Inadequate intra-operative myocardial preservation can lead to severe postoperative left ventricular (LV) dysfunction. The mainstay of myocardial protection in modern cardiac surgery is hyperkalaemic cardioplegia and hypothermia [1-3]. Despite electromechanical silence, hyperkalaemic depolarization arrest continues to consume energy and can result in myocardial stunning, arrhythmogenesis, or myocardial ischaemic injury . Antegrade delivery and distribution of cardioplegia to the myocardium is impaired in patients with severe coronary artery stenoses or aortic regurgitation. Retrograde cardioplegia delivery, an alternative technique, does prevent this [5-7].
Ischaemic preconditioning is a novel way of myocardial protection. Brief periods of ischaemia enable the myocardium to withstand subsequent prolonged ischaemia without myocardial necrosis . The decreased intracellular adenosine triphosphate (ATP) stores during ischaemia, through a variety of secondary messengers, act upon the ATP-dependent potassium (KATP) channels and open them. This causes membrane hyperpolarization, action potential duration shortening, and decreased calcium influx to induce myocyte relaxation and ATP preservation [4,9,10]. By acting on the same receptors, KATP channel openers like nicorandil bring about pharmacological preconditioning . Nicorandil, being a coronary vasodilator, may also enhance the delivery of cardioplegic solution to the myocardium [12-14]. In this study, we evaluated the myocardial protective effects of nicorandil when used as an adjuvant to hyperkalaemic cold cardioplegia in open-heart surgery.
This randomized, controlled, double-blind study was conducted between January 2002 and May 2003 at a tertiary care teaching hospital in Chandigarh, India. After obtaining informed consent, 47 patients who underwent either mitral valve replacement (MVR) or coronary artery bypass graft (CABG) under cardiopulmonary bypass (CPB) were included in the study. Patients with pre-existing liver, renal failure, myocardial infarction (MI) within 5 days prior to surgery, and diabetics on sulphonylurea treatment were excluded.
All patients were premedicated with oral diazepam 0.2 mg kg−1 and intramuscular morphine 0.1 mg kg−1. The pre-induction monitoring included pulse oximetry, intra-arterial blood pressure, electrocardiogram (ECG), central venous pressure (CVP), and pulmonary artery wedge pressure. General anaesthesia was induced with morphine 0.2 mg kg−1, propofol titrated to bispectral index score (BIS) of 45–55, and vecuronium 0.1 mg kg−1. Anaesthesia was maintained with propofol (BIS titrated to 45–55) and morphine 0.05 mg kg−1 h−1. Prophylactic use of intravenous (i.v.) nitroglycerin was avoided in all patients.
Anticoagulation was achieved with heparin (activated clotting time > 480 s) and was reversed with protamine sulphate at the end of the procedure. Cannulation for CPB included an ascending aortic perfusion cannula, a single two-stage right atrial cannula, and a vent line. A membrane oxygenator and an arterial line filter were used. The CPB technique involved non-pulsatile flow under moderate hypothermia (28–32°C), moderate haemodilution (haematocrit < 20%), and alpha-stat acid–base management. Perfusion pressures were maintained in the range of 50–80 mmHg. Hyperkalaemic cold (15°C) blood cardioplegia was infused through an ascending aortic cardioplegia cannula. The initial volume was 500 mL m−2 and the potassium concentration was 24 mmol L−1. The cardioplegia infusion was repeated every 20 min at a volume of 200 mL m−2 and a K+ concentration of 12 mmol L−1. Temperature, urine output, haemoglobin, serum potassium levels and arterial blood gases were monitored intra-operatively and appropriate measures were taken as and when required.
Using a random number table, the patients were allocated to active treatment (nicorandil, Group N) or placebo (Group P). Nicorandil 0.1 mg kg−1, or the equivalent volume of normal saline, was administered by a blinded observer of the anaesthesia team at the following time intervals:
- After aortic cannulation, but prior to start of CPB (i.v.).
- Five minutes before aortic cross-clamping (in the CPB circuit).
