Monitoring of neuromuscular block after administration of vecuronium in patients with diabetes mellitus

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1 British Journal of Anaesthesia 90 (4): 480±6 (2003) DOI: /bja/aeg089 Monitoring of neuromuscular block after administration of vecuronium in patients with diabetes mellitus Y. Saitoh 1 *, K. Kaneda 2, H. Hattori 1, H. Nakajima 1 and M. Murakawa 1 1 Department of Anesthesiology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima-City, Fukushima , Japan. 2 Department of Anesthesiology, Toride Kyodo General Hospital, Ibaraki, Japan *Corresponding author. ys@m6.people.or.jp Background. We studied the supramaximal current for ulnar nerve stimulation during electromyographic monitoring of onset and recovery of neuromuscular block using a neuromuscular transmission module (M-NMT Module, Datex-Ohmeda) in patients with Type 2 diabetes undergoing anaesthesia with nitrous oxide, oxygen, iso urane and fentanyl. Methods. Thirty-six diabetic patients were randomly assigned to a post-tetanic count (PTC) group (n=17) or train-of-four (TOF) group (n=19). In addition, 30 non-diabetic patients were divided into control PTC (n=15) and TOF groups (n=15). Results. In the diabetic patients (diabetes PTC and diabetes TOF groups), the mean supramaximal stimulating current was signi cantly higher than in the non-diabetic patients (control PTC and TOF groups) (50.5 (SD 14.1) vs 33.4 (6.1) ma, P<0.01). Onset of neuromuscular block (time to disappearance of T1) after vecuronium 0.1 mg kg ±1 in the diabetic patients did not differ signi cantly from that in the non-diabetic patients (276 (77) vs 244 (44) s, P=0.055). Time to return of PTC1 did not differ signi cantly between the diabetes and control PTC groups (21.0 (12.1) vs 15.7 (5.0) min, P=0.126). Times to return of T1 and T4 in the diabetes TOF group were signi cantly longer than in the control TOF group (T1: 37.5 (15.2) vs 25.7 (7.6) min, P=0.01; T4: 61.4 (23.7) vs 43.5 (11.4) min, P=0.01). During recovery, PTC and T4/T1 in the diabetes PTC and TOF groups were similar to those in the control PTC and TOF groups, respectively. T1/T0 in the diabetes TOF group was signi cantly less than in the control TOF group, 80±120 min after vecuronium (P<0.05). Conclusions. In diabetic patients, supramaximal current is higher than in non-diabetic patients. After vecuronium, onset of neuromuscular block and recovery of PTC or T4/T1 are not altered, but time to return of T1 or T4, and recovery of T1/T0 are delayed in diabetic patients. Br J Anaesth 2003; 90: 480±6 Keywords: neuromuscular block, vecuronium; complications, diabetes Accepted for publication: December 16, 2002 In patients with diabetes mellitus, the function of motor nerve bres and nerve endings may be impaired. 12 Partial degeneration 13 or segmental demyelination of the nerve bre, 4 and loss of motor units 56 have been reported in diabetic patients, as a result of which motor nerve conduction velocity decreases. 1±5 Muscle damage has also been described in diabetic patients. For example, muscular infarction 7±9 and muscular atrophy 7 have been demonstrated in skeletal muscles. Wilbourn 10 has reported that in most diabetic patients the quadriceps muscles have been denervated to such an extent that femoral motor responses are unelicitable or of low amplitude. This is similar to the effect noted in patients with motor neurone disease, in whom the response to non-depolarizing neuromuscular blocking drugs is exaggerated. For example, it has been noted that tubocurarine 1.5 mg given over 30 min to a man with amyotrophic lateral sclerosis caused dif culty with speech and swallowing. 11 It is likely that the stimulating current at which the maximal muscle response can be produced and the onset of and recovery from neuromuscular block will differ in such patients compared with nondiabetic patients. However, no studies have yet evaluated Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003

