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Ann Thorac Surg 1999;67:417-422
© 1999 The Society of Thoracic Surgeons

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Original Articles

Antiischemic effects of nicardipine and nitroglycerin after coronary artery bypass grafting

^a Division of Cardiothoracic Anesthesia, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA

Accepted for publication June 30, 1998.

Address reprint requests to Dr Apostolidou, Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Ave, Box 8054, St. Louis, MO 63110
e-mail: apostoli{at}notes.wustl.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusion References

 
Background. We assessed the efficacy of a continuous infusion of nicardipine and nitroglycerin in reducing the incidence and severity of perioperative myocardial ischemia during elective coronary artery bypass grafting procedures in a prospective, randomized, controlled study.

Methods. Patients received either nicardipine infusion (0.7 to 1.4 µg · kg · ^-1 · min^-1; n = 30) or nitroglycerin (0.5 to 1 µg · kg^-1 · min^-1; n = 30) or neither medication (n = 17) after aortic occlusion clamp release and for 24 hours postoperatively. Myocardial ischemic episodes (MIE) were considered to have occurred with ST-segment depressions or elevations of at least 1 mm and at least 2 mm (for both depressions or elevations), each at J + 60 ms and lasting at least 1 minute, using a two-channel Holter monitor.

Results. Only nicardipine significantly decreased the duration (p = 0.02) of the 1-mm or greater minutes per hour (3.2 ± 1.2 minutes per hour) and eliminated the number (p = 0.02) of the 2-mm or greater minutes per hour (zero minutes per hour) when compared with control patients (17.2 ± 5.6 minutes per hour and 0.17 minutes per hour, respectively) during the intraoperative postbypass period.

Conclusions. Our results suggest that nicardipine lessened the severity of myocardial ischemia shortly after coronary revascularization and could be considered as an alternative to standard antiischemic therapy.

	Introduction

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Perioperative myocardial ischemia is a frequent complication of coronary artery bypass grafting (CABG) procedures and raises the risk of adverse cardiac outcomes [1–4]. The prevention of ischemia should reduce myocardial ischemic injury and associated complications in high-risk patients undergoing coronary revascularization operations. The majority of perioperative myocardial ischemic episodes are not preceded by acute hemodynamic changes [1, 2], indicating that a decrease in myocardial oxygen supply and not an increase in demand is the main causative mechanism in the pathogenesis of myocardial oxygen imbalance. Because ischemia can occur even after myocardial revascularization and reperfusion, coronary vasomotor changes may lead to ischemia.

Coronary vasodilators, by increasing coronary blood flow and myocardial oxygen supply, may be beneficial in preventing or attenuating perioperative myocardial ischemia. Prophylactic use of nitroglycerin, however, failed to prevent the occurrence of myocardial ischemic episodes [5, 6]. In contrast, nifedipine, a dihydropyridine calcium-channel antagonist, reduced the incidence of ischemic episodes when compared with nitroglycerin in patients having CABG operations [7, 8]. Disadvantages to intravenous nifedipine use include photosensitivity, low aqueous solubility, potential negative inotropic effects [9], and unavailability in the United States. Nicardipine, a newer dihydropyridine calcium-channel antagonist, is stable in light, has greater selectivity for vascular smooth muscle than cardiac muscle, and has negligible cardiodepressant effects [10–13]. Nicardipine has been shown to reduce coronary and peripheral vascular resistance and to increase coronary blood flow [10, 11]. The myocardial protective effects of nicardipine have been demonstrated in animal models of coronary occlusion [14–16] but little data exist in cardiac surgical patients.

The purpose of this study was to evaluate the efficacy of nicardipine in preventing perioperative myocardial ischemia in patients undergoing CABG procedures compared with nitroglycerin and a control group and to assess the hemodynamic effects of nicardipine.

	Material and methods

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Study design and patient population
Seventy-seven adult patients scheduled for elective CABG operations were enrolled in this prospective, randomized, controlled clinical trial. The study protocol was approved by the Human Studies Committee of Washington University School of Medicine, and informed consent was obtained from all participating patients. The patients were randomly assigned to one of three groups using a computer-generated randomization schedule. Group NIC (n = 30) received intravenous nicardipine infusion at a rate of 0.7 to 1.4 µg · kg^-1 · min^-1; group TNG (n = 30) received intravenous nitroglycerin infusion at a rate of 0.5 to 1 µg · kg^-1 · min^-1; and group C (n = 17) received neither medication. Patients on digoxin, intravenous nitroglycerin, or inotropic drug infusion; those with preoperative ST-segment abnormalities, left bundle-branch block, and atrial fibrillation; and those with symptoms of congestive heart failure or in renal failure requiring hemodilution were excluded from the study.

