For many years, neuromuscular relaxants have been used in intensive care units (ICU). However, important differences are observed in the management of critically ill patients between Europe and North America. Recent surveys in the USA have shown that muscle relaxants were used in 20-70% of the patients. In Europe, muscle relaxants are less frequently used  and some feel that they are inappropriate. Bolus doses of muscle relaxants are sometimes given to aid intubation with less potential for trauma, but the more contentious issue is the continuous administration during prolonged stay in the ICU to facilitate artificial ventilation.
The use of suxamethonium is rarely indicated in the ICU. The most frequent indication for muscle relaxation is facilitation of mechanical ventilation [2,3]. Non-depolarizing muscle relaxants are used in patients unable to tolerate mechanical ventilation after the use of adequate doses of sedatives and analgesics. Any medical problem (alveolar hypoventilation, sepsis, pneumothorax) must be detected before administration of the muscle relaxant. Intermittent mandatory ventilation (IMV) or assisted spontaneous breathing (SIMV) contraindicate the administration of muscle relaxants. Relaxants can be used in patient with the adult respiratory distress syndrome because they may slightly improve chest wall compliance when the tone of the thoracic musculature is abolished. The risk of barotrauma may be reduced and the decrease in the activity of striated muscles could contribute to a decrease in oxygen consumption. Another indication is status asthmaticus when the patient does not respond to conventional therapy. Some authors have suggested that relaxants could be used in trauma patients with multiple fractures but there could be a potential problem resulting from the abolition of muscle tone. Muscle relaxants are used in the management of neurosurgical patients after severe head injury. The abolition of cough and resistance to the ventilator results in an improvement in cerebral perfusion and venous blood return which may limit the raise of intracranial pressure. The use of non-depolarizing muscle relaxants in patients with tetanus is indicated to reduce muscle spasms and permit intermittent positive pressure ventilation (IPPV) to be undertaken.
Choice of muscle relaxant
There are very few studies comparing the currently available relaxants for use in the ICU . For many years, pancuronium has been popular and widely used in the ICU because it was cheap and had a long duration of action. However, during renal failure a decrease in clearance is observed leading to a prolonged duration of action, because biliary excretion cannot compensate for the decrease in glomerular filtration. Plasma clearance is reduced in patients with hepatic disease and this can also lead to an accumulation. It is therefore more appropriate to administer pancuronium by bolus rather than by constant infusion in the critically ill.
Atracurium is the first muscle relaxant metabolized by ester hydrolysis and Hofmann elimination which takes place at a pH of 7.4 and a temperature of 37°C. In patients with renal failure, several pharmacokinetic and pharmacodynamic studies have shown no significant changes. Laudanosine, which has been shown to possess cerebral excitatory activity, may accumulate in patients with renal failure but the concentration attained after a continuous administration is 10 times less than toxic plasma level. Yate et al. have studied patients who were given atracurium for up to 6 days. The highest level of laudanosine was 5.1 μg ml−1 whereas the level required to produce cerebral irritation is about 14 μg ml−1 in dogs. However, the threshold for laudanosine CNS stimulation remains unknown in humans . In patients with fulminant hepatic failure the volume of distribution is significantly increased but the elimination half-life (23 min) remains unchanged.
Vecuronium is devoid of cardiovascular side effects and histamine releasing properties. Vecuronium is metabolized in the liver to 3-hydroxy vecuronium which has 50-70% of the potency of vecuronium. Although 3-hydroxy vecuronium undergoes pedominantly biliary excretion, Segredo et al. have reported prolonged neuromuscular blockade after long-term administration . The persistent high level of 3-hydroxy vecuronium in critically ill patients with renal failure could be the aetiology of some cases of prolonged neuromuscular block after termination of administration of vecuronium. Accumulation does not seem to occur when vecuronium is used in critically ill patients who have normal renal and hepatic function.
Mivacurium is metabolized in the plasma by pseudocholinesterase and has a very short half-life (17 min). Pseudocholinesterase is synthesized in the liver and the production is reduced by liver failure or sepsis. It is thus likely that the duration of action could be prolonged in the ICU. Mivacurium must be administered by continuous infusion because of its short duration of action. The consumption may be important and the cost of prolonged administration very expensive when compared with intermediate duration of action relaxants such as atracurium and vecuronium.
Cisatracurium is one of 10 isomers of atracurium. It is metabolized by Hofmann elimination; ester hydrolysis plays a limited role in humans. The two metabolites are laudanosine and a monoquaternary alcohol. Because of a greater potency than atracurium, the dose administered is less, and the production of laudanosine will be lower. Prielip et al. have suggested that cisatracurium is characterized by a more rapid recovery (68 ± 13 min) compared to vecuronium (387 ± 163 min) in ICU patients . However further studies are needed before one can draw conclusions, because of differences between the two groups.
