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* Fukushima, Toride Kyodo General Hospital,
Ibaraki, Department of Anesthesiology, Institute of Clinical Medicine,
University of Tsukuba, Ibaraki, and the Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine,
Gifu, Japan.
From the Department of Anesthesiology, Fukushima Medical University School of Medicine,
Address correspondence to: Dr. Yuhji Saitoh, Department of Anesthesiology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan. Phone: 81-24-548-2111; Fax: 81-24-548-0828; E-mail: ys{at}m6.people.or.jp
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Methods: Sixty adult patients were allocated to four groups of 15: nicorandil-post-tetanic count (N-PTC), nicorandil-train-of-four (N-TOF), control-post-tetanic count (C-PTC) or control-train-of-four (C-TOF) group. In the N-PTC and N-TOF groups, 0.1 mg•kg–1 nicorandil was given as a bolus followed by an infusion at 1 µg•kg–1•min–1. Two minutes after the bolus, 0.1 mg•kg–1 vecuronium was administered. In the C-PTC or C-TOF group normal saline was given instead of nicorandil. PTC and TOF responses were measured mechanically using a force displacement transducer.
Results: Time from the administration of vecuronium to the onset of neuromuscular block in the N-PTC or N-TOF group did not differ from that in the C-PTC or C-TOF group (241 ± 33 vs 225 ± 32 sec, mean ± SD). Times from vecuronium injection to the return of PTC in the N-PTC and C-PTC groups, and those of T1, T2, T3, and T4 (first, second, third, and fourth stimulation of TOF) in the N-TOF and C-TOF groups did not differ. Recoveries of PTC in the N-PTC and C-PTC groups followed similar time course. T1/control twitch height and TOF ratio (T4/T1) in the N-TOF group were higher than those in the C-TOF group 80-120 min and 100-120 min after administration of vecuronium, respectively.
Conclusion: Nicorandil accelerates recovery of neuromuscular block caused by vecuronium.
KATP channel agonists are being investigated as anti-ischemic drugs, which may produce cardioprotective effects and enhance functional recovery of the stunned myocardium.1–4 Because of its potential for widespread use in cardiovascular patients undergoing cardiac and non-cardiac surgery, it is important to document any potential interactions of KATP channel agonists with commonly-used neuromuscular blocking drugs. The characteristics of the interaction between KATP channel agonists and KATP channel agonists in skeletal muscle and in cardiac muscle are similar.5 KATP channel agonists enhance the membrane K+ conductance in the skeletal muscle, and increase the contraction of the skeletal muscle.6–8 Spuler et al.6 described that the KATP channel agonist may be of therapeutic benefit in patients with muscle paralysis. However, no previous studies have investigated the nicorandil-induced effect on neuromuscular block during general anesthesia in humans. We studied onset of neuromuscular block and recovery of post-tetanic count (PTC) or train-of-four (TOF) response after administration of nicorandil in anesthetized patients receiving vecuronium.
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1, 1-ß, and d are 0.10, 0.80, and 0.8, respectively, preferable number of patients in each group is 14. Premedication consisting of 0.01 mg•kg–1 atropine and 1.0 mg•kg–1 hydroxyzine im was given 30 min before induction of anesthesia. On arriving at the operating room, two surface stimulating electrodes were positioned over the ulnar nerve at the wrist. A force displacement transducer was attached to the thumb of the investigated arm.
