Dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients undergoing major abdominal surgery

T. Kaneko*,1, Y. Saito2, Y. Hikawa2, K. Yasuda2 and K. Makita1

1Department of Anesthesiology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034, Japan. 2Department of Anesthesia, Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan*Corresponding author

Accepted for publication: November 7, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Nicorandil, a nicotinamide nitrate derivative, relaxes vascular smooth muscle and reduces cardiac muscle contractility by increasing membrane potassium conductance, probably by activating ATP-sensitive potassium channels. In this prospective, randomized, double-blind, placebo-controlled clinical study, we examined the dose-dependent prophylactic effect of nicorandil on intra-operative myocardial ischaemia in 248 patients who had pre-operative risk factors for ischaemic heart disease and were undergoing major abdominal surgery. Patients in group HD (n=81) received a bolus dose of nicorandil 0.08 mg kg–1 and a continuous infusion of 0.08 mg kg–1 h–1. Patients in group LD (n=87) received nicorandil 0.04 mg kg–1 and 0.04 mg kg–1 h–1. Patients in the placebo (P) group (n=80) received the same volumes of saline. The patients were monitored with a three-lead clinical ECG monitor with an ST trending device from arrival in the operating theatre to the end of anaesthesia. Intra-operative myocardial ischaemia occurred significantly less frequently in the HD group (one patient, 1.2%) than in the LD (11 patients, 12.6%) and P groups (21 patients, 26.3%) (P<0.01), and in group LD significantly less than in group P (P<0.05). Administration of nicorandil had little effect on the patients’ heart rate or arterial pressure. Three patients in group P and none in either treatment group developed myocardial infarction after surgery.

Br J Anaesth 2001; 86: 332–7

Keywords: metabolism, ATP; metabolism, nicorandil; complications, myocardial ischaemia; surgery, abdominal


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Nicorandil, a nicotinamide nitrate derivative, relaxes vascular smooth muscle and reduces cardiac muscle contractility by increasing membrane potassium conductance, probably by activating adenosine triphosphate (ATP)-sensitive potassium channels.1 Its pharmacological effects include reductions in myocardial preload and afterload. Nicorandil is an antianginal agent that is effective for treating various types of angina pectoris2 and has been reported to be cardioprotective in several animal models of ischaemia–reperfusion injury and myocardial infarction.3 Saito and colleagues4 recently reported that, in humans, the intravenous administration of nicorandil reduced ischaemic changes in the intracoronary electrocardiograph (ECG) during percutaneous transluminal coronary angioplasty, without significant changes in systemic arterial pressure or coronary blood flow. Thus, nicorandil may have a direct cardioprotective action on the ischaemic myocardium at a clinically relevant dose. Imagawa and colleagues5 have reported that nicorandil acts to protect the heart by the same mechanism as ischaemic preconditioning, namely, the opening of ATP-sensitive potassium channels.

Cardiovascular disease, especially ischaemic heart disease, continues to be a significant cause of perioperative morbidity and mortality. Mangano and colleagues6 7 have reported that in non-cardiac surgical patients with, or at risk of, ischaemic heart disease, ischaemia is most frequent and most severe during the post-operative period and post-operative ischaemia appears to be associated with adverse cardiac outcome. However, Varma and colleagues8 have reported that intra-operative ST-segment changes are associated with a higher incidence of perioperative myocardial infarction and adverse cardiac outcome. Knorring9 has also reported that skilful anaesthesia is needed in patients at high risk of ischaemic heart disease undergoing non-cardiac surgery.

In this prospective, randomized, double-blind, placebo-controlled clinical study, we examined the dose-dependent prophylactic effect of nicorandil on intra-operative myocardial ischaemia and post-operative myocardial infarction in patients with pre-operative risk factors for ischaemic heart disease undergoing major abdominal surgery. The effect of nicorandil on arterial pressure and heart rate during anaesthesia was also studied.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study was performed at Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan, between January 1998 and December 1999. With institutional approval and written, informed consent, we studied 262 patients aged >40 yr who had at least two pre-operative risk factors for ischaemic heart disease among 1386 patients undergoing major abdominal surgery. Pre-operative risk factors for ischaemic heart disease were as described by Mangano and colleagues,6 Fleisher and Barash10 and Ishiguro and colleagues,11 namely hypertension, diabetes mellitus, hyperlipidemia, current smoker, age >70 yr, obesity, family history of ischaemic heart disease, or peripheral vascular disease. Patients with the following conditions were excluded because ECG monitoring would be unreliable: digoxin therapy, left bundle branch block, left ventricular hypertrophy and strain changes in the lateral chest leads on the pre-operative 12-lead ECG. Patients receiving anti-angina drugs, such as nitrates, calcium antagonists and ß-blockers, for ischaemic heart disease or hypertension were also excluded because these drugs would affect perioperative myocardial ischaemia.12 13

All patients were premedicated with ranitidine 150 mg taken orally 90 min before the induction of anaesthesia and with atropine 0.01 mg kg–1 and hydroxyzine 1 mg kg–1 injected i.m. 30 min before the induction of anaesthesia. Patients on antihypertensive medication continued to take these drugs until the morning of their surgery.

Before arriving in the operating theatre, 248 patients were assigned randomly to one of three groups. Patients in group HD (n=81) received an intravenous bolus dose of nicorandil 0.08 mg kg–1 after application of routine monitoring, followed by a continuous infusion of nicorandil 0.08 mg kg–1 h–1. Patients in group LD (n=87) received an intravenous bolus dose of nicorandil 0.04 mg kg–1 and a continuous infusion of 0.04 mg kg–1 h–1. Patients in the placebo group, group P (n=80), received the same volumes of saline. All physicians and nursing staff caring for the patients perioperatively were blinded to these groups.

A pulse oximeter was attached and a 20-gauge radial arterial catheter placed to monitor arterial pressure; patients were then monitored continuously with a three-lead clinical ECG monitor with an ST trending device (BSM-8502; Nihon Kohden, Tokyo, Japan) until the end of anaesthesia. This is a microprocessor-based solid state system programmed with algorithms for accurate analysis of both ischaemia and arrhythmia. The ST measurement point on the ST trending monitor was taken as the mean of three ST-segment points, namely the J point + 40–44 ms, + 44–48 ms and + 48–52 ms. Leads II and V5 were monitored for ST segment changes. An ischaemic episode was defined as a reversible ST segment shift from the baseline of >=0.1 mV depression or >=0.2 mV elevation lasting for >=1 min. All recorded ischaemic episodes of ST-segment changes were verified visually by one of the investigators blinded to assignment of the groups.

A standardized intra-operative anaesthetic technique was used. After a thoracic epidural catheter had been inserted, general anaesthesia was induced with propofol 2 mg kg–1. Vecuronium 0.1 mg kg–1 was administered to facilitate tracheal intubation. Before surgery began, buprenorphine 2 µg kg–1 was injected via the epidural catheter. Anaesthesia was maintained with 33–50% inspired oxygen, 50–67% nitrous oxide and 0.5–1.0% sevoflurane; a continuous infusion of 1% mepivacaine (0.1 ml kg–1 h–1) was injected via the epidural catheter. All patients were managed so as to maintain mean arterial pressure within 20% of pre-operative values and heart rate between 50 and 90 beats min–1. If the systolic arterial pressure dropped below 90 mm Hg, 5 mg ephedrine was given; if this had no effect, a continuous infusion of dopamine was started at 3 µg kg–1 min–1 up to a maximum of 10 µg kg–1 min–1. If the heart rate dropped below 50 beats min–1, 0.5 mg atropine was given. Acetated Ringer’s solution was infused at 7–10 ml kg–1 h–1. After completion of surgery, neuromuscular blockade was reversed with 2 mg neostigmine and 1 mg atropine and the patient’s trachea was extubated.

Both 12-lead ECG and serum creatine kinase MB isoenzyme CK-MB concentrations were obtained from all patients daily for the first 3 days after surgery. A diagnosis of a post-operative myocardial infarction required the following triad: clinical suspicion of myocardial infarction, change in the post-operative 12-lead ECG and documented increase in serum CK-MB concentrations (>50 IU litre–1).

The plasma concentration of nicorandil was measured in another 14 patients receiving the high-dose (n=7) or low-dose regimen (n=7). Blood samples (5 ml) were taken from radial arterial catheters 5, 20, 60 and 120 min after administration of nicorandil. Plasma concentrations were analysed using the HPLC system (Mitsubishi BCL, Tokyo, Japan).

Continuous parametric variables were analysed using one-way analysis of variance. Nonparametric variables were compared with Pearson’s {chi}2 test, Fisher’s exact test and the Kruskal–Wallis test. Repeated-measures analysis of variance was used for the analysis of mean arterial blood pressure and heart rate after administration of nicorandil. A P value of <0.05 was considered statistically significant; P values are reported only when significance was found. Results are expressed as the mean (SD) unless otherwise indicated.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The physical and clinical characteristics of the patients and intra-operative data are summarized in Table 1. The use of anaesthetic and inotropic drugs was similar between the groups. The mean arterial pressure and heart rate after administration of nicorandil are shown in Figures 1 and 2, respectively. There was no significant difference among the groups.


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Table 1 Physical and clinical characteristics of the patients and intra-operative data. Data are mean (SD) or number of patients. IHD=ischaemic heart disease; RPP=rate–pressure product (systolic arterial pressurexheart rate); MAP=mean arterial pressure
 


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Fig 1 Mean arterial blood pressure after administration of nicorandil. Data are mean±SD. There was no significant difference among the groups.

 


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Fig 2 Heart rate after administration of nicorandil. Data are mean± SD. There was no significant difference among the groups.

 
Intra-operative myocardial ischaemia occurred significantly less frequently in group HD (one patient, 1.2%) than in groups LD (11 patients, 12.6%) and P (21 patients, 26.3%) (P<0.01), and in group LD significantly less than in group P (P<0.05). Severe transient hypotension and ventricular arrhythmia occurred in two of 11 patients in group LD and in five of 21 patients in group P. There was no post-operative myocardial infarction in groups HD and LD, but three patients in group P had non-fatal post-operative myocardial infarction, one patient each on days 0, 1 and 2 after surgery. All three patients had intra-operative ischaemic episodes with severe transient hypotension and ventricular arrhythmia.

The plasma concentrations of nicorandil measured in 14 patients are shown in Table 2.


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Table 2 Changes in plasma nicorandil concentration after a bolus and continuous infusion. Data are mean (SD) (ng ml–1). Group LD received a bolus of 0.04 mg kg–1 and an infusion of 0.04 mg kg–1 h–1; group HD received a bolus of 0.08 mg kg–1 and an infusion of 0.08 mg kg–1 h–1
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Mangano and colleagues6 have reported that 27% of patients with, or at risk of, ischaemic heart disease undergoing non-cardiac surgery exhibited intra-operative ECG ischaemic episodes. Of these, 77% occurred without acute change in blood pressures and 4% were associated with post-operative myocardial infarction. Our data for group P are remarkably similar. Intra-operative myocardial ischaemia occurred significantly less frequently in group HD than in groups LD and P and in group LD significantly less than in group P, demonstrating the dose-dependent prophylactic effect of nicorandil on intra-operative myocardial ischaemia in patients with pre-operative risk factors for ischaemic heart disease undergoing major abdominal surgery. Although current thinking puts more emphasis on post-operative ischaemia and myocardial damage than on intra-operative ischaemia,6 7 all three of our patients who sustained a post-operative infarct had intra-operative ischaemia and hypotension. Further studies are required to assess the possible effect of nicorandil in prevention of post-operative myocardial infarction.

Administration of nicorandil by a bolus and continuous infusion had little influence on the patients’ heart rate or arterial pressure in our study. Ito and colleagues14 have reported that no side-effects occurred with a bolus dose of nicorandil 4 mg kg–1 followed by a continuous infusion of nicorandil 6 mg h–1 in patients with an anterior acute myocardial infarction. Uchino and colleagues15 have reported that the effective plasma concentration of nicorandil that had no adverse cardiovascular effects was 40–300 ng ml–1. The plasma concentration of nicorandil in our study was 70–230 ng ml–1.

Takaoka and colleagues16 have suggested that nicorandil directly protects the myocardium against ischaemic injury via ATP-sensitive potassium channels. The mechanism by which nicorandil has a direct cardioprotective action on the ischaemic myocardium is thought to be the same as the mechanism of ischaemic preconditioning.5 Ischaemic preconditioning is a phenomenon described in 1986 by Murry and colleagues17 as brief periods of ischaemia that render the myocardium resistant to a subsequent longer period of ischaemia. This endogenous protective mechanism has been shown to occur in many species.18 19 On the other hand, Dodds and colleagues20 have reported that prophylactic infusion of nitroglycerine, one of the organic nitrates, during non-cardiac surgery does not reduce intra-operative myocardial ischaemia. Therefore, the effects of nicorandil in our study may have been mediated via ATP-sensitive potassium channels rather than by its nitrate.

Our study has several potential limitations. First, we defined an ischaemic episode using the ST trending monitor (leads II and V5). Many studies have demonstrated the superiority of two-dimensional trans-oesophageal echocardiography over ECG for the intra-operative detection of myocardial ischaemia,21 and ST trending monitors have an overall sensitivity and specificity of 74% and 73% relative to two-lead Holter ECG.22 Sole reliance on ST trending monitors for the detection of myocardial ischaemia may be insufficient, although we obtained hard copies of ECG strips for visual confirmation of potential wave-form changes.

Second, patients with diabetes mellitus receiving oral sulfonylurea hypoglycaemic agents, such as glibenclamide, were included in our study. Glibenclamide antagonizes ATP-sensitive potassium channels18 19 and blocks ischaemic preconditioning in the intact rat heart18 and human myocardium.19 Nakae and colleagues23 have reported that glibenclamide does not antagonize the change in coronary blood flow caused by nicorandil, but its effect on the myocardial protective potential of nicorandil is not known. However, in our study a similar number of diabetic patients were treated with glibencamide in each group (Table 1) and pretreatment with glibencamide did not seem to obscure the protective effect of nicorandil.

Other possible drawbacks of our study are the ischaemic preconditioning-like effect of sevoflurane and the influence of thoracic epidural anaesthesia. Novalija and colleagues24 have reported that preconditioning with sevoflurane, like ischaemic preconditioning, improves not only postischaemic contractility, but also basal flow, bradykinin- and nitroprusside-induced increases in flow and effluent NO concentration in isolated pig hearts; the protective effects of both sevoflurane preconditioning and ischaemic preconditioning are reversed by ATP-sensitive potassium channel antagonism. However, these effects are unlikely to occur at the concentrations of sevoflurane used in our study.24 25 There is evidence that thoracic epidural anaesthesia (T1–5) has an effect on myocardial ischaemia through cardiac sympathetic blockade which increases the luminal diameter of stenotic epicardial coronary arteries and reduces myocardial oxygen demand.26 As all patients in our study received thoracic epidural anaesthesia, the effects of nicorandil observed were in addition to any effect of the epidural.

In conclusion, nicorandil reduced the incidence of intra-operative myocardial ischaemia without affecting heart rate or arterial pressure. We demonstrated the dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients with pre-operative risk factors for ischaemic heart disease undergoing major abdominal surgery.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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