Chest
Translating Basic Research Into Clinical PracticeDiaphragm Weakness in the Critically Ill: Basic Mechanisms Reveal Therapeutic Opportunities
Section snippets
Prevalence and Clinical Impact of Diaphragm Dysfunction in Critical Illness
Diaphragm dysfunction is present in a large proportion of critically ill patients admitted to the ICU for acute respiratory failure requiring mechanical ventilation.1, 2, 3, 4, 5 In one study of mechanically ventilated patients who underwent serial testing of diaphragm function using the objective “gold standard” of bilateral phrenic nerve stimulation over an average period of approximately 7 days, the vast majority (53% within 24 h of intubation and an additional 26% later in their course)
Brief Overview of Ventilator-Induced Diaphragm Dysfunction
Use of controlled mechanical ventilation, even in the absence of neuromuscular blockade, leads to significant diaphragm weakness within a remarkably short period of time (hours to a few days) in various animal species.9 Weakness is notably minimal to absent in the limb musculature under the same conditions. Intriguingly, the onset of ventilator-induced diaphragm dysfunction (VIDD) seems to be more rapid in smaller mammals, suggesting a possible relationship to metabolic rate.10 Diaphragm
Brief Overview of Sepsis-Induced Diaphragm Dysfunction
For the purposes of this review, we will consider sepsis-induced diaphragm dysfunction (SIDD) as encompassing diaphragm weakness associated with endotoxemia or any major infection. In a seminal study performed more than 30 years ago, endotoxemic shock in dogs was shown to induce hypercapnic respiratory failure with signs of diaphragm fatigue.19 Subsequent studies in a variety of animal models have confirmed that diaphragm force-generating capacity is profoundly decreased by sepsis.20, 21, 22, 23
Potential Shared Mechanistic Targets in VIDD and SIDD
Several common cellular and molecular mechanisms have been implicated in both VIDD and SIDD. The following brief discussion of these mechanisms is meant to highlight the potential for pharmacologic manipulation of key pathways involved in the pathogenesis of both conditions. Many of these pathways are intersecting and functionally related to one another within the muscle fiber (Fig 2).
Conclusions and Future Directions
Substantial progress has been made in our understanding of the basic mechanisms that mediate the loss of diaphragm strength in critically ill patients. As shown in Table 1, there are a number of drug compounds currently approved for human use, or in clinical trials for other conditions, that hold promise for pharmacologically targeting the key molecular drivers underlying both VIDD and SIDD. Interventions designed to modulate diaphragm muscle activity level can also affect these pathways, and
Acknowledgments
Financial/nonfinancial disclosures: The author has reported to CHEST the following: B. J. P. has received support from Canadian Institutes of Health Research and the J. T. Costello Memorial Fund.
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2022, Experimental GerontologyCitation Excerpt :Changes in the diaphragmatic muscle musculature are found in most critically ill patients admitted to ICUs. It is a specific type of muscle dysfunction and has occurred in patients soon after starting mechanical ventilation, and is associated with sepsis (Petrof, 2018). In sepsis, the diaphragm presents oxidative stress and mitochondrial alterations, causing changes in protein turnover, resulting in atrophy and compromised contractility, and leading to impairment of its functionality (Talarmin et al., 2017).
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2021, Respiratory MedicineCitation Excerpt :Unfortunately, even brief periods of MV (>12h) result in clinical diaphragm weakness (“ventilator-induced diaphragm dysfunction” – VIDD) that renders it difficult to wean patients from the ventilator. VIDD is characterized by an early loss of contractile force of diaphragm muscle fibers, and later frank atrophy of fibers, which combine to dramatically reduce the muscle's ability to generate inspiratory force [2–5]. Prolonged ventilator dependence, which often results at least in part from VIDD, occurs in up to 34% of those ventilated [6–11], and it ranks third in total inpatient charges among Medicare diagnostic groups [12].
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