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Previous Volume 330:670-674 March 10, 1994 Number 10 Next

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ABSTRACT

Background Perioperative myocardial infarction is the most common cause of morbidity and mortality in patients who have had noncardiac surgery, but its diagnosis can be difficult. The present study was designed to determine whether the measurement of serum levels of cardiac troponin I, a highly sensitive and specific marker for cardiac injury, would help establish the diagnosis of myocardial infarction.

Methods We obtained preoperative measurements of MB creatine kinase, total creatine kinase, and cardiac troponin I, in addition to base-line electrocardiograms and two-dimensional echocardiograms, in 96 patients undergoing vascular surgery and 12 undergoing spinal surgery. Blood samples were obtained every 6 hours for at least the first 36 hours after surgery, and electrocardiograms were obtained daily; a second echocardiogram was obtained approximately three days after surgery. The appearance of a new abnormality in segmental-wall motion on the postoperative echocardiogram (that is, an abnormality that had not been seen on the preoperative echocardiogram) was considered to be indicative of perioperative infarction.

Results Eight patients who underwent vascular surgery had new abnormalities in segmental-wall motion and received a diagnosis of perioperative infarction. All eight had elevations of cardiac troponin I, and six had elevations of MB creatine kinase. Of the 100 patients without perioperative infarction detected by echocardiography, 19 had elevations of MB creatine kinase, and 1 had a slight elevation of cardiac troponin I.

Conclusions The measurement of cardiac troponin I is a sensitive and specific method for the diagnosis of perioperative myocardial infarction. It avoids the high incidence of false diagnoses associated with the use of MB creatine kinase as a diagnostic marker.

Cardiac troponin I is a regulatory protein with a high specificity for cardiac injury^12,16,17. It is not found in skeletal muscle during neonatal development or during adulthood, even after acute or chronic injury of the skeletal muscle^16,17,18. Accordingly, elevations do not occur in plasma, even in patients with acute or chronic skeletal muscle disease, unless acute myocardial injury is present¹². Recent data indicate that the sensitivity of cardiac troponin I is similar to that of MB creatine kinase for the diagnosis of acute myocardial infarction^19,20. Furthermore, elevations of cardiac troponin I persist for up to five to seven days in plasma,^19,21 permitting flexibility in the timing of blood sampling. Our study was designed to determine whether the measurement of cardiac troponin I would allow for the distinction between patients with perioperative elevations of MB creatine kinase due to skeletal-muscle injury and those with elevations due to myocardial injury, and also to determine the incidence of false positive elevations of MB creatine kinase after surgery.

Methods

One hundred twenty-nine consecutive patients undergoing vascular or spinal surgery were enrolled in the study. Patients requiring vascular surgery were chosen because this group has a high incidence of coronary artery disease, which increases the risk of perioperative myocardial infarction. A smaller cohort of patients requiring surgery for spinal deformities (n = 12) was also studied, since such patients frequently have perioperative elevations of MB creatine kinase⁷. To be eligible for this study, patients had to be admitted to the hospital at least one day before surgery to allow for preoperative echocardiography. Thirteen patients were excluded because the echocardiographic views were inadequate for the evaluation of abnormalities in segmental-wall motion in any region of the left ventricle (that is, at least 80 percent of the endocardium of each segment could not be visualized on either the preoperative or postoperative echocardiogram), three were excluded because their electrocardiograms showed a left bundle-branch block or a paced rhythm, two were excluded because they had had a myocardial infarction in the previous seven days, two refused to give informed consent, and one died before blood samples could be obtained. Of the remaining 108 patients, 96 underwent vascular surgery, and 12 underwent spinal surgery. Preoperative studies in all patients included measurements of total creatine kinase activity, MB creatine kinase mass (that is, the quantity of protein per milliliter of serum), and cardiac troponin I mass, as well as electrocardiography and base-line echocardiography. The measurements were repeated every 6 hours for the first 36 hours after surgery, and electrocardiograms were obtained daily. A second echocardiogram was obtained three to five days after surgery. The protocol was approved by the Human Studies Committee of Washington University School of Medicine.

