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Continuous administration of pyridostigmine improves immobilization-induced neuromuscular weakness

Frick, Christiane G. MD; Helming, Marc MD; Martyn, J. A. Jeevendra MD, FRCA, FCCM; Blobner, Manfred MD; Fink, Heidrun MD

doi: 10.1097/CCM.0b013e3181c31297
Neurologic Critical Care

Objective: To investigate the effects of continuous pyridostigmine infusion on immobilization-induced muscle weakness. Critical illness often results in immobilization of limb and respiratory muscles, leading to muscle atrophy and up-regulation of nicotinic acetylcholine receptors. Pyridostigmine reversibly blocks acetylcholinesterase and has the potential to improve neuromuscular transmission and decrease acetylcholine receptor number.

Design: Prospective, randomized, controlled experimental study.

Setting: Animal laboratory, university hospital.

Subjects: Male Sprague-Dawley rats.

Interventions: A total of 40 rats were immobilized in one hind limb by pinning knee and ankle joints. Rats received either continuous pyridostigmine (15 mg·kg−1·day−1) or saline subcutaneously via implanted osmotic pumps.

Measurements and Main Results: After 7 days and 14 days of immobilization, neuromuscular function, atracurium pharmacodynamics, and expression of acetylcholine receptors were evaluated. At 7 days and 14 days after immobilization, muscle force decreased in all untreated groups, whereas effective doses for paralysis with atracurium and acetylcholine receptor number in the tibialis were significantly increased. Pyridostigmine-treated rats showed a significantly improved muscle force and muscle mass in the immobilized limb. This was associated with an attenuation of acetylcholine receptor up-regulation in the respective leg. At this time, the dose-response curve for atracurium on the immobilized side was shifted to the left in the pyridostigmine group. After 14 days, muscle tension was still less depressed with pyridostigmine infusion, and resistance to the effects of atracurium was still attenuated. However, there were no differences in acetylcholine receptor expression between the immobilized sides of both groups.

Conclusions: Continuous pyridostigmine infusion improves muscle weakness after 7 days and 14 days of immobilization. The up-regulation of acetylcholine receptors and the concomitant resistance to atracurium is attenuated in animals treated with pyridostigmine after 7 days of immobilization.

From the Klinik für Anaesthesiologie (CGF, MH, MB, HF), Klinikum rechts der Isar, Technische Universität München, Munich, Germany; and Department of Anesthesia and Critical Care (CGF, JAJM), Harvard Medical School, Massachusetts General Hospital, and Shriners Hospital for Children, Boston, MA.

This study was supported, in part, by institutional funds of Klinikum rechts der Isar and by Grants GM 31569-25, GM 2150-36-ProjectIV, and GM 055082-11 from the National Institutes of Health and Shriners Hospital Research Philantrophy, Tampa, FL (J.A.J.M.).

This work was presented, in part, at the 2008 Annual Meeting of the American Society of Anesthesiologists, Orlando, FL.

The authors have not disclosed any potential conflicts of interest.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins