Perioperative myocardial ischaemia is common in coronary artery bypass graft (CABG) surgery. Major electrocardiographic (ECG) changes have been reported to occur in 58% of such patients within 8 h after release of the aortic cross clamp . In that study, the criteria for myocardial infarction were met in 25% of patients. This might be due to incomplete surgical revascularization, perioperative anaesthetic management or vasospasm of arterial grafts, e.g. the internal mammary artery [2,3].
Myocardial infarction is usually diagnosed by combinations of ECG changes, echocardiographic detection of new wall motion abnormalities and biochemical markers. Of the latter, elevations of the myocardial fraction of creatine kinase (CK-MB) and troponin have been shown to correlate with the incidence of perioperative myocardial infarction as well as 30 day and long-term mortality rates [4-8].
It has been shown that continuous intraoperative administration of the short-acting calcium antagonist nifedipine decreases vasospasm of arterial grafts, thereby reducing the rate of perioperative myocardial infarction [2,9-11]. Recently, it was demonstrated that nifedipine significantly reduces vasoconstriction in radial artery segments caused by release of endothelin or norepinephrine . However, the use of nifedipine in patients with angina pectoris is controversial. There are reports of an increased risk of cardiovascular events with more myocardial ischaemia [13-15]. An increased mortality rate has also been shown [16,17]. Therefore, prophylactic use of nifedipine in patients at potential risk for myocardial ischaemia is questionable.
Milrinone, a phosphodiesterase inhibitor, has been shown in experimental models to exert vasodilatory properties in arterial grafts, e.g. the internal mammary artery [3,18-22]. However, no such study exists in the clinical setting. Therefore, we compared the effects of nifedipine and milrinone on the incidence of myocardial ischaemia and myocardial cell death in patients with reduced left ventricular function scheduled for CABG.
The protocol was approved by the Institutional Review Board of the University of Münster. The double-blinded randomized clinical study enrolled 30 adult patients with compromised left ventricular function scheduled for elective CABG after written informed consent had been obtained. Inclusion criteria were the following:
- Coronary artery disease requiring elective CABG
- No valvular lesions preoperatively
- No left bundle branch block (LBBB)
- Haemodynamic stability at the start of the study
- Compromised left ventricular function (ejection fraction <0.4)
- Coronary artery bypass grafting including the internal mammary artery as the main graft.
Anaesthesia and lung ventilation
All patients were premedicated with flunitrazepam 2 mg (Rohypnol®; Hoffmann-La Roche, Grenzach-Wyhlen, Germany) orally 90 min before induction of anaesthesia. General anaesthesia was induced with midazolam 0.1 mg kg−1 intravenously (i.v.) (Dormicum®; Hoffmann-La Roche), sufentanil 1 μg kg−1 (Sufenta®; Janssen, Beerse, Belgium) and pancuronium bromide 0.1 mg kg−1 (Pancuronium®; Organon, Oberschleißheim, Germany) while the patients inspired 100% oxygen. Anaesthesia was maintained by continuous infusions of propofol 3-8 mg kg−1 h−1 (Diprivan®; AstraZeneca GmBH, Wedel, Germany) and sufentanil 1.5-2.0 μg kg−1 h−1. After endotracheal intubation, the patients' lungs were mechanically ventilated with oxygen and air (FiO2 = 0.5). The ventilation was adjusted to maintain an arterial PCO2 in the range 4.7-5.3 kPa. In the postanaesthetic care unit (PACU), mechanical ventilation was maintained in the above-described manner. Adequate analgesia and sedation were achieved with repetitive doses of pirinitramide (piritramide) (Dipidolor®; Janssen-Cilag GmBH, Neuss, Germany) and continuous infusion of propofol according to standard procedures in our institution. The patients were extubated 6-10 h after surgery.
Administration of study drugs
Before induction of anaesthesia, baseline values were obtained. Patients were randomized to receive continuous infusions of either milrinone 0.375 μg kg−1 min−1 (Corotrop®; Sanofi Winthrop, Munich, Germany) or nifedipine 0.2 μg kg−1 min−1 (Adalat®; Bayer, Leverkusen, Germany) [10,11]. The infusions were started after anaesthesia had been induced and baseline values established. They were maintained for at least 24 h after surgery. Five minutes before the end of cardiopulmonary bypass (CPB), immediately after admission to the PACU, 4 and 24 h thereafter the following variables were determined: haemodynamics, systemic oxygen delivery and uptake, arterial and mixed venous oxygen saturation, and arterial plasma concentrations of CK, CK-MB and Troponin-I.
