J. Viby‐Mogensen

Good Clinical Research Practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents

Based on an international consensus conference held in Copenhagen in the autumn of 1994, a set of guidelines for Good Clinical Research Practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents are presented. The guidelines are intended to be a help for people working in this research field, and it is hoped that the guidelines will assist researchers, editors, and drug companies to enhance the quality of their pharmacodynamic studies of neuromuscular blocking agents.

Anaesthetic practice and postoperative pulmonary complications.

The aim of this study was to identify risk factors associated with postoperative pulmonary complications. The influence of the anaesthetic technique was evaluated (i.e. general contra regional anaesthesia and long contra intermediately acting muscle relaxants (pancuronium and atracurium)) taking into account the patients age, the presence or absence of chronic obstructive lung disease (preoperative risk factors), the type of surgery and the duration of anaesthesia (perioperative risk factors). Seven thousand and twenty‐nine patients undergoing abdominal, urological, gynaecological or orthopaedic surgery were included in the study. A total of 290 patients (4.1%) suffered from one or more postoperative pulmonary complications. Six thousand and sixty‐two patients received general anaesthesia and 4.5% of these had postoperative pulmonary complications. Of the patients admitted to major surgery receiving pancuronium, 12.7% (135/1062) developed postoperative pulmonary complications, compared to only 5.1% (23/449) receiving atracurium (P<0.05). When stratified for type of surgery and duration of anaesthesia, conventional statistics showed no difference between pancuronium and atracurium as regard postoperative pulmonary complications. However, a logistic regression analysis indicated that long‐lasting procedures involving pancuronium entailed a higher risk of postoperative pulmonary complications than did other procedures. In patients having regional anaesthesia, only 1.9% (18/967) developed postoperative pulmonary complications (P<0.05 compared to general anaesthesia). However, when stratified for type of surgery there was a significantly higher incidence of postoperative pulmonary complications only in patients undergoing major orthopaedic surgery under general anaesthesia, 11.5% compared to 3.6% in patients given a regional anaesthesia. By utilizing logistic regression, a model for prediction of postoperative pulmonary complications was developed. Six variables were found to be significant in predicting complications: high age, major abdominal surgery, emergency surgery, a history of chronic obstructive lung disease, long‐lasting general anaesthesia (≥ 180 min) involving pancuronium, and anaesthesia involving pancuronium, in the order given.

Postoperative muscle paralysis after rocuronium: less residual block when acceleromyography is used

Background: Residual muscle paralysis after anesthesia is common after pancuronium, but less common following the intermediate‐acting drugs vecuronium and atracurium. Therefore, many anesthetists do not monitor neuromuscular function when using an intermediate‐acting agent. The purpose of this prospective, randomised and double‐blind study was to establish the incidence and degree of postoperative residual block following the use of rocuronium in patients not monitored with a nerve stimulator, and to compare it with results obtained in patients monitored using acceleromyography (AMG).

Perioperative monitoring of neuromuscular transmission using acceleromyography prevents residual neuromuscular block following pancuronium.

The frequency of postoperative residual neuromuscular block following the use of the long‐acting non‐depolarizing muscle relaxants is high, and manual evaluation of the response to nerve stimulation does not eliminate the problem. In this prospective and randomized study we evaluated the hypothesis that perioperative use of acceleromyography would allow for a more rational and precise administration of the long‐acting muscle relaxant pancuronium resulting in a decrease in 1) the incidence and severity of postoperative residual neuromuscular block, 2) the amount of pancuronium used, and 3) the time from end of surgery to tracheal extubation. Forty adult patients were randomized into two groups, one managed without the use of a nerve stimulator, the other monitored using train‐of‐four (TOF) nerve stimulation and acceleromyography. All patients were anaesthetized with diazepam, fentanyl, thiopenione, nitrous oxide, and in some patients halothane, and they all received pancuronium 0.08–0.1 mg kg‐1 for tracheal intubation, and 1–2 mg for maintenance of neuromuscular block. Neostigmine 2.5 mg preceded by atropine 1 mg was administered for reversal. In the patients managed without a nerve stimulator, the trachea was extubated when the anaesthetist judged the neuromuscular function to have recovered adequately for upper airway protection and spontaneous ventilation. In patients monitored with acceleromyography, the trachea was extubaled when the TOF ratio was above 0.70. In all 40 patients, TOF ratio was measured using mechanomyography immediately after tracheal extubation and the patients were evaluated for clinical signs of residual neuromuscular block. Train‐of‐four ratios, as measured mechanically, varied between 0.26 and 0.96 (median 0.65) in the group not monitored dunng the operation with acceleromyography. Seven patients in this group were unable to sustain head lift for 5 seconds and five patients were unable to lift an arm to the opposite shoulder, as compared to 1 and 0 patients, respectively, in the group monitored using acceleromyography (P<0.05). The lime from end of surgery to tracheal extubation varied between 0 and 25 min (median 10 min) in the group not monitored as compared to 7–47 min (median 15 min) in the monitored group (P<0.01). There was no statistically significant difference in the total dose of pancuronium given in the two groups. It is concluded, that by using acceleromyography during Anaesthesia it is possible to avoid the problem of residual neuromuscular block following pancuronium. However, in this study this happened at the expense of a slightly prolonged recovery time (5 min longer). Under the conditions of the study the use of acceleromyography did not influence the amount of pancuronium used during anaesthesia.