2 Diabetes and neuromuscular block the supramaximal stimulating current or the onset and recovery of neuromuscular block speci cally in diabetic patients. This study was undertaken to investigate these variables when vecuronium was used in anaesthetized patients with Type 2 diabetes mellitus. Methods The protocol of this study was approved by our institutional ethics committee. Written informed consent was obtained from each patient. Thirty adult patients, ASA physical status II, who had had Type 2 diabetes mellitus for more than 5 yr, and 30 adult patients, ASA I or II, who were not diabetic were studied. The diagnosis of diabetes had been established in the Department of Internal Medicine of our institution. The criteria used to classify the patients as Type 2 diabetics was fasting plasma glucose repeatedly >17.8 mmol litre ±1, or a 2-h plasma glucose >11.1 mmol litre ±1 after a 75-g glucose load. An additional criterion to classify the Type 2 diabetics was that no patient had a history of diabetic ketoacidosis or a hyperglycaemic hyperosmolar state. These criteria were in accordance with those reported previously. 12 The patients studied were scheduled for elective orthopaedic surgery (total knee replacement), ear nose and throat surgery (tympanoplasty), or ophthalmological surgery (segmental buckling or vitrectomy) under general anaesthesia. The 30 patients with diabetes were randomly assigned to a post-tetanic count (diabetes PTC) group (n=15) or train-of-four (diabetes TOF) group (n=15). The 30 patients without diabetes were randomly divided into control PTC and TOF groups (15 patients in each group). All patients in the diabetes PTC and TOF groups had been treated for diabetes for 5±12 yr. They were free from diabetic neuropathy and nephropathy. They were receiving oral glibenclamide 2.5±7.5 mg daily. Oral administration of glibenclamide was stopped 3±5 days before the surgical procedure, and continuous i.v. infusion of neutral insulin 6±21 units a day started, which maintained the blood sugar level between 4.4 and 12.2 mmol litre ±1.No patient in the control PTC or TOF groups had neuromuscular, hepatic, renal or cardiac disorders, or was receiving any drugs known to interfere with the action of neuromuscular blocking drugs. Premedication consisting of atropine 0.01 mg kg ±1 ; hydroxyzine 1.0 mg kg ±1 i.m. was given 30 min before induction of anaesthesia. The number of patients in the study was determined by power analysis. If a, 1±b and d were 0.10, 0.80 and 0.8, respectively, the number of patients in each group needed to be at least 14. Monitoring of neuromuscular block After arriving in the operating theatre, two stimulating electrodes were positioned over the ulnar nerve at the wrist and two recording electrodes were attached over the adductor pollicis muscle. The forearm to be investigated and the four ngers were immobilized with vinyl belts on the arm board of the operating bed, but the thumb was allowed to move freely. The forearm and hand were covered with towels. Anaesthesia was induced with propofol 2 mg kg ±1 and fentanyl 2 mg kg ±1. After loss of the eyelid re ex, TOF stimuli were applied to the ulnar nerve using the electrical nerve stimulator of a neuromuscular transmission module (M-NMT Module, Datex-Ohmeda Inc., Helsinki, Finland). Four twitch stimuli consisting of 0.2-ms square waves were applied at 2 Hz. The corresponding electromyographic amplitudes were measured using the neuromuscular transmission module, and were displayed on an anaesthetic monitoring system (Anaesthetic Monitoring System A/S3, Datex-Ohmeda Inc., Helsinki, Finland). The height of the electromyographic responses was recorded from the anaesthetic monitoring system. In each patient, the monitoring system automatically searched for the stimulus current needed to achieve the maximal response of the adductor pollicis muscle. The search began with 10-mA single twitch stimuli of 0.2 ms duration applied every 1 s and the electromyographic response was measured. The stimulating current was increased in steps of 5 ma until the increase in current did not increase the electromyographic response. The stimulating current was then automatically increased by 15% to produce a supramaximal current. If the supramaximal current was not found or the response was too weak to determine the current, the current was set at 70 ma. In the patients in whom the supramaximal current was not found or