Therapeutic approaches to postoperative ischemia

Therapeutic Approaches to Postoperative lschemia Milton Hollenberg,

MD,

Dennis T. Mangano, PhD, MD, and The Study of Perioperative lschemia Research Group

Previous at&empts to iaentify predictors of cardiac complkatiins, an Important cause of postqerative morbidsty and mortality following noncardiac surgery, have focused mainly on the patiint’e preoperative state. Our research group, howwer, has found that adverse cardiac outcome correlates most highly with the appearance ofatleast lkchemkepisodedeterminedbycontinuous ambulatory electrocardiographic monitoring (AEM) in the early postoperative period. Such early postoperative ischemia co&ured (1) a greater than 54old increased risk of experiencing In-hospital cardiac death, nonfatal myocardkl infarction, or postoperative unstable angbta, and (2) a greater than 2-fold increased long-term (2year) risk of cardiac death, myocardial infarction, or angka requirkg coronary angioplasty or coronary artery bypass grafting (CABB). Additional~, 5 predictors of such postoperative kchemia were identified: left ventrkular hypertrophy, diabetes mellttus, hypertension, definite coronary artery disease, and preoperative digotin use. 7hese findings suggest that patients who are at high risk for postoperative myocardial kchemii warrant more intensive postoperative monttoring. Moreover, since such kchemia k potentially reversible, the testing of strategies designed to prevent or manage postoperative ischemia appears warranted and is discussed. Our group also has estab5ished the usefulness of AEM for identifying kchemic episodes in patients undergokg m. However, patients who require cardiopulmonary bypass present unique probkms regarding the interpretation of AEM recordings. We describe guidelines for the interpretation of AEM results obtained under these comlitions and suggest criteria based on the degree of interpretabillty for patient inclusion in future studies. (Am J Cardiol1994373:mB) From the Departments of Medicine and Anesthesia, Veterans Affairs Medical Center, San Francisco, and the University of California, San Francisco, California. Address for reprints: Milton Hollenberg, MD, Cardiology Section lllC3, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121.

30B

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73

c

ardiac complications following noncardiac surgery remain an important cause of postoperative morbidity and mortality. Of the 25 million patients who undergo noncardiac surgery each year, 3 million are known to have coronary artery disease (CAD) or multiple risk factors for CAD, and another 4 million patients are older than 65 years. Thus, about 7 million patients are at high risk for perioperative myocardial infarction and death.’ Since the mortality associated with perioperative infarction is still about 30-40%, the need to understand the mechanisms of such adverse cardiac events and to develop effective new therapeutic strategies is pressing. For many years, researchers have attempted to define preoperative predictors that would identify patients at highest risk for perioperative myocardial infarction.2-6 Recently, the more frequent use of diagnostic screening tests (e.g., dipyridamole and thallium-201 scintigraphy) has been advocated to assist in the identification and subsequent preoperative management of high-risk patients.7-11 However, the ability of these tests to predict adverse cardiac events is still controversial.12 Several years ago, a group of investigators at the Veterans Affairs Medical Center in San Francisco began a series of studies to identify predictors of cardiac morbidity and mortality in patients who either had or were at high risk for CAD and who were undergoing major noncardiac surgery. Whereas previous studies had discovered a variety of preoperative predictors that identified patients at high risk, we sought to identify more dynamic physiologic factors that occurred during and after surgery, which might affect outcome and were potentially reversible. We report here the results of several of these studies. PREDICTORS OF ADVERSE CARDtAC OlRCOME

In a study of 474 men who had or were at high risk for CAD and were scheduled to undergo noncardiac surgery, 5 cardiac outcome variables were analyzed: cardiac death, nonfatal myocardial infarction, unstable angina, ventricular tachycarMARCH 10, 1994

