1 Department of Anesthesiology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima-City, Fukushima 960-1295, Japan. 2 Department of Anesthesiology, Toride Kyodo General Hospital, Ibaraki, Japan
Corresponding author. E-mail: ys@m6.people.or.jp
Accepted for publication: December 16, 2002
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Abstract |
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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 significantly 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 kg1 in the diabetic patients did not differ significantly from that in the non-diabetic patients (276 (77) vs 244 (44) s, P=0.055). Time to return of PTC1 did not differ significantly 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 significantly 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 significantly less than in the control TOF group, 80120 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: 4806
Keywords: neuromuscular block, vecuronium; complications, diabetes
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Introduction |
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Methods |
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The number of patients in the study was determined by power analysis. If , 1ß 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 fingers 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 kg1 and fentanyl 2 µg kg1. After loss of the eyelid reflex, 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 1070 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.1315 During the stabilization of neuromuscular monitoring, the patients lungs were ventilated using a facemask with oxygen 6 litre min1 and isoflurane 1% inspired concentration. After recording T0, vecuronium 0.1 mg kg1 i.v. was administered to facilitate tracheal intubation.
Following vecuronium 0.1 mg kg1, 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 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 first, 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 isoflurane 0.5% end-tidal concentration. A bolus dose of fentanyl 2 µg kg1 i.v. was administered before the skin incision. When the level of anaesthesia was thought to be insufficient, a further bolus dose of fentanyl 2 µg kg1 was administered. Ventilation was controlled to maintain normocapnia (FE'CO2 4.15.0 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 KruskalWallis test and MannWhitney U-test with Bonferronis 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 MannWhitney U-test. The times to return of PTC1 were compared between the diabetes and control PTC groups using the MannWhitney U-test. Similarly, times to the return of T1, T2, T3 and T4 were compared between the diabetes and control TOF groups using the MannWhitney 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 KruskalWallis test followed by the MannWhitney U-test with Bonferronis adjustment. P<0.05 was considered statistically significant. Statistical analyses were performed using a statistical package (SYSTAT 8.0, SPSS Inc., Chicago, USA) running on a personal computer.
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Results |
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Patient characteristics were comparable in the four groups (Table 2). Similarly, duration of diabetes and total doses of glibenclamide and insulin were not significantly different between the diabetes PTC and TOF groups.
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Time from vecuronium administration to the return of PTC1 did not differ significantly between the diabetes and control PTC groups. However, times to the return of T1, T2, T3 and T4 were significantly longer in the diabetes TOF group than in the control TOF group (P<0.05) (Table 3).
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Discussion |
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In patients with diabetes, nerve endings at the neuromuscular junction are diseased,1 2 and are thought to degenerate.1 Moreover, a pathological study revealed demyelination and axon loss in the nerve endings in diabetic patients.2 The motor nerve conduction velocity decreases in diabetic patients.15 Lamontagne and Buchthal5 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 1070 mA. The true supramaximal current would have been higher than 70 mA in these patients. Thus 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, five patients in the diabetic groups had hypotension (systolic arterial pressure <80 mm Hg) during induction of anaesthesia, suggesting significant cardiovascular disease. Burgos and colleagues13 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.14 15 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 fibre, but also muscle damage has been shown in diabetic patients. Muscular infarction has been demonstrated in skeletal muscles.79 Additionally, aseptic myonecrosis, ischaemic myonecrosis, tumoriform focal muscular degeneration and muscular atrophy have been observed in diabetic patients.79 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.1619 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.14 16 17 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 significantly slower in the diabetic patients than in non-diabetic patients. These findings suggest that damage to the post-junctional region is greater than that at the pre-junctional 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. Kopman20 reported that even if recovery from neuromuscular block was significant, 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 Buchthal5 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 Locke2 reported that even in diabetic patients without neuropathy, the ulnar, median and peroneal nerve conduction velocities were decreased significantly. 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 colleagues22 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 half-life 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 significantly longer, and recovery of T1/T0 is significantly slower in diabetic than in non-diabetic patients. These findings 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.
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