Perioperative myocardial cell injury: the role of troponins

Transcription

1 British Journal of Anaesthesia 1997; 78: Perioperative myocardial cell injury: the role of troponins H. METZLER, M. GRIES, P. REHAK, TH. LANG, S. FRUHWALD AND W. TOLLER Summary Early recognition of minor myocardial cell injury and appropriate treatment may prevent development of myocardial infarction as one of the most severe postoperative cardiac complications. Troponins have been shown to be sensitive biochemical markers for the assessment of myocardial cell injury. We investigated prospectively 67 cardiac risk patients undergoing elective non-cardiac surgery. Troponin T (TNT) concentrations were measured during the perioperative period, and in those patients with increased TNT (cut-off 0.2 ng ml 1 ), troponin I (TNI) concentrations were measured additionally (cut-off 0.6 ng ml 1 ). Patients were allocated to one of three groups: group I, all patients with normal TNT concentrations had a good cardiac outcome (80.5%). In those patients with increased TNT concentrations (19.5%) TNI was also positive; group II, patients (8.8%) with only slightly increased TNT concentrations ( ng ml 1 ) also had a good outcome, indicating minor myocardial cell injury, whereas patients with cardiac complications (11.9%) had higher TNT concentrations ( ng ml 1 ) (P 0.05) (group III). With a TNT cut-off at 0.2 ng ml 1, the positive predictive value for adverse outcome was 61.5%; the negative predictive value was 100%. With a TNT cut-off at 0.6 ng ml 1, the positive predictive value for adverse outcome increased to 87.5%, but the negative predictive value was still high (98%). Most of the patients showed an increase in TNT content from the day of surgery until the third postoperative day. We conclude that serial troponin measurements during the perioperative period identify pre-, intra- and postoperative myocardial cell injury. The concentration of troponin T may reflect the degree of injury and help categorize the subsequent risk. (Br. J. Anaesth. 1997; 78: ). Key words Surgery, non-cardiac. Surgery, perioperative period. Complications, morbidity. Heart, troponins. Recently, in cardiac risk patients undergoing noncardiac surgery, a complete perioperative pattern of myocardial ischaemia has been identified. 1 7 Postoperative ischaemia appears to correlate with adverse outcome, and prolonged subendocardial ischaemia rather than acute coronary artery occlusion precedes cardiac complications. 1 2 Perioperative myocardial infarction (MI) represents the most severe complication at the end of an adverse cascade, usually initiated by episodes of myocardial ischaemia which may occur as a reversible or irreversible event. The gap between reversible myocardial ischaemia and definite death of myocardial cells of a major area may be linked by appropriate assessment of minor myocardial cell injury, which may help to prevent MI. Cardiac troponins have been established as sensitive markers for detection of major and minor myocardial cell injury, avoiding the high incidence of false positive results associated with the use of CK- MB Both troponin T (TNT) and troponin I (TNI) are currently used. TNT has the advantage of a broad diagnostic window of up to 14 days and has been shown to be a marker for minor myocardial cell damage. TNI is expressed exclusively in the myocardium of adults and is highly specific for myocardial cell injury, excluding skeletal muscle damage. To date there have been no studies evaluating myocardial cell injury in the perioperative period using both troponins. This study was designed to assess the extent of minor myocardial cell injury in cardiac risk patients undergoing elective non-cardiac surgery. The aims of the study were to examine the perioperative pattern of changes in troponin from the day before surgery until the fifth day after operation, to compare TNT and TNI concentrations in those patients with increased TNT concentrations and to compare the positive and negative predictive values of troponin T for adverse outcome. Patients and methods After obtaining approval from the Ethics Committee of the University and informed consent, we investigated prospectively 70 cardiac risk patients undergoing elective non-cardiac surgery. Subjects were included in the study according to the presence of definite or at-risk coronary artery disease (CAD). Definite CAD was defined as previous MI, typical or atypical angina with positive exercise testing or scintigraphic evidence, or previous CABG or PTCA. HELFRIED METZLER, MD, MARIA GRIES, MD, SONJA FRUHWALD, MD, WOLFGANG TOLLER, MD (Department of Anaesthesiology); PETER REHAK, PHD (Department of Surgery); THOMAS LANG, MD (Department of Clinical Chemistry); University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria. Accepted for publication: November 28, Correspondence to H. M.

2 Troponins and perioperative myocardial cell injury 387 Patients at-risk for CAD were included if they had at least three of the following cardiac risk factors: age 65 yr, hypertension, current smoker, treated diabetes mellitus (insulin or oral hypoglycaemic agents), increased serum cholesterol concentration ( 5.7 mmol litre 1 ) or previous vascular surgery. Before operation, patients were clinically evaluated; this included 12-lead ECG, chest x-ray and echocardiography. Premedication, anaesthesia and postoperative care were performed by clinicians not involved in the study and blinded to all research information. Twelve-lead ECG recordings were performed daily in the morning together with blood sampling (TNT, TNI, CK-MB) from the day before surgery until the fifth postoperative day. TROPONIN T ASSAY Serum TNT was measured using an enzyme-linked immunosorbent assay with the Enzyme-Test- System ES 300 analyser (Boehringer Mannheim, Mannheim, Germany). The method is based on a single step sandwich principle with streptavidincoated tubes as the solid phase and two monoclonal anti-human cardiac TNT antibodies. Values greater than or equal to 0.2 ng ml 1 were considered positive. TROPONIN I ASSAY Serum cardiac TNI concentrations were measured j using the Stratus Cardiac Troponin-I assay (Dade International Inc. Miami, FL, USA). This is a twosite immunoassay which uses two monoclonal antibodies that are specific for the cardiac isotype of TNI. Values greater than or equal to 0.6 ng ml 1 were considered positive. 15 CK-MB ASSAY Photometric determination of the activity of creatine kinase MB-isoenzyme (CK-MB) (N-acetylcysteineactivated) on an immunological basis (Granu Test 25, Merck, Darmstadt, Germany) was used. The reference range was 12 iu litre 1 at 25 C. ADVERSE CARDIAC OUTCOME An adverse cardiac outcome was defined as the occurrence of unstable angina, severe cardiac arrhythmias compromising cardiovascular status, decompensated congestive heart failure (CHF), MI or cardiac death. MI was diagnosed using the following criteria: CK- MB 12 iu litre 1 and electrocardiographic changes, that is development of either new Q-waves or persistent ST-elevation in the 12-lead ECG. Results Clinical data are summarized in table 1. Three patients were excluded because of incomplete samples for TNT or TNI analysis; 67 patients had complete 7-day profiles, with 469 single TNT samples and 91 TNI samples. Of these 67 patients, 54 (80.5%) had normal and 13 (19.5%) had increased TNT concentrations, at least at one measurement. The times at which TNT were increased most frequently were on days 2, 3 and 4 after operation. No patient had increased TNT concentrations 24 h before operation, but two patients had increased concentrations on the morning of surgery. Nine patients were still TNT positive at the end of the study (fig. 1). Most frequently, the first increase in TNT concentrations above the cut-off value were noted on the first and second postoperative days; two patients however, had a relatively late increase in TNT concentrations on day 4 after operation (fig. 2). Of the two patients with increased TNT concentrations Table 1 Clinical data for the 67 patients No. of Patients (%) Age <65 yr 46 (69) Sex (M/F) 50/17 (74/25) Hypertension 47 (70) Diabetes mellitus 9 (13) Current smoking 37 (55) Increased cholesterol 61 (91) Cardiac history Angina pectoris 61 (91) Unstable angina 6 (9) Previous MI 43 (64) History of congestive HF 11 (16) Previous CABG 7 (10) Previous PTCA 13 (19) Preoperative cardiac medication Nitrates 44 (66) Calcium antagonists 24 (36) β-adrenergic blockers 9 (13) Digoxin 22 (33) ACE inhibitors 22 (33) Type of surgery Vascular 38 (56,7) Abdominal 21 (31,3) Orthopaedic 8 (12) Type of anaesthesia General 63 (94) Regional 4 (6) STATISTICAL ANALYSIS For comparison of patient groups with good and adverse outcomes the non-parametric Mann Whitney test was used. P 0.05 was considered statistically significant. Changes in the TNI:TNT ratio were analysed by Friedman non-parametric two-way ANOVA. Figure 1 Number of patients with increased TNT concentrations at different measurement times.

3 388 British Journal of Anaesthesia Figure 2 Time when TNT concentrations first increased above the cut-off values. Figure 4 TNT concentrations in relation to outcome. Figure 3 Mean TNT and TNI concentrations for all patients with increased concentrations of TNT. Meansurement times are numbered from the first above the cut-off value. before operation, one developed CHF after operation. Of the six patients with an increase in TNT on the morning after surgery, four had intraoperative problems such as tachycardia, hypotension or hypertension. Two developed CHF immediately after surgery. In all 13 patients with increased TNT concentrations, TNI concentrations were also above the cut-off value, although the pattern was different (fig. 3). Individual ratios for TNI:TNT decreased significantly from a mean value of 8.8 to 1.1 (P 0.01). All patients with normal TNT concentrations had a good outcome (80.5%), except for one patient who died because of sudden severe bleeding from the femoral artery on day 10 after operation. In five patients (7.5%) TNT was positive, although there were no cardiac complications. All except one patient, however, had relatively low TNT values ( 0.06, ng ml 1 ). Eight of the 13 patients (11.9%) with increased TNT concentrations ( ng ml 1 ) had an adverse outcome: three patients suffered from unstable angina, in three patients congestive heart failure occurred, one patient developed malignant arrhythmias and another postoperative non-q-wave infarction. All eight patients had relatively high TNT values (fig. 4). The difference between groups 2 and 3 was significant (P 0.05). With a cut- off value for TNT of 0.2 ng ml 1, the positive predictive value for adverse outcome was 61% and the negative predictive value was 100%. With a change in the cut-off to 0.6 ng ml 1, the positive predictive value improved to 87%, but the negative predictive value was still high (98%). A total of 76.9% of the patients with positive TNT values underwent vascular surgical procedures, although this subgroup represented only 56.7% of the total patient population. In contrast, the orthopaedic subgroup, representing 14%, demonstrated no increases in TNT. There were no significant differences in patient characteristics between those with and without adverse outcomes or with and without increased TNT concentrations. CK-MB was positive in 14 patients. Three patients had increased CK-MB concentrations, although both TNT and TNI were negative, and four patients had normal CK-MB concentrations, although both troponins were positive. By defining myocardial cell injury as an event with an increase in troponin T and I, the sensitivity of CK-MB was 70% and specificity was 94%. With the exception of one patient with preoperative renal insufficiency (creatinine 4.4 mg/100 ml) and constant high CK-MB concentrations of approximately 500 iu litre 1, CK- MB concentrations were increased only for a short time, most often only 24 h. Seven patients with increased TNT concentrations had transient ST-segment depression on the daily 12-lead ECG and one patient with MI showed ST-segment elevation. Three patients with an increase in troponin T concentrations did not show an increase in CK-MB or electrocardiographic changes. Discussion The primary goal of postoperative biochemical monitoring of cardiac risk patients is to establish appropriate markers in order to detect early minor myocardial cell injury, to inhibit postoperative MI as one of the most threatening cardiac events and to exclude the existence of cardiac complications. Landesberg, Luria and Cotev demonstrated in major vascular surgery patients that cumulative prolonged subendocardial ischaemic events rather than shorter ischaemic periods are followed by cardiac complications. 2 Postoperative electrocardiographic STsegment changes, however, indicate myocardial

