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Rocuronium exacerbates mechanical ventilation–induced diaphragm dysfunction in rats

Testelmans, Dries MD; Maes, Karen; Wouters, Patrick MD, PhD; Gosselin, Nadège PhD; Deruisseau, Keith PhD; Powers, Scott PhD, EdD; Sciot, Raf MD, PhD; Decramer, Marc MD, PhD; Gayan-Ramirez, Ghislaine PhD

doi: 10.1097/01.CCM.0000245783.28478.AD
Laboratory Investigations
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Objective: Nondepolarizing neuromuscular blocking agents are commonly used in the intensive care setting, but they have occasionally been associated with development of myopathy. In addition, diaphragmatic atrophy and a reduction in diaphragmatic force were reported after short-term controlled mechanical ventilation in animal models. We hypothesized that infusion of rocuronium, an aminosteroidal neuromuscular blocking agent, during 24 hrs of controlled mechanical ventilation would further alter diaphragm function and would enhance activation of the ubiquitin– proteasome pathway.

Design: Randomized, controlled experiment.

Setting: Basic animal science laboratory.

Subjects: Male Wistar rats, 14 wks old.

Interventions: Rats were divided into four groups: a control group, a group of anesthetized rats breathing spontaneously for 24 hrs, and two groups submitted to mechanical ventilation for 24 hrs, receiving a continuous infusion of either 0.9% NaCl or rocuronium.

Measurements and Main Results: In vitro diaphragm force was decreased more significantly after 24 hrs of mechanical ventilation combined with rocuronium infusion than after mechanical ventilation alone (e.g., tetanic force, −27%; p < .001 vs. mechanical ventilation). Similarly, the decrease in diaphragm type IIx/b fiber dimensions was more pronounced after mechanical ventilation with rocuronium treatment than with saline treatment (−38% and −29%, respectively; p < .001 vs. control). Diaphragm hydroperoxide levels increased similarly in both mechanically ventilated groups. Diaphragm muscle RING-finger protein-1 (MURF-1) messenger RNA expression, an E3 ligase of the ubiquitin–proteasome pathway, increased after mechanical ventilation (+212%, p < .001 vs. control) and increased further with combination of rocuronium (+320%, p < .001 vs. control). Significant correlations were found between expression of MURF-1 messenger RNA, diaphragm force, and type IIx/b fiber dimensions.

Conclusions: Infusion of rocuronium during controlled mechanical ventilation leads to further deterioration of diaphragm function, additional atrophy of type IIx/b fibers, and an increase in MURF-1 messenger RNA in the diaphragm, which suggests an activation of the ubiquitin–proteasome pathway. These findings could be important with regard to weaning failure in patients receiving this drug for prolonged periods in the intensive care unit setting.

From the Respiratory Muscle Research Unit, Laboratory of Pneumology and Respiratory Division (DT, KM, NG, MD, GGR), and the Departments of Anesthesiology (PW) and Morphology and Molecular Pathology (RS), Katholieke Universiteit Leuven, Leuven, Belgium; and the Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL (KD, SP).

The authors have not disclosed any potential conflicts of interest.

Dr. Testelmans is an aspirant and Dr. Gayan-Ramirez is a postdoctoral fellow of the “Fonds voor Wetenschappelijk Onderzoek–Vlaanderen.”

Supported, in part, by “Fonds voor Wetenschappelijk Onderzoek–Vlaanderen” grants G.0389.03, KULeuven Research Foundation OT 02/44, BIL 99/19 Ministerie Vlaamse Gemeenschap, Belgium, and Astra-Zeneca Pharmaceuticals.

© 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins