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Eur J Cardiothorac Surg 1998;13:378-384
© 1998 Elsevier Science NL

Cardiac troponin I as an early marker of myocardial damage after coronary bypass surgery

^a Cardio-Vascular Intensive Care Unit, University Hospital, St. Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium
^b Cardio-vascular Surgery, University Hospital St. Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium
^c Clinical Biology Laboratory, University Hospital St. Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium

Received 20 October 1997; received in revised form 12 January 1998; accepted 19 January 1998.

Corresponding author. Tel.: +32 2 7642701; fax: +32 2 7648928.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Study objective: To evaluate the performance of cardiac specific markers, cardiac troponin I (cTnI) and CK-MB by mass assay (CK-MB mass), for the early diagnosis of myocardial ischemia and/or infarction after coronary bypass surgery. Methods: Prospective clinical, electrocardiograpic and biologic follow-up of 117 patients undergoing isolated coronary surgery with the use of intermittent anterograde normothermic blood cardioplegia. Blood samples for biochemical analysis were drawn before surgery (T₀) and at 2 (T₁), 6 (T₂), 10 (T₃) and 20 h (T₄) after aortic cross-clamp release. Without knowledge of the biochemical data, patients were classified according to the electrocardiographic evolution into two groups: group 1, uneventful recovery and group 2, evidence of ischemia/infarction based on continuous ST-T segment monitoring and 12-lead ECG. Results: No patients had abnormal markers at T₀. At T₁, although both markers were elevated, no difference was noted between the two groups. At T_2, 6 h after surgery, cTnI and CK-MB mass levels were significantly higher in group 2 than in group 1 (median=17 µg/l, Interquartile Range (IR): 14.7–27.3 vs. 3.1 µg/l, IR 1.9–5.3 for cTnI and median 42.5 µg/l, IR: 27.1–95.7 vs. 13.6 µg/l, IR: 9.5–18.5 for CK-MB mass). A receiver operating characteristic (ROC) curve analysis shows that a cTnI value of 13.1 µg/ml has 100% specificity and 90% sensitivity to separate both groups, whereas a value of 33.2 µg/ml for CK-MB mass has a specificity of 100% and a sensitivity of 73%. At T₃ and T₄, the same difference was noted between the groups. cTnI values in all six patients with a Q-wave infarction were 20 ng/ml, whereas only one of five patients with prolonged ischemia had cTnI level >20 ng/ml. Conclusion: As soon as 6 h postoperatively, cTnI and CK-MB by mass assay were able to separate those patients with an uneventful recovery from those with significant ischemia. This is particularly useful in frequent cases when the ECG is difficult to interpret.

Key Words: Troponin I • CK-MB • Myocardial ischemia • Infarction • Coronary surgery

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
The diagnosis of myocardial infarction after coronary revascularization surgery remains challenging. It is usually based upon the development of a new Q-wave on the postoperative ECG and the elevation of cardiac enzymes. However, this definition misclassifies patients with non-Q-wave infarction and does not classify those with conduction disturbances or ventricular pacing. Moreover, the interpretation of enzymatic release, is complicated by skeletal muscle damage occuring during surgery and by some degree of myocardial damage expected after cardioplegic arrest.

Cardiac troponin I (cTnI) is reported to be very specific for myocardial cell damage without cross-reactivity with the skeletal muscle isoform [1]. The specificity of cTnI has been confirmed in various situations and patients’ groups, i.e. myocardial infarction, contusion, myocarditis and renal failure patients [2] [3] [4] [5] [6] [7] [8].

Previous studies on the evaluation of cTnI after cardiac surgery have confirmed a significant release of this marker, peaking 6–8 h after aortic unclamping, even in uncomplicated cases [9] [10], and have suggested that cTnI is able to confirm the diagnosis of postoperative myocardial infarction.

Our aim was to evaluate the usefulness of cTnI as an early marker of excessive postoperative myocardial damage, when a specific therapeutic intervention can still be efficient. We also compared the performance of cTnI with the CK-MB mass assay, which is more sensitive and specific than the previous routinely used immunoinhibition assay [11] [12].

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
With institutional approval and informed consent, 117 patients scheduled for coronary surgery were investigated. Reoperations as well as combined coronary and valvular operations were excluded from the study.