4 Troponins and perioperative myocardial cell injury 389 ischaemia which may or may not be followed by definite cell injury and require continuous ECG Holter monitoring. Troponins have been introduced as sensitive biochemical markers of myocardial cell injury, both in medical patients and also in the postoperative period Katus, Schoeppenthau and Tanzeem were the first to study TNT concentrations after cardiac and non-cardiac surgery. 16 Adams, Sigard and Allen used TNI as a sensitive and specific method for the diagnosis of perioperative MI. 9 In the study of Lee, Thomas and Ludwig, increases in TNT were associated not only with MI but also with other major cardiac complications in patients without definite MI. 12 The results of our study allowed discrimination between three perioperative risk groups based on concentrations of troponin. No patient with TNT within the normal range had cardiac complications (group 1) and seven of eight patients with significantly increased values (group 3) suffered cardiac events. Between these two groups we found patients with only slightly increased TNT concentrations but without cardiac events, possibly resulting from minor, reversible myocardial cell injury. The cut-off in this series could be drawn at a concentration of 0.6 ng ml 1 with only one false positive (group 2) and one false negative (group 3) result in each group. For our study population the higher cut-off value of 0.6 ng ml 1 for troponin T appeared to better predict adverse outcome compared with 0.2 ng ml 1. The prolonged duration of our study (over 7 days), including the 24 h before surgery, allowed complete analysis of the beginning of cell damage. Although most of the injury occurred in the period from the day of surgery until the third postoperative day, two patients had a late injury profile, with normal TNT concentrations until day 3 after operation day and then an increase on day 4. Two troponins are currently recommended for the diagnosis of myocardial cell injury. Increases in TNI concentrations are highly specific In contrast with TNT, TNI is not expressed in skeletal muscle throughout ontogeny TNT is a slightly larger protein than TNI and it has been used to stratify patients into high and low risk categories based on detection of minor myocardial cell damage. 14 Studies have demonstrated that in contrast with TNT or CK-MB, increases in TNI do not occur in acute or chronic muscle disease Cross- reactivity between cardiac and skeletal TNT appears to be 1 3% and may be decreased when specific monoclonal antibodies are used. Therefore, we measured both troponins in those patients with increased TNT concentrations. Identical trends in TNT and TNI should exclude the probability of increases in TNT of non-cardiac origin. In this study, all patients with increased TNT concentrations also had positive TNI values. TNI reached the highest mean values at the first two measurement times and decreased afterwards, whereas mean TNT values increased gradually with the highest values at the fifth measurement time. We cannot account for this difference as there have been no studies comparing TNT and TNI trends in minor myocardial cell injury. The TNT and TNI content of the free cytoplasmic pool may differ. TNT has a higher molecular weight than TNI ( vs Da). Therefore, different release or clearance kinetic profiles, or both, may be responsible for this difference. In addition to skeletal muscle injury, increases in TNT without a concomitant increase in TNI may be caused by renal disease In a recent study, Bhayana, Gougoulias and Cohoe demonstrated differences between results for TNT and TNI in renal patients. 20 They hypothesized three possible mechanisms: cross-reactivity of the assay, skeletal muscle gene expression of cardiac TNT or minimal cardiac damage. One patient in our study with preoperative renal insufficiency and constant increases in CK-MB showed a transient increase, but of both troponins. The disadvantage of CK-MB as a biochemical marker of perioperative myocardial cell injury compared with troponins is not only its lower sensitivity and specificity but also the short diagnostic window of approximately 24 h. Acknowledgement The study was supported by a grant from the Austrian National Research Foundation (P09172 Med). References 1. Fleisher LA, Nelson AH, Rosenbaum SH. 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