肌肉松弛药过敏反应研究新动向

背景 肌肉松弛药(肌松药,neuromuscular blocking agents,NMBAs)存在诱发过敏反应的可能.严重的过敏反应发展迅速并危及患者生命. 目的 综述NMBAs诱发过敏反应研究的最新进展,为其安全使用提供参考. 内容 阐述NMBAs过敏反应的临床表现及特点、交叉过敏反应、诊断及治疗进展. 趋向 NMBAs过敏反应的研究能够为临床安全使用NMBAs提供指导.     

Interactions between ORG9426 and other non-depolarizing neuromuscular blocking agents in ratsin vivo

In this study, combined neuromuscular blocking effects of ORG9426 with other non-depolarizing neuromuscular blocking agents were investigated. About 20% steady state neuromuscular block was established by a continuous infusion of one of 6 neuromuscular blocking agents (ORG9426, vecuronium, pancuronium, pipecuronium, d-tubocurarine and metocurine). Then 1/7 of the ED50 of ORG9426 or one of other neuromuscular blocking agents was administered in a single injection, and the increase in the neuromuscular block was observed. The combined neuromuscular blocking effect of ORG9426 and d-tubocurarine or ORG9426 and metocurine was significantly (P 0.05) greater than that of each corresponding control (the combination of same neuromuscular blocking agent). The effect of d-tubocurarine was also potentiated by vecuronium, pancuronium and pipecuronium. These potentiations were not observed between ORG9426 and pancuronium, pipecuronium or vecuronium. Possible mechanisms of these synergistic interactions were discussed.(Watanabe K: Interactions between ORG9426 and other non-depolarizing neuromuscular blocking agents in rats in vivo. J Anesth 6: 277–283, 1992)     

Variability of pipecuronium neuromuscular blockade

The dose-response relationship and the variability of the time variables in pipecuronium neuromuscular blockade were studied in 29 patients (ASA physical status 3) during halothane anaesthesia. The ED₉₅ (twitch tension) was determined in 9 patients using the cumulative dose response technique. Another 20 patients received the resulting ED₉₅ as a single bolus. The mean ED₉₅ was 35 μg-kg^-1 (95% confidence interval: 29–41 μg.kg^-1). Following bolus injection of 1. ED₉₅, an 80–100% twitch depression was achieved within 4.6±1.3 min (mean ± s.d.). The duration from end of injection of pipecuronium to 25% twitch recovery, the time from 25% to 75% twitch recovery, and the time from 25% twitch recovery to the train-of-four ratio (TOF) returning to 0.7 was 35 ± 14, 37 ± 26, and 63 ± 27 min, respectively. The time from end of injection to TOF = 0.7 varied within a 2-h range (54–160 min). Thus, the time variables in pipecuronium neuromuscular blockade were as poorly predictable as those reported in the literature on pancuronium, alcuronium and doxacurium.     

The use of neuromuscular blocking drugs in intensive care practice

Critically ill patients represent a very different population from that of the operating theatre, but much of our knowledge of many of the neuromuscular blocking drugs is derived from intraoperative use. The diversity of clinical-practice and case-mix differences in intensive care are probably responsible for the absence of a formal consensus about the use of neuromuscular blocking drugs in the intensive care unit (ICU). Various surveys suggest that these drugs are used comparatively infrequently, but we do not know whether current usage is either safe or appropriate. In addition to the adverse effects which inevitably accompany prolonged paralysis and immobility, the steroidal relaxants, pancuronium and vecuronium, have also been associated with myopathy. This seems to be aggravated by concurrent use of pharmacologic doses of corticosteroids or the aminoglycoside antibiotics. Neither the mechanism nor the validity of the association with steroidal relaxants is known at present. Muscle dysfunction is a common feature of critical illness, and it is possible that neuromuscular blocking drugs interfere with muscle repair and regrowth. Patients with multiple organ failure present a particular challenge both because of the extent of tissue injury and because drug clearance via the liver or kidneys is generally impaired.     

