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Intensive care unit-acquired weakness, the main clinical sign of critical illness neuromyopathy, is an increasingly recognized cause of prolonged mechanical ventilation and delayed return to physical self-sufficiency. Identifying risk factors and developing preventive measures are therefore important goals. Several studies on risk factors for critical illness neuromyopathy including prospective observational studies with a multivariate analysis of potential risk factors were conducted over the last decade. A large body of data is also available from two large prospective randomized trials comparing the effect of strict vs. conventional blood-glucose control on intensive care unit mortality and on secondary outcomes including the occurrence of critical illness neuromyopathy. Five central risk factors and their related potential measures to prevent intensive care unit-acquired weakness can be identified including multiple organ failure, muscle inactivity, hyperglycemia, and use of corticosteroids and neuromuscular blockers. Although strong evidence regarding the efficacy of preventive measures is still lacking, the results of available studies are promising and cast doubt on the widespread belief that the treatment of intensive care unit-acquired weakness is essentially supportive. Early identifying and treating conditions leading to multiple organ failure, especially severe sepsis and septic shock, avoiding unnecessary deep sedation and excessive blood glucose levels, promoting early mobilization, and carefully weighing the risks and benefits of corticosteroids might contribute to reduce the incidence and severity of intensive care unit-acquired weakness.