J. Engbæk

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.

Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual neuromuscular blockade?

The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists evaluated the degree of neuromuscular blockade solely by clinical criteria. The use of a nerve stimulator was found to have no effect on the dose of relaxant given during anesthesia, on the need for supplementary doses of anticholinesterase in the recovery room, on the time from end of surgery to end of anesthesia, or on the incidence of postoperative residual neuromuscular blockade evaluated clinically. The median (and range of) TOF ratios recorded in the recovery room were 0.75 (0.33-0.96) and 0.79 (0.10-0.97) in the vecuronium groups monitored with and without a nerve stimulator, respectively. These ratios were significantly higher than those found in the pancuronium groups, which wre 0.66 (0.06-0.90) and 0.63 (0.29-0.95), respectively. However, no difference was found between the vecuronium and pancuronium groups in the number of patients showing clinical signs of residual neuromuscular blockade, as evaluated by the 5-s head-lift test.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Monitoring of the neuromuscular transmission by electromyography (I). Stability and temperature dependence of evoked EMG response compared to mechanical twitch recordings in the cat

The stability over time and the effect of muscle temperature change were evaluated for the evoked compound EMG and for the mechanomyogram of the tibialis anterior muscle of 7 anaesthetized cats. Both EMG areas and amplitudes were recorded. During stimulation for 3 h with 0.1 Hz (one leg) and train‐of‐four (TOF) (the other leg), the EMG was stable while the mechanomyogram initially increased 35–50% in the first 7–8 min and then decreased 19–22% and 5–8% over the first and second 1.5‐h period, respectively. During subsequent mean muscle temperature reduction to 28.8°C (0.1 Hz) and 29.7°C (TOF) and rewarming, an inverse linear relationship was found between temperature and both the EMG and the mechanomyogram. During temperature reduction EMG increased about 6% (areas) and 2% (amplitudes) per °C. During rewarming, parameters decreased about 4.5% and 2% per °C, respectively (P<0.05 comparing EMG areas during cooling and rewarming). TOF ratio of the EMG was not affected by temperature. A very large interindividual variation was observed for the effect of temperature on the mechanomyogram with changes ranging up to 15% per °C for some cats. TOF ratio of the mechanomyogram was reduced from 1.02 to0.94 at lowest muscle temperature. It is concluded that the evoked EMG may be preferable to the mechanomyogram in cat experiments investigating the neuromuscular transmission.

Bradycardia and Cardiac Asystole Following a Single Injection of Suxamethonium

Twenty cases of severe bradycardia, including 12 cases of cardiac asystole, following administration of a single dose of suxamethonium to 17 adult patients are presented. Treatment consisted of i.v. atropine in 16 cases, and in four cases external cardiac massage or a precordial thump was also given. Remission was complete in all cases. The mechanism is not known, but it is suggested that i.v. administration of fentanyl at induction may enhance the tendency to bradycardia following suxamethonium. Absence of preoperative atropine may also be of importance.

Acceleromyography of the orbicularis oculi muscle II: comparing the orbicularis oculi and adductor pollicis muscles

Background: The orbicularis oculi (OO) muscle has been recommended for neuromuscular monitoring when the adductor pollicis (AP) muscle is not available. We investigated whether neuromuscular block could be measured reliably from the orbital part of the OO muscle by the use of acceleromyography.

Dose‐response Curves for Vecuronium during Halothane and Neurolept Anaesthesia: Single Bolus versus Cumulative Method

The purpose of this study was to compare the incremental, cumulative dose method and the single bolus injection technique for construction of dose‐response curves for vecuronium. Dose‐response curves were determined in 77 patients divided into four groups according to the anaesthetic given and the method used for construction of dose‐response curves. The regression lines corresponding to the four dose‐response curves were found to be parallel. For vecuronium ED50 during neurolept anaesthesia was found to be 28 μg kg‐1 with the single bolus injection technique and 35.2 μg kg‐1 with the incremental, cumulative dose method (P<0.05). During halothane anaesthesia, ED50 was found to be 25.7 μg kg‐1 and 26.2 μg kg‐1, respectively (P>0.05). Potentiation of vecuronium by halothane was found with the cumulative method only. It is concluded that the incremental, cumulative dose method is not suitable for potency determinations of vecuronium.

Edrophonium and Neostigmine for Reversal of the Neuromuscular Blocking Effect of Vecuronium

The effect of edrophonium for reversal of the non‐depolarizing neuromuscular blockade produced by a continuous infusion of vecuronium was compared to that of neostigmine in 20 adult patients during neurolept anaesthesia. When antagonism was attempted at 10% twitch height recovery, reversal time to a train‐of‐four ratio of 0.7 was significantly shorter following neostigmine 0.04 mg/kg than after edrophonium 0.75 mg/kg (9.8 min and 18.7 min, respectively) but the same after edrophonium 1.5 mg/kg (10.3 min). There was no statistically significant difference in reversal time between neostigmine 0.04 mg/kg given at 10% twitch height and edrophonium 0.75 mg/kg given at 25% twitch height recovery (6.0 min). Additional doses of atropine were necessary following edrophonium 1.5 mg/kg.

Precurarization ‐ a Hazard to the Patient?

Four case histories are presented illustrating the unpleasant and serious reactions that may follow precurarization with small doses of non‐depolarizing muscle relaxants. The importance of preoperative information, the necessity of relating the dose of the precurarizing drug to the weight of the patient and the possibility of hypersensitivity to this drug are emphasized.

Differential effect of pancuronium at the adductor pollicis, the first dorsal interosseous and the hypothenar muscles. An electromyographic and mechanomyographic dose-response study

Cumulative dose‐response curves were constructed from evoked compound electromyographic (EMG) recordings in man to compare the sensitivity to pancuronium of the adductor pollicis, the hypothenar and the first dorsal interosseous muscles. Also, the EMG and mechanomyography‐based sensitivity of the adductor pollicis muscle were compared. The EMG and the mechanomyogram were evaluated in random sequence in each of 21 adult thiopental, fentanyl and diazepam anesthetized patients. The EMG‐based ED50 were 36–38 μg · kg‐1 with no differences between muscles. The EMG‐based ED90 of the adductor pollicis and the hypothenar muscles were 62–65 μg · kg‐1 compared to the 60 μg · kg‐1 of the first dorsal interosseous muscle (P<0.05). ED50 (34 μg · kg‐1), and ED90 (56 μg · kg‐1) obtained from the adductor pollicis mechanomyogram were significantly lower than those based on the EMG (P<0.05). It is concluded that differences in sensitivity to pancuronium exist between the three muscles when evaluated from the EMG, and that the apparent sensitivity of a given muscle to a muscle relaxant may depend upon whether the response is evaluated using EMG or mechanomyography.