the electromyographic response was too weak at currents of 10±70 ma, the supramaximal current was considered to be 70 ma for further analysis. Such patients were excluded from the next part of the study (i.e. the comparisons of the onset of neuromuscular block and of recovery of the PTC or TOF responses). In such circumstances, an additional patient was studied in order to maintain the numbers of patients in each group. Once the supramaximal current had been established, the electromyographic amplitude of T1 was considered to be the control response, T0. The value of T0 was determined again 10 min after starting TOF stimuli, which were applied every 15 s. 13±15 During the stabilization of neuromuscular monitoring, the patient's lungs were ventilated using a facemask with oxygen 6 litre min ±1 and iso urane 1% inspired concentration. After recording T0, vecuronium 0.1 mg kg ±1 i.v. was administered to facilitate tracheal intubation. Following vecuronium 0.1 mg kg ±1, the PTC was measured every 5 min in the diabetes and control PTC groups. A 50 Hz tetanic stimulation was delivered at the supramaximal current for 5 s, and after a pause of 3 s 20 single twitch stimuli of 0.2-ms duration square waves were given every 1 s at the supramaximal current. The number of detectable electromyographic responses to single twitch stimuli was regarded as the PTC. The times from vecuronium administration to the return of PTC1 (only one response to the 20 single twitch stimuli could be 481

3 Saitoh et al. Table 1 Characteristics of the two and four patients excluded from the diabetes PTC and diabetes TOF groups, respectively because a supramaximal current was not determined between currents of 10 and 70 ma Group Diabetes PTC Diabetes TOF Mean (SD or range) Sex (M/F) M F M M F F 3/3 Age (yr) (39±70) Height (cm) (7.7) Weight (kg) (11.6) Duration of diabetes (yr) (1.5) Total dose of glibenclamide (mg day ±1 ) (1.3) Total dose of insulin (u day ±1 ) (2.9) Table 2 Patient characteristics. Values are number or mean (SD) [range]. Sex, age, height and weight were similar among the four groups. Duration of diabetes and total dose of glibenclamide or insulin were not signi cantly different between the diabetes post-tetanic count (PTC) and train-of-four (TOF) groups Group Diabetes PTC Control PTC Diabetes TOF Control TOF (n=15) (n=15) (n=15) (n=15) Sex (M/F) 8/7 8/7 8/7 8/7 Age (yr) 57.9 [40±77] 60.1 [43±79] 61.2 [48±74] 62.2 [48±74] Height (cm) (8.4) [144±171] (10.4) [140±177] (9.6) [140±177] (9.2) [143±176] Weight (kg) 60.7 (8.8) [44±74] 60.3 (11.9) [42±80] 59.6 (10.3) [43±80] 60.3 (12.1) [40±83] Duration of diabetes (yr) 8.5 (1.8) [5±12] 8.4 (2.2) [5±11] Total dose of glibenclamide (mg day ±1 ) 5.2 (1.1) [2.5±7.5] 5.2 (1.5) [2.5±7.5] Total dose of insulin (u day ±1 ) 9.1 (3.0) [6±16] 10.9 (4.2) [6±18] elicited) were compared between the diabetes and control PTC groups. In addition, the PTC measured every 5 min was compared between the two groups. The times from vecuronium to the return of T1, T2, T3 and T4 (the rst, second, third and fourth responses of the TOF, respectively) were compared between the diabetes and control TOF groups. After the dose of vecuronium, T1/T0 and T4/T1 were recorded every 10 min, and compared between the two TOF groups. A thermometer probe to measure surface skin temperature (Terumo-Finer, Terumo Inc., Tokyo, Japan) was positioned over the adductor pollicis muscle in each patient. Anaesthetic management In each group, anaesthesia was maintained with nitrous oxide 66% in oxygen and iso urane 0.5% end-tidal concentration. A bolus dose of fentanyl 2 mg kg ±1 i.v. was administered before the skin incision. When the level of anaesthesia was thought to be insuf cient, a further bolus dose of fentanyl 2 mg kg ±1 was administered. Ventilation was controlled to maintain normocapnia (FE CO2 4.1±5.0 kpa). The end-tidal concentrations of anaesthetic and FE CO2 were measured continuously using a multiple gas monitor (Capnomac Ultima, S-31-03, Datex Inc., Helsinki, Finland). Statistical analysis Patient characteristics were compared among the four groups using the Kruskal±Wallis test and Mann±Whitney U-test with Bonferroni's adjustment. The stimulating