In the N-PTC and N-TOF groups, before induction of anesthesia, a bolus dose of 0.1 mg•kg–1 nicorandil iv was administered followed by a continuous infusion at a rate of 1 µg•kg–1•min–1. The dose of nicorandil given in this study was comparable to that administered in patients with ischemic heart disease.1,2 In the C-PTC and C-TOF groups, a bolus dose of 0.1 ml•kg–1 normal saline followed by a continuous infusion at a rate of 0.06 ml•kg–1•hr–1 was given instead of nicorandil. Immediately after the bolus injection of nicorandil or normal saline, 2 mg•kg–1 propofol iv was administered. In each group, after loss of eyelash reflex was confirmed, train-of-four (TOF) stimuli were given at 50 mA every 12 sec using an electrical nerve stimulator (Myotest DBS, Biometer International, Odense, Denmark). For TOF stimulation, four single twitch stimuli consisting of 0.2 msec duration square-waves were applied at 2 Hz. Mechanical twitch responses of the adduction of the thumb were measured using a neuromuscular transmission analyzer (Myograph 2000, Biometer International, Odense, Denmark). We ensured that mechanical responses to TOF were stabilized over about one minute, and twitch height of the T1 (the first response in TOF) was regarded as the control. Once the control had been recorded, 0.1 mg•kg–1 vecuronium was administered to facilitate tracheal intubation. The interval between the bolus administration of nicorandil or normal saline and that of vecuronium was two minutes. After the vecuronium injection, the disappearance of T1 response was regarded as onset of neuromuscular block. The times to the onset of neuromuscular block measured in the N-PTC and N-TOF groups were compared with that in the C-PTC and C-TOF groups. After the administration of vecuronium, in the N-PTC and C-PTC groups, post-tetanic count (PTC) was measured every five minutes at 50 mA. For PTC, a 50 Hz tetanic stimulation was delivered at 50 mA for five seconds, and after a pause of three seconds, 20 single twitch stimuli of 0.2 msec duration square waves were given at 50 mA. The number of detectable muscular contractions in response to single twitch stimulation, which could be shown on the paper chart of the neuromuscular transmission analyzer, was regarded as the PTC. In the N-PTC and C-PTC groups, the times from the vecuronium injection to the return of PTC1 (one response to the 20 single twitch stimuli delivered after the tetanic stimulation can be elicited) were compared. Additionally, in the N-PTC and C-PTC groups, time courses of recovery of PTC were compared. In N-TOF and C-TOF groups, TOF stimuli were applied every 12 sec at 50 mA. The times from vecuronium injection to the return of T1, T2, T3, and T4 (the first, second, third, and fourth response in TOF) were compared between the two groups. If muscular contraction in response to T1, T2, T3 or T4 could be observed on the paper chart of the neuromuscular transmission analyzer, the response to T1, T2, T3, or T4 was regarded as "present". Also, T1/control and TOF ratio (T4/T1) were recorded every 10 min, and were compared between the N-TOF and C-TOF groups. In each group anesthesia was maintained with N2O 66 %, O2 33 %, and isoflurane 0.5 % end-tidal. If the anesthetic level was thought to be insufficient, bolus doses of 2 µg•kg–1 fentanyl were administered. Patients' lungs were ventilated to maintain normocapnia (PETCO2 32-38 mmHg). The concentrations of anesthetics and PETCO2 were measured using a multiple gas monitor (Capnomac Ultima, Datex Inc., Helsinki, Finland). The peripheral temperature over the adductor pollicis muscle was monitored using a surface skin thermometer (Terumo-Finer, Terumo Inc., Tokyo, Japan).
All results are expressed as number or mean ± SD. Patient data were compared among the four groups using analysis of variance (ANOVA) and Scheffe's multiple comparison. Times to the return of PTC1 were compared between the N-PTC and C-PTC groups using unpaired t test. Similarly, times to the return of T1, T2, T3 or T4 were compared between the N-TOF and C-TOF groups using unpaired t test. The comparison of recoveries of PTC was made between the N-PTC and C-PTC groups using repeated measures ANOVA and Mann-Whitney U-test with Bonferroni's adjustment. Recoveries of T1/control or TOF ratio were compared between the N-TOF and C-TOF groups using repeated measures ANOVA and unpaired t test with Bonferroni's adjustment. A P value < 0.05 was considered to be statistically significant. Statistical analyses were performed using a statistical package (SYSTAT 8.0, SPSS Inc., Chicago, U.S.A.) running on a personal computer (NEC PC-9821 Na 15, NEC Inc., Tokyo, Japan).
