Neuromuscular transmission and its pharmacological blockade Part 3: Continuous infusion of relaxants and reversal and monitoring of relaxation

Continuous infusion is an attractive method of administration when muscle relaxation is needed for a longer period. The pharmacokinetic behaviour of a drug is an important determining factor for the suitability of relaxants for continuous infusion. At present mainly intermediately long acting relaxants are used for this purpose. At the end of surgery residual curarization may exist and thus anaesthesiologists prefer to be able to reverse the relaxants. The anticholinesterases neostigmine, pyridostigmine, and edrophonium are used clinically for this reason. Their effect is prolonged in patients with renal failure, and also affected during acid-base disturbances. Some other drugs have been used experimentally for the reversal of neuromuscular blockade, but are inadequate. Special problems can arise when reversal of a mivacurium-induced or antibiotic-induced blockade is wanted, or mivacurium was administered. Monitoring neuromuscular transmission is an important feature to determine the effect of relaxant administration or to detect residual curarization. It is based on stimulation of peripheral nerves with either single twitch, train of four, tetanic or double burst stimulation. The evoked response can be quantitated with mechanomyography, electromyography, or accelerography. The response of the various muscles to nerve stimulation varies due to the different characteristics of the muscles. Clinically, the use of the adductor polHcis muscle is advised. Accepted October 1996 When muscle relaxants are intermittently adminis­ tered a continuously changing degree of neuromus­ cular blockade is present, depending on the change in relaxant plasma concentration. Administration of relaxant by continuous infusion leads to a constant concentration, and thus a stable effect. This, however, demands high controlability of the drug, and thus pharmacodynamicaliy a rapid onset, a short duration, and a rapid recovery. This can pharmacokinetically be translated in short elimination half-life and large plasma clearance. A large plasma clearance is reached by rapid redistribution, rapid metabolism, or rapid excretion. This would mean that suxamethonium, mivacurium, atracurium, vecuro­ nium, and rocuronium are suitable for continuous infusion. Relaxants with a long duration of action are likely to accumulate, and thus will lead to prolonged duration of action when administered by infusion. The amount of relaxant that must be infused depends on the patients' weight and length, the pharmacoki­ netic characteristics of the relaxant, the presence of concurrent diseases, and the simultaneous use of other drugs. If the rate of drug delivery is equal to its plasma clearance, a steady state concentration can be reached. Such an infusion rate equals the desired plasma concentration times the clearance. It will, however, take an infusion during five to seven times the elimination half-life before the steady state is reached. This can be shortened by administration of a loading bolus dose followed immediately by the con­ tinuous infusion. Because of the high interindividual variability in effect of the relaxant it is advisable to monitor the neuromuscular function. Computer controlled closed loop systems have been used for continuous administration of muscle relaxants [5 6], With such systems a preset degree of neuromuscular blockade can be maintained. The nec­ essary device incudes a monitor, a comparator, and an infusion pump. The rate of infusion is determined by measurement of the degree of blockade. This indi­ cates that some overshoot, and undershoot, will be present, depending on the time constant of the par­ ticular relaxant administered. The shorter the time constant, i.e. the more rapid onset, and shorter dura­ tion, the better the performance of the closed loop system can be, and the smaller the over-, and under­ shoot. Versatile systems for closed-loop administra­ tion of atracurium and vecuronium have been devel­ oped [7]. Rocuronium has also been administered by continuous infusion in a closed-loop feedback control system [8]. Such closed-loop systems are operated either: 1. proportional, in which the controller gain is uni­ formly proportional to the input (change in infu­ sion speed) 2. integral, in which the controller acts with increas­ ing response to an error signal 3. derivative, in which the controller anticipates on the trend of the error signal, and thus applies a cor­ recting action ahead of this error (on-off control). Others have developed systems that hold pharmaco­ kinetic algorythms to reach a desired plasma concen­ tration [9]. In these systems there is most of the time no feed-back from the degree of neuromuscular blockade, and thus accumulation and prolonged effect may occur in individual cases. Infusion is also possible without a closes loop system. After a bolus dose of the relaxant a continu­ ous infusion is started at a particular rate. When the drugs are administered in the intensive care unit a lower dose is usually sufficient to reach adequate