The Relaxometer: a complete and comprehensive computer-controlled neuromuscular transmission measurement system developed for clinical research on muscle relaxants.

The Relaxometer is a computer-controlled system developed for reliable clinical experimental measurements on neuromuscular block. This system is based on an adapted personal computer (Atari 1040 ST) with a monochrome monitor (Atari SM 124), and a microcomputer-driven slave unit (stimulator). There are several stimulation patterns available: single twitch at 0.1 and 1 Hz, single train-of-four, continuous train-of-four every 12 seconds, and tetanic stimulation at 50 Hz for 5 seconds followed by posttetanic count. The system is equipped with a temperature module for continuous monitoring of the skin/muscle temperature and a rechargeable battery to allow uninterrupted measurements if the apparatus is disconnected from the line power. All acquired data, computer-calculated parameters (onset time, duration time, recovery index, train-of-four ratio, tetanic fade, and posttetanic count), and the mechanomyogram are presented on screen continuously, are stored on floppy disk, and can be printed in a well-organized format.

Atracurium-induced neuromuscular block in the isolated arm.

A modification of the isolated arm technique was applied in 10 females under opioid-based i.v. anaesthesia for comparison of the offset of an atracurium-induced neuromuscular block in an isolated arm to an arm with maintained circulation. The neuromuscular blocking effect of a bolus dose of atracurium 0.5 mg.kg-1 was measured bilaterally using the integrated adductor pollicis EMG response (integrated T1 EMG response in % of baseline value and T4/T1 ratio) after bilateral ulnar nerve train-of-four (TOF) stimulation. At 10% T1 recovery, one arm was isolated from the general circulation for 20 min by means of a tourniquet cuff (isolated arm), while normal circulation was maintained in the other arm (control arm). In both arms, the TOF response, peripheral skin temperature, mixed peripheral venous pH and plasma concentrations of atracurium and laudanosine were then measured and compared. Core and peripheral skin temperatures in both arms remained stable and normal throughout the study, and mixed peripheral venous pH stayed within physiological limits in both arms in all subjects. In the isolated arm, recovery of the neuromuscular block was markedly delayed compared to the control arm, the integrated EMG T1 response and TOF ratio being significantly reduced in the isolated arm after 20 min of isolation. The decline in plasma concentration of atracurium was less in the isolated arm than in the control arm, whereas laudanosine levels increased in the isolated and decreased in the control arm. Normal peripheral circulation is of major importance for termination of an atracurium-induced neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)

Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium.

The intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required.

Clinical pharmacokinetics of neuromuscular blocking drugs.

Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

A method for studying the pharmacodynamic profile of neuromuscular blocking agents on vocal cord movements in anaesthetized cats.

1. A new in vivo experimental method is described whereby the neuromuscular blocking effects of muscle relaxants can be investigated on the intrinsic laryngeal muscles of anaesthetized cats. The peripheral tibialis anterior muscle preparation is employed in the same animal to compare the blocking effect on both preparations. 2. The intrinsic laryngeal muscles react with different sensitivities to the neuromuscular blocking agents when compared to the tibialis anterior muscle. 3. The neuromuscular response in both muscle preparations is similar with steroidal agents but appeared to be different after suxamethonium or isoquinoline analogues. 4. It is concluded that this preparation may become a useful tool for studying new muscle relaxants developed to facilitate rapid intubation conditions.

Pharmacokinetics and neuromuscular blocking effects of atracurium besylate and two of its metabolites in patients with normal and impaired renal function.

The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean ( +/- SD) terminal half-life (176 +/- 84 and 516 +/- 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 +/- 8.3 minutes in patients with normal renal function to 42.5 +/- 8.3 minutes in those with impaired renal function (mean +/- SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis. The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1 Hz. The total duration of neuromuscular blockade (51.8 +/- 11.5 minutes) and the recovery index (9.6 +/- 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 +/- 7.2 and 16.7 +/- 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

Pharmacokinetics and cardiovascular dynamics of pipecuronium bromide during coronary artery surgery.

The haemodynamic effects of 200 micrograms.kg-1 pipecuronium and pancuronium were compared under etomidate/piritramide anaesthesia in 20 patients scheduled for elective coronary artery surgery. Following the completion of the haemodynamic measurements (ten minutes), anaesthesia was maintained by etomidate/sufentanil infusion. The mean changes in cardiac output were approximately -19 and -2 per cent and in heart rate -1 and +26 per cent for pipecuronium and pancuronium respectively. Plasma and urine concentrations of pipecuronium were also measured and the pharmacokinetic variables obtained indicated rapid initial decrease in plasma concentration (t1/2 = 7.6 minutes) followed by a longer terminal phase (t1/2 = 161 minutes). The central compartment volume was 102 +/- 24 ml.kg-1 and plasma clearance was 1.8 +/- 0.4 ml.kg-1 min-1. Approximately 56 per cent of the dose was recovered from the urine within 24 hours of administration and about 25 per cent of this was the metabolite, 3-desacetyl pipecuronium. High-dose pipecuronium administration under the anaesthetic regimen employed did not produce deleterious haemodynamic effects. The pharmacokinetic variables after bolus injection of pipecuronium did not deviate from those reported under normothermic conditions.

Pharmacokinetics and disposition of pipecuronium bromide in the cat.

The pharmacokinetics and hepatic disposition of pipecuronium have been investigated in cats with normal and absent renal function. A combined fluorimetric and chromatographic technique was used to determine the concentrations of pipecuronium and its metabolites in the samples. Following intravenous injection of 150 micrograms kg-1, pipecuronium disappeared from the plasma bi-exponentially with half-lives of 9.8 +/- 5.4, 77.7 +/- 9.7 min and 7.2 +/- 5.0, 100, 6 +/- 23.7 min; the Vd was 362.3 +/- 74.9 ml kg-1 and 123.7 +/- 14.6 ml kg-1 and the clearance was 5.0 +/- 0.9 ml min-1 kg-1 and 1.0 +/- 0.1 ml min-1 in the animals with and without renal function, respectively. In the animals with normal kidney function 53%, 12% and 8% of the administered dose of pipecuronium were recovered within 8 h in the urine, bile and liver, respectively. In 'nephrectomized' cats the lack of renal elimination was to a great extent compensated for by increased hepato-biliary elimination. Absence of renal function significantly altered the pharmacokinetic parameters and prolonged the time-course of the neuromuscular blocking effects of pipecuronium. Neither temporary hepatic exclusion nor intraportal administration of pipecuronium indicated any significant role of the liver in handling pipecuronium. Renal excretion seems to be the predominant route of elimination. No metabolites were found in this study.