British Journal of Anaesthesia, 2001, Vol. 86, No. 6 814-821
© 2001 The Board of Management and Trustees of the British Journal of Anaesthesia
Infusion of amino acid enriched solution hastens recovery from neuromuscular block caused by vecuronium
1Department of Anesthesiology, Fukushima Medical University School of Medicine, Fukushima, Japan and 2Department of Anesthesiology, Toride Kyodo General Hospital, Ibaraki, Japan*Corresponding author: Department of Anesthesiology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima City, Fukushima, 960–1295, Japan
Accepted for publication: January 31, 2001
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Abstract |
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We investigated the effect of an amino acid infusion on neuromuscular block produced by vecuronium, and on rectal temperature and surface temperature over the adductor pollicis muscle. Sixty adult patients undergoing general anaesthesia were randomly divided into four groups of 15 patients each: amino acid (AA)-post-tetanic count (PTC); AA-train-of-four (TOF); control (C)-PTC; or C-TOF group. In the AA-PTC and AA-TOF groups, after a bolus of vecuronium 0.1 mg kg–1, a continuous infusion of an 18 amino acid enriched solution (AMIPAREN®) was started at a rate of 166 kJ h–1. In the C-PTC and C-TOF groups, normal saline was administered. Time from vecuronium to the return of the PTC in the AA-PTC group was significantly shorter than in the C-PTC group (mean (SD), 13.3 (4.5) versus 18.0 (5.6) min, P<0.05). Times to return of T1, T2, T3, and T4 (first, second, third, and fourth twitch of TOF) in the AA-TOF group were significantly shorter than in the C-TOF group (21.1 (4.5) versus 28.0 (8.2) min for T1, P<0.05). PTC in the AA-PTC group was significantly greater than in the C-PTC group; 25–35 min after administration of vecuronium (P<0.05). T1/T0 and T4/T1 in the AA-TOF group were significantly higher than in the C-TOF group, 40–120 and 50–120 min after vecuronium respectively (P<0.05). Rectal temperature and surface temperature over the adductor pollicis muscle in the AA-PTC and AA-TOF groups were significantly higher than in the control groups 50–120 and 100–120 min after vecuronium respectively (P<0.05). Infusion of amino acid enriched solution hastens recovery from neuromuscular block.
Br J Anaesth 2001; 86: 814–21
Keywords: monitoring, neuromuscular function; neuromuscular block; temperature, body; neuromuscular block, vecuronium; pharmacology, vecuronium
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Introduction |
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Amino acid enriched solution supplies energy to skeletal muscle.1–5 Branched-chain amino acids (leucine, isoleucine, and valine), in particular, are easily available energy substrates.1–5 Nissen and colleagues1 reported that the leucine metabolite, ß-hydroxy-ß-methylbutyrate caused a significant increase in muscle strength. They suggested that this leucine metabolite prevented or slowed the process of muscle damage and partially preventing the increase in proteolysis associated with intense muscular work. Mourier and colleagues2 showed that the combination of moderate energy restriction and branched-chain amino acid supplementation induced significant and preferential losses of visceral adipose tissue and allowed maintenance of a high level of performance. It has also been reported that the decrease in body temperature that occurs during general anaesthesia can be attenuated by a continuous infusion of amino acid enriched solution.3 6–8 This thermal effect is thought to be a result of the supply of energy to skeletal muscle.3 6–8
If the temperature over the adductor pollicis is decreased, recovery from neuromuscular block in this muscle is delayed.9 10 An infusion of amino acid-enriched solution may speed recovery from neuromuscular block because amino acids prevent hypothermia. However, no previous studies have investigated the effect of amino acids on neuromuscular block and temperature over the adductor pollicis muscle during general anaesthesia. In this study, we examined the recovery of post-tetanic count (PTC) and the train-of-four (TOF) response, and changes in rectal temperature or surface temperature and the adductor pollicis muscle, during a continuous infusion of amino acid enriched solution in anaesthetized patients receiving vecuronium compared with controls.
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Methods |
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Our local ethics committee approved the procedure of this study and written informed consent was obtained from each patient. Sixty adult patients, ASA I–II, undergoing elective ear nose and throat surgery (tympanoplasty) or ophthalmological surgery (segmental buckling or vitrectomy) lasting 2–4 h under general anaesthesia were enrolled in the study. The patients were randomly divided into four groups of 15 patients each: amino acid (AA)-PTC; AA-TOF; control (C)-PTC; or C-TOF group. No patient had neuromuscular, hepatic, renal, or cardiac disorders or was receiving any drugs known to affect neuromuscular transmission. Up to 21:00 h on the evening before surgery, all patients were allowed to eat and drink freely. Thereafter, they were fasted. Anaesthesia started about 09:00.
Pre-medication consisting of atropine 0.01 mg kg–1 and hydroxyzine 1.0 mg kg–1 was given i.m. 30 min before induction of anaesthesia. On arriving at the operating theatre, two surface stimulating electrodes were positioned over the ulnar nerve at the wrist. A force displacement transducer was attached to the thumb of one arm.
Infusion of amino acids and monitoring of neuromuscular block
In each group, acetate Ringer’s solution was infused i.v. at a rate of 500 ml h–1 via an 18-gauge catheter inserted into the cubital vein. In each group, anaesthesia was induced with propofol 2 mg kg–1. After loss of the eyelash reflex, TOF stimuli were applied every 12 s using a nerve stimulator (Myotest DBS, DBS-000E, Biometer International, Odense, Denmark). Four square-wave twitch stimuli of 0.2 ms duration were applied at 2 Hz. The mechanical response of the adductor pollicis muscle was measured using a neuromuscular transmission analyser (Myograph 2000, Biometer International, Odense, Denmark). In each patient, TOF stimuli were delivered at 20, 30, 40, 50, and 60 mA. If a supramaximal response of the thumb was produced at 20, 30, 40, or 50 mA, the stimulating current for the patient was fixed at 50 mA. If the supramaximal response of the thumb could not be produced at 50 mA, the stimulating current for the patient was fixed at 60 mA. The height of the first response of the TOF was regarded as control twitch height (T0). The control value was determined 2–3 min after starting TOF stimuli. During this stabilization period, the patients’ lungs were ventilated using a facemask with oxygen 6 litre min–1 and isoflurane 1% inspired concentration.
A continuous i.v. infusion of a mixture of 18 amino acids (AMIPAREN®, Otsuka Pharmaceutical Inc., Tokyo, Japan) (Table 1) was then started in the AA-PTC and AA-TOF groups at a rate of 100 ml h–1, corresponding with 166 kJ h–1 of energy, using a syringe pump (Terufusor, TE-312, Terumo Inc., Tokyo, Japan). The infusion rate was determined according to the AMIPAREN® data sheet. There after, vecuronium 0.1 mg kg–1 was administered i.v. to facilitate tracheal intubation. In the C-PTC and C-TOF groups, the degree of neuromuscular block was monitored in the same manner as in the AA-PTC and AA-TOF groups and vecuronium 0.1 mg kg–1 was injected to facilitate tracheal intubation. Normal saline was infused continuously at a rate of 100 ml h–1 instead of the infusion of the amino acid enriched solution. All i.v. fluids were at room temperature. A warming mattress (Medi-Therm, MTA-4700, Gaymar Industries Inc., New York, NY, USA) had been laid on the operating bed, and the temperature of the warm water in the warming mattress was kept at 37°C. The monitored arm was covered with towels. The room temperature was 27–28°C.
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After administration of vecuronium in the AA-PTC and C-PTC groups, PTC was measured every 5 min. A 50 Hz tetanic stimulus was delivered at 50 or 60 mA 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 50 or 60 mA. The number of detectable muscular contractions in response to the single twitch stimuli was regarded as the PTC. The times from the vecuronium injection to the return of a PTC of 1 (only one response to the 20 single twitch stimuli could be elicited) were compared between the AA-PTC and C-PTC groups. In addition, in the two groups, time courses of recovery of PTC were compared.
In the AA-TOF and C-TOF groups, TOF stimuli were applied every 12 s at 50 or 60 mA. The times from vecuronium to the return of T1, T2, T3, and T4 (the first, second, third, and fourth response in TOF) were compared between the two groups. T1/T0 and T4/T1 were recorded every 10 min, and were also compared between the AA-TOF and C-TOF groups.