Postoperative residual block after intermediate-acting neuromuscular blocking drugs

The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of <0.8. An additional group of 10 patients received no neuromuscular blocking drugs during anaesthesia. The incidence of postoperative residual neuromuscular block was 64%, 52% and 39% after the use of vecuronium, atracurium and rocuronium, respectively. Similar numbers of patients were not able to maintain a sustained head or leg lift for 5 s on arrival in the recovery ward. The mean [range] times to attaining a train-of-four ratio of > or =0.8 after arrival in the recovery ward were 9.2 [1-61], 6.9 [1-24] and 14.7 [1.5-83] min for vecuronium, atracurium and rocuronium, respectively. None of the 10 patients who did not receive neuromuscular blocking drugs had train-of-four ratios <0.8 on arrival in the recovery ward. It is concluded that a large proportion of patients arrive in the recovery ward with a train-of-four ratio <0.8, even with the use of intermediate-acting neuromuscular blocking drugs. Although the residual block is relatively short lasting, it may occasionally be prolonged, requiring close observation and monitoring of such patients in the recovery ward.     

动力性心肌成形术远期结果

目的：报道3例扩张性心肌病患者接受动力性心肌成形术后的远期效果。方法：3例男性患者接受动力性心肌成形术,年龄分别为36、45、62岁,术前心功能Ⅲ级（NYHA）1例,Ⅳ级2例。术后对患者定期随访,分析血液动力学参数、临床心功能及心脏形态等指标。结果：患者无手术死亡,术后早期即出现血液动力学指标改善、心脏扩大趋势减缓、临床症状缓解、活动耐力增加、生活质量提高,3例患者心功能均为Ⅰ级。1例患者术后1年7个月死于心律失常;2例长期存活者3年后部分血液动力学指标下降,心脏呈扩大趋势,心功能减低。1例患者存活4年6个月死于心力衰竭;1例现仍存活,心功能Ⅱ级。结论：动力性心肌成形术在术后相当长的一段时间内能改善扩张性心肌病、心力衰竭患者的生活质量,提高心功能。     

Neuromuscular blocking agents and reversal agents

The neuromuscular junction consists of the motor nerve terminal, the synaptic cleft and post-synaptic nicotinic receptors on the motor end-plate of striated muscle. Neuromuscular blocking drugs are categorized into depolarizing and non-depolarizing agents. They are structurally related to acetylcholine (ACh), containing at least one positively charged quaternary ammonium radical that binds to the nicotinic receptor. Depolarizing agents (e.g. suxamethonium) act as agonists like ACh at the nicotinic receptor, but cause a more prolonged depolarization of the motor end-plate, thus rendering the ion channel insensitive to further action potentials. Non-depolarizing agents, in contrast, compete directly with ACh for nicotinic receptor binding sites and prevent neurotransmitter–receptor binding. These are either benzylisoquinoliniums (e.g. atracurium) or aminosteroids (e.g. rocuronium). Once recovery has commenced, neuromuscular block can be reversed with anticholinesterases (e.g. neostigmine). In contrast, the novel cyclodextrin sugammadex can be used to reverse any degree of neuromuscular block produced by rocuronium or vecuronium.     

Neuromuscular blocking agents and reversal agents

The neuromuscular junction consists of the motor nerve terminal, the synaptic cleft and post-synaptic nicotinic receptors on the motor end-plate of striated muscle. Neuromuscular blocking drugs are categorized into depolarizing and non-depolarizing agents. They are structurally related to acetylcholine (ACh), containing at least one positively charged quaternary ammonium radical that binds to the nicotinic receptor. Depolarizing agents (e.g. suxamethonium) act as agonists like ACh at the nicotinic receptor, but cause a more prolonged depolarization of the motor end-plate, thus rendering the ion channel insensitive to further action potentials. Non-depolarizing agents, in contrast, compete directly with ACh for nicotinic receptor binding sites and prevent neurotransmitter–receptor binding. These are either benzylisoquinoliniums (e.g. atracurium) or aminosteroids (e.g. rocuronium). Once recovery has commenced, neuromuscular block can be reversed with anticholinesterases (e.g. neostigmine). In contrast, the novel cyclodextrin sugammadex can be used to reverse any degree of neuromuscular block produced by rocuronium or vecuronium.     