Anesthesia was induced with midazolam (0.05 mg/kg) and sufentanyl (3 µg/kg) and muscle paralysis was obtained with vecuronicum (0.1 mg/kg). Anesthesia was maintained using a continuous infusion of sufentanyl (0.5 µg/kg per h) and propofol (0.1–0.25 mg/kg per h). According to clinical requirement, propofol infusion rate was increased or additional isoflurane was given. Cardio-pulmonary bypass was instituted with a heparin-bonded circuit. Heparin was given for an activated clotting time >450 s (300 U/kg). Cardiac arrest was obtained by intermittent infusion in the aortic root of hyperkaliemic normothermic blood. The interval between two successive infusions, that defined a period of ischemic arrest, never exceeded 15 min.

In all but one patient, at least one internal mammary artery graft was used; in 42 patients (38%), both mammary arteries were used and in 25 patients (23%), the right gastro-epiploïc artery was implanted on the right coronary artery. A median of four distal anastomoses were performed per patient (range 1–5). The mean bypass duration was 99±33 min and mean total aortic crossclamp time was 66±22 min. A median of four (range 2–6) ischemic arrest periods occured per patient with a total duration of 54±18 min.

After surgery, ST segment in two leads was continuously monitored in the operating room and in the intensive care unit (HP665^R, Hewlett-Packard or AS/3^R, Datex). Analgesia was obtained by a continuous infusion of sufentanyl (0.3 /kg per h) during 6 h and intravenous boluses of piritramide (2–4 mg) thereafter. Sedation was maintained with a propofol infusion adapted according to clinical needs (0.1–0.2 mg/Kg per h) until the patients were ready to be extubated.

Blood samples for enzymes and troponin I assays were drawn immediately before induction, 2 h (T₁), 6 h (T₂), 10 h (T₃) and 20 h (T₄) after aortic cross-clamp release. Blood samples for troponin I and CK-MB mass assay were centrifuged and the plasma frozen and stored at -20°C for later determination. Troponin I was measured using a specific enzyme-linked immunosorbent assay and CK-MB mass using a fluorometric enzyme assay (Stratus^R, Dade).

A 12-lead electrocardiogram was systematically recorded at the same time intervals. Additional recordings were obtained if ST segment changes of at least 1 mm from baseline occurred and lasted >15 min or whenever deemed clinically necessary.

An echocardiographic examination was performed 24 h after surgery in all patients with new Q-waves and in those who sustained prolonged ST segment modification.

Two patients were taken back to the operating room for bleeding and were withdrawn from the study. Five other patients were also excluded because their ECG could not be interpreted (left bundle branch block in three and ventricular pacing in two patients). According to their clinical evolution, the 110 remaining patients were divided into two groups:

Group 1 (n=99): patients with an uneventful postoperative course.

Group 2 (n=11): patients with evidence of an ischemic event. This group includes patients with a myocardial infarction (n=5, new Q-wave on ECG and new segmental wall motion abnormality on echocardiography) and patients with a prolonged ischemia (n=6, ST-T change lasting >15 min but no new Q-wave on ECG or new echocardiographic abnormality).

Non-parametric Wilcoxon rank sum tests was used for between groups comparison. As the groups were compared at four time points to keep an -level for the multiple comparisons <0.05, the P-value of each individual comparison was considered significant at a level of 0.05/4=0.012.

Receiver operating characteristic (ROC) curves were constructed and compared to assess the specificity and sensitivity of the biological markers at each time point. ROC curves were compared using the method proposed by Hanley and Mc Neil [13]. A P-value <0.05 was considered to indicate statistical significance.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Troponin I and CK-MB levels before surgery were all below the upper limit of the reference interval (<0.4 ng/ml for cTnI and <20 µg/l for CK-MB).

Median and interquartile values of cTnI and CK-MB are presented in Table 1Table 2 for the two groups at each time interval.

At T₂ ( Fig. 1 ), cTnI and CK-MB levels were significantly different in group 1 and 2 (P<0.0001). The ROC curve analysis for cTnI shows that a value of 8.4 µg/l has a sensitivity of 100% with a specificity of 89% to diagnose an ischemic event, whereas 13.1 µg/l has a specificity of 100% with a sensitivity of 90%. For CK-MB, the ROC curve reveals that 18.5 µg/l has a sensitivity of 91% combined with a specificity of 76% and the value of 33.2 µg/l has a specificity of 100% with a sensitivity of 73%. The area under the ROC curve is 0.99 for cTnI (95% confidence interval (CI)=0.94–0.998) and 0.88 for CK-MB (95% CI=0.803–0.935) which were not statistically different (P=0.086).

