Prolonged Diaphragm Weakness in Acute Lung Injury UL1TR000117, HL112085, HL113494

Abstract

Acquired skeletal muscle weakness, a devastating complication of critical illness, affects both limb and respiratory muscles. Diaphragm weakness is especially important, persisting for days to weeks, prolonging duration of mechanical ventilation and increasing in‐hospital mortality. Currently no animal model of critical illness replicates the sustained diaphragm weakness observed in patients. We sought to establish an animal model that parallels the severity and duration of diaphragm weakness observed in critically ill patients using male C57BL6 mice (n=50) treated with a single intratracheal injection of lipopolysaccharide (IT‐LPS) which induces acute lung injury (ALI). We first measured diaphragm specific force in mice treated with varying doses of IT‐LPS at several time points to determine the dose that would produce sustained diaphragm injury. We then examined diaphragm force‐frequency relationships in mice treated with 30,000 EU/gm of IT‐LPS. ALI invoked significant loss in animal body weight and hypothermia. In addition, ALI markedly reduced diaphragm specific force generation which persisted at Day 10 (150 Hz force averaged 26.4±0.5,17.7±1.7, 15.6±1.9, 15.9±1.8, 15.7±12.1, and 16.7±2.1 N/cm2 for controls, Day 1, Day 2, Day 4, Day 7, and Day 10 groups, respectively, p<0.001). This is the first study to show that a clinically relevant animal model of critical illness, acute lung injury, induces diaphragm weakness in a pattern and time course that parallels data obtained from human studies. We speculate that this model may prove useful for determining the mechanistic basis for prolonged respiratory muscle weakness as well as the pathways required for recovery of diaphragm function in critically ill patients.