence existed in the incidence of preoperative hypokalemia or other electrolyte abnormalities between the two groups [20]. In our review of 8 studies of the value of preoperative electrolyte measurements (Table 6), the incidence of abnormalities was 12.7%; only 1.8% of all tests aﬀected management. As would be expected, most abnormalities could have been predicted on clinical grounds such as diuretic use or a history of renal insuﬃciency. As an example, in the study of Kaplan et al, no unexpected abnormalities in serum potassium occurred among 514 such tests [21]. Even when identiﬁed during routine preoperative screening, hypokalemia does not appear to be a risk factor for adverse events. In the report of Turnbull and Buck, there were 14 abnormal results of serum potassium measurement among 995 patients during routine screening; only 3 values were outside of traditional action limit ranges (3.2–5.8 mEq/L) [12]. Four of the 14 patients received potassium supplements before surgery, and none of the 14 patients had a cardiac complication. Among the subset of 3 studies in our review that allow determination of adverse event rates (Table 6), the positive LR for electrolyte abnormalities was 4.3. Though this value is higher than for most other potential preoperative tests, most of these patients could have been selectively identiﬁed as candidates for testing based on clinical criteria. We therefore do not

1988 1991 1991 1995

1999

2001

Turnbull and Buck [12]

Charpak et al [4] Velanovich [53]b Narr et al [29] Perez et al [49]

Skenderis [54]

Dzankic et al [8]

b

a

Total

Prospective

Retrospective

Prospective Prospective Retrospective Retrospective

Retrospective

Cholecystectomy No known medical conditions All Elective Elective ASA class 1 Elective ASA class 1 or 2 Colectomy Colorectal cancer Noncardiac 70 years of age or order

Population characteristics

Reference range

Reference range

Reference range Reference range Author criteria Reference range

Potassium 3.5–5.5 mEq/L Reference range

Deﬁnition of normal test

Adverse outcome ¼ intraoperative dysrhythmia. Estimated based on 4% prevalence of abnormal results. Complication ¼ cardiac and metabolic.

Subtotal for studies with outcomes data

1987

Vitez et al [52]a

All

1985

Study

Prospective

Study design (prospective or Type of Year retrospective) surgery

Table 6 Electrolyte abnormalities

1665 7764

403

105

1001 520 3782 808

995

150

12.7

11.4

8.6

81.2 4.0 0.2 0.7

1.9

41.3

Percent of tests Total number that are of patients abnormal

1.8

2.9

0.1 0.5

10.5

0.4

4.3

2.7

2.4

0.9

0.78

0.84

0.97

1.07

Percent of all tests that inﬂuence LRþ LR management (CI) (CI)

18 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

19

recommend routine measurement of preoperative electrolytes. Clinicians should obtain such tests for patients with baseline renal insuﬃciency or congestive heart failure, or who are taking diuretics, digoxin, aniotensin converting enzyme (ACE) inhibitors or other medications that increase the likelihood of abnormal results. Renal function tests Over the past decade, a growing body of literature suggests that preoperative renal insuﬃciency is one of the most important risk factors for postoperative complications in both cardiac and noncardiac surgery. For example, in the revised cardiac risk index of Lee et al, preoperative serum creatinine >2.0 mg/dL was 1 of 6 predictors of risk for postoperative cardiac complications in a validated multifactorial analysis of patients undergoing noncardiac surgery [22]. The recently revised guideline on perioperative cardiac evaluation for noncardiac surgery by The American College of Cardiology and The American Heart Association also reﬂects the growing awareness of this risk factor by classifying renal insuﬃciency as an intermediate clinical risk predictor. In this guideline, renal insuﬃciency carries the same weight as mild angina, previous myocardial infarction, compensated heart failure, and diabetes [23]. Similarly, renal insuﬃciency predicts postoperative cardiac complications in patients undergoing cardiac and major vascular surgery. For example, in a large cohort of 5051 patients undergoing coronary bypass surgery, creatinine >1.9 mg/dL was second only to emergency surgery as a risk factor for postoperative morbidity and mortality [24]. This proved to be a stronger predictor than established risk factors including left ventricular dysfunction, advanced age, and diabetes. Other investigators have also shown renal insufﬁciency to be a major predictor of adverse events after aortic and valvular surgeries [25,26]. Modest renal insuﬃciency, such as that shown to be a risk factor in the above studies, will not always be clinically apparent. In our review (Table 7), 8.2% of all renal function tests (either blood urea nitrogen [BUN] or creatinine) were abnormal and 2.6% of all tests were abnormal and inﬂuenced management. This rate of inﬂuential test results is higher than that for most other potential preoperative tests. The positive LR for an abnormal renal function test was 3.3 and is clinically useful. Like all potential routine preoperative tests, the negative LR approaches one and a normal test result does not substantially reduce the likelihood of an adverse event. Though previous large studies of preoperative testing found a low prevalence of unexpected abnormal results of renal function testing, we believe that more recent data showing the power of renal insuﬃciency as a risk predictor warrant reconsideration of the indications for this test. We therefore recommend preoperative testing of renal function for patients with a substantial likelihood of renal insuﬃciency and in those undergoing major surgery. Our recommended indications include age >50 years old, diabetes,

Coronary bypass

Coronary bypass

1991 Prospective 1992 Retrospective

1996 Retrospective

1998 Prospective

1999 Retrospective

Velanovich [53]a Higgins et al [24]

Kurki and Kataja [27] Mangano et al [55]b

Skenderis [54]

Colectomy

Elective Coronary bypass

All Total hip arthroplasty

1988 Prospective 1989 Retrospective

Charpak et al [4] Sanders [9]

Cholecystectomy

1987 Retrospective

Turnbull and Buck [12]

Study

Study design (prospective or Year retrospective) Type of surgery

Table 7 Renal function abnormalities

Reference range

Deﬁnition of normal test

Reference range Reference range Otherwise healthy patients with osteoarthritis Reference range Creatinine < 1.9 mg/dL Creatinine < 1.24 mg/dL No preexisting Creatinine renal failure < 2.0 mg/dL Colorectal Reference range cancer

No known medical conditions

Population characteristics

105

2222

366

520 5051

995 95

995

3.8

14.1

13.7

11.9 3.1

26.2 1.1

0.3

Percent of tests Total number that are of patients abnormal

0.0

5.5

0.0

2.8

2.1

2.3 4.3

0.0

0.88

0.72

0.88 0.54

1.09

Percent of all tests that inﬂuence LRþ LR management (CI) (CI)

20 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

1999 Prospective

2000 Prospective

2001 Prospective

Lee et al [22]

Anderson et al [25]c

Dzankic et al [8]

c

b

a

Carotid No concurrent endarterectomy non carotid vascular surgeries Elective 50 years of age noncardiac or older Cardiac valve surgery Noncardiac 70 years of age or older Creatinine < 2.0 mg/dL Creatinine < 1.5 mg/dL Reference range

Creatinine < 1.5 mg/dL

Estimated based on 12% prevalence of abnormal results. Complication ¼ cardiac and metabolic. Adverse outcome ¼ postoperative renal dysfunction. Adverse outcome ¼ mortality.

Subtotal for studies with outcomes data Total

1999 Retrospective

Hamdan et al [56]

15437

14337

360

834

2893

1001

8.2

11.7

23.6

3.6

7.3

2.6

3.3

2.9

2.7

5.2

5.7

0.81

0.63

0.89

0.93

0.69

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 21

22

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

hypertension, known cardiac disease, use of medications that may inﬂuence renal function such as ACE inhibitors or NSAIDs, and major procedures including cardiac, vascular, chest, and abdominal surgeries.

Serum glucose Established diabetes requiring treatment is a risk factor for postoperative cardiac complications. In the recent revised cardiac risk index by Lee et al, diabetes requiring insulin therapy was 1 of 6 independent risk factors for postoperative cardiac complications; the relative risk associated with this factor was 3.0 [22]. Diabetes also increases morbidity and mortality among patients undergoing coronary artery bypass surgery [24,27]. In addition, diabetes increases the risk of sternal wound infections among patients undergoing coronary bypass grafting, and evidence exists that tighter perioperative control of blood glucose may decrease this risk [28]. These observations, however, apply to patients with established and clinically apparent diabetes that requires treatment. Whether a similar risk applies to patients without a clinical diagnosis of diabetes who are found to have an elevated serum glucose on routine preoperative screening is the subject of our discussion. Table 8 details the value of an abnormal serum glucose as part of routine preoperative testing based on our review of clinical series. Overall, 9.3% of measurements were abnormal. Most of these values occurred in patients with known diabetes. Only 0.5% of all values were abnormal and inﬂuenced perioperative management. Most abnormalities were clinically insigniﬁcant or ignored. For example, in the study of Kaplan et al, only 4 of 3100 preoperative glucose measurements were unindicated by clinical criteria and abnormal [21]. Two of these values were normal on repeat; and two were abnormal though ignored by the surgeon with no resulting postoperative complications. In a study of 3782 American Society of Anesthesiologists (ASA) class I patients, only 16 patients had abnormal serum glucose values that prompted further assessment [29]. Five patients were advised to delay surgery and lose weight; only one patient among the 3782 was found to have a new diagnosis of diabetes that required treatment. Among the subset of studies in our review that reported postoperative complications, the positive and negative LRs approached 1, being 1.68 and 0.85, respectively. Given the low incidence of unsuspected diabetes (0.5%) among patients preparing for surgery and the lack of evidence that identiﬁcation and treatment of patients with clinically occult diabetes reduces postoperative complications, we do not recommend routine preoperative measurement of serum glucose. Such measurements are helpful, however, as part of the perioperative management of patients with known diabetes, and clinicians may consider preoperative testing of serum glucose in patients with symptoms that suggest undiagnosed diabetes or in obese patients. The available litera-

a

All types Cholecystectomy No known medical conditions All Total hip Otherwise healthy arthroplasty patients with osteoarthritis Elective Elective ASA class 1 Elective ASA class 1 or 2 Colectomy Colorectal cancer Oromaxillofacial ASA class 1 or 2 surgery in oﬃce setting Noncardiac 70 years of age or older

Population characteristics

705 91

464 436

Reference range

9.4 9.3

9540

6.8

18.1 1.9 5.2 19.3 0.2

71.5 4.4

5.4 1.8

1306

251

Reference range 520 Author criteria 3782 Reference range 2760 Reference range 119 Not stated 412

Reference range Reference range

Action limits Reference range

Deﬁnition of normal test

0.5

0.6 0.2 0.0 0.0

2.1 0.0

0.4 0.0

1.68

1.50

2.14

1.01

0.85

0.62

0.83

1.00

Percent of all Total Percent of tests that number of tests that are inﬂuence LRþ LR patients abnormal management (CI) (CI)

Estimated based on 18% incidence of abnormal result. Complications ¼ cardiac, metabolic, and wound.

Subtotal for studies with outcomes data Total

2001 Prospective

Dzankic et al [8]

Prospective Retrospective Retrospective Retrospective Prospective

1991 1991 1995 1999 1999

1988 Prospective 1989 Retrospective

1985 Retrospective 1987 Retrospective

Velanovich [53]a Narr et al [29] Perez et al [49] Skenderis et al [54] Haug and Reifeis [50]

Kaplan et al [21] Turnbull and Buck [12] Charpak et al [4] Sanders et al [9]

Study

Study design (prospective or Year retrospective) Type of surgery

Table 8 Elevated serum glucose values G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 23

24

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

ture does not, however, allow a ﬁrm recommendation about the value of such screening. Hepatic tests Patients with advanced liver disease and cirrhosis have a marked increase in the risk of postoperative complications and death. The risk increases with increasing severity of liver disease, as classiﬁed by the Child-Pugh criteria. For example, among patients with cirrhosis undergoing abdominal surgery, mortality rates for Child-Pugh class A, B, and C are 10%, 31%, and 76%, respectively [30]. But few data exist to suggest that asymptomatic elevations of transaminases or alkaline phosphatase in patients without known liver disease imply a surgical risk. Relatively few studies of routine preoperative testing have evaluated the value of hepatic enzyme determinations. Table 9 summarizes the existing literature. No studies have reported the incidence of adverse events in patients with normal or abnormal hepatic enzyme results. Only 0.4% of all routine preoperative hepatic enzyme tests were abnormal. In only 0.1% of cases did this ﬁnding lead to a change in perioperative management, usually cancellation of surgery and further diagnostic evaluation. No study attributed excess morbidity to the ﬁnding of an abnormal hepatic enzyme, but speciﬁc incidences were unavailable. Clinically unsuspected abnormal hepatic enzyme levels are less frequent than other potentially routine preoperative tests. Given the very low incidence of abnormalities that inﬂuence management, we do not recommend routine testing of transaminases or alkaline phosphatase before surgery. A recent observation, however, suggests that measurement of serum albumin, often considered a liver function test, predicts postoperative morbidity. Gibbs et al prospectively studied 54,215 veterans undergoing major noncardiac surgery [31]. Mortality for patients increased from less than 1% for patients with a serum albumin of 4.6 gms/dL to 28% for patients with a serum albumin level of <2.1 gm/dL. In a multivariate analysis, serum albumin level was the single strongest predictor of perioperative morbidity and mortality, and it was more powerful than commonly used preoperative characteristics including ASA class, functional status, age, or emergency operation. It is unclear that eﬀorts to correct a low serum albumin improve surgical outcomes. Nonetheless, the discovery of a markedly reduced serum albumin should cause the clinician to pause and reconsider the need for surgery. Given the power of this risk factor, and until future studies validate this ﬁnding, we would consider measurement of serum albumin, if not recently obtained, for patients undergoing major surgery who have known liver disease, multiple serious chronic illnesses, recent major illnesses, or in whom malnutrition seems likely. Urinalysis The rationale for routine preoperative testing would be to identify asymptomatic abnormalities that would modify preoperative care or predict

1976

1989

1991

1995

1999

Sanders et al [9]

Narr et al [29]

Perez et al [49]

Skenderis et al [54]

Retrospective

Retrospective

Retrospective

Colectomy

Elective

Elective

Total hip arthroplasty

Elective

All

Type of surgery

Colorectal cancer

ASA class 1 or 2

ASA class 1

Otherwise healthy patients with osteoarthritis

Population characteristics

Abbreviations: ALT, alananine aminotransferase; AST, aspartate aminotransferase.

Total

Prospective

1975

Wataneeyawech and Kelly [58] Schemel [57]

Retrospective

Prospective

Year

Study design (prospective or retrospective)

Study

Table 9 Hepatic enzyme tests

Transaminase < 2 normal Alkaline phosphatase or AST in reference range AST < 2 normal AST or ALT in reference range Reference range

Not stated

Deﬁnition of normal test

19,257

105

1128

3782

91

7620

6540

Total number of patients

0.4

7.6

3.5

0.3

7.7

0.1

0.1

Percent of tests that are abnormal

0.1

0.0

0.0

0.0

1.1

0.1

0.1

Percent of all tests that inﬂuence management

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 25

26

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

an increased risk for postoperative complications. Potential relationships between abnormalities and adverse outcomes include pyuria and wound infection, and glucosuria and hyperglycemic complications. Table 10 summarizes the primary data sources on preoperative urinalysis. The incidence of abnormal urinalyses was 19.1%. Among the subset of studies that reported adverse outcomes, the positive and negative LRs for abnormal urinalysis were 1.67 and 0.97, respectively. These values are suﬃciently close to one to provide no predictive value for clinicians. In most cases, abnormalities could have been predicted based on clinical evaluation, such as urinary symptoms or known diabetes. Clinicians ignored the majority of these abnormal test results. Only 1.4% of all urinalyses were abnormal and changed patient management. These results are similar to those reported on admission to inpatient medical services. Akin et al studied 301 patients admitted to a general medicine unit and found abnormalities in 34% of patients, but patient management was changed in only 2.4% of patients as a result of the test [32]. Kroenke et al reported nearly identical results [33]. Using data available in 1989, Lawrence et al performed a cost-eﬀectiveness evaluation of routine preoperative urinalyses [34]. They used the example of nonprosthetic knee procedures and estimated the baseline incidence of wound infections to be 1%. Assuming that 10% of urinalyses would show infection and that a urinary tract infection would increase the risk of wound infection by 1%, then routine urinalyses could potentially prevent wound infection in 0.001% of screened patients, at cost of 1.5 million dollars per wound infection prevented. Based on the low predictive value and the cost associated with this test, we do not recommend routine preoperative urinalyses. Electrocardiogram The potential value of a routine preoperative ECG would be to detect abnormalities that would increase the risk of postoperative cardiac complications or to serve as a baseline in the event that a postoperative ECG is required. Baseline ﬁndings that may modify risk include the ﬁnding of Q waves that confer risk according to the original Goldman cardiac risk index [35]. If one uses, however, the more recent revised risk index, which outperformed the original Goldman index, any clinical evidence of coronary artery disease confers risk, and Q waves need not be present to imply risk [22]. Still, most clinicians would defer elective surgery and consider a functional evaluation of cardiovascular status if new Q waves or other ﬁndings that suggested coronary artery disease were present on a preoperative ECG. Other ECG abnormalities that confer risk according to the Goldman cardiac risk index are a rhythm other than sinus, as well as frequent atrial or ventricular ectopy. These abnormalities may also be suggested on physical examination. Common ﬁndings of unknown signiﬁcance in the prediction of postoperative cardiac complications include left ventricular hypertrophy and nonspe-

1989 Retrospective

1991 Prospective 1992 Retrospective

1995 Prospective

1999 Prospective

Sanders et al [9]

Velanovich [53]a Adams et al [61]

Bhuripanyo et al [60]

Haug and Reifeis [50]

a

Estimated based on 8% abnormal tests. Adverse outcome ¼ wound infection.

Subtotal for series with outcomes data Total

1988 Prospective 1988 Retrospective

Cholecystectomy No known medical conditions Ambulatory Elective knee 15 years of age surgery or greater, no knee trauma or prostheses Total hip Otherwise healthy arthroplasty patients with osteoarthritis All Elective inguinal hemiorrhaphy Elective 15 years of age or greater Oromaxillofacial ASA class 1 or 2 surgery in oﬃce setting

1987 Retrospective

Veterans

All

Population characteristics

1986 Retrospective

Study design (prospective or Year retrospective) Type of surgery

Johnson et al [48] Lawrence and Kroenke [59]

Muskett and McGreevy [62] Turnbull and Buck [12]

Study

Table 10 Abnormal urinalysis

Not stated

No abnormality Reference standard Author criteria

Author criteria

Author criteria Author criteria

No glucosuria or pyuria

Not stated

Deﬁnition of normal test

6.4 19.1

3666

0.8

36.6

8.1 2.4

4.0

39.2 17.0

4.3

22.4

1984

380

917

520 169

99

212 200

995

174

Percent Total of tests number that are of patients abnormal

1.4

0.0

2.9

1.8

3.0

0.5 0.0

0.1

5.2

1.7

1.6 0.0

1.0

0.0

3.0

0.97

0.97 1.07

1.00

1.01

0.90

Percent of all tests that inﬂuence LRþ LR management (CI) (CI)

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 27

28

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

ciﬁc ST segment changes. Bundle branch block, another common incidental ﬁnding, did not increase the risk of postoperative cardiac complications in a recent cohort analysis of 455 patients with this ﬁnding [36]. In our review, the incidence of any ECG abnormality was 29.6% (Table 11). This is substantially higher than the yield for abnormal tests among other commonly performed preoperative tests. Many of these abnormalities are not clinically signiﬁcant, however, and do not predict postoperative cardiac complications. In the study of Tait et al, among patients with cardiovascular risk factors undergoing general surgery, there was no diﬀerence in the rates of postoperative cardiac complications between those with normal and abnormal ECGs [37]. In the report of Gold et al, the ECG may have been potentially helpful in predicting risk in 6 of 751 patients undergoing ambulatory surgery [38]. The preoperative ECG did not predict adverse cardiac events. The risk of postoperative cardiac complications is low even for patients with an abnormal ECG. For example, in the report of Turnbull and Buck, only 4% of patients with an abnormal preoperative ECG had a postoperative complication [12]. In none of these cases was the preoperative management changed based on the abnormal ECG. In our review, among the subset of studies that reported outcomes, the positive LR was modestly increased at 2.51. Age is one of the most important factors that predict the likelihood of coronary artery disease and of an abnormal ECG. In the Framingham study, 0.65% of men and 0.26% of women aged less than 45 years old had unrecognized, silent myocardial infarctions as determined by Q waves on a screening ECG [39]. Incidences among men and women aged 75–84 years were 6.0% and 3.4%, respectively. In our review of the available literature, 19.7% of patients under age 50 years had any abnormality on a preoperative ECG; most of these were of uncertain clinical signiﬁcance. Pre-existing medical conditions known to be cardiovascular risk factors also predict abnormalities on the preoperative ECG. The ECG is twice as likely to be abnormal if cardiovascular risk factors are present than if they are absent [37]. Though we acknowledge the lack of conﬁdent evidence to support a beneﬁcial eﬀect of preoperative ECGs on reducing adverse postoperative outcomes, we recommend preoperative ECGs for patients whose age and medical comorbidities increase the likelihood of occult coronary artery disease. Such patients include men over age 40 years, women over age 50 years, and younger patients with known coronary artery disease or risk factors including diabetes or hypertension. Preoperative ECGs are probably not necessary for patients undergoing minor procedures under conscious sedation such as cataract surgery and endoscopic procedures. Chest radiograph Routine preoperative chest radiographs are more likely to be abnormal than are most other preoperative tests. For example, in a study of 3959 patients who received a preoperative chest radiograph, 23% of studies were

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29

abnormal [40]. Abnormalities included those of lung parenchyma (13%), heart (7%), pleura (2%), mediastinum (3%), and other abnormalities (2%). In our survey of 15 studies of routine preoperative chest radiographs (Table 12), 21.2% of all such studies were abnormal. Two potential indications exist for obtaining a preoperative chest radiograph. The ﬁrst would be to identify abnormalities that would require cancellation of surgery or modiﬁcation of the anesthetic technique. The second would be to serve as a baseline for the interpretation of postoperative chest radiographs in the event of a postoperative pulmonary or cardiac complication. The evidence for this second potential indication is less well established. In the subset of all studies in Table 12 that reported the frequency of postoperative complications stratiﬁed by chest radiograph results, the positive LR for an abnormal result was 2.5; the negative LR was 0.72. A normal chest radiograph, therefore, does not make a complication substantially less likely. Though the positive LR implies a modest predictive value, most patients at risk for postoperative cardiopulmonary complications can be identiﬁed on the basis of clinical evaluation with similar conﬁdence and the incremental information provided by an abnormal chest radiograph is small. In our review, only 3% of all chest radiographs were abnormal and resulted in a change in perioperative management. In a previous review and metaanalysis, 10% of all preoperative chest radiographs were abnormal, 1.3% of ﬁlms showed unexpected abnormalities, and in only 0.1% of patients were the ﬁndings of suﬃcient importance to change perioperative management [41]. This observation suggests that most abnormal ﬁlms could have been predicted based on clinical risk factors. Advanced age and the presence of pre-existing cardiopulmonary disease both predict the likelihood of an abnormal screening chest radiograph. In the largest of our cited studies by Silvestri et al, the frequency of clinically useful chest radiographs increased from 1.4% for men aged 60 years with no comorbidities and an ASA class 2 to 48% for men aged >60 years with an ASA class 3 with pre-existing pulmonary disease undergoing major surgery [42]. Charpak et al developed a selective protocol for ordering preoperative chest radiographs using similar criteria [43]. Their protocol recommended preoperative chest radiographs for patients with lung disease, cardiovascular disease, cancer, emergent surgery, current smoking history in patients >50 years of age, immune suppression, or a lack of a prior examination in immigrants. Though 52% of all radiographs were abnormal, only 4 of 271 (1.5%) unindicated radiographs impacted on patient management. In the report of Gagner and Chiasson, only 3% of patients age 50 years had an abnormal routine chest radiograph, whereas abnormal ﬁlms were present in 30% of patients over age 50 years [44]. Ninety-two percent of abnormal chest radiographs could have been predicted on the basis of symptoms or a history of known cardiopulmonary disease. In the 5 studies in our review that allow a subset analysis of patients <50 years old, only 4.9% of routine preoperative chest radiographs were abnormal.

Ambulatory All Noncardiac

1988 Prospective 1988 Prospective 1989 Retrospective

McCleane and McCoy [67] Velanovich [53]b Bhuripanyo et al [68] Gold et al [38]

All

All Noncardiac

Ambulatory

1990 Prospective

1991 Prospective 1992 Retrospective

1992 Retrospective

1987 Prospective

Cholecystectomy No known medical conditions Elective

1987 Retrospective

Mckee and Scott [65] Johnson et al [48] Charpak et al [4] Yipintsoi et al [66]a

All

1986 Retrospective

Muskett and McGreevy [62] Turnbull and Buck [12]

Not stated Any abnormality 40 years of age Author criteria or greater Author criteria

No known cardiac disease

Author criteria Author criteria Author criteria

Author criteria

Not stated

Author criteria 65 years of age Minnesota or greater Code Veterans Not stated

Ferrer [63] Seymour et al [64]

All All

1978 Prospective 1982 Prospective

Study

Population Deﬁnition of characteristics abnormal ECG

Study design (prospective or Type of Year retrospective) surgery

Table 11 Abnormal electrocardiogram

751

520 395

877

212 1610 425

323

632

145

1068 222

42.7

36.0 32.9

45.0

66.0 37.8 23.5

31.3

16.0

36.6

18.5 78.8

36.6

14.2

22.2

10.3

Percent of ECGs that are Percent abnormal Total of ECGs in patients number that are <50 years of patients abnormal old

0.8

3.0

7.3 2.1

0.6

0.0

1.4

2.7

2.7 3.1

2.6

0.5

0.98

0.94 0.98

0.98

1.11

Percent of all ECGs that inﬂuence LRþ LR management (Cl) (Cl)

30 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

1995 Retrospective

1997 Retrospective

b

a

Ambulatory

Elective noncardiac All

Elective

ASA class 1 or 2

ASA class 1 or 2

Author criteria

Not stated

Not stated

Author criteria

Excluded patients with known heart disease. Estimated based on 36% incidence of abnormal ECG. Complication ¼ cardiac.

Murdoch et al [70] 1999 Prospective Subtotal for series with outcomes data Total

Tait et al [37]

Callaghan et al [69] 1995 Prospective

Perez et al [49]

28.6

29.6

10524

43.5

24.8

10.5

154 3247

573

230

2387

19.7

12.4

0.0

2.6

5.2

0.9

1.0 1.6

1.0

1.00 0.96

1.01

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 31

Elective

1987 Prospective 1987 Retrospective

1990 Retrospective

Retrospective Prospective Retrospective Retrospective

All 60 years of age Noncardiac, general of greater anesthesia General Noncardiac Gynecologic Elective vascular

1983 Retrospective 1987 Prospective

Tornebrandt and Fletcher [73] Rucker et al [74] McKee and Scott [65] Wiencek et al [75] Boghosian and Mooradian [76]

1987 1988 1988 1988

All Elective

1982 Prospective

Loder [72] Seymour et al [64]

Mendelson et al [77] Charpak et al [43] Umbach et al [78] Tape and Mushlin [79] Gagner and Chiasson [44]

General

1978 Retrospective 1982 Prospective

Rees et al [71]

Author criteria

667

237 136

Not stated

1010

Thompson et al 332 Author criteria 1101 Any 1175 Author criteria 321

Not stated Any

7.3

18.7 51.6 10.0 31.5

42.6 52.9

12.7 37.0

47.3

9.7 57.5

18.9

3.0

4.5

5.5

11.6

Percents of tests that are Percent abnormal Deﬁnition of Total of tests in patients abnormal chest number that are < 50 years radiograph of patients abnormal old

Any 1000 65 years of age Rees et al 233 or greater 70 years of age Not stated 91 or greater Author criteria 905 Author criteria 327

1976 Prospective

Study

Elective noncardiac, nonthoracic All All

Study design (prospective or Population Year retrospective) Type of surgery characteristics

Table 12 The value of an abnormal chest radiograph before surgery

2.8

4.6

0.8

1.2

1.3 2.0 1.4

1.0

0.9

0.79 0.98 0.96

1.01

1.06

Percents of all tests that inﬂuence LRþ LR management (CI) (CI)

32 G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

1999 Prospective

Silvestri et al [42] Subtotal for series with outcomes data Total 21.2

1997 Prospective

Ishaq et al [81] 13.5

23.0

22.6

15.0

20518

1996 Prospective

Bouillot et al [40]

319

18.3 33.5

Elective

1995 Retrospective

Not stated

ASA class 1 Author criteria 2142 or 2 Non malignant, 15 years of age Any 3959 nonthoracic or greater Elective 40 years of age Rees et al 452 noncardiac, or greater, nonthoracic no known cardiac or pulmonary disease Elective Author criteria 6111 2966

All

1992 Prospective

Somerville and Murray [80] Perez et al [49]

4.9

3.5

3.0

5.1

0.2

5.4

0.9

2.5

0.72

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40 33

34

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

Based on these observations, we recommend routine preoperative chest radiographs for all patients over age 50 years, those with known pre-existing cardiopulmonary disease, and those with symptoms or ﬁndings on physical examination that suggest a likelihood of cardiopulmonary disease. Using these criteria, previously unknown abnormalities that may inﬂuence perioperative management will be detected in a small yet clinically important number of patients.

Outcomes of patients with no routine perioperative testing Our review establishes the low predictive value of most commonly obtained preoperative laboratory tests. Several recent reports have reached the same conclusion through evaluation of the outcomes of patients subjected to surgery with no routine preoperative testing. Narr et al performed a retrospective review of 1044 patients who underwent elective surgery or diagnostic procedures [45]. The patients were disproportionately young and healthy. The median age was 21 years, and 97% of patients were ASA class I or II. No deaths or major perioperative morbidities occurred in the entire group. Schein et al randomly assigned 19,557 patients undergoing cataract surgery to no testing or routine preoperative testing that included a complete blood count, electrolytes, BUN, creatinine, glucose, and an EKG [2]. The overall postoperative complication rate was 3.1% and the mortality rate was 0.03%. No signiﬁcant diﬀerences existed between the testing and no-testing groups in the rates of intraoperative complications, postoperative complications, or death. How does the observation of the limited value of preoperative testing compare with actual clinician practices? Using the example of cataract surgery, a low risk procedure where preoperative testing has been shown to be of no value, two reports have surveyed actual physicians practices related to preoperative testing. Bass et al determined that, among ophthalmologists evaluating healthy patients with cataracts, the percentage who always or frequently ordered common preoperative tests was 90% for complete blood counts (CBC), 70% for electrolytes, 89% for EKGs, 50% for chest radiographs, and 44% for urinalyses [46]. Similarly, Bellan studied institutional policies for testing before cataract surgery at 13 hospitals in Canada [82]. Ten institutions required a preoperative CBC for all patients, 7 a urinalysis, and 10 an EKG for all patients over age 50 years.

Recommendations We have shown that routine preoperative testing before elective surgery, without regard to patient-related factors that increase the likelihood of abnormal test results, leads to a low incidence of abnormal results—most of which are either ignored by clinicians or are false-positive results that

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35

do not predict an increase in the risk of postoperative complications. Several tests, in particular, BUN or creatinine, and hemoglobin measurements, are more likely to identify a subset of patients at risk for postoperative complications. The incidence of abnormalities is highest for routine chest radiographs and EKGs; most of these abnormalities can be anticipated on clinical grounds. For all potential routine tests, the negative likelihood ratio approaches one and a normal test does not signiﬁcantly reduce the likelihood of a postoperative complication. We summarize our recommendations for routine preoperative tests in Table 13.

Table 13 Recommendations for laboratory testing before elective surgery

Test

Incidence of abnormalities that inﬂuence management

LRþ

LR

Indications

Hemoglobin

0.1 %

3.3

0.90

White blood cell count

0.0 %

0.0

1.00

Platelet count

0.0 %

0.0

1.00

Prothrombin time

0.0 %

0.0

1.01

Partial thromboplastin time Electrolytes

0.1 %

1.7

0.86

Anticipated major blood loss or symptoms of anemia Symptoms suggest infection, myeloproliferative disorder, or myelotoxic medications History of bleeding diathesis, myeloproliferative disorder, or myelotoxic medications History of bleeding diathesis, chronic liver disease, malnutrition, recent or long-term antibiotic use History of bleeding diathesis

1.8 %

4.3

0.80

Renal function

2.6 %

3.3

0.81

Glucose Liver function tests

0.5 % 0.1 %

1.6

0.85

Urinalysis Electrocardiogram

1.4 % 2.6 %

1.7 1.6

0.97 0.96

Chest radiograph

3.0 %

2.5

0.72

Abbreviation: CAD, coronary artery disease.

Known renal insuﬃciency, congestive heart failure, medications that aﬀect electrolytes Age > 50 years, hypertension, cardiac disease, major surgery, medications that may aﬀect renal function Obesity or known diabetes No indication. Consider albumin measurement for major surgery or chronic illness No indication Men > 40 years, women > 50 years, known CAD, diabetes, or hypertension Age > 50 years, known cardiac or pulmonary disease, symptoms or exam suggest cardiac or pulmonary disease

36

G.W. Smetana, D.S. Macpherson / Med Clin N Am 87 (2003) 7–40

Using protocols and policy to inﬂuence testing Most institutions have established minimal criteria for routine preoperative testing. Thus, facility policies often require the physician caring for the patient to obtain a minimal set of tests before surgery. In many settings, assurance that the tests are complete is the responsibility of support staﬀ for the surgeon or anesthesiologist. If tests are not obtained before surgery, the patient’s surgery may be delayed; hence, most physicians are compliant with these policies. The establishment of an up-to-date policy regarding preoperative testing has been shown to decrease inappropriate ordering. In one study, the frequency of tests ordered decrease from 23% to 55% and without apparent increase in complication rates [83]. We are hopeful that this article will inform those who develop policy to ensure the creation of a rationale set of minimum standards at each facility and encourage institutions to implement local evidence-based guidelines and policy regarding preoperative testing. The ASA recently published a practice advisory for preanesthesia evaluation [47]. The advisory supports our recommendation that physicians should not order routine preoperative tests, and that testing should be selective based on the history, physical examination, known comorbidities, and type of planned procedure. Summary In this article, we have shown that almost all ‘‘routine’’ laboratory tests before surgery have limited clinical value. Clinicians should order only a small number of routine tests based on age as noted in Table 13. Selective use of other preoperative tests should be based on history and physical examination ﬁndings that identify subgroups of patients who are more likely to have abnormal results. In general, clinicians should order tests only if the outcome of an abnormal test will inﬂuence management. When an abnormal test results from such testing, it is critical that physicians document their thinking about the result. Most routine preoperative tests are neither expensive nor risky. For this reason, clinicians can have a low threshold for ordering these tests in patients for whom the frequency of abnormalities is increased compared with a healthy population. We believe that physicians should not be criticized for selective test ordering before surgery. Physicians and institutions recommending routine preoperative testing for all patients provide no clinical value to their patients at considerable cost. References [1] Macpherson D. Preoperative laboratory testing: should any tests be ‘‘routine’’ before surgery? Med Clin N Amer 1993;77:289–308.

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Med Clin N Am 87 (2003) 41–57

Perioperative medication management Donna L. Mercado, MD, FACPa,*, Brent G. Petty, MDb a

Medical Consultation Program, Baystate Medical Center, Tufts University School of Medicine, 759 Chestnut Street, Springﬁeld, MA 01199, USA b The Johns Hopkins University School of Medicine, 1300 Maywood Avenue, Baltimore, MD 21204, USA

The management of a patient’s usual medications in the preoperative period is often a diﬃcult and perplexing problem. Among the challenges faced by the physician when managing medication issues for surgical patients are the patient’s response to the stresses of surgery, the patient’s underlying diseases and the degree of control aﬀorded by ongoing treatment, and the likelihood of some period where oral treatment is not an option. In addition, there are few controlled trials regarding perioperative medication discontinuation and resumption, so decisions regarding management are often made based on manufacturer’s recommendations, consensus, or anecdotes. This article will attempt to provide data, when available, for adjusting medications in the perioperative setting and will provide advice when data are lacking. Because some medications are known to inﬂuence surgical risk or surgical decisions (eg, antiplatelet agents, anticoagulants, some hormonal therapies, and herbal remedies), it is important to obtain a complete medication list from the patient, including over-the-counter medications and dietary supplements. Adjusting doses or discontinuing certain potentially complicating medications in advance of surgery is one obvious reason that elective procedures are less prone to complications than emergent procedures. Most medications are tolerated well through surgery and do not interfere with anesthetic administration. Therefore, most drugs should be continued through the morning of surgery unless totally unnecessary (eg, vitamins) or contraindicated (eg, herbal products). In particular, antihypertensive, anticonvulsant, and antipsychiatric medications should be given unless speciﬁcally contraindicated. * Corresponding author. E-mail address: [email protected] (D.L. Mercado). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 6 - 3

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For medications where therapeutic monitoring may provide important information regarding subtherapeutic or supratherapeutic doses, serum levels should be checked perioperatively (eg, digoxin, theophylline, phenytoin, and carbamazepine). Necessary medications can be given with a sip of water a few hours before surgery. Medications that are known to cause a withdrawal or rebound syndrome when held (eg, clonidine) should be continued throughout the perioperative period with as little interruption as possible. Cardiac drugs Drugs with long durations of action, such as digoxin and amiodarone, can be discontinued before surgery and restarted when the patient is able to eat. If necessary, intravenous doses of either digoxin or amiodarone could be used if the duration of inability to eat is extended or if their parenteral use is clinically indicated. Beta blockers used for patients with cardiovascular disease (as opposed to use in patients with migraine syndrome, for example) should not be discontinued abruptly before surgery. Observational data have shown an increased risk of perioperative infarction and death in patients with vascular disease whose beta blockers were discontinued [1]. If patients are not able to resume oral intake of beta-blockers soon after surgery, parenteral preparations such as esmolol or propranolol could be used. For patients who usually take oral nitrates, preoperative substitution of nitroglycerin ointment or patches is not reliable because of the likelihood of poor intraoperative absorption. The severity and stability of the patients’ angina, plus their usual dose of oral nitrates, will inﬂuence the assessment of whether intravenous nitroglycerin may be needed. Perioperative and intraoperative events (eg, ST depressions on ECG monitor) may inﬂuence the anesthesiologist to start intravenous nitroglycerin, and postoperative titration and switch to outpatient agents will require ongoing assessment of response. In the postoperative period, transdermal nitroglycerin via ointment or patch is an alternative to either intravenous or oral nitrates. Patients who regularly take antiarrhythmic drugs should continue them as long as possible before surgery, but they can usually be discontinued for a few days and resumed when the patient is eating again. Class IA agents, such as quinidine, procainamide, and disopyramide, are used with much less frequency than in years past. Parenteral procainamide is available for the patient whose continued treatment with this agent would be considered essential during the perioperative period. More recent antiarrhythmics, such as ﬂecainide or sotalol, do not have an alternative, nonoral dosing route. For patients who take these agents for atrial arrhythmias (eg, atrial ﬁbrillation or atrial ﬂutter) and develop problems with these rhythms perioperatively, ventricular rate control could be attempted using intravenous diltiazem, beta blockers, or digoxin. For patients who take chronic outpatient medication for a history of monomorphic ventricular tachycardia and

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who then develop a recurrence while nil per os (NOS) perioperatively, procainamide or amiodarone can be used parenterally. For polymorphic ventricular tachycardia, lidocaine or amiodarone are options. Especially important in these patients is the need to assure normal serum magnesium, potassium, and calcium, because deﬁciences of these cations can contribute to ventricular irritability. Antihypertensives Overall, the large variety of nonoral agents available to control perioperative and intraoperative hypertension provides suﬃcient options to handle blood pressure elevations when patients cannot take their usual antihypertensives after the morning-of-procedure dose. Nevertheless, there may be hazards in introducing new agents preoperatively with unpredictable response in the individual patient in order to achieve ‘‘normal’’ blood pressure. In the perioperative period, mild degrees of elevated blood pressure may be acceptable and would be preferable to causing autonomic instability or volume depletion in the eﬀort to maximize blood pressure control. Sudden cessation of treatment with clonidine has been associated with worrisome, even dangerous, rebound hypertension. Using alternative parenteral agents or the clonidine patch may avoid acute hypertension. Such parenteral agents include esmolol, propranolol, hydralazine, diltiazem, and nitrates. Rebound hypertension also may occur after stopping guanfacine (TenexÒ, AH Robins Co., Richmond, VA), another alpha 2-adrenergic agonist, but it occurs with less frequency and later (after 2–4 days) with guanfacine, presumably because of its longer half-life. Pulmonary drugs This group of drugs consists primarily of those used to treat asthma and/ or chronic obstructive lung disease. Patients using inhalers can use them up to immediately before surgery and can resume them soon after surgery. This applies to inhaled steroids, beta agonists, and anticholinergic agents. If patients develop bronchospasm before they can resume their inhalers, then nebulized or parenteral beta agonists can be used. Because thoracic or abdominal surgery reduces lung function even in patients with normal lungs, some authorities favor nebulizers over metered-dose inhalers in the immediate postoperative period for asthmatic patients undergoing such surgeries. Another parenteral alternative is aminophylline, but both parenteral beta agonists and theophylline may cause tachycardia, hypertension, or ventricular arrhythmias. Intravenous steroids may be necessary if the bronchospasm does not respond to bronchodilators. Little is known about the implications of stopping leukotriene inhibitors, such as zaﬁrlukast (AccolateÒ, AstraZeneca Pharmaceuticals, Wilmington, DE) or montelukast (SingulairÒ, Merck and Co., West Point, PA), or

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lipoxygenase inhibitors, such as zileuton (Zyﬂo FilmtabÒ, Abbott Laboratories, Abbott Park, IL), before surgery. There are no parenteral formulations of these drugs. Because there are no known interactions between these agents and anesthetics, consider continuing them through the morning of surgery. The treatment of exacerbations of chronic obstructive pulmonary disease (COPD), which may be associated with surgery involving intubation, can follow the same principles employed for treating spontaneous acute exacerbations [2]. Diabetes Patients requiring insulin for usual management of their diabetes can generally be managed with perioperative glucometer testing and slidingscale regular insulin. Whether to use a morning dose of longer-acting insulin or to continue use of bedtime glargine insulin the night before surgery depends on how long the patients will be fasted before surgery, the severity of their diabetes, the timing of administration of intravenous solutions containing dextrose, and how soon the patients are likely to resume eating after surgery. For example, with outpatient surgery or diagnostic procedures performed under conscious or deep sedation, a common practice is to reduce the morning-of-procedure dose of long-acting insulin to 50% of the usual dose, and then use glucometer readings and sliding-scale insulin as needed to control periprocedure serum glucose. For diabetic patients adequately treated with oral agents, the drugs should be held on the morning of surgery, with sliding-scale insulin supplementation as needed. One important exception is metformin, which has been associated with the development of lactic acidosis, although rare. Metformin should be discontinued for at least 1 day before surgery and restarted after 2–3 days when it is certain that no acute renal dysfunction has developed perioperatively. In general, oral agents should be held postoperatively until patients are eating again. Antiplatelet agents and anticoagulants Aspirin inhibits platelet cyclooxygenase with subsequent irreversible platelet dysfunction. Because it takes 7–10 days to renew the circulating pool of platelets, traditional recommendations are to stop aspirin 7–10 days preoperatively. Although aspirin has been known to increase intraoperative bleeding, there is little evidence for any signiﬁcant increased morbidity or mortality [3,4]. One study showed increased use of transfusions in patients undergoing coronary artery bypass grafting (CABG) but no increase in length of stay [4]. It is prudent to stop aspirin at least 7 days before surgery where possible, especially for surgeries in which excess bleeding would cause signiﬁcant complications, such as vascular procedures, neurosurgery, and

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certain ophthalmologic procedures. It is especially important to stop aspirin in alcoholic patients, as they often have underlying platelet dysfunction secondary to alcohol. Aggrenox, which is composed of aspirin and dipyridamole, should be stopped 7–10 days in advance of surgery because of its aspirin component. The dipyridamole has a half-life of about 10 hours and has a reversible eﬀect on platelets [5]. The nonsteroidal anti-inﬂammatory COX-1 agents cause reversible inhibition of platelet cyclooxygenase. When possible, they should be stopped 1–3 days preoperatively depending on their individual half-lives. Drugs like ibuprofen and indomethacin have shorter half-lives (2–5 hours) and can be stopped 1 day before surgery, whereas naproxen and sulindac have longer half-lives (12–17 hours) and should be stopped 3 days before. The newer nonsteroidal anti-inﬂammatory drugs (NSAIDs), the COX-2 inhibitors, have little or no eﬀect on platelets. All NSAIDs can have adverse eﬀects on renal function; this eﬀect may be accentuated in the perioperative period, which is another reason for holding these drugs perioperatively. The COX-2 inhibitors should be held at least 2–3 days before surgery because of the potential renal issues [5]. Clopidogrel (PlavixÒ, Sanoﬁ-Synthelabo Inc., New York, NY) and ticlopidine (TiclidÒ, Parcor) are structurally similar agents that irreversibly inhibit platelet aggregation, probably by blockade of adenodiphosphate (ADP) binding to its receptor on the surface of platelets [6]. Because of the increased frequency of drug interactions, thrombotic thrombocytopenic purpura, and severe neutropenia with ticlopidine, its use has decreased in favor of clopidogrel. For elective procedures, both agents should be stopped 7 days preoperatively because of their irreversible eﬀect on platelets. Cilostazol (PletalÒ, Otsuka America Pharmaceutical, Inc., Rockville, MD) is a phosphodiesterase inhibitor that has both antiplatelet and vasodilatory actions. Because its action on platelets is reversible, and because it has a fairly short half-life (11–13 hours) [5], it can be stopped 3 days before surgery. One would think intuitively that it is always best to discontinue oral anticoagulants before any surgical procedure, or to at least reduce the dose to allow nearly normal coagulation. Though this is generally true, data show that cataract surgery, using current techniques, can be performed safely with the International Normalized Ratio (INR) in the therapeutic range. In fact, the studies suggest that, with cataract surgery, the risk of systemic complications from discontinuing warfarin is greater than the risk of perioperative bleeding. Antiplatelet agents, on the other hand, can increase perioperative complications of cataract surgery and should be discontinued preoperatively as described above. The use of unfractionated heparin and low-molecular-weight heparins for prophylaxis of perioperative thromboembolic complications is covered in another section. But one issue regarding stopping and restarting these perioperative medications deserves comment here. A worrisome and serious complication of deep venous thrombosis (DVT) prophylaxis with

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low-molecular-weight heparins is spinal hematoma with epidural anesthesia or analgesia [7]. This problem is most likely to occur when inserting or removing the epidural catheter. Interestingly, patients who undergo epidural anesthesia in the presence of antiplatelet agents are not at increased risk for epidural hematoma compared with patients not taking these agents. Patients receiving warfarin appear to be at intermediate risk. Recommendations regarding the time of epidural catheter manipulation in relation to doses of anticoagulants and antiplatelet agents are provided in Table 1 [8–12]. Osteoporosis agents As the population ages, and as osteoporosis awareness increases, an increasing number of patients will present for surgery while taking medications for this condition. Raloxifene (EvistaÒ, Eli Lilly and Co., Indianapolis, IN) is a selective estrogen receptor modulator (SERM) that mediates decreased resorption of bone and decreased bone turnover via binding to estrogen receptors [13]. Because it has been shown to increase risk of thromboembolic events, it should be stopped at least 1 week preoperatively for surgeries associated with a moderate to high risk of DVT, and not restarted until the patient is fully mobile postoperatively [5]. Tamoxifen, which is structurally similar, has a similar risk of DVT, but, before discontinuing it perioperatively, the patient’s oncologist should be consulted to discuss the risk/beneﬁt ratio. Estrogen is used by millions of women both to alleviate premenopausal symptoms and to prevent and treat osteoporosis. The use of hormone replacement therapy is associated with an increase in thromboembolic events by threefold [14]. This phenomenon is even more dramatic in the perioperative setting. The Heart and Estrogen/progestin Replacement Study (HERS) in 2763 postmenopausal women found that the risk for deep venous thrombosis increased approximately 6-fold for patients admitted for hip fracture, 18fold for other types of lower extremity fracture, and 5-fold for nonfracture surgeries within 90 days of surgery [15]. For elective surgery, it is unclear how far in advance of surgery estrogen should be held to decrease this risk; some have suggested stopping 4 weeks preoperatively [16]. After surgery, the risk for DVT decreases when the patient is fully ambulatory, although the HER study showed an increased risk for 90 days postoperatively [15]. Alendronate (FosamaxÒ, Merck and Co., Inc., West Point, PA) is a bisphosphonate that inhibits osteoclast-mediated bone resorption. Because of its possible upper gastrointestinal (GI) side eﬀects (esophagitis, esophageal erosions, and ulcers), there are speciﬁc guidelines regarding its administration. Patients must take it with 6–8 oz of water at least 30 minutes before ingesting the ﬁrst beverage, food, or medication of the day, and then remain upright for 30 minutes. Given the diﬃculty for hospitalized patients to comply with the requirement to remain upright, it is best held in the perioperative period. Calcitonin (MiacalcinÒ, Novartis, East Hanover, NJ) is

None None None None None

PT

PT

None None

None

aPTT

Lab tests necessary prior to discontinuation of epidural catheter

Immediately Immediately Immediately Immediately Immediately

Immediately

12–24 hours At least 24 hours after catheter removal Immediately

At least 2 hours after epidural catheter removal, providing clinical monitoring checks are within normal limits, including no apparent bleeding Immediately

Time interval before therapy may be re-instituted after catheter removed

Abbreviations: aPTT, partial thromboplastin time; INR, International Normalized Ratio; NSAIDS, nonsteroidal anti-inﬂammatory drugs; PT, prothrombin time.

Low Low Low Low Low

Low-moderate

Prothrombin time (PT) INR <1.5 prior to removal of the epidural catheter No Restriction No Restriction No Restriction No Restriction No Restriction

12–24 hours after last dose At least 12 hours after the last dose of the thrombolytic drug Prothrombin time (PT) INR <1.5 prior to removal of the epidural catheter

High High

Moderate-high

12 hours after the last dose

Low

Heparin (minidoseprophylaxis) Low molecular-weight Heparins Fibrinolytic and thrombolytic drugs Warfarin (CoumadinÒ, Dupont, Wilmington, DE, End) (Therapeutic INR > 2.0) Warfarin (CoumadinÒ, Dupont, Wilmington, DE, End) (Low dose-Prophylaxis) Aspirin Dipyridamole Ticlopidine Clopidogrel NSAIDs

4–6 hours after stopping heparin aPTT should be within normal limits prior to catheter removal

High

Suggested time interval before removal of epidural catheter

Heparin (standard) (IV or Sub-Q routes) (Therapeutic aPTT 1.5 control)

Medication

Risk of epidural hematoma with medication

Table 1 Epidural anesthesia or analgesia: special considerations for patients receiving antiplatelet or anticoagulant therapy

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given intranasally; there are no speciﬁc medication interactions or contraindications to using this drug in the perioperative period.

HIV agents Both because HIV-infected patients are living longer, and because the virus continues to spread, more and more HIV-positive patients are presenting for various types of surgery. There are a wide variety of antiretroviral medications; patients who use these medications generally are on two or more at a time. Because resistance to these drugs develops so easily, patients should not miss doses and should maintain an ‘‘all or none’’ approach to taking them. Thus, in the perioperative period, these drugs should be continued up to the time of surgery, stopped together, and then restarted together when the patient can tolerate oral medications. There are no known signiﬁcant interactions between antiretrovirals and anesthetic agents [17].

Herbal remedies The use of herbal medications has become increasingly popular over the past several years [18,19]. Many studies have found that patients often do not report use of such agents to their physicians, even in the preoperative setting, unless speciﬁcally asked [18,19]. Of concern is the fact that some of the more commonly used herbal remedies have been found to cause a variety of perioperative complications [20,21]. Many patients erroneously believe that herbal remedies are safe because they are ‘‘natural.’’ On the contrary, because they are not regulated by the U.S. Food and Drug Administration (FDA), their purity and concentrations may diﬀer signiﬁcantly between batches, and there are few well-controlled human trials to document safety [22]. Echinacea is commonly used to enhance immune function, possibly by stimulating the production of phagocytes. The enhancement of immune function, however, is thought to be a short-term eﬀect; the long-term eﬀect may actually be immunosuppression. Thus, there is a theoretical risk of problems with postoperative healing [18]. Garlic is used to lower lipid levels, but, because it inhibits platelet aggregation, patients who use large amounts of garlic could have problems with postoperative bleeding [18,23]. Ginkgo biloba has become very popular because of its purported beneﬁcial eﬀects on cognitive function. It has also been used to treat peripheral vascular disease and macular degeneration. Ginkgo has been found to inhibit platelet aggregation via inhibition of platelet-activation factor [18]. There have been rare reported cases of spontaneous bleeds, as well as one known episode of postoperative bleeding linked to the use of this herb [24].

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Ginseng is used both as a hypoglycemic agent and to protect one’s health in the face of stress. It inhibits platelet aggregation, possibly irreversibly, and has been known to cause headache, tremulousness, and mania [18]. Ma huang, or ephedra, has potent sympathomimetic eﬀects and can increase both blood pressure and pulse [18]. It should be stopped whenever possible and not restarted because of the serious potential complications associated with its use [25]. Kava is used as a sedative and can accentuate the sedative eﬀects of anesthetics. It has been associated, however, with severe liver injury, and the FDA suggests caution in using kavacontaining products [26]. St. John’s wort, because it induces cytochrome P450 enzymes, has the potential to aﬀect the metabolism of multiple drugs [23]. Valerian is used as a sedative and can aﬀect anesthetic requirements. Reports vary as to whether or not it can cause acute withdrawal upon cessation [22]. Multiple herbal preparations have been found to interfere with the action of warfarin. These include Danshen, garlic, dong quai, ginseng, ginger, and fever few [27,28]. Because there are likely drug interactions and perioperative eﬀects of herbal remedies that are yet unknown, it is safest to have patients refrain from use of these agents for 1–2 weeks preoperatively.

Neurologic medications Antiparkinsonian agents Antiparkinsonian medications should be given the morning of surgery and restarted as soon as possible postoperatively. The main problem in using these agents in the perioperative period is that very few of them have an intravenous form available for patients who are unable to take oral medications for a prolonged period. Patients who have their carbidopa/levodopa held for several hours may develop a swift return of their parkinsonian symptoms, and with prolonged cessation they can develop a levodopa withdrawal syndrome characterized by symptoms similar to neuroleptic malignant syndrome [29]. Although carbidopa/levodopa can interact with anesthetic agents leading to possible arrhythmias [16], the beneﬁts of continued treatment outweigh the risks. Selegiline (EldeprylÒ, Somerset, Tampa, FL) is a selective monoamine oxidase inhibitor used as an adjunctive treatment to carbidopa/levodopa. It has been reported to have a potentially life-threatening reaction with meperidine consisting of rigidity, hallucinations, fever, confusion, and (when severe) coma and death. It is possible for this reaction to occur with other narcotics as well [5], but it is best known for the reaction with meperidine. Meperidine should be avoided perioperatively, and the patient should be monitored carefully while on narcotics. The relatively new

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catechol-o-methyltransferase (COMT) inhibitors (entacapone and tolcapone) work by extending the duration of action of levodopa [5,30]; there are no speciﬁc contraindications regarding their use perioperatively. Like carbidopa (SinemetÒ, Merck & Co.), abrupt withdrawal can cause hyperpyrexia, rigidity, confusion, and elevated serum creatine kinase, so they should be continued as much as possible in the perioperative period. Because they can cause abnormalities of liver function tests, it is prudent to check liver enzymes before surgery [30], as abnormalities may inﬂuence anesthetic management. For patients who are NPO, there are a few eﬀective alternatives. The only antiparkinsonian agents that are available intravenously or intramuscularly are medications with anticholinergic actions that can help limit rigidity and bradykinesia. The available agents are trihexyphenidyl (ArtaneÒ, Lederle), benztropine (CogentinÒ, Merck & Co.), and diphenhydramine (BenadrylÒ, Parke, Davis) [31]. Trihexyphenidyl may be especially helpful for tremor [32]. All of these agents can cause postoperative confusion and should be used in the lowest doses possible. For patients who are NPO, but have a feeding tube, a levodopa/carbidopa solution can be delivered to the duodenum via a weighted feeding tube. The solution is prepared by pulverizing and dissolving 4 tablets of 25/250strength carbidopa in 1 L of water with 1 g of ascorbic acid (to prevent oxidation) to produce a 1 mg carbidopa/mL solution. The hourly rate of the infusion depends on what the patient’s oral dose is; a suggested starting dose is 25 mL/hr [32]. If patients can take oral medications within several hours after surgery, their usual doses of agents such as carbidopa, bromocriptine, amantadine, and pergolide can be used; there are no speciﬁc interactions known between these medications and commonly used perioperative medications. Antiseizure medications Antiseizure agents should be continued in the perioperative period whenever possible. The major antiseizure medications are central nervous system (CNS) depressants; these agents include phenytoin, carbamazepine, valproic acid, clonazepam, phenobarbital, and primidone. Their depressant eﬀects can decrease the required doses of anesthetic agents [3]. Although there is no published information regarding the use of newer agents (ie, gabapentin, topiramate) in the perioperative period, they should be continued to avoid perioperative seizure.

Psychiatric medications Antidepressants Tricyclic antidepressants act by making nonadrenergic neurotransmitters more available via presynaptic blockade of reuptake. Drugs in this class that

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are commonly used include amitriptyline, nortriptyline, imipramine, and desipramine. They have several side eﬀects, most notably anticholinergic eﬀects, as well as a variety of cardiac eﬀects, most notably a quinidine-like action such as a widened QRS and QT intervals and potential slowing of AV conduction [33]. Although there have been reports of arrhythmias in patients on tricyclic antidepressants who receive halothane, and animal studies show a proarrhythmic eﬀect in the presence of pancuronium [34], these events are rare. Because the anticholinergic eﬀects of these medications are likely to be additive with other anticholinergics, care should be taken regarding drug choices perioperatively. Monoamine oxidase (MAO) inhibitors are not commonly used at the present time, but they still may be used in cases of depression resistant to other agents. MAO inhibitors, such as pargyline and phenelzine, have been associated with life-threatening hypertensive reactions to indirect-acting sympathomimetics that are sometimes used intraoperatively. Theses agents are also known to interact with meperidine to cause a syndrome with some similarities to neuroleptic malignant syndrome (including symptoms of hyperpyrexia, hypertension, rigidity, hallucinations, coma, and death). It has been conventional practice to stop MAO inhibitors 2 weeks preoperatively to avoid perioperative medication interactions. There have been reports of patients undergoing general anesthesia while on MAO inhibitors without complication, however [35,36]. Thus, for patients undergoing elective surgery without major psychiatric risk to stopping therapy, it would be prudent to withhold MAO inhibitors; but, for patients undergoing urgent surgery or who are psychiatrically unstable without them, it appears that MAO inhibitors can cautiously be continued, along with care to avoid or minimize sympathomimetics, anticholinergics and meperidine. These patients may be particularly susceptible to complications from sympathetic responses to anesthesia. Selective serotonin reuptake inhibitors The selective serotonin reuptake inhibitors (SSRIs) have become the ﬁrstline agents for treatment of depression. This class includes ﬂuoxetine (ProzacÒ, Eli Lilly, Indianapolis, IN), sertraline (ZoloftÒ, Pﬁzer Inc., New York, NY), paroxetine (PaxilÒ, SmithKline Beecham, Philadelphia, PA), citalopram (CelexaÒ, Forest Pharmaceuticals, St. Louis, MO), and ﬂuvoxamine (LuvoxÒ, Solvay Pharmaceuticals, Marietta, GA). The most common side eﬀects are nausea, vomiting, diarrhea, agitation, anxiety, and insomnia. These agents act by inhibiting the reuptake of serotonin in the brain. There are no speciﬁc interactions between the SSRI’s and anesthetics. There are reports of development of the ‘‘serotonin syndrome’’ after concurrent use of tramadol (UltramÒ, Ortho-McNeil Pharmaceutical, Raritan, NJ) and SSRIs. The SSRIs can also increase the INR in patients who are on warfarin [37].

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Stopping SSRIs can result in a withdrawal syndrome that can start as soon as 1 day after discontinuing the agent. A wide range of symptoms is associated with this syndrome, including dizziness, agitation, lethargy, nausea, chills, myalgias, gait instability, shortness of breath, and decreased short-term memory [37]. Therefore, it is prudent to continue SSRIs in the perioperative period for patients who can tolerate oral medications. Other commonly used antidepressants (venlafaxine [EﬀexorÒ, WyethAyerst Pharmaceuticals, PA], bupropion [WellbutrinÒ, Glaxo Wellcome Inc., Research Triangle Park, NC], mirtazapine [RemeronÒ, Organon Inc., West Orange, NJ], and nefazodone [SerzoneÒ, Bristol-Myers Squibb Co., Princeton, NJ]) have not been associated with withdrawal syndromes and do not have any known interactions with anesthetic agents [37]. Antipsychotics Phenothiazines and butyrophenones are commonly used as antipsychotics; these agents can cause a wide variety of side eﬀects, including sedation, depression, dystonia, and orthostatic hypotension. These drugs include haloperidol (HaldolÒ, McNeil Consumer Healthcare, Fort Washington, PA), ﬂuphenazine (ProlixinÒ, Apothecon, Princeton, NJ), droperidol (InapsineÒ, McNeil Consumer Healthcare, Fort Washington, PA), chlorpromazine (ThorazineÒ, SmithKline Beecham, Philadelphia, PA), and risperidone (RisperdalÒ, Janssen Pharmaceutical Products, Titusville, NJ). Usually, these agents do not cause any signiﬁcant perioperative problems. But they can enhance CNS depression caused by narcotics and barbiturates. The phenothiazines can also decrease the seizure threshold in susceptible patients. They can cause a variety of ECG abnormalities such as ﬂattened T waves, ST segment depression, and prolonged QT and PR intervals. Rarely, these drugs cause ventricular irritability with resultant premature ventricular complexes (PVCs) and even torsades de pointes, recently resulting in a blackbox warning for droperidol, with recommendations for an ECG before potential treatment with droperidol, avoidance of droperidol in patients with long QT intervals, and cardiac monitoring after its use. Rarely, patients on antipsychotics can develop neuroleptic malignant syndrome, characterized by muscle rigidity, profound hyperthermia, autonomic instability, and at times ventricular irritability. Neuroleptic malignant syndrome shares many symptoms with malignant hyperthermia, which is seen intraoperatively and postoperatively in susceptible individuals. Abruptly stopping antipsychotics can cause withdrawal dyskinesia or rebound agitation [38], so these drugs should be continued perioperatively if possible. Mood stabilizers The most commonly used mood-stabilizing medication is lithium. It acts by decreasing the release of neurotransmitters mimicking the action of

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sodium [3]. It has a wide variety of side eﬀects, most commonly hypothyroidism. It can also cause ECG changes such as T-wave inversion or ﬂattening. Sinus node dysfunction and ventricular irritability are uncommonly seen [39]. Lithium can prolong the action of depolarizing and nondepolarizing muscle relaxants [3], but this has rarely been of any clinical signiﬁcance. Current practice is to continue lithium perioperatively, although it may be wise to check serum levels perioperatively to ensure that they are not in the toxic range. Other common mood stabilizers, valproic acid and gabapentin, have no contraindications for use in the perioperative period. Anxiolytics Patients who take signiﬁcant amounts of benzodiazepines require less medication for anesthesia induction and maintenance. Because abrupt cessation of benzodiazepines after chronic use can cause a signiﬁcant withdrawal syndrome, they should be continued in a modest dose perioperatively. At times, chronic benzodiazepine use can lead to higher requirements for postoperative opiates.

Endocrine agents Thyroid Patients taking levothyroxine for hypothyroidism can stay on their usual dose throughout the perioperative period. Because of the long half-life of the medication (7 days), it can be withheld for a few days if necessary without any untoward eﬀect [40]. For patients who are NPO for a prolonged period, intravenous L-thyroxine can be given. Patients who are mildly hypothyroid can undergo surgery without signiﬁcant clinical problems, but severely hypothyroid patients are at risk for major complications. For emergency surgery in such patients, they should receive a bolus of 200–500 mcg by slow infusion, then receive 50–100 mcg per day of L-thyroxine as well as hydrocortisone to treat for possible adrenal insuﬃciency [41]. Patients who are signiﬁcantly hyperthyroid who must undergo urgent or emergency surgery may develop thyroid storm perioperatively. The treatment should include intravenous beta blockers, such as propranolol or esmolol, which can decrease adrenergic activity as well as decrease the peripheral conversion of T4 to T3. Beta blockers should be given with the goal of lowering the pulse to less than 90. Propranolol can be given in doses of 2–5 mg IV every 4 hours, and then orally every 6 hours in doses as high as 320–480 mg per day to maintain heart rate control. Propylthiouracil (PTU) and methimazole inhibit synthesis of new thyroid hormone, and PTU can also prevent conversion of T4 to T3. One gram of propylthiouracil should be given as a loading dose by nasogastric tube, followed by 200 mg every 6 hours. To prevent the release of T4 and T3 from the thyroid gland, inorganic iodide should be used. Iodide can

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be given in a variety of methods but should be delayed by 1–2 hours after the antithyroid therapy with PTU or methimazole, as iodide alone will increase thyroid hormone stores and worsen the hyperthyroidism. Because adrenal gland function may be inadequate, patients should receive 100 mg of hydrocortisone every 8 hours [41]. Glucocorticoids also help to decrease the peripheral conversion of T4 to T3 [42]. Hyperthyroid patients should not receive medications such as pancuronium, ephedrine, norepinephrine, epinephrine, or atropine, which are vagolytic or sympathomimetic. Nitrous oxide, isoﬂurane,and the opioids have been found to be safe. Adrenal gland Patients who have taken steroid medications for more than 1 week in the several months prior to major surgery may be at risk for secondary adrenal insuﬃciency, and they should be considered for perioperative ‘‘stress dose’’ steroids. Study results diﬀer on what dose and duration of steroid therapy puts patients at risk. Much of the available data do suggest, however, that the hypothalamic-pituitary-adrenal (HPA) axis can be suppressed for up to 1 year after use of steroid medication of greater than 10 mg per day of hydrocortisone or equivalent doses of other steroids for 5 days or more. Evidence suggests that use of low-dose steroids (ie, 5–7.5 mg prednisone every other day or less than 5 mg per day) does not produce HPA axis suppression. In choosing doses of hydrocortisone for patients undergoing surgery, consider the degree of stress of the procedure itself. For example, major surgery is much more stressful than minor procedures and therefore requires more hydrocortisone. General anesthesia for procedures is more stressful and requires more hydrocortisone than local anesthesia, even for similar degrees of surgery. The normal adrenal gland, under nonstress conditions, produces approximately 25–30 mg of cortisol per day. Under major stress, it produces approximately 200–500 mg per day [42]. If the adrenal gland has been suppressed because of exogenous steroid use, the patient requires exogenous replacement of this amount as hydrocortisone. (Hydrocortisone is equipotent to cortisol.) After surgery, the endogenous production of cortisol remains increased for approximately 3 days, then returns to normal. A variety of closing and tapering schedules have been put forth, but none have been formally studied. It is common practice to give 100 mg hydrocortisone IV every 8 hours, starting immediately preceding the surgery. After the operative day, some practitioners continue the same dose of hydrocortisone unchanged, and then discontinue it abruptly after the third day. But this total course of hydrocortisone may be excessive, and, if the patient is not under substantial physical stress (eg, sepsis, fever, or signiﬁcant pain), the dose can usually be tapered by 50% per day, then discontinued by the fourth day. For minor procedures,

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one dose of 50–100 mg of hydrocortisone immediately before surgery may suﬃce, with another dose given 6–8 hours postoperatively [40,42,43]. Hormones It has long been known that the estrogen in oral contraceptives can cause thromboembolism in women. Given that major surgery increases the risk of thromboembolism, there is concern that patients taking either oral contraceptives or estrogen for hormone replacement therapy will have a further increase in thromboembolic risk. And, although the biologic potency of postmenopausal hormone replacement therapy is only 1/4–1/5 of the estrogen in oral contraceptives, recent evidence has shown that even this amount of hormone therapy increases the risk of postoperative venous thromboembolic events, especially for lower extremity repair of fractures [14]. Grady et al attempted to determine how long after cessation of hormone therapy the risk for thromboembolism is increased. Results showed that the relative risk was increased for at least 1 month after cessation, but the power of the study was too small to produce deﬁnite conclusions. There are no other such studies available to validate these ﬁndings, but it seems prudent to stop estrogen therapy when possible for 4 weeks preoperatively, especially for procedures with high thromboembolic risk, such as lower extremity orthopedic procedures and cancer-related procedures. Estrogen can be restarted postoperatively when patients are mobile and when the operative-related risk of venous thromboembolism is decreased (for example, 4–5 weeks after joint replacement or hip fracture repair). For patients using oral contraception, the risks and beneﬁts of perioperative thromboembolism versus perioperative pregnancy should be discussed with the patient.

Rheumatologic drugs Using methotrexate for the treatment of rheumatoid arthritis has become a more common approach, and may be considered usual treatment for patients whose disease is not adequately controlled with NSAIDs. There has been particular concern about the eﬀect of this medication on wound healing and infectious complications postoperatively. In 2001, Grennan et al published a study suggesting that methotrexate did not cause problems with healing or early postoperative complications, and that it did not need to be discontinued days or weeks before surgery [44]. Caution should be taken, however, in patients with renal failure or sepsis [45]. The new immune modulator leﬂunomide (AravaÒ, Aventis Pharmaceuticals, Parsippany, NJ) is used as an antiproliferative agent in rheumatoid arthritis. There are no known adverse eﬀects of this drug in the perioperative period, although no controlled trials have been done. Because it can rarely cause pancytopenia and hepatic dysfunction, it would be wise to check routine laboratory studies preoperatively.

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Summary One of the consultant’s roles is to make recommendations regarding the use of medications in the perioperative period. Unfortunately, the data in this area are often insuﬃcient to provide evidence-based recommendations. In this article, we have provided advice considering the pharmacokinetics of the drug, the eﬀect on the primary disease of stopping medications, and the eﬀect of the medication on perioperative risk, including potential drug interactions with anesthetic agents.

References [1] Shammash JB, Trost JC, Gold JM, et al. Perioperative beta-blocker withdrawal and mortality in vascular surgical patients. Am Heart J 2001;141:148–53. [2] Stoller JK. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;346:988–94. [3] Smith MS, Muir H, Hall R. Perioperative management of drug therapy. Drugs 1996;51: 238–59. [4] Taggart DP, Siddiqui A, Whaeatley DJ. Low-dose preoperative aspirin therapy, postoperative blood loss, and transfusion requirements. Ann Thorac Surg 1990;50:425–8. [5] Physicians Desk Reference. Montvale, NJ: Medical Economics Company; 2002. [6] Abu-Hajir M, Masseo AJ. The pharmacology of anti-thrombotic and antiplatelet agents. Anesth Clin North Am 1999;17:749–86. [7] Horlocker TT, Wedel DJ. Neurological complications of spinal and epidural anesthesia. Reg Anesth Pain Med 2000;25:83–98. [8] Enneking FK, Benzon H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med 1998;23(Suppl 2):140–5. [9] Horlocker TT, Wedel DJ. Neuraxial block and low-molecular-weight heparin: balancing perioperative analgesia and thromboprophylaxis. Reg Anesth Pain Med 1998;23(Suppl 2): 164–77. [10] Liu SS, Mulroy MF. Neuraxial anesthesia in the presence of standard heparin. Reg Anesth Pain Med 1998;23(Suppl 2):157–63. [11] Rosenquist RW, Brown DL. Neuraxial bleeding: ﬁbrinolytics/thrombolytics. Reg Anesth Pain Med 1998;23(Suppl 2):152–6. [12] Urmey WF, Rowlingson J. Do antiplatelet agents contribute to the development of perioperative spinal hematoma? Reg Anesth Pain Med 1998;23(Suppl 2):146–51. [13] Haynes B, Dowsett M. Clinical pharmacology of selective estrogen receptor modulators. Drugs Aging 1999;14:323–36. [14] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37. [15] Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increase risk for venous thromboembolic disease. Ann Intern Med 2000;132:689–96. [16] Spell NO. Stopping and restarting medications in the perioperative period. Med Clin North Am 2001;85:1117–28. [17] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. U.S. Dept. of Health and Human Services, 2002, 21. [18] Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative care. JAMA 2001;286:208–16. [19] Tsen LC, Segal S, Pothier M, et al. Alternative medicine use in presurgical patients. Anesthesiology 2000;93:148–51.

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[20] Crove S, Fitzpatrick G, Jamaluddin MF. Use of herbal medicines in ambulatory surgical patients. Anaesthesia 2002;57:203–4. [21] Kaye AD, Heavner JE, Sabar R. Nutraceuticals and risk of neuraxial bleeding. Reg Anesth Pain Med 2001;26:92–3. [22] O’Hara MA, Kiefer D, Farrell K, et al. A review of 12 commonly used medicinal herbs. Arch Fam Med 1998;7:523–36. [23] Ernst E, Pittler MH. Herbal medicine. Med Clin North Am 2002;86:149–61. [24] Fessenden JM, Wittenborn W, Clarke L. Ginkgo biloba: a case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am Surg 2001;67:33. [25] Haller CA, Banowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000; 343:1833–8. [26] Taylor CL. FDA letter to health care professionalsAvailable at: http://www.cfscan.fda.gov/ dms/ds-ltr29Accessed March 25, 2002. [27] Cheng TO. Herbal interactions with cardiac drugs. Arch Int Med 2000;160:870. [28] Vickers A, Zollman C. Herbal medicine. Brit J Med 1999;319:1050–1053. [29] Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignant like syndrome due to levodopa therapy withdrawal. JAMA 1985;254:2792–5. [30] Waters C. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. J Am Geriat Soc 2002;48:692–8. [31] Bell RD, Merli GJ. Perioperative assessment and management of the surgical patient with neurologic problems. In: Merli GJ, Weitz HH, editors. Medical management of the surgical patient. 2nd edition. Philadelphia, PA: W.B. Saunders Co.; 1998. p. 2183–312. [32] Arar MG, Dairi Y, Corman LC. Perioperative management of neurologic conditions and complications. In: Gross RJ, Caputo GM, editors. Kammerer and Gross’ medical consultation. 3rd edition. Maryland: Williams and Wilkins, Maryland; 1998. p. 553–6. [33] Drugs for psychiatric disorders. The Medical Letter 1986;28(725):99–105. [34] Edwards RP, Miller RD, Roizen MF, et al. Cardiac responses to imipramine and pancuronium during anesthesia with halothane and enﬂurane. Anesth 1979;50:421–5. [35] Michaels I, Serrins M, Shier NQ, et al. Anesthesia for cardiac surgery in patients receiving monoamine oxidase inhibitors. Anesth Analg 1984;63:1041–4. [36] El-Ganzouri AR, Ivankovich AD, Braverman B, et al. Monoamine oxidase inhibitors: should they be discontinued preopertively? Anesth Analg 1985;64:592–6. [37] Sarko J. Antidepressants, old and new. Emerg Med Clin North Am 2000;18:637–54. [38] Goldberg JF. New drugs in psychiatry. Emerg Med Clin North Am 2000;18:211–32. [39] Stoudemire A, Fogel BS, Gulley LR, et al. Psychopharmacology in the medically ill. In: Psychopharmacology in the medically ill. In: Stoudemire A, Fogel BS, editors. Psychiatric care of the medical patient. New York: Oxford University Press; 1993. p. 155–206. [40] Cygan R, Waitzkin H. Stopping and restarting medications in the perioperative period. J of Gen Int Med 1987;2:270–83. [41] McGlynn TJ, Simons RJ. Endocrine Disorders. In: Kammerer WS, Gross RJ, editors. Medical consultation. 1st edition. Baltimore, MD: Williams and Wilkins; 1990. p. 275–309. [42] Wall RT. Unusual endocrine problems. Anesth Clin North Am 1996;14:471–93. [43] McGlynn TJ, Simons RJ. Endocrine disorders. In: Gross RJ, Caputo GM, editors. Kammerer and Gross’ medical consultation. 3rd edition. Maryland: Williams and Wilkins; 1998. p. 334–40. [44] Grennan DM, Gray J, Loudon J, et al. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Ann Rheum Dis 2001;60:214–7. [45] Wluka A, Buchbinder R, Hall S, et al. Methotrexate and postoperative complications. Ann Rheum Dis 2002;61:86–7.

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Antimicrobial prophylaxis in the surgical patient Harrison G. Weed, MS, MD, FACP Division of General Internal Medicine, The Ohio State University College of Medicine, 4510 UHC Cramblett Hall, 456 West 10th Avenue, Columbus, OH 43210, USA

Although surgery has been performed for thousands of years, until modern times people underwent surgery only in desperation, in part because they were likely to die of postoperative infection. With the advent of antiseptic techniques in the late 1800s, surgery became signiﬁcantly safer; however, postoperative infection remained a major cause of operative morbidity and mortality. Soon after antimicrobials entered medical practice in the 1950s, surgeons began to use them prophylactically with the goal of preventing postoperative infections. Over the subsequent 50 years, there have been many trials investigating the beneﬁts and risks of prophylactic antimicrobials. Although many uncertainties remain, prophylactic antimicrobials are currently an important part of good perioperative care for many types of surgery.

Antimicrobial prophylaxis for surgical site infection and sepsis Postoperative infections Bacteria introduced into normally sterile body sites are the dominant cause of postoperative infection. Immunosuppression from perioperative stress, and from concomitant treatments such as blood transfusion, may also contribute to postoperative infection [1]. Although postoperative fungal infections remain much less common than bacterial infections, postoperative fungal infections are becoming more frequent, particularly in immunosuppressed patients [2,3]. The most obvious and frequent location for a

Supported in part by U.S. Department of Health and Human Services Primary Care Research Initiative Grant no. 5D12 HP00027-02. E-mail address: [email protected] (H.G. Weed). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 5 - 1

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postoperative infection is the surgical site, but pneumonia is also a common postoperative infection in susceptible patients undergoing surgeries that entail endotracheal intubation or compromise the respiratory tract, thorax, or upper abdomen [4,5]. Although we commonly talk about ‘‘wound’’ infections, these can be more explicitly referred to as surgical site infections and further characterized by the depth of infection and by the presence or absence of a foreign body or prosthetic material [3]. In addition to surgical site and pulmonary infections, bacteremia from these infections or from catheters can lead to sepsis and to endocarditis [6]. Finally, urinary tract infections occur in surgical patients, usually as a consequence of an indwelling urinary catheter [7]. Nonantimicrobial strategies for reducing postoperative infection In addition to antimicrobials and standard antiseptic surgical technique [3], some nonantimicrobial strategies have been demonstrated to reduce the incidence of postoperative infection, including maintaining normal body temperature [8], maintaining normal blood sugar levels [9], and hyperoxygenation [10]. Kurz et al [8] randomized 200 patients undergoing colorectal surgery to routine intraoperative thermal care or to supplemental warming. Blinded investigators evaluated the surgical sites for infection daily until discharge and at a 2-week follow-up clinic visit. Surgical site infection was deﬁned as culture-positive purulent drainage. Final intraoperative core temperature was 34.7°C in patients randomized to routine care and 36.6°C in patients randomized to supplemental warming. Surgical site infection occurred in 18 (19%) of 96 patients randomized to routine care, but in only 6 (6%) of 104 randomized to supplemental warming (P ¼ 0.009). Van den Berghe et al [9] randomly assigned adults who were admitted to the surgical intensive care unit (SICU) on a mechanical ventilator, to receive either conventional insulin treatment to maintain blood glucose below 210 mg/dL, or intensive insulin treatment to maintain blood glucose between 80 and 110 mg/dL. The study was terminated early, after the enrollment of 1548 patients, because 8.0% of patients receiving conventional treatment had expired in the SICU, compared with only 4.6% of patients receiving intensive treatment (P ¼ 0.04). The reduction in SICU mortality was principally caused by a reduction in multiple-organ failure with a proven septic focus in patients who were in the SICU for more than 5 days (20.2% conventional treatment, 10.6% intensive treatment, P ¼ 0.005). Intensive insulin treatment also reduced overall in-hospital mortality by 34%, and bloodstream infections by 46%. Greif et al [10] randomly assigned 500 patients undergoing colorectal resection to receive either 30% or 80% inspired oxygen during the operation and for 2 hours afterward. Blinded investigators evaluated the surgical sites for infection daily until discharge and at a 2-week follow-up clinic visit.

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Surgical site infection was deﬁned as culture-positive purulent drainage. Arterial oxygen saturation was normal in both groups; however, the arterial and subcutaneous partial pressure of oxygen was signiﬁcantly higher in the patients randomized to 80% oxygen. Surgical site infection occurred in 28 (11.2%) of 250 patients randomized to 30% inspired oxygen, but in only 12 (5.2%) of 250 patients randomized to 80% inspired oxygen (P ¼ 0.01). Although the three clinical trials described above can be criticized (for example, the control patients in Kurz’s study had an extraordinarily high infection rate, and investigators in Van den Bergh’s study were not blinded), the interventions have a solid physiologic basis and are supported by the ﬁndings of other studies in humans and other animals. Allogenic blood transfusion is another risk factor for postoperative infection [11,12]; however, blood transfusion is also a general measure of severity of illness, and randomized trials restricting allogenic blood transfusion have failed to show a signiﬁcant beneﬁt [13]. In sum, assiduous maintenance of homeostasis, including body temperature, blood glucose, and tissue oxygenation in the perioperative period can signiﬁcantly reduce postoperative infection.

Beneﬁts and risks of antimicrobials The beneﬁts of perioperative antimicrobial prophylaxis include a reduction in surgical site infection, pneumonia, sepsis, endocarditis, and urinary tract infection. The risks include allergic reactions to antimicrobials, toxic eﬀects of antimicrobials, adverse interactions of antimicrobials with other medications, selection pressure for the emergence of antimicrobial-resistant organisms, and the cost of the antimicrobials. Therefore, the use of antimicrobial prophylaxis should be limited to those operations with high infection rates or serious consequences of infection [14,15].

Principles of perioperative antimicrobial use Perioperative antimicrobial prophylaxis is directed against the most likely infecting organisms and does not have to cover every potential pathogen [16]. In surgeries not entering a chronically colonized body cavity, surgical site infections are most likely to be caused by skin organisms such as staphylococci and streptococci. Cefazolin is eﬀective against these organisms and is therefore usually appropriate for these kinds of surgeries. Although prophylactic vancomycin might be appropriate for patients at high risk for infection with methicillin-resistant staphylococci, a randomized trial in a high-risk setting failed to show beneﬁt [17], and vancomycin use promotes the emergence of resistant organisms, especially enterococci [18]. Antimicrobial prophylaxis for surgeries involving the lower gastrointestinal tract should cover gram-negative enteric bacteria and bowel anaerobes,

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especially Bacteroides fragilis. Cefoxitin and cefotetan are appropriate for such surgeries. Third-generation cephalosporins cefotaxime, ceftriaxone, cefoperazone, ceftizoxime, ceftizoxime and fourth-generation cephalosporins such as cefepime are contraindicated for antimicrobial prophylaxis because: (1) most of them are less active than cefazolin against organisms likely to cause postoperative infection such as staphylococci, (2) they are active against organisms that rarely cause postoperative infection, (3) their use promotes the emergence of resistance organisms, especially enterococci, and (4) they are more expensive than more eﬀective alternatives [19]. Penicillin allergy Patient report of penicillin allergy is notoriously unreliable. Approximately 85% of patients who report penicillin allergy do not have an allergy when assessed by skin testing [20]. Patients who are not penicillin-allergic by skin testing can safely receive penicillin [21]. Use of alternate antimicrobials, especially vancomycin, for surgical prophylaxis in patients reporting penicillin allergy increases cost and increases the prevalence of antimicrobial-resistant bacteria, such as vancomycin-resistant enterococci. A cost-eﬀectiveness analysis that did not account for the increased prevalence of antimicrobialresistant bacteria found that routine preoperative skin testing of cardiovascular surgery patients reporting penicillin allergy was more cost-eﬀective than routine use of vancomycin [22]. A 6-month clinical trial of routine preoperative skin testing in elective orthopedic surgery patients reporting allergy to penicillins or to cephalosporins found a signiﬁcant reduction in vancomycin use and no instances of immediate antimicrobial reaction [23]. Therefore, to minimize the cost of surgical antimicrobial prophylaxis, and to reduce the prevalence of antimicrobial-resistant bacteria, it is probably worth using skin testing when feasible to guide the choice of a prophylactic antimicrobial in patients reporting penicillin allergy prior to surgery. Duration of antibiotic prophylaxis after surgery Usually, a single dose of antimicrobial within 1/2 hour prior to skin incision is eﬀective infection prophylaxis [24]. An antimicrobial is measurably less eﬀective if given more than 2 hours prior to skin incision [25,26]. If the surgery lasts longer than 4 hours, or involves major blood loss, or the antimicrobial has a very short half-life (eg, cefoxitin) then additional doses of antimicrobial may be of beneﬁt. Many surgeons continue antimicrobials for 2–3 days after surgery with the rationale that surgical wound drains and intravenous catheters might lead to bacterial seeding of the surgical site; however, there is evidence that this practice does not further decrease the risk of infection [27–29].

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Considerations for speciﬁc surgeries (Table 1) Cardiac procedures Antimicrobial prophylaxis with cefazolin reduces the risk of infection after cardiac procedures, including the transvenous pacemaker placement [30]. In institutions with a high risk of infection with methicillin-resistant staphylococci, vancomycin may be an appropriate alternative, though a randomized trial in a high-risk setting failed to show beneﬁt [17]. An inception cohort study demonstrated a reduction in sternal wound infection after cardiac surgery in patients treated with intranasal mupirocin before and after surgery [31]. Gastrointestinal procedures Antimicrobial prophylaxis is not needed for routine, uncomplicated gastrointestinal endoscopy. Some clinicians use prophylaxis for sclerotherapy of varices, and for esophageal dilation. Most of them use prophylaxis for percutaneous feeding tube placement [32,33]. Antimicrobial prophylaxis reduces infection risk in esophageal procedures with obstruction, and in gastroduodenal surgery with risk factors for infection including obstruction or decreased motility, decreased gastric acidity, gastrointestinal hemorrhage, ulcer, cancer, and morbid obesity. The most appropriate antimicrobial agents are usually cefazolin or cefoxitin. Prophylaxis is also appropriate in biliary tract procedures including endoscopic retrograde cholangiopancreatography (ERCP) for patients with risk factors for infection including age over 70, acute cholecystitis, obstruction, common duct stones, and a nonfunctioning gallbladder. Prophylactic antimicrobials are unnecessary for low-risk patients undergoing elective laparoscopic cholecystectomy [34–36]. In elective colorectal surgery, selective decontamination of the gastrointestinal tract with oral neomycin and erythromycin is approximately as eﬀective as parenteral antimicrobials [37]. Many clinicians use both, but it is not clear that this is more eﬀective than either alone. A preoperative parenteral antimicrobial decreases the incidence of surgical site infection after appendectomy. If the appendix has ruptured, then an antimicrobial is recommended for treatment of the infection and should be continued as long as clinically appropriate. Although prophylactic antimicrobials are probably unnecessary in uncomplicated inguinal herniorraphy, a single dose of ampicillin-sulbactam can reduce the infection rate in herniorraphy with mesh repair [38]. Gynecologic and obstetric Antimicrobial prophylaxis can decrease the incidence of infection after both vaginal and abdominal hysterectomy [19,39]. Antimicrobials can decrease the incidence of infection, even when given during high-risk obstetrical events such as emergency cesarean section, premature rupture of membranes, and active labor in high-risk women. [40] Preoperative antimicrobial prophylaxis decreases infection risk after mid-trimester abortion, and after

Enteric gram-negative bacilli, enterococci

Enteric gram-negative bacilli, anaerobes, enterococci, group B strep Enteric gram-negative bacilli, anaerobes, enterococci, group B strep Enteric gram-negative bacilli, anaerobes, enterococci, group B strep

Gastrointestinal: esophageal, gastroduodenal, in a high-riskf patient only Genitourinary: in a high-riskg patient only

Gynecologic/obstetric: abortion, ﬁrst trimester, in a high-riskh patient only

Gynecologic/obstetric: abortion, second trimester Gynecologic/obstetric: cesarean section, in a high-riskj patient only

Enteric gram-negative bacilli, gram-positive cocci

Cefoxitin 1–2 gm IV or cefotetan 1–2 gm IV

Enteric gram-negative bacilli, anaerobes, enterococci Enteric gram-negative bacilli, enterococci, clostridia Enteric gram-negative bacilli, anaerobes, enterococci

Cefazolin 1 gm IV after cord clamping

Oral: ciproﬂoxaxin 0.5 gm PO or trimethoprimsulfamethoxazole 160–800 mg PO Intravenous: ciproﬂoxacin 0.4 gm IV trimethoprim-sulfamethoxazole 160–800 mg IV Oral: doxycycline 300 mg POi Intravenous: aqueous penicillin G 2 million units IV Cefazolin 1 gm IV

Cefazolin 1–2 gm IV, or cefoxitin 1–2 gm IV, or cefotetan 1–2 gm IV Oral: neomycin plus erythromycin basee Intravenous: cefoxitin 1–2 gm IV, or cefotetan 1–2 gm IV or cefazolin 1–2 gm IV plus metronidazole 0.5 gm IV cefazolin 1–2 gm IV

Cefazolinb 1–2 gm IV, or cefuroximeb 1.5 gm IV, or vancomycinc 1 gm IV

Staphylococci, corynebacteria, enteric gramnegative bacilli

Cardiac: pacemaker or deﬁbrillator insertion, and open heart, eg, coronary artery bypass and prosthetic valve Gastrointestinal: appendectomy without perforation Gastrointestinal: biliary tract, in a high-riskd patient only Gastrointestinal: colorectal

Antimicrobiala

Likely pathogens

Procedure

Table 1 Antimicrobial prophylaxis for surgery

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Cefoxitin 1–2 gm IV or vancomycinc 1 gm IV

Staphylococci Staphylococci, streptococci, enteric gramnegative bacilli, Pseudomonas aeruginosa

Staphylococci Staphylococci, streptococci, enteric gramnegative bacilli Staphylococci, streptococci Staphylococci, streptococci, enteric gramnegative bacilli, clostridia

Neurologic: craniotomy Ophthalmic

Orthopedic Thoracic: noncardiac

Give as a single intravenous dose completed 1-half hr prior to the ﬁrst skin incision. For prolonged procedures additional doses may be required at usual dosing interacts. b Some consultants recommend an additional dose when patients are removed from bypass during open-heart surgery. c For settings in which methicillin-resistant S aureus and S epidermidis frequently cause surgical site infection, or for patients allergic to cephalosporins. Rapid IV administration may cause hypotension, which can be exacerbated by induction of anesthesia. Infuse slowly and treat with diphenhydramine (BenadrylÒ, Parke-Davis, and others). For procedures in which enteric gram-negative bacilli are likely pathogens, such as vascular surgery in the groin, include cefazolin or cefuroxime for patients not allergic to cephalosporins. d Age >70 years, acute cholecystitis, nonfunctioning gall bladder, obstructive jaundice, or common duct stones. e After appropriate diet and catharsis, one gram each at 1 PM, 2 PM, and 11 PM the day before an 8 AM operation. f Morbid obesity, esophageal obstruction, decreased gastric acidity, or decreased gastrointestinal motility. g Urine culture positive or unavailable, preoperative bladder catheter, transrectal prostatic biopsy. h Patients with previous pelvic inﬂammatory disease, previous gonorrhea, or multiple sex partners. i Divided into 100 mg 1 hr before the abortion, and 200 mg 1 hr after. j Active labor or premature rupture of membranes. (Adapted from Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 2001;43:92–97; with permission.)

a

Vascular: arterial repair, prosthetic material, abdominal aorta Vascular: groin incision, leg amputation for arterial insuﬃciency

Cefoxitin 1–2 gm IV, or cefotetan 1–2 gm IV, or cefazolin 1–2 gm IV Ampicillin-sulbactam 1.5–3 gm IV or clindamycin 600–900 mg IV, plus gentamicin 1.5 mg/kg IV or cefazolin 1–2 gm IV Cefazolin 1–2 gm IV or vancomycinc 1 gm IV Topical drops over 2–24 hours: gentamicin, or tobramycin, or ciproﬂoxacin, or oﬂoxacin, or neomycin-gramicidin-polymyxin B Subconjunctival: cefazolin 100 mg Cefazolin 1–2 gm IV or vancomycinc 1 gm IV Cefazolin 1–2 gm IV, or cefuroxime 1.5 gm IV, or vancomycinc 1 gm IV Cefazolin 1–2 gm IV or vancomycinc 1 gm IV

Enteric gram-negative bacilli, anaerobes, enterococci, group B strep Oral anaerobes, enteric gram-negative bacilli, staphylococci

Gynecologic/obstetric: hysterectomy: vaginal or abdominal Head and neck: with incision through oral or pharyngeal mucosa

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ﬁrst-trimester abortion in high-risk women, and may decrease infection risk in all women undergoing therapeutic abortion [41]. Head and Neck Prophylactic intravenous antimicrobials decrease surgical site infections after head and neck surgeries involving incision through the oral or pharyngeal mucosa [42]. Preferred antimicrobials for prophylaxis in cleancontaminated head and neck surgeries should have activity against the gram-positive and gram-negative aerobic bacteria, and the anaerobic bacteria found in the oropharynx, and include combinations such as ampicillinsulbactam (UnasynÒ), and clindamycin plus gentamicin [43,44]. Rinsing the surgical site with antimicrobials does not further decrease the infection rate [45]. Antimicrobial prophylaxis is not indicated for endoscopic sinus surgery without nasal packing [46]. Neurologic Antimicrobial prophylaxis can decrease infection rates after craniotomy [47–49]; however, some have argued that only high-risk patients, such as those undergoing repeat tumor resection beneﬁt adequately [50]. Antimicrobial prophylaxis is probably not indicated for routine lumbar discectomy; however, it might beneﬁt patients undergoing spinal procedures that are prolonged or involve fusion or foreign materials [51]. Ophthalmic procedures Although prophylactic 1% chloramphenicol ophthalmic ointment can prevent corneal ulcer in rural patients with corneal abrasion [52]. and ciproﬂoxacin ophthalmic solution can concentrate on corneal defects [53], there are no well-controlled trials of antimicrobial prophylaxis in ophthalmic surgery. Nonetheless, because postoperative endophthalmitis is a severe complication, antimicrobial eye drops are appropriate for procedures that invade the globe, and subconjunctival antimicrobials may be appropriate for high-risk patients [54,55]. As with all surgeries, antiseptic surgical setting and technique are the foundation of infection prophylaxis [56]. Orthopedic procedures Antimicrobial prophylaxis prior to surgery reduces the incidence of both early and late surgical site infection after joint replacement, and after repair of both open and closed fractures [57,58]. Antimicrobial prophylaxis is probably not indicated for either diagnostic or therapeutic, routine arthroscopic surgery [59]. It is reasonable to oﬀer antimicrobial prophylaxis to patients with prosthetic joints who are undergoing invasive dental work and are at high risk for prosthetic joint infection [60]. Risk factors for prosthetic joint infection include recent joint placement (less than 1 year), rheumatoid arthritis, gross dental infection (eg, abscess), prolonged invasive dental work (more than 1 hour), and, possibly, diabetes mellitus and immunosuppressive

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corticosteroid treatment. Nonetheless, prosthetic joint infection from dental work is rare and the risks of prophylactic antimicrobial treatment probably outweigh the beneﬁts for most patients with prosthetic joints. Thoracic procedures There is limited information on the eﬃcacy of antimicrobial prophylaxis for noncardiac chest procedures; however, it is accepted practice to use prophylactic cephalosporin. There is a correlation between the antimicrobial susceptibilities of bacteria isolated from the lung prior to pulmonary resection, the prophylactic antimicrobial used, and the occurrence of postoperative infection [61]. Antimicrobial prophylaxis is not indicated for chest tube insertion to treat nontraumatic conditions such as spontaneous pneumothorax but is indicated for closed-tube thoracostomy after major chest trauma [62]. Urologic Prior to most urologic procedures, prophylactic antimicrobials are not indicated for patients with sterile urine; however, preoperative sterilization of the urine is indicated for patients with indwelling urethral catheters or bacteriuria. A prophylactic antimicrobial is indicated prior to transrectal prostate biopsy [63]. A single dose of ciproﬂoxacin is eﬀective and commonly used; however, trimethoprim-sulfamethoxazole is similarly eﬀective [64]. Vascular procedures Antimicrobial prophylaxis is not indicated for carotid endarterectomy or brachial artery repair; however, cephalexin decreases the incidence of postoperative surgical site infection after arterial repair, and after vascular surgeries in the abdomen or legs [65]. The implantation of prosthetic material is a risk factor for infection, and most practitioners use prophylactic antimicrobials for all vascular surgeries involving prosthetic material.

Bacterial Endocarditis The rationale for antimicrobial prophylaxis Endocarditis is an uncommon yet life-threatening infection. It usually occurs in people with abnormal or prosthetic heart valves and requires bacteremia with organisms that can reside on the valves. The source of the bacteremia can be inapparent or can be caused by a focal infection such as cellulitis, an abscess, or pneumonia. Some surgical and dental procedures can produce transient bacteremia, and, though the great majority of endocarditis is not attributable to an invasive procedure [66], periprocedure antimicrobials are administered to patients at risk with the goal of reducing the risk for this serious complication. Under the aegis of The American Heart Association, a panel of experts has devised recommendations for the use

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of antimicrobial prophylaxis to reduce the risk of bacterial endocarditis after invasive procedures [6]. Despite these guidelines, antibiotic prophylaxis against endocarditis is frequently both overused and underused [67]. At risk patients Patients at high risk for endocarditis include those with prosthetic valves, prior endocarditis, or complex cyanotic heart disease (Table 2). Patients at moderate risk include those with congenital cardiac malformations other than complex cyanotic heart disease; with rheumatic and other acquired structurally abnormal valves; hypertrophic cardiomyopathy; and with mitral valve prolapse including an abnormal, regurgitant mitral valve (Table 2). Patients at no greater risk than the general population include those with isolated secundum atrial septal defects, surgically repaired atrial and ventricular defects (more than 6 months after successful repair), surgically repaired patent ductus arteriosus (more than 6 months after successful repair), prior coronary artery bypass, implanted cardiac pacemakers and deﬁbrillators, and benign murmurs (Table 2). At risk procedures Any procedure involving infected tissue at the surgical site is associated with a signiﬁcant risk of bacteremia. Upper aerodigestive tract procedures Table 2 Patient risk categories for endocarditis High risk Prosthetic valves, including bioprosthetic and homograft valves Prior endocarditis Complex cyanotic heart disease Surgically constructed systemic-pulmonary shunts Moderate risk Congenital cardiac malformations other than complex cyanotic heart disease Rheumatic and other acquired, structurally abnormal valves Hypertrophic cardiomyopathy Mitral valve prolapse with a thickened or continuously regurgitant valve Low risk (no greater risk than the general population) Isolated secundum atrial septal defects Surgically repaired: atrial septal defects, ventricular septal defects, or patent ductus arteriosus (more than 6 months after successful repair) Prior coronary artery bypass Implanted cardiac pacemakers and deﬁbrillators Prior Kawasaki’s disease or rheumatic fever without valve dysfunction Mitral valve prolapse without a thickened or continuously regurgitant valve Benign murmurs (Adapted from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by The American Heart Association. JAMA 1997;277:1794–1801; with permission.)

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associated with some risk of bacteremia include dental extractions and implants, tonsillectomy, rigid bronchoscopy, esophageal sclerotherapy and dilation, biliary tract surgery, and other procedures violating the oral or intestinal mucosa (Table 3). Procedures with negligible risk of bacteremia include restorative dentistry, local anesthetic injection, intracanal Table 3 Procedure risk categories for endocarditis in uninfected patients Upper aerodigestive tract procedures with some risk of bacteremia Procedures violating the oral, esophageal or intestinal mucosa, including: Prophylactic cleaning with anticipated bleeding Dental extractions and implants Periodontal surgery, scaling, planing, and probing Subgingival or intraligamentary periodontic manipulation or injection Endodontic surgery beyond the apex Initial placement of orthodontic bands, but not brackets Tonsillectomy—adenoidectomy Rigid bronchoscopy Esophageal sclerotherapy and dilation Biliary tract surgery including ERCP with biliary obstruction Upper aerodigestive tract procedures with negligible risk of bacteremiaa Restorative dentistry Local anesthetic injection not into dental ligaments Intracanal endodontistry Suture removal Adjustment of orthodontic appliances Endotracheal intubation Flexible bronchoscopy Tympanostomy tube insertion Transesophageal echocardiography Gastrointestinal endoscopy with or without biopsy Lower gastrointestinal and genitourinary tract procedures with some risk of bacteremia Prostate surgery Cystoscopy Urethral dilation Lower gastrointestinal and genitourinary tract procedures with negligible risk of bacteremiaa Vaginal hysterectomy Vaginal delivery Cesarean section Uterine dilation and curettage Therapeutic abortion Tubal ligation Insertion and removal of intrauterine devices Urethral catheterization ERCP ¼ endoscopic retrograde cholangiopancreatography. a Any procedure involving infected tissue at the surgical site is asociated with a signiﬁcant risk of bacteremia. (Adapted from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by The American Heart Association. JAMA 1997; 277:1794–1801; with permission.)

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endodontistry, suture removal, adjustment of orthodontic appliances, endotracheal intubation, ﬂexible bronchoscopy, tympanostomy, transesophageal echocardiography, and endoscopy without biopsy. Lower gastrointestinal and genitourinary tract procedures associated with some risk of bacteremia include prostate surgery, cystoscopy, and urethral dilation. Procedures with negligible risk include vaginal hysterectomy, normal vaginal delivery, cesarean section, uterine dilation and curettage, therapeutic abortion, tubal ligation, insertion and removal of intrauterine devices, and urethral catheterization (Table 3). Antimicrobials Antimicrobials used in endocarditis prophylaxis are aimed at the most likely causative organisms (Table 4). In upper aerodigestive tract procedures, viridians (alpha-hemolytic) streptococci are the most likely causative organisms, and in lower gastrointestinal and genitourinary tract procedures enterococci (Enterococcus faecalis) are the most likely causative organisms. Oral amoxicillin or intravenous ampicillin is usually the antimicrobials of choice. In upper aerodigestive tract procedures, alternative antimicrobials for penicillin-allergic patients include clindamycin, cephalexin, cephadroxil, azithromycin, and clarithromycin. Erythromycin is no longer listed as an alternative because of the availability of better-tolerated alternatives. In lower gastrointestinal and genitourinary tract procedures, vancomycin is the primary alternative to ampicillin. In the highest-risk patients undergoing lower gastrointestinal and genitourinary tract procedures, combination antimicrobial prophylaxis including gentamicin is used against enterococci because enterococci are frequently resistant to antimicrobials. Special considerations As with antimicrobial prophylaxis against postoperative infection, prophylaxis against endocarditis would be expected to be most eﬀective if the antimicrobial is given within an hour prior to the procedure. Patients who chronically take antimicrobials, such as those who take penicillin for secondary prevention of rheumatic fever, may be colonized with bacteria resistant to penicillins. For these patients, it is appropriate to use an antimicrobial with a diﬀerent mechanism of action than the one taken chronically. For example, for the patient who is taking penicillin to prevent rheumatic fever, either clindamycin or azithromycin would be an appropriate alternative. Summary The primary prophylactic measure against postoperative infection is antiseptic technique in patient preparation, during surgery, and in postoperative patient care. Antimicrobial prophylaxis against postoperative infection is not indicated for procedures with a low infection rate because the expected

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Table 4 American Heart Association Recommendations for Endocarditis Prophylaxis Upper Aerodigestive Tract Procedure with Some Risk of Bacteremia (Table 3) High- or moderate-risk patient (Table 2) No contraindication to penicillins: Oral: amoxicillin 2 gm PO 1 hr prior to the procedure Intravenous: ampicillin 2 gm IV 1/2 hr prior to the procedure Penicillins contraindicated: Oral: clindamycin 600 mg PO 1 hr prior to the procedure or cephalexin 2 gm PO 1 hr prior to the procedure or cephadroxil 2 gm PO 1 hr prior to the procedure or azithromycin 500 mg PO 1 hr prior to the procedure or clindamycin 500 mg PO 1 hr prior to the procedure Intravenous: clindamycin 600 mg IV 1/2 hr prior to the procedure or cefazolin 1 gm IV 1/2 hr prior to the procedure Lower gastrointestinal or genitourinary tract procedure with some risk of bacteremia (Table 3) High Risk Patient (Table 2) No Contraindication to Penicillins: ampicillin 2 gm IV 1/2 hr prior to the procedure plus Gentamicin 1.5 mg/kg IV 1/2 hr prior to the procedure and, 6 hr later Amoxicillin 1 gm PO, or ampicillin 1 gm IV Penicillins contraindicated: vancomycin 1 gm IV 1.5 hr prior to the procedure plus Gentamicin 1.5 mg/kg IV 1/2 hr prior to the procedure Moderate-risk patient (Table 2) No contraindication to penicillins: Oral: amoxicillin 2 gm PO 1 hr prior to the procedure Intravenous: ampicillin IV 2 gm 1/2 hr prior to the procedure Penicillins contraindicated: Vancomycin 1 gm IV 1.5 hr prior to the procedure (Adapted from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by The American Heart Association. JAMA; 1997, 277:1794– 1801, with permission.)

beneﬁt of antimicrobial treatment is less than the risk of an adverse medication reaction. Antimicrobial prophylaxis has been demonstrated to be of greater beneﬁt than risk in some procedures with higher infection rates; however, because the problem is complex and the data are limited, extrapolating these ﬁndings to the practitioner’s setting and the individual patient remains a challenge (Table 1). Although antimicrobial prophylaxis for bacterial endocarditis is not effective for most patients, the seriousness of the potential infection has driven

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the creation of guidelines recommending prophylaxis for at-risk patients undergoing at-risk procedures. Applying these guidelines appropriately could help to reduce unwarranted use of antimicrobials. In the prophylactic use of antimicrobials, as in many medical interventions, the diﬃculty is balancing the risks of the intervention with the potential beneﬁts. Although we do not have either the randomized, controlled trials or the detailed, patient-speciﬁc information to estimate this balance precisely, there are general guidelines to help the clinician choose treatment for most patients.

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[40] Chelmow D, Ruehli M, Huang E. Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact membranes: a meta-analysis. Am J Obstet Gynecol 2001;184:656–61. [41] Sawaya G, Grady D, Kerlikowske K, et al. Antibiotics at the time of induced abortion: the case for universal prophylaxis based on a meta-analysis. Obstet Gynecol 1996;87: 884–90. [42] Weber R. Wound infection in head and neck surgery: implications for perioperative antibiotic treatment. Ear Nose Throat J 1997;76:790–1. [43] Callender D. Antibiotic prophylaxis in head and neck oncologic surgery: the role of gramnegative coverage. Int J Antimicrob Agents 1999;12:S21–5. [44] Rodrigo J, Alvarez J, Gomez J, et al. Comparison of three prophylactic antibiotic regimens in clean-contaminated head and neck surgery. Head Neck 1997;19:188–93. [45] Simons J. The role of topical antibiotic prophylaxis in patients undergoing contaminated head and neck surgery with ﬂap reconstruction. Laryngoscope 2001;111:329–35. [46] Annys E, Jorissen M. Short term eﬀects of antibiotics (Zinnat) after endoscopic sinus surgery. Acta Otorhinolaryngol Belg 2000;54:23–8. [47] Antimicrobial prophylaxis in neurosurgery and after head injury. Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy. Lancet 1994;344:1547–51. [48] Shapiro M, Wald U, Simchen E, et al. Randomized clinical trial of intra-operative antimicrobial prophylaxis of infection after neurosurgical procedures. J Hosp Infect 1986;8: 283–95. [49] Young R, Lawner P. Perioperative antibiotic prophylaxis for prevention of postoperative neurosurgical infections. A randomized clinical trial. J Neurosurg 1987;66:701–5. [50] Tenney J, Vlahov D, Salcman M, et al. Wide variation in risk of wound infection following clean neurosurgery. Implications for perioperative antibiotic prophylaxis. J Neurosurg 1985;62:243–7. [51] Dimick J, Lipsett P, Kostuik J. Spine update: antimicrobial prophylaxis in spine surgery: basic principles and recent advances. Spine 2000;25:2544–8. [52] Upadhyay M, Karmacharya P, Koirala S, et al. The Bhaktapur eye study: ocular trauma and antibiotic prophylaxis for the prevention of corneal ulceration in Nepal. Br J Ophthalmol 2001;85:388–92. [53] Eiferman R, Snyder J, Nordquist R. Ciproﬂoxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg 2001;27:170–2. [54] Gordon Y. Vancomycin prophylaxis and emerging resistance: are ophthalmologists the villains? The heroes? Am J Ophthalmol 2001;131:371–6. [55] Liesegang T. Perioperative antibiotic prophylaxis in cataract surgery. Cornea 1999;18: 383–402. [56] Tabbara K, al Jabarti A. Hospital construction-associated outbreak of ocular aspergillosis after cataract surgery. Ophthalmology 1998;105:522–6. [57] Boxma H, Broekhuizen T, Patka P, et al. Randomised controlled trial of single-dose antibiotic prophylaxis in surgical treatment of closed fractures: the Dutch Trauma Trial. Lancet 1996;347:1133–7. [58] Gillespie W, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev 2001;CD000244. [59] Wieck J, Jackson J, O’Brien T, et al. Eﬃcacy of prophylactic antibiotics in arthroscopic surgery. Orthopedics 1997;20:133–4. [60] Segreti J. Is antibiotic prophylaxis necessary for preventing prosthetic device infection? Infect Dis Clin North Am 1999;13:871–7. [61] Boldt J, Piper S, Uphus D, et al. Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999;68:208–11. [62] Gonzalez R, Holevar M. Role of prophylactic antibiotics for tube thoracostomy in chest trauma. Am Surg 1998;64:617–20.

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DVT prophylaxis and anticoagulation in the surgical patient Peter Kaboli, MD, MSa, Mark C. Henderson, MD, FACPb, Richard H. White, MD, FACPb,* a

Division of General Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA b Division of General Medicine, University of California—Davis, 4150 V Street/Suite 2400, PSSB, Sacramento, CA 95817, USA

To complete a comprehensive preoperative medical assessment prior to major surgery, the consultant must invariably address the issue of the prevention of postoperative thromboembolic complications. Venous thromboembolism (VTE), a term encompassing deep vein thrombosis and pulmonary embolism (PE), is one of the most common postoperative complications. In a study from Olmsted County, Minnesota, surgery was associated with an over twentyfold increase in the odds of being diagnosed with VTE [1]. In an analysis of over 2 million inpatient surgical procedures performed in California, 0.8% of cases were diagnosed with symptomatic VTE, 44% occurring during the hospitalization for surgery and the remainder within the ﬁrst 3 months after surgery [2]. Overview of thromboembolism after surgery Scope of the problem Certain procedures, such as craniotomy for brain malignancy, are associated with a 3-month incidence of symptomatic VTE as high as 7.5% [3]. Because of the absence of reliable autopsy data, it is not clear how often fatal PE occurs after surgery. In a comprehensive study of patients undergoing total hip arthroplasty, Seagroatt estimated an excess of 0.7 deaths from PE for every 1000 operations during the ﬁrst 90 days after surgery,

* Corresponding author. E-mail address: [email protected] (R.H. White). 0025-7125/03/$ - see front matter 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 4 - X

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compared with the ensuing 9-month period [4]. This compares with an estimated excess of 3.2 deaths/1000 from ischemic heart disease, 0.7 deaths/1000 from stroke, and an overall excess mortality of 6.5 deaths/1000 total hip operations. Thus, PE may account for 10% of all postoperative deaths following total hip arthroplasty. Fatal PE accounts for approximately 3–4% of all symptomatic VTE events [5]. For high-risk surgical procedures such as total hip arthroplasty, this translates to a rate of death caused by PE approximately 0.18–0.36% [6]. As discussed below, additional risk factors such as presence of a cancer, advanced age, and prolonged immobilization are likely to be associated with an increase in the incidence of fatal PE. Interpreting the literature The incidence of asymptomatic VTE is dramatically higher than that of symptomatic VTE, with asymptomatic VTE developing in 20–25% of patients after general surgery and 45–60% after orthopedic surgery involving the hip or knee [7]. Most clinical trials of thromboprophylaxis have evaluated a surrogate end point, venographic evidence of thrombosis, or asymptomatic VTE, primarily because the low incidence of symptomatic VTE events makes the sheer size and cost of conducting a suﬃciently powered study prohibitive. Unfortunately, the precise relationship between the surrogate outcome of asymptomatic VTE and symptomatic VTE is not clear [8]. Most asymptomatic clots lyse spontaneously without treatment and they do not cause postphlebitic stasis or ulceration [9]. Fewer than one in eight venographically deﬁned clots progresses to symptomatic VTE, although a somewhat higher proportion of proximal deep venous system clots become symptomatic compared with calf venous clots [7]. Relying on a one time ‘‘snapshot’’ of thrombosis using venography does not reﬂect the dynamic nature of clot formation and dissolution, a process that varies over time. For example, in one study of patients who had a negative venogram 7–10 days after total hip arthroplasty, 20% had a demonstrable clot 21 days later [10]. Unfortunately, the vast majority of thromboprophylaxis studies assess eﬃcacy based on the incidence of asymptomatic VTE at one point in time [7]. The most valuable studies of thromboprophylaxis are those that demonstrate a signiﬁcant reduction in hard end points such as incidence of symptomatic VTE or fatal PE. Implementing an optimal thromboprophylaxis regimen requires simultaneous assessment of the risks of VTE and the risks of bleeding. After combining these estimates with evidence-based knowledge regarding the eﬃcacy and safety of various thromboprophylaxis modalities, one can make an appropriate treatment recommendation. If any recommendations are going to be followed, however, the consulting internist must also establish a working relationship with the surgeon and reach an agreement about: (1) the relative risks of bleeding and thrombosis for each prophylaxis regimen, and (2) the optimal duration of prophylaxis.

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Assessing the risk of VTE The risk of symptomatic VTE is directly related to: (1) the type of surgery being performed, (2) presence of other risk factors for VTE, (3) duration and extent of postoperative immobilization, and (4) use or nonuse of speciﬁc thromboprophylactic measures. Risk factors that have been shown to aﬀect the incidence of postoperative venous VTE are outlined in Table 1. Age Essentially, all epidemiologic studies have shown that advancing age is a risk factor for incident VTE events, including postoperative VTE [1,11]. The incidence of VTE developing after surgery among patients less than 40 years old is quite low but rises linearly with age [12]. Table 1 Risk factors associated with venous thromboembolism (VTE) Risk factor

Eﬀect

References

Age Ethnicity

Exponential increase in risk Asians have two- to three fold lower risk Major associated with up to six-fold higher riska Increased risk with pelvic, femur, leg fractures Three- to fourfold higher risk Increased risk

[1,11,143] [13]

Twofold higher risk Increase with BMI Higher risk

[18,2] [5,19] [21,146]

Increased, but absolute risk low Increased Increased

[16,17,147]

Type of surgery Trauma Previous VTE Varicosities or venous stasis changes Presence of a malignancy Obesity Left or right sided heart failure, COPD Thrombophilic disorder Stroke, immobilization Hematologic disorders: Polycythemia vera, essential thrombocytosis, paroxysmal nocturnal hemoglobinuria, others Medical disorders: nephrotic syndrome, inﬂammatory bowel disease, systemic lupus erythematosus, MI Pregnancy or estrogen use a

Increased, unknown magnitude

[2] [144,145] [2]

[148–151]

[152,153]

Some increase in risk

Major: neurosurgery, abdominal, thoracic, vascular, or orthopedic surgery on lower extremity. Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; VTE, venous thromboembolism.

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Race/ethnicity Studies have shown that individuals with Asian/South Paciﬁc Islander ethnicity have an approximately threefold lower risk of VTE, and this is also true for postoperative VTE [13]. Whether this simply reﬂects the lower prevalence of factor V Leiden and other thrombophilic disorders in this population is not known [14]. African Americans have a slightly higher relative risk of developing VTE compared with Caucasians, whereas Latinos appear to have a modestly lower risk of developing VTE [13]. Surgical procedure The particular surgical procedure is perhaps the strongest risk factor for developing VTE. We recently conducted a study of patients undergoing elective and urgent surgery in California [2]. Neurosurgery involving entry into brain or meningeal tissue and orthopedic surgery involving the hip (total or hemi-arthroplasty) was associated with the highest incidence of symptomatic VTE on the order of 6% and 3%, respectively. This compares with an incidence of approximately 0.3% following laparoscopic cholecystectomy or appendectomy. Other procedures associated with a substantially increased risk of VTE include major vascular surgery involving the aorta, iliac or arteries of the leg, general surgery involving removal of a portion of the small or large bowel, radical cystectomy, gastric bypass for obesity, and kidney transplantation. Surgical procedures associated with a very low risk of VTE include radical neck dissection, inguinal hernia repair, laparoscopic cholecystectomy, transurethral resection of the prostate, and thyroid or parathyroid surgery. Prior thromboembolism Prior VTE, particularly within the past 6 months, is a major risk factor for developing postoperative VTE, with an over three-fold higher relative risk [2]. This increased risk may reﬂect a higher propensity for a clot to form because of endothelial damage of the veins, or the presence of one or more underlying genetic or acquired thrombophilic conditions. Presence of a thrombophilic disorder The interplay between thrombophilic disorders and postoperative VTE has been clariﬁed in recent years. In a large study of asymptomatic carriers of either factor V Leiden or activated protein C resistance, the absolute risk of manifesting VTE by age 65 years was small, on the order of 5–10%, but the relative risk of developing VTE was increased compared with noncarriers (relative risk [RR] ¼ 3.3, CI 1.7–6.1), particularly after surgery (RR ¼ 5.1, conﬁdence interval [CI] 2.2–11.8) [15]. Other studies have conﬁrmed these ﬁndings [16]. Based on these studies, it appears that the absolute risk of postoperative VTE among carriers is low (1 event per 100

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surgical procedures) and that patients should not be screened for inherited thrombophilic disorders prior to surgery. Presence of a lupus anticoagulant or anticardiolipin antibody in moderate or high titer among patients with no prior history of VTE is associated with a ﬁve to tenfold increase in the relative risk of developing VTE [17]. Patients with systemic lupus erythematosus plus either anticardiolipin antibodies or the lupus anticoagulant are probably at even higher risk for developing postoperative VTE. Cancer Presence of a malignancy is a potent risk factor that increases the risk of postoperative symptomatic VTE by at least twofold [2] and likely places such patients at increased risk for a longer period of time following the surgical procedure. Advanced clinical stage and pathology showing adenocarcinoma are strongly associated with VTE [18]. Obesity Obesity, deﬁned as a body mass index (BMI) over 30, appears to confer an increased risk of symptomatic VTE, at least in patients undergoing total hip arthroplasty [5,19]. This may reﬂect a combination of greater physical restriction of venous outﬂow, higher right-sided cardiac ﬁlling pressures, decreased propulsion of blood because of reduced physical activity, or the presence of an underlying inﬂammatory state associated with obesity [20]. Another factor may be inadequate thromboprophylaxis. For instance, although the dose of heparin or low molecular weight heparin (LMWH) for treatment of VTE is adjusted for weight, the recommended dose for prophylaxis is usually ﬁxed, which could potentially result in under-dosing. In addition, mechanical prophylaxis using pneumatic compression may be ineﬀective in obese individuals [19]. Medical conditions Congestive heart failure and chronic obstructive pulmonary disease (COPD) are associated with a higher incidence of VTE among hospitalized medical patients [21]. By extrapolation, it seems likely that these conditions also confer increased VTE risk in postoperative patients, with the mechanism being increased venous stasis. Immobilization-stasis Anything that leads to venous stasis likely increases the risk of VTE. Conversely, early mobilization of patients has been associated with a decreased relative risk of developing postoperative VTE [19,22]. Conditions such as marked obesity, stroke with hemiparesis, and prolonged bed rest in

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the hospital probably increase the risk of VTE by leading to increased venous stasis. Assessing the risk of bleeding Risk factors for bleeding have not been speciﬁcally deﬁned in a large cohort of surgical patients. Factors likely to contribute to the risk of postoperative bleeding include: the type of surgery, the underlying problem leading to surgery (eg. cancer), the surgical technique, and other known bleeding risk factors. Widely appreciated bleeding risk factors during medical thromboprophylaxis include a known bleeding disorder, use of antiplatelet agents or nonsteroidal anti-inﬂammatory drugs (NSAIDs), previous gastrointestinal bleeding, cancer, and hepatic or renal insuﬃciency [23]. The relationship between age and bleeding risk during anticoagulant therapy has been noted in some studies [24,25] but not in others [24,26]. Risk stratiﬁcation The American College of Chest Physicians (ACCP) criteria for VTE risk stratiﬁcation are widely endorsed (Table 2). Patients are categorized on the basis of age, type of surgery, and presence or absence of additional thromboembolic risk factors. The obvious deﬁciencies of this schema are: (1) the Table 2 Risk stratiﬁcation for thromboembolism after surgery Level of risk

Age (yrs)

Type of surgery

Additional Incidence of prox- Incidence risk factors imal DVT (%) of PE (%)

Low

<40

Minor

None

Moderate A B C

Any Minor <40 Major 40–60 Nonmajor

High A B C

>60 >40 <40

Highest risk A

B

>40

Nonmajor Major Major

0.4

<0.5

2–4

1–2

4–8

2–4

Present None None Other None Present

10–20 Hip or knee arthroplasty or hip fracture surgery Or major trauma or spinal cord injury Major Prior VTE Cancer Hypercoagulable state

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.

4–10

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absence of a precise deﬁnition of what constitutes major and nonmajor or minor surgery, and (2) absence of appropriate weighting of other known VTE risk factors. Furthermore, there is nothing magical about the ages of 40 or 60 that suddenly aﬀects the risk of VTE. Nevertheless, it provides some estimates of the risk of developing clinical VTE. Eﬃcacy and safety of available prophylaxis Before making recommendations regarding perioperative VTE prophylaxis, one must have a working knowledge of the eﬃcacy and safety of the various thromboprophylaxis modalities. This information must be combined with an appreciation of individual patient characteristics, the type of surgical procedure, and the preferences of the surgeon before an appropriate recommendation can be made. The Sixth ACCP Consensus Conference on Antithrombotic Therapy provides the most comprehensive evidence-based guidelines for the prevention of VTE in surgical patients [7]. Table 3 was adapted from the most recent literature and the ACCP review and outlines the appropriate regimens for various surgical procedures, including simple risk stratiﬁcation. Thromboprophylaxis methods can be broadly divided into nonpharmacologic and pharmacologic regimens. Nonpharmacologic interventions include: early ambulation, elastic stockings, intermittent pneumatic compression (IPC) devices, and inferior vena caval ﬁlters. Pharmacologic methods include aspirin, unfractionated heparin, warfarin, LMWH, and synthetic pentasaccharides. We will also discuss newer agents including thrombin inhibitors and recombinant hirudin as future potential options for prophylaxis. Nonpharmacologic prophylaxis Early ambulation Early ambulation should be a routine part of postoperative care for all patients, unless an absolute contraindication exits. The risks and beneﬁts of early ambulation are well established, especially among lower-extremity orthopedic surgery patients [27,28]. In total hip arthroplasty patients who began progressive weight bearing immediately after surgery, the rate of ultrasound-proven VTE was signiﬁcantly less than in patients who delayed weight-bearing rehabilitation [29]. Early ambulation has also been shown to be associated with a lower incidence of symptomatic thromboembolism after hip arthroplasty [19]. In addition, early ambulation with physical therapy after hip fracture has been associated with an earlier return to the community, shorter hospital length of stay, fewer complications, and a lower 6-month mortality [30]. Early postoperative ambulation is acceptable as VTE prophylaxis for patients undergoing low-risk surgical procedures such as general, gynecologic, and urologic surgery (Table 3). In practice, elastic stockings are often routinely used in these lowest-risk patients.

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Table 3 Venous thromboembolism prophylaxis options in surgical patients Nonpharmacologic methods

Pharmacologic methods

Early Elastic ambulation stockings IPC

Aspirin LDUH Warfarin LMWH

General surgery Low risk Moderate risk High risk Very high risk

A X X X

A A X X

A A A X

A A Aþ

A A Aþ

GYN surgery Low risk Moderate risk High risk

A X X

X X

A A

A A or þ

B A

Urologic surgery Low risk Moderate risk High risk

A X X

A X

A X

A Aþ

A Aþ

Orthopedic surgery Hip fracture THA TKA Neurosurgery Trauma

X X X X X

X X X X B or þ

X X X X B X A or þ B or þ

B X B or þ

A A A

Aa Aa Aa B or þ A

a Pentasaccharide approved. Abbreviations: A , acceptable for solo prophylaxis, with highest level of evidence; þ, combine with a nonpharmacologic method (ie, ES, IPC, or both); B, acceptable as an alternative method of prophylaxis with less evidence compared to A; X, beneﬁcial, but inadequate prophylaxis alone; ES, elastic stockings; IPC , intermittent pneumatic compression; LDUH , low-dose unfractionated heparin; LMWH , low molecular weight heparins; THA, total hip arthroplasty; TKA, total knee arthroplasty. Risk deﬁnitions General surgery • Low risk: Minor procedure, <40 years of age, and no additional risk factors for VTE • Moderate risk: Minor procedure, but having additional VTE risk factors Minor procedure between the ages 40 and 60 with no additional risk factors Major surgery, but < 40 years of age • High risk: Minor procedure and over age 60 or additional VTE risk factors Major surgery over age 40 or with additional VTE risk factors • Very high risk: Major surgery with multiple VTE risk factors GYN surgery: • Low risk: brief procedure for benign disease • Moderate risk: major surgery for benign disease, without additional VTE risk factors • High risk: extensive surgery for malignancy Urologic surgery: • Low risk: transurethral resection of the prostate or other low-risk urologic procedure • Moderate Risk: major, open urologic procedure • High risk: major procedure with additional VTE risk factors

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Elastic stockings Elastic stockings were ﬁrst shown to reduce VTE events in 1952 [31]. Their beneﬁt is attributed to improved venous ﬂow and reduced vessel wall damage caused by the passive venous dilation that occurs during surgery [32]. The relative risk reduction with stockings is estimated to be at least 60% in general, neurologic, and gynecologic surgery [33–35]. Although there is no direct evidence of beneﬁt in the lowest-risk surgery patients, there is some indirect evidence of harm. This concern comes from the observation that improperly ﬁtted stockings may cause a ‘‘garter’’ eﬀect that increases venous pressure below the knees and results in delayed venous emptying and an increased risk of VTE [36]. In a recent study of stocking use in orthopedic hip and knee surgery patients, 54% were found to have a ‘‘reversed gradient,’’ and these patients experienced a signiﬁcantly higher incidence of VTE compared with patients who had correctly ﬁtted stockings (25.6% versus 6.1%) [37]. This potential adverse eﬀect underscores the need for proper ﬁtting. Stockings should be applied preoperatively and continued throughout the hospital and rehabilitation period. There have been no controlled trials of prolonged out-of-hospital prophylaxis using stockings. It is reasonable, however, to recommend prolonged prophylaxis with stockings in patients who are relatively immobile after hospital discharge. Although stockings reduce the risk of VTE in patients undergoing higherrisk general surgery [38], orthopedic surgery [39,40], neurologic surgery [35], and trauma surgery, there is very strong evidence that other modalities are more eﬀective. Therefore, stockings are not recommended as solo prophylaxis but are recommended as an adjunct for all moderate or higher-risk patients unless the patient’s anatomy precludes proper ﬁtting. Intermittent pneumatic compression devices There are two principal types of intermittent pneumatic compression (IPC) devices used to prevent VTE. The ﬁrst provides sequential pneumatic compression of the leg, either to the level of the calf or thigh. The second is a ‘‘foot-pump’’ device that compresses the venous plantar plexus of the foot. Although the two devices have not been directly compared, they are considered to be equivalent. Individual institutions, physicians, or nurses may have a preference based on ease of use or patient comfort. The mechanism of action causing the reduced incidence of VTE is unclear. The principal mechanism is likely a direct eﬀect of pumping venous blood, thereby reducing stasis. It is also possible that there is promotion of clearance of prothrombotic clotting factors [41] and an increase in local plasminogen activators leading to enhanced ﬁbrinolysis [42]. More recent studies have not found enhanced ﬁbrinolysis [43]. In a case-control study, White et al showed that use of IPCs was associated with a striking reduction in the incidence of symptomatic VTE after total hip arthroplasty, but only among patients with a body mass index of less than 25 [19].

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These ﬁndings suggest that IPCs may not be eﬀective in obese individuals, perhaps because of failure to transmit suﬃcient pressure to the deep veins. IPC devices have an excellent safety proﬁle, with no known complications except for patient discomfort and potential for skin breakdown. The primary drawback of IPC devices is that they are only eﬀective if used continuously while patients are nonambulatory. Although the precise number of hours such devices need to be worn in order to be eﬀective is not known, presumably the longer the better. In one randomized trial, IPC devices (worn for a median of 15 hours a day) were as eﬀective as LMWH for VTE prevention after total hip replacement surgery [44]. As IPC devices have the potential to reduce ambulation, nurses and other members of the health care team must also be vigilant about encouraging patients to ambulate. The eﬃcacy of IPC devices has been evaluated after many diﬀerent types of surgical procedures. They may be used as the primary prophylaxis modality in many surgical settings, but the use of IPC is not recommended as the only thromboprophylactic modality in: (1) highest-risk general surgery patients [45], (2) high-risk urologic surgery patients [46], and (3) orthopedic surgery patients undergoing hip or knee surgery [7] (Table 3). IPC devices are the method of choice for VTE prophylaxis when patients are at increased risk for bleeding with anticoagulants. They are used extensively in conjunction with pharmacologic methods because of a presumed ‘‘additive’’ prophylactic eﬀect suggested in some studies. There are few studies that directly compare IPC devices with warfarin or LMWH [44,47,48]. A recent trial showed no diﬀerence between IPC devices and LMWH for VTE prevention in women undergoing surgery for presumed gynecologic malignancy. Interestingly, there was no diﬀerence in the incidence of bleeding between the groups [49]. Based on this study and others [50], there is good evidence to support the use of IPC devices as solo thromboprophylaxis in patients undergoing moderate to high-risk gynecologic surgery. One potential unintended beneﬁt of IPC devices is reduced bleeding at the surgical site, which has been suggested by several small studies [44,51,52]. In a meta-analysis, IPC devices were found to have a 0.0% incidence of clinically important bleeding, which was no diﬀerent from the control rate and signiﬁcantly better than in the warfarin group (1.3%, P ¼ 0.6) or LMWH group (1.8%, P ¼ 0.02) [53]. A possible physiologic explanation for this ﬁnding relates to the aforementioned eﬀects on the ﬁbrinolytic and clotting cascades. Thus, there is good evidence that IPC devices do not increase the risk of clinically apparent bleeding and may actually decrease bleeding risk. In summary, nonharmacologic VTE prophylaxis methods are widely used and very safe. Early ambulation should be a part of routine care for all postsurgical patients. If properly ﬁtted, elastic stockings (ESs) have essentially no adverse eﬀects and may be appropriate for almost all surgical patients until full ambulation is achieved. IPC devices may be used as the primary method in selected patients, and they likely have an additive eﬀect when used in conjunction with pharmacologic methods. IPC is the method

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of choice when anticoagulation is contraindicated, but eﬃcacy may be reduced in patients who are obese or who have very large legs. Inferior vena caval ﬁlters The currently accepted indications for inferior vena caval (IVC) ﬁlters include: (1) an absolute contraindication to anticoagulation, (2) life-threatening hemorrhage on anticoagulation, and (3) failure of adequate anticoagulation. When used appropriately, IVC ﬁlters are safe and eﬀective in reducing the incidence of PE to 0.3–3.8% in patients with a contraindication to anti-coagulation [54]. The risks of IVC ﬁlter placement include migration of the ﬁlter, recurrent deep vein thrombosis (DVT), IVC thrombosis, and postphlebitic syndrome. In the perioperative period, the scenario that most commonly arises is when a patient needs urgent surgery after a recent (<4 weeks) diagnosis of acute VTE. In such a patient, the risk of acute recurrent thromboembolism is signiﬁcantly higher in the ﬁrst month of treatment than after 4 or more weeks of treatment [55,56]. If anticoagulation therapy must be discontinued, placement of an IVC ﬁlter would be appropriate to prevent fatal PE. Placement of a temporary retrievable ﬁlter such as the Gunther TulipTM (Cook Inc., Bloomington, IN) or Tempoﬁlter (B. Braun Celsa, Chasseneuil Cedex, France) would be preferred, so it can be removed once the contraindication for anticoagulation has passed [57,58]. To date, there has been only one controlled trial of IVC ﬁlter use in patients with acute DVT. Use of a ﬁlter was associated with a nonsigniﬁcant reduction in the incidence of fatal pulmonary embolism, but there was a signiﬁcant increase in the incidence of subsequent recurrent deep vein thrombosis [59]. Use of a prophylactic ﬁlter is not recommended simply because a patient is undergoing a procedure associated with a high incidence of venous thromboembolism. Pharmacologic prophylaxis There are a variety of eﬀective pharmacologic agents available for preventing VTE after surgery. We will brieﬂy review the most widely used agents: low-dose unfractionated heparin (LDUH), aspirin, warfarin, low molecular weight heparins (LMWH), and synthetic pentasaccharides. Low dose unfractionated heparin Eﬃcacy LDUH is a very eﬀective prophylactic agent that clearly reduces the incidence of fatal postoperative PE [46]. Many studies performed in the late 1970s and 1980s documented the eﬃcacy of subcutaneously administered

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heparin [60,61] in doses of either 5000 international units (IU) every 12 hours or 5000 IU every 8 hours, with the ﬁrst dose being given 2 hours preoperatively. Initiating prophylaxis postoperatively also appears to be eﬀective, although randomized trials of this approach are sorely needed [62]. Studies comparing LDUH with low-dose LMWH (40 mg enoxaparin or equivalent) in general surgery patients show equivalent eﬃcacy with a moderate increase in the risk of bleeding associated with use of LDUH [63]. Use of LDUH is associated with a modestly higher incidence of bleeding compared with IPC devices [50]. Elastic stockings or IPC may provide additional protective eﬀect when added to LDUH in higher-risk patients. Safety The risks of LDUH include excess bleeding and heparin-induced thrombocytopenia (HIT). In a meta-analysis of thromboprophylaxis after total hip arthroplasty, the incidence of bleeding associated with LDUH (usually 7500 IU every 12 hours subcutaneously) was 2.6% (versus 0.3% in placebo patients) and 1.8% in patients treated with LMWH [53]. In a meta-analysis of general surgery trials, LDUH had a higher rate of minor bleeding (RR ¼ 1.3; P < .05), but a similar rate of major bleeding when compared with LMWH [64]. Another meta-analysis found increased bleeding complications with LDUH versus low-dose LMWH after general surgery [63]. Thus, the major argument for using LMWH in place of LDUH among general surgery patients is a lower risk of bleeding [65]. Indications LDUH, in addition to LMWH, is one of the recommended medical prophylactic agents for most general surgical procedures [7], as well as high-risk urologic or gynecologic surgery patients [50,66] with or without the addition of nonpharmacologic methods. Recommended dosages for LDUH are 5000 IU subcutaneously every 12 hours for moderate-risk patients and 5000 IU every 8 hours (or 7500 IU every 12 hours) for high-risk patients. LDUH (7500 IU every 12 hours subcutaneously) is less eﬀective compared with LMWH (30 mg of enoxaparin q 12 hours subcutaneously or equivalent) in very high-risk orthopedic or neurosurgical [63,65] and is therefore not the prophylactic agent of choice for very high-risk procedures. In summary, LDUH is a very eﬀective drug for the prevention of VTE, and it is the drug of choice for many indications (Table 3). It is associated, however, with a modest increase in the incidence of bleeding and HIT compared with LMWH, and it must be given 2–3 times a day. Aspirin The use of aspirin as a thromboprophylactic agent is controversial. The Sixth ACCP Consensus Conference statement does not recommend aspirin

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as sole prophylaxis for any surgical procedure (Table 3) [7]. There is some evidence from the recently conducted Pulmonary Embolism Prevention (PEP) trial that aspirin may have a beneﬁcial eﬀect in the subgroup of patients with hip fracture. Over 13,000 subjects with hip fracture in hospitals all over the world were randomized to 160 mg of aspirin per day for 5 weeks or placebo and allowed to receive routine thromboprophylaxis prescribed by their physician [67]. There was a signiﬁcant reduction in the incidence of PE diagnosed during hospitalization in the aspirin group (0.7%) compared with placebo (1.2%, P < 0.001) and an impressive 58% reduction in the incidence of fatal PE (P ¼ 002, 18 in aspirin group, 43 in placebo). Aspirin prevented approximately 4 fatal pulmonary emboli for every 1000 patients treated and resulted in 6 excess episodes of bleeding requiring transfusion. The results of the PEP study suggest that aspirin may have a role for VTE prophylaxis among hip fracture patients. A potential role for aspirin may be postdischarge prophylaxis in hip fracture patients if no other medical prophylactic agent is used. More studies are needed to evaluate the role of aspirin after other surgical procedures. The ﬁndings do provide an additional rationale for using aspirin in postoperative patients who may beneﬁt from primary or secondary prevention of cardiovascular events. Until further studies are done, however, aspirin alone is not recommended as a principal thromboprophylactic agent in surgical patients. Warfarin The use of warfarin for VTE prophylaxis has been limited primarily to very high-risk patients with lower-extremity orthopedic and neurologic surgery. Warfarin has not been commonly used in general, gynecologic, and urologic surgery patients because of the proven eﬃcacy of other available agents, including IPC devices, LDUH, and LMWH (Table 3). Warfarin requires more intensive monitoring, and the potential risk for bleeding has been a concern. It is very useful among patients who require extended thromboprophylaxis, which is necessary in certain very high-risk patients. One of the major advantages of warfarin is that the onset of its anticoagulant eﬀect is delayed for several days after starting treatment. This leads to a lower incidence of bleeding complication, which surgeons appreciate, but a higher incidence of asymptomatic thrombosis, particularly in calf veins. A large clinical study of patients undergoing total hip arthroplasty has shown that the incidence of symptomatic VTE within a 3-month period of surgery is comparable after 7–10 days of treatment with warfarin or enoxaparin [5]. Warfarin is recommended as one of the principal prophylactic agents among patients undergoing hip fracture repair, total hip arthroplasty (THA), and total knee arthroplasty (TKA) (Table 3). Numerous clinical trials [5,47,48] and meta-analyses [53,68,69] support the use of warfarin in patients undergoing such procedures. Warfarin can be initiated preoperatively using a ‘‘two-stage’’ approach of starting with a very low dose of

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warfarin 10–14 days preoperatively targeting an international normalized ratio (INR) of less than 1.5, and then increasing the dose postoperatively to a target INR of 2.5. Alternatively, warfarin can be started the night before surgery or immediately after surgery. Such a regimen is perhaps associated with a lower risk of bleeding complications [70]. Many elderly patients require very low doses of warfarin, particularly if they are acutely ill or recovering from surgery because serum albumin levels are low and result in higher levels of free warfarin. In general, an initial dose of 5.0 mg is recommended, with a lower dose of 2.5 mg for patients over 75 years old [71]. Low molecular weight heparin and pentasaccharides Available drugs In the United States, there are currently three available LMWH preparations: dalteparin (Fragmin, Kabi Vitram), enoxaparin (Lovenox, Pharmion Boulder, CO), and tinzaparin (Innohep, Aventis, Bridgewater, NJ) (Table 4). The U.S. Food and Drug Administration (FDA) recently approved a very low molecular weight product, the pentasaccharide fondaparinux (Arixtra, Organon Sanoﬁ-Synthelabo UC, Westorange, NJ), for prevention of VTE. As with LMWH, its mechanism of action is inhibition of factor Xa mediated by antithrombin [72]. Although there have been very few clinical trials that have directly compared LMWH preparations, they appear to be comparable for prevention and treatment of VTE. The dose of each agent is diﬀerent, and FDA approval for VTE thromboprophylaxis is diﬀerent for each product (Table 4). None of these products are FDA-approved for the prevention of VTE associated with pregnancy, spinal cord injury, trauma, or neurosurgery. The newest agent, fondaparinux, has been compared with enoxaparin after hip arthroplasty [72], knee arthroplasty [73], and hip fracture surgery [74]. In these studies, fondaparinux was associated with a signiﬁcantly lower Table 4 Current FDA approved indications for use of LMWH/pentasaccharide LMWH/pentasaccharide preparation Indication

Enoxaparin

Dalteparin

Tinzaparin

Fondaparinux

Abdominal surgery Total hip arthroplasty Extended prophylaxis (THA) (3 weeks) Total knee arthroplasty Hip fracture surgery DVT treatment—in hospital DVT treatment—out-patient Prophylaxis—high-risk medical patient (hospitalized)

Yes Yes Yes

Yes Yes No

No No No

No Yes No

Yes No Yes Yes Yes

No No No No No

No No Yes No No

Yes Yes No No No

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incidence of venographically documented thrombi, but with no diﬀerence in the incidence of symptomatic VTE events. For example, following knee arthroplasty, the incidence of venographically deﬁned thrombosis was 12.5% eleven days after surgery in the fondaparinux group and 27.8% in the enoxaparin group [73]. The incidence of symptomatic VTE was 0.5% in each group. Diﬀerences in the dose and timing of the administration of fondaparinux and the comparison drug, enoxaparin, make it diﬃcult to know if the apparent eﬃcacy is caused by the drug, the dose, or earlier administration of the drug. In this study of knee arthroplasty patients, there was an increase in the incidence of major bleeding in the fondaparinux group (P < 0.009) [72]. If the postmarketing experience of surgeons suggests that the incidence of bleeding is acceptably low, use of this agent may become widespread. Indications Among general and urologic surgery patients, some surgeons prefer LMWH as there is evidence indicating a modestly lower incidence of bleeding compared with LDUH [53,61,63,65,75]. Although LDUH is recommended for most patients undergoing general surgery, LMWH is approved for general surgical patients. It can be used in patients in all VTE prophylaxis categories, with the exception of low-risk patients who do not warrant pharmacologic prophylaxis [61,65]. In gynecologic surgery, use of LMWH is considered a second-line agent, as there is considerable evidence supporting the use of IPC devices or LDUH in moderate and high-risk patients, as noted above. In neurosurgery, IPC is the prophylaxis modality of choice because of the minimal risk of bleeding. LMWH is eﬀective in preventing VTE, however, and safe when compared with placebo in terms of bleeding complications [76]. In trauma surgery, LMWH has become the agent of choice if the risk of bleeding is judged to be low [77]. But if bleeding risk is signiﬁcant, elastic stockings and/or IPC devices are preferred in this high-risk group. A large number of clinical trials have evaluated the eﬃcacy of enoxaparin after major orthopedic surgery. It has been shown to be more eﬀective than LDUH with equivalent safety after THA [53,77–79] and TKA [80]. LMWH appears to be comparable to warfarin when administered for comparable periods of time [5], although some studies have shown lower rates of venographically proven VTE with LMWH, particularly after total knee arthroplasty [81]. Dosing recommendations for LMWH and fondaparinux are shown in Table 5. Tinzaparin has been directly compared with enoxaparin after THA, and it appears that these two agents are comparable [82]. Safety Bleeding is the primary complication associated with pharmacologic prophylaxis. As noted above, LMWH has similar eﬃcacy as LDUH, with a lower

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Table 5 Acceptable dosing of low molecular weight heparins and pentasaccharide Drug Enoxaparin

Dalteparin

Tinzaparin

Fondaparinux

Prophylaxis: orthopedic surgery

Extended prophylaxis after hip arthroplasty

Prophylaxis: general surgery

30 mg q 12 hr (60 mg/day) Given every 12 hr starting 12–24 hours after surgery or 40 mg q 24 hr starting evening before surgery 5000 IU daily Or 2500 IU within 2 hr presurgery and 2500 IU at least 6 hr after surgery 75 IU/kg Daily started 1–2 hr preoperatively or 4500 IU once daily started preoperatively 2.5 mg Begin 6 hr post surgery

4000 IU (40 mg) Once daily

4000 IU (40 mg) Once daily starting 1–2 hr before surgery 2500 IU Once daily starting 1–2 hr before surgery

Abbreviation: IU, international unit.

reported incidence of clinically important bleeding [53,61,63,65,75,78]. When compared with IPC devices, however, the zincidence of bleeding complications is equivalent or higher in LMWH-treated patients. In a 1996 survey of U.K. orthopedists, 48% of those who had used LMWH discontinued use because of perceived excessive bleeding, and of those who continued using LMWH, 88% witnessed excessive bruising, and 53% reported wound bleeding and hematomas [81]. Because of the perceived risk of bleeding associated with the use of LMWH after orthopedic surgery, agreement must be reached with the surgeon prior to recommending these agents. Epidural catheters An important complication of LMWH is the potential for epidural/spinal hematoma when administered prior to removal of an epidural catheter placed for anesthesia and/or analgesia. This was initially reported in 1997 after several reports of hematoma development following concurrent use of enoxaparin prophylaxis and regional epidural or spinal anesthesia or spinal puncture [83]. Subsequent guidelines for use of LMWH and regional anesthesia have been developed and include [7,84]: (1) regional anesthesia should be avoided in patients with an abnormal bleeding history or those receiving drugs that aﬀect hemostasis; (2) spinal needle insertion should be delayed for 10–12 hours after the initial LMWH prophylaxis dose, and regional anesthesia should be avoided in patients with a hemorrhagic aspirate during spinal needle placement; (3) single-dose anesthetic is preferable to continuous epidural anesthesia; (4) in patients receiving continuous epidural anesthesia, the epidural catheter should be left indwelling overnight

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and removed the next day; (5) subsequent LMWH doses should be delayed for at least 2 hours after spinal needle placement or catheter removal; and (6) if LMWH prophylaxis is started postoperatively, the initial dose should be delayed at least 2 hours after catheter removal. Other agents Adjusted dose unfractionated heparin (ADH) has been utilized and studied [85]. Its use in practice and clinical trials, however, has all but disappeared since the emergence of LMWH. Although there is evidence to support its use in some surgical procedures for VTE prophylaxis, it is more cumbersome than other eﬀective methods and, therefore, was not included in Table 4 and our review. Direct thrombin inhibitors are a new class of anticoagulant drugs in various stages of development and testing. Desirudin, the recombinant form of hirudin, was tested for VTE prophylaxis after THA and was found to have a similar safety proﬁle as enoxaparin, and was more eﬀective in preventing VTE [86]. Lepirudin (Reﬂudan, Berlex, Montville, NJ), another form of recombinant hirudin, has been approved for the treatment of HIT. Argatroban, (Glaxo Smith Klein Research triangle Park, NC) is another thrombin inhibitor that has been approved for the treat of HIT. The newest of the class, ximelagatran, an oral thrombin inhibitor, was recently tested in a phase 2 dose-ﬁnding trial compared with enoxaparin. When given after TKA surgery, ximelagatran (Exanta Astrozeneca Wilmington, DE) had a similar safety and eﬃcacy proﬁle as enoxaparin [87]. These and other agents will continue to be developed in an eﬀort to discover the optimal VTE prophylaxis in surgical patients in terms of safety and eﬃcacy. Timing of prophylaxis In most patients, it is appropriate to initiate VTE prophylaxis as soon as the risk of developing thrombosis begins. For trauma patients, this means as soon as they are hospitalized. For elective surgery patients, it is as soon as they are taken to the operating room. For recently immobilized patients, it may be prior to admission to the hospital. Stockings and IPC devices should be initiated preoperatively as soon as the risk of immobility increases, then continued during the procedure and throughout the hospital stay. If aspirin is part of the VTE prophylaxis regimen, it should be started preoperatively [67]. Warfarin can be started at a low-dose 10–14 days preoperatively, or at a therapeutic dose on the night prior to surgery. For LMWH, the optimal timing to maximize eﬃcacy and minimize bleeding is not yet clear (Table 5). Options include initiating LMWH 12 hours preoperatively, immediately prior to surgery, as soon as hemostasis is achieved after surgery, or 12–24 hours postoperatively. The clinical practice in North America tends to be to dose LMWH

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postoperatively, whereas in European countries it is begun preoperatively. There is data to support both regimens; however, a 1999 meta-analysis by Hull et al found that LMWH initiated preoperatively was associated with lower rates of venographically proven VTE and lower rates of major bleeding [88]. The timing of pharmacologic prophylaxis should always be clariﬁed with the anesthesia team, particularly if spinal or epidural anesthesia (or analgesia) is planned. The use of preprinted orders, computer reminders, or practice guidelines may be an eﬀective method for prompting appropriate VTE prophylaxis [89]. Duration of prophylaxis The optimal duration of thromboprophylaxis is not known. In the 1970s and 1980s when hospitalizations were longer, patients were given thromboprophylaxis for their 7–10 day stay in the hospital. As the duration of hospitalization decreased in the 1990s, the duration of thromboprophylaxis also decreased. Early studies looking for asymptomatic VTE after hospital discharge noted a high incidence of asymptomatic thrombosis [90], and this prompted many more studies, both in orthopedic surgery and after some general surgical procedures [91–93]. General surgery A 1998 Danish trial evaluated extended thromboprophylaxis with tinzaparin in 118 patients who had undergone major abdominal and noncardiac thoracic surgery. At 4 weeks, there was no diﬀerence in the rate of venographic DVT in the control group (10%) and the placebo (5.2%) groups [94]; however, the study had low power. In a larger study, Bergqvist et al found that extended duration prophylaxis (27–31 days) with enoxaparin, 40 mg/day, led to a signiﬁcant (P ¼ 0.02) reduction (4.8%) in the asymptomatic VTE after abdominal or pelvic surgery for cancer compared with control patients (12%) who were treated for only 6–10 days [95]. The cost of extended thromboprophylaxis using enoxaparin (40 mg/day, $16.00) or dalteparin (5000 IU/day, $12.00) in the United States is signiﬁcant [23]. A cost-eﬀectiveness analysis from 1996 concluded that prolonged DVT prophylaxis in general surgery patients could prevent out-of-hospital DVT, but at a marginal cost that was deemed inappropriate for routine use [96]. Orthopedic surgery There is evidence that extended prophylaxis is important for patients undergoing lower-extremity orthopedic surgery, particularly total hip arthroplasty. A recent meta-analysis of eight hip arthroplasty studies and two knee arthroplasty studies found that extended prophylaxis using LDUH or LMWH signiﬁcantly reduced the frequency of symptomatic and asymptomatic VTE [97]. Extended prophylaxis for 30–42 days was associated with a

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signiﬁcantly lower incidence of symptomatic VTE (1.3%) than placebo (3.3%), or one fewer symptomatic VTE for every 50 patients treated. A case control study also found that extended prophylaxis with warfarin was associated with absence of VTE [19]. Extended prophylaxis is associated with a modest increase in the risk of minor bleeding compared with placebo (3.7% versus 2.5%), or one more minor bleed for each 83 patients treated [97]. Extended prophylaxis does not appear to beneﬁt patients who undergo total knee arthroplasty [92]. Knee arthroplasty patients develop symptomatic VTE early after surgery, with few additional cases diagnosed 3 or more weeks after the day of surgery, whereas symptomatic VTE is frequently diagnosed in hip arthroplasty patients up to 2 months after the day of surgery [98]. Recommendations The only procedure for which there is strong evidence in favor of extended prophylaxis is total hip arthroplasty, and, although the most optimal duration of prophylaxis after this procedure is not known, 4–6 weeks appears reasonable. Existing evidence to support extended prophylaxis after hip fracture and total knee arthroplasty is weak, and more studies are needed to determine the optimal duration of thromboprophylaxis. Nevertheless, because the length of hospitalization after surgery is becoming so short, some extenuation in the duration of prophylaxis is certainly logical. Because of cost and safety concerns, it would be reasonable and appropriate to risk-stratify patients and recommend extended prophylaxis for the higher-risk patients. Unfortunately, there is not a validated risk stratiﬁcation tool available at this time. The risk factors that are probably most important are: obesity (BMI > 30) and sedentary lifestyle, being bed- or wheelchairbound, and a history of prior VTE [19]. Patients who have active cancer may also be excellent candidates for extended prophylaxis, but the optimal duration of prophylaxis is unknown. Continued use of well-ﬁtted elastic stockings after patients are discharged from the hospital is reasonable, although there is no evidence to support this recommendation. Finally, it is reasonable to consider aspirin prophylaxis, particularly in patients who have risk factors that would warrant prophylaxis for cardiovascular disease. If extended prophylaxis is recommended, the two logical choices are LMWH (enoxaparin 40 mg or dalteparin 5000 IU) or warfarin (target INR ¼ 2.5). Three diﬀerent cost-eﬀectiveness studies suggest the diﬀerence in cost between warfarin and LMWH is small, but these conclusions are highly dependent on the cost of the drug and cost of monitoring [99–101]. Given the high price of LMWH in the United States, warfarin is currently cheaper and more cost-eﬀective than LMWH [102]. Role of screening for asymptomatic VTE This is a controversial topic. As noted earlier, most VTE events (including PE) are asymptomatic. Thus, screening using venous ultrasound imaging

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is most likely to detect asymptomatic thrombi that are unlikely to become symptomatic. In addition, venous ultrasound is less accurate when used in asymptomatic individuals than in symptomatic individuals. In one randomized study of patients undergoing total hip or knee arthroplasty who received warfarin prophylaxis, screening with ultrasound did not reduce the incidence of symptomatic VTE but lead to treatment of 2.5 times more patients, one of whom developed a major bleeding complication [103]. Other studies have concluded that screening ultrasound testing is not cost-eﬀective and not warranted [104–106]. Perioperative management of patients on long-term oral anticoagulation Indications for long-term oral anticoagulation therapy (OAT) include prevention of systemic embolization in patients with prosthetic heart valves or atrial ﬁbrillation (AF), as well as primary or secondary prevention of VTE. Other potential indications for chronic OAT include mitral stenosis, left ventricular aneurysm, severe left ventricular systolic dysfunction, coronary artery disease, previous inferior vena cava (IVC) ﬁlter placement, and presence of synthetic peripheral arterial bypass grafts. There is a paucity of clinical data available on the perioperative management of patients on longterm OAT, and experts’ recommendations vary widely [55,107–109]. Perioperative management of patients on chronic OAT must be individualized, balancing the risks of thromboembolism if OAT is interrupted versus the risk of bleeding if such therapy is continued. Options for perioperative anticoagulation include the following regimens: (1) continue OAT and perform surgery with the patient fully anticoagulated; (2) discontinue OAT preoperatively, give prophylactic subcutaneous heparin perioperatively during hospitalization, and reinstitute OAT as soon as possible postoperatively; and (3) discontinue OAT preoperatively and administer ‘‘bridging therapy’’ with full-dose intravenous heparin or LMWH during the time that the INR is subtherapeutic. The risk of thromboembolism in patients who temporarily discontinue OAT depends on the particular indication and other patientspeciﬁc factors, which are discussed below. Bleeding risk Risk of bleeding depends on the operative procedure and characteristics of the individual patient. Patient-related factors include: a prior history of bleeding problems, concurrent use of antiplatelet agents (aspirin, NSAIDs, etc.), age >65, and acquired conditions associated with increased bleeding, such as chronic renal or liver disease and cancer. Bleeding risk is highly dependent on the type of surgery, the vascularity of the tissues, and the ability of the surgeon to control bleeding either by compression or other physical means (packing, cautery, topical coagulants) [110]. Guidelines for perioperative management of anticoagulation can be developed according to the patient’s risk of bleeding.

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Management of patients at low risk for bleeding complications Procedures that appear to be associated with a low risk of bleeding despite OAT include cataract extraction [111,112], laparoscopic cholecystectomy [113], dermatologic procedures [114], and possibly transurethral resection of the prostate [115]. In general, patients who undergo these low-bleeding risk procedures may either continue OAT or have the intensity of OAT reduced to ‘‘low’’ therapeutic levels (ie, an INR of approximately 2.0) [108]. Delayed bleeding after colonoscopic polypectomy is not unusual and may be associated with OAT [116,117], so that many endoscopists recommend discontinuation of OAT if polypectomy is to be performed. Dental procedures Although many dentists recommend temporary interruption of OAT prior to tooth extractions and other dental procedures, a recent review found that serious bleeding is distinctly unusual when OAT is continued during tooth extraction, or during gingival and alveolar surgery [118]. Tranexamic acid mouthwash, a local ﬁbrinolytic agent, has been shown to decrease bleeding in patients who undergo oral surgery while continuing to take OAT [119]. Most experts recommend that outpatient dental procedures be performed without discontinuing OAT or by slightly lowering the INR (to approximately 2.5) [110,118]. A recent prospective cohort study of 104 patients with a tilting disk or a bileaﬂet mechanical heart valve demonstrated that temporarily interrupting therapeutic OAT prior to tooth extraction and immediately restarting the normal daily dose of warfarin on the evening after surgery was both safe and eﬀective [120]. There were 2 minor bleeding complications (treated with local measures) and no thromboembolic complications reported after 3 months, even though 40% of the patients had atrial ﬁbrillation, a marker of high thromboembolic risk. The authors discontinued warfarin 2 days prior to the procedure if the INR was therapeutic (2.0–4.5) at the time, resulting in a mean procedural INR of 1.87. Management of patients with high risk for bleeding complications Surgical considerations Neurosurgery in particular and almost all other major surgical procedures are considered high risk for bleeding [121], necessitating the transient discontinuation of OAT. Options include temporary discontinuation of OAT without ‘‘bridging’’ anticoagulation, or the use of perioperative bridging therapy. Whether or not bridging therapy should be used depends on underlying patient-speciﬁc risk factors for thromboembolism if OAT is stopped. Patient considerations Aside from the dental literature [118,120], there is very little clinical trial data available to inform the clinician about the risk of thromboembolism

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during transient cessation of OAT for surgery or other procedures. Risk estimates must be extrapolated from epidemiologic studies of patients at risk for thromboembolism (prosthetic heart valves, atrial ﬁbrillation [AF]) but who are not receiving OAT for a variety of reasons including gastrointestinal bleeding [122,123]. Such data suggest that patients at high risk for thromboembolism while not taking OAT include those with: mechanical prosthetic heart valves [124], AF, prior stroke or multiple stroke risk factors [125,126], and recent (<1 month) acute venous thromboembolism [55,56]. Using this epidemiologic data, estimates of the daily thromboembolic risk [55,108] among patients in whom OAT is discontinued range from 0.2–1% with VTE < 3 months and 0.04% with VTE > 3 months [56,127], 0.02% with mechanical prosthetic valves [124], and 0.003–0.05% with atrial ﬁbrillation [125]. It should be kept in mind that these estimates may not apply to patients who temporarily interrupt anticoagulation to undergo surgery. There is also a possibility of a rebound hypercoagulable state following the cessation of OAT [128,129]. Some authors also feel that patients with inherited or acquired hypercoagulable states and recent or life-threatening thrombosis are also at high risk if OAT is interrupted [108]. Venous thromboembolism and atrial ﬁbrillation As mentioned above, there have been no clinical trials that have addressed the perioperative anticoagulation management of patients with either AF or VTE. Such patients may be managed as outlined in Table 6, with patients deemed at highest thromboembolic risk being treated with bridging therapy using either intravenous heparin or subcutaneous LMWH. The stroke risk in patients with AF increases with age (particularly if age is greater than 75 years), prior transient ischemic attack (TIA)/stroke or systemic embolus, hypertension, diabetes, reduced left ventricular function, prosthetic valves, and rheumatic mitral valve disease [125]. In patients with nonvalvular AF, those with previous TIA or stroke have the highest risk of recurrence (13%/year) [125,126] and should probably be given bridging therapy. VTE recurs commonly in the ﬁrst 3 months after an acute event [56,130], and recurrence rates may be as high as 40% at 1-month without anticoagulation therapy [155]. Therefore, many experts recommend bridging therapy in patients who have had VTE in the preceding 3 months. In the ﬁrst month after the diagnosis of acute VTE, full-dose anticoagulation with LMWH or intravenous heparin is recommended as bridging therapy. If a procedure is to be performed more than 1 month after acute VTE, some experts recommend that these patients be bridged with lower, prophylactic doses of LMWH (enoxaparin 40 mg or dalteparin 5000 IU). Patients with history of VTE occurring greater than 3 months earlier may be managed by simply interrupting OAT, without bridging therapy. Remember, prophylactic LDUH or LMWH is indicated in the perioperative period for many surgical procedures and should be administered to most hospitalized

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Table 6 Suggested anticoagulation regimens for patients on chronic OAT undergoing noncardiac surgery Clinical situation

Anticoagulation regimen

Procedures associated with low bleeding risk (dental, cataract, skin) Aortic valve prosthesis with no additional TE risk factorsa, AF and low stroke risk

Continue OAT at usual dose or reduce dose to achieve INR in the low therapeutic range (target INR ¼ 2.0) Discontinue OAT 4–5 days prior to surgery [154], operate when INR 1.5; resume normal daily dosage on day of surgery if possible. Administer prophylactic dose SC heparin perioperatively if clinically indicated. Discontinue OAT 3–5 days prior to surgery; start IV heparin (target APTT 2.0–3.0 control) when INR falls below 2.0; stop heparin 6 h prior to surgery; restart subscataneous heparin prophylaxsis and oral anticoagulation as soon as possible; stop heparin when INR becomes therapeutic on 2 consecutive daysb.

Mitral or multiple valve prostheses; aortic valve prosthesis with TE risk factorsa; recent VTE (<3 months); AF and high stroke risk

a TE risk factors include: atrial ﬁbrillation, previous embolism, caged-ball valves, BjorkShiley single tilting disk valves, severe left ventricular dysfunction, and a hypercoagulable state (eg, surgery for cancer). b Low-molecular-weight heparin in currently being investigated as an alternative agent, but is not approved for use with mechanical prosthetic valves. Treatment doses not clear, but experts suggest: enoxaparin 1 mg/kg q 12 h, dalteparin 100 IU/kg q 12 h, or tinzaparin 175 IU/ kg q day. Abbreviations: AF, atrial ﬁbrillation; APTT, activated partial thromboplastin time; INR, International Normalized Ratio; OAT, oral anticoagulation therapy; SC, subcutaneous; TE, thromboembolic; VTE, venous thromboembolism.

patients not receiving bridging therapy. Discontinuation of OAT for major surgery is not an indication for IVC ﬁlter placement and should be avoided in this setting because several studies have documented an increased longterm risk of lower extremity DVT [56,59]. Patients being treated with OAT for mitral stenosis, coronary artery disease, left ventricular dilatation, previous IVC ﬁlter placement, and synthetic arterial bypass grafts can probably be managed with temporary interruption of therapy [110]. Mechanical prosthetic heart valves Several clinical studies of the management of patients with mechanical prosthetic valves have been published and may help to risk stratify these patients. In such patients, OAT is usually given to prevent arterial embolism (stroke, myocardial infarction) and prosthetic valve thrombosis, which are both potentially lethal complications. A retrospective study of 159 patients with mostly caged-ball (Starr-Edwards) prostheses undergoing 180 noncardiac procedures at the Mayo Clinic in Rochester, Minnesota, reported a low incidence of thromboembolism with discontinuation of OAT for an average of 3 days preoperatively and 3 days postoperatively [131]. Katholi

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performed the only prospective study, a small nonrandomized cohort of 39 patients with older generation caged-ball aortic valves and caged-disk mitral valves undergoing noncardiac procedures. No thromboemboli occurred in 18 aortic valve patients undergoing 19 procedures who had OAT discontinued 3–5 days preoperatively and resumed 2 days postoperatively. Similarly, no thromboemboli were observed in 21 mitral valve patients undergoing 26 procedures who had rapid reversal of OAT using vitamin K [132]. A recent retrospective study of 235 patients with newer generation, bileaﬂet mechanical valves undergoing major noncardiac operations demonstrated a very high thromboembolic complication rate for tilting disk mitral valves despite bridging therapy being administered to most patients. Thromboembolic event rates were lowest for bileaﬂet aortic valves (0.7%). In a multivariate analysis, thromboembolic events were associated with surgery for malignancy and tilting disk mitral valves [133]. These studies and others suggest that the following factors are associated with a high risk for thromboembolic complications: all mitral prostheses, single tilting disk or Bjork-Shiley valves, double-position prosthetic valves, atrial ﬁbrillation, severe left ventricular dysfunction, previous embolic event [134], and a hypercoagulable state (eg, cancer) [107,109,124]. It appears that OAT can be temporarily interrupted without bridging therapy in patients with isolated mechanical aortic valve prostheses who have none of the above risk factors. Patients with mitral prostheses or other embolic risk factors should receive bridging therapy (Table 6). Most authors also recommend that patients on chronic OAT receive prophylactic subcutaneous LDUH or LMWH any time their INR falls to below 2.0 [109,110]. Aspirin is often prescribed to patients with mechanical valves as an adjunct to OAT for prevention of systemic embolization [135,136]; it should be discontinued approximately 1 week prior to major surgery and resumed as soon as deemed safe by the surgeon [107]. Bridging therapy with low molecular weight heparins LWMH is currently being investigated as a less costly alternative for bridging therapy because of the potential to avoid hospitalization prior to major surgery [137]. LMWH is not FDA-pproved for use in patients with mechanical heart valves, although there is preliminary data suggesting that enoxaparin [138] and dalteparin [139] may be safe alternatives for bridging therapy during minor surgical procedures. Other preliminary studies have reported excess bleeding events in patients undergoing noncardiac surgery [140]. A recent small trial of 24 patients undergoing 26 procedures using subcutaneous dalteparin (200 anti-Xa IU/kg/day subcutaneously for an average of 5 days) for patients with high thromboembolic risk resulted in only 2 minor bleeding complications and 1 transient ischemic attack but avoided 2 days of hospitalization preoperatively [141]. Other LMWH regimens that have been used for bridging therapy include: dalteparin (100 anti-Xa IU/kg

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SC q 12 h), enoxaparin (1 mg/kg SC q12 h or 1.5 mg/kg once daily), and tinzaparin (175 anti-Xa IU/kg SC once daily). Some experts recommend the following bridging regimen: start LMWH on the day the INR is anticipated to fall below 2.0, give the last preoperative dose on the morning prior to surgery; reinstitute OAT on the evening after surgery; restart LMWH at least 24–48 hours after the procedure (or when risk of postoperative bleeding becomes suﬃciently low); and continue LMWH until the INR is therapeutic on 2 consecutive days [110]. The safety, eﬃcacy, and optimal dosing regimens for LMWH as bridging therapy remain speculative and should be substantiated by further clinical studies. Recommending and implementing a postoperative thromboprophylaxis regimen In order to implement a thromboprophylaxis regimen successfully, consulting internists must balance the bleeding risk of using prophylactic agents such as heparin, LMWH, and warfarin against the risk of thromboembolism associated with the operative procedure. VTE risks and the eﬀect of prophylaxis can be estimated from the literature, although clinical data on bleeding risks are much more limited. Bleeding complications such as wound hematomas tend to be very troublesome for surgeons, particularly when such bleeding may be harmful or even catastrophic [eg, central nervous system (CNS) surgery]. On the other hand, VTE is a major cause of morbidity and mortality, including over 150,000 deaths from PE each year in the United States [142], making this disorder the most common preventable cause of hospital death. Because internists care for large numbers of patients with VTE (but very few bleeding complications) and surgeons deal with bleeding complications (but very few VTE complications), it can be very diﬃcult to reach consensus on the relative harms of a VTE versus a wound hematoma. Regardless, internists should recommend eﬀective thromboembolic regimens but recognize the potential harms caused by such recommendations. We strongly recommend direct consultation with the primary surgeon to determine the risk/beneﬁt ratio of each thromboprophylaxis regimen. It is inappropriate to recommend intensive thromboprophylaxis when it is clear that the surgeon opposes this strategy and will obviously not follow your recommendation. Consensus must be reached before the time of surgery, and decisions based on a review of the available evidence. Multi-disciplinary approaches include development of local guidelines that are endorsed by all interested parties (administration, internists, surgeons, anesthesia team, pharmacists, and nurses) under the umbrella of a clinical pathway for postoperative VTE prevention. Other important considerations include the availability and cost of the various options, whether or not the patient’s insurance covers the prophylactic agent, and of course, whether or not the risk/beneﬁt ratio is acceptable to the patient.

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Preoperative risk evaluation and perioperative management of patients with coronary artery disease Steven L. Cohn, MD, FACPa,b,*, Lee Goldman, MD, MPHc a

Division of General Internal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA b Medical Consultation Service, Kings County Hospital, Brooklyn, NY, USA c Department of Medicine, University of California at San Francisco, San Francisco, CA, USA

A signiﬁcant proportion of patients who undergo surgery each year have either known coronary artery disease (CAD) or risk factors for cardiovascular disease. The fear of perioperative cardiac complications is often the concern that prompts preoperative medical consultation. Preoperative cardiac evaluation requires the consultant to assess the patient’s probability, severity, and stability of CAD, placing these in perspective regarding the likelihood of a perioperative cardiac complication based on the planned surgical procedure. Over the past 25 years, numerous studies have examined potential risk factors, and various risk indices, guidelines, and algorithms have been published on the topic of cardiac risk stratiﬁcation. This article will review these concepts as they pertain to CAD, citing some of the pros and cons of various risk assessment tools, and then move on to the next level evaluating prophylactic measures to decrease this risk in high-risk patients. Other cardiovascular diseases or risk factors such as hypertension, congestive heart failure, valvular heart disease, and arrhythmias will be addressed in a subsequent article.

* Corresponding author. Division of General Internal Medicine, State University of New York, Downstate Medical Center, 470 Clarkson Avenue, Box 68, Brooklyn, NY 11203. E-mail address: [email protected] (S.L. Cohn). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 3 - 8

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Goals The goals of preoperative cardiovascular evaluation are: (1) to assess clinically the patient’s current medical status and provide a clinical risk proﬁle; (2) to decide whether further cardiac testing is indicated prior to surgery; and (3) to make recommendations concerning the risk of perioperative cardiac complications and alter management in an attempt to reduce that risk. Risk indices and clinical guidelines are intended to assist physicians in clinical decision-making, but the ultimate judgment regarding the care of any individual patient must be made by the physician and patient in light of all circumstances presented. The overriding theme of clinical guidelines and algorithms is that no test should be performed unless the result is likely to alter patient management. Overview of cardiac risk indices Over the years a number of risk indices have been proposed (Table 1). Of these approaches, only the American College of Cardiology (ACC)/American Heart Association (AHA) [1–3] and ACP guidelines [4] and Lee’s index [5] were developed in the past decade. A comparison of some of these risk indices is shown in Table 2. Because a number of the studies are often quoted or misquoted, a few comments about them are necessary. The American Society of Anesthesiologists (ASA) classiﬁcation [6] was intended to be a global assessment of the patient’s overall physical status and to predict overall morbidity and mortality. Although it was never speciﬁcally intended to predict cardiac risk, there is correlation. The New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) [7] functional classiﬁcations were originally used for risk stratiﬁcation of Table 1 Cardiac risk indices ASA [6] NYHA/CCS [7] Goldman (1977) [8] Cooperman (1979) [14] Detsky (1986) [15,16] Larsen (1987) [9] Eagle (1989) [20] Pedersen (1990) [18] Vanzetto (1996) [21] ACC/AHA (1996) [3] ACP (1997) [4] Lee (1999) [5] ACC (Updated 2002) [1,2] Abbreviations: ACC, American College of Cardiology; ACP, American College of Physicians; AHA, American Heart Association; ASA, American Society of Anesthesiologists; CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association.

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medical patients with angina, but they have been adapted for use in surgical patients. Goldman’s cardiac risk index [8] was the ﬁrst large, prospective, multivariate analysis of patients undergoing noncardiac surgery. Using hard end points of cardiac death, ventricular tachycardia, conﬁrmed myocardial infarction, and pulmonary edema, Goldman et al found nine independent risk predictors of these cardiac complications. Although it has been validated by many investigators [9–12], the Goldman study underestimated the risk in major vascular surgery [13] and, despite including 1001 patients, had inadequate numbers of patients with certain conditions, such as severe angina, to assess the importance of less frequent clinical characteristics. In response to the underestimation of risk in vascular surgery patients, Cooperman [14] published a study listing six risk factors but requiring an antilog table to calculate risk. Detsky [15,16] modiﬁed Goldman’s cardiac risk index by giving the type of surgery a separate pretest probability based on the experience in one’s institution. He then modiﬁed the congestive heart failure (CHF) variables and expanded the factors associated with CAD to include recent or previous myocardial infarction and severity of angina. The point values associated with these risk factors were also changed to multiples of 5, and the clinical end points were expanded to include coronary insuﬃciency and CHF in addition to Goldman’s end points. A likelihood ratio nomogram based on this total point score was then used to determine the post-test probability (average risk for a patient with a similar score) of a severe cardiac complication. It is important to note that Goldman’s study population consisted of unselected consecutive patients undergoing noncardiac, non-neurologic surgery, whereas Detsky’s 455 patients were referred to a general medical consultation service because of known or suspected cardiac disease. In prospective testing, this index has performed no better than the original index [5,11,17]. Larsen’s index [9] included 2609 patients over 40 years old and was the ﬁrst to make a distinction between a myocardial infarction more than 3 months (as opposed to 6 months) before surgery and also included diabetes as a risk factor. Pederson [18] combined factors for a cardiopulmonary risk index. In a prospective study of 4315 patients 50 years old undergoing elective major noncardiac procedures, Lee et al developed a Revised Cardiac Risk Index [5] consisting of 6 independent predictors of complications: high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/dL. Major cardiac complications occurred in 56 (2%) of 2893 patients assigned to the derivation cohort. Rates of major cardiac complication with 0, 1, 2, or 3 of these factors were 0.5%, 1.3%, 4%, and 9%, respectively, in the derivation cohort and 0.4%, 0.9%, 7%, and 11%, respectively, among 1422 patients in the validation cohort. This index has been proposed as a simpliﬁed tool to identify patients at higher risk for complications and to help guide further tests or interventions, and it appears to be more accurate than older indexes in predicting major postoperative cardiac complications [5,19].

Goldman [8]

Congestive heart failure

Angina

S3/JVD

Ischemic heart disease MI <6 mo

Risk Factor

11

10

5

10 20 10 10

5

CCS Class III CCS Class IV Unstable Pulm edema <1 wk

Pulmonary edema ever

10

3

11

No. of points

CHF

1

Hx of 1 ischemic heart disease (nonrevascularized)

No. of points Lee [5]

Persistent 12 pulmonary congestion No congestion 8 but previous pulm edema Neither, but 4 previous heart failure

>3 mo or angina

<3 mo

No. of points Larsen [9]

>6 mo

<6 mo

No. of points Detsky [15]

Table 2 Comparison of cardiac risk indices Level of risk

Compensated or prior CHF

Decompensated CHF

Intermediate

Major

Unstable Major coronary syndromes (MI < 1 mo, class 3–4 or unstable angina) Prior MI (>1 mo), Intermediate mild stable angina (class 1–2)

ACC/ AHA [2]

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Yes

Emergency operation

4

5 3

Yes

10

5

5

PO2<60, pCO2>50, k<3, bicarb<20, BUN>50, Cr>3, abn AST, chronic liver disease, bedridden pt >70 yr Procedure considered separately

3

3

7

Other than 5 nonsinus or APCs on last EKG > 5 PVCs/min 5 at any time Suspected critical 20 AS — —

7

Other intraperitoneal or pleural Yes

— Aortic

3

3

5

Creatine > 1.5 2

—

— High-risk surgery

CVA DM requiring insulin Creatine > 2

— DM 3

—

—

—

—

1

1

1 1

Yes

Advanced age Procedure considered separately

Creatine > 2; Low functional capacity, uncontrolled systemic hypertension

Abnormal EKG, nonsinus rhythm Severe valvular disease CVA DM

Hemodynamically signiﬁcant arrhythmias

(go to OR)

Minor (high intermediate, low risk)

Intermediate; minor

Minor Intermediate

Major

Minor

Major

Abbreviations: APC, atrial premature contraction; AS, aortic stenosis; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CHF, congestive heart failure; CVA, cerebrovascular accident; DM, diabetes mellitus; HX, history of; JVD, jugular venous distention; MI, myocardial infarction; OR, operating room; Pt, patient; PVC, premature ventricular contraction.

>70 yr Intraperitoneal, intrathoracic, aortic

Age Type of surgery

Other than nonsinus or APCs on last EKG > 5 PVCs/min at any time Valvular heart Important AS disease CVA — Diabetes — mellitus General pO2<60, medical pCO2>50, status K<3, bicarb <20, BUN>50, Cr>3, abn AST, chronic liver disease, bedridden pt

Cardiac rhythm

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In a shift from risk indices to patient management, Eagle [20] and Vanzetto [21] each determined clinical variables to be used in deciding whether no testing, noninvasive testing, or coronary angiography should be done. The ACC-AHA [3] and ACP [4] guidelines included speciﬁc algorithms designed to guide whether additional cardiac testing or medical therapy was indicated before a patient could undergo surgery. Most recently, the ACC/ AHA has published an updated version of their original guidelines [1,2]. These will be discussed in more detail later. Approach to the patient History A detailed medical history is probably the most important factor in assessing a patient’s clinical risk of having a postoperative cardiac complication. Certain questions must be asked, and relevant information must be obtained regarding the patient’s current clinical status (Table 3). Age has been found to be an independent risk predictor in a number of studies and risk indices. The usual number that is quoted is over age 70; however, age represents a continuum for risk rather than the dichotomous variable. It is not age per se that predicts risk but rather the fact that age serves as a marker for decreased cardiac reserve and subclinical heart disease. In the most recent large study [22], age was not an independent risk Table 3 Approach to the surgical patient with cardiac disease History Age Prior cardiac disease (MI, angina, CHF, arrhythmias, valvular disease) Prior cardiac intervention (CABG, PCI) Prior cardiac evaluation (noninvasive test, angiography) Risk factors (HTN, DM, dyslipidemia, smoking) Associated diseases (PVD, CVA, CRI, COPD) Current status (chest pain, dyspnea) Functional capacity Medications Physical Exam Vital signs Carotid bruit JVD Murmur (AS, MS) or gallop (S3) Rales/wheezing Edema Peripheral pulses Neurologic deﬁcit Abbreviations: CABG, coronary artery bypass grafting; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CRI, chronic renal insuﬃciency; HTN, hypertension; MI, myocardial infarction; MS, mitral stenosis; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

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factor for cardiac complications of major noncardiac surgery after adjusting for other, more predictive, factors. History of any prior cardiac disease must be investigated: angina, myocardial infarction (MI), congestive heart failure or pulmonary edema, arrhythmias, or valvular heart disease. In patients with a conﬁrmed history, the consultant needs to determine the severity and stability of angina, when a myocardial infarction occurred, and what if any cardiac work-up or intervention was done at that time or subsequently. Questions must be worded in a manner that a patient understands, rather than asking only if they had these diseases. Patients with a recent MI, unstable angina, Class III-IV angina, decompensated heart failure, or symptomatic aortic stenosis are at high risk for perioperative cardiac complications and should not undergo elective surgery without further evaluation or intervention. Mild stable angina (Class I-II), history of an old MI (with stable or no symptoms), and compensated CHF do not carry the same risk, and although these patients are at increased risk compared with patients with no cardiac disease, the absolute risk is lower. Such patients can usually undergo low- to intermediaterisk surgical procedures without further cardiac testing because the risk of coronary angiography and percutaneous coronary intervention (PCI) or preoperative coronary artery bypass grafting (CABG) would expose them to comparable or greater risks than the noncardiac procedure. First, do no harm. In the absence of known disease, the patient may have risk factors for CAD, and therefore the possibility of subclinical disease. These risk factors include diabetes mellitus, hypertension, dyslipidemia, and cigarette smoking. Diabetics, particularly those requiring insulin, are more likely to have vascular disease in general and are at increased risk for perioperative complications. Unless the patient has severe hypertension (stage 3), there is little evidence that it increases surgical risk. A patient may have other diseases associated with CAD and/or heart failure such as peripheral vascular disease, cerebrovascular disease, or renal insuﬃciency. The presence of coexisting respiratory disease such as chronic obstructive pulmonary disease should also be noted. It is important to ascertain and document the patient’s functional capacity, which also plays a role in the risk of postoperative complications. It is not enough to ask if the patient has chest pain or dyspnea without the knowledge of their usual daily activities or capabilities [23]. One should ask how many blocks a patient can walk and how many ﬂights of stairs he or she can climb without symptoms, as well as what limits this activity. Patients who report being unable to walk four blocks or two ﬂights had an increased risk of perioperative complications (cardiac and others), and this risk was inversely proportional to the number of blocks walked [24]. Similarly, the inability to climb two ﬂights of steps was associated with an increased risk of cardiopulmonary complications in patients undergoing major thoracic, vascular, and abdominal surgeries [25].

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A complete list of medications and dosage, including prescription drugs, over-the-counter medications, and herbal preparations, should also be obtained. Physical examination The physical exam should be directed toward uncovering evidence of cardiac disease that the patient is unaware of as well as conﬁrming ﬁndings suggested by the history. Vital signs will indicate the presence of hypertension, hypotension, tachycardia, bradycardia, various arrhythmias, and respiratory distress. The presence of jugular venous distension or an S3 gallop were signiﬁcant predictors of postoperative cardiac complications in Goldman’s original risk index. Other evidence of congestive heart failure including rales and edema should be sought as well. The presence and signiﬁcance of any cardiac murmurs should be evaluated. A carotid bruit, hemiparesis, pulsatile abdominal mass, or decreased peripheral pulses may suggest the presence of cerebrovascular or peripheral vascular disease. Electrocardiogram In addition to the history and physical exam, a preoperative ECG is usually the third component in routine cardiac risk evaluation; however, its ﬁndings rarely change perioperative management. The ECG should be evaluated for evidence of previous myocardial infarction, ischemia, arrhythmias, conduction defects, left ventricular hypertrophy, and nonspeciﬁc ST-T wave changes. The most important ﬁnding would be evidence of a silent MI, especially one that was not present on a recent prior ECG. The presence of left ventricular hypertrophy (LVH) serves as an indicator of more severe or long-standing hypertension and the possible existence of hypertensive heart disease. Many arrhythmias are detectable on physical examination, but conduction defects would otherwise go undetected. Signiﬁcant ST segment depression (>0.5 mm) and left bundle branch block may be a markers of CAD, but there is no current evidence that such asymptomatic ECG ﬁndings increase perioperative risk in patients with or without known CAD. Previous cardiac work-up If the patient had undergone coronary evaluation in the past, it is important to obtain the results of any tests, including an exercise ECG, resting two-dimensional echocardiogram, stress thallium scan, dipyridamole thallium imaging, dobutamine stress echocardiogram, or coronary angiography. It is not enough to state that the test was normal or abnormal; full details are required.

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Clinical risk assessment Based on these items, the consultant should be able to identify whether the patient is in a low-, intermediate-, or high-risk group. In general, patients in low-risk groups require no further evaluation prior to surgery. Noninvasive testing in this group is unlikely to yield useful information as the likelihood of a positive test is low, and positive tests may frequently be false-positives. Previous guidelines have recommended against noninvasive testing in high-risk patients but in favor of routine noninvasive testing in intermediate-risk patients as identiﬁed by clinical criteria. The rationale was that high-risk patients did not need further risk stratiﬁcation but rather should be considered directly for coronary angiography and revascularization, whereas noninvasive testing would help dichotomize intermediate risk patients into low-risk (no further intervention required) or high-risk (angiography) groups [26]. More recent data on the beneﬁt of perioperative beta blockers has led to a major change in the incremental value of noninvasive testing, with our recommendation that it be used selectively in patients whose risk despite beta blockers is suﬃciently high that coronary revascularization would be considered seriously. The ACC and ACP guidelines created algorithms to facilitate preoperative cardiac assessment and assist the consultant in deciding whether to proceed directly to surgery or to order further investigations or therapy. ACC-AHA guidelines Initially published in 1996 [3], the ACC/AHA guidelines were recently updated (2002) [1,2] to include additional data supporting much of the original document but also new information on beta-blockers, arrhythmias, and coronary evaluation and interventions. The ACC algorithm (Fig. 1) employs a strategy, using the urgency of surgery, history of previous coronary evaluation or treatment, clinical risk predictors, surgery-speciﬁc risk, and a patient’s functional capacity. Clinical predictors are classiﬁed as major (unstable coronary syndromes; recent MI (7–30 days), unstable angina, Class III-IV angina, decompensated CHF, signiﬁcant arrhythmias, and severe valvular heart disease); intermediate (stable Class I-II angina, prior MI (>30 days), compensated or prior CHF, diabetes mellitus, and renal insuﬃciency (creatinine >2.0); and minor (advanced age, abnormal EKG, nonsinus rhythm, low functional capacity, prior cerebrovascular accident [CVA], and uncontrolled hypertension). Functional capacity was deﬁned as poor (<4 metabolic equivalents [METS]), moderate (4–7 METS), or good-excellent (>7–10 METS) based on evaluation of the patient’s daily activity. A cutoﬀ of 4 METS was used as the dividing line between adequate and inadequate exercise capacity for purposes of decision-making in the algorithm. The ability to climb at least one ﬂight of stairs carrying a bag of groceries, walk up a hill, or walk on level ground at 3–4 mph should indicate a functional capacity 4 METS.

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Fig. 1. Stepwise approach to preoperative cardiac assessment. Reprinted with permission from the American College of Cardiology. Journal of the American College of Cardiology 2002;39:542–53.

Surgery-speciﬁc risk as grouped by high, intermediate, or minor risk procedures (with cardiac risk >5%, 1–5%, or <1%, respectively) is deﬁned by the type of surgery and its associated hemodynamic stress. High-risk procedures include emergent major operations, aortic and peripheral vascular surgery, and prolonged surgical procedures associated with large ﬂuid shifts and/or blood loss. Intermediate-risk procedures include carotid endarterectomy, major head and neck surgery, intraperitoneal and intrathoracic surgery, and major orthopedic procedures. Low-risk procedures are usually superﬁcial and include endoscopic procedures, breast surgery, and cataract surgery. If surgery were emergent (or very urgent), time would not permit coronary evaluation or intervention and the patient would proceed to surgery without any further cardiac tests. Emergency surgery increases risk twoto ﬁvefold compared with elective operations [8,9,27]. If elective, one would proceed to the next step in the algorithm.

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Fig. 1 (continued )

If a patient had undergone coronary revascularization in the past 5 years or coronary evaluation within the past 2 years and was clinically stable without symptoms or any change in angina, no further work-up or testing was recommended. On the other hand, if a patient either did not have a recent coronary evaluation or revascularization procedure or had recurrent or different symptoms, the physician was directed to the clinical risk factors in the algorithm to determine the need for further testing or treatment.

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Patients with major clinical risk predictors should undergo further evaluation, testing, or treatment prior to elective surgery. Those with intermediate clinical predictors scheduled for low-risk procedures could proceed to surgery without further testing, and those undergoing high-risk surgical procedures should have noninvasive testing ﬁrst. If the surgical procedure were an intermediate one, the decision for further testing would depend on the patient’s functional capacity. In patients with minor or no clinical predictors, only those with poor exercise capacity and scheduled for highrisk surgery should be considered for noninvasive testing. The decision to proceed to noninvasive testing can be simpliﬁed if two of the following three factors are present: intermediate clinical predictors, poor functional capacity, or high-risk surgical procedure. The updated ACC/AHA guidelines also recommended perioperative beta blocker therapy for (1) patients who require them to control angina, symptomatic arrhythmias, or hypertension; (2) patients who are undergoing vascular surgery and are at high cardiac risk from ischemia on preoperative testing; and (3) possibly patients who have untreated hypertension, known coronary artery disease, or major risk factors for CAD.

ACP guidelines The ACP algorithm [4] uses the urgency of surgery, variables from Detsky’s Modiﬁed Cardiac Risk Index (<20 versus 20 or more points), and ‘‘low risk variables’’ from either Eagle’s or Vanzetto’s criteria. They divided surgical procedures into vascular or nonvascular and did not consider exercise capacity in their algorithm. The ACP guidelines are purely evidence-based, and, in the absence of adequate evidence, they made no recommendation. Strict adherence to the ACP algorithm would therefore result in fewer recommendations for noninvasive testing compared with the ACC algorithm. Because these recommendations antedated the publication of the Lee index and more recent studies on self reported exercise capacity, dobutamine stress echocardiography in non-vascular surgery, and the beneﬁt of perioperative beta-blockers, we believe they have been superseded by new information and by other, newer guidelines and recommendations.

Our recommendations We favor a modiﬁcation of the ACC/AHA guidelines in conjunction with the Revised Cardiac Index to decide whether the patient should be referred for further testing, medical therapy (primarily beta blockers), or no additional treatment or evaluation prior to proceeding to surgery. Our approach will be illustrated and discussed in the section on perioperative management.

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Noninvasive tests to assess functional capacity and CAD risk These tests can be divided into resting tests, exercise tests, and pharmacologic tests with myocardial perfusion imaging or echocardiography. Table 4 is a summary of noninvasive tests before major noncardiac surgery. Resting echocardiography On echocardiography, a left ventricular (LV) ejection fraction (EF) of <35% may predict postoperative heart failure and, in severely ill patients, mortality; however, it does not reliably predict perioperative ischemic events. The assessment of resting left ventricular function is not routinely recommended for preoperative screening, but the severity of LV dysfunction by echocardiography adds incremental information in patients with heart failure. In these patients, an echocardiogram is part of the routine evaluation and follow-up, and a preoperative echocardiogram is advised if no prior echocardiogram has been obtained or the patient’s clinical status has worsened since that echocardiogram. In any patient with suspected valvular

Table 4 Noninvasive testing before major noncardiac surgery Positive predictive value (PPV)

Negative predictive value (NPV)

Test

na

Postoperative cardiac eventsb

Exercise testing Peripheral vascular/ AAAc Peripheral vascular/ noncardiac Myocardial perfusion imagingd Vascular Nonvascular Dobutamine stress echocardiography Vascular Nonvascular ST segment ambulatory monitoring

1302 1104

72/919 (8%) 64/721 (9%)

55/334 (18%) 53/293 (18%)

568/585 (97%) 417/428 (97%)

198

8/198 (4%)

2/41 (5%)

151/157 (96%)

3508

238 (7%)

180/1397 (13%)

1527/1550 (99%)

2834 674 1657

189 (7%) 49 (7%) 83 (5%)

145/1181 (12%) 35/216 (16%) 74/484 (15%)

1192/1211 (98%) 335/339 (99%) 1162/1171 (99%)

1001 656 869

48 (5%) 35 (5%) 51 (6%)

39/260 (15%) 35/224 (16%) 21/215 (10%)

730/739 (99%) 432/432 (100%) 624/654 (95%)

a

Not all screened patients had surgery. Events are cardiac death and MI except for a few exercise EKG studies including UA, CHF, arrhythmias. c Excludes one study with 808 patients only reporting PPV (21%, 19/89) but not event rate or NPV. d Patients with ﬁxed defects were omitted from calculations of PPV and NPV. Data modiﬁed from Tables 6–9 in Eagle et al. ACC/AHA guideline update, 2002. http:// www.acc.org/clinical/guidelines/perio/dirIndex.htm.2002; with permission. Abbreviations: AAA, abdominal aortic aneurysm; NPV, negative predictive value; PPV, positive predictive value; UA, unstable angina. b

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heart disease [28,29] or hypertrophic cardiomyopathy [30,31], a preoperative echocardiogram is advised. Evaluation and perioperative management of valvular heart disease is discussed in a subsequent article. Exercise stress testing Exercise ECG stress testing, with or without imaging, is usually preferable to resting or pharmacologic stress in ambulatory patients. Treadmill is preferred, but bicycle exercise is an alternative. One of the main limitations of ECG exercise tests is that only about half of the patients tested achieve peak exercise heart rates greater than 75% of their age-predicted maximum. Ischemia induced by low-level exercise indicates high risk. In the absence of positive ﬁndings, the inability to reach the heart rate goal makes the test inadequate for excluding myocardial ischemia; unless a normal workload is achieved despite the lower heart rate, such patients are at increased risk for perioperative complications based on their poor functional capacity. A negative test in a patient who achieves the targeted heart rate-blood pressure product is usually associated with low risk for perioperative cardiac complications. For example, pooled data on exercise testing prior to peripheral vascular surgery or aortic aneurysm repair in 1104 patients with 64 cardiac events revealed the positive predictive value of an abnormal test to be 18% (range 5–81%) and the negative predictive value to be 97% (range 90–100%) [2] (Table 4). It is important to obtain and document as much information as possible regarding the details of a patient’s exercise ECG rather than stating it was normal or abnormal. The peak heart rate, systolic blood pressure, and rate-pressure product (or double product) should be noted, as well as the number of METS achieved, percent of target heart rate achieved, and presence of any ECG changes, symptoms, or arrhythmias occurring during the test. Similarly, a patient with symptoms or ischemia at a lower workload is potentially at increased risk compared with a patient able to reach a higher metabolic threshold. Ischemia that occurs at a speciﬁc double product is fairly reproducible for an individual patient. The anesthesiologist should be aware of this information to help manage the patient’s blood pressure and heart rate intraoperatively so that the double product remains below the ischemic threshold. Non-exercise stress testing In patients unable to exercise, pharmacologic agents can induce a hyperemic response (dipyridamole or adenosine) or increase oxygen demand (dobutamine). The decision of which test to use should be based on the expertise in one’s institution, consideration of relative contraindications to dipyridamole or dobutamine, and other factors that might favor one test over another. Stress echocardiography may be somewhat less sensitive for detecting ischemia than stress scintigraphy, but stress echocardiography appears to have a higher speciﬁcity and positive predictive value. In patients

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with left bundle-branch block, false positive reversible septal defects may occur with exercise or dobutamine. In these cases, vasodilator stress and myocardial perfusion studies may be preferable [2]. Myocardial perfusion imaging Thallium or technetium are the usual nuclear imaging agents used. Dipyridamole decreases inactivation of endogenous adenosine by adenosine deaminase and also inhibits phosphodiesterase, thereby increasing cyclic adenosine monophosphate (cAMP). These actions increase coronary blood ﬂow in normal coronary arteries but result in no signiﬁcant change in occluded or severely stenotic vessels. The presence of myocardial defects initially during stress followed by subsequent resolution after redistribution of blood on delayed scanning indicates myocardial ischemia and predicts perioperative events. By comparison, a ﬁxed defect that is seen with stress but persists after resting is more likely to represent a myocardial scar from a prior MI and is less predictive of perioperative cardiac events. Prior to testing, patients should avoid theophylline preparations and caﬀeine because of their antagonistic eﬀect on dipyridamole. Side eﬀects associated with the use of dipyridamole include bronchospasm, chest pain, headache, and dizziness; these symptoms often can be reversed by administration of IV aminophylline [32]. Relative contraindications to IV dipyridamole testing include bronchospasm and signiﬁcant carotid stenosis. Pooled data on myocardial perfusion imaging prior to vascular surgery in 2834 patients with 189 perioperative cardiac events (MI or cardiac death) revealed the positive predictive value of reperfusion defects to be approximately 12% (range 4–20%) and the negative predictive value to be almost 99% (range 95–100%). Pooled data prior to nonvascular surgery for 674 patients with 49 perioperative events (MI or death) showed reperfusion abnormalities to have a positive predictive value of 16% (range 6–67%) and a negative predictive value of almost 99% (range 98–100%) [2] (Table 4). Cardiac risk increases with increasing size and number of reperfusion defects [33–37], and scoring or quantiﬁcation of the scan abnormalities has been recommended to improve risk assessment. Nearly all of these data come, however, from patients selected to undergo such tests. When applied to unselected, consecutive patients, the predictive value of dipyridamole thallium scintigraphy is not nearly so good [38]. Dobutamine stress echocardiography Among 1657 patients with 83 cardiac events reported prior to 2000, a positive dobutamine stress echocardiogram had a positive predictive value of 15% (range 7–25%) and a negative predictive value of 99% (range 93–100%). Comparison of the 3 studies of 656 patients undergoing nonvascular surgery with 9 studies totaling 1001 patients undergoing vascular surgery revealed similar positive and negative predictive values [2] (Table 4). The extent and severity

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of new or worsening wall motion abnormalities, particularly at low ischemic thresholds, is predictive of both short- and long-term outcome. Dobutamine testing should be avoided in patients with signiﬁcant arrhythmias, marked hypertension or hypotension, and suspected critical aortic stenosis. Ambulatory ECG monitoring A number of studies have examined the predictive value of preoperative ST segment changes (usually depression of 1 mm) using 24–48-hour ambulatory ECG monitoring. Although protocols diﬀered in various studies in pooled data on 869 patients, the positive predictive value for perioperative MI and death was approximately 10% (range 4–15%), with negative predictive value of 95% (range 84–99%) [2] (Table 4). The use of this test is limited, however, because a signiﬁcant number of patients may have baseline ECG abnormalities precluding analysis, and because the monitoring requires 24 hours prior to surgery.