dia, and congestive heart failure.13 The first 3 I TABLE I Reasons for Uninterpretable Ambulatory (cardiac death, nonfatal myocardial infarction, and Electrocardiographic Monitoring Recordings unstable angina) were grouped as ischemic events. Proportion of An adverse cardiac outcome occurred in 82 paUnlnterpretable Characteristic Tracings (%) tients (17%), but only 15 patients (3%) had an ischemic event. When all 5 cardiac outcome variRight bundle branch block 25 Small QRS complexes ( < 5 mm) 22 ables were considered, 4 significant predictors Left bundle branch block 12 emerged: (1) preoperative use of digoxin for congeslntraventricular conduction defect 6 tive heart failure; (2) history of arrhythmia; (3) Atrioventricular or ventricular pacing 4 vascular surgery; and (4) postoperative ischemia on Superior axls 3 ambulatory electrocardiographic monitoring Combinations of above 15 (AEM). However, postoperative ischemia on AEM Other (e.g., leads off, nolse) 13 became the sole significant predictor when only the ischemic outcomes were considered (cardiac death, nonfatal myocardial infarction, and unstable an- CABG. We found that 9% of all AEM recordings gina). Patients who experienced at least 1 postop- obtained in the preoperative period and 23% of all erative ischemic episode had a greater than 9-fold recordings obtained in the combined intraoperaincreased risk of experiencing 1 of these ischemic tive and postoperative periods were uninterpretevents. We also identified the following preopera- able. The reasons for such uninterpretable results tive patient characteristics that were associated are listed in Table I. Because patients had varying amounts of uninwith an increased risk of ischemia occurring within terpretable AEM recordings in the different perio48 hours following noncardiac surgery: (1) left perative periods, minimal criteria for patient incluventricular hypertrophy detected by electrocardiography (odds ratio [OR] = 3.2; p <0.002); (2) sion in our studies had to be established. The diabetes mellitus (OR = 1.9; p 6 hours in the preoperative period (OR = 1.6; p <0.03); and (5) the use of digoxin and > 10 hours in the combined intraoperative and postoperative periods (when this latter amount (OR = 2.1; p <0.03).14 exceeded 50% of the total time monitored in the Thus, the identification of postoperative ischcombined intraoperative and postoperative periemia as the most important predictor of adverse cardiac outcome created possibilities for new thera- ods). When these inclusion criteria were used, the pies, since such ischemia is potentially amenable to AEM recordings of 190 patients (31%) were deemed unusable for analysis. In the remaining treatment or reversible. Moreover, we identified, preoperatively, those high-risk subgroups of pa- 427 patients, only 1% of the preoperative tracings tients in which postoperative ischemia was most and 7% of the intraoperative and postoperative likely to develop and in which patients might tracings were uninterpretable. Thus, after excludbenefit most from more intensive monitoring. Be- ing 31% of our patients because of inadequate or cause of these findings, we focused our subsequent unacceptable quality tracings, we obtained a mean investigations on the immediate postoperative pe- value of 13.6 hours of interpretable recordings per patient during the preoperative period and 42.5 riod, which had previously received little attention. hours per patient in the combined intraoperative and postoperative periods. We believe, therefore, CONTINUOUS PERIOPERATWE that continuous recordings from patients who unELEClROCARDlOGRAPHlC MONITORING dergo CABG provide useful and valid information We are now proposing similar studies to identify if rigid criteria for electrocardiographic interpretimportant predictors of poor outcome in patients ability and patient exclusion are established. who require coronary artery bypass grafting (CABG). However, these studies will be more EFFECTS OF ANESTHETICS ON ISCHEMIA difficult to perform and to interpret, since patients An earlier, much smaller study of 50 patients being weaned from cardiopulmonary bypass have undergoing CABG was designed to determine many electrocardiographic changes that compli- whether the stress of anesthesia and surgery would cate the interpretation of the AEM recordings. increase the frequency and/or severity of myocarWe addressed the feasibility of obtaining high- dial ischemia during the intraoperative and postopquality tracings and interpreting such recordings in erative periods when compared with the preoperaa recent study of 617 patients who underwent tive period.15 Our findings did not support this A SYMPOSIUM:

SILENT

MYOCARDIAL

ISCHEMIA

31B

anesthesia and surgery might not represent the most stressful period and that anesthesia might be protective came from patients undergoing noncardisc surgery. For example, in a patient with many ischemic episodes before, during, and after surgery, the only sustained period in which the patient was free of ischemia corresponded exactly to the period of anesthesia, which began at 7:58 A.M. and was associated with a low and stable heart rate. When the patient began to be weaned from the anesthetic at about 1:15 P.M., the heart rate increased significantly and the ischemic episodes recurred.

.z 0.35 .g 0.30 E 0.25 5

0.20-

g

0.15 -

g

O.lO-

i

0.05 -

g

0

Preop

'21

i&O .- .Ck

lntraop

Postop

T

8 ri

I

.iJ;j & Preop

Postop

lntraop

l p 4.05. FlGURE 1. Comparison of the number of kchemk episodes and total duration of lscheunla, both expressed per hour of monRorlng. *p eO.05 when lschemk minutes par hour for the intraoperatlve (Intraop) period ls compared wlth the postoperathfe (Postop) period. Preop = preoperative.

hypothesis. When compared with the preoperative period, the number of ischemic episodes and total duration of ischemia (expressed per hour of monitoring) in the intraoperative and postoperative periods did not differ significantly (Figure 1). Moreover, anesthesia even appeared to be protective during surgery, since the ischemic minutes per hour of monitoring were slightly fewer during the intraoperative than the postoperative period. Further evidence that the immediate period of

EFFECTS OF HEART RATE ON SCHEMA Several of our studies illustrated this association between high heart rates in the recovery period after surgery and the occurrence of ischemic episodes. Figure 2 illustrates the distribution of heart rate during the preoperative, intraoperative, and postoperative periods. Along the vertical axis is shown the percentage of the total time monitored that the heart rate falls within the indicated intervals. The heart rate is well controlled during anesthesia and approximates the rates that were seen preoperatively. Postoperatively, however, a greater percentage of time is spent at higher heart rates, especially > 100 beats/min.15 Such high heart rates persist throughout the first week postoperatively, and rates > 100 beats/min account daily for a mean of 22-35% of the total daily monitored time through postoperative day 7.16 Not only do these high heart rates reflect the excess sympathetic drive that exists in the postoperative period, but they may directly precipitate myocardial ischemia by increasing myocardial oxygen demand beyond

Heart rate (beats/m) ~100-119 I 60-79 I >I20 I 80-99

q 160 \

\ /

FlGURE 2. Dktof heart ~Preope-elY(preop),loperathrely (Intraop), and po~topemtk@ (Postop) In 50 patle* whoundewentcorowyartey hP==mfm&

\ I .

\ / \ /

I .

lntraop

Preop 32B

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

Postop 73

MARCH

10, 1994

TABLE II Therapeutic Strategies to Decrease Perioperative lschemia Extension of anesthesia/analgesia into the immediate postoperative period Anesthetics Analgesics/sedative hypnotics, including epidural adminrstration Newer agents (a,-adrenergic receptor agomsts, e.g., clonrdme) Anti-ischemrc agents Intravenous B-adrenergic receptor blockers Other new agents, e.g., adenosrne-regulating

agents

Antithrombotics Antiplatelet agents Anticlottingfactors Sympatholytics a,-Adrenergic

receptor agonists

the ability of an impaired coronary arterial system to supply such oxygen. Thus, from the results of the foregoing studies, it seems desirable to reduce the stress and sympathetic responses that occur in the postoperative period. Some possible therapeutic strategies are shown in Table II. Many of these interventions are now being tested under experimental protocols. The first of these strategies, the extension of the period of anesthesia into the recovery period, has already been tested. l7 Patients undergoing CABG received standard anesthesia with a high-dose narcotic, sufentanil. During cardiopulmonary bypass, they were divided into 2 groups: one received sufentanil, and the other morphine. In the intensive care unit, 1 group continued to receive intravenous sufentanil continuously for 18 hours while the other group was given intermittent intravenous morphine for pain as needed. Although the frequency of ischemia was similar in the 2 groups, the severity of ischemia as detected on AEM tracings was greater for the group receiving intermittent morphine. The duration of the ischemic episode, the depth of the maximal ST-segment depression, and the area under the ST-segment-time curve all were greater in the morphine group. Thus, continuation of anesthetics in the intensive care unit appears to suppress the severity of the myocardial ischemic episode. CONCLUSION Postoperative myocardial ischemia is the best predictor of adverse cardiac outcome in patients undergoing noncardiac surgery. It occurs with greatest frequency during the early postoperative period, a period associated with high heart rates. By contrast, during the intraoperative period, heart rates are well controlled by anesthetic agents that appear to be protective, even when extended into the intensive care period. Other strategies to re-