All patients received aprotinin 2 000 000 KIU (Trasylol®; Bayer, Leverkusen, Germany) before CPB, another 2 000 000 KIU in the pump prime and a continuous infusion of 500 000 KIU h−1 during CPB. Anticoagulation was achieved with heparin (initial bolus of 400 IU kg−1 i.v. (Heparin-Natrium®; Braun Melsungen AG, Melsungen, Germany), targeting an activated clotting time (ACT) of ≥440 s) and monitored by a Hemochrome® Jr II system (International Technidyne Corporation, New York, NY, USA).
Management of extracorporeal circulation was standardized with pump flows of 2.3-2.8 L min−1 m−2, mild hypothermia (35.5°C) and an α-stat regulation of arterial blood gases. Cold cardioplegic arrest was induced with antegrade Bretschneider-HTK solution (Custodiol®; Köhler, Inc., Alsbach, Germany, 15 mL kg−1) and topical cooling. Mechanical ventilation of the lungs was stopped and the lungs were kept deflated during cold cardioplegic arrest. The perfusion pressure was maintained at ≥60 mmHg by increasing pump flow, volume loading and, if necessary, an infusion of norepinephrine. After aortic declamping, the lungs were ventilated with 100% oxygen. Reperfusion time before weaning from CPB was at least one-third of the aortic clamp time. Subsequently, FiO2 was adjusted to maintain an arterial oxygen saturation >95%. A positive end-expiratory pressure of 5 cmH2O was applied after CPB. Heparin was neutralized in a standardized manner by administration of protamine. Patients were weaned from CPB with nitroglycerin 0.5 μg kg−1 min−1 (Perlinganit®, Schwarz Pharma, Monheim, Germany). Dobutamine (Dobutamine Solvay®; Solvay Arzneimittel GmBH, Hannover, Germany) or epinephrine (Suprarenin®; Hoechst, Bad Soden, Germany) and/or norepinephrine (Arterenol®; Hoechst, Bad Soden, Germany) were added when needed.
Routine monitoring before induction of anaesthesia consisted of the ECG (including lead V5), and an intra-arterial catheter in the left radial artery. After induction of anaesthesia, a flow-directed balloon-tipped 7-Fr Edwards thermodilution catheter (Edwards Laboratory, Santa Ana, CA, USA) was passed from the right internal jugular vein into the pulmonary artery and positioned to obtain a reliable pulmonary capillary wedge pressure tracing during balloon inflation. Cardiac output was measured by thermodilution using cold saline as indicator. The mean of three measurements was calculated and used for statistical evaluation.
Perioperative Holter ECG
Continuous three-channel Holter ECG was performed in all patients for at least 12 h before surgery until 48 h after surgery (Memo Port SRP 10®; Marquette Hellige, Freiburg, Germany). The device complied with the recommendations of the American Heart Association (diagnostic quality 0.05-100 Hz). The ST-segment trends of leads II and V5 were monitored continuously 60 ms after the J-point of the QRS complex. Serial traces of ECG leads II and V5 were calibrated to 10 mm mV−1. The criteria used to validate ischaemia were: new horizontal or downward-sloping ST-segment depression of at least 0.1 mV at the J-point + 60 ms, or ST-segment elevation of at least 0.2 mV at the J-point + 60 ms. The software supported examination of the tape recordings via computerized ST-segment analysis. During surgery, ST-segment monitoring was achieved with the intraoperative standard five-lead ECG monitor (Solar 8000®; Marquette-Hellige, Freiburg, Germany). The ECG was considered to be uninterpretable for detecting ST-segment deviation during ventricular pacing, LBBB and intraventricular conduction defects. ST segment deviation was measured 60 ms after the J-point. Episodes lasting at least 1 min and of at least 1 mm peak ST segment deviation from the local baseline were retained.
