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
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Abstract |
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Br J Anaesth 2001; 86: 3327
Keywords: metabolism, ATP; metabolism, nicorandil; complications, myocardial ischaemia; surgery, abdominal
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Introduction |
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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.
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Patients and methods |
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All patients were premedicated with ranitidine 150 mg taken orally 90 min before the induction of anaesthesia and with atropine 0.01 mg kg1 and hydroxyzine 1 mg kg1 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 kg1 after application of routine monitoring, followed by a continuous infusion of nicorandil 0.08 mg kg1 h1. Patients in group LD (n=87) received an intravenous bolus dose of nicorandil 0.04 mg kg1 and a continuous infusion of 0.04 mg kg1 h1. 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 + 4044 ms, + 4448 ms and + 4852 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 kg1. Vecuronium 0.1 mg kg1 was administered to facilitate tracheal intubation. Before surgery began, buprenorphine 2 µg kg1 was injected via the epidural catheter. Anaesthesia was maintained with 3350% inspired oxygen, 5067% nitrous oxide and 0.51.0% sevoflurane; a continuous infusion of 1% mepivacaine (0.1 ml kg1 h1) 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 min1. 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 kg1 min1 up to a maximum of 10 µg kg1 min1. If the heart rate dropped below 50 beats min1, 0.5 mg atropine was given. Acetated Ringers solution was infused at 710 ml kg1 h1. After completion of surgery, neuromuscular blockade was reversed with 2 mg neostigmine and 1 mg atropine and the patients 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 litre1).
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 Pearsons 2 test, Fishers exact test and the KruskalWallis 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.
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Results |
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The plasma concentrations of nicorandil measured in 14 patients are shown in Table 2.
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Discussion |
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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 kg1 followed by a continuous infusion of nicorandil 6 mg h1 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 40300 ng ml1. The plasma concentration of nicorandil in our study was 70230 ng ml1.
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 (T15) 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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References |
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