currents were compared between the diabetic (diabetes PTC and diabetes TOF) and non-diabetic (control PTC and control TOF) groups using the Mann±Whitney U-test. The times to return of PTC1 were compared between the diabetes and control PTC groups using the Mann±Whitney U-test. Similarly, times to the return of T1, T2, T3 and T4 were compared between the diabetes and control TOF groups using the Mann±Whitney U-test. The time course of recovery of the PTC was compared between the diabetes and control PTC groups, and of T1/T0 and T4/T1 between the diabetes and control TOF groups using the Kruskal±Wallis test followed by the Mann±Whitney U-test with Bonferroni's adjustment. P<0.05 was considered statistically signi cant. Statistical analyses were performed using a statistical package (SYSTAT 8.0, SPSS Inc., Chicago, USA) running on a personal computer. Results A supramaximal current was not determined between 10±70 ma in two and four patients in the diabetes PTC and diabetes TOF groups, respectively. These patients were included in the analysis when the supramaximal currents were compared between the diabetic and the non-diabetic groups, but they were excluded when the onset of neuromuscular block and the recovery of the PTC and TOF responses were compared. Two and four extra patients in whom the supramaximal current could be determined 482

4 Diabetes and neuromuscular block between 10 and 70 ma were studied in the diabetes PTC and TOF groups, respectively. Data from the excluded patients are given in Table 1. When the onset and recovery of neuromuscular block were compared, the number of patients studied was 15 in both the diabetes PTC and diabetes TOF groups. In all patients in the non-diabetic groups the supramaximal currents were less than 46 ma. In three and two patients in the diabetes PTC group and diabetes TOF group respectively, systolic pressure measured every 2 min decreased to <80 mm Hg after administration of propofol and fentanyl, although it returned to normal after the trachea was intubated. No other patients had severe hypertension (systolic pressure >200 mm Hg) or hypotension (systolic arterial pressure <80 mm Hg), severe tachycardia (heart rate >120 beats min ±1 ) or severe bradycardia (heart rate <50 beats min ±1 ). Patient characteristics were comparable in the four groups (Table 2). Similarly, duration of diabetes and total doses of glibenclamide and insulin were not signi cantly different between the diabetes PTC and TOF groups. In the diabetic groups, the mean stimulating current at which the maximal response to T1 could be elicited was Table 3 Times from vecuronium 0.1 mg kg ±1 to the return of post-tetanic count (PTC)1 in the diabetes and control PTC groups, and to the return of T1, T2, T3 and T4 in the diabetes and control train of four (TOF) groups. Data are mean (SD) times in min (n=15 for all groups) Group Diabetes PTC or TOF Control PTC or TOF PTC (12.1) 15.7 (5.0) NS T (15.2) 25.7 (7.6) T (18.4) 35.1 (9.1) T (22.7) 40.7 (10.8) T (23.7) 43.5 (11.4) P signi cantly higher than in the non-diabetic groups (48.7 (SD 14.5) vs 33.4 (6.1) ma (P<0.01)). Onset of neuromuscular block in the diabetic groups did not signi cantly differ from that in the non-diabetic groups (276 (77) vs 244 (44) s). Time from vecuronium administration to the return of PTC1 did not differ signi cantly between the diabetes and control PTC groups. However, times to the return of T1, T2, T3 and T4 were signi cantly longer in the diabetes TOF group than in the control TOF group (P<0.05) (Table 3). Recovery of the PTC in the diabetes PTC and control PTC groups followed similar time courses (Fig. 1). T1/T0 was signi cantly lower in the diabetes TOF group than in the control TOF group, 80±120 min after administration of vecuronium (P<0.05) (Fig. 2). In contrast, T4/T1 in the diabetes TOF group did not differ signi cantly from that in the control TOF group (Fig. 3). In no patient did the peripheral skin temperature over the adductor pollicis decrease to less than 32 C. Discussion This study shows that the supramaximal stimulating current is higher in diabetic than in non-diabetic patients. The onset of neuromuscular block caused by vecuronium 0.1 mg kg ±1 did not differ signi cantly between diabetic and nondiabetic patients. Also, time to return of the PTC1 and recovery of PTC or T4/T1 did not signi cantly differ between diabetic and control patients. However, in diabetic patients, times to the return of T1, T2, T3 and T4 were signi cantly longer and recovery of T1/T0 was signi cantly slower than in non-diabetic patients. In patients with diabetes, nerve endings at the neuromuscular junction are diseased, 12 and are thought to degenerate. 