Effect of milrinone on vecuronium-induced neuromuscular block

We examined the effect of milrinone, a phosphodiesterase III inhibitor, on neuromuscular block induced by vecuronium. Thirty adult patients were randomly assigned to one of two equal groups: the milrinone group and the control group. Subjects in the milrinone group received an intravenous loading dose of milrinone 5 microg x kg-1x min-1 for 10 min, followed by an infusion at a rate of 0.5 microg x kg-1x min-1. Subjects in the control group received normal saline at a rate of 0.1 ml x kg-1 x h-1. Thirty minutes after the beginning of the infusion of milrinone, anaesthesia was induced with intravenous thiopental 4 mg x kg-1 and fentanyl 2 microg x kg-1, and was maintained with isoflurane in oxygen and nitrous oxide. Neuromuscular blockade was monitored electromyographically at the adductor pollicis muscle. The times from the administration of vecuronium 0.1 mg.kg-1 to the onset of neuromuscular block and the return of the first, second, third, and fourth response of the train-of-four were compared between the two groups. Times to the recovery of the ratio of the first twitch to the control twitch to 25%, 50% and 75%, and times to the recovery of train-of-four ratio to 25%, 50% and 75% were also compared between the two groups. The onset of neuromuscular block in the milrinone group was significantly slower than in the control group. The times to the returns of the four twitches of the train-of-four, times to recovery of the ratio of the first twitch to the control twitch to 25% and 50%, and the times to the recovery of the train-of-four ratio to 25% and 50% were significantly shorter in the milrinone group than in the control group. We conclude that milrinone delays the onset of neuromuscular blockade but hastens its recovery in anaesthetised patients receiving vecuronium.     

The neuromuscular blocking effect of Org 9426

Org 9426, a new steroidal non-depolarising muscle relaxant, which is stable in solution, was studied in 30 anaesthetised (thiopentone, fentanyl, nitrous oxide) male patients, ASA 1 or 2. A dose-response curve for Org 9426 was constructed and the ED90, mean (SD), was found to be 0.36 (0.031) mg/kg. The onset of action was 3.8 (1.8) minutes, the clinical duration 17.4 (3.2) minutes, the total duration of action 31.9 (6.2) minutes and the recovery time 9.96 (3.2) minutes. No signs of histamine release or cardiovascular effects were observed. Org 9426 thus has a faster onset of action than vecuronium bromide or atracurium dibesylate.     

Inhibition of human plasma cholinesterase and erythrocyte acetylcholinesterase by nondepolarizing neuromuscular blocking agents

Purpose. The kinetics of the inhibition of human plasma cholinesterase (ChE) and erythrocyte acetylcholinesterase (AChE) by alcuronium, atracurium, d-tubocurarine, pancuronium, pipecuronium, and vecuronium were studied in blood drawn from 35 surgical patients. Methods. The activities of plasma ChE and erythrocyte AChE were determined by the calorimetric method of Ellman et al., using acetylthiocholine as the substrate. Lineweaver-Burk plots and Dixon plots were used for the analysis of the kinetics of both enzymes. Results. The dissociation constants (K _m) of plasma ChE and erythrocyte AChE were 5.00 × 10⁻⁵ M and 5.28 × 10⁻⁵ M, respectively, indicating that both enzymes have similar affinity to acetylthiocholine. Both Lineweaver-Burk plots and Dixon plots indicated that the six nondepolarizing neuromuscular blocking agents (NMBAs) at different concentrations induce linear mixed-type inhibition. The apparent inhibition constants (K _i) of pancuronium (8.72 × 10⁻⁸ M) and vecuronium (3.53 × 10⁻⁷ M) for plasma ChE inhibition were lower than that of neostigmine (7.36 × 10⁻⁷ M), whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly higher than that of neostigmine. Conclusions. Both plasma ChE and erythrocyte AChE were inhibited by six nondepolarizing NMBAs, and the pattern of inhibition of both enzymes was of mixed type. The inhibitory potencies of pancuronium and vecuronium for plasma ChE were larger than that of neostigmine, whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly lower than that of neostigmine. The rank order of relative potency for plasma ChE was pancuronium > vecuronium > pipecuronium > alcuronium > d-tubocurarine > atracurium. Received for publication on May 10, 1999; accepted on September 22, 1999     

Effects of avoidance or use of neuromuscular blocking agents on outcomes in tracheal intubation: a Cochrane systematic review

