Infusions of rocuronium and cisatracurium exert different effects on rat diaphragm function

Abstract

Objective: Aminosteroidal and benzylisoquinoline neuromuscular blocking agents are used in the intensive care unit to facilitate mechanical ventilation. The use of these agents has been associated with development of critical illness myopathy; however, the relative frequency of myopathy development among agents is not known. The aim of our study was to compare the effects of 24 h infusion of rocuronium or cisatracurium on the diaphragm in mechanically ventilated rats. Design: Randomized, controlled experiment. Setting: Basic animal science laboratory. Subjects: Male Wistar rats, 14 weeks old. Interventions: Rats were divided into four groups to receive either saline, rocuronium (low dose) or cisatracurium (low or high dose). Measurements and results: After 24 h, in vitro diaphragm tetanic force was decreased after rocuronium (-33% vs. saline), while the force was more preserved after cisatracurium, even in the high-dose group. Cross-sectional areas of the different diaphragm and gastrocnemius fibers were unaltered. Diaphragmatic MURF-1 mRNA was increased after rocuronium (+44% vs. saline), while unchanged in both cisatracurium groups. Calpain activity was increased after rocuronium (+75% vs. saline) and unchanged in the cisatracurium groups. MURF-1 mRNA expression and calpain activity were negatively correlated with diaphragm force. Conclusions: Cisatracurium infusion during controlled mechanical ventilation exerted less detrimental effects on diaphragm function and proteolytic activity than infusion of rocuronium, even with the higher effective dose. These data suggest that increased calpain activity and increased activation of the ubiquitin proteasome system play a role in the different effects of these agents.

Ventilator-induced diaphragm dysfunction: cause and effect

“…A possible complication of using neuromuscular-blocking agents in the ICU is skeletal muscle myopathy and contractile dysfunction. In this regard, two investigations reveal that use of the neuromuscular-blocking agent rocuronium increases the magnitude of MV-induced diaphragmatic contractile dysfunction in rats (108,109). In contrast, another recent study using a porcine model of MV concluded that treatment of animals with rocuronium does not have an additive effect on MVinduced diaphragm dysfunction (78).…”

The Use of Paralytics in Patients with Acute Respiratory Distress Syndrome

“…Moreover, the use of steroid NMBAs and duration of infusion exceeding 48 hours seem to further favor the occurrence of myopathies. 40,41 Confirming these data, in the ACURASYS study, in which patients received a short course of nonsteroid NMBAs, 6 the incidence of ICU-acquired paresis (evaluated based on the Medical Research Council 33 score on day 28 or at the time of ICU discharge) was not higher in paralyzed patients than in the control group. Furthermore, in the meta-analysis by Alhazzani and colleagues, 25 the use of NMBAs was not associated with an increased risk of ICUAW.…”

Clinical Predictors of Duration of Action of Cisatracurium and Rocuronium Administered Long-Term

“…42 NBDs have been defined as a risk factor for critical illness polyneuropathy and myopathy, conditions manifested by muscle weakness in critically ill patients. [11][12][13][14]42 Moreover, infusion of rocuronium 12 and cisatracurium 14 for a single day in rats compromises diaphragmatic function by a myopathic mechanism that does not involve neuromuscular transmission failure. 12 Moreover, the combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of myofibers in the diaphragm of humans.…”

“…[8][9][10] Moreover, long-term administration of NBDs is a risk factor for the development of critical illness polyneuropathy. [11][12][13][14] Finally, recent animal data suggest that a constant neuromuscular blockade with rocuronium and cisatracurium over only a single day evokes a myopathy that significantly decreases diaphragmatic force. 12,14 Therefore, we feel it is important for clinicians to get information about variables that predict the duration of action of NBDs administered long-term.…”

“…[11][12][13][14] Finally, recent animal data suggest that a constant neuromuscular blockade with rocuronium and cisatracurium over only a single day evokes a myopathy that significantly decreases diaphragmatic force. 12,14 Therefore, we feel it is important for clinicians to get information about variables that predict the duration of action of NBDs administered long-term. We aimed at determining predictors of duration of action of cisatracurium and rocuronium administered long-term.…”