duce the incidence of postoperative myocardial ischemia are now being tested; these strategies include the use of epidural narcotics, intravenous P-adrenergic receptor blockers, and cw2-adrenergic receptor agonists. It is hoped that one or all of these lines of investigation will lead to improved perioperative management of the high-risk patient in the future. Additionally, we have proposed standards for the interpretation of AEM tracings obtained from patients who undergo CABG as well as guidelines for the inclusion of such patients in future prospective studies. REFERENCES L Mangano DT. P&operative cardiac morbidity. Anesthesiu~~ 1990,72:15> 184. 2. Arkins R, Smessaert AG Hicks RG. Mortality and morbidity in surgical patients with coronary artery disease. JAMA 1964;1%?485-488. 3. Tarhan S, Moffitt EA, Taylor WF, Giuliani ER. Myoardial infarction after general anesthesia. JAMA 1972;220:1451-1455. 4. Goldman L, Caldera DL Nussbaum SR, Southwick FS, Krogstad D, Murray B, Burke DS, O’MaIley TA, Goroll AH, Caplan CH, Nolan J, CarabeIlo B, Slater EE. Multifactorial index of cardiac risk in noncardiac surgical procedures. N EQ$./ Med 1977;297:84~50. 5. Detsky AS, Abram HB, McLaughlin JR, Drucker DJ, Sasson Z, Johnston N, Scott JG, Forbath N, Hill&d JR. Predicting cardiac complications in patients undergoing noncardiac surgery. J Gen Inrem Med 1986,1:211-219. 6. van Knoning J. Postoperative myocardial infarction: a prospective study in a risk group of surgical patients. Surgery 1981;90:55X0. 7. Cutler BS, Wheeler HB, Paraskos JA, Cardullo PA. Assessment of operative risk with electrocardiographic exercise testing in patients with peripheral vascular disease. Am J Sq 1979;137:484489. 8. Carliner NH, Fisher ML, Plotnick GD, Garbart H, Rapport A, Kelemen MH, Moran GW, Gadacz T, Peters RW. Routine preoperative exercise testing in patients undergoing major noncardiac surgery. Am J Cardio~ 1985;56:51-58. 9. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Eq$ J Med 1985;312:389-394. l0. L.eppo J, Plaja J, Gionet M, Turn010 J, Paraskos JA, Cutler BS. Noninvasive evaluation of cardiac risk before elective vascular surgery. J Am Co[l Cardiol 1987;9:269-276. ZL Eagle KA, Coley CM, Newell JB, Brewster DC, Darling RC, Strauss HW, Guiney TE, Boucher CA. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Arm Intern Med lY89;l l&85%866. 12. Mangano DT, London MJ, Tubau JF, Browner WS, HolIenberg M, Kmpski W, Layug EL, Massie B, and the Study of Perioperative Ischemia Research Group. Dipyridamole thallium-201 scintigraphy as a preoperative screening test: a reexamination of its predictive potential. Circulation 1991;84:49%502. 13. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM, and the Study of Perioperatiw Ischemia Research Group. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N En@ J Med 1990;323:1781-1788. 14. Hollenberg M, Mangano DT, Browner WS, London MJ, Tubau JF, Tateo IM, for the Study of Perioperative Ischemia Research Group. Predictors of postoperative myocardial ischemia in patients undergoing noncardiac surgery. JAM4 1992;268:W5-209. 15. Knight AA, Hollenberg M, London MJ, Tubau J, Varier E, Browner W, Mangano DT, and the S.P.I. Research Group. P&operative myocardial ischemia: importance of the preoperative ischemic pattern. An&haiolo~ 1988;68: 681488. l6. Smith RC, Leung JM, Mangano DT, and the S.P.I. Research Group. Postoperative myocardial ischemia in patients undergoing coronay artery bypass graft surgery. Anesthesiology 1991;74:464-473. 17. Mangano DT, Siliciano D, HoIlenberg M, L.eung JM, Browner WS, Goehner P, Merrick S, Verrier E, the Study of Perioperative Ischemia (SPI) Research Group. Postoperative myocardial ischemia: therapeutic trials using intensive analgesia following surgery. Anesthesiology lY92;76:342-353.

A SYMPOSIUM:

SILENT

MYOCARDIAL

ISCHEMIA

336