View larger version (25K): [in this window] [in a new window]   Fig. 1. Upper panels: individual data plot and box-and-whisker plot (median, interquartile range, minimum and maximum values, isolated dots beyond the whiskers correspond to outliers defined as a value that is smaller than the lower quartile-1.5xthe interquantile range or larger than the upper quartile+1.5 times the interquartile range) of cTnI and CK-MB at 6 h postoperatively (T2). Lower panels: ROC curve for cTnI and CK-MB at T2.

View larger version (28K): [in this window] [in a new window]   Fig. 2. Upper panels: individual data plot and box-and-whisker plot of cTnI and CK-MB at 10 h postoperatively (T3) in groups 1 and 2. In small, box-and-whisker plot of cTnI and CK-MB for the subgroups ‘infarction’ and ‘prolonged ischemia’. Lower panels: ROC curve for cTnI and CK-MB at T3.

View larger version (25K): [in this window] [in a new window]   Fig. 3. Upper panels: individual data plot and box-and-whisker plots of cTnI and CK-MB at 16 h postoperatively (T4) in groups 1 and 2. Lower panel: ROC curve for cTnI and CK-MB at T4.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Also, some degree of intraoperative myocardial damage is expected during the aortic cross-clamping time, leading to elevated levels of specific markers even in patients with an uneventful recovery, as found by Mair et al. [10].

It is then mandatory to define the expected normal range of this marker after coronary surgery and to correlate its blood levels with an independent sign of myocardial cell ischemia and/or necrosis.

New Q-wave on the ECG is highly specific of myocardial infarction but not very sensitive, especially for the diagnosis of non-transmural infarction. We tried to detect all the ECG modifications suggestive of prolonged ischemia, whether or not evolving towards a transmural necrosis. Routine continuous ST segment monitoring allows detection of ST modifications into two leads. Of course, a 12-leads monitoring would be more accurate to detect localized ischemia but unfortunately is not yet routinely available. Patients were included in the group if ST changes lasted >15 min. This threshold was chosen for practical reasons (time delay necessary for the detection of the changes and the confirmation by a 12-lead recording) as well as for theoretical reasons (no cell necrosis is usually detected for ischemia lasting <15–20 min in experimental conditions) [14] [15].

If the occurrence of a prolonged ischemic episode is considered as criterion of an abnormal post-operative evolution, the dosage of cTnI dosage allows the classification of the patients with a high degree of certitude as soon as at the sixth postoperative hour (T₂).

An early identification of the patients seems interesting for several reasons. First, in situations where one cannot interpret the ECG (left bundle branch block, ventricular pacing), cTnI dosage would inform us of the presence of myocardial suffering that could otherwise be neglected. Secondly, when ECG changes are difficult to interpret (pericardial inflammation, ventricular hypertrophy), the concomitant dosage of cTnI would allow a better assessment of the ECG and prompt adequate therapeutic interventions.

At the sixth hour, we anticipate that an adequate therapeutic intervention can still salvage myocardium at risk: studies on thrombolysis after myocardial infarction suggest, indeed, that reperfusion within 6 h after the onset of coronary occlusion can limit cell necrosis. It seems thus reasonable, in peculiar cases based upon the ECG and cTnI level, to consider the possibility of a diagnostic angiography or even a resternotomy to limit myocardial cell necrosis.

When we compared cTnI to CK-MB, that is widely used for the diagnosis of myocardial infarction, no statistically significant difference was noticed. As expected, CK-MB by mass assay also had a high sensitivity and specificity for the diagnosis of prolonged ischemia. However, the ROC curve analysis disclosed a better performance of cTnI but did not reach the level of statistical significance.

For both markers, the measurements at 10 h after aortic unclamping confirmed the diagnosis of ischemia/infarction with high accuracy. In all patients with a Q-wave infraction, cTnI levels were 20 mg/ml, whereas only one of five patients with ischemia had a level 20 mg/ml.

Later determinations (24 h after surgery) performed identically for both markers, probably because all the episodes of prolonged ischemia in this series occurred during the first 4 postoperative hours.

The values presented in this study are calculated on a limited number of true positive patients because, fortunately, ischemia and infarction are rare events after coronary surgery. However, sensitivity and specificity are very high and would probably remain significant in a larger cohort of patients.

In conclusion, as soon as 6 h postoperatively, at a time that transmural necrosis is potentially still preventable by means of a therapeutic intervention, cTnI dosage allows differentiation of patients with an uneventful course (cTnI <8.3 µg/l) from those presenting with a prolonged ischemia and/or infarction (cTnI >13 µg/l). If the levels are between 8.3 and 13 µg/l, some degree of uncertainty persists and patient's management depends on whether sensitivity or specificity is favoured in an individual situation.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

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