Measurement of rectal temperature and surface temperature over adductor pollicis muscle
About 5 min before induction of anaesthesia, a thermometer probe was inserted 10–15 cm into the rectum and the rectal temperature was monitored on an anaesthesia monitoring system (Anesthesia System/3, AS/3, Datex-Ohmeda Division Instrumentarium Corp. Inc., Helsinki, Finland). A surface skin thermometer probe (Terumo-Finer, CTM-303, Terumo Inc., Tokyo, Japan) was positioned over the adductor pollicis muscle in each patient.
Control rectal temperature and temperature over the adductor pollicis muscle were recorded. From the beginning of the infusion of the amino acid enriched solution, the two temperatures were noted every 10 min. The rectal temperatures recorded in the AA-PTC and AA-TOF groups were compared with that evaluated in the C-PTC and C-TOF groups. Similarly, the temperature over the adductor pollicis muscle in the AA-PTC and AA-TOF groups was compared with that in the C-PTC and C-TOF groups every 10 min.
Anaesthetic management
In each group, anaesthesia was maintained with nitrous oxide 66% in oxygen and 0.5% end-tidal isoflurane. A bolus dose of fentanyl 2 µg kg–1 was administered i.v. If the depth of anaesthesia was thought to be insufficient, a further bolus dose of fentanyl 2 µg kg–1 was given. Ventilation was controlled to maintain normocapnia (PE'CO2 4.1–5.0 kPa). The anaesthetic concentrations and PE'CO2 were measured continuously using a multiple gas monitor (Capnomac Ultima, S-31–03, Datex Inc., Helsinki, Finland).
Statistical analyses
All results are expressed as number or mean (SD). Patient characteristics were compared among the four groups using analysis of variance (ANOVA) and Scheffe’s multiple comparison. The times to return of PTC1 between the AA-PTC and C-PTC groups were compared using the unpaired t-test. Similarly, times to return of T1, T2, T3, or T4 were compared between the AA-TOF and C-TOF groups using the unpaired t-test. Comparison of time courses of recovery of PTC between the AA-PTC and C-PTC groups was made using Kruskal–Wallis test followed by Mann–Whitney U-test with Bonferroni’s adjustment. The time courses of recovery of T1/T0 and T4/T1 were compared between the AA-TOF and C-TOF groups using ANOVA followed by unpaired t-test with Bonferroni’s adjustment. The comparison of the changes in rectal temperature between the AA-PTC and AA-TOF groups, and the C-PTC and C-TOF groups, and the comparison of the changes in the temperature over the adductor pollicis muscle between the AA-PTC and AA-TOF groups and the C-PTC and C-TOF groups were made using ANOVA followed by the unpaired t-test with Bonferroni’s adjustment. A P value <0.05 was considered statistically significant. Statistical analyses were performed using a statistical package (SYSTAT 8.0, SPSS Inc., Chicago, IL, USA) running on a personal computer.
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Results |
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Patient characteristics were comparable among the four groups (Table 2). In all patients, a supramaximal response of the adductor pollicis muscle could be elicited at 30, 40, or 50 mA. The nerve stimuli were therefore applied at 50 mA in all patients.
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Time from vecuronium injection to the return of PTC1 in the AA-PTC group was significantly shorter than in the C-PTC groups (P<0.05). Also, times to the return of T1, T2, T3, and T4 in the AA-TOF group were significantly shorter than in the C-TOF group (P<0.05) (Table 3).
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PTC in the AA-PTC group was significantly higher than in the C-PTC groups 25–35 min after administration of vecuronium (P<0.05) (Fig. 1). T1/T0 and T4/T1 in the AA-TOF group were significantly higher than in the C-TOF group 40–120 and 50–120 min after administration of vecuronium respectively (P<0.05) (Figs 2 and 3).
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At the final time point, 120 min after administration of vecuronium, in the AA-TOF and C-TOF groups, T1/T0 was 0.95 (0.16) [0.73–1.30] and 0.75 (0.16) [0.38–1.01] (mean (SD) [range]) respectively. In five patients in the AA-TOF group, T1/T0 returned to greater than 1.0. Similarly, 120 min after administration of vecuronium, in the AA-TOF and C-TOF groups, T4/T1 was 0.88 (0.12) [0.57–1.00] and 0.61 (0.19) [0.33–0.92] (mean (SD) [range]) respectively.