1 Moreover, a pathological study revealed demyelination Fig 1 Mean (SD) recoveries of post-tetanic count (PTC) after administration of vecuronium 0.1 mg kg ±1 in the diabetes and control PTC groups. No signi cant difference was observed between the two groups. 483

5 Saitoh et al. and axon loss in the nerve endings in diabetic patients. 2 The motor nerve conduction velocity decreases in diabetic patients. 1±5 Lamontagne and Buchthal 5 reported loss of motor units and denervation in the skeletal muscles of the upper and lower extremities and the quadriceps femoris muscle in diabetic patients. They also noted that, when assessed electromyographically, the mean duration of the action potential and amplitude of the evoked response measured in the skeletal muscles were at least 20% and 50% lower, respectively, in diabetic patients. Furthermore, it has been reported that in most diabetic patients, the quadriceps femoris may have been denervated to such an extent that femoral motor responses recorded from it are unelicitable or of low amplitude. 10 We assumed that, because the adductor pollicis muscle is also denervated in diabetic patients, the supramaximal stimulating current would be higher than in non-diabetic patients. In this study, when the diabetic and non-diabetic groups were compared the supramaximal current was regarded as 70 ma in the patients in whom it was not detected at currents of 10±70 ma. The true supramaximal current would have been higher than 70 ma in these patients. Thus Fig 2 Mean (SD) recoveries of T1/T0 after administration of vecuronium 0.1 mg kg ±1 in the diabetes and control train-of-four (TOF) groups. *P<0.05 between the two groups. Fig 3 Mean (SD) recoveries of T4/T1 after administration of vecuronium 0.1 mg kg ±1 in the diabetes and control train-of-four (TOF) groups. 484

6 Diabetes and neuromuscular block although the mean supramaximal current was considered to be 50.5 ma in the diabetic patients, in reality it would have been higher than this. Other monitoring techniques or use of stimulators with a higher current output may be useful in determining supramaximal current in diabetic patients. If the motor neurone is impaired in diabetic patients, the onset of vecuronium-induced neuromuscular block may also be faster. However, in this study, the onset of neuromuscular block caused by vecuronium in the diabetic patients was comparable to that in the non-diabetic patients. A decrease in cardiac output, left ventricular dysfunction and impaired stroke volumes have been reported in diabetic patients. 12 In the current study, ve patients in the diabetic groups had hypotension (systolic arterial pressure <80 mm Hg) during induction of anaesthesia, suggesting signi cant cardiovascular disease. Burgos and colleagues 13 reported that diabetic patients often suffered from hypertension, but might have hypotension for some minutes following tracheal intubation. As the cardiac output decreases, the onset of neuromuscular block is delayed. Even if diabetic patients are more sensitive to neuromuscular blocking drugs, onset of block may not be faster because the sensitivity is offset by a decrease in cardiac output. Not only impairment of the motor nerve bre, but also muscle damage has been shown in diabetic patients. Muscular infarction has been demonstrated in skeletal muscles. 7±9 Additionally, aseptic myonecrosis, ischaemic myonecrosis, tumoriform focal muscular degeneration and muscular atrophy have been observed in diabetic patients. 7±9 These pathophysiological changes could be caused by arteriosclerosis, true sclerotic obliterans and autoimmune phenomena. 9 Time from administration of the neuromuscular blocking drug to return of the PTC or T4/T1 is thought to represent the degree of pre-junctional neuromuscular block. 