Factors Underlying the Early Limb Muscle Weakness in Acute Quadriplegic Myopathy Using an Experimental ICU Porcine Model

Julien Ochala,Karsten Ahlbeck,Lars Larsson,Peter J Radell,Lars I Eriksson

doi:10.1371/journal.pone.0020876

Abstract

The basic mechanisms underlying acquired generalized muscle weakness and paralysis in critically ill patients remain poorly understood and may be related to prolonged mechanical ventilation/immobilization (MV) or to other triggering factors such as sepsis, systemic corticosteroid (CS) treatment and administration of neuromuscular blocking agents (NMBA). The present study aims at exploring the relative importance of these factors by using a unique porcine model. Piglets were all exposed to MV together with different combinations of endotoxin-induced sepsis, CS and NMBA for five days. Peroneal motor nerve conduction velocity and amplitude of the compound muscle action potential (CMAP) as well as biceps femoris muscle biopsy specimens were obtained immediately after anesthesia on the first day and at the end of the 5-day experimental period. Results showed that peroneal nerve motor conduction velocity is unaffected whereas the size of the CMAP decreases independently of the type of intervention, in all groups after 5 days. Otherwise, despite a preserved size, muscle fibre specific force (maximum force normalized to cross-sectional area) decreased dramatically for animals exposed to MV in combination with CS or/and sepsis. These results suggest that the rapid declines in CMAP amplitude and in force generation capacity are triggered by independent mechanisms with significant clinical and therapeutic implications.

Highlights

The severe neuromuscular dysfunction in critically ill intensive care unit (ICU) patients is associated with significant morbidity and mortality
acute quadriplegic myopathy (AQM) is associated with a decreased compound muscle action potential (CMAP) amplitude, related to a decreased muscle membrane excitability [3], muscle fibre atrophy and disrupted function of the contractile apparatus related to a general decline in myofibrillar protein content and a preferential partial or complete loss of myosin and myosinassociated proteins [4,5]
Primary disease and sepsis contribute to the weakness, but there is heterogeneity of underlying diseases and pharmacological treatments among patients with similar outcomes. In this context it is likely that several common components of ICU treatment, such as prolonged mechanical ventilation with subsequent immobilization (MV), administration of systemic corticosteroid (CS) and/or neuromuscular blocking agents (NMBA) are involved in the pathogenesis behind this disorder [1,2,6]

Summary

Introduction

The severe neuromuscular dysfunction in critically ill intensive care unit (ICU) patients is associated with significant morbidity and mortality. Primary disease and sepsis contribute to the weakness, but there is heterogeneity of underlying diseases and pharmacological treatments among patients with similar outcomes In this context it is likely that several common components of ICU treatment, such as prolonged mechanical ventilation with subsequent immobilization (MV), administration of systemic corticosteroid (CS) and/or neuromuscular blocking agents (NMBA) are involved in the pathogenesis behind this disorder [1,2,6]. These factors have all been proposed to be important triggering factors [6,7], but their relative importance remains unknown. Different experimental animal models have been introduced that have given valuable insights [8], but most of these animal models do not include concurrent ICU conditions such as prolonged mechanical ventilation, sedation, immobilization and sepsis together with common interventions used in modern anesthesiology and intensive care, i.e. systemic CS and NMBA administration [8]

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Conclusion