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The time from vecuronium injection to the return of PTC1 in the N-PTC group did not differ from that in the C-PTC group. Also, times to return of T1, T2, T3, and T4 in the N-TOF group did not differ from those in the C-TOF group (Table II).
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), but reached to significant differences for T1/control and TOF ratio measured 80-120 min and 100-120 min after administration of vecuronium, respectively (Figures 2,3).
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During anesthesia, no patient demonstrated severe hypertension (systolic arterial pressure > 200 mmHg) or hypotension (systolic arterial pressure < 80 mmHg), severe tachycardia (heart rate > 120 bpm), or bradycardia (heart rate <50 bpm), or arrhythmia.
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KATP channel agonists increase the membrane K+ conductance and improve the contractile strength.6–8 However, a bolus dose of 0.1 mg•kg–1 nicorandil followed by an infusion at 1 µg•kg–1•min–1 given two minutes before the bolus injection of vecuronium did not alter the onset of neuromuscular block. Additionally, PTC did not differ in the N-PTC and C-PTC groups. Also, nicorandil did not decrease the times to the return of PTC1, T1, T2, T3, and T4. T1/control and TOF ratio in the N-TOF group became higher than those measured in the C-TOF group as long as 80-120 min and 100-120 min after the beginning of the administration of vecuronium, respectively. In other words, the onset of nicorandil-induced effect on neuromuscular block may be slow. However, Spuler et al.6 noted that cromakalim, a KATP channel agonist-induced effect on healthy human skeletal muscle had a rapid onset. In their study, membrane K+ conductance was enhanced only a few minutes after administration of cromakalim. Colquhoun et al.9 reported that after administration of d-tubocurarine, the ion channel of the frog muscle end-plates was blocked in a dose-dependent manner. So we presume that when the degree of neuromuscular block was intense, nicorandil could not open the blocked KATP channel, but as the level of neuromuscular block became weak, the KATP channel opened and nicorandil could enhance the K+ conductance. Thus, nicorandil-induced potentiation of the muscular contraction may not have a slow onset, but may become apparent as the degree of neuromuscular block subsides.
Spuler et al.6 reported that, in the absence of neuromuscular relaxant, KATP channel agonist enhanced muscular response rapidly in patients who had the following diseases: myotonic dystrophy, chondrodystrophic myotonia, hypokalemic periodic paralysis, recessive generalized myotonia, amyotrophic lateral sclerosis, and myositis, and, in patients without neurological diseases, whilst Oyanagi et al.10 reported that, in the absence of neuromuscular relaxant, nicorandil did not affect single twitch height in the rat phrenic nerve-diaphragm. Spuler et al.6 noted that after administration of a KATP channel agonist, the membrane K+ conductance was enhanced within a few minutes. In this study the control twitch height of T1 was recorded two minutes after the bolus administration of 0.1 mg•kg–1 nicorandil. In the N-PTC and N-TOF groups, after the bolus administration of nicorandil, control twitch height of T1 might increase rapidly. If control twitch height of T1 was enhanced in the N-TOF group, T1/control should have been underestimated.
As noted above, Oyanagi et al.10 investigated the effect of nicorandil on the neuromuscular block induced by vecuronium in the rat phrenic nerve-diaphragm. In their study, in the absence of vecuronium, nicorandil did not change single twitch height. But after vecuronium injection, nicorandil enhanced the depression of the single twitch height. This contradicted our results. However, in their study, TOF ratio increased when nicorandil was administered. This finding was similar to our findings. Although we are not able to explain why the nicorandil-induced effect on neuromuscular response in the previous study6 differed from our data, the nicorandil-induced effect on neuromuscular response might be variable in the several sorts of species.
The onset time of neuromuscular block is partly determined by cardiac index.11,12 Utoh et al.1 showed that, after a bolus injection of nicorandil 0.1 mg•kg–1, although mean arterial pressure decreased, heart rate and cardiac index did not differ. Tsutamoto et al.13 reported that a continuous infusion of 2.4 µg•kg–1•min–1 nicorandil did not alter heart rate, mean arterial pressure, or cardiac index.