Cohort studies have indicated that avoidance of neuromuscular blocking agents (NMBA) is a risk factor for difficult tracheal intubation. However, the impact of avoiding NMBA on tracheal intubation, possible adverse effects, and postoperative discomfort has not been evaluated in a systematic review of randomised trials. We searched several databases for trials published until January 2017. We included randomised controlled trials comparing the effect of avoiding vs using NMBA. Two independent authors assessed risk of bias and extracted data. The risk of random errors was assessed by trial sequential analysis (TSA). We included 34 trials (3565 participants). In the four trials judged to have low risk of bias, there was an increased risk of difficult tracheal intubation with no use of NMBA [random-effects model, risk ratio (RR) 13.27, 95% confidence interval (CI) 8.19–21.49, P<0.00001, TSA-adjusted CI 1.85–95.04]. The result was confirmed when including all trials, (RR 5.00, 95% CI 3.49–7.15, P<0.00001, TSA-adjusted CI 1.20–20.77). There was a significant risk of upper airway discomfort or injury by avoiding NMBA (RR=1.37, 95% CI 1.09–1.74, P=0.008, TSA-adjusted CI 1.00–1.86). None of the trials reported mortality. Avoiding NMBA was significantly associated with difficult laryngoscopy, (RR 2.54, 95% CI 1.53–4.21, P=0.0003, TSA-adjusted CI 0.27–21.75). In a clinical context, one must balance arguments for using NMBA when performing tracheal intubation.     

A comparison of antagonism of rocuronium-induced neuromuscular blockade during sevoflurane and isoflurane anaesthesia

Volatile anaesthetic agents potentiate neuromuscular blocking agents and retard their rate of reversal. We hypothesised that there was a difference in the rate of reversal of rocuronium-induced neuromuscular blockade based on the selection of inhalation agent. Thirty-eight patients undergoing elective surgical procedures received either sevoflurane or isoflurane, by random allocation. Neuromuscular blockade was induced using rocuronium 0.6 mg.kg-1 followed by continuous intravenous infusion to maintain 90% suppression of the single twitch response. Upon completion of surgery, the rocuronium infusion was discontinued, neostigmine 50 microg.kg-1 and glycopyrrolate 10 microg.kg-1 were administered. Times from reversal to T1 = 25, 50 and 60% and train-of-four ratio = 0.6 were recorded. The mean (SD) times to train-of-four ratio = 0.6 in the isoflurane and sevoflurane groups were 327 (132) and 351 (127) s, respectively. The mean (SD) times to single twitch response T1 = 25, 50 and 60% in the isoflurane group were 81 (33), 161 (59) and 245 (84) s, respectively, and in the sevoflurane group were 95 (35), 203 (88) and 252 (127) s, respectively. It is concluded that reversal of rocuronium-induced neuromuscular blockade is similar during isoflurane and sevoflurane anaesthesia.     

小儿不同剂量顺式阿曲库铵的肌松作用

目的通过观察小儿不同剂量顺式阿曲库铵的肌松作用,评价是否存在封顶效应,探讨小儿合适的麻醉诱导剂量。方法45例择期手术的息儿,年龄15～50月,ASAⅠ或Ⅱ级,随机分为3组(n=15):顺式阿曲库铵0.1 mg/kg组(A组)、顺式阿曲库铵0.15 mg/kg组(B组)、顺式阿曲库铵0.2 mg/kg(C组)。采用TOF-Guard肌松监测仪对尺神经行连续四个成串(TOF)刺激,监测拇内收肌肌颤搐变化;静脉注射异丙酚2 mg/kg、芬太尼2μg/kg及相应剂量顺式阿曲库铵麻醉诱导,吸入O2-N2O和静脉持续输注异丙酚维持麻醉;评价气臂插管条件评估分级,监测诱导期间血液动力学变化,记录起效时间(肌松药注毕至T1达最大抑制的时间)、临床肌松维持时间(肌松药注毕至T1恢复5%的时间)、临床肌松有效作用时间(T1从最大抑制至恢复25%的时间)、恢复指数(T1恢复从25%至75%的时间)、体内肌松作用时间(肌松药注毕至T1恢复95%的时间)。结果3组气管插管条件评估分级比较差异无统计学意义;三组T1达最大抑制时心率、平均动脉压组间和组内比较差异均无统计学意义。与A组相比,B组、C组起效时间较短,临床肌松维持时间、临床肌松有效作用时间、体内肌松作用时间较长(P<0.01);三组恢复指数差异无统计学意义。与B组相比,C组起效时间差异无统计学意义,但临床肌松维持时间、临床肌松有效作用时间、体内肌松作用时间较长(P<0.05或0.01)。结论小儿芬太尼复合异丙酚时,顺式阿曲库铵0.15 mg/kg(3倍ED95)是麻醉诱导的适宜剂量。     

Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP)

In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.