Creatine kinase (CK) and creatine kinase-MB (CK-MB)
CK and CK-MB concentrations were measured by radioimmunoassay (Boehringer, Mannheim, Germany). In our laboratory, the following values indicate evidence for myocardial infarction: (a) CK > 170-190 IU L−1, (b) CK-MB > 24 IU L−1 and (c) CK-MB/CK > 6%.
The cardiac-specific contractile protein troponin-I serum level was measured on an autoanalyser using an enzyme immunomethod (Troponin-I Assay®; Abbott GmBH, Wiesbaden, Germany). In our laboratory, troponin-I concentrations <0.4 ng mL−1 are normal, and concentrations >2.5 ng mL−1 are highly suggestive of myocardial infarction.
Data are presented as mean ± SD or as the median with 25% and 75% percentiles. All study variables were analysed with Friedman and subsequent Wilcoxon signed rank sum tests by using the Statistical Package for the Social Science (SPSS, Inc, Chicago, IL, USA). The matched-pair rank test compared different observation time points with initial values. Differences between the groups were subjected to a U-test. To reduce the probability of a Type-1 error (α-error), the significance level α of single Wilcoxon signed rank sum and U-tests was additionally corrected according to the numbers of tests. Occurrence of new ST elevations ≥0.2 mV or new ST depression ≤0.1 mV was evaluated using Fisher's exact test. The calculated P that indicated statistical significance is given in Table 2 and Figures 1 and 2.
All patients were successfully weaned from CPB. Patient characteristic data are summarized in Table 1. There were no significant differences between the groups in any of these variables. All patients received an internal mammary artery bypass graft to the left anterior descending artery. The number of vein grafts was not significantly different between groups. There were no significant differences in the amounts of vasoactive drugs, although the use of catecholamines was higher in the nifedipine group.
Haemodynamic data of patients are given in Table 2. There were no intergroup differences in haemodynamic variables at any time point.
In both groups, there was an increase in CK-MB with a maximum for the milrinone group after 4 h (6.53 + 2.42 IU L−1) and for the nifedipine group after 24 h (20.93 + 21.17 IU L−1). Twenty-four hours postoperatively, CK-MB was significantly higher in the nifedipine group (Fig. 1).
Troponin-I increased continuously in both groups during the observation period. Means and medians for milrinone, however, were lower throughout the whole observation period, reaching statistical significance after 24 h (5.89 ± 3.41 ng mL−1 (milrinone) versus 25.25 + 18.98 ng mL−1 (nifedipine)) (Fig. 2).
New ST elevations ≥0.2 mV or new ST depression ≤0.1 mV occurred in five of 15 patients in the milrinone group (33.33%), and in 13 of 15 patients in the nifedipine group (86.6%). These differences were statistically significant (P = 0.008; Fisher's exact test).
Long-term (1 yr) follow-up
In the nifedipine group, one patient died after 2 months due to ventricular dysrhythmia. One patient in the milrinone group died after 7 months due to a newly diagnosed myocardial infarction. There were no statistical differences in long-term outcome (Table 3). One patient in the nifedipine group was lost to follow-up.
During CABG, diffuse necrosis of myocytes with possible adverse effects on function and prognosis may occur. This may not necessarily result in a new Q-wave but serum concentrations of CK-MB are increased [1,5,7]. Cardiac troponin is a new sensitive and specific marker of perioperative myocardial infarction, which avoids the high incidence of false-positive results associated with the use of CK-MB . It has been used in cardiac as well as in non-cardiac surgery [23-26].
Nifedipine has been widely used in Germany for the prevention and treatment of vasospasm of arterial grafts in experimental and clinical settings. It has been shown that nifedipine is fully effective in antagonizing arterial graft spasm [11,12,27,29]. On the other hand, it has also been shown that the use of nifedipine in patients with ischaemic heart disease - not undergoing CABG - may lead to episodes of increased angina  and to a dose-related increase in mortality rate in patients with coronary artery disease [14,17]. These data have recently been paralleled by case control studies in hypertensive patients, which also suggest adverse cardiac effects and outcome from the use of predominantly short-acting formulations of nifedipine as compared with β-adrenoceptor blocking drugs . It is therefore surprising that nifedipine is still widely used during coronary artery surgery. The results are in line with these caveats. We found significantly less myocardial ischaemia (Holter ECG) and significantly less myocardial cell damage (lower levels of CK-MB and troponin-I) in the milrinone group. Furthermore, in patients with impaired left ventricular function, the negative inotropic effects of nifedipine may result in a higher likelihood of low cardiac-output syndromes.