Perioperative management Identiﬁcation of the patient at increased risk for perioperative cardiac complications is the ﬁrst step; however, the objective is to be able to lower that risk to prevent complications. A number of modalities have been advocated as a means to protect patients from potential adverse outcomes. It is beyond the scope of this article to discuss all of them, but the major ones include medical therapy, revascularization procedures (CABG and PCI), and invasive monitoring. The questions that need to be answered are: (1) do these interventions improve outcome? (2) if so, how long does their protective action last? and (3) which patients are most likely to beneﬁt? Medical therapy A number of medications have been evaluated regarding their eﬀect in reducing perioperative cardiac complications after noncardiac surgery. These include beta-blockers, alpha-agonists, nitroglycerin, and calcium channel blockers. Several other medications [sodium/hydrogen exchange inhibitors (cariporide) and purine nucleosides (acadesine)] have been studied in patients undergoing CABG but not yet in noncardiac surgery. Studies on prophylactic calcium channel blockers are limited and inconclusive. Similarly, studies using nitroglycerin in noncardiac surgery are also limited [39,40], and only one study of 45 patients undergoing carotid endarterectomy demonstrated decreased ischemia but not MI or death using intraoperative nitroglycerin [39]. This therapy may also lead to increased hypotension during anesthesia and cannot be recommended prophylactically at this time. The following discussion will focus on beta-blockers and alpha agonists, which have demonstrated the most promising results.

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Beta-blockers Poldermans et al [41] studied the eﬀect of bisoprolol, started at least 7 days preoperatively, and continued for at least 30 days postoperatively, in 112 patients with abnormal dobutamine stress echocardiograms undergoing vascular surgery. In these patients, bisoprolol signiﬁcantly decreased the rate of cardiac death (3.4% versus 17%) and nonfatal MI (0% versus 17%) compared with placebo. This high-risk subgroup represented a small sample from the total cohort of 1351 patients that was reanalyzed by Boersma et al [42], taking into account the patient’s clinical risk factors (using Lee’s revised cardiac index). Patients with 0–2 clinical risk factors receiving bisoprolol had fewer cardiac complications than those receiving placebo (0.8% versus 2.3%). Patients taking bisoprolol who had 3 or more clinical risk factors and a dobutamine stress echocardiogram with 4 segments with new wall motion abnormalities had a lower risk of cardiac complications compared with the placebo group (2.3% versus 10.6%). The small group with 5 segments involved had no diﬀerence in outcome with or without bisoprolol. This study demonstrated both the potential beneﬁt of perioperative bisoprolol as well as the use of clinical criteria and selective dobutamine stress echocardiograms in reducing cardiac complications. Although bisoprolol beneﬁted all but the patients with extensive ischemia, its beneﬁt was most marked in those with three or more clinical risk factors, and within that group, those with more wall motion abnormalities. This study was subsequently extended to follow the long-term outcome in 101/112 surviving patients remaining on bisoprolol compared with those receiving standard care [43]. With a median follow-up time of 22 months, the bisoprolol group had a decreased risk of MI or cardiac death compared with the standard care group (12% versus 32%). In an earlier study, the Multicenter Study of Perioperative Ischemia Research Group [44,45] evaluated the use of atenolol, started immediately preoperatively and continued for the duration of the hospital stay, compared with placebo in 200 patients with, or at risk for, coronary artery disease undergoing noncardiac surgery. There was no diﬀerence in perioperative MI or death, but ischemic episodes were decreased in the atenolol group compared with those receiving placebo (24% versus 39%). The 192 surviving patients were then followed for 2 years, and those originally assigned to the atenolol group had decreased mortality (9 versus 21 deaths) and combined cardiac events (16 versus 32 events) at the end of the followup period. The principal eﬀect in the atenolol group was attributed to a reduction in death in the ﬁrst 6–8 months, and, although there was no diﬀerence after that, these early diﬀerences were preserved over the 2-year followup period. There was no obvious reason why a short course of atenolol should result in this long-term eﬀect, and several uncertainties persist about this study. The groups diﬀered in their preoperative use of medications and history of angina or MI, and there was no control over the medications the patients took after hospital discharge.

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Other smaller studies have examined the role of various beta-blockers in diﬀerent perioperative settings and have generally found a reduction in ischemic events [46]. There may even be a beneﬁt of giving beta-blockers intraoperatively to patients who have not received them preoperatively. For example, a small study demonstrated a decrease in the incidence and duration of ischemic episodes using intraoperative esmolol and postoperative metoprolol in patients undergoing total knee arthroplasty [47]. It is important to note the patient inclusion criteria, type of surgery (vascular versus general), outcome measured (ischemia versus MI/death), and how the beta-blockers were used diﬀered among the various studies. The beneﬁts seen in clinical trials in which strict protocols were followed and beta-blocker doses were titrated (to maintain heart rate < 65) may not translate to similar outcomes using diﬀerent regimens elsewhere. Alpha-agonists Clonidine [48] was shown to decrease the incidence of myocardial ischemia in a study of 297 patients undergoing vascular surgery (24% versus 39%) [49] and in another small study of 52 patients undergoing noncardiac surgery (4% versus 21%) [50]. Mivazerol, another alpha agonist not currently available in the United States, was studied perioperatively in 2854 patients with known CAD or signiﬁcant risk factors undergoing noncardiac surgery [51]. Although it was not shown to decrease the rate of perioperative MI, it reduced cardiac death rate in patients undergoing general surgery and reduced both the death rate and the combined end point of cardiac death and MI in patients undergoing vascular surgery. The Multicenter Study of Perioperative Ischemia Research Group studied 300 patients undergoing noncardiac surgery and reported less myocardial ischemia in the mivazerol-treated group compared with the placebo group but found no diﬀerences in perioperative MI or cardiac death [52]. Preoperative coronary artery bypass grafting There are no randomized, controlled trials addressing the issue of whether prophylactic CABG is beneﬁcial overall for the noncardiac surgical patient. Certain patient subgroups, such as those with peripheral vascular disease, are at increased risk of having CAD. In a study of 1001 consecutive patients scheduled to undergo major vascular surgery, coronary angiography revealed signiﬁcant CAD meeting criteria for CABG in almost 50%, including 34% of those with known CAD but also 14% of patients without clinical CAD [53]. The incidence of cardiac death in the group undergoing vascular surgery after preoperative CABG was 1.5% and was comparable to those patients with no CAD or mild to moderate disease (1.4–1.8%), and lower than in patients with severe, uncorrected, or inoperable disease (3–14%). But after taking into account the operative mortality of the CABG in that study, there was no short-term beneﬁt. Similarly, review of a group of patients

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from the Coronary Artery Bypass Study (CASS) who underwent CABG and sometime thereafter had a noncardiac surgical procedure demonstrated a statistically signiﬁcant lower incidence of perioperative cardiac death (0.9% versus 2.4%) but a nonstatistically signiﬁcant incidence of perioperative myocardial infarction (0.7% versus 1.1%) compared with the group treated medically [54]. A subsequent review of CASS study patients having ‘‘higher risk’’ noncardiac procedures revealed a statistically signiﬁcant lower risk of death (1.7% versus 3.3%) and nonfatal MI (0.8% versus 2.7%) in patients who had prior CABG compared with those who had not undergone CABG [55]. For ‘‘lower risk’’ noncardiac procedures, the risks of myocardial infarction or death were low and not signiﬁcantly aﬀected by having prior bypass surgery. Once again, however, when one takes into account the morbidity and mortality of the CABG, there is no short term beneﬁt. The recommendation is therefore to perform coronary angiography and CABG using the same indications as in the nonsurgical setting. It is rarely necessary to use prophylactic CABG for the sole purpose of improving perioperative outcome in patients undergoing noncardiac surgery. Is a patient who previously had coronary artery bypass surgery at lower risk than a similar patient who did not undergo a revascularization procedure? Patients most likely to beneﬁt were those with more severe disease undergoing higher risk surgical procedures. This protective eﬀect tends to decrease over time as the likelihood of graft occlusion increases [56]. Data from the CASS study patients suggested that protection aﬀorded by prior CABG was maintained for 4–6 years [55], and the ACC guidelines implied that CABG was probably protective against perioperative MI or cardiac death for at least 5 years assuming the patient remained medically stable without recurrent ischemic symptoms. Percutaneous coronary intervention Once again, there are no randomized clinical trials demonstrating that prophylactic angioplasty (PTCA) or stent placement prior to noncardiac surgery reduces perioperative ischemia, MI, or death. Review of published studies with 50 patients or more undergoing noncardiac surgery after PTCA demonstrates a perioperative mortality ranging from 0–2.7% and a perioperative infarction rate from 0–5.6% [2]. These results appear to be better than expected based on historical controls. The mean time from PTCA to surgery ranged from 9 days to a year or more, but the recommendations regarding timing of the subsequent noncardiac surgery varied. The ACC guidelines recommend waiting at least 1 week after balloon angioplasty to allow time for the vessel injury at the site to heal. Only one study [57] evaluated outcomes in patients receiving stents. Forty patients who had stents placed less than 6 weeks before noncardiac surgery had perioperative mortality, myocardial infarction, and major bleeding rates of 20%, 16.8%, and 27.5%, respectively. All deaths and MIs and 8/11 major

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bleeding episodes occurred in patients who had stents placed less than 14 days before surgery. The complication of stent thrombosis is most common in the ﬁrst 2 weeks after stent placement and is rare after 2–4 weeks. Aspirin and clopidogrel are usually given for 2–4 weeks after stent placement to prevent stent thrombosis while endothelialization takes place. If these drugs are stopped prematurely, the risk of thrombosis increases, but if they are continued during noncardiac surgery, the risk of bleeding is increased. If restenosis is to occur, it is usually after 8 weeks. The recommendation is to wait from 2–4 weeks to no more than 8 weeks after stent placement before performing noncardiac surgery in order to allow the patient enough time to complete the course of antiplatelet therapy but insuﬃcient time for restenosis to occur. If restenosis has not occurred by 8–12 months, it is unlikely to occur, and, therefore, PCI may provide the patient with some degree of protection against adverse perioperative cardiac events. One report [56] compared the protective eﬀect of PCI with CABG prior to noncardiac surgery in patients with mult-vessel disease from the Bypass Angioplasty Revascularization Investigation (BARI). Both groups had a similar frequency of perioperative MI and cardiac death (1.6%) after having undergone PTCA or CABG. This risk was lower if the revascularization procedure was done less than 4 years before the noncardiac surgery, compared with 4 or more years before the surgery (0.8% versus 3.6%).

Pulmonary artery catheters Although the pulmonary artery catheter can provide hemodynamic information about a patient’s status that might be otherwise unknown, it has yet to be clearly demonstrated that this information, or changes in patient management that result from it, have improved patient outcome. Studies involving pulmonary artery catheters versus central venous pressure catheters, as well as monitoring in aortic and vascular surgical patients, have shown no diﬀerence in perioperative MI or cardiac death [58–61]. A recent study by Polanczyk et al [62] reported an increased risk of postoperative congestive heart failure in patients in whom a pulmonary artery catheter was used. It is possible that no beneﬁt has been found by using a pulmonary artery catheter because the patients in whom it was used may have been at higher risk. Preliminary data from a randomized trial of pulmonary artery catheters for noncardiac surgery also showed no beneﬁt, however [63,64]. Although it is possible that pulmonary artery catheters may beneﬁt certain high-risk patients, it is not possible to make strong recommendations for their routine use [65]. If a pulmonary artery catheter is indicated in a patient whose ﬂuid status is uncertain, it should ideally be left in place for as brief a time as is necessary to obtain diagnostic information and guide therapy.

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Anesthetic considerations At this time, there is no deﬁnite evidence of a best anesthetic technique for myocardial protection, and the choice of anesthesia is best left to the anesthesiologist. Eﬀective perioperative pain management is important, but the best analgesic technique has yet to be proven. Maintenance of normothermia may reduce risk of perioperative cardiac morbidity [66]. Our approach Based on the most current guidelines and risk indices combined with recent new information on prophylactic beta-blockade, we recommend a

Fig. 2. Perioperative beta-blockers for elective surgery: patient selection and preoperative risk stratiﬁcation. Modiﬁed from Auerbach AD, Goldman L. Beta-blockers and reduction of cardiac events in noncardiac surgery. JAMA 2002;287:1441; with permission.

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Table 5 Eligibility criteria for perioperative b-blockers Minor criteria (Mangano) [36] Age 65 Hypertension Current smoker Serum cholesterol >240 mg/dL Diabetes mellitus not requiring insulin Revised cardiac risk index criteria (Lee) [19] 1. High risk surgical procedure Intraperitoneal Intrathoracic Suprainguinal vascular 2. Ischemic heart disease Prior MI or Q waves Previous or current angina Use of NTG, positive exercise test Ischemic chest pain despite prior CABG or PCI 3. Cerebrovascular disease History of TIA or CVA 4. Diabetes mellitus requiring insulin 5. Chronic renal insuﬃciency (Cr 2.0) Abbreviations: NTG, nitroglycerin; TIA, transient ischemic attack. Contraindications to b-blockers include: COPD/asthma, hypotension, bradycardia, heart block, and acute CHF/pulmonary edema. Modiﬁed from Auerbach AD, Goldman L. Beta-blockers and reduction of cardiac events in noncardiac surgery. JAMA 2002;287:1441; with permission.

modiﬁcation of the ACC [1] and Auerbach/Goldman [46] algorithms (Fig. 2 and Table 5). Using this algorithm, we incorporate the urgency of surgery, results of previous cardiac work-up or treatment, and presence of major clinical predictors from the ACC guidelines in the schematic proposed by Auerbach/Goldman for risk stratiﬁcation with the Revised Cardiac Risk Index and recommendations for perioperative beta-blockade. Patients with major clinical predictors (ACC) should not undergo elective surgery without further cardiac evaluation (often coronary angiography) or medical management and risk factor modiﬁcation. Although complication rates for some groups with intermediate risk who receive beta-blockers are unknown, and the beta-blocker data were derived from vascular surgery patients, we think that, until more data become available, it is likely that all patients with risk factors may beneﬁt from prophylactic beta-blockade, and we would therefore recommend it pending additional studies. Summary We have reviewed the methods of evaluating a patient’s cardiac risk preoperatively using a careful history, physical examination, and EKG. Based on this information, various risk indices, guidelines, and algorithms can further assist the physician in deciding which patients can undergo surgery without

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further testing and which patients might beneﬁt from further cardiac evaluation or medical therapy prior to surgery. The physician must keep in mind that a test should not be ordered if it is unlikely to alter the patient’s management, and it is rarely necessary to perform a revascularization procedure with the sole purpose of getting a patient through surgery. Ongoing research is likely to lead to improvement in perioperative medical therapy. References [1] 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). J Am Coll Cardiol 2002;39:542–53. [2] Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: 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). American College of Cardiology Web site http://www.acc.org/clinical/guidelines/ perio/dirIndex.htm, 2002. [3] Eagle KA, Brundage BH, Chaitman BR, et al. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 1996;27:910–48. [4] Palda VA, Detsky AS. Perioperative assessment and management of risk from coronary artery disease. Ann Intern Med 1997;127:313–28. [5] 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. [6] American Society of Anesthesiologists. New classiﬁcation of physical status. Anesthesiology 1963;24:111. [7] Campeau L. Letter: grading of angina pectoris. Circulation 1976;54:522–3. [8] Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977;297:845–50. [9] Larsen SF, Olesen KH, Jacobsen E, et al. Prediction of cardiac risk in non-cardiac surgery. Eur Heart J 1987;8:179–85. [10] Prause G, Ratzenhofer-Comenda B, Pierer G, et al. Can ASA grade or Goldman’s cardiac risk index predict peri-operative mortality? A study of 16,227 patients. Anaesthesia 1997; 52:203–6. [11] Taylor LM Jr, Yeager RA, Moneta GL, et al. The incidence of perioperative myocardial infarction in general vascular surgery. J Vasc Surg 1992;15:52–9;discussion 59–61. [12] Zeldin RA. Assessing cardiac risk in patients who undergo noncardiac surgical procedures. Can J Surg 1984;27:402–4. [13] Jeﬀrey CC, Kunsman J, Cullen DJ, et al. A prospective evaluation of cardiac risk index. Anesthesiology 1983;58:462–4. [14] Cooperman M, Pﬂug B, Martin Jr EW, et al. Cardiovascular risk factors in patients with peripheral vascular disease. Surgery 1978;84:505–9. [15] Detsky AS, Abrams HB, Forbath N, et al. Cardiac assessment for patients undergoing noncardiac surgery. A multifactorial clinical risk index. Arch Intern Med 1986;146:2131–4. [16] Detsky AS, Abrams HB, McLaughlin JR, et al. Predicting cardiac complications in patients undergoing non-cardiac surgery. J Gen Intern Med 1986;1:211–9.

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[17] Gilbert K, Larocque BJ, Patrick LT. Prospective evaluation of cardiac risk indices for patients undergoing noncardiac surgery. Ann Intern Med 2000;133:356–9. [18] Pedersen T, Eliasen K, Henriksen E. A prospective study of risk factors and cardiopulmonary complications associated with anaesthesia and surgery: risk indicators of cardiopulmonary morbidity. Acta Anaesthesiol Scand 1990;34:144–55. [19] Kumar R, McKinney WP, Raj G, et al. Adverse cardiac events after surgery: assessing risk in a veteran population. J Gen Intern Med 2001;16:507–18. [20] Eagle KA, Coley CM, Newell JB, et al. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med 1989;110:859–66. [21] Vanzetto G, Machecourt J, Blendea D, et al. Additive value of thallium single-photon emission computed tomography myocardial imaging for prediction of perioperative events in clinically selected high cardiac risk patients having abdominal aortic surgery. Am J Cardiol 1996;77:143–8. [22] Polanczyk CA, Marcantonio E, Goldman L, et al. Impact of age on perioperative complications and length of stay in patients undergoing noncardiac surgery. Ann Intern Med 2001;134:637–43. [23] McGlade DP, Poon AB, Davies MJ. The use of a questionnaire and simple exercise test in the preoperative assessment of vascular surgery patients. Anaesth Intensive Care 2001;29: 520–6. [24] Reilly DF, McNeely MJ, Doerner D, et al. Self-reported exercise tolerance and the risk of serious perioperative complications. Arch Intern Med 1999;159:2185–92. [25] Girish M, Trayner Jr E, Dammann O, et al. Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest 2001;120: 1147–51. [26] L’Italien GJ, Paul SD, Hendel RC, et al. Development and validation of a Bayesian model for perioperative cardiac risk assessment in a cohort of 1,081 vascular surgical candidates. J Am Coll Cardiol 1996;27:779–86. [27] Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990;72:153–84. [28] Raymer K, Yang H. Patients with aortic stenosis: cardiac complications in non-cardiac surgery. Can J Anaesth 1998;45:855–9. [29] Torsher LC, Shub C, Rettke SR, et al. Risk of patients with severe aortic stenosis undergoing noncardiac surgery. Am J Cardiol 1998;81:448–52. [30] Haering JM, Comunale ME, Parker RA, et al. Cardiac risk of noncardiac surgery in patients with asymmetric septal hypertrophy. Anesthesiology 1996;85:254–9. [31] Thompson RC, Liberthson RR, Lowenstein E. Perioperative anesthetic risk of noncardiac surgery in hypertrophic obstructive cardiomyopathy. JAMA 1985;254:2419–21. [32] Ranhosky A, Kempthorne-Rawson J. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Intravenous Dipyridamole Thallium Imaging Study Group. Circulation 1990;81:1205–9. [33] Brown KA, Rowen M. Extent of jeopardized viable myocardium determined by myocardial perfusion imaging best predicts perioperative cardiac events in patients undergoing noncardiac surgery. J Am Coll Cardiol 1993;21:325–30. [34] Hendel RC, Whitﬁeld SS, Villegas BJ, et al. Prediction of late cardiac events by dipyridamole thallium imaging in patients undergoing elective vascular surgery. Am J Cardiol 1992;70:1243–9. [35] Lette J, Waters D, Bernier H, et al. Preoperative and long-term cardiac risk assessment. Predictive value of 23 clinical descriptors, 7 multivariate scoring systems, and quantitative dipyridamole imaging in 360 patients. Ann Surg 1992;216:192–204. [36] Lette J, Waters D, Cerino M, et al. Preoperative coronary artery disease risk stratiﬁcation based on dipyridamole imaging and a simple three-step, three-segment model for patients undergoing noncardiac vascular surgery or major general surgery. Am J Cardiol 1992;69: 1553–8.

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[37] Levinson JR, Boucher CA, Coley CM, et al. Usefulness of semiquantitative analysis of dipyridamole-thallium-201 redistribution for improving risk stratiﬁcation before vascular surgery. Am J Cardiol 1990;66:406–10. [38] Baron JF, Mundler O, Bertrand M, et al. Dipyridamole-thallium scintigraphy and gated radionuclide angiography to assess cardiac risk before abdominal aortic surgery. N Engl J Med 1994;330:663–9. [39] Coriat P, Daloz M, Bousseau D, et al. Prevention of intraoperative myocardial ischemia during noncardiac surgery with intravenous nitroglycerin. Anesthesiology 1984;61:193–6. [40] Dodds TM, Stone JG, Coromilas J, et al. Prophylactic nitroglycerin infusion during noncardiac surgery does not reduce perioperative ischemia. Anesth Analg 1993;76:705–13. [41] Poldermans D, Boersma E, Bax JJ, et al. The eﬀect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999;341:1789–94. [42] Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001;285:1865–73. [43] Poldermans D, Boersma E, Bax JJ, et al. Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001;22:1353–8. [44] Mangano DT, Layug EL, Wallace A, et al. Eﬀect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713–20. [45] Wallace A, Layug B, Tateo I, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology 1998;88:7–17. [46] Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery: scientiﬁc review. JAMA 2002;287:1435–44. [47] Urban MK, Markowitz SM, Gordon MA, et al. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg 2000;90:1257–61. [48] Nishina K, Mikawa K, Uesugi T, et al. Eﬃcacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 2002;96:323–9. [49] Stuhmeier KD, Mainzer B, Cierpka J, et al. Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery. Anesthesiology 1996;85:706–12. [50] Ellis JE, Drijvers G, Pedlow S, et al. Premedication with oral and transdermal clonidine provides safe and eﬃcacious postoperative sympatholysis. Anesth Analg 1994;79: 1133–40. [51] Oliver MF, Goldman L, Julian DG, et al. Eﬀect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). Anesthesiology 1999;91:951–61. [52] McSPI–Europe Research Group. Perioperative sympatholysis. Beneﬁcial eﬀects of the alpha 2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. Anesthesiology 1997;86:346–63. [53] Hertzer NR, Beven EG, Young JR, et al. Coronary artery disease in peripheral vascular patients. A classiﬁcation of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199:223–33. [54] Foster ED, Davis KB, Carpenter JA, et al. Risk of noncardiac operation in patients with deﬁned coronary disease: The Coronary Artery Surgery Study (CASS) registry experience. Ann Thorac Surg 1986;41:42–50. [55] Eagle KA, Rihal CS, Mickel MC, et al. Cardiac risk of noncardiac surgery: inﬂuence of coronary disease and type of surgery in 3368 operations. CASS Investigators and

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Preoperative assessment and perioperative management of the patient with nonischemic heart disease Jonathan B. Shammash, MDa,*, William A. Ghali, MD, MPHb a

Weill Medical College of Cornell University, and General Medicine Consultation Service, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Center, 1484 First Avenue, Suite 2R, New York, NY 10021, USA b Faculty of Medicine, University of Calgary, 3330 Hospital Drive North West, Calgary, Alberta T2N 4N1, Canada

The goal here is to provide a review of important topics related to the preoperative assessment and perioperative management of patients with nonischemic heart disease (issues related to ischemic heart disease are addressed thoroughly in another section). We will review the recommended components of the preoperative examination and the focused use of preoperative testing. We will then discuss the perioperative signiﬁcance and management of four areas of nonischemic heart disease: hypertension, congestive heart failure (CHF), arrhythmias and conduction defects, and valvular heart disease.

Preoperative assessment History A careful history may be the most valuable tool in assessing a patient’s risk of perioperative cardiovascular complications. It should identify the presence of hypertension, hemodynamically signiﬁcant atrial and ventricular arrhythmias, conduction defects, congestive heart failure, and valvular heart * Corresponding author. E-mail address: [email protected] (J.B. Shammash). Dr. Ghali is supported by a Government of Canada Research Chair in Health Services Research and by a Health Scholar Award from the Alberta Heritage Foundation for Medical Research. 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 2 - 6

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disease. The presence of a pacemaker or implantable cardioverter-deﬁbrillator device should be noted. Comorbid diseases that are related to or can aﬀect cardiac function should be identiﬁed, such as asthma, obstructive pulmonary disease, renal or hepatic impairment, peripheral or cerebral vascular disease, and diabetes mellitus. A complete medication list must be obtained and documented, with particular attention to over-the-counter and herbal medications that might aﬀect blood pressure or hemostasis [1]. Exercise-functional capacity must be assessed, as it has recently been shown to have independent prognostic signiﬁcance for determining the risk of cardiopulmonary complications in the perioperative setting. Patients who report being unable to walk four blocks or climb two ﬂights of steps have been found to have an increased risk of a range of perioperative complications [2] and the inability to climb two ﬂights of steps has recently been associated with an increased risk of cardiopulmonary complications in patients undergoing major thoracic, vascular, and abdominal surgeries [3]. Physical examination A careful cardiovascular examination should include measurement of blood pressure in both arms, carotid pulse contour and assessment for bruits, jugular venous pressure and pulsations, auscultation of the lungs, precordial palpation and auscultation, abdominal palpation, and examination of the extremities for edema and vascular integrity [4]. Physical ﬁndings are particularly important in assessing patients with a history of CHF or valvular disease. Of note, pulmonary crackles may be absent in patients with chronic CHF. An elevated jugular venous pressure or a positive hepatojugular reﬂux are more reliable signs of hypervolemia in these patients [5]. Careful cardiac auscultation may yield a murmur, and the clinician must determine its signiﬁcance. Signiﬁcant aortic stenosis may be of greatest signiﬁcance, as its presence has been associated with an increased risk of cardiac complications in noncardiac surgery [6]. Aortic regurgitation or mitral regurgitation may place the patient at increased risk of endocarditis should postoperative bacteremia occur, and therefore endocarditis prophylaxis may be indicated. Laboratory data Blood chemistries and counts for the assessment of renal and hepatic function and to evaluate for the presence of hematologic abnormalities are indicated in patients at risk for, or with a history of, nonischemic heart disease. Patients with renal and/or hepatic insuﬃciency will require adjusted medication dosing to reduce the risk of medication-related toxicity. Inadequate electrolyte homeostasis, especially with regard to potassium levels, has been associated with an increased incidence of cardiac complications in both cardiac (increased risk of perioperative arrhythmia and need for

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cardiopulmonary resuscitation [CPR] with preoperative serum potassium below 3.5 mmol/L [53] and noncardiac surgery [6]). Electrocardiography The ECG can provide evidence of conduction disturbances or arrhythmias that may aﬀect perioperative outcome, in addition to providing evidence of prior ischemic heart disease (eg, presence of Q waves). Expert panels consider the ECG to be part of a basic clinical evaluation [4], and it is necessary for assessing perioperative cardiac risk by multiple risk indices [6–8]. Echocardiography Though resting transthoracic echocardiography has not been found to be an eﬀective screening tool to predict perioperative cardiac ischemic events [9], it is a valuable tool for assessing the presence and signiﬁcance of valvular disease. The clinician’s threshold for ordering preoperative echocardiography to assess a cardiac murmur will likely depend on his or her conﬁdence in ruling in or out signiﬁcant valvular disease by auscultation alone. Poor left ventricular function may predict postoperative heart failure [4]. Therefore, by gathering history, physical examination, laboratory, and electrocardiographic data, the clinician identiﬁes the patient’s cardiac disease processes and/or risks for adverse cardiac outcome that will require further evaluation and management.

Hypertension Prevalence and risk factors Perioperative hypertension is a common occurrence, given that approximately 25% of all U.S. adults [10] and over 50% of individuals older than 65 years [11] have hypertension. Perioperative hypertension or hypotension occurs in about 25% of hypertensive patients undergoing surgery [12]. Controversies surrounding management of perioperative hypertension include: whether or not hypertension is a risk factor for postoperative complications; at what level of blood pressure there is risk; and whether surgery should be postponed to achieve better blood pressure control [13]. Two preoperative predictors of perioperative hypertensive events include preoperative stage 3 hypertension (diastolic BP > 110 mm Hg or systolic BP > 180) [4,12, 14,15] and surgery type (abdominal aortic aneurysm resection and peripheral vascular surgeries) [12]. The severity of the blood pressure elevation, duration of control, use of antihypertensive medications, presence of end

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organ damage, or unusual etiology (eg, pheochromocytoma) may also inﬂuence risk of developing perioperative hypertension or hypotension. Of note, mild to moderate hypertension has not been found to be an independent predictor of major postoperative cardiac complications [6]. But patients with a systolic blood pressure of >140 mm Hg or diastolic blood pressure of >90 mm Hg at the time of hospital admission who were subsequently normotensive during hospitalization were at risk for a signiﬁcant hypertensive response during endotracheal intubation [16]. Perioperative hypertension can occur during and after surgery, often in situations causing increased sympathetic stimulation that lead to adrenergic-mediated vasoconstriction. Intraoperative etiologies include laryngoscopy and intubation, inadequate (‘‘too light’’) anesthesia, surgical incision and manipulation, ﬂuid overload (iatrogenic), ventilatory inadequacy, or use of vasopressors. Postoperatively, extubation, emergence and arousal from anesthesia, pain, hypothermia with shivering, hypoxia or hypercarbia, or intravascular volume overload can precipitate a hypertensive response, as can withdrawal from standing preoperative antihypertensive medications, especially beta blockers and clonidine. Other etiologies potentially responsible for postoperative hypertension developing 24–48 hours after surgery include the failure to restart the patient’s usual preoperative antihypertensive medication, decreasing eﬀect or dose of analgesics and sedatives, and mobilization of ﬂuids from the extravascular space. Treatment Investigators have conﬁrmed the value of eﬀective preoperative blood pressure control among patients with established hypertension [12,17], and experts therefore recommend that antihypertensive medications be continued during the perioperative period [4]. It is important to avoid withdrawal of beta blockers and clonidine because of a potential rebound increase in heart rate and blood pressure. Of note, the blood pressure-lowering eﬀect of anesthetic induction is increased in patients chronically treated with angiotensin converting-enzyme (ACE) inhibitors and in patients given angiotensin II (AII) receptor antagonists [18]. These patients may require vasopressin-system agonists if the hypotension does not respond to sympathomimetic agents. There are no expert consensus guidelines to hold the dose of ACE inhibitors, AII receptor antagonists, or diuretics on the morning of surgery, although some practitioners might do so. Clinicians should remember, however, the potential beneﬁts of continuing ACE inhibitor and AII receptor antagonist therapy in maintaining control of hypertension and/ or preventing exacerbation of congestive heart failure. Oral agents may need to be changed to parenteral or transdermal routes perioperatively until the resumption of oral intake. Additional information about speciﬁc antihypertensive medications can be found in the chapter on perioperative medication management.

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Initial treatment of postoperative hypertension should focus on reversing precipitating factors, such as pain, hypervolemia, hypoxia, hypercarbia, and hypothermia. If this fails or the patient has signiﬁcant cardiovascular disease or has undergone neurosurgery, antihypertensive therapy may be instituted. True hypertensive emergencies are uncommon after noncardiac surgery and are deﬁned as situations requiring immediate blood pressure reduction (although not necessarily to normal) to limit or prevent target- organ damage. These situations will usually require treatment with a parenteral antihypertensive agent, as would be done in the nonsurgical setting.

Congestive heart failure Epidemiology, diagnosis, and etiology Congestive heart failure (CHF) is increasing in prevalence in the U.S. population, aﬀecting 6–10% of individuals older than age 65 [19]. The presence of CHF by history [20], physical signs (including a third heart sound or jugular venous distension [6] or including crackles on lung exam) [7], or a diagnosis of alveolar pulmonary edema by chest radiography [7] has been associated with an increased risk of perioperative cardiovascular complications. It is important to determine the etiology of CHF to direct treatment properly. Most processes result in left ventricular systolic dysfunction (70%) versus those causing diastolic dysfunction (30%). CHF may be caused by myocardial dysfunction related to ischemia, infarction, hypertension, valvular and pericardial disease, and cardiomyopathy. Arrhythmias, either tachycardic or bradycardic, may also precipitate perioperative CHF. Noncardiac causes of perioperative CHF that increase demand for cardiac output include anemia, fever, and hypoxia. The risk for postoperative CHF appears to be greatest immediately after surgery and then for 24–48 hours afterward. Initial postoperative risk may be caused by intraoperative ﬂuctuations in blood pressure, myocardial ischemia, ﬂuid administration, sympathetic stimulation, cessation of positive-pressure ventilation, and hypoxia. Subsequent risk may relate to reabsorption of interstitial ﬂuid, myocardial ischemia, and potentially from eﬀects of withdrawal from long-term preoperative oral CHF medications in patients whose medications have been held. Treatment Patients with active signs or symptoms of CHF preoperatively should have their medical therapy optimized, eg, through diuresis and afterload reduction. Studies have assigned a higher risk of perioperative cardiac complications in patients with pulmonary edema within 1 week of surgery [7], so it is recommended that elective surgery be postponed for at least 1 week after a patient’s CHF has been stabilized [21].

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Perioperative right heart catheterization Relatively few controlled studies have evaluated pulmonary artery catheterization (PAC) in relation to clinical outcomes. A recent randomized trial of PAC placement in elective vascular surgery patients showed no diﬀerence in complication rate, overall length of stay, or in surgical intensive care unit length of stay [22]. A case-control analysis of a subset of 215 matched pairs of patients who did and did not undergo right heart catheterization (RHC), adjusted for propensity of RHC and type of procedure, showed that patients who underwent RHC had an increased risk of postoperative CHF (odds ratio [OR] 2.9; 95% conﬁdence interval [CI] 1.4–6.2) and of major noncardiac events (OR 2.2; 95% CI 1.4–4.9) [52]. But a recent randomized multicenter controlled trial of PAC use in 1994 patients age 60 or more who were classiﬁed as American Society of Anesthesiologists (ASA) class 3 or 4, and who underwent urgent or elective major surgery (abdominal, thoracic, major vascular, or orthopedic), showed no statistically signiﬁcant diﬀerence in in-hospital mortality between the control (7.7%) and PAC (7.8%) groups (Chi-square P ¼ 0.918) [24]. The ASA has published guidelines on PAC insertion that focus on the inter-relationship between 3 variables: patient disease (clinical evidence of signiﬁcant cardiovascular disease that would include recent CHF, signiﬁcant left ventricular dysfunction, critical aortic stenosis, unstable angina, recent myocardial infarction (MI) or myocardial ischemia, pulmonary dysfunction, hypoxia, renal insuﬃciency, or other conditions associated with hemodynamic instability), surgical procedure (procedures associated with an increased risk of complications from hemodynamic changes, including damage to the heart, kidneys, lungs, or brain, such as those associated with signiﬁcant intraoperative and postoperative intravascular ﬂuid shifts, substantial changes in preload or afterload, and signiﬁcant risk of perioperative myocardial ischemia), and practice setting (the physician must be skilled in the insertion of the PAC and educated in the interpretation of PAC data, and there must be adequate technical support provided by nursing staﬀ and ancillary services) [25]. The American College of Cardiology/American Heart Association guidelines provide recommendations with a similar focus on appropriate patient- and surgery-speciﬁc risks [4]. In summary, we concur with the expert panels that PAC use should be determined on an individual patient basis according to unique hemodynamic risks presented by the patient’s underlying disease processes and the nature of the proposed procedure. Cardiomyopathy It is most important to determine the etiology of the cardiomyopathy before noncardiac surgery, as the disease process may be more likely to cause systolic or diastolic dysfunction. Hypertrophic obstructive cardiomyopathy (HOCM) presents particular challenges to patient management. Reduction of blood volume, decreased systemic vascular resistance, and

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increased venous capacitance may cause a reduction in left ventricular volume and thereby potentially increase a tendency to outﬂow obstruction [4]. Conversely, patients may be at increased risk of diastolic dysfunction from decreased compliance of the hypertrophied ventricle, and aggressive perioperative ﬂuid administration may lead to increased left ventricular end diastolic pressure and increased pulmonary capillary pressure, causing alveolar pulmonary edema. Two small retrospective studies have assessed the incidence of adverse cardiac events in patients with HOCM undergoing noncardiac surgery. Thompson et al [26] reviewed 35 patients with asymmetric septal hypertrophy (ASH) who underwent general surgical procedures (speciﬁc information on surgery type was not provided). There were no perioperative cardiac deaths, and the one patient who sustained an MI and developed CHF had preoperative two-vessel coronary disease. The most common complications were atrial dysrhythmias requiring treatment (14%) and hypotension requiring vasoconstrictors (13%). A subsequent retrospective study of an echocardiographic database identiﬁed 77 patients with ASH on echocardiography within 24 months of surgery. Thirty-ﬁve patients underwent intra-abdominal or intrathoracic surgery (designated major surgery), and 42 patients underwent minor surgeries. Important predictors of adverse outcome were: type of surgery (major versus minor, P < 0.05), longer duration of surgery (P < 0.01), and increased intensity of hemodynamic monitoring (no monitoring versus intra-arterial versus right atrial versus pulmonary artery catheter, P < 0.05). Neither echocardiographic features–including magnitude of resting left ventricular outﬂow tract gradient and left ventricular dysfunction–nor history of prior MI were associated with adverse cardiac events. There were no perioperative deaths and one patient suﬀered a MI and ventricular tachycardia requiring emergent cardioversion. Twenty-ﬁve percent of patients experienced stable dysrhythmia (ie, not requiring urgent cardioversion), sixteen percent had CHF, fourteen percent had transient hypotension, and twelve percent developed myocardial ischemia [27]. In summary, common adverse events for patients with hypertrophic obstructive cardiomyopathy include perioperative CHF, myocardial ischemia, stable dysrhythmias, and transient hypotension, and appear to be associated with intra-abdominal or intrathoracic surgery and longer duration of surgery. The incidence of death and/or myocardial infarction is quite low, however.

Arrhythmias and conduction disorders Epidemiology and clinical signiﬁcance Cardiac arrhythmias are common in the perioperative period, and most are benign. Early studies noted that transient perioperative arrhythmias occurred in 60–80% of patients, most of which were caused by transient

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bradyarrhythmias and premature atrial and ventricular depolarizations. The risk indices developed by Goldman and Detsky both included supraventricular and ventricular arrhythmias as clinical risk predictors for postoperative cardiac complications. Newer guidelines do not consider hemodynamically insigniﬁcant arrhythmias to be signiﬁcant risk factors as more recent studies found that asymptomatic ventricular arrhythmias were not associated with an increase in postoperative cardiac complications; however, their presence in the perioperative period may unmask underlying cardiopulmonary disease and should provoke a search for myocardial ischemia, drug toxicity, or metabolic derangements [4]. Hypercapnea, hypoxia, hypokalemia, acidosis, and anemia increase arrhythmogenic potential, especially when they develop in association with general anesthesia [28]. A recent study of 4181 patients 50 years or older who had major nonemergent noncardiac procedures and were in sinus rhythm preoperatively found that 317 patients (7.6%) developed supraventricular arrhythmia (SVA). Atrial ﬁbrillation (4.1%) and supraventricular tachycardia (3.7%) without discernible P waves were the most common types of SVA. Multiple regression analysis identiﬁed several independent correlates of SVA, most notably surgery type [intrathoracic surgery (OR 9.2) and abdominal aortic aneurysm repair (OR 3.9)], history of supraventricular arrhythmia (OR 3.4), signiﬁcant valvular disease on physical examination (murmur grade 3, OR 2.1), history of asthma (OR 2.0), premature atrial complexes on the preoperative ECG (OR 2.1), and ASA Class 3 or 4 (OR 1.4) [23]. Patients with perioperative acute major cardiac and noncardiac (including bacterial pneumonia, bacteremia, pulmonary embolism, gastrointestinal bleeding, and cerebrovascular accident) events had an increased risk of perioperative SVA, and SVA was associated with a 33% increase in length of stay after adjustment for other clinical data (P < 0.001). A recent 2-year retrospective review of 13, 696 noncardiac, nonthoracic surgeries at one hospital identiﬁed 51 (0.37%) patients who developed atrial ﬁbrillation within 30 days of surgery. Median age was 74 years, 59% of cases occurred in abdominal and vascular surgeries, and atrial ﬁbrillation most commonly occurred on postoperative day 1. Two thirds of these patients had at least one of the following risk factors: hypertension, prior atrial ﬁbrillation not present at the time of surgery, valvular heart disease, or myocardial infarction. Other common predisposing factors were positive ﬂuid balance, hypokalemia, hypomagnesemia, and hypoxemia. Six patients (12%) remained in atrial ﬁbrillation upon hospital discharge, thirty-six (71%) were discharged on new antiarrhythmic medications, and six patients (12%) died [29]. Therefore both of the above studies note that perioperative atrial ﬁbrillation is associated with a signiﬁcant impact on morbidity and length of stay. Though complex ventricular ectopy is common during and after surgery, serious symptomatic or sustained ventricular arrhythmias are rare. Kuner et al. noted that 95 out of 154 patients undergoing surgery had 195 episodes of cardiac arrhythmia, but only 5 patients had ventricular tachycardia [30]. Patients at risk of

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developing signiﬁcant perioperative ventricular arrhythmias usually have structural heart disease with depressed ventricular function [28]. Common causes of acute ventricular arrhythmias in the perioperative period include acute myocardial ischemia, hypoxemia, hypokalemia, hypomagnesemia, and central venous catheters [31]. Management The presence of an arrhythmia in the perioperative setting should lead the clinician to evaluate the patient carefully for underlying cardiopulmonary disease, ongoing myocardial ischemia, drug toxicity, or metabolic derangements [4]. In atrial ﬁbrillation, the patient’s hemodynamic stability and the presence of myocardial ischemia or congestive heart failure dictate whether the initial goal of therapy should be to restore sinus rhythm with direct current (DC) cardioversion, or to control the ventricular response rate if the arrhythmia is well tolerated [31]. Acute rate control of atrial ﬁbrillation may best be achieved by intravenous infusion of diltiazem, with esmolol and verapamil available as alternative intravenous agents. Beta blockers, however, are the most eﬀective agent for controlling the ventricular response during atrial ﬁbrillation [32], and they have been shown to accelerate the conversion of postoperative supraventricular arrhythmias to sinus rhythm as compared with diltiazem [33]. Digoxin’s slow rate of onset limits its eﬀectiveness for acute rate control, but it is still the drug of ﬁrst choice for ventricular rate control in patients with decompensated heart failure because of its positive inotropic eﬀect. It may best be used in addition to a beta blocker or calcium channel blocker [31]. Amiodarone has been proven to be eﬀective in preventing postoperative atrial ﬁbrillation in cardiac surgery (as have beta blockers) [34], and may be a more eﬀective prophylactic agent in patients with prior atrial ﬁbrillation. In addition, amiodarone is likely the most eﬀective drug for maintaining sinus rhythm after cardioversion from atrial ﬁbrillation [31]. In summary, the ACC/AHA recommends that physicians have a low threshold at which they institute prophylactic beta blocker therapy in patients at increased risk of developing a perioperative or postoperative arrhythmia (including those in whom arrhythmias are present during the preoperative evaluation) [4]. Two recent studies have demonstrated that beta blocker therapy can reduce the incidence of postoperative arrhythmias [35,36] in patients undergoing thoracic surgery (ie, a high-risk population). As mentioned above, hemodynamically signiﬁcant ventricular arrhythmias occur rarely. Neither asymptomatic ventricular premature contractions nor asymptomatic hemodynamically insigniﬁcant nonsustained ventricular tachycardia (VT) require medical therapy in the perioperative period [31], although serum potassium, magnesium, and calcium levels must be monitored and carefully managed. Patients with nonsustained VT require a prompt evaluation for the presence of structural heart disease, for if the patient has evidence of prior myocardial infarction or of depressed left

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ventricular systolic function, an electrophysiologic study must be considered [31,37]. Sustained ventricular tachycardia or ventricular ﬁbrillation (VF) in the perioperative period should be treated according to Advanced Cardiovascular Life Support (ACLS) protocol [38,39]. These guidelines allow the use of biphasic deﬁbrillators, vasopressin in place of epinephrine, and amiodarone. After the patient is stabilized, a thorough evaluation for reversible causes is undertaken, and the patient must be evaluated for the presence of underlying structural heart disease [31]. If no precipitating causes are found, the patient should undergo electrophysiologic study and may require implantable cardioverter-deﬁbrillator (ICD) placement, as the AVID study found that 3-year survival with ICD placement was superior to antiarrhythmic drugs in patients who had been resuscitated from near-fatal VF or who had undergone cardioversion from sustained VT [51]. Bradyarrhythmias and conduction disorders Patients with sinus bradycardia do not necessarily have sinus node dysfunction. Asymptomatic patients with persistent marked sinus bradycardia not readily explained by alterations in autonomic tone should, however, be evaluated further by assessing their response to atropine (0.02 mg/kg) or to exercise. Increase in heart rate to 90 or greater suggests that sinus node function is normal and that heart rate will increase appropriately during surgery. Atropine should be avoided in patients with angina at rest or with minimal exercise, glaucoma, or with symptoms consistent with bladder outlet obstruction [28]. Several studies, both from the 1970s and the 1990s, have shown that patients with bifascicular block [40] or left bundle branch block (BBB) with a prolonged PR interval [41] have an extremely low risk of developing complete heart block in the perioperative period, and, therefore, do not merit prophylactic preoperative temporary pacemaker insertion. Severe bradycardia with or without hemodynamic compromise requiring medical therapy has, however, been found to occur in about 8 percent of these patients [41]. Transthoracic pacing units should be readily available, especially in patients with pre-existing left BBB who require perioperative pulmonary artery catheterization (PAC), as complete heart block may develop in up to 8.5% of these patients receiving PAC [25]. Implanted pacemakers and ICDs Guidelines for implantation of cardiac pacemakers and antiarrhythmia devices have been recently published [42], and the indications in the perioperative setting are usually similar to those in the nonoperative setting. The main perioperative management issues with these devices have related to the potential for electrical magnetic interference with an implanted device from electrocautery or cardioversion. The electrical current generated by

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electrocautery or cardioversion can cause a variety of temporary or permanent responses by the implanted device, including: (1) resetting to a back-up, reset, or noise-reversion pacing mode; (2) inhibition of pacemaker output; (3) increase in pacing rate caused by activation of the rate-responsive sensor; (4) ICD ﬁring caused by activation by electrical noise; or (5) myocardial injury at the lead tip that may cause failure to sense and/or capture [4]. The probability for adverse interaction has been reduced by the almost-universal use of bipolar electrocautery leads (which reduces the probability of electrical-magnetic interference), and improved pacemaker and ICD design [43]. Though no formal guidelines for the perioperative management of pacemakers and ICDs have been developed, the following general recommendations can be made: (1) pacemaker rate-responsive modes and ICDs should be programmed oﬀ during surgery; (2) current path (electrode tip to ground plate) should be arranged as far away as possible from the pulse generator; (3) pulse oximetry or peripheral pulse should be monitored to follow heart rate during electrocautery, as QRS complexes may not be seen; (4) electrocautery should not be applied directly over the pacemaker pulse generator; (5) electrocautery on or near the lead tip should be avoided because this may cause burning of the lead-tissue interface; and (6) if pacemaker inhibition is detected by the absence of pacing, a magnet may be applied over the pulse generator [31]. If there is any question regarding ICD or pacemaker function perioperatively, consultation with the cardiologist should be obtained, with a low threshold to interrogate the ICD or pacemaker before and after the surgical procedure.

Valvular heart disease Despite the decreasing incidence of rheumatic fever in developed countries, medical consultants continue to frequently encounter patients with various forms of valvular heart disease in the context of perioperative medical consultation. Lee et al [8] noted a 4% prevalence of history or physical examination showing signiﬁcant valvular heart disease in 4315 patients undergoing elective major noncardiac procedures in a tertiary-care teaching hospital. Careful cardiac auscultation is therefore an essential element of the preoperative assessment, as this maneuver often identiﬁes valvular abnormalities that necessitate speciﬁc precautions and perioperative interventions. In the context of perioperative medical assessment, the most important considerations relating to valvular disease are (1) whether severe aortic stenosis is present; (2) whether the identiﬁed valvular problem is associated with cardiac dysfunction and congestive heart failure; and (3) whether the combination of valve lesion and type of surgery dictate a need for endocarditis prophylaxis. Severe aortic stenosis (AS) has consistently been identiﬁed to be a risk factor for adverse outcome after noncardiac surgery. AS was the most

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heavily-weighted prognostic factor for predicting the occurrence of adverse cardiac events in the Detsky cardiac risk index [7]. In the study by Goldman et al [6], the proportion of patients with AS experiencing adverse cardiac events was 17.3%, whereas Detsky et al reported a similarly high rate of events. These early studies led many to conclude that patients with severe AS should generally not undergo elective noncardiac surgery, and experts recommend that patients with severe and symptomatic AS undergo aortic valve replacement prior to elective yet necessary noncardiac surgery [4]. This recommendation causes diﬃculties, however, when the noncardiac surgical procedure is relatively urgent, or when patients are not candidates for (or refuse) aortic valve replacement. Fortunately, Raymer and Yang [44] and Torsher et al [45] have more recently demonstrated that patients with even severe aortic stenosis can undergo noncardiac surgery with adverse event rates that approach those of patients without aortic stenosis (9% major complication rate similar to controls in the Raymer study, and 7% mortality rate in the Torsher study that included emergency surgeries and a patient cohort with more severe aortic stenosis), provided that the care providers— and especially the anesthesiologist—are aware of the presence of aortic stenosis. With advance knowledge, the anesthesiologist can carefully select anesthetic agents and vasopressor agents, and can use invasive arterial blood pressure monitoring to closely follow intraoperative blood pressures. The key thus is advance knowledge of the presence of severe aortic stenosis, generally achieved through a combination of careful clinical examination for signs of severe stenosis (slow rate of rise of the carotid pulse, mid-tolate peak intensity of the murmur, decreased intensity of the second heart sound, and maximal murmur intensity at the second right intercostal space) [46,47] and judicious use of echocardiography when clinical examination is indeterminate. Mitral stenosis, mitral regurgitation, and aortic regurgitation can similarly be detected through careful auscultation with or without supporting echocardiography. Once these valvular conditions are detected, it is then important to assess whether the valvular disease is associated with clinical evidence of congestive heart failure and ventricular dysfunction. More severe forms of these valvular conditions can be managed as necessary to optimize cardiac function and reduce the risk for perioperative congestive heart failure. Speciﬁc management considerations include: (1) avoidance of tachycardia in mitral stenosis to maintain an adequate diastolic ﬁlling time; (2) judicious use of afterload reducing agents in both aortic regurgitation and mitral regurgitation to optimize cardiac function without causing excessive hypotension; and (3) avoidance of excessive intravenous ﬂuid administration in all valvular conditions to limit risk of volume overload and associated congestive heart failure. For all forms of valvular heart disease, an assessment should be made regarding indications for antibiotic prophylaxis for prevention of endocarditis, as per the American Heart Association guidelines published in 1997 [48].

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Brieﬂy, these guidelines dictate that the need for prophylaxis relates to both the cardiac abnormality and the type of surgical procedure. Endocarditis prophylaxis is discussed in the chapter on antibiotic prophylaxis of the surgical patient. An important caveat to these guidelines is that most cases of endocarditis are not attributable to an invasive procedure, and that there are no published randomized trials demonstrating that prophylaxis lowers the risk of developing endocarditis [48]. Nevertheless, the recommendations made in the American Heart Association guidelines are widely accepted as reasonable suggestions based on both sound observational data and expert opinion. Perioperative management of anticoagulation in patients with valvular heart disease, and speciﬁcally with a mechanical prosthetic valve, depends of the invasive nature of the procedure and on the risk of thromboembolism without anticoagulation. Experts recommend that patients undergoing minimally invasive procedures (eg, dental work, superﬁcial biopsies) should have their international normalized ratio (INR) brieﬂy reduced to the low or subtherapeutic range and resume their normal dose of oral anticoagulation immediately after the procedure [4]. Perioperative heparin therapy is recommended for patients in whom the risk of bleeding with oral anticoagulation is high, and/or the risk of thromboembolism without anticoagulation is also high (mechanical valve in the mitral position, Bjork-Shiley valve, recent [<1 year] thrombosis or embolus, or 3 or more of the following risk factors: atrial ﬁbrillation, previous embolus at any time, hypercoagulable condition, mechanical prosthesis and left ventricular ejection fraction [LVEF] <30%) [49]. More recent consensus guidelines have been published that reach similar conclusions [50]. Additional discussion on anticoagulation can be found in the articles on perioperative medication and in deep veinous thrombosis (DVT) prophylaxis and anticoagulation.

Summary We have reviewed important issues relating to hypertension, congestive heart failure, arrhythmias and conduction defects, and valvular heart disease in caring for the patient with nonischemic heart disease in the perioperative period. Careful assessment by history and physical examination along with targeted testing will allow the clinician to identify potential complications, provide guided medical therapy, and better utilize other resources to reduce perioperative risk. References [1] Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative care. JAMA 2001;286:208–16. [2] Reilly DF, McNeely MJ, Doerner D, et al. Self-reported exercise tolerance and the risk of serious perioperative complications. Arch Intern Med 1999;159:2185–92.

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[3] Girish M, Trayner E, Dammann O, et al. Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest 2001;120: 1147–51. [4] Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: 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). American College of Cardiology Web site. 2002 Available: www.acc.org/clinical/ guidelines/perio/update/periupdate_index.htm. Accessed November 15, 2002. [5] Butman SM, Ewy GA, Standen JR, et al. Bedside cardiovascular examination in patients with severe chronic heart failure: importance of rest or inducible jugular venous distension. J Am Coll Cardiol 1993;22:968–74. [6] Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977;297:845–50. [7] Detsky AS, Abrams HB, McLaughlin JR, et al. Predicting cardiac complications in patients undergoing non-cardiac surgery. J Gen Intern Med 1986;1:211–9. [8] 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. [9] Halm EA, Browner WS, Tubau JF, et al. Echocardiography for assessing cardiac risk in patients having noncardiac surgery. Ann Intern Med 1996;125:433–41. [10] Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the U.S. adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 1995;25:305–13. [11] American Heart Association. Heart and stroke statistical update. Available at: http:// www.americanheart.org/downloadable/heart/10148328094661013190990123HS_State_02.pdf. Accessed November 15, 2002. [12] Goldman L, Caldera DL. Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979;50:285–92. [13] Fleisher L. Preoperative evaluation of the patient with hypertension. JAMA 2002;287: 2043–6. [14] Prys-Roberts C. Isolated systolic hypertension: pressure on the anesthesiologist? Anaesthesia 2001;56:505–10. [15] Prys-Roberts C, Meloche R, Foex P. Studies of anaesthesia in relation to hypertension: cardiovascular responses to treated and untreated patients. Br J Anaesth 1971;43: 122–37. [16] Bedford RF, Feinstein B. Hospital admission blood pressure: a predictor for hypertension following endotracheal intubation. Anesth Analg 1980;59:367–70. [17] Stone JG, Foex P, Sear JW, et al. Risk of myocardial ischemia during anaesthesia in treated and untreated hypertensive patients. Br J Anaesth 1998;61:675–9. [18] Brabant SM, Bertrand M, Eyraud D, et al. The hemodynamic eﬀects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists. Anesth Analg 1999;88:1388–92. [19] Ho K, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 1993;22:6A–13A. [20] Rao TL, Jacobs KH, El-Etr AA. Reinfarction following anesthesia in patients with myocardial infarction. Anesthesiology 1983;59:499–505. [21] Weitz HH. Perioperative cardiac complications. Med Clin North Am 2001;85:1151–69. [22] Bender JS, Smith-Meek MA, Jones CA. Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery. Ann Surg 1997;226:229–37. [23] Polanczyk CA, Goldman L, Marcantonio ER, et al. Supraventricular arrhythmia in patients having noncardiac surgery: clinical correlates and eﬀect on length of stay. Ann Intern Med 1998;129:279–85.

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Med Clin N Am 87 (2003) 153–173

Preoperative evaluation for postoperative pulmonary complications Ahsan M. Arozullah, MD, MPHa,b,*, Michelle V. Conde, MDc, Valerie A. Lawrence, MD, MScc a

Veterans Aﬀairs Chicago Healthcare System, Westside Division, Chicago, IL, USA b Section of General Internal Medicine, University of Illinois College of Medicine, Chicago, IL, USA c Audie Murphy Division, South Texas Veterans Health Care System and Section of General Internal Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Postoperative pulmonary complications are associated with substantial mortality and morbidity. Nearly one fourth of deaths occurring within 6 days postoperatively are related to postoperative pulmonary complications [1]. Estimates of the incidence and prevalence of these complications vary greatly, however, depending on the patient population, type of surgery, and deﬁnition of complication. For example, complication rates are higher in patients with severe obstructive lung disease undergoing major abdominal surgery (up to 56%) [2,3] and are also increased with aortic aneurysm repair [4–8], upper abdominal [4,5,9–11], thoracic [2,4,5,12], and neck surgery [4,5,13]. Studies classify atelectasis [9,12,14], pneumonia [1,5,14,33], respiratory failure [4,6,13,14], acute respiratory distress syndrome [11,13], and pleural eﬀusion [14,15] as postoperative pulmonary complications. Although the clinical implications and risk factors of each complication vary, many studies combine distinct complications into an overall pulmonary complication rate [9,12–14]. Preoperative evaluation for pulmonary embolus and hypoxemia risk is not directly addressed in this article.

* Corresponding author. Section of General Internal Medicine (M/C 718), University of Illinois College of Medicine, 840 South Wood Street, Suite 440-M, Chicago, IL 60612-7323. E-mail address: [email protected] (A.M. Arozullah). Grant support: Dr. Arozullah is a Research Associate in the Career Development Award Program of the Veterans Aﬀairs Health Services Research and Development Service. 0025-7125/03/$ - see front matter Published by Elsevier Science (USA). PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 1 - 7

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A preoperative medical evaluation enables clinicians to accomplish two distinct yet related goals: (1) to predict the risk of postoperative complications, and (2) to reduce the risk of complications. The ﬁrst goal is usually accomplished through risk assessment indices that predict the incidence of complications. The evidence necessary to develop and validate risk indices is obtained through observational, cohort, and case-control studies. The second goal is accomplished through preoperative and perioperative risk reduction interventions. The evidence necessary to prove that interventions reduce the incidence or severity of complications is obtained through randomized, controlled trials. Some preoperative tests assist in risk assessment but do not provide targets for risk reduction. For example, low albumin level is a signiﬁcant risk factor for postoperative respiratory failure and mortality [4,16], although improving the albumin level preoperatively does not improve complication rates [17]. Conversely, other preoperative tests may improve perioperative management but are not needed for accurate risk assessment. For example, preoperative pulmonary function test results may guide perioperative management but do not improve preoperative risk assessment [18]. The primary purpose of this article is to present strategies for preoperative risk assessment of major postoperative pulmonary complications (PPCs) for patients undergoing noncardiac surgery. A secondary purpose is to distinguish between factors that are useful for preoperative risk assessment and those that provide potential targets for reducing the risk of pulmonary complications. Literature search and identiﬁcation strategy This article is based on the results of a broad literature search that systematically identiﬁed recent evidence about preoperative risk assessment and perioperative interventions related to postoperative pulmonary complications. We queried Medline from January 1995 to March 2002 for articles indexed with any of the following terms as their primary focus: intraoperative complications, postoperative complications, preoperative care, intraoperative care, and postoperative care. Citations were limited to studies about humans published in English. The following publication types were excluded because of the focus on primary data: letter, editorial, case report, and clinical conference proceedings. Because the article is directed to general internists, studies including pediatric, cardiopulmonary surgery, and/or immunosuppressed patients (eg, organ transplantation, acquired immunodeﬁciency syndrome) were excluded. We excluded studies from developing countries because of potential diﬀerences in respiratory and intensive care technology. Three physician reviewers each evaluated one third of approximately 17,000 citation titles and abstracts to identify potentially relevant publications. These potentially relevant publications were obtained and reviewed for a ﬁnal determination of relevancy.

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Patient-related risk factors There are numerous patient-related risk factors for PPCs. As outlined in Table 1, these risk factors are related to the patient’s general health, nutritional, respiratory, neurologic, ﬂuid, and immune status. General health and nutritional status Risk factors for PPCs that are related to general health and nutritional status include increasing age [4,5], lower albumin level [4], dependent functional status [4,5], weight loss [4,5], and possibly obesity [9]. Patients greater than 60 years old are at increased risk for postoperative pneumonia and

Table 1 Risk factors for postoperative pulmonary complications General health and nutritional status Age Low albumin Functional status Obesity (?) Weight loss > 10% ASA class Goldman class Charlson Index Respiratory status COPD history Tobacco use Sputum production Pneumonia Dyspnea OSA

Incision near diaphragm Thoracic surgery Upper abdominal surgery AAA repair Other types of surgery Neck surgery Peripheral vascular surgery Neurosurgery

Anesthesia Nasogastric tube duration > 2 hours Pain control with General anesthesia parenteral narcotics versus epidural Not using analgesia neuroaxial blockade Use of long-acting neuromuscular blockade

Emergency surgery Surgery technique Open versus laparoscopic

Neurologic status Impaired sensorium CVA history Fluid status CHF history Renal failure Blood urea nitrogen Blood transfusion Immune status Chronic steroid use Alcohol use Diabetes Abbreviations: AAA, abdominal aortic aneurysm; ASA, American Society of Anesthesiologists; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; OSA, obstructive sleep apnea.

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respiratory failure (Table 2) [4,5]. Low serum albumin is associated with respiratory failure [4], as well as higher 30-day postoperative mortality and morbidity rates [11,16]. Moreover, mortality increases exponentially as albumin falls below 4.0 g/dL [16]. Dependent functional status, with respect to activities of daily living, is also associated with an increased risk of PPCs [4,5]. Patients with greater than 10% weight loss in the 6 months prior to surgery are at increased risk for respiratory failure and pneumonia [4,5]. Obese patients (body mass index greater than 27 kg/m2) undergoing abdominal surgery are at greater risk for developing atelectasis and pneumonia [9]. Among thoracic surgery patients, however, the risk of PPCs is not increased when stratiﬁed by body mass index [12]. The conﬂicting evidence about obesity as a risk factor reﬂects diﬀerences in the measurement of co-morbid conditions in prior studies [19]. Respiratory status Risk factors for PPCs related to respiratory status include chronic obstructive pulmonary disease (COPD), smoking, preoperative sputum production and pneumonia, dyspnea, and obstructive sleep apnea (Table 1). Stable patients with COPD may become unstable in the perioperative period because of the detrimental respiratory eﬀects of surgery and anesthesia [2,3]. Among noncardiac surgery patients, active smokers within 2 weeks of surgery are at increased risk for respiratory failure [4], and those who smoked within 1 year of surgery are at increased risk for pneumonia [5] (Table 2). Among abdominal surgery patients, higher pack-years of smoking are associated with increased risk of PPCs in univariate analysis but are not statistically signiﬁcant in multivariable analysis [10]. Preoperative sputum production [14] and preoperative pneumonia [4] are independent risk factors for PPCs among patients undergoing elective noncardiothoracic surgery. Dyspnea, at rest or on minimal exertion, is also associated with an increased incidence of respiratory failure [4]. Obstructive sleep apnea (OSA) is associated with an increased risk of PPCs. In OSA patients undergoing hip or knee replacement surgery, 39% of patients with OSA (versus 18% in the control group) develop a serious pulmonary or cardiac complication [20]. Common PPCs include acute hypercapnia and episodic hypoxemia, with the majority occurring within 24 hours postoperatively. Serious complications necessitating ICU transfer occur in 24% of patients with OSA versus 9% in the control group. Neurologic status Risk factors related to neurologic status associated with PPCs include impaired sensorium [4,5,9] and previous stroke [4,5]. Patients with impaired sensorium or stroke with residual deﬁcit have an odds ratio of 1.5 for

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pneumonia risk and 1.2 for respiratory failure risk (Table 2). These patients are less mobile postoperatively leading to a higher risk of atelectasis. They are also unable to protect their airway leading to higher risks of aspiration pneumonia and respiratory failure. Fluid status Risk factors for PPCs associated with ﬂuid status include congestive heart failure [4], acute renal failure [4,7,8], and blood transfusion [4,5,21]. Patients with these conditions are at increased risk for pulmonary edema and pleural eﬀusions that may lead to atelectasis, pneumonia, and even respiratory failure. High and low blood urea nitrogen levels are associated with pulmonary complications [4,5], implying that careful ﬂuid management is needed in high-risk patients. In addition, patients with primary pulmonary hypertension are particularly sensitive to volume changes and may be diﬃcult to manage once acute right heart failure occurs [22]. Immune status Chronic steroid use is associated with an increased risk of postoperative pneumonia, but not respiratory failure (Table 2). The increased risk of pneumonia may be secondary to immune suppression from the steroid medications in addition to the impact of diseases treated with steroids such as rheumatoid arthritis. Patients with alcohol use (greater than 2 drinks per day) within 2 weeks of surgery have 20% increased odds of pneumonia and respiratory failure (Table 2). Chronic alcohol use may be associated with diminished B-cell mediated immunity leading to an increased risk of pneumonia. Patients with insulin-treated diabetes mellitus are at slightly increased risk for respiratory failure, but not for pneumonia (Table 2).