Clinical monitoring of neuromuscular blockade
Although not all authors implicate the lack of monitoring as a factor in prolonged neuromuscular blockade, the use of a nerve stimulator can provide useful guidelines when administering muscle relaxants in the ICU . Some authors recommend the use of a train-of-four (TOF) at the adductor pollicis, retaining at least one twitch response, as a means of preventing prolonged neuromuscular block. It must be highlighted that peripheral muscles such as the adductor pollicis may be blocked with a dose insufficient to block the diaphragm and other respiratory muscles because the latter are more resistant to muscle relaxants. Absence of the TOF response at the adductor pollicis does not eliminate the possibility of hiccups or cough when suctioning because the laryngeal adductor muscles and the diaphragm recover more quickly than the adductor pollicis .
Complications and prolonged weakness
The risk of disconnection from the ventilator must be reduced by the mandatory use of a disconnection alarm. Some authors have suggested that the risk of pulmonary infection could be enhanced by the use of muscle relaxants in the ICU because of ventilation-perfusion impairment and sputum retention due to the absence of a cough reflex. However, this hypothesis has never been confirmed. Adequate sedation and analgesia should always be established before the administration of muscle relaxants to reduce the risk of awareness.
It is difficult to assess the neurological state of a fully paralysed patient. Diagnosis of a complication such as the expansion of a subdural haematoma in a paralysed patient may be missed. Although muscle relaxants can be used in patients with raised intracranial pressure, they should be discontinued at regular intervals to allow neurological assessment of the patient.
Tachyphylaxis to relaxants may occur in ICU patients. This resistance begins to develop after 2-4 days. It has been suggested that the resistance is related to an increase in the number of extrajunctional receptors following chronic administration even in the absence of immobilization . Chronic partial neuromuscular blockade may induce the same response as a partial or complete deafferentation injury, different from immobilization.
Chronic administration can induce prolonged neuromuscular dysfunction after discontinuation of the drug. Op de Coul et al. were the first to report patients who developed severe tetraparesis with areflexia after discontinuation of pancuronium . These cases of tetraparesis or quadraparesis, initially described in patients who received either pancuronium or vecuronium [8,12], have also been observed in critically ill patients paralysed by atracurium . A muscle biopsy in some patients has demonstrated acute severe neurogenic atrophy . It was suggested that the muscle relaxant had caused a blockade of neuromuscular transmission, severe enough to lead to actual denervation of some muscle fibres. This prolonged weakness is different from the typical critical illness polyneuropathy which is a sensorimotor polyneuropathy and can occur during sepsis in patients who are not treated by muscle relaxants. A significant incidence of prolonged weakness has been reported in patients receiving a steroid muscle relaxant in combination with corticosteroids during status asthmaticus or organ transplantation. Muscle biopsy can demonstrate atrophy, muscle necrosis and regeneration without inflammation which is compatible with deafferentation or muscle injury. Segredo et al. observed persistent high levels of 3-OH vecuronium in some patients with renal failure, which could accumulate in tissues and contribute to prolonged weakness. Metabolic acidosis with elevated plasma concentrations of magnesium could also contribute to prolonged neuromuscular blockade .
In burnt patients, a decreased sensitivity to non-depolarizing muscle relaxants has been described. Resistance is linearly related to the extent of the burn. The most important factor is the decreased sensitivity of the postsynaptic ACh receptor together with an upregulation of ACh release.
Non-depolarizing muscle relaxants must not be used alone, but in association with analgesics or sedative drugs. When used by continuous administration, neuromuscular monitoring is helpful to adjust the rate of infusion, although it does not prevent the development of a myopathy or polyneuropathy. Guidelines on the use of muscle relaxants, aimed at minimizing complications, are given in Table 1.
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6 Yate PM, Flynn PM, Arnold RW, Weatherley B, Simmonds RJ, Dopson T. Clinical experience and plasma laudanosine concentrations during atracurium infusion in the intensive therapy unit. Br J Anaesth
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8 Segredo V, Caldwell JE, Matthay M, Sharma ML, Gruenke LD, Miller RD. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med
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11 Hogue CW, Ward JM, Itani S, Martyn JAJ. Tolerance and upregulation of acetylcholine receptors following chronic infusion of d-tubocurarine. J Appl Physiol
12 Gooch JL, Suchyta MR, Balbierz JM, Petajan JH, Clemmer TP. Prolonged paralysis after treatment with neuromuscular junction blocking agents. Crit Care Med
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Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997
This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.