Before induction of anaesthesia, the rectal temperature in the AA-PTC and AA-TOF groups and that in the C-PTC and C-TOF groups did not significantly differ (36.8 (0.3) versus 37.0 (0.6)°C, NS). Similarly, before induction of anaesthesia, the temperature over the adductor pollicis muscle in the AA-PTC and AA-TOF groups was comparable with that in the C-PTC and C-TOF groups (33.1 (1.3) vs 32.9 (1.1)°C, NS). Rectal temperature decreased by approximately 0.2 and 0.5°C respectively in patients receiving an amino acid infusion or controls during the study period of 120 min. Rectal temperature in patients receiving an amino acid infusion became stable about 80–100 min after starting the administration of amino acid. In contrast, rectal temperature in patients in the control groups continued to decrease gradually during the study period. The peripheral temperature over the adductor pollicis muscle increased by about 2.7 and 2.0°C in patients receiving amino acids and in the control group respectively. The increases in the peripheral temperature in patients receiving amino acids and in the control group were rapid for the first 30 min, became stable within about 40–60 min. The decrease in the rectal temperature was less and the increase in the surface temperature over the adductor pollicis muscle was greater in the AA-PTC and AA-TOF groups than in the C-PTC and C-TOF groups 50–120 and 100–120 min after the beginning of administration of amino acid enriched solution respectively (P<0.05) (Figs 4 and 5).
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In no patient did the rectal or peripheral temperature over the adductor pollicis muscle decrease to less than 35.6 or 30.2°C respectively. In two and four patients in the amino acid groups and control groups respectively, when vecuronium was given, the peripheral temperature over the adductor pollicis muscle was less than 32°C. However, in these patients, 10 min after vecuronium, the peripheral temperature over the adductor pollicis muscle had increased to more than 32°C.
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Discussion |
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This study indicates that a continuous infusion of amino acid enriched solution speeds recovery from vecuronium-induced neuromuscular block in anaesthetized patients. During continuous administration of the amino acid enriched solution, the times from vecuronium to the return of PTC1, T1, T2, T3, and T4 were shortened. Also, the rates of recovery of the PTC, T1/T0, and T4/T1 was hastened. The decreases in rectal temperature in the AA-PTC and AA-TOF groups were significantly less than those in the C-PTC and C-TOF groups. The increases in temperature over the adductor pollicis muscle in the AA-PTC and AA-TOF groups were significantly greater than those in the C-PTC and C-TOF groups.
Amino acids are readily available energy substrates for skeletal muscle.1–5 Several studies have demonstrated amino acid-induced thermogenesis in patients during general anaesthesia.3 6–8 The infusion of amino acid enriched solution prevents hypothermia.4–8 It has been postulated that amino acid-induced heat production is mainly a result of the delivery of energy substrates to skeletal muscle.3 6 Approximately 75% of amino acid-induced thermogenesis during anaesthesia seems to be produced here.3 6
The amino acid-induced thermic effect is more apparent in patients under general anaesthesia than in awake subjects.6 11 The reason for this is unknown. It has been reported that most anaesthetic agents considerably reduced whole body oxidative metabolism and hence the production of heat.7 For example, volatile anaesthetics directly depress protein synthesis and induce hypothermia.6 Amino acid enriched solution may reverse the cooling effect of the volatile agents.
Mourier and colleagues2 reported that even when wrestlers were subjected to moderate energy restriction, branched-chain amino acid supplementation allowed maintenance of a high level of sports performance. Similarly, Nissen and colleagues1 demonstrated that the leucine metabolite, ß-hydroxy-ß-methylbutyrate, produced a significant increase in muscle strength. The amino acid-induced thermic effect may be related to this increase in muscle strength. The solution increased muscle strength may also prevent the hypothermia.
This study showed that the amino acid-induced effect on recovery of neuromuscular block had a very rapid onset. For example, the mean time from vecuronium injection to the return of PTC1 in the C-PTC group was 18.0 min, but in the AA-PTC group was only 13.3 min. Also, Selldén and Lindahl6 and Selldén and colleagues7 have reported that during general anaesthesia, the body temperature in patients who were given the amino acid enriched solution becomes significantly higher than that in patients who did not receive it within 20 min.