Operation-related risk factors Several operation-related risk factors including surgical incision site, type of surgery, and surgical technique are associated with increased risk for PPCs (Table 1). Though these risk factors may not be modiﬁable, they are important to identify a priori for risk stratiﬁcation. Surgical incision site and type of surgery Operations with incision sites near the diaphragm, such as thoracic and upper abdominal surgeries, are associated with the highest risk for PPCs [19]. Perioperative changes in lung volumes and ventilation patterns can lead to hypoxemia and atelectasis [23,24]. Diaphragmatic dysfunction contributes to these perioperative changes, even with adequate pain relief [25,26]. Depending on the PPC deﬁnition used, PPC rates range from 10–40% for

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Table 2 Comparison of the risk factors included in The Postoperative Pneumonia and Respiratory Failure Risk Indices

Risk factors

Postoperative Pneumonia Risk Index (OR [95% CI])

Type of surgery AAA repair Thoracic Upper abdominal Neck Neurosurgery Vascular Emergency surgery General anesthesia

4.29 3.92 2.68 2.30 2.14 1.29 1.33 1.56

Age 80 years 70–79 years 60–69 years 50–59 years 50 years 70 years 60–69 years 60 years

5.63 3.58 2.38 1.49 1.00 — — —

Point value

Respiratory Failure Risk Index (OR [95% CI])

Point value

(3.34–5.50) (3.36–4.57) (2.38–3.03) (1.73–3.05) (1.66–2.75) (1.10–1.52) (1.16–1.54) (1.36–1.80)

15 14 10 8 8 3 3 4

14.3 8.14 4.21 3.10 4.21 4.21 3.12 1.91

(12.0–16.9) (7.17–9.25) (3.80–4.67) (2.40–4.01) (3.80–4.67) (3.80–4.67) (2.83–3.43) (1.64–2.21)

27 21 14 11 14 14 11 —

(4.62–6.84) (2.97–4.33) (1.98–2.87) (1.23–1.81) (referent)

17 13 9 4 — — — —

— — — — — 1.91 (1.71–2.13) 1.51 (1.36–1.69) 1.00 (referent)

— — — — — 6 4 —

Functional status Totally dependent Partially dependent Independent

2.83 (2.33–3.43) 1.83 (1.63–2.06) 1.00 (referent)

10 6 —

1.92 (1.74–2.11) 1.92 (1.74–2.11) 1.00 (referent)

7 7 —

Albumin < 3.0 g/dL > 3.0 g/dL

— —

— —

2.53 (2.28–2.80) 1.00 (referent)

9 —

1.92 (1.68–2.18) 1.33 (1.12–1.58)

7 3

1.37 (1.19–1.57)a —

— —

1.24 (1.08–1.42) — 1.72 (1.55–1.91)

2 — 5

1.19 (1.07–1.33)a 1.15 (1.00–1.33)a 1.81 (1.66–1.98)

— — 6

1.28 (1.17–1.42) —

3 —

— 1.24 (1.14–1.36)a

— —

—

—

1.70 (1.35–2.13)a

—

— — —

— — —

1.69 (1.36–2.09)a 1.21 (1.09–1.34)a 1.00 (referent)

— — —

Weight loss > 10% (within 6 months) Chronic steroid use Alcohol > 2 drinks/day (within 2 weeks) Diabetes—insulin treated History of COPD Current smoker Within 1 year Within 2 weeks Preoperative pneumonia Dyspnea At rest On minimal exertion No dyspnea

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Table 2 (continued )

Risk factors

Postoperative Pneumonia Risk Index (OR [95% CI])

Impaired sensorium History of CVA History of CHF Blood urea nitrogen < 8 mg/dL 8–21 mg/dL 22–30 mg/dL > 30 mg/dL Preoperative renal failure Preoperative transfusion (> 4 units)

Point value

Respiratory Failure Risk Index (OR [95% CI])

Point value

1.51 (1.26–1.82) 1.47 (1.28–1.68) —

4 4 —

1.22 (1.04–1.43)a 1.20 (1.05–1.38)a 1.25 (1.07–1.47)a

— — —

1.47 1.00 1.24 1.41

(1.26–1.72) (referent) (1.11–1.39) (1.22–1.64)

4 — 2 3

1.00 1.00 1.00 2.29

— — — 8

— 1.35 (1.07–1.72)

— 3

1.67 (1.23–2.27)a 1.56 (1.28–1.91)a

(referent) (referent) (referent) (2.04–2.56)

— —

Adapted from Arozullah AM, et al. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Annals of Internal Medicine 2001;135:847–57, and from Arozullah AM, et al. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Annals of Surgery 2000;232(2):242–53; with permission. a Risk factor was statistically signiﬁcant in multivariable analysis but was not included in the Respiratory Failure Risk Index.

thoracic surgery and 13–33% for upper abdominal surgery, compared with 0–16% for lower abdominal surgery [19]. Two validated multifactorial risk indices from the largest surgical cohort to date reinforce the importance of the incision location and type of surgery (Table 2). Type of surgery is the strongest predictor of PPCs in both The Postoperative Respiratory Failure Risk Index and The Postoperative Pneumonia Risk Index (Table 2) [4,5]. In these indices, abdominal aortic aneurysm repair, thoracic surgery, and upper abdominal surgery carry the highest risk, conﬁrming results from previous smaller studies. In addition, neck, peripheral vascular, neurosurgery, and emergency surgery are independently associated with increased PPC risk. Neurosurgery and neck surgery may be associated with increased risk for perioperative aspiration pneumonia. Surgical technique Modifying the surgical approach or extent of surgery may reduce operative time and incision-related risk in high-risk patients. In addition, randomized trials indicate that some laparoscopic procedures, despite longer anesthesia time, have lower PPC risk compared with open procedures. The PPC rate for patients undergoing laparoscopic cholecystectomy is 2.7% versus 17.2% for those undergoing open cholecystectomy [27]. In a randomized

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trial of laparoscopic versus open fundoplication, laparoscopic fundoplication is associated with signiﬁcantly better FEV1 and FVC, shorter hospital stay, and decreased need for analgesics [28]. In two small cohort studies of open versus laparoscopic colectomy, however, there is no diﬀerence in pneumonia rates, but there is shorter hospital stay in the laparoscopic group [29,30].

Anesthesia-related risk factors Though internists usually restrict recommendations to their area of expertise, knowledge of anesthesia-related risk factors can optimize patient care through improved communication between the medical, surgical, and anesthesia teams. General and spinal anesthesia are associated with reduction in vital capacity and functional residual capacity. Perioperative impairment of mucociliary clearance mechanisms can also increase the risk of postoperative infection [1]. The immediate postoperative period may be associated with hypoventilation from residual anesthetic eﬀect and deep breathing impairment secondary to incision pain. These routine anesthesia-related changes do not typically result in clinical complications. Nevertheless, duration, route of administration, and type of anesthesia are risk factors for PPCs. Duration of anesthesia is a well-established risk factor for PPCs [15], with studies showing an increasing incidence of PPCs with longer anesthesia especially greater than 2–6 hours [3,6,14,31–34]. Route and type of anesthesia administration There is debate about the eﬃcacy of regional (epidural or spinal) anesthesia versus general anesthesia in reducing PPCs. In a large observational study of over 9,000 elderly patients with hip fracture, 30-day mortality and pneumonia rates are similar between regional and general anesthesia groups [35]. Conversely, a meta-analysis of 16 hip fracture surgery trials found that regional anesthesia, compared with general anesthesia, is associated with decreased mortality at 1 month [36]. The ‘‘stress response’’ caused by general anesthesia increases sympathetic and neuroendocrine activity, but it may be attenuated with regional anesthesia delivered through spinal or epidural anesthesia [37]. A systematic review of 141 trials that randomized patients to epidural or spinal anesthesia (with or without general anesthesia) versus general anesthesia alone supports the use of epidural or spinal anesthesia [38]. Most trials included were published before 1991 with samples of less than 50 patients. The review ﬁnds that epidural or spinal anesthesia, compared with general anesthesia, is associated with a 40% reduction in postoperative pneumonia and nearly one third reduction in 30-day mortality. The incidence of deep venous thrombosis, pulmonary embolism, myocardial infarction, renal failure, transfusion requirements, and respiratory depression also decreases with regional anes-

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thesia. The authors conclude that the addition of regional anesthesia, not the avoidance of general anesthesia, imparts beneﬁt. The increasing use of combined general and regional anesthesia as well as postoperative epidural analgesia may antiquate the debate about general anesthesia alone versus regional anesthesia alone [39]. Another anesthesia-related risk factor for PPCs is the use of long-acting neuromuscular blocking agents that result in hypoventilation [40]. A prospective, randomized trial compared the incidence of PPCs following the use of pancuronium (long-acting neuromuscular blocker) versus two intermediate-acting agents, atracurium and vecuronium [41]. The incidence of residual neuromuscular block was 26% in the pancuronium group versus 5.3% in the intermediate-acting group. In the pancuronium group, patients with residual block were approximately four times more likely to develop PPCs than patients without residual block. In the intermediate-acting group, the incidence of PPCs was not signiﬁcantly diﬀerent between those with or without residual block. Risk factors related to postoperative care Risk factors for PPCs related to postoperative care include nasogastric tube use and pain control using parenteral narcotics. In a systematic review of blinded studies predicting PPCs, postoperative nasogastric tube placement is one of only two predictors that are signiﬁcant in more than one study [15]. One of these studies, however, has a small sample size (n ¼ 148) with only 16 PPCs and no independent validation of the ﬁndings [14]. Furthermore, the ﬁnal multivariable model reported did not include age, type of surgery, smoking, or other potential confounding variables— making the positive association between nasogastric tube placement and PPCs suspect [14]. Contrary to these ﬁndings, pre-emptive gastrointestinal (GI) tract management, including intraoperative nasogastric tube placement, in patients undergoing elective thoracotomy decreases aspiration and respiratory mortality rates [42]. The beneﬁt of preventing large-volume aspiration through nasogastric tube placement may outweigh the risks of ineﬀective coughing and oropharyngeal aspiration in high-risk patients. Pain control is particularly important for patients with incisions close to the diaphragm. Though adequate pain control improves deep breathing, resulting in decreased atelectasis and pneumonia, narcotic pain medications may increase aspiration risk through GI slowing and also increase the risk of PPCs by reducing the ventilatory response to hypoxia and hypercapnia [43]. In a retrospective review of elective abdominal aortic aneurysm repairs, patients receiving an epidural catheter for postoperative pain control have signiﬁcantly fewer pulmonary and cardiac complications than those receiving standard parenteral opioid analgesia [44]. In addition, patients receiving epidural analgesia have fewer ICU days, less intubation time, and lower hospital charges compared with the standard treatment group [44].

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Other methods for controlling postoperative pain and reducing PPCs include fascial inﬁltration of local anesthetic at incision closure and intercostal block. However, neither method is consistently found to reduce PPCs. In a randomized, controlled trial of elective laparotomy patients, fascial inﬁltration of bupivacaine (long-acting local anesthetic) fails to show any beneﬁt over controls in atelectasis rate, change in vital capacity or expiratory reserve volume, or total analgesic amount taken [45]. In patients undergoing biliary surgery through a subcostal incision, those receiving intercostal blocks have a PPC rate of 6% compared with 11% for those given centrally acting analgesics [46]. In the same study, however, patients with a midline incision receiving intercostal blocks have a higher rate of PPCs.

Risk indices for preoperative assessment Risk indices are used routinely for preoperative cardiac risk assessment. Similarly, several risk indices predict PPCs, including modiﬁed versions of indices originally developed for predicting mortality, cardiac complications, or wound infections [47,48]. These indices are limited to speciﬁc types of surgery, rarely validated in independent samples, and combined pulmonary complications with diﬀerent clinical implications into a single outcome [47–49]. Using data from a large, multi-center, observational study, Arozullah et al developed and validated separate risk indices and scoring systems for predicting postoperative pneumonia and respiratory failure [4,5]. The large sample size enables the investigators to examine many potential risk factors simultaneously and to validate their ﬁndings in independent samples. The risk factors in The Postoperative Pneumonia and Respiratory Failure Risk Indices, their associated odds ratios, and assigned point values are displayed in Table 2. These risk indices can provide preoperative PPC risk estimates using the scoring system and risk class assignment displayed in Table 3. Table 3 Risk class assignment by Postoperative Pneumonia and Respiratory Failure Risk Index Scores

Risk class

Postoperative Pneumonia Risk Index (point total)

Predicted probability of pneumonia (%)

Respiratory Failure Risk Index (point total)

Predicted probability of respiratory failure (%)

1 2 3 4 5

0–15 16–25 26–40 41–55 > 55

0.2 1.2 4.0 9.4 15.3

0–10 11–19 20–27 28–40 > 40

0.5 2.2 5.0 11.6 30.5

Adapted from Arozullah AM, et al. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Annals of Internal Medicine 2001;135:847–57, and from Arozullah AM, et al. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Annals of Surgery 2000;232(2):242–53; with permission.

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The main limitation of these risk indices is that they are developed and validated using observational and retrospective chart review data from Veterans Administration hospitals. The patients are predominantly male and have high levels of comorbid conditions so that the risk indices may not generalize to healthier populations. Although risk factors such as age and smoking are likely to be signiﬁcant risk factors in women, risk index calibration may not accurately predict PPC risk in this population. The validation of these risk indices in independent patient samples, however, provides some conﬁdence in their usefulness for providing reasonable estimates of preoperative risk.

Preoperative testing Chest radiography As discussed in an earlier article, routine preoperative chest roentgenograms in healthy adults add minimal incremental value to a thorough history and physical for predicting PPCs and rarely change perioperative management. Whereas chest roentgenograms do not improve preoperative risk assessment, they may provide baseline ﬁndings useful for postoperative care in chronic lung disease or frail, elderly patients when a history is diﬃcult to obtain. Arterial blood gas analysis Routine arterial blood gas analysis does not appear to improve preoperative pulmonary risk assessment. Small case series identify hypercarbia as a risk factor for the development of PPCs [50,51]. But these patients may be identiﬁed as high risk by other factors that do not require arterial blood gas analysis. A systematic review of blinded studies does not ﬁnd hypercarbia to be a useful predictor of PPCs [15]. Pulmonary function testing The role of pulmonary function testing in risk assessment prior to noncardiothoracic surgery is not clear. Spirometry ﬂow rates that are commonly measured include forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Spirometry accurately diagnoses airﬂow obstruction and its severity [52] despite variability in ﬂow rates and substantial individual day-to-day variability [53]. Though patients with signiﬁcant obstructive lung disease have more PPCs compared with normal patients, individual pulmonary function test abnormalities do not predict PPC risk. Pulmonary function tests (PFTs) became a routine part of the preoperative evaluation because of the erroneous assumption that accurate diagnosis of COPD translates into improved preoperative risk assessment. One inﬂuential study shows an increased risk of PPCs among abdominal surgical patients with abnormal spirometry [54]. In spite of major limitations, including small

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sample size, lack of standard deﬁnitions for PPCs, and no blinding of outcome assessments, several subsequent studies recommend preoperative PFTs for patients undergoing elective abdominal surgery [55–58]. In a 1990 consensus statement, The American College of Physicians (ACP) recommends preoperative PFTs in patients undergoing lung resection, coronary bypass surgery, or upper abdominal surgery with a history of tobacco use or dyspnea, patients undergoing lower abdominal surgery if there were unexplained pulmonary disease with anticipated prolonged or extensive surgery, or patients undergoing head and neck or orthopedic surgery with unexplained pulmonary disease [59]. The aggregate expense of ordering routine PFTs can be wasteful. One economic analysis estimates that roughly 40% of PFTs ordered do not meet ACP guidelines [60]. Improving guideline adherence in ordering PFTs may provide potential annual savings of $29–100 million overall and $8–20 million for Medicare [60]. More recent studies about the utility of spirometry before abdominal operations reach conﬂicting conclusions. Studies concluding that spirometry is predictive of PPCs rely on univariate analysis without adequate adjustment for potential confounding risk factors [6,61,62]. One study demonstrates the value of spirometry in smokers with severe airﬂow obstruction, but only for predicting bronchospasm [63]. A critical review concludes that preoperative spirometry is not useful in predicting pulmonary complications after abdominal operations [18]. The review concludes that previous studies have important methodological ﬂaws, including poor standardization, inadequate blinding of observers, selection bias, inadequate control for cointerventions, and inclusion of questionable clinical outcomes such as microatelectasis. In another systematic review, preoperative PFTs predict PPCs in only one out of ﬁve blinded studies [15]. Several studies demonstrate the superiority of clinical ﬁndings over PFTs in predicting PPCs. Two investigations of patients with severe COPD (FEV1 < 50% predicted) conclude that preoperative PFTs do not predict PPCs [2,32]. By contrast, overall general medical condition (described by ASA class) is helpful in predicting PPCs. One prospective study ﬁnds that PFTs are weakly predictive of PPCs, whereas chronic mucous hypersecretion is a stronger independent predictor [64]. In a case-control study of abdominal surgery patients, no component of spirometry predicts PPCs, though abnormal results of lung examination (decreased breath sounds, prolonged expiration, rales, wheezes, or rhonchi), abnormal chest radiograph, cardiac, and overall comorbidity are all signiﬁcant risk factors for PPCs [10]. In summary, routine PFTs should not be ordered solely for risk assessment purposes prior to abdominal surgery or other high-risk surgeries. It is reasonable, however, to obtain preoperative PFTs for unexplained dyspnea or exercise intolerance, as recommended in the nonoperative setting. Preoperative PFTs may enhance postoperative management in patients with obstructive lung disease by providing measurement of baseline airﬂow obstruction, but PFTs do not appear to predict PPC risk.

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Risk reduction strategies A preoperative medical evaluation enables clinicians to recommend preoperative and perioperative risk reduction strategies. But the evidence available to support risk reduction strategies is limited compared with the evidence available regarding risk assessment for PPCs. Preoperative smoking cessation, perioperative lung expansion maneuvers, and postoperative analgesia are risk reduction strategies supported by some evidence. Clinically intuitive strategies for elective surgery include optimization of pulmonary function in patients with COPD and asthma, and delaying surgery for patients with acute exacerbations of chronic lung disease or upper respiratory infection. There is no clear role for prophylactic antibiotic use in preventing PPCs. Preoperative smoking cessation Conﬂicting evidence exists regarding the beneﬁts and ideal timing for preoperative smoking cessation. Short-term smoking cessation reduces carboxyhemoglobin and nicotine blood levels, and results in gradual improvement in mucociliary function and upper-airway hypersensitivity [65–67]. Brief abstinence before surgery, however, is associated with a paradoxical increase in PPCs. One cohort study in veterans undergoing noncardiac surgery ﬁnds that smoking cessation within 1 month of surgery is not associated with a reduction in PPCs [68]. Current smokers who reduce smoking are almost seven times more likely to develop PPCs, with the greatest risk among those who reduce smoking closest to the surgery date. Another cohort study of 200 consecutive patients undergoing coronary artery bypass grafting ﬁnds that patients who smoke for 2 months or less prior to surgery have a fourfold increased risk of PPCs compared with those abstaining for longer than 2 months (57.1% versus 14.5%) [69]. Patients not smoking for more than 6 months have a rate similar to patients who never smoked (11.1% versus 11.9%). The rate of PPCs is highest in patients who stop smoking 2–4 weeks prior to surgery. The authors conclude that abstinence from smoking for greater than 8 weeks prior to coronary artery bypass grafting (CABG) is needed to reduce the incidence of PPCs. This study does not control, however, for many patient-related risk factors, and the most common PPCs are bronchospasm requiring bronchodilator therapy and respiratory secretions requiring more than the usual chest physical therapy or inhalation therapy. It is unclear if these complications are selflimited or progress to more serious complications. In a retrospective study of 288 consecutive patients who underwent pulmonary surgery, the incidence of PPCs is 43.6% for current smokers (smoking within 2 weeks), 53.8% for recent smokers (duration of smoke-free period of 2–4 weeks), 34.7% for ex-smokers (duration of smoke-free period >4 weeks), and 23.9% for never-smokers [70]. The risk of developing PPCs after abstinence for 10 weeks appears to be similar to that in never-smokers.

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After controlling for gender, age, PFTs, and duration of surgery, there is a trend toward increased PPC risk for current and recent smokers compared with never-smokers. But the most common PPC is air leak or eﬀusion requiring chest tube drainage for >7 days, making the results less applicable to nonthoracic surgery patients. A randomized trial of 120 hip and knee replacement patients examines the eﬀect of a smoking-cessation intervention on complications [71]. Patients are randomized 6–8 weeks before surgery to an intervention of counseling and nicotine replacement versus standard care with little or no information about risks of smoking and smoking cessation. The intervention group has signiﬁcantly fewer complications overall, signiﬁcantly fewer wound complications, trends toward fewer cardiac complications and need for second surgery, and signiﬁcantly fewer hospital days on nonorthopedic services. As expected, the rate of PPCs is low with only one case of respiratory insuﬃciency in each group. The study does not address the question of the ideal time for preoperative smoking cessation. The paradoxical increase in PPCs observed with short-term abstinence or reduced smoking may be caused by ineﬀective sputum removal [68,69]. Reduced smoking may decrease bronchial irritation and the stimulus for coughing; at the same time, bronchial hypersecretion of mucus is still present or even transiently increased [68,69,72]. This cascade may result in increased sputum retention. An alternative explanation may be that sicker patients tend to quit smoking closer to surgery [5]. Thus, short-term abstinence may simply be a marker for higher comorbid burden. In conclusion, the preoperative evaluation presents an opportunity to discuss and encourage life-long smoking cessation. Short-term abstinence or reduced smoking may increase PPCs, although the evidence is marked by methodological limitations. Abstinence for at least 8 weeks prior to surgery probably decreases PPC risk. But clinicians and patients rarely have 8 weeks notice before surgery.

Perioperative lung expansion maneuvers One long-standing hypothesis is that collapsed areas of the lung provide a nidus for the development of PPCs [1]. Lung expansion maneuvers inﬂate collapsed areas of the lung and may prevent the development of PPCs. The literature on the eﬃcacy of diﬀerent types of lung expansion maneuvers is conﬂicting and diﬃcult to interpret for several reasons: the lack of controlled trials; inadequate descriptions of control arms in controlled studies; inconsistency in administration of lung expansion techniques; and variability in the deﬁnition used for PPCs [1]. Lung expansion maneuvers include incentive spirometry and chest physical therapy consisting of various combinations of the following: deep breathing exercises, postural drainage, percussion and vibration, cough, suctioning, and mobilization. Other

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lung expansion maneuvers include intermittent positive pressure breathing (IPPB) and continuous positive airway pressure. Although incentive spirometry is used routinely, a systematic review of 48 studies concludes that current evidence does not support routine incentive spirometry for the prevention of PPCs following cardiac or abdominal surgery [73]. Thirty-ﬁve of the 48 studies have signiﬁcant methodological ﬂaws. Three of the eleven remaining studies evaluate short-term physiologic markers, eg, vital capacity, and do not demonstrate an improvement with incentive spirometry. The results of the remaining 8 trials are summarized in Tables 4 and 5. Although the authors conclude that the evidence does not support the use of incentive spirometry, it is noteworthy that the majority of studies do not include control groups. Rather, most studies compare incentive spirometry to other lung expansion maneuvers, and, for the most part, incentive spirometry is equal in clinical eﬃcacy. The authors report that one study in the CABG population does have a control arm; however, the control group underwent early mobilization [74]. The other two arms of the study consist

Table 4 Incentive spirometry and cardiac surgery Trial

Comparison groups

Administration

Outcome

Result

Gale GD, et al [82]

IS (n ¼ 52) IPPB (n ¼ 57)

20 minutes qid

Atelectasis

No diﬀerence

Dull JL, Dull WL [74]

EM (n ¼ 16) EM þ IS (n ¼ 17) EM þ DB (n ¼ 16)

EM: bid IS/DB: 10 breaths qid

PPCs; PFTs

No diﬀerence

Stock MC, et al [83]

IS (n ¼ 12) CPAP (n ¼ 13) DBC (n ¼ 13)

15 min every 2 hrs during waking hours from 2nd to 72nd hr post extubation

PFTs

No diﬀerence

Matte P, et al [84]

Chest PT þ IS (n ¼ 30) Chest PTþ CPAP (n ¼ 30) Chest PTþ Bilevel PAP (n ¼ 30)

IS: 20 breaths every 2 hrs CPAP: 1 hr every 3 hrs Bilevel PAP: 1 hr every 3 hrs

PFTs; venous admixture

CPAP, Bilevel PAP superior to IS

Abbreviations: IS, incentive spirometry; IPPB, intermittent positive pressure breathing; EM, early mobilization (included ankle exercises, range of motion to all extremities, 3 maximal coughs, encouragement and assistance for turning side to side, sitting, or standing); DB, deep breathing; DBC, deep breathing and cough; CPAP, continuous positive airway pressure; Chest PT, chest physiotherapy, Bilevel PAP, bilevel positive airway pressure; PFTs, pulmonary function testing; PPCs, postoperative pulmonary complications. Adapted from Overend TJ, et al. The eﬀect of incentive spirometry on postoperative pulmonary complications: a systematic review. Chest 2001;20(3):971–8; with permission.

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Table 5 Incentive spirometry and abdominal surgery Comparison groups

Administration

Outcome

Results

Celli BR, et al [75]

No treatment (n ¼ 44) IS (n ¼ 42) IPPB (n ¼ 45) DBE (n ¼ 41)

IS: 10 breaths (over 15 min) qid IPPB: 15 min qid DBE: 10 maneuvers qid

PPCs

IS, IPPB, DBE Better than no treatment IS, IPPB, DBE Equal in eﬃcacy

Stock MC, et al [85]

CDB (n ¼ 20) IS (n ¼ 22) CPAP (n ¼ 23)

PPCs; PFTs

No diﬀerence

Schwieger I, et al [76]

No treatment (n ¼ 20) IS (n ¼ 20)

15 minutes every 2 hours during waking period IS: 150–200 breaths/day

PPCs

No diﬀerence

Trial

Rickstein SE, Chest PT þ IS et al [86] (n ¼ 15) Chest PT þ PEP (n ¼ 15) Chest PT þ CPAP (n ¼ 13)

Chest PT: BID IS/PEP/CPAP: 30 breaths every 1 waking hour

Radiography, CPAP and PEP Gas exchange, superior to IS Lung volumes

Adapted from Overend TJ, et al. The eﬀect of incentive spirometry on postoperative pulmonary complications: a systematic review. Chest 2001;20(3):971–78; with permission.

of early mobilization, plus incentive spirometry or deep breaths. There are no signiﬁcant diﬀerences among the three groups. There are two abdominal surgery studies including a control group [75,76]. One study of incentive spirometry versus no respiratory therapy in elective cholecystectomy ﬁnds no signiﬁcant diﬀerences in PPCs [76]. Conversely, the second study ﬁnds that the use of incentive spirometry is associated with a reduction in PPCs following abdominal surgery [75]. Incentive spirometry use versus no respiratory therapy is also associated with decreased length of hospital stay in upper abdominal surgery. The proportion of smokers is higher, however, in the second study—implying that incentive spirometry may be beneﬁcial only in high-risk patients undergoing abdominal surgery. Chest physical therapy appears to be beneﬁcial for reducing PPCs depending on the type of surgery. Fagevik et al demonstrate the superiority of chest physical therapy, consisting of breathing exercises with pursed lips, huﬃng, and coughing hourly, and information about the importance of changing position in bed and early mobilization versus no respiratory therapy for upper abdominal surgery [77]. But there is no diﬀerence between chest physical therapy and no respiratory therapy in patients undergoing laparoscopic abdominal surgery [78].

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Intermittent positive pressure breathing assists patients in achieving an involuntary maximal inspiration but has the side eﬀect of abdominal distension [75]. A meta-analysis evaluating incentive spirometry, deep breathing exercises, and intermittent positive pressure breathing after upper abdominal surgery ﬁnds that the three modalities are similar in eﬃcacy and better than no respiratory therapy [79]. The deﬁnition of PPCs includes atelectasis or pneumonia, but if radiographic results are unclear or unavailable, a combination of historical and physical ﬁndings is used to deﬁne a PPC. Thus, some reported PPCs might be of limited clinical signiﬁcance. Continuous positive airway pressure (CPAP) appears to be equally eﬀective or better than these three modalities, with the advantage that it is eﬀort-independent. CPAP is expensive, however, requires special equipment, and causes patient discomfort, gastric distension, hypoventilation, and barotrauma [80]. In summary, the use of incentive spirometry following abdominal surgery may reduce PPCs, particularly in high-risk patients. No speciﬁc lung expansion maneuver is clearly superior, but CPAP may be beneﬁcial in patients unable to perform deep breathing exercises or incentive spirometry. Patient education in lung maneuvers initiated preoperatively is more eﬀective in reducing pulmonary complications versus education initiated postoperatively [77,81]. Summary Preoperative risk assessment for postoperative pulmonary complications is essential when counseling patients about the risks of surgery because of their signiﬁcant associated morbidity and mortality. There are many patient-related, operation-related, and anesthesia-related risk factors for the development of PPCs. Though many of these risk factors are not modiﬁable, they can be useful in evaluating preoperative risk, especially when combined into formal risk indices [4,5]. Preoperative risk assessment enables clinicians to target preoperative testing and perioperative risk reduction strategies to high-risk patients. Reducing PPC risk at the patient level will require a greater understanding of the impact of modifying risk factors through interventional trials. Reducing hospital PPC rates will require future research into the processes of care associated with PPCs through controlled observational and interventional trials. References [1] Brooks-Brunn JA. Postoperative atelectasis and pneumonia. Heart Lung 1995;24:94–115. [2] Kroenke K, Lawrence VA, Theroux JF, et al. Postoperative complications after thoracic and major abdominal surgery in patients with and without obstructive lung disease. Chest 1993;104:1445–51. [3] Wong DH, Weber EC, Schell MJ, et al. Factors associated with postoperative pulmonary complications in patients with severe chronic obstructive pulmonary disease. Anesth Analg 1995;80:276–84.

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Med Clin N Am 87 (2003) 175–192

Perioperative evaluation and management of the patient with endocrine dysfunction Robert L. Schiﬀ, MDa,*, Gail A. Welsh, MDb a

General Medical Consult Service, Loyola University Medical Center, Maywood, IL, USA b Mayo Medical School, Rochester, MN, USA

Over the past two decades the worldwide prevalence of diabetes mellitus has steadily risen. In the United States, an estimated 16 million people have diabetes mellitus [1]. Factors contributing to the increased prevalence of diabetes include the proliferation of obesity, lower levels of physical activity, and the aging of the population. Individuals with diabetes mellitus often require surgery sometime during their life [2]. Physicians in many specialties are involved in the perioperative care of patients with diabetes mellitus including internists, surgeons, anesthesiologists, and endocrinologists.

Diabetes mellitus and surgery Patients with diabetes mellitus who undergo surgery have an increased risk of developing perioperative complications [2,3]. They are particularly at greater risk for infectious, metabolic, electrolyte, renal, and cardiac complications during and after surgery [4–6]. The primary goal of perioperative care for the diabetic patient undergoing surgery is a safe and eﬀective outcome without complications. Steps involved in achieving that outcome include the preoperative evaluation, a plan for managing diabetes during surgery, and postoperative diabetic care. The timing of the surgery is also important, particularly when other medical conditions coexist with diabetes (eg, cardiac, renal, or infectious problems). Communication and coordination of care between the internist or endocrinologist and the surgical team (surgeon and anesthesiologist) are often important for achieving a safe outcome.

* Corresponding author. E-mail address: rschiﬀ@lumc.edu (R.L. Schiﬀ). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 0 - 5

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Perioperative metabolic changes Many metabolic changes occur during surgery that have an eﬀect on diabetes mellitus. With the onset of anesthesia and surgery, there is an increase in the secretion of epinephrine, norepinephrine, cortisol, and growth hormone [2,7]. The extent of the metabolic changes is related to the type of surgery, the length of surgery, and the stress of surgery. Whether the surgery is an elective or emergent procedure also aﬀects the extent of metabolic changes. Epinephrine, norepinephrine, cortisol, and growth hormone are all insulin antagonists and cause insulin resistance at the tissue level. In addition, epinephrine causes a decrease in insulin secretion [2,6]. All of these metabolic changes contribute to hyperglycemia during and after surgery. The stresses of anesthesia and surgery also cause an increase in gluconeogenesis. There is mobilization of gluconeogenesis precursors, including amino acids, free fatty acids, and glycerol [7,8], and an increase in the metabolic rate during surgery. There is also a net protein catabolism during and after surgery [6]. These perioperative changes can result in poor control of blood glucose, ketosis, and acidosis [2,7]. Factors that aﬀect the extent of the endocrine and metabolic changes during and after surgery include the type of diabetes, preoperative diabetic control, the magnitude of the surgery, and perioperative complications. Patients with diabetes mellitus are also at risk for hypoglycemia in the perioperative period. Hypoglycemia in the anaesthetized or sedated diabetic patient may be unrecognized if appropriate glucose monitoring is not done. Factors that may contribute to perioperative hypoglycemia in patients with diabetes mellitus include prolonged fasting, hypoglycemic medications, inadequate nutritional therapy, sedation, and postoperative gastrointestinal problems (eg, vomiting, gastroparesis, and ileus). Ramiﬁcations of perioperative hyperglycemia One of the most important consequences of perioperative hyperglycemia is impaired wound healing. Phagocytic function of granulocytes is adversely aﬀected by hyperglycemia, particularly when blood glucoses are greater than 250 [9]. Collagen synthesis is suppressed by hyperglycemia when glucose levels are higher than 200mg/dL. Granulocyte chemotaxis is also decreased by hyperglycemia. The higher prevalence of vascular disease and renal disease in patients with diabetes mellitus also contributes to the greater frequency of postoperative wound infections [6]. Impaired wound healing contributes to the increased rate of postoperative infections in patients with diabetes mellitus. These infections, including wound infections, skin infections, pneumonia, and urinary tract infections, are a major cause of morbidity, accounting for about two thirds of all postoperative complications [10] and 20% of all postoperative deaths [11] in patients with diabetes. There is evidence from in vitro studies that hyperglycemia impairs wound healing. The best method for tightly controlling diabetes mellitus during

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major surgery is with a continuous IV insulin and glucose infusion [7,12,13]. Is there evidence that better control of diabetes in the perioperative period decreases morbidity or mortality? At this time, there are no prospective studies that document better perioperative outcomes from tighter control of diabetes mellitus. Some retrospective studies show that higher glucose levels perioperatively are associated with an increased risk of infection in patients with diabetes mellitus [5,14]. A recent prospective study randomly assigned 1548 critically ill patients admitted to a surgical intensive care unit to intensive insulin therapy or conventional insulin therapy [15]. Only 13% of these patients had a history of diabetes mellitus. Two thirds of the patients had undergone cardiothoracic surgery. In the intensive insulin therapy group, an insulin infusion was started if the blood glucose level exceeded 110 mg/dL, and, in the conventional insulin therapy group, it was started if the blood glucose exceeded 215 mg/dL. Patients in the intensive insulin group had a mean A.M. blood glucose of 103 mg/dL, and in the conventional insulin group it was 153 mg/ dL [15], but hypoglycemia occurred in 5% of the intensive insulin group compared with 1% in the conventional group. The 12-month mortality rate for the intensive insulin therapy group was 4.6% which was signiﬁcantly lower than the 8.0% mortality rate for the conventional insulin group. The intensive insulin therapy group had 46% fewer episodes of septicemia and a 34% lower in-hospital mortality rate [15]. A retrospective study of 411 adults with diabetes mellitus who had coronary artery bypass surgery divided these patients into four quartiles based on their mean postoperative blood glucose levels [14]. Mean postoperative blood glucose levels ranged from 121–206 mg/dL in quartile 1 to 253–352 mg/dL in quartile 4. One hundred patients (24.3%) developed one or more postoperative infections. In adjusted risk models (adjusting for confounding variables such as age and comorbid conditions), those patients in the higher postoperative glucose quartiles had an increased risk for postoperative infections [14]. Another retrospective study examined the incidence of deep sternal wound infections in diabetic patients undergoing open heart surgery before and after instituting a continuous intravenous insulin infusion protocol [4]. Their control group included 968 patients who received sliding scale subcutaneous insulin and had a mean glucose of 206 on postoperative day 1. The study group of 1499 patients received a continuous intravenous insulin infusion and had a mean glucose of 176 on postoperative day 1. Institution of the continuous intravenous insulin infusion protocol resulted in a signiﬁcant decrease in the incidence of deep sternal wound infections to 0.8%, compared with the rate of 1.9% in the subcutaneous insulin therapy group [4]. Preoperative evaluation The objectives for the preoperative assessment of patients with diabetes mellitus include evaluation of the status of their diabetes, identifying other

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medical problems, consideration of the type of surgery planned to assess the surgical risk, and measures to minimize the risk of surgery. It is important to identify both the type and duration of diabetes mellitus. Patients with diabetes for more than 10 years are more likely to have complications from diabetes. The patient’s current therapy for diabetes should be ascertained including diet, oral medication(s) and doses, and any insulin therapy including the type and dose. The status of diabetes control should be assessed by evaluating recent blood glucoses and hemoglobin A1C. The patient should be queried about any complications from diabetes. Because patients with diabetes mellitus are at increased risk for coronary artery disease, a cardiac history should be obtained prior to surgery. The preoperative physical exam should include an evaluation of cardiovascular status including blood pressure, heart rate and rhythm, and a cardiac exam. An abdominal exam and neurologic exam should also be undertaken. Certain preoperative tests should be done for all patients with diabetes mellitus before surgery. A chemistry panel to evaluate electrolytes and renal function should be ordered before surgery. An electrocardiogram should be taken before any major surgery for patients with diabetes mellitus. Whether any additional tests are indicated would depend on the patient’s medical problems and the type of surgery planned. Management of diabetes during surgery How a patient’s diabetes will be managed during surgery is dependent on several patient speciﬁc issues and several surgical factors. Patient issues to consider include whether the patient is being treated with diet alone, with oral hypoglycemic agent(s), or with insulin as well as the degree of glycemic control. Surgery-speciﬁc factors to consider are the type of anesthesia (local, regional, or general) and whether major or minor surgery is scheduled. How long the patient is expected to be nil per os (NPO) should also be considered. For example, an early morning knee arthroscopy may enable the patient to eat lunch, whereas an early morning laparoscopic cholecystectomy may preclude a normal lunch. For patients who undergo minor surgery (eg, cystoscopy, dilation and curettage, laparoscopic hernia repair) therapy for diabetes mellitus should be modiﬁed (Table 1). Patients undergoing minor surgery whose diabetes mellitus is controlled with diet alone or with oral hypoglycemic agents usually do not need insulin during surgery. For all patients with diabetes mellitus, a bedside blood glucose should be checked preoperatively and every 1–2 hours during minor surgery. Patients who are taking oral hypoglycemic agents should omit these on the morning of surgery or 24–48 hours preoperatively if on metformin or chlorpropamide. These patients can restart their usual oral hypoglycemic medication when they are able to resume their usual diet. Diabetic patients controlled with oral hypoglycemic medications who undergo major surgery usually do not need insulin during surgery. Patients on oral

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Table 1 Management of diabetes mellitus during surgery

DM controlled with diet alone: DM controlled with oral meds: DM poorly controlled with oral meds: DM on insulin therapy:

Minor surgery

Major surgery

No insulin during surgery

No insulin during surgery

No insulin during surgery

Insulin may be required during surgery IV insulin infusion during surgery IV insulin infusion during surgery

Insulin may be required 1/2–2/3 of usual AM insulin SQ

Abbreviations: DM, diabetes mellitus; SQ, subcutaneous.

hypoglycemic medications with poorly controlled diabetes should receive an insulin and glucose infusion during major surgery (Table 1). Insulin-treated patients should have their insulin dose modiﬁed before minor surgery. One half to two thirds of their usual morning insulin can be given. Less insulin should be given (eg, one half their usual dose) if it is anticipated that they will be NPO past their noon meal. Their IV ﬂuids during surgery should be D5W/0.45NS at 100cc/hr to prevent hypoglycemia. When they are able to resume their usual diet, they can restart their preoperative insulin treatment. Patients with diabetes mellitus on insulin who undergo major surgery should receive a continuous IV insulin and glucose infusion during surgery [7]. An insulin infusion is the best method to control glucose levels and can be easily adjusted depending on the stress of surgery, the length of surgery, and the patient’s insulin requirements [7,11]. There is a wide variation in how much insulin is needed during surgery for these patients ranging from 0.7–4.2 units of regular insulin/hr [11]. A continuous IV glucose infusion should also be given to prevent hypoglycemia and to provide a source of carbohydrate to minimize the risk for ketosis and acidosis during fasting and the stress of surgery. Potassium chloride should be included in the insulin and glucose infusion (Table 2) unless the patient has hyperkalemia or chronic renal failure. It is inappropriate to use only IV push insulin to manage diabetes perioperatively, because IV push insulin has a half-life of only 5–10 minutes [7]. IV insulin and glucose infusion When a patient is started on a continuous IV insulin and glucose infusion for surgery, the usual insulin and oral hypoglycemic medication(s) should be held on the morning of surgery. Prior to starting the infusion, a bedside blood glucose should be checked. One IV line should be used for the insulin and glucose infusion, and a second IV line for any other ﬂuids, medications, and/or blood products that are needed during surgery. The IV insulin infusion should be started at 1.0 units/hr of regular insulin by infusion pump.

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Table 2 Protocol for perioperative IV insulin infusion

Check bedside blood glucose. Hold usual morning diabetes medications. Begin insulin and glucose infusion: 1. Discard ﬁrst 50 mL of insulin infusion 2. Start insulin infusion at 1.0 units/hr of regular insulin by infusion pump 3. Start D5W/0.45NS with 20 meq of KCL at 100 cc/hr Maintain one IV line for insulin and glucose infusion, and a separate IV access for any ﬂuids, blood products, or medications. Monitor bedside blood glucose every 1–2 hs before surgery and every 1 hr during surgery. Aim for glucose of 100–200 mg/dL by adjusting insulin infusion rate in 0.5 unit/hr increments.

The ﬁrst 50–60 mL of the insulin infusion should be ﬂushed through the plastic tubing and discarded because insulin binds to plastic tubing, and this will saturate the insulin binding sites on the plastic tubing. When the insulin infusion is started, the glucose infusion should also be started with 1000 cc of D5W/0.45NS with 20 mEq of KCL to run at 100cc/hr. The bedside blood glucose should be checked every 1–2 hours (every 1 hour during surgery) and adjusted to maintain a glucose of 100–200 mg/DL. The insulin infusion can be adjusted in 0.5 unit/hr increments. For example, if at 1 hour the glucose is 250 mg/dL, then the infusion rate should be increased to 1.5 units/hr. If at 1 hour the glucose is 70 mg/dL, the infusion rate should be decreased to 0.5 units/hr. The IV glucose infusion should be maintained during these adjustments at 100cc/hr. For a very low glucose (eg, 50mg/dL) 1 ampule of D50 should be given IV push and the insulin infusion rate should be decreased by 0.5units/hr. For patients undergoing open-heart procedures, the metabolic changes that cause hyperglycemia are accentuated [13]. Diabetic patients undergoing open-heart procedures will usually require higher hourly infusion rates of IV insulin. What are the advantages of continuous IV insulin infusion compared with giving subcutaneous insulin during surgery? The absorption of subcutaneous insulin may be erratic and highly variable during surgery. Continuous IV insulin has the ﬂexibility to control diabetes better, whether the surgery and its peak stresses occur early in the morning, late in the morning, or later in the day. The IV insulin infusion can be easily adjusted in response to complications that occur during or after surgery and can be individualized to meet the insulin requirements of each patient. Diabetes therapy after surgery The metabolic and hormonal stresses of surgery persist during the early postoperative period after major surgery. These metabolic changes can continue for up to 4 days after major surgery [8,17] but are most pronounced on the day of surgery and the ﬁrst postoperative day. While the patient remains NPO, the insulin and glucose infusion can be continued. The insulin

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and glucose infusion can usually be stopped when the patient begins eating, although they are often unable to initially tolerate their usual diet. Until their usual diet is tolerated, subcutaneous regular insulin can be given every 6 hours based on bedside blood glucoses. When a patient’s dietary intake improves, their usual insulin dosing (or a reduced long-acting insulin dose) can be resumed. Patients on oral hypoglycemic agents who require an insulin and glucose infusion can restart their oral hypoglycemic medications when they resume their usual diet.

Surgery in the hypothyroid patient Hypothyroidism aﬀects many bodily systems that can inﬂuence perioperative outcome, including myocardial function, pulmonary ventilation, hemostasis, gastrointestinal (GI) motility, and free water balance. There are no randomized, prospective studies looking at surgical outcomes in hypothyroid patients versus controls. Older case studies reported intraoperative hypotension, cardiovascular collapse, and extreme sensitivity to narcotics, sedatives, and anesthesia in undiagnosed hypothyroid patients [18,19] There are also case reports of myxedema coma developing after surgery [20–22]. Thus for many years, expert opinion encouraged clinical and chemical euthyroidism prior to any surgery. Two retrospective case-matched control studies from the 1980s evaluated the hypothyroid patient undergoing surgery. Weinberg et al [23] reviewed anesthetic and surgical outcomes in 59 hypothyroid patients and 59 paired euthyroid controls. There were no diﬀerences between the groups in surgical outcome, perioperative complications, or hospital length of stay. There were also no diﬀerences in outcome among subsets of hypothyroidism determined by level of thyroxine, though only a few were severely hypothyroid. The authors concluded that there was no evidence to justify deferring needed surgery in patients with mild to moderate hypothyroidism, and insuﬃcient evidence to make recommendations for patients with severe hypothyroidism. Another retrospective study by Ladenson et al [24] looked at perioperative complications in 40 hypothyroid patients compared with 80 matched controls. Hypothyroid patients had more intraoperative hypotension in noncardiac surgery and more heart failure in cardiac surgery. They also had more postoperative GI and neuropsychiatric complications and were less likely to mount a fever with infection. There were no diﬀerences between the groups in duration of hospitalization, perioperative arrhythmias, delayed anesthetic recovery, pulmonary complications, or death, however. Patients with mild to moderate hypothyroidism may undergo urgent or emergent surgery without delay. Elective surgery in patients with mild hypothyroidism is probably safe, though minor complications such as ileus, postoperative delirium, or infection without fever may occur. Elective surgery should be postponed for patients with moderate and severe hypothyroidism.

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Patients with severe hypothyroidism who require urgent or emergent surgery should be treated perioperatively with intravenous T3 or T4 and glucocorticoids. Deﬁnitions of mild, moderate, and severe hypothyroidism are often vague and vary between studies. A useful deﬁnition of a severely hypothyroid patient includes one with myxedema coma; one with severe complications of the disease such as delayed mentation, pericardial eﬀusions, or heart failure; or one with very low levels of thyroxine [25]. Thyroid replacement can be started or continued in the patient with mild to moderate disease going to surgery, with the same schedule as therapy in the outpatient setting. Levothyroxine has a half-life of 5–9 days, and so doses can be missed for several days if the patient is not eating. Initiation of thyroid replacement in the patient undergoing cardiovascular surgery or catheterization has been controversial. The risk of precipitating or worsening unstable coronary syndromes with thyroid hormone conﬂicts with the concern that untreated hypothyroidism might worsen heart failure or hypotension in the cardiac surgery patient. Studies of cardiac patients found no adverse outcomes in cardiac patients going to surgery or catheterization without thyroid replacement [26,27]. The need for thyroid hormone replacement should be assessed in each patient on an individual basis, with the knowledge that most patients can begin their replacement after the cardiac intervention. Myxedema coma is a rare complication of surgery and should be considered in any patient who develops seizures, coma, unexplained heart failure, or hypothermia perioperatively. Undiagnosed hypothyroidism should be suspected in any postoperative patient with diﬃculty weaning from ventilatory support, unexplained heart failure, prolonged ileus, or postoperative delirium.

Surgery in the patient with hyperthyroidism The eﬀect of thyrotoxicosis on the heart carries perioperative risk for the hyperthyroid patient. T3 and T4 exert direct inotropic and chronotropic eﬀects on cardiac muscle. Left ventricular ejection fraction may not increase normally during exercise, and increased cardiac output may limit cardiac reserves during surgery in the hyperthyroid patient. Atrial ﬁbrillation is present in 10–20% of patients [28–31]. The greatest risk to the perioperative thyrotoxic patient is thyroid storm, a rare but life-threatening complication that presents with fever, tachycardia, and confusion and may quickly lead to cardiovascular collapse and death. It can occur in the inadequately treated or undiagnosed hyperthyroid patient during or soon after surgery [16,32]. Patients with mild hyperthyroidism can go to surgery with preoperative beta blockade [33], but elective surgery should be postponed in those with moderate to severe disease until they are euthyroid. Propranolol has been the beta-blocker of choice at doses of 10–40 mg q.i.d., though cardioselective beta-blockers can also be used. The latter may be better tolerated in

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patients with asthma. Longer acting beta-blockers such as atenolol taken before surgery may maintain adequate heart rate control until the patient is able to take oral medication postoperatively [34]. The thyrotoxic patient undergoing urgent or emergent surgery needs premedication with antithyroid agents, beta blockade, and possibly corticosteroids. Close perioperative assessment and management of cardiac function is essential. Antithyroid medications include thionamides, iodine, and iopanoic acid. The thionamides, methimazole, and propylthiouracil (PTU) block thyroid hormone synthesis. Iodine blocks release of T4 and T3 from the thyroid, and iopanoic acid blocks T4 to T3 conversion. Iopanoic acid contains iodine and thus also blocks release of thyroid hormone. Euthyroidism can be achieved in 3–8 weeks with thionamides alone. Methimazole reverses hyperthyroidism sooner than PTU. There are other published combination regimens that can prepare a patient more rapidly for urgent surgery in 10 days or less [35,36]. Adrenal reserve may be low in the thyrotoxic patient. If time does not allow for completely adequate preparation prior to emergent surgery in the patient with severe hyperthyroidism or if thyroid storm occurs, hydrocortisone can be given 100 mg every 8 hours. This will not only treat possible adrenal insuﬃciency but may block peripheral conversion of T4 to T3 as well. One study showed improved outcomes in patients with thyroid storm treated with corticosteroids [37]. Thyroid storm should be considered in any patient who develops fever, tachycardia, and confusion in the postoperative period. Laboratory values do not diﬀer between thyrotoxicosis and decompensated hyperthyroid crisis, and treatment may need to start before results of thyroid function tests are available. Burch devised a point system based on cardiac, neuropsychiatric, and other physical ﬁndings to help with diagnosis [38]. Treatment of thyroid storm includes beta blockade, thioamides, iodinated contrast agents, iodine, and corticosteroids. Thioamides should be given at least 1 hour prior to iodine to prevent uptake of iodine by the thyroid as substrate for more hormone production. Methimazole and PTU are available rectally, and PTU can be given intravenously [39–41]. Supportive care in the intensive care unit (ICU) setting is essential and should include hydration, nutrition with glucose and vitamins, antipyretics, cooling blankets, and treatment of cardiac complications such as heart failure and atrial ﬁbrillation that may develop. Acetaminophen is the antipyretic of choice, as aspirin may increase thyroid hormone concentrations by interfering with protein binding of T4 and T3.

Perioperative management of the patient with pheochromocytoma Rarely is communication between surgeon, anesthesiologist, and internist more vital than in the preoperative preparation and perioperative management of the patient with a pheochromocytoma. In case series before 1961,

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surgical mortality ranged from 24–45% [42]. Introduction of alpha adrenoreceptor blockade in the 1950s, improved anesthetic drugs and management, and better localization techniques from the 1970s onward are the probable reasons for signiﬁcantly improved surgical outcome [43]. With appropriate medical preparation and an experienced anesthesiologist and surgical team, survival of excision of a pheochromocytoma is 93.3–100% [44,45]. Pheochromocytoma is an uncommon neuroendocrine tumor of the chromaﬃn cell that is a cause of less than 0.2% of hypertension [46]. The most common sign of the tumor is hypertension, which can be paroxysmal. The tumor’s intermittent catecholamine surges can cause a variety of symptoms, including headache, chest pain, palpitations, diaphoresis, dyspnea, anxiety, and dizziness. Surgical excision can prevent the life-threatening complications of hypertensive crises, stroke, arrhythmias, and myocardial infarction. Preoperative preparation Catecholamine excess causes vasoconstriction that leads to both hypertension and hypovolemia. Pheochromocytoma patients can die intraoperatively from severe hypertensive crisis or hypotension that leads to cardiovascular collapse. When tumor veins are ligated during surgery, the sudden drop in circulating catecholamines can lead to vasodilatation. The catecholamine output of the contralateral adrenal may be suppressed from previous catecholamine excess. In the hypovolemic patient, this can lead to hypotension, shock, and death. Alpha adrenergic blockade has been the cornerstone of preoperative preparation in the past, as it treats both hypertension and vasoconstriction and improves circulating plasma volume prior to surgery. After alpha-blockers are initiated, beta-blockers are added if not contraindicated by heart failure or asthma to prevent the reﬂex tachycardia associated with nonselective alpha-receptor blockade. Beta-blockers may also prevent perioperative arrhythmias and cardiac complications. Beta blockade should not be given alone in a patient with pheochromocytoma, as it augments eﬀects of catecholamines at the alpha adrenoreceptors, blocks beta receptor-mediated vasodilatation in skeletal muscle, and can cause higher blood pressure. Particular attention should be paid to preoperative evaluation of myocardial function. Not only can long-standing hypertension cause left ventricular hypertrophy and dysfunction, but chronic catecholamine excess can cause cardiomyopathy. The intraoperative hypotension that often occurs after excision of the tumor can be refractory in the patient with low cardiac output [47]. Regimens vary among centers, but usually alpha blockade for at least 10– 14 days prior to surgery is recommended. Normotension (140/90) is a preoperative goal, and one anesthesia review recommended no blood pressure greater than 160/90 in the 24 hours prior to surgery [54]. A recent retrospective case-series review showed a correlation that approached statistical sig-

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niﬁcance between the level of preoperative hypertension and perioperative complications [45]. The long-acting, nonselective alpha blocker phenoxybenzamine has been the past drug of choice. Doses are initiated at 5– 10 mg by mouth b.i.d. and increased by 10 mg every few days to a dose of 0.5–1 mg/kg/day or until blood pressure is controlled. The average dose is 40–80 mg per day. It has signiﬁcant side eﬀects including somnolence, orthostasis, and stuﬀy nose. If phenoxybenzamine is not tolerated, the selective alpha 1 receptor blockers prazosin, doxazosin, or terazosin can be used. One study showed that doxazosin did not cause the prolonged duration of postoperative hypotension that can occur with phenoxybenzamine [48]. Some authors recommend metyrosine (alpha-methyl-p-tyrosine) at doses of 1–4 mg per day in addition to alpha blockade. It competitively inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis. Patients who received it in combination with alpha blockade had better blood pressure control, as well as less need for intraoperative antihypertensives and pressors compared with patients who were on alpha blockade alone [49,50]. Propranolol, metoprolol, and atenolol have all been recommended for beta blockade. They should be begun several days after alpha blockade and at least a few days prior to surgery. Liberalization of salt in the diet along with alpha blockade should expand plasma volume. Though some centers admit patients preoperatively for blood pressure management, at least one retrospective study has documented the safety of outpatient preoperative preparation [51]. A few authors have argued that alpha adrenergic blockers are not necessary for safe surgery. Half of 60 patients at one institution underwent excision without preoperative alpha blockade. There were no strokes or myocardial infarctions, and there was only one postoperative death, which was caused by a pre-existing cerebral tumor [52]. As calcium ion transport is essential for release of catecholamines from chromaﬃn cells, calcium channel blockers are used for control of blood pressure and preoperative preparation at some centers. There are several case reports and a French study of pheochromocytoma patients treated with calcium channel blockers alone [48,53] prior to surgery. In another study of 113 patients, those who received preoperative alpha blockade had more perioperative cardiovascular complications and required more perioperative ﬂuid than those receiving calcium channel blockers [54]. Studies have shown no diﬀerence in intraoperative hemodynamics and blood loss between open versus laparoscopic approaches, and patients leave the hospital sooner with laparoscopic surgery [55]. Splenic injury and splenectomy can be a complication in an open anterior abdominal approach [45]. The postoperative patient may remain hypertensive up to 2 weeks after excision. If hypertension persists, urinary catecholamines should be checked to ensure no additional tumor remains. If catecholamines are normal, the patient may be one of about 25% of pheochromocytoma patients whose

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hypertension persists after surgical excision caused by other concomitant disease, such as essential or renal hypertension [56]. Because norepinephrine and epinephrine contribute to insulin resistance, hypoglycemia may develop and persist into the postoperative period once the tumor is removed [57]. Glucose should be included in perioperative ﬂuids, and blood sugars should be monitored frequently intraoperatively and postoperatively. Of course, those patients who undergo bilateral adrenalectomy for bilateral disease will need steroid replacement. Partial bilateral adrenalectomies are being done more frequently in patients with bilateral disease to prevent the need for lifelong replacement, but these patients need to be monitored closely for recurrent disease [58].

The patient on chronic glucocorticoids Surgery is a physiologic stress that activates the hypothalamic-pituitaryadrenal (HPA) axis and results in increased corticotropin (ACTH) and cortisol secretion. Exogenous glucocorticoids can suppress the HPA axis, and the patient on chronic glucocorticoids may not produce suﬃcient levels of ACTH and cortisol during and after surgery to meet physiologic needs. Adrenal insuﬃciency with hypotension and shock may occur. The evidence that this does in fact occur is mainly anecdotal. There are a few case studies, however, that show conﬁrmed clinical and biochemical evidence of intraoperative adrenal insuﬃciency in patients who did not receive perioperative glucocorticoids after stopping them shortly before surgery [59]. To prevent this life-threatening complication, supplemental glucocorticoids (‘‘stress dose’’ steroids) are given perioperatively to those patients with documented or presumed HPA axis suppression. Two questions need to be answered by the provider caring for the patient on chronic glucocorticoids who is going to surgery: Is it likely that the patient’s dose and duration of glucocorticoid therapy has caused HPA suppression? If the patient is suppressed, what dose of supplemental glucocorticoids should be given? Suppression of the HPA axis There is wide variability in HPA suppression in patients on exogenous glucocorticoids that in general does not correlate well with age, sex, duration, or amount of dose. Nevertheless, it seems fairly clear from studies that oral glucocorticoids equivalent to less than 5 mg of prednisone in a single morning dose for any duration of time, alternate day short-acting glucocorticoids (cortisone, hydrocortisone, prednisone, prednisolone, or methylprednisolone) given in a morning dose, and any dose of glucocorticoids given for less than 3 weeks do not cause clinically signiﬁcant suppression of the HPA axis [60– 62]. By contrast, any patient who has taken more than 20 mg of prednisone or its equivalent per day for more than 3 weeks or who is clinically cushingoid

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has probable suppression of the HPA axis [63]. HPA suppression in patients on intermediate regimens is much more variable and may depend on individual rates of drug metabolism and clearance [62,64]. Superpotent topical steroids at doses of 2 g per day have caused HPA axis suppression in patients [65,66]. HPA suppression can occur in patients treated with inhaled corticosteroids at doses of.0.8 mg/day or more of ﬂuticasone propionate, though clinically signiﬁcant adrenal insuﬃciency is rare [67,68]. The duration of functional HPA axis suppression after glucocorticoids have been stopped is debatable. Older studies showed delayed biochemical recovery on tests of pituitary and adrenal function up to 1 year after cessation of glucocorticoids [69,70], but the clinical importance of these test results is unclear. Because of these studies, however, most anesthesia and endocrine texts recommend perioperative supplemental glucocorticoids in patients who have had HPA axis suppressive doses of glucocorticoids within 1 year of surgery. Testing the HPA axis Patients who are on intermediate doses of glucocorticoids or who cannot give a good history of dose, duration, or tapering of therapy can undergo testing of the HPA axis if there is suﬃcient time to do so before surgery. Because the high dose (250 lg) ACTH stimulation test is supraphysiologic, response to it may mask a partially suppressed adrenal gland, and many now recommend the low dose (1 lm) ACTH stimulation test for assessment of the HPA axis [71]. Patients may have a normal response to surgical stress despite laboratory evidence of HPA suppression. In two studies, patients on chronic steroids were given their usual daily glucocorticoid dose but no glucocorticoid supplementation while hospitalized for surgery or medical illness. HPA suppression was evaluated with an ACTH stimulation test. No patient with an abnormal ACTH test developed clinical adrenal insuﬃciency [72,73]. The studies raise interesting questions, and some have used them to argue that supplemental glucocorticoids are unnecessary. The number of patients studied was small, however, and for now, the data are insuﬃcient to discount the ACTH test or its results in surgical patients. Supplemental glucocorticoid regimens Because the status of the patient’s HPA axis is often uncertain, the decision to give perioperative supplemental glucocorticoids must weigh the risk of additional glucocorticoids in the perioperative period against the likelihood of adrenal insuﬃciency developing without them. Glucocorticoids have many side eﬀects that can aﬀect surgical outcome, including hypertension, ﬂuid retention, psychiatric disturbance, increased risk of infection, gastrointestinal bleeding, impaired wound healing, and hyperglycemia. One

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way to mitigate the risks of additional glucocorticoids is to give the lowest protective dose for the shortest period of time necessary. Older regimens for glucocorticoid replacement included high doses of up to 300 mg of hydrocortisone per day for several days. A consensus paper [59] recommended that clinicians replace glucocorticoids only in amounts equivalent to the normal physiologic response to surgical stress, which in turn depends on the type and duration of surgery. ACTH and cortisol rise during induction of anesthesia, surgery, extubation, and recovery from anesthesia [74]. Up to 200–500 mg of cortisol can be secreted per day during severe stress but rates of more than 200 mg per day in the 24 hours after surgery are rare [59], Cortisol levels may average 50–75 mg per day for 1–2 days in a moderate stress surgery and 100–150 mg per day for 2–3 days for major stress surgery [75]. Table 3 makes speciﬁc recommendations on supplemental glucocorticoids based on likely HPA axis suppression and the anticipated stress of surgery. As the physiologic stress of local anesthesia or minor surgery is low, Table 3 Perioperative supplemental glucocorticoid regimens

No HPA axis suppression: 1. Less than 5 mg of prednisone or equivalent per day for any duration 2. Alternate-day single morning dose of short-acting glucocorticoid of any dose or duration 3. Any dose of glucocorticoid for less than 3 weeks Rx: Give usual daily glucocorticoid dose during perioperative period HPA axis suppression documented or presumed: 1. More than 20 mg of prednisone or equivalent per day for 3 weeks or more 2. Cushingoid appearance 3. Biochemical adrenal insuﬃciency on low-dose ACTH stimulation test 1. Minor procedures or local anesthesia Rx: Give usual glucocorticoid dose before surgery No supplementation 2. Moderate surgical stress Rx: 50 mg IV hydrocortisone prior to induction of anesthesia, 25 mg hydrocortisone every 8 hours thereafter for 24–48 hours, then resume usual dose 3. Major surgical stress Rx: 100 mg IV hydrocortisone prior to induction of anesthesia, 50 mg hydrocortisone every 8 hours for 48–72 hours, then resume usual dose HPA axis suppression uncertain: 1. 5–20 mg of prednisone or its equivalent for 3 weeks or more 2. 5 mg of greater of prednisone or its equivalent for 3 weeks or more in the year prior to surgery 1. Minor procedures or local anesthesia Rx: Give usual glucocorticoid dose before surgery No supplementation 2. Moderate or major surgical stress Check low-dose ACTH stimulation test to determine HPA axis suppression or Give supplemental glucocorticoids as if suppressed. Abbreviations: ACTH, adrenocorticotropic hormone; HPA, hypothalamic–pituitary–adrenal axis.

