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 reported with increased use of these drugs. The purpose of this study was to investigate the mechanisms underlying acute quadriplegic myopathy.


METHODS
Percutaneous muscle biopsy samples were obtained, and electrophysiologic examinations were performed during the acute phase and during recovery in patients with acute quadriplegic myopathy. Regulation of muscle contraction and myofibrillar protein synthesis was studied using cell physiologic techniques, ultrasensitive electrophoresis, in situ hybridization, and histopathologic techniques.


METHODS
All patients were seen in the intensive care unit of different university hospitals.


METHODS
All patients were critically ill with sepsis. They had been given massive doses of corticosteroids in combination with variable doses of neuromuscular blocking agents. All patients developed paralysis of spinal nerve-innervated muscles. On the other hand, cranial nerve-innervated muscle and sensory and cognitive functions were well maintained after discontinuation of treatment with neuromuscular blocking agents.


METHODS
Muscle biopsy samples were obtained and electrophysiologic examinations were performed in all patients.


RESULTS
The major observations in patients with acute quadriplegic myopathy were, as follows: a) a general decrease in myofibrillar protein content; b) specific but highly variable partial or complete loss of myosin and myosin-associated proteins; c) very low thick-filament/thin-filament protein ratios; d) absence of myosin messenger RNA; and e) a dramatically impaired muscle cell force-generating capacity in the acute phase of acute quadriplegic myopathy. During clinical improvement, normal expression of myosin messenger RNAs, reexpression of thick-filament proteins, and increased specific tension were observed.


CONCLUSIONS
Acute quadriplegic myopathy is associated with a specific decrease in thick-filament proteins related to an altered transcription rate. Although the decreased content of thick-filament proteins is important for prolonged muscle weakness, it is not the primary cause of muscle paralysis in the acute stage, during which impaired muscle membrane excitability probably plays a more significant role. Several factors contribute to this condition, but the action of corticosteroids seems to be the predominant one, along with potentiation by neuromuscular blocking agents, immobilization, and probably also concurrent sepsis.
Larsson
L
L
Noll Physiological Research Center, Pennsylvania State University, University Park 16802-6900, USA. lgl5@psu.edu
Li
X
X
Edström
L
L
Eriksson
L I
LI
Zackrisson
H
H
Argentini
C
C
Schiaffino
S
S
D000208:Acute Disease; D000305:Adrenal Cortex Hormones / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D004359:Drug Therapy, Combination; D004576:Electromyography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D009210:Myofibrils / Q000378:metabolism; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D003473:Neuromuscular Nondepolarizing Agents / Q000009:adverse effects*; D011782:Quadriplegia / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial; D018805:Sepsis / Q000150:complications / Q000188:drug therapy
D000305:Adrenal Cortex Hormones; D003473:Neuromuscular Nondepolarizing Agents; D012333:RNA, Messenger; D009218:Myosins