All echocardiograms were obtained with an ultrasound imaging system (HP 77600; Hewlett-Packard, Andover, Mass.) with either a 2.5- or 3.5-MHz transducer. Two-dimensional echocardiographic images were obtained in the parasternal short- and long-axis views, apical two- and four-chamber views, and subcostal views, as recommended by the American Society of Echocardiography²². All echocardiograms were interpreted by an expert echocardiographic reader who was unaware of the clinical and biochemical information. The reader was not told which echocardiogram was obtained preoperatively, and which postoperatively. A 16-segment model, as recommended by the American Society of Echocardiography, was used to detect and quantify any abnormalities of regional-wall motion,²³ which were classified as 1 (normal), 2 (hypokinetic), 3 (akinetic), or 4 (dyskinetic). The development of postoperative akinesis or dyskinesis in any segment that had been normal or hypokinetic on the preoperative echocardiogram was considered indicative of an infarction. Thirty-three echocardiograms, including all those with differences between the preoperative and postoperative studies, were reread to determine the intraobserver variability. The concordance between the initial and subsequent readings for the diagnosis of myocardial infarction was 100 percent. The same echocardiograms were read by a second expert echocardiographer to determine the interobserver variability. The presence or absence of a difference between preoperative and postoperative studies was concordant in 32 of the 33 echocardiograms. In one, the second reader thought that the views obtained were inadequate for a diagnosis.

Evaluation of Molecular Markers

Blood samples were drawn into tubes with no preservatives and centrifuged at 2000 x g for 15 minutes. Serum was stored at -70 °C, thawed once, and assayed in batches. Total creatine kinase, MB creatine kinase, and cardiac troponin I are stable when handled in this manner^21,24,25. Assays and determinations of abnormal values were performed by technicians who were unaware of the clinical and echocardiographic data.

Total creatine kinase activity (upper reference limit, 220 IU per liter; limit of detection, 25) was measured on a Flexigem centrifugal analyzer (Electro-Nucleonics, Columbia, Md.)²⁵.

Mb creatine kinase mass (upper reference limit, 6.7 ng per milliliter; limit of detection, 2.2) was measured with a commercially available immunoassay (Stratus CK-MB; Baxter Diagnostics, Miami)²⁴.

Cardiac troponin I mass was measured with an immunoassay in a preliminary application on the Baxter Stratus analyzer, which uses two monoclonal antibodies specific for cardiac troponin I that recognize different epitopes²¹. Cardiac troponin I is undetectable in normal volunteers. A parametric analysis of this assay in hospitalized patients without myocardial infarction has established that the upper limit of the reference range is 3.1 ng per milliliter, given a 95 percent cutoff value; the limit of detection is 1.5 ng per milliliter. The immunoassay has no detectable cross-reactivity with human skeletal-muscle troponin I²¹.

Statistical Analysis

The significance (two-tailed test) and confidence intervals for differences in the incidence of elevations of cardiac troponin I and MB creatine kinase were calculated by McNemar's test²⁶.

Results

Table 1 shows the demographic and clinical characteristics of the 108 patients enrolled in the study. Eight patients had new abnormalities of segmental-wall motion on the postoperative echocardiogram and received a diagnosis of perioperative myocardial infarction. All eight patients had elevated cardiac troponin I values (Figure 1), and six of the eight had elevated MB creatine kinase values (Figure 2). The cardiac troponin I values in the eight patients with infarction are shown in Figure 3. Nineteen of the patients without echocardiographic evidence of a myocardial infarction (8 of whom had undergone spinal surgery, and 11 vascular surgery) had elevated values of MB creatine kinase; only 1 patient had an elevated level of cardiac troponin I. The difference between the specificity of cardiac troponin I (99 percent) and that of MB creatine kinase (81 percent) was significant (P<0.005). The standard error for this 18 percent difference was 4.1 percent, and the confidence interval was 10 to 26 percent. The lone patient who had an elevation of cardiac troponin I but no new abnormality of regional-wall motion had prolonged severe hypotension (systolic pressure, 60 mm Hg) and sinus tachycardia (heart rate, 150 beats per minute) immediately after surgery, with new deep depression of the ST segments in the inferolateral leads. Subsequently, she had a minor elevation of cardiac troponin I to 3.3 ng per milliliter (upper reference limit, 3.1) and an increase (and then a decrease) in MB creatine kinase to a peak level of 6.5 ng per milliliter (upper reference limit, 6.7). However, no new abnormalities of segmental-wall motion were identified. Two of the eight patients with perioperative myocardial infarction had Q waves on subsequent electrocardiograms; the other six had only ST-segment or T-wave changes (that is, none had Q-wave infarctions); two had symptoms (hypotension, shortness of breath, or both). Thirty-two of the 100 patients without evidence of an infarction on echocardiography and without elevations of cardiac troponin I also had nonspecific changes in the ST segment or T wave after surgery.

View this table: [in this window] [in a new window]   Table 1. Characteristics of 108 Patients Undergoing Noncardiac Surgery.

 

View larger version (7K): [in this window] [in a new window]   Figure 1. Peak Cardiac Troponin I Mass in Patients with and without Perioperative Myocardial Infarction. The upper reference limit for cardiac troponin I mass is 3.1 ng per milliliter. The triangles denote patients undergoing spinal surgery, and the circles those undergoing vascular surgery.