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patients need take only their usual daily glucocorticoid dose prior to these procedures. If a patient’s daily glucocorticoid dose is equivalent to the target cortisol levels of the surgery, no supplemental glucocorticoids are necessary. Though it is common to do so, it is not necessary to taper supplemental glucocorticoids over the duration of time they are given [59]. Topical and inhaled corticosteroids can suppress the HPA axis but rarely cause clinical adrenal insuﬃciency. These patients do not need supplemental glucocorticoids prior to surgery. Finally, it is important to remember that supplemental glucocorticoids may need to be resumed or continued at higher doses or for longer periods of time if the patient develops a signiﬁcant postoperative complication such as infection or infarction. Summary Whenever possible, endocrine disorders should be identiﬁed and evaluated prior to surgery. A plan for perioperative management of diabetes should be based on the type of diabetes, what diabetes medications are taken, the status of diabetes control, and what type of surgery is planned. Perioperative management of diabetes must include bedside glucose monitoring. Patients with mild hypothyroidism can safely proceed with elective surgery. Elective surgery should be postponed for patients with moderate or severe hypothyroidism. Patients who have mild hyperthyroidism can undergo elective surgery with preoperative beta blockade. Elective surgery should not be done on patients with moderate or severe hyperthyroidism until they are euthyroid. Patients with pheochromocytoma need to be identiﬁed and properly treated before surgery to prevent perioperative cardiovascular complications. Patients who take endogenous steroids should have the status of their HPA axis determined prior to surgery. If the patient is undergoing moderate or major surgical stress and has documented or presumed HPA suppression, then stress doses of steroids should be give perioperatively. References [1] Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care 1998;21:518–24. [2] Hirsch IB, McGill JB. Role of insulin in management of surgical patients with diabetes mellitus. Diabetes Care 1990;13:980–91. [3] Stagnaro-Green A. Perioperative glucose control: does it really matter? The Mount Sinai Journal of Medicine 1991;58:299–304. [4] Furnary AP, Zerr KJ, Grunkemeier GL. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac sugical procedures. Ann Thorac Surg 1999;67:352–62. [5] Pomposelli JJ, Baxter JK, Babineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. Journal of Parenteral and Enteral Nutrition 1998;22:77–81.

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[6] Scherpereel PA, Tavernier B. Perioperative care of diabetic patients. Eur J Anaesthesiol 2001;18:277–94. [7] Hirsch IB, McGill JB, Cryer PE. Perioperative management of surgical patients with diabetes mellitus. Anesthesiology 1991;74:346–59. [8] Naito Y, Tamai S, Shingu K, et al. Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery. Anesthesiology 1992; 77:426–31. [9] Gallacher SJ, Thomson G, Fraser WD, et al. Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabet Med 1995;12:916–20. [10] DiPalo S, Ferrari G, Castoldi R, et al. Surgical septic complications in diabetic patients. Acta Diabetol Lat 1988;25:49–54. [11] Schiﬀ RL, Emanuele MA. The surgical patient with diabetes mellitus: Guidelines for management. J Gen Intern Med 1995;10:154–61. [12] Pezzarossa A, Taddei F, Cimicchi MC. Perioperative management of diabetic subjects: subcutaneous versus intravenous insulin administration during glucose-potassium infusion. Diabetes Care 1988;11:52–8. [13] Thomas DJB, Hinds CJ, Rees GM. The management of insulin dependent diabetes during cardiopulmonary bypass and general surgery. Anaesthesia 1983;38:1047–52. [14] Golden SH, Peart-Vigilance C, Kao WHL. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999;22: 1408–14. [15] Van Den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359–67. [16] Strube PJ. Thyroid storm during beta-blockade. Anaesthesia 1984;39:343–6. [17] Goschke H, Bar E, Girard J, et al. Glucagon, insulin, cortisol, and growth hormone levels following major surgery: their relationship to glucose and free fatty acid elevations. Horm Metab Res 1978;10:465–70. [18] Abbott TR. Anaesthesia in untreated myxoedema. Br J Anaesth 1967;39:510–4. [19] Kim JM, Hackman L. Anesthesia for untreated hypothyroidism: report of three cases. Anesth Analg 1977;56(2):299–302. [20] Appoo JJ, Morin JF. Severe cerebral and cardiac dysfunction associated with thyroid decompensation after cardiac operations. J Thor Card Surg 1997;114(3):496. [21] Catz B, Russell S. Myxedema, shock and coma. Arch Intern Med 1961;108:407–17. [22] Holvey DN, Goodner CJ, Nicoloﬀ JT, et al. Treatment of myxedema coma with intravenous thyroxine. Arch Intern Med 1964;113:89–95. [23] Weinberg AD, Brennan MD, Gorman CA. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983;143(5):893–7. [24] Ladenson PW, Levin AA, Ridgway EC, et al. Complications of surgery in hypothyroid patients. Am J Med 1984;77(2):261–6. [25] Bennett-Guerrero E, Kramer DC, Schwinn DA. Eﬀect of chronic and acute thyroid hormone reduction on perioperative outcome. Anesth Analg 1997;85(1):30–6. [26] Drucker DJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145(9):1585–7. [27] Myerowitz PD, Kamienski RW, Swanson DK, et al. Diagnosis and management of the hypothyroid patient with chest pain. J Thorac Cardiovasc Surg 1983;86(1):57–60. [28] Forfar JC, Muir AL, Sawrers SA, et al. Abnormal left ventricular function in hyperthyroidism. N Engl J Med 1982;307:1165–70. [29] Klein I, Ojamaa K. Mechanisms of disease: thyroid hormone and the cardiovascular system. N Engl J Med 2001;344(7):501–9. [30] Sawin CT, Geller A, Wolf PA. Low serum thyrotropin concentration as a risk factor for atrial ﬁbrillation in older patients. N Engl J Med 1994;331:1249–52. [31] Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992;327:94–7. [32] McArthur JW, Rawson RW, Means JH, et al. Thyrotoxic crisis. JAMA 1947;132:868.

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[57] Akiba M, Kodama T, Ito Y, et al. Hypoglycemia induced by excessive rebound secretion of insulin after removal of pheochromoctyoma. World J Surg 1990;14:317–24. [58] Neumann HP, Reincke M, Bender BU, et al. Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab 1999;84:2608–10. [59] Salem M, Tainsh RE, Bromberg J, et al. Perioperative glucocorticoid coverage: a reassessment 42 years after the emergence of a problem. Ann Surg 1994;219:416–25. [60] Ackerman GL, Nolsn CM. Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 1968;278:405–9. [61] Fauci AS. Alternate-day corticosteroid therapy. Am J Med 1978;64:729–31. [62] LaRochelle GE, LaRochelle AG, Ratner RE, et al. Recovery of the hypothalamicpituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 1993;95(3):258–64. [63] Christy NP. Corticosteroid withdrawal. In: Bardin CW, editor. Current therapy in endocrinology and metabolism. 3rd edition. New York: BC Decker; 1988. p. 113. [64] Schlaghecke R, Kornely E, Santen RT, et al. The eﬀect of long-term glucocorticoid therapy on pituitary-adrenal response to exogenous corticotropin-releasing hormone. N Engl J Med 1992;326:226–30. [65] Katz HI, Hien NT, Prawer SE, et al. Superpotent topical steroid treatment of psoriasis vulgaris- clinical eﬃcacy and adrenal function. J Am Acad Dermatol 1987;16:804–11. [66] Walsh P, Aeling JI, Huﬀ L, et al. Hypothalamic-pituitary-adrenal axis suppression by superpotent topical steroids. J Am Acad Dermatol 1993;29:501–3. [67] Lipworth BJ. Systemic adverse eﬀects of inhaled corticosteroid therapy: a systematic review and meta-anyalysis. Arch Intern Med 1999;159:941–55. [68] Wong J, Black P. Acute adrenal insuﬃciency associated with high dose inhaled steroids. BMJ 1992;304:1415. [69] Graber AL, Ney RL, Nicholson WE, et al. Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab 1965;25:11. [70] Livanou T, Ferriman D, James VHT. Recovery of hypothalamic-pituitary-adrenal function after corticosteroid therapy. Lancet 1967;2:856–9. [71] Tordjman R, Jaﬀe A, Grazas N, et al. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995;80:1301–5. [72] Bromberg JS, Alfrey EJ, Barker CF, et al. Adrenal suppression and steroid supplementation in renal transplant recipients. Transplantation 1991;51:385–90. [73] Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid requirements in secondary adrenal insuﬃciency. Surgery 1997;121:123–9. [74] Udelsman R, Norton JA, Jelenich SE, et al. Responses of the hypothalamic-pituitaryadrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metab 1987;64(5):986–94. [75] Lamberts SW, Bruining HA, deJong FH. Corticosteroid treatment in severe illness. N Engl J Med 1997;337:1285–92.

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Perioperative care of the patient with renal failure Anthony J. Joseph, MDa,*, Steven L. Cohn, MD, FACPb a

Division of Nephrology, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 52, Brooklyn, NY 11203, USA b Division of General Internal Medicine, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 68, Brooklyn, NY 11203, USA

Chronic kidney disease is increasingly prevalent in the United States [1]. The Third National Health and Nutrition Examination Survey from 1988 to 1994 estimated that 8 million individuals had moderate to severe chronic kidney disease characterized by a glomerular ﬁltration rate (GFR) lower than 60 mL/min/1.73m2 [1]. According to the 2001 report of the U.S. Renal Data System (USRDS), moreover, the point prevalent count of patients with end-stage renal disease (ESRD) on December 31, 1999, was 328,695 [2]. As the number of Health Maintenance Organizations (HMOs) has escalated, general practitioners and internists have become the central or main physicians for many suﬀering from chronic kidney disease and ESRD. Additionally, surgeons, intensivists, and hospitalists care for people who undergo surgery—one of the most common therapeutic interventions associated with acute renal failure (ARF). For example, 27% of the 748 cases of ARF reported by Liano and Pascual were thought to originate in the postoperative period [3]. Because of the complexity and pervasiveness of renal failure, it is important that non-nephrologists be acquainted with perioperative care in those aﬄicted with this disorder. This article addresses the prevention of postoperative ARF as well as the perioperative care of ESRD patients undergoing surgery.

* Corresponding author. E-mail address: [email protected] (A.J. Joseph). 0025-7125/03/$ - see front matter 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 2 - 9

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Postoperative acute renal failure Epidemiology ARF is broadly deﬁned as a sudden deterioration of renal function resulting in retention of nitrogenous wastes including urea and creatinine [4]. In many reports, the deﬁnition of ARF is based on serum creatinine which is a poor marker of renal function. The degree of creatinine elevation necessary to fulﬁll the diagnosis of ARF varies among authorities. For some researchers, ARF is present when there is a 25–50% increase in the serum concentration from baseline. Irrespective of a lack of consensus on the definition of ARF, two important facts should be remembered. Firstly, preexisting chronic kidney disease is a strong risk factor for the development of ARF [5–7]. Secondly, signiﬁcant impairment of renal function, characterized by creatinine levels >1.5–3.0 mg/dL, introduces a serious risk that imposes a major threat to patients who have had surgery [8–10]. Chertow et al reported that acute renal failure requiring renal replacement therapy occurred in 1.1% of 42,773 individuals from 43 Veterans Aﬀairs (VA) medical centers who had cardiac surgery [5] and 0.6% of 87,078 general surgery patients from the National VA Surgical Risk Study [11]. ARF is independently associated with early mortality following cardiac surgery, even after adjustment for comorbidity and postoperative complications. For example, the ﬁrst aforementioned study also revealed that the 30day mortality for subjects with acute renal failure was 63.7% compared with 4.4% for those with normal renal function (P < 0.0001) [5]. Furthermore, in a recent report by Conlon et al. analyzing data from 2672 patients undergoing coronary artery bypass grafting (CABG), 211 (7.9%) individuals developed surgery-induced ARF. The mortality for patients who contracted ARF was 14% (odds ratio 15, P ¼ 0.0001) compared with 1% among those without ARF. In addition, mortality for CABG patients who received some form of dialysis was 28% (odds ratio 20, P ¼ 0.0001) as opposed to 1.8% among people who did not require renal replacement therapy [12]. Pathophysiology Usually, postoperative ARF is categorized as prerenal, intrinsic or renal, and postrenal. This classiﬁcation may prove useful in determining the physiologic mechanism responsible for the GFR reduction or in establishing a diﬀerential diagnosis. Prerenal ARF results from diminished renal perfusion caused by volume depletion and/or hypotension. Intraoperative hormonal changes, secondary to stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone axis, compromise GFR by inducing aﬀerent arteriolar renal vasoconstriction. Simultaneously, angiotensin II modulates its own vasoconstrictive impact by stimulating renal release of prostaglandins. In the postoperative period, decreased glomerular perfusion may be caused by volume depletion, redistribution of extracelluar ﬂuid or cardiac

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malfunction as in myocardial infarction, congestive heart failure, and tamponade [13,14]. As indicated by several reports, people with the renal or intrinsic type of ARF have diminished baseline GFR because of diabetes, hypertension, or vascular disease. Sustained hypotension and volume depletion, prolonged cardiopulmonary bypass or supra-aortic clamping time, sepsis, and nephrotoxin exposure (aminoglycosides, radiocontrast materials, myoglobin, hemoglobin) may precipitate acute renal failure [5–7,9,15–20]. Postrenal ARF occurs because of tubular obstruction exempliﬁed by sulfonamide and acyclovir crystals or bladder dysfunction [21]. Pelvic or ureteral obstruction caused by blood clots, sloughed papillae, and retroperitoneal hematoma causes ARF only when bilateral or unilateral in a patient with a single functioning kidney. Clinical and laboratory evaluation The approach to patients with postoperative ARF necessitates a thorough history and chart review and a comprehensive physical examination in combination with key laboratory measurements such as complete blood count with leukocyte diﬀerential, metabolic panel, coagulation proﬁle, microscopic urinalysis, and urine electrolytes. Focused history and record analysis provide important information about volume depletion, hypotension, cardiopulmonary bypass or supraaortic clamping time, arrhythmia, and exposure to endogenous (myoglobin, hemoglobin) and exogenous (drugs) nephrotoxins. A good physical examination yields valuable clues. Skin inspection for rash, purpura, livedo reticularis, gangrene, and digital cyanosis provides clues to raising the diagnosis of acute interstitial nephritis, renal artery, or atheromatous embolism. A thorough evaluation of the cardiovascular and volume status is the most important facet in the diagnosis and management of ARF, as prerenal azotemia is a correctable condition. Assessing daily ﬂuid intake, output, and body weights is valuable when estimating volume status. Heart rate and blood pressure should be measured in the supine and seated with dangled legs positions whenever possible. Careful evaluation of heart and lungs is paramount. The care of severely ill people with sepsis, peripheral edema, third-spacing losses, or underlying heart disease may require insertion of a Swan-Ganz catheter to measure capillary wedge pressure, cardiac output, and systemic vascular resistance. Abdominal palpation may reveal upper quadrant tenderness secondary to ureteral obstruction or renal infarction, as well as a palpable bladder caused by a blocked bladder catheter or prostatic enlargement. Look for leg edema and muscle tenderness from rhabdomyolysis. Occasionally, patients manifest signs of uremic encephalopathy including confusion, stupor, coma, and seizures. Note that altered mental status is also one of the signs of systemic atheroembolism. Elevation of BUN and serum creatinine concentration is the hallmark of renal failure. In cases of prerenal azotemia and in some patients with

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obstructive uropathy, the serum BUN/creatinine ratio is elevated above 20:1 because of enhanced reabsorption of urea. Urinalysis (UA) is the most important test in the diagnostic work up of ARF. A normal UA is compatible with prerenal and postrenal azotemia, whereas the presence of many brown granular casts, renal tubular epithelial cells signals the possibility of ischemic or nephrotoxic ARF. A dipstick reading strongly positive for heme pigments in the absence of a signiﬁcant number of red blood cells suggests rhabdomyolysis or intravascular hemolysis. Eosinophiluria discerned by Hansel’s stain associated with fever, rash, and peripheral eosinophilia are typical manifestations of acute interstitial nephritis [22]. The combination of eosinophiluria and ARF following an arteriographic procedure or in a patient with peripheral vascular disease evokes the diagnosis of atheroembolic renal disease. The fractional excretion of sodium (FENa), calculated from a random urine specimen, is a useful tool in this setting [23]. FENa (%) is deﬁned as: {(Urine [Na] /Plasma [Na]) ‚ (Urine [Cr]/Plasma [Cr])} 100. An FENa < 1% favors the diagnosis of prerenal azotemia whereas, in acute tubular necrosis, it is usually >1%. There are exceptions, however. For example, some subjects with ARF secondary to severe burns or underlying liver disease have a FENa < 1%. Conversely, a patient with prerenal azotemia caused by administration of a loop diuretic may have a FENa > 1% [23]. The creatinine clearance can be quickly estimated by using the CockcroftGault equation [24]: For men: (140-age) lean body mass (kg) ¼ creatinine clearance in mL/min 72 serum creatinine (mg/dL) For women: 0.85 value for men For men, lean body mass (LBM) ¼ 106 lb for the ﬁrst 60 inches, then 6 lb for each additional inch of height. For women, LBM ¼ 100 lb for the ﬁrst 60 inches, then 5 lb for each additional inch of height. Severe renal dysfunction may exist in presence of a normal serum creatinine. Consider the case of an 85-year-old woman who weighs 48 kgs and has a serum creatinine of 1.3 mg/dL. The estimated creatinine clearance by the Cockroft-Gault formula is 24 mL/min, which is compatible with severe renal failure. Renal ultrasonography usually detects dilatation of the collecting system and ureters when obstructive uropathy causes ARF. Prevention of postoperative acute renal failure The high mortality rate of postoperative ARF, particularly after cardiac surgery, makes prevention a key objective in the overall management of this renal disease. Before surgical interventions, particularly those capable of inducing renal ischemia, one must identify potential risk factors such as volume depletion, hypotension, sepsis, nephrotoxin exposure, obstructive jaun-

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dice, and pre-existing chronic kidney disease. Elective surgery should be delayed until those abnormalities are improved. Correction of certain risk factors reduces the threat and ameliorates the consequences of this devastating complication, meaning postoperative ARF. Chertow et al have designed a preoperative renal risk stratiﬁcation for subjects scheduled to have coronary artery bypass grafting. The goal is not to withhold or advise against required cardiac surgery, but to target high-risk patients for interventions [5]. Volume depletion and hypotension must be corrected promptly. If persistent, they can induce renal ischemia and tubular cell apoptosis with tubular obstruction of sloughed papillae [25]. Sepsis, by causing hypotension, direct renal vasoconstriction, and release of cytokines can provoke postoperative ARF [26]. Hospital-acquired infections should be prevented and treated whenever possible with non-nephrotoxic drugs [27,28]. Acute renal failure secondary to aminoglycoside nephrotoxicity occurs in 10–20% of patients given these drugs [18]. For most patients, it should not be diﬃcult to avoid aminoglycosides. Nonsteroidal anti-inﬂammatory drugs (NSAIDs), including ketorolac, a parenteral compound, can cause hemodynamically-mediated ARF by inhibiting the synthesis of prostaglandins which act to preserve renal blood ﬂow and GFR in subjects with volume depletion, pre-existing renal insuﬃciency, congestive heart failure, and liver cirrhosis [29,30]. Selective cyclooxygenase (COX)-2 inhibitors, like other NSAIDs, must be used cautiously or not at all in patients with predisposing diseases [31]. Because of their inhibitory eﬀect on the eﬀerent arterioles, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockade (ARB) drugs may worsen ARF and should be withheld. Radiocontrast nephrotoxicity, perhaps caused by alterations in nitric oxide production and direct toxic eﬀects of contrast agents, is another major cause of ARF [32,33]. Prevention, which is the best treatment for this type of kidney disease, includes avoidance of contrast media in at-risk subjects whenever possible, minimization of contrast load, and hydration before and after radiographic procedure [34,35]. A highly encouraging report indicates that pretreatment with N-acetylcysteine may protect against radiocontrastinduced nephropathy [36]. In the postoperative period, eﬀort should be made to diagnose ARF early, eliminate causative agents, and prevent further insults. For example, we should be alert for tamponade caused by large pericardial eﬀusion after cardiac surgery. Immune complex-mediated glomerulonephritis secondary to visceral abscesses subsides with drainage and appropriate antibiotherapy [27]. Early and aggressive hydration followed by mannitol and sodium bicarbonate infusion may minimize pigment-induced ARF, complicating major vascular surgery [37,38]. Obstructive uropathy can be easily treated by relieving the obstruction. Throughout the world, physicians including nephrologists have employed several pharmacologic maneuvers with the hope of preventing or improving

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ARF, precluding the need for dialysis, and reducing mortality. At this date, no hard data has proven their eﬃcacy in humans, and some may even be harmful. Brown et al, in a controlled and randomized trial, showed that a high dose of furosemide (3 g) given intravenously or orally over 24 hrs prevented or reversed oliguria in 24 of 28 patients of the test group versus 2 of 27 of the control group, but the number of dialyses, duration of renal failure, and mortality were not diﬀerent in the two groups. Moreover, deafness occurred in two individuals given furosemide and was permanent in one [39]. Many physicians believe that low-dose dopamine aﬀects the outcome of ARF. Recently, Bellomo et al, in a multicenter, randomized, double-blind, placebo-controlled study of 328 patients admitted to 23 intensive care units, found that low-dose dopamine conferred no signiﬁcant protection from renal dysfunction. There was no diﬀerence between the dopamine and placebo groups in peak serum creatinine concentration during treatment (245 versus 249 micromol/L; P ¼ 0.93), in the number of patients whose creatinine level exceeded 300 micromol/L (56 versus 56; P ¼ 0.92), or who required renal replacement therapy (35 versus 40; P ¼ 0.55) [40]. Another group of researchers, in a well-designed trial, concluded that dopamine and furosemide did not have any renoprotective eﬀect during cardiac surgery. Their study suggested, furthermore, that furosemide caused renal dysfunction [41]. Improvement in renal function and histopathology in laboratory animals with renal failure, treated atrial natriuretic peptide (ANP), and prompted the study of anaritide, a synthetic form of ANP, in patients with ARF. The Auriculin Anaritide Acute Renal Failure Study Group conducted a multicenter, randomized, double-blind, placebo-controlled trial of anaritide in 504 critically ill patients with acute tubular necrosis. Study subjects received a 24-hour intravenous infusion of either anaritide or placebo. The primary end point was dialysis-free survival for 21 days after treatment. The rate of dialysis-free survival was not diﬀerent in the two groups (43% in the anaritide group versus 47% in the placebo group, P ¼ 0.35). In a subgroup of 120 subjects with oliguria, dialysis-free survival was 27% in the anaritide group and 8% in the control group (P ¼ 0.008). Conversely, nonoliguric patients had inferior survival with anaritide, 48% versus 59% dialysis-free survival with placebo, P ¼ 0.03 [42]. A similarly designed trial, enrolling only patients with oliguric acute renal failure, failed to confer any advantage to anaritide [43]. At this time, ANP and its synthetic form, anaritide, are not employed in the management of acute renal failure. Beside conservative management of ARF complications, renal replacement therapy is widely utilized to manage patients with ﬂuid overload, electrolyte abnormalities, particularly hyperkalemia, or acid-base perturbation. Because the mortality rates of ARF have remained elevated, several clinical trials have examined the role of membrane biocompatibility, timing, type, and adequacy of renal replacement therapy on clinical outcomes. At this

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writing, none of those dialysis-related variables have been securely linked to improved survival in people aﬀected by ARF [44,45]. Frequently, the decision as to which membrane or technique for dialysis is selected depends on patients’ condition, costs, and local circumstances such as the availability of an on-site (in the ICU) skilled nurse for hemodialysis and/or a nephrologist familiar with continuous renal replacement therapy. Whether or not dialysis adequacy has an impact on survival of patients with postoperative ARF, erring in favor of too much dialysis is preferred. Perioperative care of ESRD patients According to the 2001 report of the U.S. renal data system, diabetes and hypertension in 1999 were listed as the chief causes of end-stage renal disease in North America, accounting for 68.2% of incident ESRD patients funded by Medicare [2]. Hypertensive and especially diabetic individuals suﬀering from ESRD have serious comorbid conditions such as myocardial dysfunction, coronary artery, and peripheral vascular diseases. Furthermore, the loss of renal reserve hampers their ability to handle ﬂuids, sodium, and acid loads, eliminate potassium, and excrete and/or metabolize medications including antibiotics, analgesics, and anesthetics. Consequently, they may be unable to compensate for normal stresses of surgery. For instance, hyperkalemia resulting from blood products, muscle trauma, hemolysis, metabolic acidosis, and hematoma resorption occurs frequently after surgery. People with ESRD are immunosuppressed and more susceptible to infections. An imprecise number of uremic patients furthermore have bleeding diathesis secondary to platelet dysfunction. Therefore, it is not surprising that individuals with ESRD have an increased surgical morbidity and mortality whose rates vary according to the burden of associated ailments, and the type and emergent nature of the operation. Kellerman, analyzing data from eight studies, reported that the overall mortality of ESRD patients undergoing general surgery was approximately 4%, ranging from 0–47% in emergency cases [13]. The morbidity rate was 54%, varying from 12–64%. In another review involving 13 studies, the same author indicated mortality and morbidity rates were 10% and 46%, respectively, in patients undergoing cardiac surgery [13]. Clinical and laboratory evaluation Perioperative care of people with known ESRD begins with an in-depth interview, physical examination, electrocardiogram, and screening laboratory tests including a blood count, metabolic panel, serum magnesium, and phosphorus levels, as well as a coagulation proﬁle. The initial goal is detect comorbid conditions that might adversely impact morbidity and mortality perioperatively. Typically, ESRD patients scheduled to have surgery may become symptomatic with coronary artery disease or myocardial dysfunction,

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ﬂuid and electrolyte abnormalities, hypotension or uncontrolled hypertension, anemia, and a bleeding diathesis. Therefore, the main objective is to correct or improve those disorders before and/or after surgery. Prevention of infections, adjustment of medications, and glycemic control should also be a concern. Cardiac evaluation Cardiac disease is the leading cause of death in both diabetic and nondiabetic patients with ESRD. It accounts for almost 50% of deaths among prevalent ESRD patients whose cardiovascular mortality rates are approximately 10–20 times that of the general population [2,46]. Coronary artery disease (CAD), the key factor in the pathogenesis of cardiac disease, is common among ESRD patients, with a prevalence close to 40% [46]. Congestive heart failure, with a prevalence of 40% among hemodialysis and peritoneal dialysis patients, is an independent predictor of death [46]. Beside coronary artery disease, left ventricular hypertrophy whose prevalence is 75% also constitutes a risk factor for the development of CHF [46]. Clearly, cardiovascular disease can complicate perioperative care in individuals with renal failure. For the general population, clinicians integrate information from the history, physical examination, and electrocardiogram in order to develop an initial estimate of perioperative risks. In people aﬀected by chronic renal disease, deﬁning a cardiovascular risk proﬁle based on clinical variables is difﬁcult. Although many subjects with both kidney failure and coronary artery disease have a typical history of exertional dyspnea and angina or hypotension-induced chest pain during dialysis, 23–40% have silent ischemia documented by Holter monitoring on and oﬀ dialysis [47,48]. Several researchers found, furthermore, that approximately 75% of their diabetic patients with angiographically signiﬁcant CAD were asymptomatic [49,50]. The inverse situation, namely angina without CAD, is also common. Rostand et al indicated that 47% of their patients complaining of angina had trivial or absent coronary artery occlusion [51]. Assessing functional capacity in ESRD patients is often impossible because of anemia or dialysis-induced weakness, diabetic neuropathy, claudication, or joint and bone pain secondary to renal osteodystrophy and amyloidosis. Also, clinical manifestations of CHF may be diﬀerent in dialysis patients from those in other patient cohorts. Ultraﬁltration, in very compliant subjects, minimizes ﬂuid accumulation and negates the typical symptoms and signs of CHF. Intradialytic hypotension may be the only indication of left ventricular dysfunction [46]. These points should be kept in mind when evaluating ESRD patients. Because typical manifestations of cardiac disease may be lacking in ESRD patients, we have to turn to noninvasive tests such as echocardiography, thallium stress testing, dipyridamole thallium imaging, combined dipyridamole-exercise thallium scintigraphy, and dobutamine stress echo-

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cardiography. Echocardiography in 433 subjects at initiation of renal replacement therapy revealed that 15% had systolic dysfunction, 32% demonstrated left ventricular dilatation with preserved systolic function, and 74% displayed concentric left ventricular hypertrophy [52]. The practicability of exercise testing, even combined with thallium imaging, is limited because patients’ physical drawbacks or their inability to reach target heart rate. There are also concerns about diﬃculties in the interpretation of exercise electrocardiographic tracings in the presence of left ventricular hypertrophy (LVH). Additionally, though thallium stress imaging has a sensitivity of 90% for detection of CAD, its speciﬁcity is only 68% [53]. As an alternative to stress testing in ESRD patients, dipyridamole thallium imaging is hampered by widely varying sensitivities and speciﬁcities. In nonuremic subjects without diabetes, the sensitivity and speciﬁcity of myocardial perfusion imaging have been reported to be 79% and 76% [54]. For ESRD patients, sensitivity and speciﬁcity vary respectively from of 37% to 86% and from 73% to 79% [55]. Fortunately, a promising report indicates that the combination of dipyridamole and exercise thallium imaging may be more accurate in dialysis patients [56]. Dipyridamole-exercise thallium imaging and coronary angiography were both performed prospectively in 60 asymptomatic hemodialysis patients. The sensitivity, speciﬁcity, positive and negative predictive values, and overall accuracy of thallium imaging were 92, 89, 71, 98, and 90%, respectively. After a median follow-up of 2.8 years, the probability of surviving without a coronary event was signiﬁcantly higher in patients with normal thallium image than in those with an abnormal test (adjusted risk ratio 9.2; P < 0.005) [56]. Dahan et al explain their ﬁndings by suggesting that dipyridamole is a less sensitive stimulus for detection of CAD than maximal exercise, but its use with submaximal exercise may be as accurate as maximal exercise alone. Dobutamine stress echocardiography (DSE) has been very valuable in ﬁnding CAD in renal transplant patients when the clinical event rate is used for test validation [57,58]. Conversely, DSE is an imperfect screening test when quantitative coronary angiography (QCA) is used to detect CAD. The sensitivity and speciﬁcity of DSE for CAD diagnosis were 52% and 74%, respectively, compared with QCA stenosis of 50% or greater; 75% and 71% compared with QCA stenosis >70%; and 75% and 76% for stenosis >75% by visual estimate [59]. The noninvasive detection of CAD in people aﬀected by ESRD remains problematic. Coronary angiography, the gold standard for the diagnosis of CAD, is invasive and costly and cannot be used as a screening method. It should be reserved for people with a high risk of CAD and for those who would beneﬁt from revascularization. For the general ESRD population, no published practice guidelines have been devised for perioperative cardiovascular evaluation for noncardiac surgery. De Lemos and Hillis, proposing a diagnostic management strategy for

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screening for renal transplantation, stratiﬁed their patients into groups with low, intermediate, and high risk [60]. Transplant candidates younger than 50 years, without diabetes or symptoms suggestive of CAD or CHF but with a normal EKG, had a low cardiovascular risk and did not require invasive cardiac evaluation. Individuals older than 50 years or diabetic without symptoms of CAD or CHF were at intermediate risk and should have noninvasive testing and subsequently coronary angiography if either dipyridamole thallium imaging or dobutamine echocardiography is positive. All high-risk patients, meaning those with symptoms of CAD, electrocardiographic evidence of previous myocardial infarction, or congestive heart failure should have cardiac catheterization before renal transplantation. This management strategy is derived from studies involving renal transplant candidates who are, in general, healthier than the rest of the ESRD population. Also, renal transplantation is an intermediate cardiac risk procedure. Although the ESRD patient may be able to tolerate the surgical procedure short-term, the long-term prognosis is equally important because of the limited availability of donor kidneys. In emergency cases, one has to weigh the beneﬁts of the surgical procedure against the risk of a fatal or nonfatal cardiac event. Fluid and electrolyte management Whether or not dialysis has been initiated, euvolemia should be attained when ESRD patients are being prepared for surgery. For those individuals not on replacement therapy, a euvolemic state can be achieved with diuresis or hydration as appropriate. In other instances, euvolemia is securable with dialysis. Currently, there is no very good measure of adequacy for ﬂuid removal in dialysis patients. In practice, notion of dry weight, the lowest weight tolerated without intradialytic symptoms or hypotension in the absence of overt ﬂuid overload, is employed [61]. Subjects who have a stable dry weight with minimal ﬂuid gain between treatments can undergo emergency surgery without dialytic therapy, provided there is no other indication for dialysis. Establishing the quantity of ﬂuid to be removed is diﬃcult when ﬂuid overload is accompanied by muscle mass wasting or left ventricular dysfunction exists. Fluid overload is deﬁnitely an indication for preoperative dialysis. Cautious volume extraction is preferable to prevent unwanted bouts of intradialytic hypotension. Furthermore, excessive ﬂuid loss may also worsen hypotension secondary to anesthesia-induced vasodilation. At times, ultraﬁltration or dialysis must be oﬀered postoperatively in patients receiving a large ﬂuid volume during surgery. It is unusual to ﬁnd major changes in serum sodium concentration in ESRD. Subjects receiving dialysis have an obvious and ready means for adjusting water surplus or deﬁcit [62]. Hyperkalemia may occur before and after surgery. Dialysis is the treatment of choice in both instances when the serum potassium exceeds

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6 mEq/L. Medical treatment of hyperkalemia has to be initiated when surgery is emergent or dialysis is not readily available [62,63]. If the EKG shows signs of a dangerous arrhythmia, cardioprotection or membrane stabilization is accomplished by infusing 10 mL of calcium gluconate with ECG monitoring. Insulin is very eﬀective in driving potassium into the cells of patients with renal failure by stimulating the activity of a Na-K-ATPase pump. Consequently, it increases the net movement of extracellular potassium into the intracellular ﬂuid. Although glucose infusion induces endogenous insulin secretion, it is less eﬀective in the management of hyperkalemia. Patients should be monitored carefully for hypoglycemia. b2-adrenergic agonists also shift potassium into the cells through Na-KATPase stimulation. Caution is warranted with b2-agonists because of the risk of tachycardia and arrhythmias which can be dangerous in patients with CAD or with the administration of anesthesia. Serum potassium reduction with sodium bicarbonate is negligible unless there is moderate or severe metabolic acidosis. b2-agonists, sodium bicarbonate, glucose, and insulin drive potassium from one milieu to another and correct hyperkalemia only temporarily. Removing a potassium surfeit is accomplished with sodium polystyrene sulfonate. Forty grams of the resin dissolved in 80 mL of sorbitol is a standard oral dose. Alternatively, 50–100 g in 200 mL of water is given as a retention enema. Oral or rectal dose of resin should be repeated every 2–4 hours. It is important to remember that the resin can cause intestinal necrosis, especially when it is given with sorbitol within the ﬁrst week after surgery. Anemia and bleeding diathesis The ideal hemoglobin level for people with ESRD remains a controversial issue. The Anemia Work Group of the National Kidney FoundationKidney Disease Outcome Quality Initiative (NKF-K/DOQI) recommends that the hemoglobin level be maintained between 11 and 12 g/dL [64]. By consensus, transfusion is appropriate for people with hemoglobin levels of 8–10 g/dL when extensive surgery is contemplated or excessive blood loss is a possibility. For elective surgery, the target level of hemoglobin can be reached over weeks by increasing erythropoietin dose, adding intravenous iron if necessary, and by transfusion of packed red blood cells. Postoperative bleeding occurs for many reasons and a speciﬁc cause must be sought. Heparin-induced bleeding is unusual as the drug is withheld during dialysis on the day of surgery. During the postoperative period, dialysis patients undergo heparin-free dialysis for at least 24 hours. Uremic patients may have platelet dysfunction resulting in an increased bleeding tendency manifested by a prolonged bleeding time [65]. Individuals with a prior history of uremic bleeding must be treated before surgery. Dialysis, desmopressin (dDAVP, l-desamino-8-d-arginine vasopressin) administered intravenously or intranasally at a dose of 0.3 lg/kg, and cryoprecipitate are

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capable of stopping the bleeding [66]. Raising the hematocrit to 30% improves uremic bleeding [67]. Intravenous conjugated estrogens (0.6 mg/ kg) are an adequate alternative when they are given 4 or 5 days before surgery [68]. Hypotension and hypertension Hypotension or hypertension may aﬄict dialysis patients. Hypotension can be episodic and intradialytic or persistent [69]. The ﬁrst type occurs in up to 20% of the dialysis population and is caused by several factors such as rapid or excessive ﬂuid removal, left ventricular and autonomic dysfunction, low sodium concentrate, and intake of antihypertensive drugs before dialysis. Usually, the renal team corrects those abnormalities by adjusting the dry weight, increasing dialysate sodium concentration, and by employing steady ultraﬁltration [69]. Treating anemia with erythropoietin, increasing the dialysate calcium concentration, and using cool temperature hemodialysis may improve cardiovascular performance in many dialysis patients [69]. Approximately, 5% of long-term patients suﬀer from persistent, chronic hypotension which limits ﬂuid removal during hemodialysis. Midodrine, a selective alpha-1 adrenergic agonist, is useful in this condition [70]. During the postoperative period, hypotension may occur because hemorrhage, arrhythmia, pericardial tamponade, or sepsis. Appropriate treatment of the causative factor will improve hypotension. Fluid retention, augmented sympathoadrenal discharge, endothelin increase, and nitric oxide reduction likely represent the primary factors underlying the hypertension of renal failure [62,71]. Optimization of ﬂuid status with dialysis and ultraﬁltration lowers elevated blood pressure. Preoperative anxiety and withholding of antihypertensive drugs worsen hypertension. When ﬂuid removal is not successful or dialysis cannot be performed immediately, labetalol, enalaprilat, or hydralazine can be administered intravenously. In the intensive care units, intravenous nitroprusside can be used for 1 or 2 days. Accumulation of thiocynate, a metabolite of nitroprusside, can occur and cause anorexia, disorientation, and toxic psychosis in ESRD patients. Drug therapy Adverse drug response occurs more frequently in uremic patients than in people with normal GFR [72]. Abnormalities of drug metabolism with renal failure consist of prolonged half-life of drugs and active metabolites excreted by the kidneys as well as changes in bioavailability, volume of distribution, and protein binding [73]. Adverse drug reactions can aﬀect all organs including the failing kidneys. It is prudent to abstain from prescribing nephrotoxic drugs for subjects with renal failure. Some reports suggest that the presence of residual renal function is associated with a lower mortality risk in dialysis

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patients [74,75]. As a rule, before administering any drug to subjects with renal failure, one should determine if a dosage reduction is necessary or if a particular drug should be avoided. The American College of Physicians and the American Society of Internal Medicine published comprehensive guidelines for drug prescribing in renal failure. Medication dosing varies with the degree of renal failure, drug biotransformation, and type of renal replacement therapy [73]. Sedative premedication with benzodiazepines is advised only in reduced doses because chronic renal failure increases the free fraction of those preparations. For example, dialysis patients receiving alprazolam may develop psychomotor and memory abnormalities [76]. Meperidine, whose metabolite is normeperidine, can produce excitatory central nervous system eﬀects including seizures and should be avoided [77]. Caution is warranted with morphine because its conjugation with glucuronic acid results in morphine-6-glucuronide which possesses opioid activity and is excreted by the kidney [78]. Fentanyl is metabolized in the liver, with only 7% excreted unchanged in the urine. It is moderately bound to plasma protein and its volume of distribution is large. Premedication with fentanyl is safe in ESRD [79]. Inhaled anesthetics proﬀer advantage over intravenous agents because they are eliminated primarily via the lungs and not the kidneys. Halothane, desﬂurane, and nitrous oxide can be administered to kidney failure patients [79]. Absence of signiﬁcant change in protein binding and clinical eﬀects of metabolites associated with hepatic metabolism make propofol a suitable agent for the induction of general anesthesia [80,81]. Succinylcholine, used without diﬃculty in people with renal failure, can cause hyperkalemia— particularly in traumatized, burned, or neurologically injured patients. Succinylcholine, in large doses, should be avoided as its metabolite, succinylmonocholine, is weakly active and excreted by the kidney [79]. Nondepolarizing muscle relaxants like atracurium are the blocking agents of choice for ESRD patients [79]. Antibiotic treatment is common during the perioperative period either for prophylaxis or treatment of infections. Some studies indicate that preoperative antibiotics reduce the risk of infections following vascular access procedures or peritoneal catheter placement [82,83]. The use of low-molecular-weight heparins remains controversial. Data concerning their pharmacokinetic and pharmacodynamic proﬁles in patients with renal failure are limited. It has been suggested that their doses be decreased by 50% when the GFR is lower than 10 mL/min [73]. Glycemic control Surgical stress and certain anesthetic agents stimulate the release of counter-regulatory hormones such as glucagon, growth hormone, cortisol, epinephrine, and norepinephrine, whose combined eﬀect worsens insulin deﬁciency and resistance [84]. Consequently, hyperglycemia and even

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ketogenesis in type 1 diabetic patients may take place during or after surgery. Additionally, those receiving insulin or oral agents are at risk for hypoglycemia because of necessary preoperative fasting. The goal in managing diabetic uremic patients is to maintain plasma glucose levels between 150 and 200 mg/dL during surgery to protect against hypoglycemia [85]. After surgery, targeting blood glucose levels between 120 and 180 mg/dL reduces morbidity attributed to ﬂuid and electrolyte imbalance, decreases the risk of infection, and perhaps accelerates the wound-healing rate [86]. In planning management, the type of diabetes and surgical procedure, the current therapeutic regimen, and degree of recent glycemic control are considered. Numerous protocols have been suggested for treating diabetic patients undergoing surgery. Generally, no intraoperative treatment is recommended for people treated with diet alone or diet and oral hypoglycemic agents if glycemic control is acceptable (80–200 mg/dL). Subjects receiving insulin or poorly controlled type 2 patients require insulin during the perioperative period. Preoperative insulin recommendations are complex. Key to proper management is reliance on frequent ﬁnger stick glucose measurements [85]. For early-morning procedures, insulin can be administered subcutaneously. Continuous insulin infusion is the most rational and physiologic approach for insulin-treated patients undergoing long, complex operative procedures or for people requiring surgery while in ketoacidosis [64,84– 87]. After outpatient surgery, a preoperative regimen can be reinstituted when patients resume eating. Diabetic control is diﬃcult in those with gastroparesis or when surgical procedures interdict oral intake. Summary Preventing postoperative ARF, especially in subjects with pre-existing chronic kidney disease, and caring for ESRD patients undergoing surgery are challenging and best accomplished by a team comprised of primary care physician, nephrologist, cardiologist, surgeon, anesthesiologist, endocrinologist, and nutritionist. Elimination of risk factors for ARF whenever possible, as well as early diagnosis, may improve the outcome of this devastating illness. Drugs capable of preventing or changing the course of postoperative ARF may be available soon. For uremic patients, a comprehensive approach is necessary to minimize morbidity and mortality imposed by numerous comorbid conditions. References [1] NKF-K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classiﬁcation, and stratiﬁcation. Am J Kidney Dis 2000;37(suppl 1):S1–S266. [2] United States Renal Data System. USRDS 2001 Annual data report: atlas of end-stage renal disease in the United States. Bethesda, MD: National Institute of Health, National Institute of Diabetes and Kidney Diseases; 2001.

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[3] Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter community-based study. Kidney Int 1996;50(3):811–8. [4] Anderson RJ, Schrier RW. Clinical spectrum of oliguric and non-oliguric acute renal failure. In: Brenner BM, Stein JH, editors. Acute renal failure (Contemporary issues in nephrology, vol. 6). New York: Churchill Livingstone; 1980. [5] Chertow G, Lazarus JM, Christiansen CL, et al. Preoperative renal risk stratiﬁcation. Circulation 1997;95(4):878–84. [6] Godet G, Fleron MH, Vicaut E, et al. Risk factors for acute postoperative renal failure in thoracic or thoracoabdominal aortic surgery: a prospective study. Anesth Analg 1997; 85(6):1227–32. [7] Suen WS, Mok CK, Chiu SW, et al. Risk factors for development of acute renal failure (ARF) requiring dialysis in patients undergoing cardiac surgery. Angiology 1998;49(10):789–800. [8] Anderson RJ, O’Brien M, MaWhinney S, et al. Renal failure predisposes patients to adverse outcome after coronary bypass surgery. VA Cooperative Study #5. Kidney Int 1999;55(3):1057–62. [9] Anderson RJ, O’Brien M, MaWhinney S, et al. Mild renal failure is associated adverse outcome after cardiac valve surgery. Am J Kidney Dis 2000;35(6):1127–34. [10] Levy EM, Viscoli CM, Horwitz RL. The eﬀect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275(19):1489–94. [11] Chertow GM, Henderson W, Khuri S, et al. Acute renal failure after non-cardiac surgery: results from the national VA surgical risk study. J Am Soc Nephrol 1997;8:123A. [12] Conlon PJ, Staﬀord-Smith M, White WD, et al. Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999;14(5):1158–62. [13] Kellerman PS. Perioperative care of the renal patient. Arch Intern Med 1994;154(15): 1674–88. [14] Rudnick MR, Bastl CP, Elﬁnbein IB, et al. The diﬀerential diagnosis of acute renal failure. In: Brenner BM, Lazarus JM, editors. Acute renal failure. New York: Churchill Livingstone; 1988. [15] Adiseshiah M, Round JM, Jones DA. Reperfusion injury in skeletal muscle: a prospective study in patients with acute limb ischaemia and claudicants treated by revascularization. Br J Surg 1992;79(10):1026–9. [16] Charlson ME, MacKenzie CR, Gold JP, et al. Postoperative renal dysfunction can be predicted. Surg Gyndcol Obstet 1989;169(4):303–9. [17] Choundry D, Ahmed Z. Drug-induced nephrotoxicity. Med Clin North Am 1997;81: 705–11. [18] Humes HD. Aminoglycoside nephrotoxicity. Kidney Int 1988;33(4):900–11. [19] Neveu H, Kleinknecht , Briet F, et al. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. Nephrol Dial Transplant 1996;11(2):293–9. [20] Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. Kidney Int 1995;47(1):254–61. [21] Perazella MA. Crystal-induced acute renal failure. Am J Med 1999;106(4):459–65. [22] Nolan CR, Anger MS, Kelleher SP. Eosinophiluria: a new method of detection and deﬁnition of the clinical spectrum. N Engl J Med 1986;315(24):1516–9. [23] Brady HR, Brenner BM, Clarkson MR, et al. Acute renal failure. In: Brenner BM, Rector FC, editors. The kidney. Philadelphia: WB Saunders Company; 2000. [24] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41. [25] Rose BD. Pathogenesis and prevention of postischemic acute tubular necrosis. In: Rose BD, editor. UpToDate. Release 10.1;2002. [26] Rose BD. Postischemic and postoperative acute tubular necrosis. In: Rose BD, editor. UpToDate. Release 10.1;2002. [27] Beauﬁls M, Morel-Maroger L, Sraer JD, et al. Acute renal failure of glomerular origin during visceral abscesses. N Engl J Med 1976;295(4):185–9.

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Surgery in the patient with liver disease Mohammed K. Rizvon, MBBSa,b,*, Calvin L. Chou, MD, PhDc,d a

Medical Consultation Service, Nassau University Medical Center, East Meadow, NY, USA b Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA c Department of Medicine, University of California, San Francisco, CA, USA d Medical Consultation Service, San Francisco Veterans Aﬀairs Medical Center, San Francisco, CA, USA

Patients with liver disease undergoing surgery face signiﬁcant postoperative complications. The complex functions of the liver, perioperative stresses, and the unpredictable eﬀects of medications and anesthesia in these patients make preoperative evaluation challenging. A preoperative risk assessment should take into consideration the type of liver disease, the degree of hepatic impairment, and the operative risks associated with the procedure. This article discusses the preoperative evaluation and perioperative management of patients with liver disease scheduled for nontransplant and noncardiac surgeries. Preoperative assessment Asymptomatic patients The preoperative evaluation of patients with liver disease begins with a careful history and physical examination. For many asymptomatic patients, this simple tool serves as a valuable screening test for patients with occult liver disease. Careful attention to history of prior surgeries, jaundice or blood transfusions, use of alcohol and other recreational drugs including use of intravenous drugs, sexual history, and a system review for liver disease including pruritus, easy fatigability, excessive bleeding after minor trauma, abdominal distention, and weight gain should be elicited. Physical * Corresponding author. Medical Consultation Service, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554. E-mail address: [email protected] (M.K. Rizvon). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 3 - 0

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examination should focus on signs of liver disease, such as icterus, pallor, ascites, hepatomegaly, splenomegaly, testicular atrophy, palmar erythema, spider nevi, and gynecomastia. Any suspicion of liver disease should be investigated with blood testing for hepatic function, coagulation studies, electrolytes, and liver enzymes. Routine preoperative testing of liver function, however, is not recommended because of its questionable predictability and low prevalence [1]. In a series of 7620 elective surgical admissions, Schemel [2] found 11 patients with abnormal liver function tests. Elective surgery was canceled in all of these patients. Three patients developed clinical jaundice, but all 11 patients were subsequently found to have liver disease on further testing. Other studies reported signiﬁcant liver disease on follow-up of asymptomatic patients with deranged liver tests [3,4]. In an older study [5], 12 of the 73 patients with postoperative liver dysfunction had unsuspected preoperative liver disease. Asymptomatic patients with signiﬁcantly abnormal liver tests should have elective surgery postponed and investigated to reassess the perioperative risks. Acute and chronic hepatitis Most of the studies in acute hepatitis are old [6–9] and showed signiﬁcant mortality following surgery in patients with liver disease (Table 1). It was common practice more than half a century ago to perform laparotomy for unexplained jaundice lasting more than 6 weeks [10]. A signiﬁcant concern in these patients was the need to diﬀerentiate between medical and surgical causes of jaundice. Strauss et al [9] reported 13% mortality in 73 patients with subacute jaundice who underwent laparotomy for decompression of the common bile duct. Harville and Summerskill [8] reported a postoperative mortality of 10% in 42 patients who had laparotomy done for acute hepatitis. Some

Table 1 Risks of surgery in patients with hepatitis Investigators

Risk factors

Type of surgery

Mortality (%)

Strauss et al [9] Harville and Summerskill [8] Bourke et al [10] Greenwood et al [7]

Viral hepatitis Acute viral hepatitis

Biliary tract surgery Laparotomy

13 10

Hepatitis Alcoholic hepatitis

Laparotomy Open liver biopsy Percutaneous liver biopsy Major surgery

0 58 10

Giller et al [6] Powell-Jackson et al [11]

Alcoholic and viral hepatitis Viral hepatitis, alcoholic hepatitis, and chronic persistent hepatitis

Explorative laparotomy

42 100 in viral and alcoholic hepatitis, 43 in patients with chronic hepatitis

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studies reported higher mortalities. In one study [11] all patients with viral and alcoholic hepatitis died after exploratory laparotomy. Greenwood et al [7] reported a mortality of 58% following open liver biopsy and 10% after percutaneous liver biopsy in patients with acute alcoholic hepatitis. Bourke et al [10] reported no postlaparotomy deaths among 155 patients with various causes of jaundice, although only two of them had hepatitis. Fortunately, with the advent of more advanced laboratory testing and superior imaging techniques, many of these patients do not have to undergo major surgery. It is prudent to postpone elective surgeries during the acute phase of hepatitis and wait until transaminases have returned to the normal range. Patients with milder forms of chronic hepatitis (formerly chronic persistent hepatitis) tolerate surgery well. Runyon [12] reported operative mortality on 20 patients with chronic hepatitis. About two thirds of these patients had chronic active hepatitis, of which four had cirrhosis. There was no postoperative mortality or liver failure. In a recent study, patients with chronic hepatitis C who underwent laparoscopic cholecystectomy had no deaths or complications [13]. Alcoholic liver disease The complications of surgery in patients with alcoholic liver disease depend on the severity of liver pathology. Patients with fatty liver tolerate general surgery well, but patients with alcoholic hepatitis and cirrhosis have increased postoperative mortality and morbidity. In selected cases, preoperative liver biopsy is helpful in knowing both the liver pathology and the extent of steatosis. Elective surgery should be postponed in patients with acute alcoholic hepatitis until liver function tests have returned to normal. Patients with a history of alcohol abuse have increased postoperative complications, such as poor wound healing, infections, delirium, and bleeding. Patients should abstain from using alcohol to improve liver function or should be monitored carefully perioperatively for signs of alcohol withdrawal. Other problems in the perioperative period in these patients include drug interactions of alcohol with commonly administered agents, such as acetaminophen. Cirrhosis Patients with cirrhosis have altered hepatic blood ﬂow [14] that worsens liver function and decreased metabolism of commonly administered drugs. Cirrhotic patients may have nutritional disorders; ascites; abnormal coagulation proﬁle; renal dysfunction; and encephalopathy (or a signiﬁcant risk of developing it) postoperatively. There are more data regarding postoperative complications in cirrhotics than in patients with other liver diseases (Table 2 [17,19,20,22–25,90,92–100]). Postoperative deaths and complications historically have been high, but better preoperative assessment and newer anesthetics and operative techniques show improving survival rates in these patients.

Biliary tract surgery Biliary tract

Various surgeries

Umbilical herniorrhaphy Abdominal surgery

Biliary tract Abdominal surgery

Colectomy

Trauma

Surgery for peptic ulcer disease (Billroth, total gastrectomy, suture, excision, total or partial vagotomies) Abdominal surgery Thoracotomy

Schwartz, 1981 [97] Aranha et al, 1982 [22]

Doberneck et al, 1983 [24]

Pescovitz, 1984 [96] Garrison et al, 1984 [17]

Cryer et al, 1985 [90] Aranha and Greenlee, 1986 [23]

Metcalf et al, 1987 [94]

Tinkoﬀ et al, 1990 [98]

Lehnert and Herfarth, 1993 [93]

Jakab et al, 1993 [92] Ueda et al, 1994 [99]

Type of surgery

Investigators (publication year)

Table 2 Risks of non-laparoscopic surgery in patients with cirrhosis

21 0

54

30

15 83 if PT increased by 2.5 seconds 19.6 Emergency surgery: 45.8 13 Child’s A 10, B 31, C76 Emergency surgery: 57 21 67 Emergency surgery: 86 24

Mortality rate (%)

Child’s score, prothrombin time, and increased WBC Included Child’s C patients

Encephalopathy, ascites, hypoalbuminemia, decreased hemoglobin Ascites, elevated total bilirubin, prolonged PT, hx motor vehicle accident, multiple traumas, blunt abdominal trauma requiring laparotomy. Preoperative hemoglobin < 12g/dL, SBP < 100 mm Hg, prolonged PT, presence of portal hypertension. Unable to calculate Child’s score because of emergent nature of surgery.

Ascites, prolonged PT, low albumin < 3.5 mg/dL Ascites, prolonged PT, need for emergent surgery

Bilirubin > 3.5, alk phos > 70, increased PT > 2 s, increased PTT > 2s, emergency surgery, GI tract surgery, ascites, blood loss >IL, and postoperative complications 96 Total cases; emergent surgery associated with increased mortality Child class, increased bilirubin, decreased albumin, ascites, malnutrition, active infection, increased WBC, increased PT, increased PTT, need for emergency surgery

High bilirubin, blood transfusion, prolonged PT Increased PT > 2.5 s

Prognostic factors/comments

214 M.K. Rizvon, C.L. Chou / Med Clin N Am 87 (2003) 211–227

Abdominal surgeries

Abdominal surgeries

Trauma (emergent expl lap)

TURP

Mansour et al, 1997 [19]

Ziser et al, 1999 [20]

Wahlstrom et al, 2000 [100]

Nielsen et al, 2001 [95]

6.7

47

Child’s A 10 B 30, C 82 Emergency surgery: 50 11.6

28

Male sex; a high Child-Pugh score; ascites; a diagnosis of cirrhosis other than primary biliary cirrhosis (especially cryptogenic cirrhosis); elevated serum creatinine; COPD; infection; preoperative UGI bleeding; a high ASA severity status; a high surgical severity score; respiratory tract surgery; and the presence of intraoperative hypotension. 17 Patients; four times increased risk of mortality when compared with noncirrhotic control group. Advanced age, comorbidity, and acute admission

Encephalopathy, CHF, emergent surgery, infection, elevated total bilirubin, INR > 1.6, low albumin, elevated creatinine. Authors state that Child-Pugh classiﬁcation was not a useful indicator, but all six patients in the study with Child’s class C cirrhosis died. Child’s class, emergent surgery, encephalopathy, ascites, and prolonged PT.

Adapted from Friedman LS, Maddrey WC. Surgery in the patient with liver disease. Med Clin North Am 1987;71:453–76; with permission [91]. Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; GI, gastrointestional; INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time; TURP, transurethral prostatic resection; UGI, upper gastrointestinal; WBC, white blood cell count.

Mixed (mostly abdominal but including CABG and orthopedic surgery

Rice et al, 1997 [25]

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Risks of surgery in patients with cirrhosis correlate well with the severity grading introduced by Child and Turcotte [15]. Five factors were found to be signiﬁcant factors aﬀecting mortality after portosystemic shunt surgery in patients with cirrhosis: (1) ascites, (2) albumin, (3) bilirubin, (4) encephalopathy, and (5) nutritional status. Three of the ﬁve prognostic factors (severity of ascites, nutritional status, and grade of encephalopathy), however, are subjective. In the absence of large prospective studies, Child’s classiﬁcation [15] and the Child-Pugh [16] score are useful tools for preoperative assessment, which have been validated in a number of studies [17–20]. Two separate studies [17,19] done 13 years apart show that postoperative mortality is reproducibly linked to Child’s class: patients with class A cirrhosis have a postoperative mortality of 10%; patients with class B and C cirrhosis have mortality rates of 30% and 80%, respectively. Cirrhotic patients beneﬁt from preoperative aggressive treatment of coagulopathy, ascites, and encephalopathy. Recent studies have shown the beneﬁt of converting inoperable Child’s class C patients to Child’s B preoperatively with improved survival and no signiﬁcant problems [21]. Coagulopathy is a common ﬁnding in patients with cirrhosis and needs to be corrected before surgery. Some studies have suggested a high mortality rate in patients with prolonged prothrombin time [17,22–24]. Cholestasis, malnutrition, and decreased hepatic synthesis of coagulation factors are some of the reasons for altered coagulation tests in these patients. Coagulopathy in these patients can be managed preoperatively with vitamin K administration; however, vitamin K does not correct the prothrombin time if there is decreased hepatic synthesis. In these cases, fresh frozen plasma infusions usually bring the prothrombin time to normal limits. Cryoprecipitate is helpful when vitamin K and fresh frozen plasma fail to reduce the prothrombin time to within three seconds of normal. Cirrhotic patients undergoing surgery may have encephalopathy preoperatively, or are at high risk of becoming encephalopathic in the postoperative period. In a retrospective study of 40 patients with chronic liver failure undergoing nonhepatic surgery, presence of encephalopathy was associated with a high risk of mortality (88%), even higher than emergent surgery (50%) [25]. Constipation, infection, upper gastrointestinal bleeding, uremia, alkalosis, and overuse of sedatives are known precipitating factors of encephalopathy. Prevention of encephalopathy by correction of electrolyte abnormalities, appropriate gastrointestinal prophylaxis, and restriction of sedatives in these patients is essential. Avoiding nephrotoxic agents, such as aminoglycoside antibiotics and nonsteroidal agents, is important in preventing renal dysfunction [26]. Ascites can aﬀect postoperative course in a number of ways. It can cause respiratory compromise from poor lung expansion leading to atelectasis, hypoxia secondary to hepatopulmonary syndrome, and wound dehiscence [27]. Ascites should be managed aggressively preoperatively with diuretics and paracentesis. Ascitic ﬂuid analysis is important to rule out spontaneous

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bacterial peritonitis, which is associated with a high postoperative mortality. Large-volume paracentesis can be done safely preoperatively with the simultaneous administration of albumin to minimize worsening of renal function. Intraoperative risks Patients with liver disease are particularly susceptible to anesthetic eﬀects; unpredictable intraoperative hemodynamic factors; and deleterious eﬀects of medications, especially sedatives and skeletal muscle relaxants. Administration of anesthesia by inhalational or spinal routes leads to decreased hepatic blood ﬂow. Because the liver is endowed with dual blood supply, it is usually able to adapt to the altered blood ﬂow. Experimental animal studies have shown that under conditions of stress, hepatic blood ﬂow increases to compensate for reduced portal blood ﬂow [28]. Patients with liver disease, especially cirrhotics, are unable to compensate adequately for this decrease in portal blood ﬂow, which may result in postoperative hepatic dysfunction [14]. In addition to anesthetic agents, direct consequences of surgery, such as excessive bleeding, periods of hypotension, mechanical ventilation, application of positive end-expiratory pressure, and increased splanchnic resistance, can all cause decreased hepatic blood ﬂow, leading to hepatic ischemia and postoperative liver dysfunction [29]. Hepatitis following administration of anesthetic agents has been well described in the literature. One of the most well-known complications, halothane-induced hepatitis, occurs rarely (1 in 35,000 exposures) [30]. Risk factors for complications following halothane administration are age over 60, obesity, multiple exposures to halothane, short intervals between exposures, bilirubin over 10 mg/dL, and prothrombin time longer than 20 seconds. Isoﬂurane rarely causes hepatitis and is the preferred agent in patients with liver disease. A number of factors can aﬀect the metabolism of the drugs commonly used in the perioperative period. Hepatocellular dysfunction, cholestasis, altered drug binding caused by decreased serum albumin, and decreased blood ﬂow can all delay metabolism of these drugs, prolonging their duration of action and formation of toxic metabolites. It is prudent to decrease the dose of narcotic analgesics, such as morphine and meperidine, by as much as 50% [31]. In addition, a decrease in pseudocholinesterases leads to enhanced activity and toxicity of neuromuscular blocking agents [30]. Speciﬁc conditions Improved outcomes in laparoscopic procedures There is increasing evidence to suggest that laparoscopic procedures, when compared with their open laparotomy counterparts, may decrease operative morbidity and mortality in patients with cirrhosis. Eight case

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series of laparoscopic cholecystectomy have been reported: seven studies reported no mortality in a total of 119 patients with cirrhosis who underwent laparoscopic cholecystectomies [21,32–38]. Three patients in one of these studies were originally classiﬁed as being Child’s class C (one of these died); all others were Child’s class A or B. One prospective study [39] examined cirrhotic patients undergoing open or laparoscopic cholecystectomy. Blood loss and wound infections were increased in patients undergoing the open procedure; however, no mortality in either group was reported. The immunologic function of cirrhotic patients postoperatively may partially explain these diﬀerences: when compared with patients having undergone open procedures, patients undergoing laparoscopic cholecystectomy exhibit increases in circulating CD3 and CD4 cells, and decreased circulating tumor necrosis factor-a and interleukin-1b [40]. In addition, four retrospective studies examining outcomes of laparoscopic cholecystectomy have compared patients with cirrhosis with healthy patients [41–44]. A comparable percentage of patients in both groups underwent conversion to open cholecystectomy. Patients with cirrhosis experienced a higher incidence of hemorrhage. Otherwise, morbidity and mortality in the groups were similar. Only one study included patients with Child’s class C cirrhosis, and one of these patients died [42]. Patients with cirrhosis also have an eightfold increased mortality risk when undergoing open appendectomy [45]. With laparoscopic appendectomy, however, they have signiﬁcantly decreased wound infections, bleeding, hospital stay, and ratings of postoperative pain [46]. Hepatic resection Hepatectomy remains a therapeutic option in patients with hepatocellular carcinoma. Patients scheduled for hepatic resection, however, need specialized testing to assess the dynamic functions of the liver. Prognostic factors favoring lower morbidity and mortality in cirrhotic patients after hepatectomy include the following: Demographic factors Smaller (<5 cm), unifocal tumors without local or vascular spread Recent surgery (since 1996) Child’s-Pugh class A cirrhosis Biochemical factors Low indocyanine green retention rate after 15 minutes (ICGR15) Normal serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) Normal lactate level Normal hippurate ratio Pathologic factors Lack of portal hypertension Lack of active hepatitis Higher residual hepatic volume after proposed resection

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Numerous studies have attempted to identify prehepatectomy factors that predict postoperative outcomes. First, it seems clear that patients with nonﬁbrotic, noncirrhotic livers generally fare well after hepatectomy with little morbidity or mortality [47]. Multiple retrospective studies have also shown that over the last 15 years, morbidity and mortality in all patients have declined, probably because of increased surgeon experience and possibly earlier detection [48,49]. In patients with cirrhosis, liver failure is the most common cause of postoperative death. Most patients in all hepatectomy studies have Child’s-Pugh class A cirrhosis with a solitary focus of hepatocellular carcinoma. Patients with Child’s-Pugh class B or C cirrhosis had higher mortality rates and earlier recurrence rates [50]. Patients 70 years of age and older do not seem to be at excess surgical or mortality risk [51]. Additional biochemical factors that are commonly used to determine patients’ liver reserve and assumed ﬁtness for surgery are normal serum liver function (total bilirubin, aspartate transaminase, and ALT levels); the trimethadione tolerance test [52]; and the level of indocyanine green dye retention after 15 minutes [53]. Other biochemical tests, including lactate levels and calculated hippurate ratios, and the use of a tactile sensor to predict liver stiﬀness as a measure of ﬁbrosis, also seem correlative [54–56]. In addition, presence of portal hypertension, pathologic evidence of active hepatitis, and low expected remnant liver volume are correlated with increased surgical morbidity and mortality [57–60]. Postoperative 30-day mortality after hepatoma resection ranges from 3% to 8% [61,62], representing a small decrease from mortality rates of up to 12.5% in older studies [60,63]. Two recent studies report zero mortality. In one series of 277 hepatectomies, preoperative intravenous nutritional support, intraoperative administration of fresh frozen plasma with aggressive blood transfusions as necessary, and administration of hydrocortisone and prophylactic antibiotics in one study led to a 0% mortality rate. Although no Child’s class data were reported, no patient had uncontrollable ascites or a total bilirubin of greater than 2 mg/dL [64]. Another series of 107 cases seemed to select patients with smaller tumors and lower Child’s class [65]. Despite the decrease in operative complications and postoperative mortality, the risk of recurrence of hepatocellular carcinoma after resection has not markedly decreased. Tumors of diameter 5 cm and less are associated with better prognoses; however, 5-year survival rates after hepatectomy remain relatively consistent at 25% to 40%, with disease-free 5-year survival at 10% to 30% [61,66]. Factors that predict increased survival include youth, female gender, small solitary hepatomas, and normal underlying liver [62]. Patients with hepatocellular carcinoma are candidates for liver transplantation, particularly with solitary small tumors without vascular invasion. The relative paucity of cadaveric livers and the length of the transplant listing process, however, during which time the tumors can continue to grow and disseminate, make orthotopic liver transplantation a less dependable option [58].