16±19 In contrast, time from administration of the neuromuscular blocking drug to return of T1, T2, T3, T4, the single twitch response and T1/T0 demonstrate the level of block at the post-junctional region of the neuromuscular junction. This study demonstrated that time from vecuronium to the return of PTC1 and recovery of T4/T1 were comparable between diabetic and non-diabetic patients but time to return of T1, T2, T3 and T4 and recovery of T1/T0 were signi cantly slower in the diabetic patients than in nondiabetic patients. These ndings suggest that damage to the post-junctional region is greater than that at the prejunctional region in diabetic patients. In this study the degree of neuromuscular block was monitored electromyographically. It has been reported that when the level of neuromuscular block is profound, the height of T1/T0 measured electromyographically tends to be slightly greater than that assessed mechanically using a force transducer, and the electromyograph is more sensitive than the mechanical twitch response in detecting a TOF response during profound neuromuscular block. 20 When the degree of block is slight, the neuromuscular response evaluated electromyographically may also be different from that assessed mechanically. Kopman 20 reported that even if recovery from neuromuscular block was signi cant, T1/T0 recorded electromyographically tended to return to only 0.8. In this study, the average T1/T0 returned to only about 0.75, even in non-diabetic patients. We studied only Type 2 diabetic patients. Type 1 diabetic patients usually have markedly elevated fasting glucose levels and raised serum levels of ketone bodies compared with Type 2 diabetic patients. 21 However, Lamontagne and Buchthal 5 showed that neither the duration nor severity of diabetic neuropathy was related to the duration of diabetes. So the difference in the neuromuscular response after vecuronium may be independent of the type or duration of diabetes. In the present study, diabetic patients without diabetic neuropathy were examined. Lawrence and Locke 2 reported that even in diabetic patients without neuropathy, the ulnar, median and peroneal nerve conduction velocities were decreased signi cantly. They also showed that the nerve conduction velocities in diabetic patients with neuropathy were even less than in diabetic patients without neuropathy. If diabetic patients with neuropathy were studied, recovery from neuromuscular block might be further prolonged. Additionally, we did not study diabetic patients with nephropathy. In these diabetic patients, a decreased plasma clearance and prolonged elimination half-life of vecuronium might be expected. Lynam and colleagues 22 noted that the duration of action of vecuronium was increased in patients with chronic renal failure, which might be related to decreased plasma clearance and prolonged elimination halflife of the drug in the disease state. In conclusion, when neuromuscular block is monitored in diabetic patients, the supramaximal stimulating current is higher than in non-diabetic patients. The onset of neuromuscular block and time course of recovery of PTC or T4/ T1 are similar between diabetic and non-diabetic patients receiving vecuronium. However, time from the administration of vecuronium to the return of T1, T2, T3 and T4 is signi cantly longer, and recovery of T1/T0 is signi cantly slower in diabetic than in non-diabetic patients. These ndings may be the result of the more marked impairment of the post-junctional region than the pre-junctional nerve endings in the neuromuscular junctions of diabetic patients. References 1 Woolf AL, Malins JM. Changes in the intramuscular nerve endings in diabetic neuropathy. J Path Bact 1957; 73: 316±8 2 Lawrence DG, Locke S. Motor nerve conduction velocity in diabetes. Arch Neurol 1961; 5: 483±9 3 Skillman TG, Johnson EW, Hamwi GJ, et al. Motor nerve conduction velocity in diabetes mellitus. Diabetes 1961; 10: 46±51 4 Abu-Shakra SR, Cornblath DR, Avila OL, et al. Conduction block in diabetic neuropathy. Muscle Nerve 1991; 14: 858±62 485

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