Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: Mechanisms at the cellular and molecular levels

Objective: Long-term treatment with nondepolarizing neuromuscular blocking agents and corticosteroids in the intensive care unit is not benign, and an increasing number of patients with acute quadriplegic myopathy have been r eported with increased use of these drugs, The purpose of this study was to investigate the mechanisms underlying acute quadriplegic myopathy, Design: Percutaneous muscle biopsy samples were obtained, and electrophysio logic examinations were performed during the acute phase and during recover y in patients with acute quadriplegic myopathy, Regulation of muscle contra ction and myofibrillar protein synthesis was studied using cell physiologic techniques, ultrasensitive electrophoresis, in situ hybridization, and his topathologic techniques. Setting: All patients were seen in the intensive care unit of different uni versity hospitals. Patients: All patients were critically ill with sepsis, They had been given massive doses of corticosteroids in combination with variable doses of neu romuscular blocking agents. All patients developed paralysis of spinal nerv e-innervated muscles. On the other hand, cranial nerve-innervated muscle an d sensory and cognitive functions were well maintained after discontinuatio n of treatment with neuromuscular blocking agents. Intervention: Muscle biopsy samples were obtained and electrophysiologic ex aminations were performed in all patients. Measurements and Main Results: The major observations in patients with acut e quadriplegic myopathy were, as follows: a) a general decrease in myofibri llar protein content; b) specific but highly variable partial or complete l oss of myosin and myosin-associated proteins; c) very low thick-filament/th in-filament protein ratios; d) absence of myosin messenger RNA; and e) a dr amatically impaired muscle cell force-generating capacity in the acute phas e of acute quadriplegic myopathy, During clinical improvement, normal expre ssion of myosin messenger RNAs, reexpression of thick-filament proteins, an d increased specific tension were observed. Conclusions: Acute quadriplegic myopathy is associated with a specific decr ease in thick-filament proteins related to an altered transcription rate. A lthough the decreased content of thick-filament proteins is important far p rolonged muscle weakness, it is not the primary cause of muscle paralysis i n the acute stage, during which impaired muscle membrane excitability proba bly plays a more significant role. Several factors contribute to this condi tion, but the action of corticosteroids seems to be the predominant one, al ong with potentiation by neuromuscular blocking agents, immobilization, and probably also concurrent sepsis.