Atracurium dibesilate

Cardiovascular

There have been reports of hypotension [ ] attributed to histamine release by atracurium. A large prospective surveillance study involving more than 1800 patients given atracurium showed a 10% incidence of adverse reactions, with moderate hypotension (20–50% decrease) in 3.5% of patients [ ]. In one study cardiovascular stability was maintained with atracurium up to doses of 0.4 mg/kg [ ]. However, at higher doses (0.5 and 0.6 mg/kg) arterial pressure fell by 13% and 20% and heart rate increased by 5% and 8% respectively. These effects were maximal at 1–1.5 minutes. Since these cardiovascular effects were associated with facial flushing, it was suggested that they might have resulted from histamine release. In a subsequent study the same investigators linked significant cardiovascular changes to increased plasma histamine concentrations at a dose of atracurium of 0.6 mg/kg [ ]. Injecting this dose slowly over 75 seconds caused less histamine release and adverse hemodynamic effects [ ]. However, other investigators found no correlation between histamine plasma concentrations and hemodynamic reactions after atracurium administration [ ].

Cardiovascular effects, apart from those resulting from histamine release, appear to be almost entirely limited to bradycardia. From animal studies, vagolytic [ ] and ganglion-blocking [ ] effects are very unlikely to occur at neuromuscular blocking doses, and these predictions appear to be borne out by investigations in man, cardiovascular effects being reported only at high dosages associated with signs suggestive of histamine release [ , , ]. The bradycardia [ ] is occasionally severe, but, as with vecuronium, the explanation seems to be that the bradycardic effects of other agents used during anesthesia are not attenuated by atracurium as they are by alcuronium, gallamine, or pancuronium, which have vagolytic (or sympathomimetic) effects. The possibility that bradycardia can be caused by one of the metabolites, such as laudanosine [ ], which is structurally similar to apomorphine, has yet to be excluded. An animal study has suggested that noradrenaline release from sympathetic nerve terminals can be increased by very large doses of atracurium, probably because of high concentrations of laudanosine [ ]. Clinically, cardiovascular effects from this source would only be expected in circumstances that produced much higher than usual laudanosine concentrations.

Hypoxemia has been incidentally reported [ ], and most probably resulted from an increase in left cardiac shunting (in a patient with a ventricular septal defect and pulmonary atresia). Atracurium (0.2 mg/kg) may have produced a fall in systemic vascular resistance, perhaps from histamine release; pancuronium was subsequently given without incident.

Nervous system

The major metabolite of atracurium, laudanosine, can cross the blood–brain barrier (CSF/plasma ratios of 0.3–0.6 are found in dogs) [ ] and produce strychnine-like nervous system stimulation, which at high plasma concentrations (around 17 ng/ml) leads to convulsions in dogs [ ]. CSF/plasma ratios of laudanosine in man have been reported to be between 0.01 and 0.14 after a 0.5 mg/kg dose of atracurium in a study in which the highest laudanosine concentration was 14 ng/ml [ ]. Much higher CSF laudanosine concentrations (mean 202 ng/ml, highest 570 ng/ml) were measured after larger atracurium doses (0.5 mg/kg/hour) during intracranial surgery [ ].

Patients in whom the blood–brain barrier is not intact, such as during neurosurgical procedures, may be at risk from exposure of the brain to unpredictable concentrations of laudanosine (and other drugs). Two patients had fits but these were not thought to be related to laudanosine [ ]. Under normal circumstances plasma concentrations in man will be far below those required for significant central nervous stimulation. However, the half-life of laudanosine [ ] is considerably longer than that of atracurium [ ], so that there is a possibility of laudanosine accumulation if many repeated doses or prolonged infusions of atracurium are given.

Skin

Minor skin reactions lasting 5–30 minutes occur in 10–50% of patients according to various studies and are not usually associated with obvious systemic effects [ , ]. They are probably due to histamine release. A 42% incidence of cutaneous flushing has been reported in 200 patients; the effect was dose-dependent, being 18% at 0.4 mg/kg, 33% at 0.5 and 0.6 mg/kg, and 73% at 1 mg/kg [ ]. One patient in this study, in the 1 mg/kg group, developed generalized erythema, hypotension, tachycardia, and bronchospasm.

Immunologic

There have been reports of angioedema [ ] and bronchospasm [ , ], attributed to histamine release. A large prospective surveillance study involving more than 1800 patients given atracurium showed a 10% incidence of adverse reactions, with bronchospasm in 0.2% of patients [ ].

Extreme sensitivity to an intradermal skin test (0.003 mg), some 24 hours after a severe skin reaction to the intravenous administration of atracurium, has been described [ ].

Severe systemic reactions after atracurium administration may be due to antibody-mediated anaphylaxis [ ] rather than non-specific histamine liberation. It has been suggested that systemic effects from non-specific histamine release are dose-dependent.

Fetotoxicity

Placental transfer of atracurium occurs [ ]. In 46 patients undergoing cesarean section [ ], while the Apgar scores did not differ between neonates whose mothers had received atracurium (0.3 mg/kg) or tubocurarine (0.3 mg/kg), the neurological and adaptive capacity scores (NACS) at 15 minutes (but not at 2 and 24 hours) after birth were lower after atracurium. The NACS values were normal in 83% of the babies in the tubocurarine group and in 55% of those in the atracurium group. The difference was primarily due to lower scores for active contraction of the neck extensor and flexor muscles. These results cannot be satisfactorily explained by partial curarization in some neonates of the atracurium group because the placental transfer of atracurium was lower in the atracurium group; the umbilical vein concentrations of atracurium after clamping of the umbilical cord being approximately one-tenth of the EC50 for block of neuromuscular transmission in neonates.