Identification of human plasma cholinesterase variants in 6,688 individuals using biochemical analysis

In 1973, a Cholinesterase Research Unit was established in Denmark (DCRU). The primary aim was to provide a central sendee for determining genotypes and activity of plasma cholinesterase (BChE) in patients showing abnormal response after succinylcholine. The purpose of the present study was, on the basis of 20 years experience with this Unit, to establish accurate reference intervals for BChE activity and inhibition values for the different genotypes of BChE. Also we wanted to evaluate the influence of age and sex on the BChE activity in genotypically normal patients. Plasma cholinesterase activity was measured using benzoylcholine as substrate. The genetic variations of the enzyme were identified using differential inhibitors, i.e: Dibucaine, Sodium Fluoride, Succinylcholine, Urea and Ro‐2–0683. We investigated 6,688 patients. The reference values for the 13 genotypes represented agree with previous findings. In genotypically normal patients, no age or sex differences were found in BChE activity in children below the age of 10 years. From the age of 10 years the activity decreased significantly in both males and females, the activity in females being significantly lower than in males. In females the activity was lowest in the age group 30–40 years, returning to prepuberty level at about 60 years of age. In males the activity decreased slightly up to 50–60 years of age. Hereafter the activity was stable or tended to increase slightly. Most genotypes could be recognized using the results of the different inhibition studies. We found the inhibitors Dibucaine, Sodium fluoride, Urea and Ro‐2–0683 most helpful, whereas succinylcholine was of less value. We conclude that though most genotypes can be recognized biochemically, several variants with heterozygous occurrence of an abnormal and a usual gene are still very difficult or impossible to differentiate in this way. This, together with the increasing number of possible genotypes, have increased the need for tests based on DNA analyses.

Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients

The significance of plasma cholinesterase (pChe) activity for the duration of action of mivacurium in phenotypically normal patients was evaluated in 35 patients during neurolept anaesthesia. The response to train‐of‐four nerve stimulation was recorded using a Myograph 2000. Ten patients with normal pChe (Group 1) and five patients with decreased pChe activity (Group 2) were given a small test dose of mivacurium 0.03 mg kg‐1. Mivacurium 0.1 mg kg‐1 was administered following spontaneous recovery from the first dose. The mean suppression of the height of the first (T1) of the train‐of‐four responses following mivacurium 0.03 mg kg‐1 patients with normal and decreased enzyme activity was 40% and 56%, respectively, and the mean T1 suppression after mivacurium 0.1 mg kg‐1 was 100% in both groups. The times to different levels of twitch height recovery following the 0.1 mg kg‐1 dose did not differ between the two groups of patients. Another 20 patients with normal or decreased pChe activity (Group 3) were given mivacurium 0.2 mg kg‐1. In this group the time to maximum block was 1.4 min (1.0–4.0) mean (range) and the time to reappearance of the T1 response was 15.0 min (7.4–22.7) (range). An inverse relationship was found between the patients pChe activity and the time to first response. It is concluded that mivacurium is short‐acting in patients with normal pChe phenotype and normal to low‐normal pChe activity. No patient with very low pChe activity was included in the study. A prolonged response to mivacurium may, however, be expected in these patients.

Plasma cholinesterase and abnormal reaction to succinylcholine: twenty years' experience with the Danish Cholinesterase Research Unit

For more than 20 years, the Danish Cholinesterase Research Unit (DCRU) has collected information about patients showing an abnormal response to succinylcholine.

