Diaphragm Ultrasound in the Evaluation of Diaphragmatic Dysfunction in Lung Disease

The diaphragm is the most important respiratory muscle, and its function may be limited by acute and chronic diseases. A diaphragmatic ultrasound, which quantifies dysfunction through different approaches, is useful in evaluating work of breathing and diaphragm atrophy, predicting successful weaning, and diagnosing critically ill patients. This technique has been used to determine reduced diaphragmatic function in patients with chronic obstructive pulmonary disease and interstitial diseases, while in those with COVID-19, diaphragmatic ultrasound has been used to predict weaning failure from mechanical ventilation.

Phrenic nerve stimulation prevents diaphragm atrophy in patients with respiratory failure on mechanical ventilation

Background Diaphragm atrophy and dysfunction is a major problem among critically ill patients on mechanical ventilation. Ventilator-induced diaphragmatic dysfunction is thought to play a major role, resulting in a failure of weaning. Stimulation of the phrenic nerves and resulting diaphragm contraction could potentially prevent or treat this atrophy. The subject of this study is to determine the effectiveness of diaphragm stimulation in preventing atrophy by measuring changes in its thickness. Methods A total of 12 patients in the intervention group and 10 patients in the control group were enrolled. Diaphragm thickness was measured by ultrasound in both groups at the beginning of study enrollment (hour 0), after 24 hours, and at study completion (hour 48). The obtained data were then statistically analyzed and both groups were compared. Results The results showed that the baseline diaphragm thickness in the interventional group was (1.98 ± 0.52) mm and after 48 hours of phrenic nerve stimulation increased to (2.20 ± 0.45) mm (p=0.001). The baseline diaphragm thickness of (2.00 ± 0.33) mm decreased in the control group after 48 hours of mechanical ventilation to (1.72 ± 0.20) mm (p<0.001). Conclusions Our study demonstrates that induced contraction of the diaphragm by pacing the phrenic nerve not only reduces the rate of its atrophy during mechanical ventilation but also leads to an increase in its thickness – the main determinant of the muscle strength required for spontaneous ventilation and successful ventilator weaning. Trial registration: The study was registered with ClinicalTrials.gov (18/06/2018, NCT03559933, https://clinicaltrials.gov/ct2/show/NCT03559933).

Nox4 Knockout Does Not Prevent Diaphragm Atrophy, Contractile Dysfunction, or Mitochondrial Maladaptation in the Early Phase Post-Myocardial Infarction in Mice

Background/Aims: Diaphragm dysfunction with increased reactive oxygen species (ROS) occurs within 72 hrs post-myocardial infarction (MI) in mice and may contribute to loss of inspiratory maximal pressure and endurance in patients. Methods: We used wild-type (WT) and whole-body Nox4 knockout (Nox4KO) mice to measure diaphragm bundle force in vitro with a force transducer, mitochondrial respiration in isolated fiber bundles with an O2 sensor, mitochondrial ROS by fluorescence, mRNA (RT-PCR) and protein (immunoblot), and fiber size by histology 72 hrs post-MI. Results: MI decreased diaphragm fiber cross-sectional area (CSA) (~15%, p = 0.015) and maximal specific force (10%, p = 0.005), and increased actin carbonylation (5-10%, p = 0.007) in both WT and Nox4KO. Interestingly, MI did not affect diaphragm mRNA abundance of MAFbx/atrogin-1 and MuRF-1 but Nox4KO decreased it by 20-50% (p < 0.01). Regarding the mitochondria, MI and Nox4KO decreased the protein abundance of citrate synthase and subunits of electron transport system (ETS) complexes and increased mitochondrial O2 flux (JO2) and H2O2 emission (JH2O2) normalized to citrate synthase. Mitochondrial electron leak (JH2O2/JO2) in the presence of ADP was lower in Nox4KO and not changed by MI. Conclusion: Our study shows that the early phase post-MI causes diaphragm atrophy, contractile dysfunction, sarcomeric actin oxidation, and decreases citrate synthase and subunits of mitochondrial ETS complexes. These factors are potential causes of loss of inspiratory muscle strength and endurance in patients, which likely contribute to the pathophysiology in the early phase post-MI. Whole-body Nox4KO did not prevent the diaphragm abnormalities induced 72 hrs post-MI, suggesting that systemic pharmacological inhibition of Nox4 will not benefit patients in the early phase post-MI.

PREVENTION OF RESPIRATORY MUSCLE DYSFUNCTION DUE TO DIAPHRAGM ATROPHY IN CHILDREN WITH RESPIRATORY FAILURE

The aim of the study was to determine whether diaphragm-protective mechanical ventilation can prevent diaphragm atrophy in children with respiratory failure. Materials and methods. We complete the prospective single-center cohort study. Data analysis included 82 patients 1 month - 18 years old, divided into I group (lung-protective MV) and II group (diaphragm-protective in addition to lung-protective MV). Patients were divided into age subgroups. Stages of the study: 1st day (d1), 3rd (d3), 5th (d5), 7th (d7), 9th (d9), 28th (d28). We studied changes in diaphragm thickness at the end of exhalation and compared them with these indicators at patient`s admission to the study (baseline). Primary endpoint was length of stay in ICU, secondary endpoints were complications (prolonged MV). Results are described as arithmetic mean (X) and standard deviation (σ) with level of significance p. Results. There were significant differences in length of stay in ICU among patients of the 1st and 5th age subgroups: in 1st age subgroup this data was in 1.3 times lower in II group, compared with I group (p <0,05); in 5th age subgroup the situation was the opposite - length of stay in ICU was in 1.4 times higher in II group, compared with I group (p<0.05). There were no patients who required lifelong mechanical ventilation in any of the groups. Changes in the thickness of the diaphragm, which indicate its atrophy, were the most significant among patients of the first, second, third and fourth age subgroups and the severity of atrophy was higher among patients of group I, compared with patients of group II. Conclusions. Diaphragm-protective mechanical ventilation significantly prevents diaphragm atrophy in children with respiratory failure in 2nd, 4th, and 5th age subgroups. Providing goal-directed diaphragm-protective MV might reduce the length of stay in ICU among patients of 1st and 5th age subgroups. There were no observed complications like lifelong mechanical ventilation in both patient`s group.

Is Mitochondrial Oxidative Stress the Key Contributor to Diaphragm Atrophy and Dysfunction in Critically Ill Patients?

Diaphragm dysfunction is prevalent in the progress of respiratory dysfunction in various critical illnesses. Respiratory muscle weakness may result in insufficient ventilation, coughing reflection suppression, pulmonary infection, and difficulty in weaning off respirators. All of these further induce respiratory dysfunction and even threaten the patients’ survival. The potential mechanisms of diaphragm atrophy and dysfunction include impairment of myofiber protein anabolism, enhancement of myofiber protein degradation, release of inflammatory mediators, imbalance of metabolic hormones, myonuclear apoptosis, autophagy, and oxidative stress. Among these contributors, mitochondrial oxidative stress is strongly implicated to play a key role in the process as it modulates diaphragm protein synthesis and degradation, induces protein oxidation and functional alteration, enhances apoptosis and autophagy, reduces mitochondrial energy supply, and is regulated by inflammatory cytokines via related signaling molecules. This review aims to provide a concise overview of pathological mechanisms of diaphragmatic dysfunction in critically ill patients, with special emphasis on the role and modulating mechanisms of mitochondrial oxidative stress.