The sick and the weak: Neuropathies/ myopathies in the critically ill

Abstract

Friedrich O, Reid MB, Van den Berghe G, Vanhorebeek I, Hermans G, Rich MM, and Larsson L. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. Physiol Rev 5: 1025-1109, 2015; Published July 1, 2015; doi:10.1152/physrev.00028.2014.— Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complica- tions of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventila- tion, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require strin- gent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, pref- erential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excit- ability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction con- tributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca2dysregulation is present through altered Ca2homeostasis. We highlight clinical hall-marks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.