 

View larger version (9K): [in this window] [in a new window]   Figure 2. Peak MB Creatine Kinase Mass in Patients with and without Perioperative Myocardial Infarction. The upper reference limit for MB creatine kinase mass is 6.7 ng per milliliter. The triangles denote patients undergoing spinal surgery, and the circles those undergoing vascular surgery.

 

View larger version (26K): [in this window] [in a new window]   Figure 3. Time Course of Changes in Cardiac Troponin I Levels after Surgery in Eight Patients with Acute Infarction. Initial elevations were present in six patients on day 1 and in two patients on day 2. The broken lines denote the upper limit of normal values. Preoperative values are indicated by the first symbol in each curve.

 
The patients with perioperative myocardial infarction generally had higher ratios of MB creatine kinase to total creatine kinase (Figure 4). With the use of peak values and a cutoff ratio of 2.5,¹⁰ which is equivalent to a cutoff value of 5 percent if activity rather than mass is measured,¹¹ calculation of this ratio yielded a sensitivity of 62.5 percent.

View larger version (8K): [in this window] [in a new window]   Figure 4. Ratio of MB Creatine Kinase Mass to Total Creatine Kinase Activity in Patients with and without Perioperative Myocardial Infarction. The suggested reference limit for the ratio is 2.5. The triangles denote patients undergoing spinal surgery, and the circles those undergoing vascular surgery.

 
Three patients undergoing vascular surgery died during hospitalization. Each had a perioperative myocardial infarction diagnosed on the basis of changes in cardiac troponin I and confirmed by serial echocardiograms. No other patients died. None of the patients undergoing surgery for spinal deformities had a perioperative myocardial infarction. The patients who had infarctions were hospitalized longer than those who did not (mean [±SD], 29 ±24.6 days vs. 9.8 ±7.4 days, respectively).

Discussion

These data indicate that serial measurements of cardiac troponin I provide a highly accurate method of detecting perioperative myocardial infarction or excluding the diagnosis. There was a concordance between the development of abnormalities in segmental-wall motion, as detected by echocardiography, and elevations in cardiac troponin I in 107 of the 108 patients in the study. In one patient, a minor elevation of cardiac troponin I occurred after prolonged hypotension, tachycardia, and electrocardiographic changes, but new wall-motion abnormalities were not detected by echocardiography. This patient may have had a small amount of myocardial damage. It is likely that cardiac troponin I, a sensitive marker of myocardial injury, detects smaller amounts of myocardial damage than even high-quality serial echocardiograms. In contrast, MB creatine kinase was elevated in 19 percent of the patients without perioperative cardiac injury, including two thirds of those undergoing spinal surgery, which is consistent with the results of previous studies^6,7. Among the patients undergoing vascular surgery, false positive elevations of MB creatine kinase were more common than true positive elevations (occurring in 11 and 6 patients, respectively). It is unlikely that the high incidence of false positive increases in MB creatine kinase was due to more sensitive detection of infarction. Although MB creatine kinase may be more sensitive than even serial echocardiograms in some cases, we and others have documented that measurements of cardiac troponin I and MB creatine kinase have a similar sensitivity for the diagnosis of acute infarction^19,21. In addition, our data are consistent with an extensive literature documenting elevations of MB creatine kinase in association with acute and chronic skeletal-muscle injury^6,7,13,27,28. Our study protocol provided for an extensive perioperative cardiovascular evaluation in an attempt to exclude the possibility of even small amounts of myocardial injury. Our data strongly support the view that in many cases perioperative elevations of MB creatine kinase result from damage to skeletal muscle rather than a cardiac injury. Thus, the measurement of a highly sensitive, cardiac-specific marker such as cardiac troponin I should improve the perioperative evaluation and care of patients who undergo noncardiac surgery. Our data do not establish the superior sensitivity of cardiac troponin I as compared with MB creatine kinase, only its superior specificity for the detection of perioperative infarction.

Although a few patients had obvious infarctions, most had a smaller degree of myocardial injury, which can be more difficult to diagnose. Thirty-two patients had nonspecific electrocardiographic changes of uncertain importance, and 25 of the 32 had increased MB creatine kinase values, but only 6 of these 32 patients (19 percent) were found to have echocardiographic evidence of myocardial injury. Thus, although electrocardiographic monitoring frequently detects episodes of perioperative myocardial ischemia that are not otherwise apparent,⁵ this approach is not specific for perioperative myocardial infarction. Our data suggest that the use of the ratio of MB creatine kinase mass to total creatine kinase activity improves the accuracy of creatine kinase as a diagnostic marker but does not provide the sensitivity afforded by the measurement of cardiac troponin I. Furthermore, in many situations, the use of this ratio is inaccurate in differentiating skeletal-muscle injury from myocardial injury^12,13,27.

The patients with perioperative myocardial infarctions had increased morbidity and mortality during hospitalization, as compared with the patients who did not have infarctions. Three of the eight patients with infarctions died before discharge. This finding is consistent with previous reports of a mortality rate of 36 to 70 percent associated with perioperative myocardial injury^2,3,29. The patients with perioperative cardiac injury also required a longer hospitalization than those without infarction. In some cases the myocardial infarction may have been responsible, but in others the cardiac injury appeared to be due to noncardiovascular complications. Although knowledge of the presence of myocardial damage might have facilitated the care of these patients, aggressive hemodynamic monitoring was routinely employed. Further studies will be necessary to determine whether the detection of cardiac injury in such patients can improve their prognosis.

The greater specificity of cardiac troponin I, as compared with MB creatine kinase, for the detection of myocardial injury is consistent with their molecular properties. The B subunit of creatine kinase, though prevalent in fetal skeletal muscle, is produced to only a small extent in healthy adult skeletal muscle⁹. Like many proteins, including cardiac troponin T, that are expressed during fetal development, B-chain creatine kinase increases substantially in adult skeletal muscle after injury³⁰. In contrast, there are molecular forms of troponin I with unique amino acid sequences in slow- and fast-twitch skeletal muscle and cardiac muscle³¹. Thus, unlike both MB creatine kinase and other troponin proteins, cardiac troponin I is produced only in myocardium throughout development^16,18,32. At present, cardiac troponin I is the only known molecular marker of myocardial injury that is not expressed in regenerating skeletal muscle^16,27,33,34. For this reason, it is not elevated in plasma from patients with acute or chronic muscle disease unless a cardiac injury has occurred^12,17. Although not directly proved in our study, it is likely that the specificity of cardiac troponin I is not affected by the type of surgery that patients undergo.

Since elevations of cardiac troponin I persist for five to seven days after myocardial injury, the use of this marker to diagnose perioperative myocardial infarction will probably require one of two diagnostic strategies. One strategy is to measure cardiac troponin I only if a myocardial injury is suspected and the values of MB creatine kinase are elevated. An alternative strategy is to obtain a preoperative value for comparison with postoperative values. A refined method of detecting perioperative infarction should improve the ability to predict which patients are at risk of an infarction and to determine its effect on the short- and long-term prognosis.

The variable results reported in the extensive literature on this topic probably reflect the difficulties of diagnosing myocardial injury perioperatively. For example, among the patients in our study who underwent vascular surgery, the incidence of perioperative myocardial infarction (8.3 percent) and death (3.1 percent) was higher than in previous studies, including one from our institution^{1,4,29,35,36,37}. The likely explanation is that we diagnosed infarctions that might have been missed in other studies. In addition, since the patients in our study had to be admitted at least one day before surgery in order to obtain a preoperative echocardiogram, patients at low risk admitted just before surgery could not be enrolled. Finally, all the patients in our study who had vascular surgery underwent extensive procedures (Table 1). Thus, enrollment in our study was biased in favor of patients with an increased risk of cardiovascular injury.

The measurement of cardiac troponin I is an accurate method to confirm or exclude the diagnosis of perioperative cardiac injury. Its use should be simpler and more cost effective than the routine use of echocardiography. Moreover, the improved detection of perioperative myocardial infarction should help clarify the true incidence, predictive factors, and prognostic importance of perioperative cardiac injury.

Supported in part by grants (training grant 5-T32-ESO-7066 and Specialized Center of Research grant in Coronary and Vascular Diseases HL 17646) from the National Institutes of Health and by Baxter Diagnostics.

Dr. Ladenson is a consultant to Baxter Diagnostics, and Dr. Jaffe is a consultant to Abbott Laboratories in the use of markers of myocardial injury. There are licensing agreements between Washington University and Baxter Diagnostics in the field of biochemical cardiovascular markers.

We are indebted to Dr. William Hopkins for the echocardiographic review, to Dr. Philip Miller for statistical consultation, to V. Landt for technical assistance, to S. Gilvary, R.D.C.S., for echocardiographic assistance, and to S. Viviano for assistance in the preparation of the manuscript.

Source Information

From the Cardiovascular Division (J.E.A., V.G.D.-R., A.S.J.), the Department of Surgery, Vascular Surgery Section (G.A.S., B.T.A.), the Division of Orthopedic Surgery (K.H.B., L.G.L.), and the Division of Laboratory Medicine (J.H.L.), Washington University School of Medicine, St. Louis; and the Division of Laboratory Medicine, Vanderbilt University, Nashville (G.S.B.).

Address reprint requests to Dr. Jaffe at Washington University School of Medicine, 660 S. Euclid, Box 8086, St. Louis, MO 63110.

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