Systemic inflammation leads to resistance to atracurium without increasing membrane expression of acetylcholine receptors

Background: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha(1)-acid glycoprotein in a rat model of systemic inflammation. Methods: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atra-curium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using I-125-alpha-bungarotoxin. alpha(1)-Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. Results: The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 mug/ml) compared with control rats (4.23 +/- 0.82 mug/ml). The alpha(1)-acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6-52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. Conclusion: Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha(1)-acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.