Milrinone is a phosphodiesterase inhibitor that exerts positive inotropic and vasodilatory properties. It is widely used in cardiac surgery and is a preferred agent in patients with compromised left ventricular function and down-regulation of β-adrenergic receptors. It has also been shown to increase gastrointestinal perfusion during surgery with CPB  and to improve blood flow in arterial grafts [3,19,21,31]. Whether the improved outcome in the milrinone group is due to prevention of vasospasm in the internal mammary artery cannot be proven by our study. However, the significantly lower incidence of myocardial ischaemia and myocardial cell death seems to verify the hypothesis of better coronary flow with milrinone compared with nifedipine.
Limitations of the present study
In our institution, the present management of patients undergoing CABG includes prophylactic infusion of nifedipine, mainly for prevention of internal mammary artery spasm. Therefore, we could not provide a group only treated with placebo or nitroglycerin. However, the latter has previously been shown to be inferior to nifedipine in this setting .
We cannot conclude absolutely whether nifedipine is harmful or milrinone is beneficial. However, the incidence of myocardial ischaemia and myocardial cell death in the nifedipine group was notably high in this study, suggesting an adverse effect of nifedipine at the recommended doses. The potential harmful effects of nifedipine are further demonstrated by the increases of CK-MB and troponin in the immediate postoperative period with peak values measured 24 h after surgery. Conversely, milrinone infusion resulted in a significantly lower incidence of ischaemia and myocardial cell necrosis in patients with impaired left ventricular function. These findings demonstrate the beneficial effects of milrinone on the incidence of myocardial ischaemia and its sequelae in this setting. However, we can only speculate that this was achieved by the already experimentally demonstrated vasodilatory properties of milrinone in arterial grafts [3,18-22].
Myocardial cell damage in association with coronary artery surgery can also be caused by other mechanisms than vasospasm of the internal mammary artery. These include direct trauma by sewing needles, focal trauma from surgical manipulation of the heart, global ischaemia from inadequate perfusion or poor myocardial cell protection, and coronary artery or bypass graft embolism . A portion of this damage may be unavoidable. However, we tried to minimize reasons related to inadequate surgical and anaesthetic techniques by limiting the number of surgeons and anaesthesiologists to the most experienced ones in our department (two surgeons, two anaesthesiologists). No biochemical marker can distinguish damage due to an acute infarction from the usually small quantity of myocardial cell damage associated with the procedure itself. Nevertheless, the higher the value for the cardiac marker after the procedure, the greater the amount of damage to the myocardium, irrespective of the mechanism of injury.
In conclusion, perioperative continuous infusion of milrinone in patients with compromised left ventricular function scheduled for elective CABG, including an internal mammary artery graft, resulted in a significantly lower incidence of myocardial ischaemia and myocardial cell damage than continuous infusion of nifedipine. Milrinone should therefore be preferred to nifedipine as a prophylactic agent in these patients.
The study was supported financially by Sanofi Winthrop, Munich, Germany, for laboratory analyses, and by Marquette-Hellige, Freiburg, Germany, for the Holter monitoring equipment.
1. Jain U, Laflamme CJ, Aggarwal A, et al.
Electrocardiographic and hemodynamic changes and their association with myocardial infarction during coronary artery bypass surgery. A multicenter study. Multicenter Study of Perioperative Ischaemia (McSPI) Research Group. Anesthesiology
2. Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg
3. Huraux C, Makita T, Montes F, Szlam F, Levy JH. A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology
4. Carrier M, Pelletier LC, Martineau R, Pellerin M, Solymoss BC. In elective coronary artery bypass grafting, preoperative troponin T level predicts the risk of myocardial infarction. J Thorac Cardiovasc Surg
