Ventilator-induced diaphragm dysfunction in critical illness

Abstract

Mechanical ventilation (MV) is life-saving for patients with acute respiratory failure but also causes difficult liberation of patients from ventilator due to rapid decrease of diaphragm muscle endurance and strength, which is termed ventilator-induced diaphragmatic damage (VIDD). Numerous studies have revealed that VIDD could increase extubation failure, ICU stay, ICU mortality, and healthcare expenditures. However, the mechanisms of VIDD, potentially involving a multistep process including muscle atrophy, oxidative loads, structural damage, and muscle fiber remodeling, are not fully elucidated. Further research is necessary to unravel mechanistic framework for understanding the molecular mechanisms underlying VIDD, especially mitochondrial dysfunction and increased mitochondrial oxidative stress, and develop better MV strategies, rehabilitative programs, and pharmacologic agents to translate this knowledge into clinical benefits.

Keywords: Acute lung injury; endotoxemia; mitochondria; nuclear factor-κB; toll-like receptor 4; ventilator-induced diaphragm dysfunction.

Figure 1.

Schematic of the signaling pathway implicated in VIDD development. Endotoxin- or hyperoxia-induced augmentation of mechanical stretch-mediated ROS generation and diaphragm injury are associated with diaphragm proteolysis, apoptosis, mitochondrial dysfunction, autophagy, as well as activation of the caspase-3, calpain, and ubiquitin–proteasome pathways. Diaphragm weakness can be attenuated by administering iPSCs, antioxidants, theophylline, levosimendan, or rapamycin, or through partial support MV or diaphragm pacing through PI3K/Akt, Src, and TLR4 pathway inhibition. Akt: serine/threonine kinase/protein kinase B; Bax: Bcl2-associated X; Bim: Bcl2-interacting mediator; Bnip3: Bcl-2 nineteen-kilodalton interacting protein 3; FoxO1: Class O of forkhead box1; iPSCs: Induced pluripotent stem cells; LC3: light chain 3; mTOR: mammalian target of rapamycin; MuRF-1: muscle ring finger-1; NADPH: nicotinamine adenine dinucleotide phosphate; NF-κB: nuclear factor kappa B; PI3-K: phosphoinositide 3-OH kinase; ROS: reactive oxygen species; TLR4: toll-like receptor 4; VIDD: ventilator-induced diaphragm dysfunction. (A color version of this figure is available in the online journal.)