- Five minutes before declamping of the aorta (in the CPB circuit).
The following variables were studied:
- Time until electromechanical arrest after cardioplegia administration (Tarrest).
- Time taken for return of electromechanical activity after aortic cross-clamp removal (Trecovery).
- Significant dysrhythmias (ventricular tachycardia, ventricular fibrillation, or any non-sinus rhythm requiring DC shocks or anti-dysrhythmic drug therapy after aortic cross-clamp removal or in the postoperative period.
- Heart rate (HR), mean arterial pressure (MAP), pulmonary arterial pressure (PAP), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP) and thermodilution cardiac out-put (CO) were measured at the following time points: (i) before induction of anaesthesia, (ii) after sternotomy, (iii) before drug administration, (iv) 5 min after drug administration, (v) half an hour after CPB, (vi) 6 h after surgery, (vii) 24 h after surgery.
- Serum creatine kinase-muscle band (CK-MB) was measured before CPB and postoperatively at 6, 24 and 72 h.
- New ECG changes suggestive of MI (new Q waves, ST segment changes > 1 mm in two contiguous leads and lasting for at least 12 h). A diagnosis of postoperative MI required ECG changes as above and serum CK-MB >75 IU L−1.
- Intra- or postoperative low output syndrome (cardiac index <2 L min−1 m−2) requiring intra-aortic balloon counterpulsation (IABP) and/or high-dose inotropic drug support for more than 12 h (dopamine >10 μg kg−1 min−1 and/or epinephrine >0.2 μg kg−1 min−1).
- Other adverse clinical outcome before discharge, including death due to cardiac cause and new focal or global neurological deficits, were also noted.
The data was analysed using SPSS-10 software package and values expressed as means ± standard deviation. Comparison of the unpaired parametric data was done using t-test (normal distribution) or U-test (non-normal distribution) respectively. Changes in haemodynamic variables after drug administration were tested with paired t-test. Comparison of postoperative CK-MB levels with baseline was done using repeated measures of ANOVA. Categorical data for the two groups were compared with Fisher's exact test. A P value < 0.05 was taken as significant difference.
Twenty-three patients underwent MVR, and 24 patients had CABG. Of the MVR patients, 11 received nicorandil (Group N) and 12 received placebo (Group P). In the CABG group, there were 13 nicorandil patients (Group N) and 11 placebo patients (Group P). There were no significant differences in preoperative patient data between the groups (Table 1). The CPB and aortic cross clamp times and the total amount of potassium chloride administered through cardioplegia were also similar (P > 0.05) between Groups N and Group P (Table 2).
The onset of electromechanical arrest after cardioplegia administration (Tarrest) was significantly faster in Group N (P < 0.05, Table 2). Tarrest > 10 s was noted in only three nicorandil patients (27%), as compared to 9 patients (75%) in Group P (P < 0.05). The return of electromechanical activity after aortic cross-clamp removal tended to be faster in Group N than in Group P, but this was not statistically significant (Table 2). After aortic cross-clamp removal, 5 patients (45%) in Group N and 8 patients (66%) in Group P developed cardiac dysrhythmias that required DC shocks to revert to a stable cardiac rhythm. However, the incidence of dysrhythmias was not significantly different.
In both Group N and Group P, the CK-MB levels showed significant increases at 6 and 24 h postoperatively as compared to baseline (P < 0.01, Table 3). The CK-MB peak was at 6 h in Group N, and at 24 h in Group P. Though the mean values did not differ significantly between the two groups at any of the measured time points, the number of patients with postoperative CK-MB levels >75 IU L−1 was significantly lower in Group N (3 patients) than in Group P (9 patients).
None of the patients showed new Q waves after surgery. Two patients in Group P developed low output syndrome and required high-dose inotropic support to maintain the MAP above 70 mmHg in the postoperative period. One patient from Group P had postoperative focal seizures with secondary generalization. There were no deaths, significant dysrhythmias causing haemodynamic instability, or stroke in the postoperative period in either of the two groups.
Tarrest in Group N was significantly shorter than in Group P (P < 0.01, Table 2). Three patients in Group N and 8 patients in Group P had Tarrest > 10 s (P < 0.05). There was a non-significant tendency for faster Trecovery in Group N than in Group P (P > 0.05, Table 2). After cross-clamp removal, 2 patients in Group N developed significant cardiac dysrhythmias, vs. 6 patients in Group P (P > 0.05).
In both the groups, the postoperative (6 and 24 h) serum CK-MB levels showed a significant rise from baseline (P < 0.01, Table 3). However, there was no significant difference between the two groups at any of the measured intervals. Four patients in Group N and 2 in Group P had postoperative elevations of CK-MB > 75 IU L−1 (P > 0.05). Interestingly, 5 of these 6 patients were diabetic.
Postoperative ECG showed new changes consistent with MI in 4 Group N patients and 3 Group P patients. All of these patients, except 1 in Group P, also had CK-MB > 75 IU L−1. The incidence of postoperative MI, as diagnosed by ECG changes and CK-MB levels, was not significantly different between the two groups (P > 0.05).
One patient in Group N developed low output syndrome and required high-dose inotropes and IABP to maintain the MAPs. No death due to cardiac cause, significant dysrhythmias causing haemodynamic instability or postoperative stroke occurred in either of the two groups.
Haemodynamic effects of nicorandil
The administration of the nicorandil bolus (0.1 mg kg−1) did not bring about any major haemodynamic perturbations in either MVR or CABG patients. There was no significant difference between Group N and Group P in HR, systemic and pulmonary pressures and cardiac indices at any of the measured intervals (P > 0.05).
Nicorandil administration significantly accelerated the onset of electromechanical arrest after cardioplegia administration in both MVR and CABG patients (P < 0.05). The proportion of patients with Tarrest > 10 s was also significantly lower after administration of nicorandil (P < 0.05). Hayashi and colleagues  reported similar findings in CABG patients receiving nicorandil as an adjuvant to hyperkalaemic cold cardioplegia. Adenosine, another drug with KATP channel opening properties, has also been shown to hasten induction of cardioplegia . The mechanism responsible for this is not clear. Hypothermia actually increases membrane potential to > −60 mV and abolishes any polarizing effect of KATP channel openers. Thus, hyperpolarized arrest cannot be achieved under clinical conditions . A more likely mechanisms for the rapid induction of cardioplegia by the potassium channel openers could be coronary vasodilatation and an increase in collateral blood flow [12-14]. This enhances delivery of cardioplegia. Also, in the presence of high extracellular potassium levels, the potassium channel openers can increase potassium permeability and cause rapid sinus node arrest .
Rapid electromechanical arrest enhances myocardial preservation by decreasing the duration of cardiac contractions against a cross-clamped aorta. Continued ventricular fibrillation after aortic cross-clamping rapidly exhausts the myocardial ATP stores and results in myocardial ischaemia, acidosis, cellular oedema and postoperative myocardial dysfunction . Thus, the faster induction of electromechanical arrest in patients given nicorandil may enhance cardioplegic myocardial protection.
There was a non-significant trend for shorter Trecovery in both MVR and CABG patients pretreated with nicorandil. This rapid return of electromechanical activity after aortic cross-clamp removal may be again due to the coronary vasodilating effect of nicorandil, facilitating a faster rewarming of the heart and washout of cardioplegia from the coronary circulation.
A rise in serum CK-MB is inevitable in the immediate post-cardiac surgery period due to surgical handling itself. A postoperative serum CK-MB level > 75 IU L−1 has a sensitivity of 87% and specificity of 82%, when used as a marker of significant myocardial injury in cardiac surgical patients .
In our study, MVR patients who received nicorandil had a lower incidence of significant elevation of postoperative serum CK-MB levels. This suggests lesser intra-operative myocardial damage and probably better myocardial protection. The peak levels were attained at 6 h in Group N and at 24 h in Group P. The delayed CK-MB peak in the placebo group suggests ongoing myocardial injury in the postoperative period possibly due to a reperfusion injury. Nicorandil administration 5 min prior to aortic declamping may have attenuated this due to its anti-inflammatory properties [20-22].
In the CABG patients, 4 from Group N and 2 from Group P had significantly elevated serum CK-MB levels. Interestingly, all but one were diabetic. Failure of ischaemic preconditioning or pharmacological preconditioning with potassium channel openers has been shown in previous studies [23,24]. To avoid this confounding factor, we excluded patients on sulphonylureas. Irrespective of group, diabetic patients had a higher incidence of postoperative MI (66%) as compared to non-diabetics (11%). A recent study showed that diabetes per se can impair myocardial protection, and both diabetes mellitus and sulphonylureas can act in synergism to inhibit activation of KATP channels in patients undergoing coronary angioplasty . Ghosh and colleagues have demonstrated that failure to precondition the diabetic heart is due to a defective signal transduction pathway and not mitochondrial KATP channel dysfunction .
In acute ischaemia, the potassium channel openers are regarded as potentially arrhythmogenic due to shortening of the action potential duration and, hence, the effective refractive period . On the contrary, we found that CABG patients who received nicorandil had a lower incidence of dysrhythmias after declamping. This may be due better myocardial preservation by nicorandil, and hence lesser myocardial irritability, rather the direct effect of the drug on the effective refractory period.
In our study, the 0.1 mg kg−1 i.v. boluses of nicorandil did not cause significant haemodynamic changes in either MVR or CABG patients. Previous studies have reported decreases in mean arterial and pulmonary pressures, systemic and pulmonary vascular resistances, pulmonary arterial wedge pressure and LV end-diastolic pressure. Stroke index and cardiac index have been reported to increase [14,28-30]. This disagreement may be due to discontinuation of all other cardiac medications before subjecting the patients to nicorandil in the previous studies. To evaluate the acute haemodynamic effects of nicorandil in patients with chronic severe regurgitant valvular lesions, Yadav and colleagues had withdrawn all cardiac medications 5 days prior to study . In a cardiac surgery setting of polypharmacy, the haemodynamic effects brought about by a single drug may be difficult to demonstrate.
Although previous reports about the efficacy of potassium channel openers in cardiac surgery are conflicting, most of them suggest enhanced myocardial protection with nicorandil [15,31-34]. However, none of the above studies showed significant improvement in clinical outcome, such as death due to cardiac cause, low output syndrome or postoperative stroke. We did not find any statistically significant difference in these clinical outcomes between the nicorandil and placebo groups. However, in the MVR patients nicorandil was associated with a lower incidence of postoperative MI and low output syndromes.
Our study has several limitations. Postoperative echocardiograms could not be obtained in our patients to identify new regional wall motion abnormalities. Hence, we relied on ECG criteria and postoperative CK-MB measurements to diagnose postoperative MI. In cardiac surgical patients, ST segment changes may be due to non-ischaemic causes like electrolyte imbalances, hypothermia, chest drains, digitalis medications or postoperative pericarditis. Though CK-MB is a commonly used enzyme marker for postoperative MI, the levels can be elevated by myocardial incisions, e.g. during cannulation for CPB. This makes diagnosis of postoperative MI difficult in cardiac surgical patients . Another limitation of our study is the relatively limited number of patients studied.
In conclusion, nicorandil accelerated the onset of electromechanical arrest in both MVR and CABG patients. In the MVR patients, there were significantly fewer patients with high (>75 IU L−1) postoperative CK-MB levels after nicorandil as compared to placebo. This may indicate that nicorandil enhanced the myocardial protective effect of hypothermia and hyperkalaemic cardioplegia. In the cardiac surgery setting, 0.1 mg kg−1 boluses of nicorandil did not cause any significant haemodynamic.
We are indebted to the patients for their participation in our study. We also thank our colleagues in Departments of anaesthesia and intensive care, and cardiothoracic surgery for their co-operation and encouragement during the course of the study.
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