The effect of peripheral hypothermia on a vecuronium‐induced neuromuscular block

Seven healthy patients were investigated during midazolam‐fentanyl nitrous oxide‐oxygen anaesthesia. The mechanical twitch response of the adductor pollicis muscle was recorded simultaneously during bilateral supramaximal train‐of‐four (TOF) stimulation of the ulnar nerves at the wrist. Intense neuromuscular block was evaluated using the post‐tetanic count (PTC) method. Core temperature and the peripheral skin temperature of one arm were kept normal and stable. Following cooling of the other arm to a peripheral hand skin temperature of 27d̀C, vecuronium was administered in a bolus dose of 0.05 mg‐kg‐1 followed by maintenance doses of 0.02 mg‐kg‐1. In the hypothermic and the normothermic arm the onset time following the bolus dose was 180 ± 40 (mean ± s.d.) seconds and 140 ± 30 s, respectively, the duration of action was 26.4 ± 4.5 and 16.5 ± 4.0 min and the recovery time was 265 ± 90 and 130±60 s (P<0.01). The time course of action following maintenance doses showed a similar marked difference between the hypothermic and the normothermic arm. In the normothermic arm a close correlation was found between the number of posttetanic twitches and the time to first response to TOF stimulation. In contrast, in the hypothermic arm the number of post‐tetanic twitches showed great variation with a poor correlation to the duration of intense neuromuscular block. It is concluded that the time course of action of a vecuronium‐induced neuromuscular block is markedly prolonged during peripheral hypothermia and intense neuromuscular block cannot reliably be assessed using the PTC method at low peripheral temperature. Normal core and peripheral temperature is essential for correct evaluation of a neuromuscular block.

Twitch tension and train‐of‐four ratio during prolonged neuromuscular monitoring at different peripheral temperatures

In eight healthy patients, the influence of the train‐of‐four (TOF) response of prolonged neuromuscular monitoring and of different peripheral temperatures was studied during normal core temperature. Anaesthesia was induced and maintained with midazolam‐fentanyl and a 70/30% mixture of nitrous oxide and oxygen. The mechanical TOF response of the adductor pollicis muscle (twitch tension and TOF ratio), was recorded simultaneously in both hands using supramaximal TOF stimulation of the ulnar nerve at the wrist. One arm was kept normothermic. The other arm was cooled using cold infusions and cold packings. Skin, muscle and core temperatures were continuously measured. In the normothermic arm (skin temperature >32.0d̀C), the twitch tension and TOF ratio were unchanged following 130–230 min of continuous nerve stimulation. In the hypothermic arm the twitch tension and TOF ratio showed only minor variations above a skin temperature of 32.0d̀C (corresponding to a mean muscle temperature of 34.50.3d̀C). Below a skin temperature of 32.0d̀C a progressive decrease in TOF response was recorded. A linear relationship was found between skin temperature and TOF response as well as between muscle temperature and TOF response. At a skin temperature of 27.0d̀C (corresponding to a mean muscle temperature of 30.80.4d̀C), an approximate 20d̀ reduction in twitch tension and a 10% decrease in TOF ratio were recorded with a considerable interindividual variation. We conclude that prolonged TOF nerve stimulation does not change the mechanical twitch response in patients with a normal central and peripheral temperature. A peripheral skin temperature below 32.0d̀C with sustained and normal body temperature is, however, associated with changes in both twitch tension and TOF ratio that may be a source of error when evaluating neuromuscular function.

Adverse Reactions and Interactions of the Neuromuscular Blocking Drugs

SummaryThe adverse reactions seen following administration of neuromuscular blocking agents are mainly cardiovascular. Due to the lack of specificity for the nicotinic receptor at the neuromuscular junction, these agents may interact with receptors in autonomic ganglia and muscarinic receptors in the heart. Furthermore, muscle relaxants may have histaminereleasing properties. The cardiovascular effects vary with potency and specificity of the drug, depending mainly on the chemical structure. Pancuronium, fazadinium and especially gallamonium block cardiac muscarinic receptors, and tachycardia may be seen. Atracurium, metocurine and in particular d -tubocurarine have histamine-releasing properties and may cause flushing, hypotension and tachycardia. Vecuronium has no effect on the cardiovascular system. The effect of succinylcholine on heart rate differs between children, where bradycardia is seen, and adults in whom tachycardia may follow. However, bradycardia may occur in adults following a single dose. Succinylcholine increases plasma potassium, especially in patients with nerve damage, and arrhythmias may be observed. The neuromuscular adverse effects of succinylcholine, such as fasciculations and increased gastric and intraocular pressure, may be prevented by precurarisation.Many drugs interact with neuromuscular blocking agents and there is often a potentiation of the neuromuscular effect. This is of clinical importance in the case of antibiotics, inhalational anaesthetics, lithium and cyclosporin. Difficulty in reversing the block may occur with calcium channel blockers and polymyxin. However, some drugs, such as phenytoin, carbamazepine and lithium, may cause resistance to neuromuscular blocking agents. Furthermore, clinically important interactions exist between individual neuromuscular blocking drugs. Precurarisation with a non-depolarising drug prolongs the onset of succinylcholine, and conversely a prolonged effect of non-depolarising drugs is seen following succinylcholine. The effect of succinylcholine is markedly prolonged if the drug is administered during recovery from pancuronium blockade or following neostigmine for reversal. Succinylcholine is hydrolysed by plasma cholinesterase, and drugs which decrease the activity of this enzyme may produce a prolonged block, i.e. contraceptive pills, cyclophos-phamide, echothiopate and organophosphate.