Anesthetic management
Patients received all routine medications until the morning of the operation. Premedication consisted of intramuscular or subcutaneous morphine (0.05 to 0.1 mg/kg) and scopolamine (0.2 to 0.4 mg), and oral lorazepam (1 to 2 mg). Anesthesia was induced with intravenous etomidate, fentanyl (5 to 10 µg/kg), and isoflurane, and vecuronium (0.15 mg/kg) was given for muscle relaxation. Anesthesia maintenance was with a fentanyl infusion (4 µg · kg^-1 · h^-1), pancuronium (30 µg · kg^-1 · h^-1), isoflurane (end-tidal concentration, 0.5% to 1%), and intravenous lorazepam (2 to 4 mg). Hypothermic cardiopulmonary bypass with membrane oxygenators was used, and myocardial protection was accomplished with intermittent cold potassium cardioplegia and topical cooling during the aortic cross-clamping ischemic period.

Drug infusion
Infusion of nicardipine or nitroglycerin was initiated immediately after the release of the aortic occlusion clamp and was continued into the postoperative period for 24 hours. The rate of infusion was adjusted to maintain systolic arterial pressure between 100 and 130 mm Hg. Persistent systolic blood pressure > 130 mm Hg was treated with intravenous sodium nitroprusside starting at 0.5 µg · kg^-1 · min^-1.

Hemodynamic measurements
All patients were monitored with a radial artery catheter and an oximetric pulmonary artery catheter (Opticath pulmonary artery fiberoptic catheter, Abbott Laboratories, North Chicago, IL). The hemodynamic measurements obtained included heart rate and rhythm, systolic and diastolic arterial pressures, systolic and diastolic pulmonary arterial pressures, central venous pressure, pulmonary capillary wedge pressure, and mixed venous oxygen saturation. Cardiac output was obtained in triplicate using room temperature injectate. Cardiac index and systemic and pulmonary vascular resistances were estimated using standard formulas. The above measurements were recorded at the following time points: before and after induction of general anesthesia, every 15 minutes after separation from cardiopulmonary bypass, after chest closure, and at the end of the procedure.

Electrocardiographic monitoring
Patients were connected to a two-channel (lead II and V₅) Holter monitor (Marquette Holter monitors, series 8500, Milwaukee, WI) 12 hours before the operation, and the electrocardiographic (ECG) monitoring was continued throughout the intraoperative period and for the first 24 hours postoperatively. Holter tapes were scanned using a Marquette series 8000 computer using standard QRS labeling techniques. Secondary editing was performed to ensure correct labeling of normal QRS complexes and elimination of ectopic beats and noise. A continuous ST-segment trend was generated for each lead at 60 ms from the J point. Hard copy of all ECG episodes of myocardial ischemia were reviewed by two investigators blinded to treatment group. Inclusion of an episode as an ischemic event required the consensus of both reviewers.

A myocardial ischemic episode was defined as a reversible ST-segment depression or elevation from the baseline, lasting at least 1 minute and occurring in one or both Holter channels. Analysis was performed separately using ST-segment cutoffs: reversible shifts of at least 1 mm (0.1 mv) or 2 mm (0.2 mv). The analyzed characteristics of the myocardial ischemic episodes included frequency, episode duration, and the area under the ST time curve (integral of the ST-segment change versus time, AUC). Number of episodes, their duration, and the AUC of the ST-segment change were normalized to hours of Holter monitoring.

Statistical analysis
The Holter monitoring intervals were divided into four periods: period 1, from Holter monitor attachment until anesthesia induction; period 2, from anesthesia induction until initiation of cardiopulmonary bypass; period 3, the time from discontinuation cardiopulmonary bypass until the end of the operation; period 4, the first 24 postoperative hours.

