From the Departments of Anesthesiology, Critical Care Medicine, Vascular Surgery, Clinical Biochemistry, and Cardiology, Hadassah Medical Center, Jerusalem, Israel
More than 4% of patients who are diagnosed with coronary artery disease (CAD) or have risk factors for CAD and undergo major noncardiac surgery have postoperative myocardial infarction (MI) and major cardiac complications.1,2 Perioperative MI is often difficult or even impossible to diagnose clinically based on only two of the classical triad of factors—cardiac symptoms, typical electrocardiographic (ECG) findings, and biochemical markers. The silent nature of perioperative infarction, the subtle and transient ST-segment depression ECG changes resulting in non—Q-wave infarction,3 and the claimed low specificity of CK-MB isoenzyme4 lead to inconsistencies in the diagnosis, making the long-term significance of perioperative markers of MI uncertain. Based on continuous 12-lead ECG monitoring and long-term survival, our study sought to determine whether elevated postoperative troponin has significant prognostic implications, and the plasma concentrations of cardiac troponin I and T and CK-MB that correlate with postoperative MI.
Patients and methods
The study included 447 consecutive patients who underwent 231 carotid endarterectomies, 77 abdominal aortic operations, and 193 lower-extremity bypass procedures at the Hadassah University Hospital, for a total of 501 major vascular surgical procedures. Before anesthesia was administered, patients were connected to a continuous 12-lead ECG monitor wired to a Cardiac Review station (ST-Guard, Marquette Electronics). All 12-lead ECG complexes were automatically stored every minute, and the absolute and relative ST-segment deviation at 60 milliseconds after the J point in all leads was measured compared with preoperative baselines.
Patients were monitored for at least 48 hours and up to 72 hours. We measured cardiac troponin I or T, or both, and CK-MB in all patients immediately after surgery and every morning for the first three postoperative days. We examined three cutoff levels of cardiac troponin: (1) troponin I levels above 1.5 ng/mL and/or troponin T levels above 0.1 ng/mL, which were the receiver—operator characteristic curve medical decision cutoffs for MI defined by the manufacturers of these assays; (2) troponin I levels above 0.6 ng/mL and/or troponin T levels above 0.03 ng/mL, which corresponded to the lowest levels with less than 10% imprecision or coefficient variance (coefficient variation) for these assays5; and (3) troponin I levels above 3.1 ng/mL and/or troponin T levels above 0.2 ng/mL. The upper limit of normal for CK total was 170 IU, and the upper limit of normal for CK-MB/total CK was 10% in our lab. We also investigated the cutoff level of 5%.
If troponin I levels above 1.5 ng/mL and/or troponin T levels above 0.1 ng/mL were associated with typical ischemic symptoms, ECG changes indicative of ischemia, or new pathological Q-waves, a diagnosis of clinical MI was made by the treating physicians independent of this study. The hospital’s information system, which is continuously updated by the Israeli Ministry of the Interior with all newly deceased individuals, was used to track long-term survival.
Myocardial ischemia. Sixty-six patients had 104 ischemic episodes during the 25,622 patient-hours of continuous 12-lead ECG monitoring (51.4 ± 15.7 hours/patient). All episodes but one were denoted by ST-segment depression alone. The longest ischemic episode lasted over 30 minutes in 44 (9.8%) of the patients and over 60 minutes in 23 (5.1%) of the patients.
Myocardial infarction. Depending on the biochemical criteria used, 14 (2.9%) to 107 (23.9%) patients had a postoperative MI, but only 17.7% to 61.9% had signs or symptoms of MI (table 1). None of the patients had new Q-waves. Each of the biochemical criteria for MI was associated with prolonged postoperative ischemia, and a higher incidence of prolonged postoperative ischemia was found among those who had higher troponin and CK-MB levels (table 1). Based on the combination of elevated cardiac troponin with ECG findings, prolonged chest pain, or both, 16 patients (3.6%) were diagnosed by the treating physicians as having postoperative MI, 12 (2.8%) of whom had symptoms related to MI.
Long-term survival. There were 82 deaths (18.3%) during the 5-year follow-up period (mean, 32.3 ± 13.8 months). Results of the multivariate Cox survival analysis of the pre- and postoperative predictors of survival are shown in table 2. The only preoperative predictors of long-term survival, according to the multivariate Cox regression analysis, were age, type of vascular surgery (lower-extremity bypass surgery), previous MI, and renal insufficiency. By univariate analysis (data not shown), all cutoff levels of CK-MB, cardiac troponin, and ischemia duration predicted long-term survival (figure). When all postoperative biochemical markers were included with the preoperative predictors in the multivariate analysis, only the CK-MB levels above 10% and troponin I levels above 0.6 ng/mL and/or troponin T levels above 0.03 ng/mL were independent predictors of mortality (odds ratio [OR] = 4.21 and 1.96; P = .002 and .005, respectively). Using only the lowest cutoff levels of CK-MB and troponin, both CK-MB above 5% and troponin I above 0.6 ng/mL and/or troponin T above 0.03 ng/mL independently predicted mortality (OR = 2.14 and 1.89; P = .018 and .01, respectively).