In previous studies,6 8 rectal temperature decreased by approximately 0.5°C and 1.0–1.5°C respectively during general anaesthesia in patients receiving an amino acid infusion or controls. In contrast, in this study, the maximum decreases in the rectal temperature were only 0.2 and 0.5°C respectively. We are not able to explain the reason for this difference. However, El-Gamal and colleagues12 reported that an operating room temperature around 26°C is effective in preventing a decrease in core temperature during general anaesthesia. In this study, the operating room temperature was 27–28°C, in contrast with 20–23°C in the previous studies.6 8
It has been noted that if the temperature over the adductor pollicis muscle is less than 32°C, recovery of neuromuscular block is delayed.9 10 Hypothermia is associated with a decrease in acetylcholine release.9 10 The present results may be because of in part the prevention of hypothermia at the adductor pollicis muscle. But in two patients in the AA-PTC and AA-TOF groups and four in the C-PTC and C-TOF groups, when vecuronium was given, the peripheral temperature over the adductor pollicis muscle was less than 32°C. Accordingly, in these patients, recovery of neuromuscular block might have been delayed. However, by 10 min after vecuronium, the peripheral temperature over the adductor pollicis muscle had increased to more than 32°C in these patients.
In this study, the peripheral temperature over the adductor pollicis muscle increased by about 2.7 and 2.0°C in patients receiving amino acids and in the control group respectively. In all patients, the peripheral temperature became stable within 40–60 min. These results were comparable with the findings of Sessler and colleagues,13 although in their study, the increase in the surface skin temperature over the hand was greater than 4°C. They noted that the increase in the surface skin temperature was a result of the redistribution of heat from the warm central compartment to cooler peripheral tissues.
Neuromuscular monitoring was started after loss of the eyelid reflex, but 1% isoflurane was then used for maintenance of anaesthesia for the 2 or 3 min before control readings of the TOF were taken. The use of isoflurane might have affected the neuromuscular response. However, it has been reported that 10 min exposure to isoflurane is insufficient to affect spontaneous recovery from mivacurium.14 We do not think that in this study any isoflurane-induced effect was of clinical importance.
All patients were pre-medicated with atropine 0.01 mg kg–1. Atropine inhibits the activity of sweat glands, and the skin becomes hot and dry. Brown15 noted that sweating may be depressed sufficiently to raise the body temperature, although only after large doses of atropine are given.15 Although Brown15 did not define the dose of atropine that caused hyperthermia, he noted that therapeutic doses of 0.5–1.0 mg did not do so.
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1 Nissen S, Sharp R, Ray M, et al. Effect of leucine metabolite ß-hydroxy-ß-methylbutyrate on muscle metabolism during resistance-exercise training. J Appl Physiol 1996; 81: 2095–104
2 Mourier A, Bigard AX, de Kerviler E, et al. Combined effects of caloric restriction and branched-chain amino acid supplemen tation on body composition and exercise performance in elite wrestlers. Int J Sports Med 1997; 18: 47–55
3 Selldén E, Bränström R, Brundin T. Augmented thermic effect of amino acids under general anaesthesia occurs predominantly in extra-splanchnic tissues. Clin Sci 1996; 91: 431–9
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8 Selldén E, Bränström R, Brundin T. Preoperative infusion of amino acids prevents postoperative hypothermia. Br J Anaesth 1996; 76: 227–34
9 Eriksson LI, Viby-Mogensen J, Lennmarken C. The effect of peripheral hypothermia on a vecuronium-induced neuro muscular block. Acta Anaesthesiol Scand 1991; 35: 387–92[Medline]
10 Eriksson LI, Lennmarken C, Jensen E, Viby-Mogensen J. Twitch tension and train-of-four ratio during prolonged neuromuscular monitoring at different peripheral temperatures. Acta Anaesthesiol Scand 1991; 35: 247–52[Web of Science][Medline]
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12 El-Gamal N, El-Kassabany N, Frank SM, et al. Age related thermoregulatory differences in a warm operating room environment (approximately 26°C). Anesth Analg 2000; 90: 694–8
13 Sessler DI, McGuire J, Moayeri A, et al. Isoflurane-induced vasodilation minimally increases cutaneous heat loss. Anesthesiology 1991; 74: 226–32[Web of Science][Medline]
14 Jalkanen L, Meretoja OA. The influence of the duration of isoflurane anaesthesia on neuromuscular effects of mivacurium. Acta Anaesthesiol Scand 1997; 41: 248–51[Web of Science][Medline]
15 Brown JH. Atropine, scopolamine, and related antimuscarinic drugs. In: Gilman AG, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th Edn. New York: Pergamon Press, 1990; 150–65
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