Data were expressed as mean ± SD or SE. Categorical variables were analyzed using the ² test or Fisher’s exact test, and normally distributed, continuous variables were analyzed using one-way analysis of variance with Bonferroni correction if appropriate. Nonnormally distributed, continuous variables or variables with unequal variances were analyzed with the rank sum test. Probability values 0.05 were considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Conclusion References

 
There were no statistically significant differences between the three groups regarding patients’ demographics, history, and operative data. (Table 1). The frequency of myocardial ischemia between the three groups in terms of monitoring period is shown in Figure 1. During period 3, none of the patients in group NIC experienced myocardial ischemic episodes of at least 2 mm, compared with 3 patients (10%, p = 0.24) in group TNG and 4 patients (24%, p = 0.01) in group C.

View larger version (25K): [in this window] [in a new window]   Fig 1. Percent of patients with myocardial ischemic episodes in the three groups using 1 mm (1) and 2 mm (2) criteria versus each perioperative period. (NIC = nicardipine; TNG = nitroglycerin; C = control; P1 = period 1; P2 = period 2; P3 = period 3; P4 = period 4; *p 0.05 compared with C.)

Pattern of myocardial ischemia
The number and duration of normalized myocardial ischemic episodes and the integral of the change in ST segment versus time are shown in Table 2. During the preoperative and prebypass period no differences were noted in the number, duration, and AUC of myocardial ischemic episodes between the three groups. During the postbypass period (period 3, study drug infusion), using the at least 1 mm criteria, there was statistically significant lower duration (p = 0.02) and significantly smaller AUC (p = 0.05) of the myocardial ischemic episodes in group NIC (3.2 ± 1.2 min/h and 5.7 ± 15.7 AUC/h) when compared with group C (17.2 ± 5.6 min/h and 30.1 ± 49 AUC/h), and a trend (p = 0.09) for a lower frequency in group NIC (0.4 ± 0.2 episodes/h) than in group TNG and C (0.8 ± 0.3 and 0.9 ± 0.3 episodes/h, respectively). Using the at least 2 mm criteria, during the same period 3, a statistically lower number of myocardial ischemic episodes (p = 0.02) was observed in group NIC (0 episodes/h) when compared with group C (0.17 ± 0.36 episodes/h). During the postoperative period (period 4, study drug infusion), there were no differences in the number, duration, and AUC of myocardial ischemic episodes between the three groups.

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusion References

 
Our data suggest that prophylactic infusion of nicardipine decreases the severity of postbypass myocardial ischemic episodes in patients undergoing coronary revascularization procedures compared with patients in the control group. Administration of nicardipine, but not nitroglycerin, prevented the occurrence of the 2-mm or greater ST-segment deviation ischemic episodes during the vulnerable, immediate postrevascularization period.

Multiple investigators have demonstrated that myocardial ischemia in the early period after cardiopulmonary bypass is strongly related to myocardial infarction, myocardial injury assessed by creatine kinase-MB elevation, heart failure, and cardiac death [1–4]. Consequently, multiple therapeutic approaches have been examined to limit myocardial ischemic injury. Intensive early postoperative analgesia with administration of high infusion rates of opioids was shown to diminish the severity of myocardial ischemia after myocardial revascularization [17]. However, high-dose opioids may necessitate prolonged mechanical ventilation and may have limited application for many patients in whom early tracheal extubation is planned or early postoperative evaluation of neurologic status is needed.

Multiple factors may contribute to the pathogenesis of perioperative ischemia, such as coronary vasospasm, increased sympathetic activity, calcium homeostasis, and incomplete revascularization. Pharmacologic interventions with coronary vasodilators may reduce coronary artery blood flow and optimize the myocardial oxygen supply and demand balance. The prophylactic antiischemic therapeutic value of nitroglycerin in patients undergoing cardiac or noncardiac surgical procedures is not well established and remains controversial [5, 6]. A disadvantage to the use of nitroglycerin is the potential for tolerance development in patients treated with nitrates before operation. Prophylactic infusion of nifedipine, a dihydropyridine calcium-channel antagonist, was found to reduce the incidence of transient ischemia and myocardial infarction in a small series of clinical trials [7, 8]. Nicardipine may offer advantages over nifedipine because it is not photosensitive and is available in parenteral form. Moreover, nicardipine produces less negative inotropic effects than nifedipine at concentrations causing coronary vasodilation [18].