The level of neuromuscular block is affected by temperature14 and blood fow15–17 in the muscle studied. As the muscle temperature decreases, the response evaluated at the muscle increases.14 To evaluate the degree of neuromuscular block properly, the surface temperature over the muscle studied should be maintained, as in this study, > 32°C.15 If muscle blood flow increases, the onset of neuromuscular block assessed at the muscle hastens15–17 but the change in muscle blood flow caused by nicorandil is likely small.
Although we did not ensure that supramaximal muscular response could be elicited at a current of 50 mA, it is recognized that in a majority of patients ulnar nerve stimulation at 30 mA can yield supramaximal muscular contraction of the adductor pollicis muscle.18 We ensured that mechanical responses to TOF were stabilized over about one minute, and twitch height of the T1 was regarded as the control twitch height. Lee et al.16 and McCoy et al.17 described that before the injection of a muscle relaxant, the control twitch height increased gradually for about 10 min. Also, Viby-Mogensen et al.15 recommended that a stable control response should be established for 10 min before a muscle relaxant is given. With regard to these findings, in our study, the control twitch height might have been less than that established after the long stabilization time of control twitch height.
We conclude that nicorandil does not reduce the onset time of neuromuscular block caused by vecuronium, but modestly accelerates recovery of neuromuscular block in anesthetized patients.
Accepted for publication September 22, 2000.
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2 Koyama K, Kaneko I, Mori K. The effects of nicorandil on perioperative hemodynamics in CABG patients. Anesth Analg 1998; 86: S77.
3 Murayama S, Yamakado T, Nakano T. Effects of nicorandil, an antianginal potassium channel opener, on left ventricular systolic and diastolic function in patients with chronic coronary artery disease. Am J Cardiol 1997; 79: 1685–9.[Medline]
4 Sakata Y, Kodama K, Komamura K, et al. Salutary effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction. Am Heart J 1997; 133: 616–21.[Medline]
5 Allard B, Lazdunski M. Pharmacological properties of ATP-sensitive K+ channels in mammalian skeletal muscle cells. Eur J Pharmacol 1993; 236: 419–26.[Medline]
6 Spuler A, Lehmann-Horn F, Grafe P. Cromakalim (BRL 34915) restores in vitro the membrane potential of depolarized human skeletal muscle fibres. Naunyn Schmiedebergs Arch Pharmacol 1989; 339: 327–31.[Medline]
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Hong SJ, Chang CC. Hyperpolarization of denervated skeletal muscle by lemakalim and its antagonism by glybenclamide and tolbutamide. J Pharmacol Exp Ther 1991; 259: 932–8.
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Colquhoun D, Dreyer F, Sheridan RE. The actions of tubocurarine at the frog neuromuscular junction. J Physiol 1979; 293: 247–84.
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14 Santanen OAP, Paloheimo MPJ. Effects of small peripheral temperature changes on the evoked baseline electromyographic response. Acta Anaesthesiol Scand 1999; 43: 338–42.[Medline]
15 Viby-Mogensen J, Engbæk J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 59–74.[Medline]
16 Lee GC, Iyengar S, Szenohradszky J, et al. Improving the design of muscle relaxant studies. Stabilization period and tetanic recruitment. Anesthesiology 1997; 86: 48–54.[Medline]
17 McCoy ÉP, Mirakhur RK, Connolly FM, Loan PB. The influence of the duration of control stimulation on the onset and recovery of neuromuscular block. Anesth Analg 1995; 80: 364–7.[Abstract]
18 Kopman AF, Lawson D. Milliamperage requirements for supramaximal stimulation of the ulnar nerve with surface electrodes. Anesthesiology 1984; 61: 83–5.[Medline]
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) groups. Values are mean ± SD. PTC = post-tetanic count. No difference was observed between the two groups.