5. Hong MK, Mehran R, Dangas G, et al.
Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation
6. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med
7. Alexander JH, Sparapani RA, Mahaffey KW, et al.
Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation. PURSUIT Steering Committee. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. JAMA
8. Deng MC, Dasch B, Erren M, Möllhoff T, Scheld HH. Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Ann Thorac Surg
9. Podesser B, Schwarzacher S, Zwolfer W, et al.
Combined perioperative infusion of nifedipine and metoprolol provides antiischemic and antiarrhythmic protection in patients undergoing elective aortocoronary bypass surgery. Thorac Cardiovasc Surg
10. Dupuis JY, Nathan HJ, Laganiere S. Intravenous nifedipine for prevention of myocardial ischaemia after coronary revascularization. Can J Anaesth
11. Seitelberger R, Zwolfer W, Huber S, et al.
Nifedipine reduces the incidence of myocardial infarction and transient ischaemia in patients undergoing coronary bypass grafting. Circulation
12. Bond BR, Zellner JL, Dorman BH, et al.
Differential effects of calcium channel antagonists in the amelioration of radial artery vasospasm. Ann Thorac Surg
1035-1040; discussion: 1040-1041.
13. Pahor M, Psaty BM, Alderman MH, et al.
Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized controlled trials. Lancet
14. Sleight P. Calcium antagonists during and after myocardial infarction. Drugs
15. Stason WB, Schmid CH, Niedzwiecki D, et al.
Safety of nifedipine in angina pectoris: a meta-analysis. Hypertension
16. Yusuf S. Calcium antagonists in coronary artery disease and hypertension. Time for reevaluation? Circulation
17. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation
18. Gitter R, Anderson JM Jr, Jett GK. Influence of milrinone and norepinephrine on blood flow in canine internal mammary artery grafts. Ann Thorac Surg
19. He GW, Yang CQ. Inhibition of vasoconstriction by phosphodiesterase III inhibitor milrinone in human conduit arteries used as coronary bypass grafts. J Cardiovasc Pharmacol
20. Lobato EB, Urdaneta F, Martin TD, Gravenstein N. Effects of milrinone versus epinephrine on grafted internal mammary artery flow after cardiopulmonary bypass. J Cardiothorac Vasc Anesth
21. Salmenpera M, Levy JH. The in vitro
effects of phosphodiesterase inhibitors on the human internal mammary artery. Anesth Analg
22. Thorin-Trescases N, Dimitri WR, Dominiczak AF, Hamilton CA, Reid JL. Vasorelaxant properties of isolated human internal mammary arteries and saphenous veins: comparative effects of milrinone and sodium nitroprusside. J Cardiovasc Pharmacol
23. Adams JE III, Sicard GA, Allen BT, et al.
Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med
24. Alyanakian MA, Dehoux M, Chatel D, et al.
Cardiac troponin I in diagnosis of perioperative myocardial infarction after cardiac surgery. J Cardiothorac Vasc Anesth
25. Loick HM, Schmidt C, Van Aken H, et al.
High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg
26. Bonnefoy E, Filley S, Kirkorian G, et al.
Troponin I, troponin T, or creatine kinase-MB to detect perioperative myocardial damage after coronary artery bypass surgery. Chest
27. He GW, Rosenfeldt FL, Buxton BF, Angus JA. Reactivity of human isolated internal mammary artery to constrictor and dilator agents. Implications for treatment of internal mammary artery spasm. Circulation
28. Prida XE, Gelman JS, Feldman RL, et al.
Comparison of diltiazem and nifedipine alone and in combination in patients with coronary artery spasm. J Am Coll Cardiol
29. Uydes-Dogan BS, Nebigil M, Aslamaci S, et al.
The comparison of vascular reactivities of arterial and venous grafts to vasodilators: management of graft spasm. Int J Cardiol
30. Möllhoff T, Loick HM, Van Aken H, et al.
Milrinone modulates endotoxemia, systemic inflammation, and subsequent acute phase response after cardiopulmonary bypass (CPB). Anesthesiology
31. Liu JJ, Doolan LA, Xie B, Chen JR, Buxton BF. Direct vasodilator effect of milrinone, an inotropic drug, on arterial coronary bypass grafts. J Thorac Cardiovasc Surg
32. Myocardial infarction redefined - a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol