Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats.
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.


METHODS
Randomized, controlled experiment.


METHODS
Basic animal science laboratory.


METHODS
Male Wistar rats, 14 wks old.


METHODS
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.


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.
Testelmans
Dries
D
Respiratory Muscle Research Unit, Laboratory of Pneumology and Respiratory Division, Katholieke Universiteit Leuven, Leuven, Belgium.
Maes
Karen
K
Wouters
Patrick
P
Gosselin
Nadège
N
Deruisseau
Keith
K
Powers
Scott
S
Sciot
Raf
R
Decramer
Marc
M
Gayan-Ramirez
Ghislaine
G
D000732:Androstanols / Q000009:adverse effects*; D000818:Animals; D003964:Diaphragm / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009133:Muscular Atrophy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003473:Neuromuscular Nondepolarizing Agents / Q000009:adverse effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial / Q000009:adverse effects*; D000077123:Rocuronium; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics
D000732:Androstanols; D008054:Lipid Peroxides; D009124:Muscle Proteins; D003473:Neuromuscular Nondepolarizing Agents; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D000077123:Rocuronium