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Obstructive jaundice Obstructive jaundice is frequently associated with sepsis, coagulation disorders, and impaired wound healing. These patients also run the risk of signiﬁcant postoperative renal dysfunction, a severe complication ﬁrst described by Clairmont and Von Haberer [67]. Renal dysfunction is considered to be caused by a number of factors including endotoxemia, altered hemodynamics, coagulation defects, and impaired renal permeability. Postoperative renal failure occurs in about 8% of patients with obstructive jaundice [68]. The mean postoperative mortality in patients with obstructive jaundice is 14% [68]. Dixon et al [69] reported the association of three factors with high perioperative mortality: (1) hematocrit of less than 30%, (2) plasma bilirubin of greater than 11 mg/dL, and (3) a malignant cause of obstruction. In the absence of all these risk factors, postoperative mortality was 5% but rose to 60% when all three factors were present. Additionally, preoperative transfusions did not help in the improvement of mortality in these patients [70]. Patients with obstructive jaundice need to be managed carefully to avoid postoperative complications, such as renal failure, wound dehiscence, and sepsis. Lactulose and oral bile salts have been suggested to decrease the eﬀect of endotoxemia. Patients often developed diarrhea, however, with the dose of lactulose used [71]. Perioperative use of mannitol has been advocated to prevent renal dysfunction caused by its osmotic diuretic action and its ability to increase renal blood ﬂow and prevent endothelial swelling [72]. In another study [73], however, the renal protective eﬀect of mannitol was questioned and in fact shown to be more associated with a fall in creatinine clearance. Perioperative use of dopamine has not been found to be helpful [74]. Preoperative biliary drainage was proposed and used extensively to improve postoperative complications and mortality. In a prospective study, however, Pitt et al [75] showed that preoperative percutaneous therapeutic drainage did not reduce operative risk but did increase hospital costs. Biliary drainage is not routinely recommended now but is useful in patients with infection and severe malnutrition [76]. Aly and Johnson [77] have highlighted the potential complications involved with these procedures and have reported no improvement of postoperative morbidity and mortality. The perioperative approach to reduce complications in patients with obstructive jaundice should include appropriate ﬂuid management with preoperative volume expansion to keep a steady urine output. Mannitol and dopamine are not helpful and should be avoided [67]. Preoperative administration of prophylactic antibiotics signiﬁcantly reduces wound infection rates after biliary tract surgery. Oral co-trimoxazole (trimethoprim-sulfamethoxazole) [78] is the preferred agent, but b-lactams and ﬂuoroquinolones are also helpful. Nephrotoxic drugs, such as aminoglycoside antibiotics and nonsteroidal analgesics, should be avoided.

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Postoperative jaundice The incidence of postoperative jaundice varies from less than 1% of all patients following elective abdominal surgery to rates as high as 17% following major surgery [79]. Evans et al [80] reported an incidence of 3.7% for severe jaundice and 16.5% for mild jaundice following 218 major surgeries. There are three major pathologic mechanisms: (1) increased pigment load, (2) impaired hepatocellular function, and (3) extrahepatic causes [81,82]. Increased pigment load could be secondary to hemolysis of transfused erythrocytes, drug-induced hemolysis, or resorption of hematomas. Hepatocellular injury is usually caused by the eﬀects of anesthesia, a fall in blood pressure during surgery, sepsis, or viral hepatitis. Acalculous cholecystitis, sepsis, and benign postoperative jaundice are important extrahepatic causes of postoperative jaundice. Acalculous cholecystitis frequently occurs after surgery or in critically ill patients with trauma and burns. In contrast to the usual young, female patient with cholelithiasis and cholecystitis, these patients are often older men. Diagnosis is made by a combination of clinical signs and radiologic tests. Patients often have symptoms of calculous cholecystitis, such as fever, abdominal pain, and leukocytosis. Various imaging studies have been used in establishing the diagnosis, but gallbladder ultrasound remains an important diagnostic tool. In a recent study [83] to establish diagnosis in children, gallbladder distention, nonshadowing echogenic materials or sludge, and pericholecystic ﬂuid collections were found in most of the patients, and increased gallbladder wall thickness (>3.5 mm) was found in all the patients with acute acalculous cholecystitis. This study also showed the utility of serial ultrasound examinations in these patients in monitoring improvement or worsening thereby requiring surgical intervention. Many of these same ﬁndings associated with acalculous cholecystitis, however, are often found in critically ill patients not suspected of having acalculous cholecystitis [84]. Cholecystectomy in patients with acalculous cholecystitis is associated with high mortality and morbidity [85,86]. Patients beneﬁt, however, from early surgical intervention. Surgical treatment within 48 hours of onset of symptoms is associated with 8% gallbladder wall perforation as opposed to 25% to 40% if surgery was done after 48 hours [87,88]. It is important that postoperative jaundice is evaluated methodically and treatment instituted early.

Summary Management of the surgical patient with liver disease begins with a careful preoperative assessment (Fig. 1). Any clues to liver disease on history and physical examination should be investigated to ascertain the cause of the clinical ﬁnding. More data on surgical patients with unexpected liver disease are

Fig. 1. Perioperative assessment of the patient with liver disease.

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now available [89]. Patients undergoing emergent surgery are at signiﬁcant risk of developing liver dysfunction. Child’s class still correlates strongly to postoperative complications. Cornerstones of perioperative management in these patients are medical treatment of complications of chronic liver disease, such as ascites; coagulopathy; prevention of encephalopathy; and rapid treatment of dangerous postoperative complications, such as acute acalculous cholecystitis. Evolving knowledge of the eﬀects of anesthesia, improving surgical techniques, and use of better diagnostic tests will help in the reduction of perioperative complications in these patients. References [1] Robbins JA, Mushlin AI. Preoperative evaluation of the healthy patient. Med Clin North Am 1979;63:1145–56. [2] Schemel WH. Unexpected hepatic dysfunction found by multiple laboratory screening. Anesth Analg 1976;55:810–2. [3] Hay JE, Czaja AJ, Rakela J, et al. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients. Hepatology 1989;9: 193–7. [4] Hultcrantz R, Glaumann H, Lindberg G, et al. Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases. Scand J Gastroenterol 1986;21:109–13. [5] Dykes MH, Walzer SG. Preoperative and postoperative hepatic dysfunction. Surg Gynecol Obstet 1967;124:747–51. [6] Giller S, Berliner S, Shoenfeld Y, et al. Surgery in patients with hepatitis. Med Interna 1981;19:211–5. [7] Greenwood SM, Leﬄer CT, Minkowitz S. The increased mortality rate of open liver biopsy in alcoholic hepatitis. Surg Gynecol Obstet 1972;134:600–4. [8] Harville DD, Summerskill WHJ. Surgery in acute hepatitis. JAMA 1963;184:257–61. [9] Strauss AA, Siegfried SF, Schwartz AH, et al. Decompression by drainage of the common bile duct in subacute and chronic jaundice: a report of 73 cases with hepatitis or concomitant biliary duct infection as cause. Am J Surg 1958;97:137–40. [10] Bourke JB, Cannon P, Ritchie HD. Laparotomy for jaundice. Lancet 1967;2:521–3. [11] Powell-Jackson P, Greenway B, Williams R. Adverse eﬀects of exploratory laparotomy in patients with unsuspected liver disease. Br J Surg 1982;69:449–51. [12] Runyon BA. Surgical procedures are well tolerated by patients with asymptomatic chronic hepatitis. J Clin Gastroenterol 1986;8:542–4. [13] O’Sullivan MJ, Evoy D, O’Donnell C, et al. Gallstones and laparoscopic cholecystectomy in hepatitis C patients. Ir Med J 2001;94:114–7. [14] Crosti PF, Giovannelli CF, Bardi U, et al. Hepatic blood ﬂow in cirrhosis. Lancet 1971;2:322. [15] Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal hypertension. Philadelphia: WB Saunders; 1964. p. 1–85. [16] Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646. [17] Garrison RN, Cryer HM, Howard DA, et al. Clariﬁcation of risk factors for abdominal operations in patients with hepatic cirrhosis. Ann Surg 1984;199:648–55. [18] Isozaki H, Okajima K, Morita S, et al. Surgery for cholelithiasis in cirrhotic patients. Surg Today 1993;23:504–8. [19] Mansour A, Watson W, Shayani V, et al. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 1997;122:730–5; discussion 735–6.

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Evaluation and management of anemia and bleeding disorders in surgical patients Barbara Armas-Loughran, MD, Rakhi Kalra, MD, Jeﬀrey L. Carson, MD* Division of General Internal Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 125 Patterson Street, Professional Building, 4th Floor, New Brunswick, NJ 08903, USA

Anemia is commonly encountered and blood transfusion is frequently administered in the perioperative setting. The goals in the evaluation of an anemic patient are to determine the cause of anemia, assess its physiologic impact during surgery, and determine the need for its correction. Clinicians also commonly encounter patients at risk of bleeding. This article reviews the preoperative evaluation of anemia, physiologic consequences of anemia, and observational and clinical trial studies evaluating the eﬃcacy of transfusion, and provides recommendations on the use of transfusion in the perioperative period. Also described is the approach to patients at risk for bleeding.

Anemia and red blood cell transfusion The preoperative evaluation of the anemic patient The basic work-up of an anemic patient includes a detailed history and physical, complete blood count with indices, a reticulocyte count, peripheral smear, and stool guaiac. With this information, a diﬀerential diagnosis is quickly established and further testing can be done to determine the speciﬁc etiology. The history should focus on symptoms of bleeding, such as melena, hematochezia, hematemesis, hematuria, or signiﬁcant blood loss during menses. Questions should be asked regarding a past medical history of anemia; need for blood transfusions; dietary habits; medications; and a history of * Corresponding author. E-mail address: [email protected] (J.L. Carson). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 4 - 2

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hematologic, liver, renal, or endocrine disorders. Family histories of anemia, splenectomy, or early onset cholelithiasis place congenital hemolytic disorders higher in the diﬀerential diagnosis. The physical examination should focus on the skin for jaundice, mucous membranes for pallor, and examination for hepatosplenomegaly. Stool and urine should be checked for occult blood loss. Once an acute bleed has been ruled out, the reticulocyte count and mean corpuscular volume are the most helpful indices in determining the cause of anemia. A hemolysis work-up is often indicated in patients with an increased reticulocyte count. This includes direct and indirect Coombs’ tests, lactate dehydrogenase, indirect and direct bilirubin, and haptoglobin levels. Iron deﬁciency and thalassemia are the most common causes of microcytic anemias. Ferritin, serum iron, and total iron-binding capacity should be ordered in these patients. Further work-up involves hemoglobin electrophoresis to determine hemoglobin A2 (in thalassemia minor) and a bone marrow biopsy to evaluate iron stores. Normocytic anemias are most commonly seen in neoplastic, chronic inﬂammatory, or infectious conditions. Work-up includes the aforementioned iron studies and an assessment of liver and renal function. Questions should also be asked regarding a history of medications or radiation that could lead to marrow suppression. Macrocytic anemias require an initial measure of vitamin B12 and folate levels. Further assessment might include thyroid function tests, liver function tests, and a bone marrow biopsy. Physiologic changes associated with anemia It is helpful to understand some of the important physiologic consequences of anemia when making decisions regarding the need for its correction. Physiologic changes in the anemic patient aim to preserve tissue oxygenation in the setting of decreased oxygen-carrying capacity. One adaptation to anemia is an increased production of 2,3-diphosphoglycerate, which causes a shift to the right in the oxyhemoglobin dissociation curve [1–3], increasing the oxygen delivered to the tissues at a given PO2. Anemia also aﬀects cardiac output. Many well-controlled studies have demonstrated an inverse relationship between hemoglobin levels and cardiac output [4–6]. There are conﬂicting data, however, concerning the hemoglobin level at which this occurs. Studies have shown a threshold hemoglobin level for this inverse relationship that varies from 7 to 12 g/dL [4]. In the setting of normal cardiac function, increased cardiac output is thought to be mediated by increased sympathetic activity and decreased blood viscosity. As a result, myocardial contractility and venomotor tone are augmented, and left ventricular preload and afterload are increased and decreased, respectively [7]. The body’s cardiovascular and systemic response to acute blood loss is mediated by both the amount and rapidity of blood loss, and patient characteristics. The latter include age, comorbid illnesses, pre-existing volume

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status, hemoglobin values, and the use of medications that have cardiovascular or peripheral vascular eﬀects. Laboratory studies that investigated the eﬀect of normovolemic anemia on the coronary circulation have shown that, in the setting of a normal coronary circulation, there are few consequences with hemoglobin levels as low as 7 g/dL [8–10]. Evidence pertaining to transfusion in the perioperative setting Transfusion practices vary widely in the perioperative setting. Red blood cell transfusions are given to increase oxygen-carrying capacity. Two observational studies of orthopedic patients undergoing total hip and knee arthroplasty conﬁrmed this variability [11,12]. Diﬀerences in transfusion practices have been attributed to several factors including lack of established transfusion guidelines [13], diﬀerences in the availability of autologous units for transfusions, and training diﬀerences between hospitals [14]. Risks and beneﬁts must be weighed when making decisions and counseling patients regarding blood transfusions. Knowledge of the level of anemia at which blood transfusions prevent adverse outcomes is integral to the decision-making process. Studies in patients who declined blood transfusion provide important insights into the risk of anemia. In the largest consecutive series of patients who declined blood transfusion, the risk of postoperative mortality or morbidity rose as the preoperative hemoglobin fell below 10 g/dL and was substantially higher in patients with cardiovascular disease compared with patients without cardiovascular disease [15]. The risk was extremely high when the preoperative [15] and postoperative hemoglobin fell below 5 to 6 g/dL [16]. Two large observational studies evaluated the eﬀect of anemia or transfusion practices in the perioperative setting [17,18]. The largest study involved a cohort of 8787 consecutive hip fracture patients who underwent surgical repair and who had postoperative hemoglobin levels less than 10 g/dL [17]. In this study hemoglobin levels as low as 8 g/dL did not seem to aﬀect 30- or 90-day mortality, suggesting that this level might be safe in orthopedic surgery patients. Another study looked at 2202 patients undergoing coronary artery bypass graft surgery [18]. In this study patients were divided into three groups based on their hematocrit level when they entered the intensive care unit. The groups were designated as high (hematocrit 34%), medium (hematocrit 25% to 33%), or low (hematocrit <24%). Interestingly, patients in the high group were more than twice as likely to have a myocardial infarction as patients in the low group. Ten randomized clinical trials exist that compare the eﬀects of diﬀerent transfusion thresholds [19]. Three of these investigated patients in the perioperative setting. One study looked at 428 patients undergoing ﬁrst-time elective coronary artery bypass surgery [20]. The patients were randomized to transfusion triggers of 9 g/dL versus 8 g/dL. The event rates were low and no diﬀerences in mortality or morbidity were detected between the two

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groups. Another trial involved 127 patients undergoing knee arthroplasty [21]. Patients were randomized to receive either two units of autologous packed red blood cells immediately after surgery or to receive autologous blood if the hemoglobin level fell below 9 g/dL. The mean diﬀerence between the two groups in postoperative hemoglobin levels was 0.7 g/dL. Again, there were no diﬀerences in outcome. A third pilot study evaluated 84 hip fracture patients who were undergoing surgical repair [22]. They were randomized to a 10 g/dL transfusion threshold versus transfusion for symptoms or if the hemoglobin level was less than 8 g/dL. The lowest hemoglobin level in the symptomatic group was 8.8 g/dL and the highest level in the threshold group was 11.1 g/dL. No signiﬁcant diﬀerences were found between the groups for functional recovery, mortality, and morbidity. Sixty days after surgery, however, there were ﬁve deaths in the symptomatic group and two deaths in the 10 g/dL group. The only study that is adequately powered to evaluate clinical outcomes relative to anemia and transfusion practices is the Transfusion Requirement in Critical Care [23]. Although this study involved patients in the intensive care unit rather than in a perioperative context, the authors believe it nonetheless provides valuable information. In this study, 838 volume-resuscitated intensive care unit patients were randomized to either a restrictive or liberal transfusion threshold. The restrictive group received allogeneic red blood cell transfusions at hemoglobin levels of 7 g/dL and then was maintained between 7 and 9 g/dL, whereas the liberal group received red blood cells at hemoglobin levels of 10 g/dL and was maintained between 10 and 12 g/dL. The mean hemoglobin levels in the two groups were 8.5 and 10.7 g/dL and the average numbers of red blood cell units transfused were 2.6 and 5.6, respectively. Although the ﬁndings were not statistically signiﬁcant, the 30-day mortality was lower in the restrictive transfusion group (18.7% versus 23.3%). Transfusion in patients with cardiovascular disease The presence of cardiovascular disease reduces tolerance to anemia. Healthy animals can tolerate hemoglobin levels between 3 and 5 g/dL after normovolemic hemodilution [24]. In animals with experimentally induced coronary stenosis varying from 50% to 80%, however, ST-segment changes or locally depressed cardiac function occurred at hemoglobin levels in the range of 7 to 10 g/dL [25,26]. These ﬁndings were conﬁrmed in 1958 adult surgical patients who decline blood transfusion for religious reasons. Mortality rates rose as hemoglobin levels fell and were substantially higher in patients with cardiovascular disease than those without cardiovascular disease [15]. These results suggest that anemia is not tolerated as well in the presence of cardiovascular disease. Several observational studies also suggest that patients with cardiovascular disease are beneﬁted by maintaining higher hemoglobin levels. In an analysis of Medicare claims data in 78,974 patients 65 years of age and older

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with acute myocardial infarction, mortality was lower in patients who received a transfusion with hemoglobin less than 11 g/dL than patients who did not receive a transfusion [27]. These ﬁndings were consistent with two small studies in surgical patients. Patients undergoing a prostatectomy or vascular surgery with hematocrit levels less than 28% and who received blood transfusion had fewer cardiac events than patients not receiving transfusion [28,29]. There are no randomized clinical trials that have evaluated transfusion thresholds in patients with cardiovascular disease. Correction of speciﬁc anemias Nutritional deﬁciencies are usually easy to treat. Oral iron supplements correct iron deﬁciency anemia within 2 to 3 months and increase the reticulocyte count within 10 days. Parenteral vitamin B12 or oral folate therapy can lead to an increased reticulocyte count in 3 days and correct the anemia within several weeks. Erythropoietin is used for anemias from radiation, chemotherapy, or chronic renal failure. Full recovery can take weeks to occur. The use of blood transfusion in the preoperative care of patients with sickle cell disease is controversial. Sickle cell anemia, the most common hemoglobinopathy in the United States, is caused by a point mutation leading to a structural defect of b-globin. Patients suﬀer from recurrent painful crises as a result of vaso-occlusion from clusters of sickled red blood cells. As a result, patients can have signiﬁcant organ dysfunction, especially of the heart and liver. A recent randomized study examined perioperative complications in patients who received a conservative transfusion regimen versus patients who had an aggressive regimen [30]. The former group was transfused to a hemoglobin level of greater than 10 g/dL, whereas the latter underwent exchange transfusion to achieve hemoglobin S less than 30%. No diﬀerence in adverse outcome was noted between the two groups, although the group transfused to 10 g/dL had fewer transfusion-related complications. Most patients in the study, however, were neither at high surgical risk nor did they undergo high-risk procedures. The authors suggest avoiding transfusion for minor procedures but transfusing to hemoglobin greater than 10 g/dL for moderate high-risk procedures. Thalassemias are caused by ineﬀective hemoglobin production. Patients with thalassemia minor are usually at low risk and the decision to transfuse should be based on considerations used in other patients with anemia who do not have thalassemia. Thalassemia major patients often have multiorgan dysfunction as a result of iron overload from many transfusions. These patients need very careful assessment of their cardiac, pulmonary, renal, and hepatic function when considering transfusion. Autologous blood transfusion The advent of autologous blood donation coincided with the recognition in 1982 that HIV could be transmitted by blood transfusions. As a

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result, the number of autologous blood donations for elective surgeries increased from fewer than 5% 15 years ago [31] to 50% to 75% for certain procedures [32]. When making decisions regarding autologous blood donation, patients need to be informed of the advantages and disadvantages. Advantages include the prevention of transfusion-transmitted infectious disease, the avoidance of red-cell alloimmunization, the prevention of some adverse transfusion reactions, and the provision of compatible blood for patients with alloantibodies [32]. Many of the risks of allogeneic blood transfusions, however, are also found in autologous transfusions. These include bacterial contamination, volume overload, and administrative errors regarding ABO incompatibility causing hemolysis [33]. One study showed a risk of adverse reactions severe enough to cause hospitalization in autologous donation (1 in 16,783) to be 12 times that of the risk in healthy volunteer donations [34]. The fact that autologous blood donation costs more than allogeneic [32] and that up to half the autologous blood that is collected is discarded [35] must also be taken into account. Furthermore, donating blood before surgery increases the risk of postoperative anemia and the likelihood of the need for transfusion [32]. Autologous predonation only reduces allogeneic blood exposure if between the time of donation and surgery the patient replaces some of the blood donated. Administration of erythropoietin at the time of predonation is an eﬀective but expensive method to stimulate production of red blood cells. Despite the widespread use of predeposit autologous transfusion, the authors advise against its use unless it is combined with erythropoietin. It should also be reserved for patients with anticipated blood loss large enough to require allogeneic transfusion. Guidelines for transfusion There are limited data to guide transfusion decisions in the perioperative period (Table 1). The only adequately powered randomized clinical trial

Table 1 Indications for red blood cell transfusion Clinical situation

Transfusion threshold

Cardiovascular disease Symptoms of anemia (cardiac chest pain, congestive heart failure symptoms, orthostatic hypotension unresponsive to ﬂuids, weakness) Bleeding patient

9–10 g/dL When symptoms develop

Otherwise stable patient

Initiate if anticipated blood loss will result in hemoglobin level below transfusion threshold or rapid bleeding Consider if hemoglobin level < 7 g/dL

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regarding risks of anemia involved intensive care unit patients; it showed that it was safe to withhold red blood cell transfusions until the hemoglobin fell below 7 g/dL. There are insuﬃcient studies involving patients with cardiac disease, but the weight of the evidence suggests patients may beneﬁt from higher blood levels. The decision to transfuse should take into account whether the patient is actively bleeding and the presence of symptoms. In patients who are actively bleeding, an estimate of the rate and degree of blood loss must be made and measures must be taken to stop the bleeding. Blood should be given at the estimated rate of blood loss. It is the authors’ opinion that a transfusion threshold of 7 g/dL can be used in patients who are asymptomatic and who have no underlying cardiovascular disease. In patients with cardiovascular disease, a higher transfusion threshold of 9 to 10 g/dL is recommended. Symptomatic patients should be transfused to a hemoglobin level that relieves their symptoms. One unit of blood increases the hemoglobin level about 1 g/dL and the hematocrit by 3%. In most patients 1 unit of blood is given over 1 to 2 hours, but in patients at risk of ﬂuid overload, the rate of transfusion should be reduced to 1 mL/kg hour. In addition, furosemide can be given to such patients before transfusions. After each transfusion the patient should be reassessed and a hemoglobin level measured.

Bleeding disorders Preoperative testing A careful history and physical is the most important component of the assessment for bleeding disorders in the preoperative setting. The history should include questions regarding a personal or family history of bleeding tendencies. Histories of bleeding after dental extractions or surgeries are particularly relevant. Pertinent questions also address any history of hematuria, menorrhagia, gastrointestinal bleeds, easy bruising, epistaxis, and hemarthroses. Knowledge of the patients’ medications, medical conditions (especially hematologic, liver, or kidney diseases), and any unusual dietary habits is also essential. The physical examination should focus on the skin and mucous membranes, looking for evidence of bruises, petechiae, or bleeding. Adenopathy, hepatosplenomegaly, and signs of hepatic insuﬃciency, such as jaundice, telangiectasias, and gynecomastia, should also be assessed. The decision regarding which preoperative coagulation tests are needed is then based on this information in combination with the knowledge of the type of procedure being performed. Patients with a normal bleeding history and physical examination who undergo low-risk procedures do not need preoperative coagulation screening. Several studies have led to this conclusion [36]. In one study, prothrombin time (PT) was measured on 301 patients admitted to a Veterans’ Administration hospital who had been screened during a history and

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physical examination for liver disease or bleeding disorders. Only 1 of 107 patients with a negative history and physical examination had a prolonged PT. In contrast, 41 of 121 patients with a positive history or physical examination had a prolonged PT [37]. Another study showed no predictive value in partial thromboplastin time (PTT) screening to predict postoperative bleeding in low-risk patients, although it did have some predictive value in higher-risk populations. The value of preoperative coagulation tests in patients with normal bleeding histories who undergo high-risk procedures, such as cardiac, vascular, and emergency procedures, is also questionable. Most texts recommend at least a platelet count, PT, and PTT in such patients. One retrospective study, however, found frequent abnormalities in preoperative tests of hemostasis, yet they did not need more transfusions than patients with normal tests [38]. It seems the main use of preoperative tests of hemostasis is to obtain baseline values to help evaluate bleeding problems that occur after cardiopulmonary bypass and to monitor anticoagulation. Preoperative coagulation studies are indicated if the patient has a history of abnormal bleeding or cannot provide a history, if the surgery is high risk for bleeding complications, if the patient has liver disease or malabsorption, or if the patient uses anticoagulants. It has been suggested that patients with histories of possible bleeding problems should have ﬁbrinogen and von Willebrand’s factor panel checked in addition to the PT, PTT, and platelet count [39]. Further testing is then based on the results of these tests. Other tests that might be considered include thrombin time, platelet aggregation, a2-antiplasmin, and factor XIII assays. The bleeding time has been shown not to correlate with surgical bleeding complications [40]. Furthermore, when performed by inexperienced staﬀ, results are unreliable. Patients with highly suggestive histories might need extensive testing to elucidate the bleeding diathesis. Management of patients with known coagulopathies Coagulation is achieved by the interaction of three major components: (1) the vascular endothelium, (2) coagulation proteins, and (3) platelets. Table 2 summarizes some common causes of abnormal coagulation tests. Intact hepatic activity is essential for adequate coagulation, because all the coagulation proteins except factor VIII are primarily synthesized in the liver. A prolonged PT reﬂects a defect in the extrinsic pathway and is usually caused by hepatic insuﬃciency or a vitamin K deﬁciency from poor absorption, nutrition, or cholestasis. It can usually be corrected by a 10-mg injection of vitamin K. Vitamin K is ineﬀective, however, if impaired hepatic synthesis exists. A prolonged PTT reﬂects a deﬁciency in the intrinsic pathway. If a prolonged PTT is detected, further work-up should include a 1:1 mixing of patient plasma and normal plasma. If the PTT corrects, a factor deﬁciency is most likely implicated; if there is no correction, the presence of

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Table 2 Diﬀerential diagnosis (selected) of bleeding disorders based on results of coagulation studies Abnormal result

Diﬀerential diagnosis

Prolonged prothrombin time

Liver disease, vitamin K deﬁciency, severe factor VII deﬁciency Deﬁciency of factor VIII, IX, XI, or XII; lupus anticoagulant; von Willebrand’s disease Disseminated intravascular coagulation, deﬁciencies of factors II, V, or X; coagulation factor inhibitor von Willebrand’s disease, thrombocytopenia, functional platelet disorders Pseudothrombocytopenia, splenic sequestration, decrease production, increase destruction

Prolonged partial thromboplastin time

Prolonged prothrombin time and partial thromboplastin time Prolonged bleeding time Thrombocytopenia

a factor inhibitor or lupus anticoagulant is more likely. Speciﬁc factor assays can be done to assess for deﬁciency and further specialized tests are needed to assess for the factor inhibitors. Surgery must be planned carefully in patients who have coagulation factor disorders. The most common inherited factor deﬁciencies are hemophilia A and B, which are caused by deﬁciencies of factor VIII and IX, respectively. Hemophilias occur in mild, moderate, and severe forms, correlating with factor levels of 6% to 30%, 2% to 5%, and 1%, respectively [41]. Patients with mild hemophilia usually only bleed after surgery or trauma. Laboratories that can measure factor levels rapidly and easily should be present in all hemophiliacs undergoing surgery. Patients should also have preoperative screening for factor inhibitors. A target of 100% factor VIII has been set for the ﬁrst 5 to 7 days postoperatively in major surgery and for 50% after postoperative day 1 in minor surgery [42]. Recombinant factor concentrates and plasma concentrates can both be used, although recombinant factors are preferred in mild hemophiliacs who have had little exposure to blood products. Patients with mild hemophilia undergoing low-risk procedures can be treated with desmopressin (DDAVP), which increases the release of von Willebrand’s protein and circulating levels of factor VIII [42]. Patients with hemophilia B are treated similarly to those with hemophilia A. Antiﬁbrinolytics are to be avoided in such patients, however, because factor IX concentrates contain small amounts of activated clotting factors, which increase the risks of thrombosis. Patients with hemophilia C (factor XI deﬁciency) have variable tendencies to bleed, which often do not correlate well with the factor level [42]. Fresh frozen plasma usually contains adequate amounts of factor XI for replacement, although a plasma-derived virally inactivated factor XI concentrate also exists. The concentrate, however, has been found to be thrombogenic in certain individuals and, if used, a target of 70% of factor levels

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should not be surpassed. In patients with acquired inhibitors of coagulation factors, eﬀorts need to be made both to achieve immunosuppression of the antibodies and to replace the aﬀected factors. High-dose steroids, intravenous immunoglobulins, and alkylating agents can be used for immunosuppression. Patients with a lupus anticoagulant are not at increased bleeding risk, but instead have an increased risk of thrombosis. These patients should also be checked for thrombocytopenia and often require deep venous thrombosis prophylaxis. Thrombocytopenia Signiﬁcant platelet abnormalities are infrequent but can lead to lifethreatening bleeding [43]. If a patient is thrombocytopenic, pseudothrombocytopenia caused by platelet aggregation is excluded by direct examination of the peripheral smear. Thrombocytopenia in a patient with splenomegaly is caused by splenic sequestration and these patients rarely have clinical bleeding because their total platelet mass is normal [44]. Massive transfusion may lead to dilutional thrombocytopenia. Thrombocytopenia can be caused by increased platelet destruction or decreased platelet production. Surgery must be delayed in these patients until the underlying illness is corrected. In disseminated intravascular coagulation, it is essential to correct the underlying disorder (ie, sepsis). Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes accompanied by thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and neurologic abnormalities. Treatment is diﬃcult and involves total plasma exchange with cryoprecipitate supernatant plasma in the replacement ﬂuid. In idiopathic thrombocytopenia purpura, platelets are destroyed by antibodies. These patients are treated with intravenous immunoglobulin, corticosteroids, immunosuppressive agents, and occasionally splenectomy. Before surgery, platelet counts of 80,000 to 100,000 are sought. Drugs must be always considered when evaluating the cause of thrombocytopenia. The usual mechanism is destruction of platelets by antibody formation. This binding is usually weak and reversible, however, so cessation of the drug should lead to resolution of the thrombocytopenia. In conditions causing thrombocytopenia from decreased platelet production, patients can be transfused if necessary. There is limited evidence to guide platelet transfusions. A report by the American Society of Anesthesiologists’ Task Force on Blood Component Therapy in 1996 recommends that the decision to transfuse platelets should be made after taking into consideration not only platelet count but also various other factors [45]. It was suggested that platelet transfusion is rarely indicated when thrombocytopenia is caused by increased platelet destruction, or if platelet count is greater than 100,000. For platelet counts from 50,000 to 100,000 the decision should be made based on the risk of bleeding.

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Platelet transfusion is indicated in a bleeding patient with platelet count less than 50,000. Platelet dysfunction may lead to bleeding in the perioperative time period. Bleeding time is a measure of platelet function and is indicated in a patient with mucocutaneous bleeding and normal PT, PTT, and platelet count. If prolonged then further studies are needed to evaluate von Willebrand’s factor and platelet aggregation studies [46,47]. These tests should be performed in patients with a high clinical suspicion even with a normal bleeding time [48,49]. The bleeding time is not a useful preoperative screening test because results are variable, and not highly predictive of perioperative bleeding [40]. Drugs are the most common cause of platelet dysfunction. Aspirin is the most common drug to cause irreversible platelet inhibition and should usually be stopped 5 to 7 days before surgery. Nonsteroidal anti-inﬂammatory drugs, vasodilators, and calcium channel blockers have a milder and reversible eﬀect on platelet function. Von Willebrand’s disease is the most common inherited coagulation disorder with prevalence in the general population of 1% [50]. Platelet adhesion and aggregation are dependent on von Willebrand’s factor. Von Willebrand’s disease occurs when von Willebrand’s factor is deﬁcient or qualitatively abnormal. Type I is the most frequent category of disease and caused by reduced functional von Willebrand’s factor. DDAVP is recommended for diagnostic procedures and mucosal biopsies, but a factor VIII concentrate that contains a high concentration of high-molecular-weight von Willebrand’s factor is recommended for therapeutic procedures. Type II is caused by a qualitative abnormality and type III is the most severe and caused by markedly reduced levels of von Willebrand’s factor in the plasma. Type II and III both need a concentrate of factor VIII and von Willebrand’s factor. Renal disease is another very common cause of platelet dysfunction. Patients with either acute or chronic renal insuﬃciency may have increased bleeding [51], but some of these patients may actually be hypercoagulable [52]. If there is active bleeding, the treatment options include correction of anemia, DDAVP, cryoprecipitate, estrogens, or dialysis. In the dialysis patient undergoing surgery, the timing of dialysis with heparin must be coordinated so that the coagulation proﬁle returns to normal before surgery. In emergent cases, however, protamine may be administered.

Summary The perioperative period oﬀers a unique hemostatic and physiologic challenge. Evaluation of anemia and the decision to transfuse play an important role in the perioperative period. Achievement of adequate hemostasis is important. A bleeding-oriented history and physical, along with some

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baseline tests, may help alert the physician to the possibility of a bleeding disorder. Finally, some patients may need correction of their bleeding disorder before surgery or careful monitoring in the perioperative period.

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Perioperative issues in patients with cancer Ellen F. Manzullo, MD, FACPa,*, Harrison G. Weed, MS, MDb a

Department of General Internal Medicine, Ambulatory Treatment, and Emergency Care, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 437, Houston, TX 77030, USA b Division of General Internal Medicine, The Ohio State University College of Medicine, 4510 UHC Cramblett Hall, 456 West 10th Avenue, Columbus, OH 43210, USA

General internists and family practice physicians frequently act as primary care physicians or consultants in the perioperative assessment and management of patients with cancer. Among patients with cancer, approximately 75% undergo surgical resection for cure [1], and about 90% for cure or palliation [2]. The perioperative care of a cancer patient can be challenging because of several disease-related considerations. Perhaps the primary consideration is the patient’s diagnosis, including the extent of disease and planned cancer-related treatment to be performed in addition to surgery. The natural history of the cancer and the eﬀects of any previous chemotherapy or radiation therapy should also be considered. In managing care of these patients, as with any preoperative evaluation, the physician should have a basic understanding of the surgical procedure and should know whether the surgery is intended for cure or palliation. The physician must also obtain a thorough medical history and physical examination to assess adequately comorbid conditions, such as hypertension, diabetes, cardiac, pulmonary, or renal disease. The preoperative medical evaluation should include an assessment of the patient’s nutritional status, functional status, and pain. In general, organ dysfunction is managed with standard treatments, regardless of whether a patient has cancer. Physicians should pay particular attention to pain management, which is overlooked too frequently by clinicians despite the high priority patients often place on this aspect of their care. Finally, because most patients with cancer who are

Dr. Weed is supported in part by Department of Health and Human Services Primary Care Research Initiative Grant No. 5D12 HP00027-02. * Corresponding author. E-mail address: [email protected] (E.F. Manzullo). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 7 - 8

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undergoing surgery have many caregivers, including surgeons, oncologists, radiation oncologists, and possibly other medical subspecialists, one role of the general internist often is to coordinate the patient’s overall care. Frequently, the physician knows the patient well enough to have a frank conversation with the patient and the patient’s family about the expectations of treatment. This conversation can provide an opportunity to ascertain the patient’s wishes regarding resuscitation. In sum, general internists frequently play an important and complex role in the perioperative care of patients with cancer. Indeed, the complexity of this role has led to proposals that hospitals should implement coordination mechanisms to improve delivery of multidisciplinary care to patients with cancer [3].

Direct and indirect eﬀects of cancer Performance status Patients with cancer vary widely in their performance status. Some patients are ambulatory and fully functional in activities of daily living, whereas others are severely debilitated. A patient’s performance status depends on many factors, including the type of cancer, extent of disease, side eﬀects of cancer-related treatments, and presence of comorbid medical conditions. Performance status reﬂects many disparate parameters and is a general and robust prognostic indicator for surgical outcome and mortality [4]. Malnutrition Patients with cancer can be signiﬁcantly malnourished for a variety of reasons. They can have impaired eating and drinking functions because of pain, nausea, stomatitis, or tumor of the oropharynx or gastrointestinal tract. Vigorous nutritional replacement for 1 week before surgery in patients with at least moderate undernutrition has been shown to reduce perioperative mortality and morbidity, including postoperative wound infection [5,6]. Both parenteral and enteral nutritional replacements have been eﬀective, and the use of nutrients that modulate the immune system might have additional beneﬁts [7]. Pain Cancer, particularly in cases of advanced disease, is frequently accompanied by pain recalcitrant to standard therapies. Treating the patient’s pain and addressing the concerns of the patient and his or her family about addiction to pain medication are important aspects of the preoperative evaluation. Referral to a pain specialist may be appropriate, but the physician can usually provide signiﬁcant palliation in the immediate perioperative period. One fundamental approach to treatment includes (1) a base of

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scheduled acetaminophen or a nonsteroidal anti-inﬂammatory drug; with (2) an opiate (scheduled or as needed); and (3) if needed, a low dose of a sedating tricyclic antidepressant, such as amitriptyline, 10 to 50 mg, at bedtime for sleep. In some patients, nonsteroidal anti-inﬂammatory drugs should be avoided in the preoperative period because of the potential for platelet inhibition and additional operative blood loss. The speciﬁc opiate used and the route of administration should be individualized on the basis of the likely palliative eﬀect and toxic eﬀects for that patient. It is important to discuss the inevitable sedation and constipation that accompany opiate use and to guide patients on how to manage these side eﬀects. Cardiopulmonary considerations Patients with tumors in or adjacent to the upper airway are at risk for airway obstruction. Laryngeal obstruction is the most common type of airway obstruction among patients with head and neck tumors. Stridor or other concerning ﬁndings at the time of preoperative medical evaluation should be assessed on the same day by an otolaryngologist. High-dose steroids, such as dexamethasone, can eﬀectively relieve obstruction by reducing edema. High-dose steroids, however, are likely to cause insulin resistance and can cause delirium. Furthermore, even with preoperative steroids, some patients require tracheotomy to bypass laryngeal obstruction before tumor resection. In patients with an anterior or middle mediastinal mass, airway obstruction or cardiopulmonary arrest can develop in any phase of general anesthesia [8]. The preoperative evaluation of a patient with an anterior or middle mediastinal mass should include a detailed review for respiratory symptoms including stridor, dyspnea, wheezing, and orthopnea. In addition, a CT or MRI of the chest should be obtained and echocardiography, to look for cardiac compression by the mass, and spirometry, including inspiratory and expiratory ﬂow volume loops [9]. Patients with any evidence of tracheobronchial tree or cardiac compression may require special anesthetic care and precautions including (1) ﬁberoptic intubation while awake; (2) spontaneous ventilation throughout surgery; (3) capability quickly to reposition the patient to lateral, prone, or sitting position as needed; (4) availability of a rigid bronchoscope in the event of a collapsed airway; and (5) standby femoral-femoral cardiopulmonary bypass in the event of cardiovascular collapse [9]. Among patients with cancer, pericardial eﬀusion can be caused by chemotherapy or infection, but is most commonly caused by metastases to the pericardium. Patients with a signiﬁcant pericardial eﬀusion may have progressive dyspnea, chest discomfort, and, sometimes, upper abdominal discomfort that is usually relieved when the patient leans forward. Findings on physical examination in patients with pericardial eﬀusion include jugular venous distention; narrowed pulse pressure; distant heart sounds; and excessive respiratory variation in blood pressure (pulsus paradoxus). Electrocardiograms show low voltage. Echocardiography conﬁrms the diagnosis and

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allows assessment of the impact of the eﬀusion on diastolic ﬁlling and global cardiac function [10]. Furthermore, echocardiography can help guide transcutaneous pericardial drainage performed with local anesthesia [11]. Sclerosis sometimes provides lasting treatment; the eﬀusion is drained, and 30 to 60 mg of bleomycin is infused through the drainage catheter [12]. Although deﬁnitive drainage of a malignant pericardial eﬀusion can be obtained with subxiphoid pericardotomy [13], systemic chemotherapy can also often provide substantial palliation [14]. In patients with cancer, pleural eﬀusions can develop, owing either to toxicity of treatment or, more likely, to the cancer itself. Preoperative thoracentesis is not always necessary; however, spirometry should be performed and arterial blood gases measured before elective surgery for patients with symptomatic or otherwise evident pleural eﬀusions. Tisi et al [15] have suggested criteria for identifying patients who require thoracentesis. In the postoperative period, patients who have undergone thoracentesis should be monitored closely and regularly for the reaccumulation of pleural ﬂuid (eg, monitor with chest radiography). Endocrine and metabolic Hyponatremia in patients with cancer can be a direct consequence of a brain tumor, a result of a paraneoplastic syndrome, or a toxic side eﬀect of medication, and can be exacerbated by poor oral intake. Common presentations of hyponatremia include malaise, fatigue, and confusion, but delirium seizure, coma, and death do occur. Furthermore, even among patients who do not have brain tumors, focal neurologic deﬁcits can be a presenting symptom of hyponatremia [16]. Patients with a rapid decrease in serum sodium concentration are more likely to have symptoms; however, patients with serum sodium above 130 mEq/L are rarely symptomatic. The proximate cause of hyponatremia is often the syndrome of inappropriate secretion of antidiuretic hormone. Some cancers, such as small cell lung cancer, are more frequently associated with syndrome of inappropriate secretion of antidiuretic hormone. Criteria for diagnosis of syndrome of inappropriate secretion of antidiuretic hormone are a serum sodium level less than 135 mEq/L, plasma osmolality less than 280 mOsm/kg, urine sodium greater than 20 mEq/L, and urine osmolality greater than 500 mOsm/kg. In addition, patients with syndrome of inappropriate secretion of antidiuretic hormone usually have normal renal, adrenal, and thyroid functions, and a normal extracellular ﬂuid volume. In managing patients with hyponatremia, the physician must carefully review all medications, because excretion of free water can be impaired by many medications, including morphine, cyclophosphamide, vincristine, chlorpropamide, amitriptyline, cloﬁbrate, and thiazide diuretics. Discontinuation of such medication and restriction of ﬂuids is the ﬁrst line of treatment in mild cases of hyponatremia. Recalcitrant cases require acute therapy, which includes intravenous administration of saline and treatment with a

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loop diuretic to induce excretion of free water. Long-term treatment for recalcitrant cases can include both restriction of ﬂuids to 500 to 1000 mL/d and orally administered demeclocycline, 300 to 600 mg twice daily. Treatment of the cancer, however, such as chemotherapy for patients with small cell lung cancer, may be the most eﬀective therapy for hyponatremia. Although it is preferable to correct hyponatremia before surgery, asymptomatic hyponatremia is not associated with increased perioperative risk, provided that the patient maintains a normal extracellular ﬂuid volume [17]. Hypercalcemia is a common complication of cancer, occurring in up to 5% of all cancer patients [18]. The cancers most commonly associated with hypercalcemia are breast cancer, non-small cell lung cancer, and multiple myeloma. Hypercalcemia also occurs in patients with renal cell carcinoma and squamous cell cancer of the upper orodigestive tract. In general, the prognosis is poor because hypercalcemia is a manifestation of advanced cancer [19]. Exceptions are hypercalcemia caused by breast cancer or multiple myeloma, which may respond well to treatment. Regardless of the malignancy, treatment of the hypercalcemia is beneﬁcial because it can help to relieve symptoms and improve quality of life. The symptoms of hypercalcemia are nonspeciﬁc and include fatigue, nausea, abdominal pain, constipation, depression, and delirium. Patients with a serum calcium concentration greater than 14 mg/dL usually are symptomatic. As with hyponatremia, symptoms are usually a function of both the degree of hypercalcemia and the rapidity with which it develops. Findings of electrocardiography include a prolonged QT interval and a ﬂattened T wave. The severity of the hypercalcemia should determine the aggressiveness of the therapy. Patients with signiﬁcant hypercalcemia are usually dehydrated. Acute treatment includes vigorous intravenous hydration and concomitant diuresis with a loop diuretic. In the perioperative period, the therapeutic goal is to normalize both the intravascular volume and the calcium level. Although it is preferable to correct hypercalcemia before surgery, asymptomatic hypercalcemia is associated with minimal risk in euvolemic patients if the corrected calcium concentration is maintained at less than 12 mg/dL [20,21]. Longer-term treatment has traditionally included focal radiation therapy to shrink bone metastases; however, intravenous or oral bisphosphonates act systemically to prevent and treat cancer-related osteoporosis and to relieve bone pain. Determining the best type of bisphosphonate to use and the optimal route of administration and dosing schedule is an active area of research.

Hematologic considerations Hypercoagulability should be assumed in patients with cancer and may be caused by increased plasma levels of clotting factors, cytokines, cancer procoagulant A, or increased release of tissue plasminogen activator. Several tumor types are more commonly associated with thrombosis, especially

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mucin-producing adenocarcinomas, such as those arising from the pancreas, lung, and gastrointestinal tract. The risk of postoperative deep vein thrombosis is as high as 29% among all patients with cancer [22] and is even higher among patients with additional risk factors for deep vein thrombosis, such as obesity, advanced age, orthopedic or neurologic surgery, and impaired mobility. In evaluating a patient with cancer before surgery, the physician faces the challenging task of estimating the risk for perioperative deep vein thrombosis and, in collaboration with the surgeon, determining the appropriate level of prophylactic treatment. A range of eﬀective, prophylactic treatments is available. Static compression stockings are eﬀective and have few substantial side eﬀects. Pneumatic compression stockings are even more eﬀective, but are more expensive and many patients ﬁnd them less comfortable and more diﬃcult to use. Stockings can be combined with medication for anticoagulation, which decreases the risk of clotting, but increases the risk of bleeding. The least aggressive and simplest medication for anticoagulation is low-dose, unfractionated heparin, 5000 U administered subcutaneously twice or three times daily. More aggressive and more expensive, but better controlled treatment is titrated, intravenously administered unfractionated heparin, or subcutaneous low-molecular-weight heparin at prophylactic doses. The same anticoagulant medications at higher (ie, treatment) doses provide the most aggressive prophylactic therapy against deep vein thrombosis. The goal of therapy is to balance the patient’s risk of deep vein thrombosis with the risk of bleeding complications, a diﬃcult clinical judgment for which no formula or protocol is available. Determining the duration of anticoagulation after surgery is also a challenging task. Several studies have indicated that, in high-risk patients, such as those undergoing surgery for abdominal or pelvic cancer, 1 month of postoperative anticoagulation is superior to shorter durations [23].

Thrombocytosis Thrombocytosis in patients with cancer can be a consequence of splenectomy, iron deﬁciency, or more commonly a subacute inﬂammatory condition. Treatment with anagrelide (Agrylin) to reduce the platelet count must be based on a consideration of the individual’s risk for thrombosis, but this drug generally is used at doses needed to maintain a platelet count below 1,000,000/mm3.

Granulocytosis Granulocytosis or leukemoid reaction to the cancer without infection occurs with a variety of solid tumors and lymphomas. Evaluation of the patient’s history, physical examination, and limited laboratory testing is appropriate to rule out infection, but speciﬁc treatment is rarely needed.

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Neurologic considerations Neurologic problems are common in patients with cancer [24]. Except for routine chemotherapy, neurologic complications are the most common reason for hospitalization of patients with cancer. Brain metastases are the most frequent neurologic complication, occurring in up to one third of patients with cancer in some settings. The most typical presenting symptoms are headache, confusion, delirium, and focal neurologic deﬁcit. Papilledema is an unreliable sign of central nervous system metastases, occurring in only about one fourth of patients with such metastases. Leptomeningeal metastases and epidural spinal cord compression are also common. Leptomeningeal metastases should be suspected in patients who develop multifocal neurologic deﬁcits, especially multifocal cranial neuropathies. Lung and breast cancers, melanoma, and lymphoma are common causes of leptomeningeal metastases. Emergent treatment of spinal cord compression with high-dose corticosteroid, radiation therapy, or surgical decompression is often necessary to preserve neurologic function. Delirium is not always caused by metastatic tumor; cancer and treatment-related metabolic encephalopathy are common nonmetastatic causes of delirium. Stroke can be caused by a variety of tumor-related conditions, including direct tumor invasion; side eﬀects of chemotherapy; and cancer-related coagulopathy, such as thrombotic (marantic) endocarditis. Radiation therapy is the most commonly used palliative treatment for brain metastases. Chemotherapy or surgical resection of tumors may be appropriate for selected patients. Paraneoplastic syndromes that aﬀect neuromuscular function are relatively rare but are of particular concern in the perioperative period because treatment with anesthetic agents can exacerbate neuromuscular dysfunction, leading to respiratory failure or delayed extubation. For example, myasthenia gravis occurs in up to 50% of patients with thymoma, and Lambert-Eaton myasthenia occurs in up to 5% of patients with small cell lung cancer [25]. Symptoms of Lambert– Eaton syndrome include proximal muscle weakness, diminished or absent deep tendon reﬂexes, and autonomic neuropathy. Treatment of the cancer can mitigate these symptoms, whereas calcium channel antagonists can exacerbate the symptoms and are contraindicated [26].

Eﬀects of cancer therapy Chemotherapy When evaluating a cancer patient before surgery, the physician should obtain a list of the chemotherapeutic agents the patient has received and the dose, schedule of administration, and dates of therapy. Toxicity of chemotherapy can develop months after administration is completed and can aﬀect many organ systems. The toxicity of some agents, such as bleomycin and doxorubicin, is strongly correlated with the cumulative dose.

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Pulmonary toxicity Bleomycin can have signiﬁcant pulmonary toxicity in up to 10% of patients, at least in part because lung tissue is deﬁcient in the enzymes that inactivate this drug. Bleomycin pulmonary ﬁbrosis is usually associated with cumulative doses greater than 450 U; however, there are reports of this eﬀect at lower doses [27]. Advanced patient age, the presence of pre-existing lung disease, and a history of radiation therapy can lower the total dose at which toxicity is likely to be seen [28]. In the preoperative evaluation of patients with suﬃcient cumulative doses of bleomycin the physician must look for pulmonary symptoms, including dyspnea, pleuritic chest pain, and nonproductive cough, and physical ﬁndings, including basilar ﬁne crackles. Patients who have any such symptoms should be evaluated fully with spirometry, arterial blood gases, and assessment of diﬀusing capacity. Patients with restrictive lung disease, an increased alveolar-arterial oxygen gradient, and a decreased diﬀusing capacity are likely to beneﬁt from special pulmonary care in the perioperative period [29]. In addition to bleomycin, many other chemotherapeutic agents can also cause interstitial pneumonia or pulmonary ﬁbrosis, including busulfan; chlorambucil; cyclophosphamide; melphalan; methotrexate; nitrosoureas (carmustine BCNU, lomustine CCNU, or semustine-methyl CCNU, all of which cause pulmonary complications in up to 25% of patients); and vinca alkaloids with mitomycin. Many of these agents have also been associated with other speciﬁc pulmonary toxic eﬀects including bronchiolitis obliterans with organizing pneumonia, pulmonary inﬁltrates with eosinophilia, noncardiac pulmonary edema, and pleural eﬀusion. Vinca alkaloids with mitomycin have also been reported to induce or exacerbate asthma [30]. Cardiac toxicity Doxorubicin and daunorubicin can have considerable adverse eﬀects on the heart. A dose-dependent drug-induced cardiomyopathy can manifest as sinus tachycardia, premature atrial or ventricular contractions, nonspeciﬁc ST and T-wave changes, and low-voltage QRS complex [31]. The potentially toxic cumulative doses are 550 mg/m2 for doxorubicin, and 600 mg/m2 for daunorubicin [31]. Patient characteristics and exposures, such as pre-existing heart disease, radiation therapy, and exposure to other chemotherapeutic agents, can lower the cumulative dose at which a cardiomyopathy develops. Hepatotoxicity Several chemotherapeutic agents are potentially hepatotoxic. Methotrexate commonly causes transient, mild elevations of serum transaminases; however, daily administration of the drug for several months can also cause hepatic ﬁbrosis [32]. Other potentially hepatotoxic chemotherapeutic agents include L-asparaginase; cytosine arabinoside; plicamycin (mithramycin); and 6-mercaptopurine. Although most hepatotoxicity caused by chemotherapeu-

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tic agents is transient, hepatic function should be assessed in patients with potential hepatotoxicity. In patients with potential for chemotherapy-related hepatotoxicity, prothrombin time is an appropriate test to ensure that the patient has adequate hepatic synthetic function before surgery is performed. Nephrotoxicity Several chemotherapeutic agents are potentially nephrotoxic. For example, cis-platinum commonly causes a dose-dependent, transient toxicity to the distal tubular epithelium leading to hypomagnesemia. Streptozotocin frequently causes renal tubular toxicity that can progress to Fanconi’s syndrome [33]. Other agents that cause renal toxicity are mitomycin-c, mithramycin, and high-dose methotrexate. For virtually all patients who have recently undergone chemotherapy serum blood urea nitrogen, creatinine, and electrolyte levels should be measured before surgery. Myelosuppression In general, chemotherapeutic agents that interfere with DNA synthesis and repair cause myelosuppression. Physicians must try to anticipate the timing of chemotherapy-related myelosuppression and avoid scheduling elective surgery for periods when the patient is neutropenic and thrombocytopenic. If feasible, surgery should be delayed until the myelosuppression has resolved. Recombinant hematopoietic growth factors should be used as necessary to shorten the period of neutropenia (< 500/mm3). A platelet count of at least 50,000/mm3 is generally considered adequate for most surgical procedures, but the speciﬁc procedure, and the functionality of the platelets, must also be considered. Diabetes mellitus High-dose corticosteroid treatment is frequently a component of chemotherapy for lymphoma or an adjunctive treatment to reduce edema or nausea. Such treatment also causes insulin resistance and frequently induces diabetes mellitus in patients with cancer. Patients receiving corticosteroids should undergo frequent monitoring of blood glucose and receive insulin or oral hypoglycemic agents as needed. In addition, streptozocin [33], L-asparaginase [34], interleukin-2 [35], and interferon-a [36] can damage or suppress pancreatic islet cells and cause insulin-deﬁcient diabetes mellitus. Patients who have received these agents also should undergo frequent glucose monitoring and receive insulin as needed. Adrenal insuﬃciency Most commonly, adrenal insuﬃciency in patients with cancer is secondary to suppression of the hypothalamic-pituitary-adrenal axis because of corticosteroid treatment. A course of corticosteroid lasting at least 2 weeks

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can cause measurable suppression for up to 1 year. Other agents that can cause adrenal insuﬃciency are aminoglutethimide and metyrapone, which are used in the treatment of prostate, breast, and adrenocortical cancers, and mitotane, which is used in the treatment of adrenocortical cancer. If time permits, patients with potential adrenal insuﬃciency should undergo assessment of the hypothalamic-pituitary-adrenal axis using a corticotropin stimulation test to determine if stress-dose steroid is needed. If such testing cannot be performed before surgery, the following general rules might be useful. Patients taking corticosteroid medication should continue to receive this treatment at the usual dose up to the day of surgery [37]. For procedures involving only minor physiologic stress, the patient’s usual dose of steroid should be continued throughout the perioperative period; however, for more stressful procedures, supplemental steroid treatment is indicated. Patients taking prednisone at a dose of 5 mg/d or less usually do not require steroid supplementation. Patients taking prednisone at doses greater than 5 mg/d might have a suppressed hypothalamic-pituitary-adrenal axis and should receive supplemental steroid for physiologically stressful procedures. Furthermore, patients taking prednisone at doses of at least 5 mg/d who develop perioperative complications might also beneﬁt from use of a supplemental steroid. For example, for a procedure involving minor stress, such as inguinal herniorrhaphy, a single dose of either hydrocortisone hemisuccinate, 25 mg, or methylprednisolone, 5 mg, administered intravenously at the start of surgery should be adequate. For a more stressful procedure, such as cholecystectomy or hemicolectomy, hydrocortisone hemisuccinate, 50 mg intravenously every 8 hours, or methylprednisolone, 10 mg administered intravenously every 6 hours starting at the time of surgery and tapered over 1 to 2 days should be adequate. For a major surgery, such as major cardiothoracic or abdominal surgery, hydrocortisone hemisuccinate, 100 mg administered intravenously every 8 hours, or methylprednisolone, 20 mg administered intravenously every 6 hours tapered over 2 to 3 days, should be adequate. Although corticosteroid therapy can be life-saving in selected patients, used of steroid therapy should be limited to minimize consequent osteoporosis, glucose intolerance, and other associated adverse eﬀects.

Radiation therapy When performing a preoperative evaluation of a patient with cancer or a history of malignancy, the physician should ascertain whether the patient has received radiation therapy, and, if so, what part of the body was irradiated. Radiation-induced scarring of the jaw and neck can cause airway narrowing or limit neck ﬂexibility, but more commonly causes glandular hypofunction, leading to xerostomia, primary hypothyroidism, and primary hypoparathyroidism. Concomitant radical neck dissection or hemithyroidectomy increases the risk of hypothyroidism and hypoparathyroidism

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[38,39]. The greater the dose of radiation, the greater the risk of radiationinduced scarring [40,41]. Among patients who received mantle radiation for Hodgkin’s lymphoma, the threshold radiation dose for hypothyroidism seems to be about 10 Gy. In one study, 45% of patients who received 30 Gy or more had hypothyroidism 20 years after treatment [39]. In another study, 60% of such patients had an elevated level of thyroid-stimulating hormone 10 to 18 years after treatment [42]. Before surgery the serum thyroidstimulating hormone level should be measured in patients who have more than a 10 Gy total dose of radiation to the neck. Hypoparathyroidism is less common but should be considered in patients who have hypothyroidism caused by neck radiation. Hypothalamic-pituitary dysfunction can be caused by radiation therapy to the brain, base of the skull, or upper neck [43]. The total radiation dose and the rate of delivery are proportionate to the severity of the dysfunction. The development of radiation-induced hypothalamic dysfunction is usually insidious and can occur many years after radiation treatment. Panhypopituitarism manifests as hypotension, hypothermia, and hypoglycemia; however, nonspeciﬁc fatigue and weakness are the usual presenting symptoms. Testing for serum levels of pituitary hormones can be reserved for patients with symptoms of this condition who have received radiation therapy to areas near the pituitary gland. Patients who have received radiation therapy to the chest can develop pulmonary and cardiac toxicity. Lymphocytic radiation pneumonitis can develop up to several months after chest irradiation, and may occur outside the radiation ﬁeld. Chronic pulmonary scarring may also develop [44]. Although focal pulmonary scarring in patients who have received radiation for neck or breast cancer does not usually require any additional testing, patients who have received radiation therapy to more than one third of the chest or who have symptoms might beneﬁt from spirometry and arterial blood gas testing. Chronic radiation-induced pulmonary damage manifests as decreased lung volume and compliance, and an impaired diﬀusing capacity [27,45]. Radiation therapy to the mediastinum without adequate heart shielding can cause pericarditis. In one study, pericarditis was found in approximately 5% of patients who received at least 40 Gy to more than half their heart volume [46]. Pericarditis can present months to years after radiation treatment and can present as acute pericarditis, as an asymptomatic eﬀusion, as cardiac tamponade, or as constrictive pericarditis [47]. Radiation of the heart is also associated with conduction abnormalities and with premature coronary artery disease [48]. For those who have previously received mediastinal irradiation, preoperative screening with electrocardiography is appropriate, even in young patients. Summary The perioperative care of patients with cancer can be an exciting challenge. The physician must consider many factors, including the cancer

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[21] Sieber FE. Evaluation of the patient with endocrine disease and diabetes mellitus. In: Rogers MC, Tinker JH, Covina BG, editors. Principles and practice of anesthesiology. St. Louis: Mosby; 1992. p. 285. [22] Rickles FR, Levine MN. Venous thromboembolism in malignancy and malignancy in venous thromboembolism. Haemostasis 1998;28(suppl 13):43–9. [23] Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346:975–80. [24] Newton HB. Neurologic complications of systemic cancer. Am Fam Physician 1999;59: 878–86. [25] Lambert EH, Eaton LM, Rooke ED. Defect of neuromuscular conduction associated with malignant neoplasms. Am J Physical 1956;187:612–3. [26] McEvoy KM, Windebank AJ, Duabe JR, Low PA. 3, 4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 1989;321:1567–71. [27] Blum RH, Carter SK, Agre K. A clinical review of bleomycin-a new antineoplastic agent. Cancer 1973;31:903–14. [28] Einhorn LH, Krouse M, Hornback N, et al. Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 1976;37:2414–6. [29] Klein DS, Wilds PR. Pulmonary toxicity of antineoplastic agents: anesthetic and postoperative implications. Can Anaesth Soc J 1983;30:399–405. [30] Copper Jr JAD. Drug-induced lung disease. Adv Intern Med 1997;42:231–68. [31] Von Hoﬀ DD, Rozencweig M, Piccart M. The cardiotoxicity of anticancer agents. Semin Oncol 1982;9:23–33. [32] Dahl MG, Gregory MM, Scheuer PJ. Methotrexate hepatotoxicity in psoriasis comparison of diﬀerent dose regimens. BMJ 1972;1:654–6. [33] Schein PS, O’Connell MJ, Blom J, et al. Clinical antitumor activity and toxicity of streptozotocin (NSC085998). Cancer 1974;34:993–1000. [34] Gillette PC, Hill LL, Starling KA, Fernback DJ. Transient diabetes mellitus secondary to L-asparaginase therapy in acute leukemia. J Pediatr 1972;81:109–11. [35] Almawi WY, Tamim H, Azar ST. Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type 1 (insulin-dependent) diabetes. J Clin Endocrinol Metab 1999;84:1497–502. [36] Fabris P, Betterle C, Greggio NA, et al. Insulin-dependent diabetes mellitus during alphainterferon therapy for chronic viral hepatitis. J Hepatol 1998;28:514–7. [37] Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insuﬃciency. JAMA 2002;287:236–40. [38] Grande C. Hypothyroidism following radiotherapy for head and neck cancer: multivariate analysis of risk factors. Radiother Oncol 1992;25:31–6. [39] Tami TA, Gomez P, Parkers GS, et al. Thyroid dysfunction after radiation therapy in head and neck cancer patients. Am J Otolaryngol 1992;13:357–62. [40] Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med 1991;325:599–605. [41] Schimpﬀ SC, Diggs CH, Wiswell JG, et al. Radiation-related thyroid dysfunction: implications for the treatment of Hodgkin’s disease. Ann Intern Med 1980;92:91–8. [42] Peerboom PF, Hassink EA, Melkert R, et al. Thyroid function 10–18 years after mantle ﬁeld irradiation for Hodgkin’s disease. Eur J Cancer 1992;28A:1716–8. [43] Littley MD, Shalet SM, Beardwell CG. Radiation and hypothalamic-pituitary function. Baillieres Clin Endocrinol Metab 1990;4:147–75. [44] Rosenow EC. The spectrum of drug-induced pulmonary disease. Ann Intern Med 1972;77:977–91. [45] Goldiner PL, Schweizer O. The hazards of anesthesia and surgery in bleomycin-treated patients. Semin Oncol 1978;6:121–4. [46] Stewart JR, Fajardo LF. Radiation-induced heart disease: clinical and experimental aspects. Radiol Clin North Am 1971;9:511–31.

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Surgery in the patient with neurologic disease Frank Lefevre, MDa,*, Judi M. Woolger, MDb a

Division of General Internal Medicine, Northwestern University Medical School, 675 North Saint Clair, 18-200, Chicago, IL 60611, USA b Division of Internal Medicine, Medical Consultation Service, University of Miami School of Medicine, 1475 North West 12 Avenue, M866, Miami, FL 33101, USA

Neurologic disorders comprise a wide spectrum of conditions, many of which present distinct issues and challenges when the need for surgery arises. The approach to these patients varies greatly depending on the type of neurologic disease present, the planned procedure, the urgency of the procedure, and other clinical characteristics of the patient. This article discusses surgery in the patient with neurologic disorders in three broad categories. First, patients with existing neurologic disease may need preoperative medical evaluation before general surgery. In this situation, the emphasis is usually on assessment of operative risk, although the consultant may also have substantial participation in perioperative management. The second category of patients is those who present for neurosurgery. The neurosurgical procedure is often essential or urgent, and the role of the medical consultant is geared more toward optimizing the preoperative medical regimen and managing medical problems perioperatively. Finally, there are a number of medical management issues that tend to coexist commonly with neurologic disease, and the third section of this article discusses some of these. The management issues discussed are hypertension, deep vein thrombosis (DVT) prophylaxis, postoperative delirium, and hyponatremia. General surgery in the patient with pre-existing neurologic disease Cerebrovascular disease Patients with cerebrovascular disease typically present with a history of stroke or transient ischemic attack, or vascular dementia. Patients with a * Corresponding author. E-mail address: [email protected] (F. Lefevre). 0025-7125/03/$ - see front matter 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 6 - 6

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history of prior stroke or transient ischemic attack have an increased risk of recurrent perioperative stroke. In the largest series in the literature, 173 patients with a prior stroke underwent general anesthesia, and recurrent stroke occurred in 2.9% (5 of 173) [1]. This compares with an estimated risk for perioperative stroke in unselected general surgery patients of 0.2% to 0.7% [2]. The length of time since the previous stroke is probably also an important consideration. DeWeese et al [36] reported in 1968 that mortality for patients undergoing surgery following a cerebrovascular accident was 34% for patients undergoing surgery within 24 hours of stroke, 15% for patients with a stroke 1 to 13 days previously, and 0% for patients undergoing surgery greater than 2 weeks following a stroke [3]. Other series have not demonstrated a deﬁnite correlation between the time since the prior stroke and recurrent perioperative stroke [2] but these more recent studies are limited by the small number of patients who undergo surgery shortly after an acute stroke. In the absence of deﬁnitive evidence, many experts currently recommend that general surgery should be avoided within 2 to 3 weeks of an acute stroke if possible, and elective surgery should be delayed for 2 to 3 months. In estimating the overall risk of perioperative stroke, a number of other risk factors have been identiﬁed. Prominent among these is atrial ﬁbrillation, which is present in approximately one third of perioperative strokes [2,3]. Additional risk factors that should be considered are advanced age, hypertension, smoking, and prior neurologic symptoms [2]. The types of procedures with the highest incidence are cardiac, carotid, and aortoiliac surgery with rates of perioperative stroke in the range of 1% to 5% [2,3]. In perioperative management, particular attention should be given to perioperative blood pressure control, because patients with cerebrovascular disease are more susceptible to cerebral hypoperfusion. Residual neurologic deﬁcits following a cerebrovascular accident indicates an increased risk for postoperative complications, and more aggressive aspiration precautions, lung expansion measures, and DVT prophylaxis may lessen postoperative complications. Attention to physical needs, such as early ambulation, often with the involvement of physical or occupational therapy, is also likely to be of beneﬁt. Mental status should be assessed systematically, and potential factors contributing to postoperative delirium should be monitored and treated when possible. Preoperative evaluation of carotid bruits The ﬁnding of an asymptomatic carotid bruit during the preoperative work-up is a common occurrence. The prevalence of asymptomatic bruits has been estimated at 10% for patients undergoing general surgery and 16% for patients undergoing peripheral vascular surgery [4]. In the general population, a carotid bruit is a marker for vascular disease and is associated with a higher rate of subsequent stroke and myocardial infarction. Data from prospective, population-based studies have estimated that patients

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with an asymptomatic bruit have a threefold to fourfold increase in the risk of stroke over a 3- to 5-year period [4]. The signiﬁcance of this ﬁnding in the preoperative period is less certain, however, because an asymptomatic bruit alone may not increase the risk for perioperative stroke [4]. Data from several series of general surgery patients report similar rates of postoperative stroke for patients with or without an asymptomatic bruit [4]. High-grade carotid stenosis, however, may increase the risk of perioperative stroke [4], but the degree of stenosis is only weakly correlated with the presence of a bruit. The presence of an asymptomatic bruit may or may not signify signiﬁcant carotid stenosis. Ultrasonography of the carotid artery can evaluate the degree of stenosis, and this information might be useful for risk stratiﬁcation in a minority of patients. There may be little that can be done, however, to reduce the risk other than avoiding surgery. Carotid endarterectomy (CEA) is seldom if ever indicated as a preoperative treatment to reduce the risk of perioperative stroke. Like coronary artery bypass graft, the decision to perform CEA should be made independently of the need for general surgery, and guidelines exist for estimating the risk-beneﬁt of this procedure [5]. Dementia As the patient population becomes older and more debilitated, it is not uncommon to encounter patients with dementia who need surgical intervention. This same cognitively impaired, older population is at higher risk for postoperative complications, especially postoperative delirium. Because these complications can greatly increase morbidity, length of stay, and costs, it is important to recognize risks preoperatively, and attempt to minimize risks when possible. Dementia is a clinical syndrome of cognitive impairment, marked by failing memory in association with behavioral or personality changes [6]. There are a vast array of potential causes, but Alzheimer’s disease and multi-infarct dementia account for most cases seen in general practice. Other causes include hypothyroidism, HIV disease, Wernicke-Korsakoﬀ syndrome, vitamin B12 deﬁciency, infections, and hereditary disorders. Although up to 50% or more of cases are not treatable, it is particularly important to assess the possibility of reversible dementia in the preoperative setting. There are dementias, such as those caused by alcohol abuse, drug abuse, vitamin deﬁciencies, subdural hematomas, normal pressure hydrocephalus, or tumors, that may be at least partially reversible if treated preoperatively. On examination, it is important to establish the baseline level of attention and cognitive function, both to determine severity of disease and to have a benchmark for comparison in the postoperative period. It may be necessary to speak to family members and other physicians to ensure complete and thorough information. If a thorough evaluation of the dementia has not

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previously been done, an appropriate preoperative evaluation should be undertaken. This evaluation should be guided by the severity of the cognitive impairment, the most likely causes, and the potential treatability. Multiple sclerosis Multiple sclerosis is a relatively common disease of demyelination aﬀecting almost 1 million young adults [7]. The disease is chronic and often progressive, with exacerbations occurring at irregular intervals. Although stress can precipitate exacerbations, there is no evidence that surgery necessarily causes either the onset or worsening of multiple sclerosis [8]. The consultant should assess the patient with multiple sclerosis for severity of deﬁcits, the pattern of recent relapses, and a careful history of medication use. The prior use of corticosteroids needs to be assessed, because use of high-dose steroids within the past year raises the possibility of adrenal suppression. A careful assessment of the pulmonary status should be made, because patients with restrictive lung disease caused by neuromuscular impairment may be at increased risk for postoperative complications and may warrant more intensive preoperative and postoperative lung expansion maneuvers. For patients on chronic therapy with baclofen for spasticity, a change may be made to diazepam. Baclofen cannot be given intravenously, and abrupt withdrawal may precipitate seizures or hallucinations if the patient is unable to take oral medications postoperatively. Platelet aggregation is increased in patients with multiple sclerosis [9], and consideration should be given to use of heparin for prophylaxis, especially in those patients with other risk factors for thrombosis. Postoperative urinary retention is a common manifestation of spinal cord disease. Preoperatively, these patients need to be assessed carefully for infection. Recommendations for intermittent catheterization or use of anticholinergic agents may be necessary, along with prompt recognition and treatment of urinary infections. Seizure disorders In the general population, the prevalence of seizure disorders is as high as 0.5% to 1%. The occurrence of a grand mal seizure during a surgical procedure or postoperatively may lead to signiﬁcant complications. Preoperative goals are to identify patients at risk for seizures and to minimize the risk of perioperative seizures. The primary methods for minimizing the risks of seizures are optimal medication management and attention to factors that might alter the seizure threshold, such as metabolic derangements. For patients on medications that can be given parenterally, the normal daily dose can be administered on the day of surgery and continued in the intravenous form until the patient has resumed oral intake. For those who are taking medications that have no parenteral form, phenytoin or phenobarbital

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should be substituted if it is anticipated that the patient will be on a nonoral status for a prolonged period postoperatively. The parenteral form of both medications is associated with hypotension, so the rate of administration needs to be slow. Patients with allergies to both of these medications need to be premedicated with high-dose steroids to help prevent allergic reactions. Parkinsonism Parkinson’s disease includes symptoms of muscle rigidity, slowness of movement, resting tremor, stooped posture, and blunted facial expression. Although treatment with dopamine agonists and anticholinergics is relatively successful in ameliorating some of the symptoms, they are also responsible for most of the potential complications that may occur in the surgical setting. The dopamine agonists complicate anesthesia by creating hypertension, hypotension, or even cardiac arrhythmias [8]. Stopping the medication the night before surgery may help minimize this risk; however, therapy needs to be resumed as soon as possible to avoid worsening the symptoms of Parkinson’s disease. Marked muscle rigidity may decrease pulmonary reserve, and the patient with severely slowed movements is at increased risk of atelectasis, pneumonia, and even decubitus ulcers. Preoperative evaluation for dementia should be thorough because it is estimated that 15% of patients with Parkinson’s disease also have dementia. Severity of mental decline needs to be documented before surgery so that careful follow-up can be arranged after the surgery. The neurosurgical patient In this section, four common neurosurgical conditions that often warrant the involvement of the primary care provider are discussed: (1) CEA, (2) subarachnoid hemorrhage (SAH), (3) surgery for brain tumors, and (4) spinal surgery. Although a comprehensive discussion of neurosurgical conditions is beyond the scope of this article, these disorders are used to highlight some general principles of neurosurgical care that might be encountered by the primary care physician. Carotid endarterectomy There has been a steady increase in the number of CEAs performed from the early 1970s into the 1990s [10]. The distribution of indications for the procedure has likewise changed, with a greater percentage of asymptomatic patients now undergoing endarterectomy. By combining a thorough clinical assessment of preoperative risk [34] with an understanding of the strengths and limitation of the literature evidence, the medical consultant can be helpful in assessing the risk-beneﬁt ratio for CEA. Determination of the risk-beneﬁt ratio for CEA can be a challenge because multiple competing factors impact both the risks and beneﬁts of the procedure. Current practice

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is driven by several recent, randomized, controlled trials that provide evidence for a net beneﬁt for CEA in carefully selected patients and in hospitals with a documented low rate of complications [11–13]. Concern has been expressed as to whether the magnitude of beneﬁt reported in these trials is attainable in actual practice, because data from nonclinical trial settings show somewhat less favorable results [10,14]. Some examples of the disparity in outcomes from research and nonresearch settings are shown in Table 1. The outcomes of CEA also vary signiﬁcantly according to the indication for the procedure and the setting in which it is performed. In general, a higher level of neurologic symptoms before the operation indicates a larger potential beneﬁt from CEA, but also a greater surgical risk. Patients who are asymptomatic have lower rates of morbidity and mortality than patients who are symptomatic, but also less potential beneﬁt [35]. There is also wide variability in outcomes by hospital. This is explained partly by the relationship between volume of surgery and outcome, which seems to be particularly strong for CEA [15]. All of these factors, in addition to the general assessment of cardiac and pulmonary risk, must be considered in estimating the risks of CEA for individual patients. The beneﬁt of the procedure may only be attained under a best-case scenario, such as the conditions in a clinical trial. The beneﬁt may be mitigated, or in some cases outweighed, by single or multiple indicators of high risk. This risk-beneﬁt analysis is particularly important for patients undergoing surgery for asymptomatic carotid lesions, where the beneﬁt accrued from surgical intervention is more limited. Stroke and myocardial infarction are the two most common adverse outcomes following CEA (see Table 1). Heightened postoperative surveillance

Table 1 Comparison of outcomes of CEA by indication and study type Clinical trials— asymptomatic patients

N

Stenosis (%)

Mortality (%)

Stroke— major

327 90 455

70–99 >50 70–99

0.6 3.3 0.9

1.5 1.1 2.9

4 2.2 3.7

Clinical trials— asymptomatic patients ACAS CASANOVA

825 171

>60 50–90

0.4 1.2

1.9a 2.7

— 0.3

Clinical series—multisite Brook McCrory

1302 1160

Any Any

3 1.4

6.6a 3.4a

— —

NASCET VA Cooperative ECST

Stroke— minor (%)

MI (%) 0.9 2 NR

NR 0 1.7 2.1

a Reported combined major and minor stroke rate. Adapted from Arron MA, Lefevre F, Chadha V, Cohn SL. Perioperative medical evaluation and care of the patient undergoing neurosurgery. In: Batjer H, Loftus P, editors. Textbook of neurosurgery, Batjer edition. New York, NY: Williams & Wilkins; in press; with permission.

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with EKGs and serum troponin-I is often warranted for patients at high risk of ischemia, for those with perioperative hemodynamic instability, and for patients with postoperative symptoms consistent with ischemia. Although mild postoperative ﬂuctuations in blood pressure are typically transient and benign, sustained systolic blood pressure above 180 to 220 mm Hg or diastolic blood pressure above 110 mm Hg has been associated with stroke and transient ischemic attack following CEA [16]. Given the consequences of marked postoperative hypertension, arterial pressure should be controlled before surgery, because preoperative blood pressure control predicts postoperative control. The hyperperfusion syndrome develops in a subset of patients, usually those who have had a long-standing, high-grade stenosis [15]. It is typically characterized by a severe, unilateral headache that improves with upright posture, and is thought to be precipitated by a sudden increase in blood ﬂow to a chronically hypoperfused region of the brain. Although the syndrome is usually self-limited, cerebral edema, increased intracranial pressure, seizures, and hemorrhage may develop. Conﬁrmation of the clinical impression of hyperperfusion can be sought by transcranial Doppler examination. Strict perioperative control of blood pressure is important for both the prevention and treatment of cerebral hyperperfusion. SAH and aneurysm Nontraumatic SAH is usually caused by the abrupt rupture of an intracranial aneurysm. Patients must be assessed quickly for aneurysm location and size, medically stabilized before aneurysm clipping, and closely managed postoperatively. The medical consultant can be most helpful regarding perioperative blood pressure control, the assessment and treatment of cardiac instability, and the management of hyponatremia and other ﬂuid and electrolyte disorders. The treatment of hypertension requires immediate attention. Elevated postoperative blood pressure should ﬁrst be addressed by providing adequate analgesia, oxygenation, ventilation, sedation, and laxatives. Blood pressure before clipping should be maintained within 5% to 10% of the patient’s premorbid values. If the patient’s prior blood pressure is not known, many experts recommend that systolic blood pressure should be kept below 150, diastolic blood pressure below 90 mm Hg diastolic, or a mean arterial pressure below 110 mm Hg [17]. Cardiac dysfunction following SAH includes dysrhythmias, heart failure, and ischemia. Large clinical series indicate that 50% to 100% of patients experience at least one ECG abnormality during the acute stage of SAH [18]. They can include peaked P waves, Q waves, increased QRS voltage, ST segment elevation or depression, peaked or inverted T waves, prolonged QT interval, large U waves, and rhythm disturbances [18]. EKG abnormalities, however, are usually transient and do not usually represent clinically signiﬁcant cardiac dysfunction. Given the

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reduced speciﬁcity of electrocardiography following SAH, other diagnostic modalities must be used to detect cardiac dysfunction accurately. The troponin-I can be used in conjunction with ECG to help determine whether echocardiography or other testing is needed. Echocardiographically proved left ventricular dysfunction provides more deﬁnitive evidence of cardiac dysfunction following SAH. Echocardiography may reveal regional wall motion abnormalities caused by ischemia or global left ventricular dysfunction. In the setting of SAH, global dysfunction may be caused by previous left ventricular dysfunction, or may be the result of increased catecholamine production leading to diﬀuse myocardial damage [19], a condition also termed myocytolysis. The clinical signiﬁcance of this ﬁnding is unclear. Spinal surgery Spinal surgery is most commonly performed on the cervical or lumbar regions. The most common indications for cervical spine surgery are spondylosis (42%); herniated disk (28%); trauma (17%); ossiﬁcation of the posterior longitudinal ligament (5%); rheumatoid arthritis (4%); and tumor (4%) [20]. Mortality for cervical spinal surgery is low. Recent clinical series have reported a perioperative death rate of 0.8% in 4589 patients undergoing any cervical spine surgery [20] and a mortality rate of 0.13% among 10,416 patients undergoing routine cervical diskectomy [21]. Local injury to spinal nerves, nerve roots, or peripheral nerves occurs at a rate of 0.2% to 0.6% [21]. Factors inﬂuencing perioperative risk are the complexity and diﬃculty of the planned procedure, the duration of anesthesia, and the expected perioperative blood loss. Most lumbar operations are performed for intervertebral disk disease, spondylosis, spondylolisthesis, and vertebral fractures. Mortality following lumbar surgery is low, with recent series reporting mortality rates of less than 1% [22]. In general, most patients can undergo spinal surgery with acceptably low morbidity and mortality, but particular concern should be given to the elderly patient with multiple medical illnesses who is scheduled to undergo a prolonged and complex procedure. For patients undergoing prolonged operations or procedures that are expected to have a large amount of blood loss, volume status should be optimized preoperatively and monitored closely. Frequent electrolyte measurements may be warranted. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion may develop in up to 5% of patients following spinal surgery [23], and is more common in patients undergoing spinal fusion, patients with large spinal deformities, and following operations with greater than usual blood loss. Medical evaluation before surgery for brain tumors Despite advances in chemotherapy and radiation therapy, surgery remains the preferred form of treatment for most primary brain tumors. The primary

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risk following surgery is for local neurologic complications, but these patients are also susceptible to a wide range of medical complications either caused by the surgery itself or as a result of impaired neurologic status. A signiﬁcant number of patients undergoing surgery for brain tumors have intracranial hypertension preoperatively or postoperatively, and the medical consultant should be familiar with the treatments and complications of increased intracranial pressure. A variety of therapies are eﬃcacious. Elevating the head above the level of the chest and limiting ﬂexion or rotation of the neck facilitate venous outﬂow and reduce intracranial pressure [24]. Medications that reduce brain volume, such as corticosteroids, osmotic agents, and loop diuretics, are also eﬀective. Reducing the arterial concentration of carbon dioxide and inducing an alkalosis through hyperventilation have important roles in treatment. Eﬀective control of seizures is also of paramount importance [25]. Patients with increased intracranial pressure likely receive high doses of systemic corticosteroids preoperatively. This raises several important issues related to the potential for adrenal suppression and other complications of high-dose corticosteroid therapy. Patients undergoing craniotomy who have postoperative neurologic deficits are at a higher risk for aspiration and nosocomial pneumonia. In addition to cognitive status, the lack of an eﬀective cough, dysphonia, and the lack of a gag reﬂex have been shown to be predictive of aspiration [26]. Aggressive aspiration precautions, lung expansion measures, and close attention to respiratory status are warranted in this situation.

Common issues in perioperative management DVT prophylaxis Patients with neurologic disease are at increased risk of developing DVT, largely because of the venous stasis induced by immobility. Patients undergoing neurosurgery may be at additional risk because of a secondary hypercoagulable state. The highest incidence has been reported in patients with stroke, spinal cord injury, and brain tumors, with respective rates for DVT of 42%, 42%, and 30% [27]. Multiple risk factors for DVT often coexist in these patients. In addition to the neurologic condition, other risk factors, such as advanced age, prolonged immobility, leg weakness, or a secondary hypercoagulability state, may be present. Mechanical methods seem to be eﬀective in preventing DVT in the neurosurgical population and are often used as the sole method of prophylaxis. A recent review using pooled data from randomized trials estimated the risk reduction to be 60% for elastic stockings and 66% for intermittent pneumatic compression, as compared with 73% for low-dose unfractionated heparin (LDUH) [28]. Mechanical agents are not recommended, however, as single agents for patients with acute stroke or spinal cord injury. Anticoagulation with LDUH or low-molecular-weight heparin (LMWH) is indicated

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for patients with acute stroke or spinal cord injury, and LMWH is probably more eﬃcacious in these settings. Anticoagulants remain controversial, however, for general prophylaxis of neurosurgical patients. Although the eﬃcacy of these agents in reducing DVT has been well established in clinical trials, the risk of increased bleeding complications is less well deﬁned. Some studies have reported no diﬀerence in central nervous system bleeding, whereas others have reported increased central nervous system bleeds with LMWH [28]. These clinical trials have not been powered to assess this uncommon, but potentially catastrophic, outcome accurately. It is diﬃcult to assess accurately the risk-beneﬁt ratio, and many surgeons continue to prefer mechanical means of prophylaxis. The recommendations for DVT prophylaxis in patients with neurologic disease [28,29] are to use LMWH for patients with acute ischemic stroke or spinal cord injury. For neurosurgery patients, prophylaxis with intermittent pneumatic compression, intermittent pneumatic compression plus elastic stockings, LDUH, or LMWH is acceptable. Combination therapy with mechanical and pharmacologic methods may be more eﬀective than either alone, but are accompanied by the potential risk of anticoagulation. In general, prophylaxis should be started preoperatively and continued until the patient is ambulatory. Hypertension For patients with neurologic disease, blood pressure control is often of paramount importance. Guidelines for blood pressure control in the general surgical patient, however, are not generally applicable to the patient with neurologic disease. Patients with neurologic impairment may have areas of relative hypoperfusion and impaired cerebral autoregulation of blood ﬂow. This makes them both more vulnerable to cerebral hypoperfusion and more likely to suﬀer serious consequences if it occurs. When autoregulation is impaired cerebral perfusion is dependent largely on the systemic perfusion pressure, and the maintenance of blood pressure in the optimal range may have a direct bearing on the adequacy of cerebral perfusion. As a result, more aggressive management of blood pressure is warranted, and often targeted to a speciﬁc desired range. Intravenous medications are usually used for their eﬃcacy, rapidity of action, ease of titration, and because most patients hospitalized with neurologic disease are not able to take medications orally. There are a variety of available intravenous agents (Table 2). The choice of speciﬁc agent may depend on the disorder being treated, comorbidities, and individual preferences. The goals of blood pressure control may vary depending on the speciﬁc condition being treated and the local practice patterns. The premorbid blood pressure, if known, and the blood pressure on presentation can be used as guides for target blood pressure. For example, in the setting of an acute ischemic stroke, the target blood pressure in the ﬁrst 24 hours should be a reduction of 20% to 25%

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Table 2 Intravenous antihypertensive drugs for postoperative neurosurgery patients Agent

Continuous infusion

Bolus

Dosage

Nitroprusside

Yes

No

Nicardipine

Yes

Yes

Initial: 0.5 lg/kg/min Infusion: 0.25–0.50 g/kg/min Bolus: 1–2 mg Infusion: 5–7 mg/h (gradual) 10–15 mg/h (more rapid) Loading dose: 500 lg/kg/min over 1 min Infusion: 50 lg/kg/min over 4 min Titrate: loading dose with increase of 50 lg/kg/min up to 200 lg/kg/min Immediate control: bolus of 1 mg/kg followed by 150 lg/kg/min 1.25 to 5 mg IV Q 6 h Bolus: 20 mg IV or approx 0.25 mg/kg Titration: 40–80 mg every 10 min up to a cumulative dose of 300 mg 5–10 mg IV Q 20 min 5–100 g/min

Esmolol

Yes

Yes

Enalapril Labetalol

No Yes

Yes Yes

Hydralazine Nitroglycerin

No Yes

Yes No

Onset of action

Titratable

Very rapid

Yes

Rapid

Yes

Rapid

Yes

Variable Rapid

No Yes

Rapid Very rapid

No Yes

Adapted from Arron MA, Lefevre F, Chadha V, Cohn SL. Perioperative medical evaluation and care of the patient undergoing neurosurgery. In: Batjer H, Loftus P, editors. Textbook of neurosurgery, Batjer edition. New York, NY: Williams & Wilkins; in press; with permission.

from the presenting pressure to preserve cerebral perfusion. In contrast, for a SAH the blood pressure should be reduced more aggressively, generally to a systolic blood pressure less than 150. Patients with a previous history of hypertension who are being evaluated for neurosurgery should be assessed for the presence of cardiac and other vascular disease. Elective operations are usually postponed if the preoperative diastolic blood pressure is greater than or equal to 110 mm Hg [24], but as previously noted, a lower threshold may be appropriate for patients undergoing neurosurgery, as it is for patients with underlying heart disease. This is particularly true for operations, such as CEA and craniotomy for brain tumors. Postoperative delirium Delirium is a confusional state that is characterized by an acute alteration in attention and cognition. It is relatively common in the postoperative setting, and more common in patients with neurologic disorders. Delirium can often go unrecognized, especially in the postoperative period when

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diﬀerences in attention may be thought to be related to anesthesia, pain, or pain medications [30]. Because delirium is associated with an increase in perioperative morbidity and mortality, prompt recognition and management may improve outcomes. In addition to the neurologic procedure and its potential complications, such as intracranial hemorrhage and cerebral edema, several other medical problems may precipitate or exacerbate delirium. Medications (especially anesthetics, analgesics, and psychoactive agents) and infections are probably the most common causes of mental status changes in hospitalized patients [31]. Metabolic derangements, such as hypoxemia, hypercarbia, hyperglycemia, and hyponatremia, are also frequent causes of postoperative delirium. Cardiac ischemia and pulmonary embolism may present in the postoperative period primarily as mental status changes. Patients with pre-existing dementia are particularly prone to postoperative mental status changes and may develop delirium as a result of alterations in sensory and environmental stimuli. In the preoperative evaluation, certain factors have been found to be predictors of postoperative delirium [31,32]. These include prior history of delirium, age greater than 70, pre-existing cognitive or functional impairment, abuse of alcohol or narcotics, and abnormal laboratory studies. Preoperative recommendations in those patients at risk may include delaying surgery until detoxiﬁcation has been accomplished, providing treatment for underlying medical issues, and re-evaluating blood tests at a later time. The origin of delirium is often multifactorial and cannot be attributed to one deﬁnite cause. Potential complications related to the surgical procedure should be pursued actively and potentially serious cardiac or pulmonary disorders should be investigated. Metabolic and hemodynamic factors should be assessed carefully and any detected abnormalities corrected. Signs of infection should be sought diligently and treated appropriately. Any nonessential psychotropic drugs should be withheld. The role of sensory deprivation and other contributing aspects of the physical environment should be considered and modiﬁed whenever possible. Hyponatremia Hyponatremia is a common medical problem in patients with central nervous system injury. Although the SIADH secretion classically is associated with neurologic disease, cerebral salt wasting (CSW) also makes up a large number of cases of hyponatremia in this setting and may be unfamiliar to the medical consultant. Other less common medical causes of hyponatremia, such as adrenal insuﬃciency and hypothyroidism, are important to consider because they require speciﬁc treatment. A variety of medications, most prominent of which are the diuretics, can reduce serum sodium levels. Fluid overload states, such as cirrhosis, heart failure, and nephrotic syndrome, can cause secondary hyponatremia. Pseudohyponatremia from

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hyperglycemia, hypertriglyceridemia, and paraproteinemias should be considered. The major distinction that often must be made is between SIADH secretion and CSW. This distinction is important because the treatment for SIADH is ﬂuid restriction, whereas the appropriate therapy for CSW is hydration and sodium replacement. CSW is deﬁned as the renal loss of sodium induced by intracranial disease leading to hyponatremia and volume depletion. The serum and urine osmolalities and electrolytes may be similar in the two disorders, but volume status and the response to ﬂuid and salt replacement diﬀerentiate CSW and SIADH. Hypovolemia may be recognized by signiﬁcant weight loss, a negative ﬂuid balance, or by physical and laboratory evidence of volume contraction. For example, orthostatic hypotension, hypokalemia, and prerenal azotemia are seen with CSW, but are virtually never seen in SIADH [33]. This clinical picture is more compatible with CSW than SIADH. Table 3 gives a summary of the features of each of these two syndromes.

Summary Patients with neurologic disease who require surgery present distinct issues and challenges for the medical consultant. Although it is not possible to oﬀer a uniﬁed approach to neurologic patients, the primary care consultant should understand the clinical issues that are common to these patients, and the individual considerations necessitated by the nature of the neurologic disorder and the clinical characteristics of the patient. The preoperative evaluation combines elements of literature evidence on risk assessment with Table 3 Diﬀerentiating features of the CSW Syndrome and the SIADH secretion

Plasma volume Salt balance Signs or symptoms of dehydration Weight Pulmonary capillary wedge pressure Central venous pressure Hematocrit Osmolality BUN/Cr ratio Serum protein concentration Urine sodium concentration Serum potassium concentration Serum uric acid concentration

CSW

SIADH

ﬂ Negative Present ﬂ ﬂ ﬂ › › or normal › › ›› › or no change Normal

› Variable Absent › or no change › or normal › or normal ﬂ or no change ﬂ Normal Normal › ﬂ or no change ﬂ

Adapted from Arron MA, Lefevre F, Chadha V, Cohn SL. Perioperative medical evaluation and care of the patient undergoing neurosurgery. In: Batjer H, Loftus P, editors. Textbook of neurosurgery, Batjer edition. New York, NY: Williams & Wilkins; in press; with permission.

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a thorough understanding of the planned procedure and local practice patterns, and clinical judgment as to the estimated risk-beneﬁt ratio. Perioperative management necessitates attention to many general principles of perioperative care, such as awareness of the potential for cardiopulmonary complications and the need for DVT prophylaxis. In addition, there are management issues for neurologic patients, such as blood pressure control and evaluation of hyponatremia, which may diﬀer from other surgical patients. In these circumstances, the interaction of the neurologic condition with the medical condition and the implications of treatment on the underlying neurologic process also need to be considered. References [1] Landercasper J, Merz BJ, Cogbill TH, et al. Perioperative stroke risk in 173 consecutive patient with a past history of stroke. Arch Surg 1990;125:986–9. [2] Kam PCA, Calcroft RM. Peri-operative stroke in general surgery patients. Anaesthesia 1997;52:879–83. [3] Wong DHW. Perioperative stroke. Part I: General surgery, carotid artery disease, and carotid endarterectomy. Can J Anaesth 1991;38:347–73. [4] Sauve JS, Laupacis A, Ostbye T, et al. Does this patient have a clinically important carotid bruit? JAMA 1993;270:2843–5. [5] Biller J, Feinberg WM, Castaldo JE, et al. AHA Scientiﬁc Statement: guidelines for carotid endarterectomy. Circulation 1998;97:501–9. [6] Adams R, Victor M. Principles of neurology. 5th edition. New York: McGraw-Hill; 1993. p. 353–64. [7] Rudick RA, Cohen JA, Weinstock-Guttman B, et al. Management of multiple sclerosis. N Engl J Med 1997;337:1604–11. [8] Jones RM, Healy TEJ. Anaesthesia and demyelinating disease. Anaesthesia 1980;35: 879–84. [9] Goldman D, Brown F, Guarnieri D. Perioperative medicine. 2nd edition. New York: McGraw-Hill; 1994. p. 351–9. [10] Mattos MA, Modi JR, Mansour MA, et al. Evolution of carotid endarterectomy in two community hospitals: Springﬁeld revisited – seventeen years and 2243 operations later. J Vasc Surg 1995;21:719–28. [11] European Carotid Surgery Trialists’ Collaborative Group. MRC European carotid surgery trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991;337:1235–43. [12] Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991;266:3289–94. [13] North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneﬁcial eﬀect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–53. [14] Brook RH, Park RE, Chassin MR, et al. Carotid endarterectomy for elderly patients: predicting complications. Ann Intern Med 1990;113:747–53. [15] Casanova Study Group. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 1991;22:1229–35. [16] Wong JH, Findlay JM, Suarez-Almazor ME. Hemodynamic instability after carotid endarterectomy: risk factors and associations with operative complications. Neurosurgery 1997;41:35–43. [17] Miller J, Diringer M. Management of aneurysmal subarachnoid hemorrhage. Neurol Clin 1995;133:451–78.

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[18] Mayer SA, LiMandri G, Sherman D, et al. Electrocardiographic markers of abnormal LV wall motion in acute SAH. J Neurosurg 1995;83:889–96. [19] Pollick C, Cujec B, Parker S, et al. Left ventricular wall motion abnormalities in subarachnoid hemorrhage: an echocardiographic study. J Am Coll Cardiol 1988;12:600–5. [20] Zeidman SM, Ducker TB, Raycroft J. Trends and complications in cervical spine surgery: 1989–1993. J Spinal Disord 1997;10:523–6. [21] Romano PS, Campa DR, Rainwater JA. Elective cervical discectomy in California: postoperative in-hospital complications and their risk factors. Spine 1997;22:2677–92. [22] Young HF. Complications of spinal surgery and trauma. In: Greenﬁeld LJ, editor. Complications in surgery and trauma. 2nd edition. Philadelphia: JB Lippincott; 1990. p. 713–22. [23] Brown CA, Eismont FR. Complications in spinal fusion. Orthop Clin N Am 1998;29: 679–99. [24] Shapiro HM, Drummond JC. Neurosurgical anesthesia. In: Cucchiarra RF, Miller ED, Reves JG, et al, editors. Anesthesia. 4th edition. New York: Churchill Livingstone; 1994. p. 1897–946. [25] Thapar K, Rutka JT, Laws ER. Brain edema, increased intracranial pressure, vascular eﬀects and other epiphenomena of human brain tumors. In: Kaye AH, Laws ER, editors. Brain tumors: an encyclopedic approach. Edinburgh: Churchill Livingstone; 1995. p. 163–89. [26] Arron MA, McDermott MM, Dolan N, et al. Management of medical complications associated with stroke. Heart Dis Stroke 1994;3:103–9. [27] Hamilton MG, Hull RD, Pineo GF. Venous thromboembolism in neurosurgery and neurology: a review. Neurosurgery 1994;34:280–96. [28] Geerts WH, Heit JA, Clagett CP, et al. Prevention of venous thromboembolism. Chest 2001;119(Suppl):1325–1755. [29] Clagett GP, Anderson FA, Geerts W, et al. Prevention of venous thromboembolism. Chest 1998;114:531S–60S. [30] Litaker D, Locala J, Franco K, et al. Preoperative risk factors for postoperative delirium. Gen Hosp Psychiatry 2001;23:84–9. [31] Francis J, Strong S, Martin D, et al. Delirium in elderly general medical patients; common but often unrecognized. Clin Res 1998;36:711A. [32] Marcantonio ER, Goldman L, Mangione CM, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994;271:134–9. [33] Harrigan MR. Cerebral salt wasting: a review. Neurosurgery 1996;38:152–60. [34] Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: 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). American College of Cardiology Web site. 2002. Available at: www.acc.org/ clinical/guidelines/perioi/update/periupdate_index.htm. Accessed June 10, 2002. [35] Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid stenosis. JAMA 1995;273:1421–8. [36] DeWeese JA, Rob CG, Satran R, et al. Surgical treatment for occlusive disease of the carotid artery. Ann Surg 1968;168:85–94.

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Perioperative care for the elderly patient Margaret M. Beliveau, MDa,*, Mark Multach, MDb a

Division of General Internal Medicine, Mayo Clinic, 200 First Street, South West, Rochester, MN 55905, USA b Division of General Internal Medicine, University of Miami School of Medicine, P.O. Box 016760 (M-841), Miami, FL 33101, USA

In 1927, as a young Professor of Surgery at Tulane Medical School, I taught and practiced that an elective operation for inguinal hernia in a patient older than 50 years was not justiﬁed. Alton Ochsner, MD

The perioperative management of the elderly has undergone major changes over the past eight decades. This has become increasingly the case with the dramatic shift in the population toward the elderly with the aging of the baby boom of the 1950s. The age group 65 years and older is the fastest growing segment in the United States, expected to comprise 20% of the population by 2025. Changes are increasingly apparent as the population ages and older patients are considered for surgery with greater frequency. In England, for example, surgical admissions for the elderly now outnumber nonsurgical admissions. One half of individuals over the age of 65 will undergo major surgery during their lifetime, with most procedures in patients in their sixth decade and beyond. The diseases for which surgery is performed, the surgical procedures performed, and the goals of the intervention also are changing with the aging of the surgical population. There is a pronounced shift from minor surgical procedures, trauma surgery, and surgery for nonmalignant disease to surgery for ocular, orthopedic, coronary artery, peripheral vascular, and neoplastic (especially pulmonary, colorectal, and genitourinary) diseases. Despite the rapidly increasing need for surgery in the elderly, a scarcity of literature exists studying the perioperative care of the elderly. Perioperative care becomes more complicated with age. The initial presentation of a surgical problem is more likely to be of greater severity. In the extreme, the presentation requires emergent surgery more frequently in the elderly (eg, * Corresponding author. E-mail address: beliveauﬁ[email protected] (M.M. Beliveau). 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 5 5 - 4

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it is much more common to see intestinal obstruction as the surgical justiﬁcation for surgery in colorectal cancer in the elderly compared with a younger population). Disease at presentation is more advanced, whether malignant (cervical or colorectal cancer); vascular (coronary artery or peripheral artery disease); or other (degenerative disease of the spine). As a result of these and other factors, the goal of the surgery is more often palliative than curative. Elderly patients for surgery are more likely to have surgery canceled for comorbid conditions after admission than a younger cohort. Hospitalizations for surgery are prolonged on average in the aged, independent of the presence of comorbid conditions. Evaluating the perioperative risk of these patients is very important. The study of perioperative assessment and care of the elderly patient has lagged behind the science of perioperative management in general. Much of the art of perioperative care in the elderly is extrapolated from literature on younger populations. The literature in perioperative care is primarily descriptive as opposed to outcome derived. The individual patient conditions’ contribution to surgical risk is related to a combination of physiologic changes associated with underlying diseases, combined to a lesser degree with age-related physiologic changes. Research over the past several decades has clariﬁed perioperative risk factors, showing that age by itself is at most a minor risk factor for perioperative complication [1,2]. As one author has noted, ‘‘Increased risk, when present, is attributable to both normal aging, because of decreased physiologic reserve, and pre-existing disease or pathologic changes not uniformly seen in all geriatric patients.’’ The impact of age on surgical risk comes through a physiologic decrease in vital organ function, leading to a decreased ability to respond to perioperative stress. Functional status changes associated with aging seem to be more important risk factors in the elderly. Demographics Surgery is performed more frequently in the elderly (136 procedures per 100,000 aged 40 to 64 years and 190 per 100,000 over 65). One third of all surgeries in the United States are performed in patients 65 years and older. Age is less of a risk factor than several age-associated changes, including increased prevalence of chronic diseases; increased need for emergent surgery (eg, patients over the age of 65 are more than twice as likely to present for emergent surgery as younger patients, 37% versus 17%); and overall alterations in functional status in major organs. All of these factors combined lead to a sicker population presenting for surgery (eg, approximately 80% of patients over the age of 89 present with American Society of Anesthesiology class III) as evidenced by the identical mortality rates by American Society of Anesthesiology score independent of age (Table 1).

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Table 1 Age versus physical status % Mortality Age

I

II

III

IV

V

1–30 31–50 51–70 >70

6 2 1 0

8 11 8 5

22 25 29 25

28 37 39 45

36 25 23 25

Finally, the incidence of chronic diseases and disabilities is increased in the elderly. On average, a patient over the age of 74 has three disabilities or diseases. In patients over the age of 65, 20% present with no problems and 30% have more than three problems. Complicating this is the increased diﬃculty in the recognition of diseases in the elderly. One example is the assessment of cardiac disease that is complicated by the increased presence of silent ischemia, underreporting of symptoms, and decreased physical activity, among many factors obscuring the diagnosis. The physician must have heightened awareness of atypical presentations of disease (typical angina less commonly, atypical presentations become more common). Cardiovascular functional assessment is made more diﬃcult as patients decrease activity. Even in nursing home–bound, inactive patients, however, risk in selected populations can be relatively low (2.3%). The pattern of atypical presentations is seen in many illnesses, both cardiac and those involving other organ systems.

Impact of age-related physiologic and anatomic changes Age-related changes lead to altered organ function. Although allowing normal day-to-day functioning, the impact of changes leads to decreased functional reserve of the individual. The individual’s response to stress is compromised. Several changes are of critical importance when discussing perioperative risk: cardiac, pulmonary, renal, and changes leading to altered pharmacology and pharmacokinetics. Cardiac The heart undergoes many changes. There is no inevitable decrement in rest cardiac function, in the absence of coexisting heart disease. However, cardiac output, in response to stressors is blunted. In part this is caused by a decreased responsiveness to catecholamines. Older patients have increased ectopy in the absence of cardiac dysfunction. Accompanying these physiologic changes are anatomic ones. There is an increase in ventricular mass (left ventricular hypertrophy); increased ﬁbrosis within the myocardium and conduction system; and calciﬁcation of the

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aortic and mitral valve skeletons. Clinically this is manifested as congestive heart failure from diastolic dysfunction. The hypertrophied myocardium responds to decreased ﬁlling with decreased exercise tolerance; cough (especially dependent); dyspnea; and fatigue. Late in the process, the obliteration of the left ventricular cavity, with low ﬁlling volumes, may lead to symptoms of low cardiac output. Pulmonary The changes in the respiratory system include changes in the chest wall, respiratory musculature, and the lung parenchyma. The thorax becomes stiﬀer with age, increasing the work of breathing and decreasing lung volumes. The strength and endurance of the musculature decrease with age. Parenchymal changes include decreased ciliary function and number and interstitial stiﬀening. The clinical eﬀect of these changes is a gradual decrease in PO2, increased dead space, and decreased expiratory volume and ﬂow rate. The net result is an overall decline in pulmonary function. More important is the narrowing of the gap between tidal volume and closing volume, leading to increased risk of postoperative respiratory complications. Renal Renal changes include a decrease in numbers of functional units, and decreased functional status of the units (decreased blood ﬂow and decreased glomerular ﬁltration). These changes are primarily manifested in response to rapid volume changes rather than as baseline dysfunction. In fact, the traditional methods of estimating renal function (serum creatinine and creatinine clearance) typically overestimate actual values because of the decreased muscle mass. In the elderly, a more accurate estimate of renal function comes from the Crockroft-Gault equation (females, multiply by 0.85): ð140-ageÞ weightðkgÞ 72 serum creatinine Nutritional An increasingly important factor is nutritional status. Several studies have documented the negative eﬀect of poor nutritional status on surgical outcome and complications. Other studies have documented an associated decrease in perioperative complications (although not in overall outcome) in patients undergoing oncologic procedures given nutritional supplementation for at least 1 week preoperatively. Laboratory abnormalities The prevalence of abnormal test results varies according to the test. Abnormalities of common laboratory tests occur in 0.5% to 15% in an

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asymptomatic, low-risk geriatric population. As in younger populations, the abnormalities found in this manner (asymptomatic polychemistry proﬁle testing) do not correlate with a higher morbidity or mortality. Altered pharmacokinetics Changes occur in both the uptake and metabolic handling of drugs, which lead to an increased incidence of complications and toxicity. Included are changes in altered gastrointestinal motility and blood ﬂow; renal function; decreased hepatic function and blood ﬂow; decrease in serum drugbinding proteins; and altered volume of distribution (caused by decreased lean body mass and reciprocal increase in total body fat). Finally, as noted in cardiac changes, there may an altered receptor response to drugs.

Predicting and preventing postoperative complications Delirium Delirium is a clinical syndrome in which there is an acute disruption of attention and cognition. Up to 20% of elderly surgical patients experience delirium as a postoperative complication. Orthopedic surgery patients, especially those with hip fracture, may have an incidence of delirium of 28% to 60% [3,4]. The development of postoperative delirium has been associated with increased morbidity and mortality. Marcantonio et al [3] found that the development of delirium was associated with increased risk of major complications (myocardial infarction, pulmonary edema, pneumonia, respiratory failure, and so forth). In their study (as in many others) delirium was associated with an increased risk of death, increased length of stay, and an increased rate of discharge to long-term care facilities. Additionally, patients with hip fracture were found to have poor functional recovery at 1 month if delirium developed in the postoperative setting [5]. Although all elderly patients may be at some risk for the development of postoperative delirium, it may be possible to identify patients at highest risk preoperatively and focus interventions on this group. Marcantonio et al [3] developed a clinical prediction rule for postoperative delirium based on preoperative risk factors, including age, history of alcohol abuse, pre-existing cognitive dysfunction, pre-existing physical impairment, type of surgery, and the presence of metabolic abnormalities. Patients with three or more of these risk factors had a 50% risk of postoperative delirium. Evaluation of the elderly patient who develops delirium requires consideration of preoperative, intraoperative, and postoperative factors [4]. Preoperative factors include pre-existing dementia, polypharmacy, drug or alcohol use/abuse, metabolic derangements, and depression. All eﬀorts should be made to correct metabolic abnormalities before surgery and anesthesia.

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Medication lists should be reviewed carefully and any unnecessary medications stopped. Patients should be questioned carefully about the use of overthe-counter drugs and supplements. Intraoperative factors that have been associated with postoperative delirium include the type of surgery and the anesthetic drugs used [4]. Among the highest-risk surgical procedures are cardiac surgery; hip fracture surgery (especially femoral neck fractures); and ophthalmologic surgery [5,6]. Anticholinergic agents have been associated with postoperative delirium. Barbiturates and benzodiazepines may also play a role. There seems, however, to be no increased risk when general anesthesia is compared with regional anesthesia [5,7]. Intraoperative hypotension or hypoxemia may also be risk factors for postoperative delirium. Postoperative causes of delirium may be similar to preoperative causes. Postoperative hypoxia and hypotension may contribute to delirium. Pain and pain medications, particularly meperidine, may also play a role. Other psychoactive agents (eg, benzodiazepines and sedatives) may be used more frequently postoperatively [8]. Sepsis and metabolic abnormalities need to be considered in this setting, as does myocardial infarction. Withdrawal from alcohol or drugs should be suspected in any patient with a preoperative history of use. Environmental changes and altered sensory input (decreased visual acuity because glasses are not available and decreased auditory acuity because hearing aids are not available) can contribute to the development of delirium, especially in patients with pre-existing cognitive impairment. There are many etiologic factors to consider in a patient with postoperative delirium. There are considerable data that help identify patients at risk [3,6,7]. Once these high-risk patients have been identiﬁed, one must be able to intervene to prevent the onset of delirium. Several studies have looked at measures designed to reduce the incidence of postoperative delirium [9– 12,20]. Most studies have focused on comprehensive, multidisciplinary geriatric assessment as a key component of reducing the incidence of delirium. This intervention must occur before the onset of delirium. Once delirium developed, the interventions were not as eﬀective, although the severity may have been reduced [9]. Careful preoperative assessment, ongoing postoperative assessment, cautious use of medications, correction of metabolic abnormalities, and attention to environmental factors remain the most eﬀective ways to prevent postoperative delirium. Comprehensive geriatric assessment and follow-up seems to be eﬀective because it focuses on minimizing these risk factors. Postoperative confusion can be associated with signiﬁcant consequences for the patient, the nursing staﬀ, and the family. Once it has developed, etiologic factors should be identiﬁed quickly and corrected if possible. Any drugs that may be contributing should be stopped or decreased in dosage. Haloperidol or risperidone can be used to help manage behavior that may place the patient at risk for self-harm. Benzodiazepines should be used in patients suspected of having delirium tremens. Thiamine should also be

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given to these patients. Physical restraints may increase the risk of injury and should be avoided if possible. Patients need frequent orientation to time, place, and circumstances. Clocks and calendars may help with orientation. Lighting in the room should mimic day-night cycles. Glasses and hearing aids should be used if needed. Patients should be out of bed as soon as possible. These simple measures may help shorten the course and improve the outcome of postoperative delirium. Immobility Immobility can be devastating to an elderly patient who has recently undergone surgery. Multiple organ systems can be aﬀected by immobility, including the skin, the cardiovascular system, the lungs, the musculoskeletal system, and the gastrointestinal and genitourinary tracts. In addition, there may be signiﬁcant psychosocial consequences of prolonged bed rest. The elderly, however, may be more likely to be at bed rest postoperatively because of underlying frailty and debility; increased frequency of musculoskeletal problems (arthritis and muscle weakness); and increased caregiver time and expense required to encourage mobility. Pressure ulcers are a signiﬁcant source of morbidity and mortality for postoperative patients. The elderly are particularly at risk. Hip fracture patients have a high incidence of pressure ulcers [13], and these ulcers are associated with an increased mortality. Although there are many studies of pressure ulcer development in hospitalized patients, there are surprisingly little data looking at the perioperative setting. Age, length of surgery, nutritional status, and type of surgery are all potential risk factors. In addition, emergency surgery and critical illness may increase risk. Shorter surgeries may actually increase the risk of pressure ulcers because careful pressure relief may be neglected [14]. Elderly patients, especially those with hip fractures, are at increased risk for osteoporosis. Bed rest increases that risk substantially. Zerwekh et al [15] studied the eﬀects of bed rest on bone mineral metabolism. They found a signiﬁcant increase in bone resorption by both biopsy and biochemical markers. There was no change in the rate of new bone formation, which led to a signiﬁcant decrease in bone mineral density, especially at the greater trochanter. This could contribute to risk of future fractures and impair fracture healing if not corrected. Pulmonary risks associated with immobility include atelectasis, increased risk of aspiration and pneumonia, and increased risk of venous thrombosis and pulmonary embolism. Early ambulation is the most eﬀective technique for reducing the risk of postoperative pulmonary complications. Cardiovascular deconditioning also occurs. This can be associated with a decrease in cardiac output, decreased stroke volume, or orthostatic hypotension. Cardiac atrophy is associated with a reduction in left ventricular size and distensibility, which alters the Starling mechanism [16].

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Immobility also has a number of metabolic eﬀects, including negative nitrogen balance, decreased tissue sensitivity to insulin, and altered calcium metabolism [17]. Oral intake may be impaired by the anorexia induced by bed rest [16]. Conﬁnement to bed or chair can also lead to sensory deprivation, loneliness, and depression, and may increase the risk of postoperative delirium. Immobility may also be associated with constipation and fecal impaction. This can create a vicious cycle of decreased oral intake and increased malnutrition. Mobilization can decrease the risk of constipation, impaction, and ileus. All of these potential complications can lead to only one conclusion: despite many factors that may impair mobility in elderly postoperative patients, these patients need an aggressive mobilization strategy that is multidisciplinary in nature. Physical and occupational therapists, nurses, physicians, family members, and most especially the patients themselves must participate in the mobilization program. Rehabilitation programs must start early and continue as long as is necessary for maximal functional recovery. Malnutrition In industrialized countries, the elderly are perhaps at most risk of being malnourished. Many elderly patients live on limited incomes. Many more have decreased access to transportation. These factors may limit availability of nutritionally valuable foods. Appetite is often decreased because of medications, alterations in taste and smell, coexisting medical illness, and decreased activity. Little is known about the requirements for vitamins, minerals, and trace elements in older people. Surgical disease (eg, gallbladder disease or abdominal ischemia) and preoperative testing may further increase the risk of preoperative malnutrition. Serum albumin can be used as a marker for malnutrition. Gibbs et al [18] showed that serum albumin levels were excellent predictors of 30-day postoperative mortality. This was true even for patients who were otherwise considered to be low risk. Malnutrition must be identiﬁed preoperatively. Elderly patients with preoperative malnutrition may develop protein-calorie malnutrition from the stress of surgery. Negative nitrogen balance depletes visceral protein stores. This leads to loss of muscle mass, which impedes eﬀorts at postoperative rehabilitation and ambulation. This vicious cycle leads to increased risk of postoperative pulmonary complications and other consequences of immobility. Impaired immune response may lead to diﬃculty with wound healing. Prevention of malnutrition should begin preoperatively with identiﬁcation of patients at highest risk. Nutritional status should be monitored and addressed from the ﬁrst postoperative day. Elderly patients, especially those with pre-existing malnutrition, should not be allowed to ‘‘fall behind’’ nutritionally. Voluntary food intake should be monitored and nutritional supplements introduced promptly in patients with inadequate intake. Although

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nasogastric feeding is an attractive option, many patients tolerate it poorly. Oral supplementation, if monitored carefully, is probably adequate [16]. Parenteral feeding should be used only as a last resort for patients with altered gastrointestinal tract function. Elderly patients are particularly vulnerable to complications of parenteral feeding. Infections Postoperative infections are an important source of morbidity and mortality in elderly patients. The most common sites of postoperative infection are urinary tract infection, surgical site infection, and pneumonia [17]. Elderly patients may have diminished immune function, which predisposes them to infection, although there is little known about speciﬁc decreases in immunologic competence [17]. Urinary tract infection is almost always caused by prolonged catheterization. Elderly patients are at increased risk to be catheterized because of medication side eﬀects; pre-existing incontinence; and decreased mobility, which impedes toileting. Symptoms of urinary tract infection in the elderly may be subtle. For example, postoperative confusion may be the ﬁrst and only sign of a urinary tract infection. Avoidance of catheterization if possible and early removal of the catheter are the most important steps in preventing urinary tract infections postoperatively. Pneumonia is a leading cause of postoperative mortality in elderly patients. Vigorous pulmonary toilet and aggressive early mobilization are needed to decrease the risk of this complication. Additional risk is conferred by nasogastric tubes, dementia, and immobility. Malnutrition and impaired immune function may increase the mortality associated with postoperative pneumonia. Continence Incontinence is never a normal consequence of aging and should not be an accepted complication of surgery. Every eﬀort should be expended to maintain continence perioperatively. The development of incontinence may prolong the length of stay or may result in an elderly patient entering a nursing home. Indwelling catheters should be removed as soon as possible postoperatively (or avoided altogether, if possible). Urinary retention can be managed with intermittent catheterization [19]. Factors that contribute to incontinence and urinary retention should be eliminated. Immobility, anticholinergic medications, intravenous ﬂuids, delirium, constipation, and urinary tract infection may all be contributing factors. Systematic toileting and prompt responses to requests help maintain continence. Outcomes of surgery in the elderly As the population ages, we are faced with increasingly diﬃcult and complex decisions about health care in elderly patients. Until recently, many

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patients were denied necessary surgical procedures (both elective and emergent) solely on the basis of chronologic age. Over the last two decades, signiﬁcant insights have been gained into the risks faced by those over 65 who undergo surgery and anesthesia. It has been learned, ﬁrst of all, that many of these patients can safely be treated surgically. At times, one needs to elucidate carefully the goals of the surgical procedure proposed. When discussing risks and beneﬁts, one must consider not only the risks of the surgery but also the risks of no surgery [21]. Emergency surgery has clearly been associated with an increased risk of postoperative morbidity and mortality in all age groups, but particularly in the elderly [21]. Patients should be advised to have surgical disease managed electively to avoid the risk of complications that might require emergency surgery. Why are elderly patients at such increased risk? Is it age alone or are other issues at play? Comorbidities, such as diabetes, hypertension, heart disease, and arthritis, can contribute substantially to the risk of poor postoperative outcomes. Indeed, many studies [21–23] have suggested that other medical problems, which are more frequent with age, are responsible for the increase in perioperative complications seen in older patients. Polanczyk et al [24] recently demonstrated that age in and of itself was associated with an increase in perioperative complications and longer length of stay. The encouraging ﬁnding of this study was that overall perioperative mortality was quite low, even in patients over the age of 80. Magnuson et al [25] studied laparoscopic cholecystectomy in elderly patients. Their ﬁndings suggest that laparoscopic cholecystectomy for uncomplicated gallbladder disease could oﬀer the same beneﬁts to older patients that have become apparent in younger patients: decreased pain, shorter hospital stays, and earlier return of preoperative functional status. Because return to baseline functional status is particularly important in the elderly, laparoscopic cholecystectomy might oﬀer even more beneﬁt to this group. Elderly patients, however, were more likely to present with complicated gallbladder disease (acute cholecystitis, gallstone pancreatitis, and common bile duct stones), which is more likely to require conversion to open cholecystectomy. Unfortunately, many elderly patients with known gallstone disease were not oﬀered surgical therapy until complications developed. This delay resulted not only in increased conversion to open procedures but also in increased perioperative morbidity and prolonged length of stay. Elective surgical therapy when possible may be the best way to improve perioperative outcomes in the elderly. Careful preoperative assessment and optimization of medical problems should allow elderly patients to take advantage of minimally invasive surgery with signiﬁcantly less risk [26,27]. Cardiac and pulmonary complications are the most frequent causes of perioperative morbidity and mortality in the elderly. Particular attention should be directed toward minimizing these complications. A thorough history and physical examination is the cornerstone of preoperative risk assessment. Preoperative functional status is

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particularly important in the elderly. Physically ﬁt, active patients, who can perform at least four metabolic equivalents (METS) of work, have decreased risk of perioperative complications. Unfortunately, many elderly patients have limitations on functional status because of musculoskeletal problems (eg, osteoarthritis). Cardiopulmonary ﬁtness is more diﬃcult to assess in this group. Elderly patients tend to have decreased cardiovascular reserve, although the degree of decline varies from individual to individual. The prevalence of coronary heart disease increases with age, as does the presence of other types of heart problems, such as valvular disease, congestive heart failure, and rhythm disturbances. Decreased reserve and increased disease contribute to an overall increased risk of perioperative cardiac complications in the elderly [24]. The optimal strategy for cardiac risk stratiﬁcation in this age group is unclear. The American Heart Association and American College of Cardiology guideline cites age as a minor clinical predictor of perioperative risk. This guideline also focuses on functional status as a signiﬁcant factor in preoperative risk stratiﬁcation. Because this may be more diﬃcult to ascertain in elderly patients, optimal preoperative testing is less clear. One may need to resort to nonexercise stress testing (eg, stress echocardiography) for moderate- and high-risk surgical procedures when functional capacity is unclear. Although one generally can identify higher-risk patients, strategies for risk reduction remain unclear. b-Adrenergic blockers seem to oﬀer the most promise for decreasing perioperative cardiac risk. Whether other modalities are beneﬁcial remains to be seen. Timing, dosage, and duration of therapy remain unknown. Elderly patients should be considered for b-blocker therapy unless a contraindication exists. Postoperative pulmonary complications can pose a signiﬁcant threat to elderly patients. Age-related decline in pulmonary reserve and changes in pulmonary function caused by surgery and anesthesia increase risk of postoperative pulmonary complications. Abdominal and thoracic surgical procedures cause a decrease in vital capacity, functional residual capacity, respiratory muscle dysfunction and changes in chest wall mechanics. All of these changes increase the likelihood of early airway closure and atelectasis, which can lead to a ventilation-perfusion mismatch. The presence of pulmonary disease further increases the risk of postoperative pulmonary complications. Neurologic problems, such as stroke and dementia, increase the risk of aspiration. Preoperative pulmonary function tests, however, are rarely useful in predicting risk of postoperative pulmonary complications. As with cardiac risk, functional status is a more important predictor of postoperative pulmonary complications. Prevention is the key to minimizing the risk of postoperative pulmonary complications. Patients and their families should be educated preoperatively about the importance of deep breathing, coughing, incentive spirometry, and early postoperative ambulation. Smoking cessation should be encouraged, although optimal timing is unclear [28]. Patients with chronic obstructive pulmonary disease should be evaluated in a timely fashion to ensure

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that there is no evidence of acute exacerbation. Adequate postoperative analgesia should help with deep breathing, coughing, and early ambulation. Care must be taken, however, to avoid oversedation. Polypharmacy and alterations in drug metabolism may lead to an increased risk of perioperative complications. Multiple medications may precipitate or exacerbate postoperative delirium. Diuretic use can cause electrolyte disturbances, which in turn may increase the risk of postoperative delirium and cardiac arrhythmias. Drugs with anticholinergic eﬀects may cause delirium or may precipitate urinary retention and constipation. Alterations in drug metabolism can occur at many sites. Age-related changes in renal and hepatic function all aﬀect the absorption and metabolism of drugs. Older patients may have decreased absorption of medications because of decreased blood ﬂow to the gastrointestinal tract and of alterations with gastric acidity. Gastric motility may be decreased, especially in patients with diabetes. Kidney function is subject to the same age-related decline as other organ systems. Serum creatinine may not rise, even with signiﬁcant renal dysfunction, because of decreased muscle mass. Comorbidities, such as diabetes, hypertension, vascular disease, and congestive heart failure, may further impair renal function. Renal dose adjustment should be made in elderly patients, especially if the glomerular ﬁltration rate is less than 80 mL/min. Nephrotoxic drugs should be avoided. Hepatic blood ﬂow is responsible for drug delivery to the liver. Hepatic mass determines the availability of hepatic enzymes for drug metabolism. Both of these functions may be decreased with age. The metabolism and clearance of many drugs used perioperatively are aﬀected by this decrease in hepatic function. Any drugs that are hepatically metabolized should be used with caution in the elderly. This is particularly true of benzodiazepines, which can have a prolonged half-life in this group of patients. Additionally, elderly patients can have a paradoxical response to benzodiazepines. Volume of distribution is also substantially altered in the elderly. Many older patients have decreased total body water and increased total body fat, with decrease in lean body mass. This can lead to an increased volume of distribution of fat-soluble drugs and a decreased volume of distribution of water-soluble drugs [17]. Serum albumin may be decreased and protein binding may be altered. Anticipation and avoidance are the key to minimizing the problems associated with polypharmacy. Medication lists should be reviewed carefully preoperatively. Patients should be questioned about the use of alcohol and over-the-counter medications and supplements. Medication regimens should be simpliﬁed as much as possible preoperatively. Any unnecessary or duplicated medicines should be discontinued. Where possible, drug levels should be checked preoperatively to avoid toxicity and ensure therapeutic eﬃcacy. Patients and their families should be given clear written and verbal instructions about preoperative changes in their medication regimens.

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The do-not-resuscitate status in the perioperative setting More and more, elderly patients are being encouraged to make decisions about end-of-life care. As older patients become sicker, they need to think seriously about which life-prolonging measures they would consider appropriate and which they would like to avoid as noxious or overly burdensome [29]. Many elderly patients execute do-not-resuscitate (DNR) orders because of a combination of comorbidities rather than a single terminal illness. These patients should not be denied surgical procedures simply because of the existence of a DNR order. Institutional policies diﬀer with respect to DNR policies in the operating room [31]. Some institutions require that DNR orders be suspended automatically during anesthesia. The assumption underlying this policy is that anesthesia is an iatrogenic situation and a cardiac arrest in this situation is potentially reversible. Proponents of this viewpoint argue that this is fundamentally diﬀerent from allowing an underlying disease to ‘‘take its course.’’ This is an important consideration in this group of patients, who are more likely to undergo surgery to relieve pain or improve quality of life. Patients with DNR orders who suﬀered perioperative cardiopulmonary arrest were unlikely to survive to hospital discharge. There seemed to be no beneﬁt in attempting to resuscitate a patient with a DNR order who suffered an arrest [31,32]. Are patients being denied surgical procedures because of the presence of a DNR order? The SUPPORT investigators [30] found that this was generally not the case, once other variables were adjusted for (estimate of 2-month survival, diagnosis, age, and severity of illness). What happens to the DNR order perioperatively? Clemency and Thompson [33] studied the attitudes of internists, anesthesiologists, and surgeons. Most anesthesiologists assumed that the DNR order was suspended in the perioperative period. Internists and surgeons underestimated this assumption. All three groups believed that the internist, surgeon, anesthesiologist, and patient should share the responsibility for deﬁning the DNR status perioperatively. They also believed that this issue should not be decided by hospital policy. Although there are little data available, it seems that patients with preexisting DNR orders who undergo surgery do have a slightly increased risk of cardiopulmonary arrest intraoperatively or postoperatively [7]. Walker [33] has likened the DNR order to the Jehovah witness’s right to refuse blood transfusion. He notes that this refusal of treatment should not deny the patient the right to a surgical procedure. He advocates a more ﬂexible approach to this problem. Patients and their physicians (surgeons, internists, and anesthesiologists) should enter into a dialogue about how the DNR order will be interpreted in the perioperative period. All risks and beneﬁts should be discussed (and carefully documented). The patient’s preference, however, should determine the ﬁnal outcome of this decisionmaking process.

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Role of the generalist in the perioperative management of the elderly patient As reviewed, the generalist has a vital role in the perioperative care of the elderly patient. Many functions are similar to those for all patients: 1. Assessing risk for perioperative complications: Speciﬁc disease-related risk Physiologic changes associated with aging 2. Developing a diagnostic or therapeutic plan for optimizing the patient’s physical status and minimizing risk 3. Developing a plan for monitoring for perioperative complications in patients at increased risk 4. Examining for the presence and status of other illnesses not necessarily related to perioperative risk 5. Developing a therapeutic plan for the perioperative management of these illnesses 6. Deﬁning the risks and beneﬁts for the individual patient, which may be signiﬁcantly altered in the elderly as already discussed (relief of suﬀering or improvement in functioning and quality of life become more overriding issues rather than simply prolongation of life) 7. Becoming intimately involved as part of the team that follows-up maintaining patient functioning postoperatively and following discharge from the hospital

Summary As the population survives longer, surgery has become a much more common consideration. Preoperative management of these patients requires a working knowledge of changes associated with aging and the physiology of surgery and anesthesia. Using this information, patients can be clinically evaluated eﬀectively and plans made for their perioperative care to minimize complications.

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