The results of our study showed that even minor elevations in cardiac troponin or CK-MB during the first 3 postoperative days predict increased risk of long-term mortality after major vascular surgery. Those with higher levels of biochemical markers, indicating a larger volume of myocardial injury or infarction, had worse survival. Levels of CK-MB above 10% and troponin I levels above 1.5 ng/mL and/or troponin T levels above 0.1 ng/mL predicted a 3.75- and 2.06-fold increase in long-term mortality, respectively, independent of the preoperative predictors, such as the patient’s age, type of vascular surgery, previous MI, and renal failure. Levels of CK-MB above 5% and troponin I levels above 0.6 ng/mL and/or troponin T levels above 0.03 ng/mL independently
predicted a 2.15- and 1.89-fold increase in mortality, respectively. As found in a previous study, there was a strong correlation between prolonged postoperative ischemia and elevated troponin levels (table 1). Prolonged postoperative ischemia longer than 30 minutes’ duration was associated with a 2.6-fold increase in adjusted long-term mortality, and ischemic episodes longer than 60 minutes were associated with a 3.7-fold increase (table 2).
Our study supports the findings of two previous studies that inves-tigated the effect of postoperative cardiac troponin measurements on
6-month outcome following noncardiac surgery.6,7 Our in-depth analysis of the biochemical markers, including low-level troponin elevations as well as perioperative ischemia, and longer follow-up expand on the findings of these studies.
Debate over which cutoff levels of troponin should be used to define a clinically important MI continues. The conventional cutoff values, those obtained by titration of troponin to a population of patients with a medical diagnosis of MI using receiver—
operator characteristic curve analyses, were troponin I levels above 1.5 ng/mL and troponin T above 0.1 ng/mL for the assays used in our study. On the other hand, in their consensus document for redefinition of MI, the American College of Cardiology/European Society of Cardiology (ACC/ESC) task force held that even minor increases to levels above the 99th percentile of the normal population, in the setting of documented myocardial ischemia, should be considered as MI because cardiac troponins are so specific to myocardial necrosis.8 Most troponin assays, however, are not precise enough at this low range. Therefore, somewhat higher cutoff levels are suggested based on less than 10% imprecision or coefficient variance. Troponin I and T levels above 0.6 and 0.03 ng/mL, respectively, were used for the assays in our study.
Creatine kinase-MB predicted long-term mortality independent of cardiac troponin. Patients with both elevated CK-MB and troponin, however, had a 4.19-fold increase in mortality compared with a 2.0- to 2.2-fold increase in mortality among those with only one of these markers.
Clinically evident infarction. Only 25 patients (5.6%) met the conventional World Health Organization (WHO) clinical definition of MI. The WHO definition requires at least two of the following criteria: prolonged chest pain, elevated CK-MB or cardiac troponin, and ischemic ECG changes. Even in these 25 patients, the diagnosis of MI could not be made without the routine postoperative biochemical markers and continuous ECG monitoring because only 16 (3.6%) had prolonged chest pain or congestive heart failure suspicious of overt MI. Our data support the findings of Kim and colleagues,7 who reported that 12% of the patients had elevated troponin I on routine postoperative surveillance, but only 3% had clinical infarction based on the WHO definition. Routine monitoring of cardiac troponin, CK-MB, and silent ischemia in the first postoperative day, therefore, may help predict the short- and long-term risks of those who undergo major vascular surgery.
Our study findings are also important with regard to the pathophysiology of perioperative MI. Recent studies have stressed that even minor elevations of cardiac troponin have prognostic importance in patients with unstable coronary syndromes. Those undergoing elective major vascular surgery represent a different type of cardiac patient than those with unstable coronary syndromes. The former often have long-standing, yet stable CAD. Their postoperative cardiac events are usually the result of stress-induced, ST-segment depression-type ischemia leading to infarction.4
Our findings showed that cardiac troponin, CK-MB, and prolonged postoperative ischemia predict long-term mortality after major vascular surgery. Elevated troponin and CK-MB levels independently predict long-term survival, and when combined, are associated with an even worse prognosis. Further studies are needed to determine how cost-effective routine measurement of postoperative cardiac markers is, and whether more aggressive diagnostic and treatment strategies will improve survival in patients with postoperative MI.