The antiischemic effects of nicardipine as demonstrated in the present study could be explained by its potent coronary vasodilatory properties, which produce a decrease in coronary vascular resistance and an increase in coronary blood flow and myocardial oxygen supply [10–13]. Nicardipine decreased calcium overload into the myocardial cells during the periods of ischemia and reperfusion and exhibited membrane-stabilizing effects [16]. Another major beneficial effect of nicardipine is direct myocardial protection by decreasing calcium overload during periods of ischemia and reperfusion and membrane stabilization. Koolen and associates [15] found patients who received nicardipine infusion before the aortic occlusion clamp exhibited no myocardial lactate production at 15 minutes after the release of the aortic clamp compared with a control group. In addition, patients with impaired left ventricular function (defined as ejection fraction 25% to 50% or left ventricular end-diastolic pressure > 20 mm Hg preoperatively) who received nicardipine had a significantly greater improvement of the regional area ejection fraction than the control group at the time of sternal closure. Finally, in patients who were pretreated with intracoronary injection of 0.2 mg nicardipine distal to the coronary artery stenosis, myocardial lactate and hypoxanthine production was significantly less than in the untreated group, 1 and 4 minutes after balloon deflation during percutaneous transluminal angioplasty [14].

The antiplatelet properties may contribute to its antiischemic effects. Nicardipine inhibits platelet aggregation to collagen and arachidonic acid in vitro [19]. The clinical significance of the effects of nicardipine on the hemostatic mechanism and on the pathogenesis of myocardial ischemia warrant further investigation.

In our study the beneficial effects of nicardipine did not extend to the later postoperative time raising the possibility of different pathogenetic mechanisms of ischemia during this period from the immediate postbypass period. Further research in this area may provide important answers to this observation and lead to the development of different therapeutic approaches.

Hemodynamic changes
The increase in cardiac index and mixed venous oxygen saturation produced by nicardipine are consistent with results of previous studies. The clinical significance of the reported slight depression of left ventricular contractile function in patients who received intracoronary nicardipine during cardiac catheterization [10] appears to be minimal when nicardipine is used intravenously at the recommended doses [11]. Moreover, in patients with New York Heart Association class II and III congestive heart failure, nicardipine infusion improved cardiac performance by increasing the cardiac index and left ventricular ejection fraction and decreasing left ventricular end-diastolic pressure [20]. Although it is known that nicardipine produces an increase in the heart rate reflectively [10–13], our results did not show any differences between groups. However, a high percentage of our patients were paced after CABG operation.

The number of patients requiring sodium nitroprusside for blood pressure control was smallest in the nicardipine group. Although nicardipine is an effective antihypertensive agent during cardiac or noncardiac surgical procedures, the need for sodium nitroprusside was probably related to the administration of a lower nicardipine dose than necessary for optimal control of hypertension.

Limitations of the study
There are certain limitations of Holter continuous ECG monitoring. Several nonischemic conditions can affect ST segment perioperatively, such as hypothermia, conduction abnormalities, defibrillation, ventricular pacing, electrolyte disturbances, different medications, pericarditis, and ventricular aneurysm. By excluding all patients with preoperative ST-segment changes, we minimized the influence of the above factors. Myocardial enzymes, such as creatine kinase-MB, total creatine kinase, and cardiac troponin I, were not measured because of the low specificity and sensitivity of creatine kinase-MB for assessment of myocardial injury and because of the lack of standardized criteria for the diagnosis of perioperative myocardial infarction during cardiac surgery. Preliminary analysis demonstrating favorable results in the groups receiving infusion of either nicardipine or nitroglycerin necessitated the early discontinuation of the control group. Finally, although our results are encouraging, the small sample size of this study precludes determination of any relationship between the ischemic protective effects of nicardipine and either short- or long-term cardiac outcomes.

	Conclusion

Top Abstract Introduction Material and methods Results Comment Conclusion References

 
Our results demonstrated that nicardipine lessened the duration and severity of myocardial ischemia in the intraoperative postbypass period and could be considered as an alternative to standard antiischemic therapy during cardiac revascularization procedures. Further, larger studies are indicated to advance our understanding of the antiischemic benefits of calcium-channel antagonists and lead to the development of therapies that maintain and enhance coronary stability during this vulnerable postrevascularization period.

	References

Top Abstract Introduction Material and methods Results Comment Conclusion References

 

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