Diaphragmatic Dysfunction Research Articles

Sex-Specific Patterns of Diaphragm Phospholipid Content and Remodeling during Aging and in a Model of SELENON-Related Myopathy

Growing evidence shows that the lipid bilayer is a key site for membrane interactions and signal transduction. Surprisingly, phospholipids have not been widely studied in skeletal muscles, although mutations in genes involved in their biosynthesis have been associated with muscular diseases. Using mass spectrometry, we performed a phospholipidomic profiling in the diaphragm of male and female, young and aged, wild type and SelenoN knock-out mice, the murine model of an early-onset inherited myopathy with severe diaphragmatic dysfunction. We identified 191 phospholipid (PL) species and revealed an important sexual dimorphism in PLs in the diaphragm, with almost 60% of them being significantly different between male and female animals. In addition, 40% of phospholipids presented significant age-related differences. Interestingly, SELENON protein absence was responsible for remodeling of 10% PL content, completely different in males and in females. Expression of genes encoding enzymes involved in PL remodeling was higher in males compared to females. These results establish the diaphragm PL map and highlight an important PL remodeling pattern depending on sex, aging and partly on genotype. These differences in PL profile may contribute to the identification of biomarkers associated with muscular diseases and muscle aging.

Evaluation of Diaphragmatic Thickness and Dysfunction by Ultrasonography in Mechanically Ventilated Children for Assessment of Extubation Success

This study aimed to evaluate diaphragm thickness (DT) and diaphragmatic thickening fraction (DTF) in mechanically ventilated children, and study the association of these measurements with extubation success. Consecutive children aged one month to 18 years, who required mechanical ventilation (MV) for more than 24 hours at our institution, were enrolled between April, 2019 to October, 2020. Ultrasonographic measure-ments of DT were documented, and DTF was calculated from baseline (within 24 hours of MV) until 14 days of MV, and up to three days post-extubation. Of the 54 children-enrolled, 40 underwent planned extubation trial, of which 9 (22.5%) had extubation failure. Pre-extubation and post-extubation DTF between children in extubation-success and extubation-failure groups were comparable (P=0.074). There was no significant difference in the diaphragm atrophy rate between the two groups (P=0.819). Binary logistic regression showed significantly decreased probability of successful extubation with total ventilation duration (P=0.012) and mean DTF% before extubation (P=0.033). Despite evidence of diaphragmatic atrophy in critically ill children receiving mechanical ventilation, there was no significant difference in DTF between extubation success and failure groups.

Assessment of excursion and thickness of diaphragm by ultrasound during acute exacerbation of chronic obstructive pulmonary disease and correlation with severity of airway obstruction

Background: Diaphragm dysfunction in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) leads to increased morbidity and mortality. Early diagnosis of diaphragm dysfunction and aggressive management to improve the diaphragm function and may improve the outcome in AECOPD. Aims and Objectives: This study aimed to assess diaphragmatic excursion by ultrasound during AECOPD and correlation with the severity of airway obstruction. Materials and Methods: Sixty patients admitted with AECOPD were evaluated. Ultrasonography was done to assess the diaphragm excursion and thickness. Airway obstruction was classified as moderate, severe, and very severe by measuring forced expiratory volume in 1 s (FEV1). Comparison of excursion and thickness of the diaphragm in the study patients was done with normal values and analyzed using Student's t-test. Values of measured FEV1 were correlated with the normal values of excursion and thickness of the diaphragm and statistical analysis was done by ANOVA test. Results: Forty-six males and four females were included in the study. Thirty-four percent (17) had moderate COPD, 60% (30) had severe COPD, and 6% (3) had very severe COPD. The mean excursion and thickness of the diaphragm in the study patients were less when compared to the normal values. In moderate COPD, the mean excursion of the diaphragm was 29.94 mm, whereas in those with severe and very severe COPD, the mean excursions were 26.77 mm and 23.33 mm, respectively. Statistical analysis by ANOVA test was done to compare the diaphragm excursion and severity of COPD. The P = 0.039 was considered statistically significant. Patients with moderate COPD (34%) showed a mean diaphragm thickness of 2.82 mm, and those with severe (60%) and very severe (6%) COPD showed a diaphragm thickness of 2.23 mm and 2.00 mm, respectively. Statistical analysis by ANOVA test was done to compare the diaphragm thickness and severity of COPD. The P < 0.001 was considered statistically significant. Conclusions: Patients with AECOPD have reduced excursion and thickness of the diaphragm in comparison with normal subjects. Diaphragm dysfunction increases as the severity of airflow obstruction in COPD increases.

Diaphragmatic Dynamics and Thickness Parameters Assessed by Ultrasonography Predict Extubation Success in Critically Ill Patients.

A frequent cause of weaning and extubation failure in critically ill mechanically ventilated patients is diaphragm muscle dysfunction. Ultrasound (US) evaluation of the diaphragm yields important data regarding its thickness (diaphragm thickening fraction [TFdi]) and its movement or excursion (diaphragmatic dynamics) that reveal the presence of diaphragmatic dysfunction. Cross-sectional study, which included patients older than 18 years with invasive mechanical ventilation with an expected duration of more than 48 h, in a tertiary referral center in Colombia. The excursion of the diaphragm, inspiratory and expiratory thickness, and TFdi were evaluated by US. Prevalence and use of medications were evaluated, and the association with failure in ventilatory weaning and extubation was analyzed. Sixty-one patients were included. The median age and APACHE IV score were 62.42 years and 78.23, respectively. The prevalence of diaphragmatic dysfunction (assessed by excursion and TFdi) was 40.98%. The sensibility, specificity, positive predictive value, and negative predictive value for TFdi < 20% was 86%, 24%, 75%, and 40%, respectively, with an area under the receiver operating characteristic (ROC) curve of 0.6. The ultrasonographic analysis of excursion of the diaphragm, inspiratory and expiratory thickness, and TFdi (>20%) allow in its set and with normal values, predict success or failure for the extubation with an area under the ROC curve of 0.87. Diaphragmatic dynamics and thickness parameters together assessed by ultrasonography could predict the success of extubation in critically ill patients in Colombia, based on the finding of diaphragmatic dysfunction.

Association of Hoover's Sign with Maximal Expiratory-to-Inspiratory Pressure Ratio in Patients with COPD.

In chronic obstructive pulmonary disease (COPD) some patients develop paradoxical inspiratory rib motion, which is termed Hoover's sign. Our objective was to determine whether Hoover's sign is associated with a difference in the maximal expiratory pressure (MEP), the maximal inspiratory pressure (MIP), the MEP/MIP ratio, and other features on pulmonary function tests (PFTs). This observational prospective single-center cohort study enrolled patients with an established diagnosis of COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3 (severe) and 4 (very severe) based on PFTs. Respiratory pressure measurements were also collected. Patients were examined for the presence or absence of Hoover's sign on physical examination by 2 internal medicine resident physicians trained in examining for Hoover's sign by a pulmonologist. A total of 71 patients were examined for the presence of Hoover's sign. Hoover's sign was present in 49.3% of patients. Observer agreement (k statistic) was 0.8 for Hoover's sign. Median MEP/MIP was significantly greater in patients with Hoover's sign than those without Hoover's sign (1.88 versus 1.16, p<0.001). Patients with Hoover's sign also had a significantly lower MIP (39.0 versus 58.0, p<0.001) and higher residual volume (RV) to total lung capacity (TLC) ratio indicating a higher degree of air trapping (65 versus 59.5, p<0.014). The presence of Hoover's sign in patients with COPD is associated with a higher MEP/MIP ratio. This suggests respiratory pressure measurements can predict diaphragm dysfunction in patients with GOLD stage 3 and 4 COPD. Patients with Hoover's sign were also found to have a lower MIP and more air trapping.

Morphological aspects of diaphragm dysfunction in COVID-19-associated pneumonia

To assess morphological changes in the diaphragm and phrenic nerve in patients who died from COVID-19. In a case-control study, an analysis was made of autopsy material of the diaphragm and phrenic nerve of those who died from COVID-19 infection complicated by SARS-CoV-2-associated pneumonia, confirmed in vivo by the presence of SARS-CoV-2 RNA (Group 1, n=12), and those who died with a diagnosis of acute cerebrovascular accident of the ischemic type without parenchymal respiratory failure (Group 2, n=3). The main histopathological features in the diaphragm of the 1st group were the edema of the pericellular spaces of muscle fibers, edema of perivascular spaces, diapedese hemorrhages, plethora in arteriolas, in most veins and capillaries, red blood clots were revealed; in the diaphragmatic nerve - swelling of the perineral space, severe edema around the nerve fibers inside the nerve trunk. In the diaphragm of group 2, edema of pericellular spaces of muscle fibers and edema of perivascular spaces were less pronounced (p<0.001), hemorrhages were not determined; in the diaphragmatic nerve, moderate edema of the perineral space, mild swelling inside the nerve trunk around the nerve fibers was revealed (p<0.001). The glycogen content in the muscle cells of group 1 is significantly lower compared to group 2 (p<0.001). The study confirms the characteristic pathological picture of organ damage in COVID-19. However, the leading pathological mechanism of organ damage requires further investigation.

Skeletal muscle Nox4 knockout prevents and Nox2 knockout blunts loss of maximal diaphragm force in mice with heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) experience diaphragm weakness that contributes to the primary disease symptoms of fatigue, dyspnea, and exercise intolerance. Weakness in the diaphragm is related to excessive production of reactive oxygen species (ROS), but the exact source of ROS remains unknown. NAD(P)H Oxidases (Nox), particularly the Nox2 and 4 isoforms, are important sources of ROS within skeletal muscle that contribute to optimal cell function. There are reports of increased Nox activity in the diaphragm of patients and animal models of HFrEF, implicating these complexes as possible sources of diaphragm dysfunction in HFrEF. To investigate the role of these proteins on diaphragm weakness in HFrEF, we generated inducible skeletal muscle specific knockouts of Nox2 or Nox4 using the Cre-Lox system and assessed diaphragm function in a mouse model of HFrEF induced by myocardial infarction. Diaphragm maximal specific force measured in vitro was depressed by ∼20% with HFrEF. Skeletal muscle knockout of Nox4 provided full protection against the loss of maximal force (p<0.01), while the knockout of Nox2 provided partial protection (7% depression, p<0.01). Knockout of Nox2 from skeletal myofibers improved survival from 50 to 80% following myocardial infarction (p=0.026). Our findings show an important role for skeletal muscle NAD(P)H Oxidases contributing to loss of diaphragm maximal force in HFrEF, along with systemic pathophysiological responses following myocardial infarction.

Technical Report.

Diaphragmatic structure and function assessment can be performed using grayscale as well as M-mode ultrasound. This article discusses the application of M-mode ultrasound in the assessment of diaphragmatic dysfunction.

Ultrasonographic evaluation of diaphragm function in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Some studies have reported using ultrasonic evaluations to assess diaphragm function in patients with chronic obstructive pulmonary disease (COPD). However, they have limitations and thus cannot provide strong evidence to support ultrasound evaluations for diaphragm function and dysfunction severity assessments in this patient population. Additionally, quantitative studies on the relationship between ultrasound evaluations and diaphragm function do not exist. Therefore, we performed a systematic review and meta-analysis to explore the usefulness of ultrasonography for evaluating diaphragm function in patients with COPD. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biomedical Literature Database, Wanfang Data, China National Knowledge Network, and Chinese Scientific Journal Database (i.e., VIP) databases were searched for literature about ultrasonic evaluations of diaphragm function in patients with COPD for systematic review. We extracted patient demographic, diaphragm mobility, diaphragm thickness, diaphragm thickening score, and other related parameter data using RevMan 5.3 software for the meta-analysis. We included 13 articles in the systematic review, 8 of which (494 participants) were included in the meta-analysis. The degree of diaphragm offset in patients with COPD was significantly lower than that in healthy controls (weighted mean difference [WMD] = -1.34; 95% confidence interval [CI]: -2.15, 0.53; P < .05). The diaphragm deviation was lower in the severe COPD group than in the mild-to-moderate COPD group (WMD = 0.50; 95% CI: -0.01, 1.01; P = .06), but the difference was not significant. Ultrasonography effectively evaluates diaphragm function in patients with COPD. The diaphragm offset can be used as an auxiliary diagnostic index for COPD, which is also related to disease severity.

Ultrasonography Comparison of Diaphragm Morphological Structure and Function in Young and Middle-Aged Subjects with and without Non-Specific Chronic Low Back Pain: A Case-Control Study.

It is reported that impaired postural control in patients with non-specific chronic low back pain (NCLBP) was associated with "core" trunk muscle incoordination. However, as the diaphragm is an important component of the "core" deep trunk muscle group, we still know little about the potential relationship between diaphragm dysfunction and NCLBP. This case-control study is intended to investigate the changes of diaphragm morphological structure and function in young and middle-aged subjects with and without NCLBP by ultrasound evaluation and its possible validity in predicating the occurrence of NCLBP. 31 subjects with NCLBP (NCLBP group) and 32 matched healthy controls (HC group) were enrolled in this study. The diaphragm thickness at the end of inspiration (T ins) or expiration (T exp) during deep breathing was measured through B-mode ultrasound, and the diaphragm excursion (T exc) was estimated at deep breathing through M-mode ultrasound. The diaphragm thickness change rate (T rate) was calculated by the formula: T rate=(T ins - T exp)/T exp × 100%. Compared with the HC group, the NCLBP group had a significant smaller degree of Tins (t = -3.90, P < 0.001), T exp (Z = -2.79, P=0.005), and T rate (t = -2.03, P=0.047). However, there was no statistical difference in T exc between the two groups (t = -1.42, P=0.161). The binary logistic regression analysis indicated that T rate (OR = 16.038, P=0.014) and T exp (OR = 7.714, P=0.004) were potential risk factors for the occurrence of NCLBP. The diaphragm morphological structure and function were changed in young and middle-aged subjects with NCLBP, while the diaphragm thickness change rate (T rate) and diaphragm thickness at the end of expiration (T exp) may be conductive to the occurrence of NCLBP. Furthermore, these findings may suggest that abnormal diaphragm reeducation is necessary for the rehabilitation of patients with NCLBP.

An implantable soft robotic ventilator augments inspiration in a pig model of respiratory insufficiency

Severe diaphragm dysfunction can lead to respiratory failure and to the need for permanent mechanical ventilation. Yet permanent tethering to a mechanical ventilator through the mouth or via tracheostomy can hinder a patient’s speech, swallowing ability and mobility. Here we show, in a porcine model of varied respiratory insufficiency, that a contractile soft robotic actuator implanted above the diaphragm augments its motion during inspiration. Synchronized actuation of the diaphragm-assist implant with the native respiratory effort increased tidal volumes and maintained ventilation flow rates within the normal range. Robotic implants that intervene at the diaphragm rather than at the upper airway and that augment physiological metrics of ventilation may restore respiratory performance without sacrificing quality of life.

Bilateral diaphragm paralysis: a clinical case

Diaphragm dysfunction is a rare cause of respiratory distress with a variety of clinical manifestations that complicate diagnosis and treatment. The given clinical case demonstrates the possibility of detecting bilateral diaphragm paralysis using available general clinical and instrumental diagnostic methods. Among the physical data, high standing of the lower borders of the lungs with limited mobility and paradoxical movement of the diaphragm during the Mueller test have a high diagnostic value. Chest X-ray demonstrates the high standing of both domes of the diaphragm and subsegmental atelectasis in the basal parts of the lungs. Severe hypoxemia developed: oxygen saturation in clino- and orthostasis was 72 and 96%, respectively. The tests of pulmonary function showed significant restrictive impairments, a decrease in the vital capacity of the lungs was also determined. Ultrasound examination of the diaphragm revealed hyperechogenicity, lack of inspiratory thickening, and respiratory mobility of the domes of the diaphragm. Electromyography confirmed gross right and left phrenic nerve axonopathy. An idiopathic variant of diaphragm dysfunction can be assumed based on the patient stabilization during CPAP therapy, physiotherapy exercises, chest massage, followed by the disappearance of signs of bilateral diaphragm paralysis. Conclusion. The presented case demonstrates the difficulties of diagnosing bilateral diaphragm paralysis. The final diagnosis was made through the use of specific research methods recommended for suspected diaphragm dysfunction. The prognosis of the idiopathic variant of bilateral diaphragm paralysis, as in this case, is favorable. Spontaneous remission was observed.

MEASUREMENT OF DIAPHRAGMATIC DYSFUNCTION AND PHRENIC NERVE PALSY IN PATIENTS UNDERGOING THORACIC SURGERY FOR LUNG- OR ESOPHAGEAL CANCER

<h3>Introduction and Objective</h3> Thoracic surgery carries a substantial risk of postoperative pulmonary complications. Recent studies have shown that the risk of postoperative pulmonary complications is significantly higher in patients suffering from postoperative diaphragmatic dysfunction. Diaphragmatic dysfunction may be accompanied by phrenic nerve palsy. However, the extent of phrenic nerve palsy and its association with diaphragmatic dysfunction following thoracic surgery is unknown. Therefore, we aimed to quantify changes in diaphragmatic function and phrenic nerve conductance in patients undergoing thoracic surgery for lung- or esophageal cancer using ultrasonographic measures and phrenic nerve conduction studies. <h3>Design and Methods</h3> This was a prospective observational study including patients scheduled for pulmonary lobectomy or esophageal resection. Examinations were carried out the day prior to surgery and respectively 3 days and 10-14 days after surgery. Endpoints for diaphragmatic function included ultrasonographic measurements of diaphragmatic excursion of the posterior part of the right hemidiaphragm, excursion of the hemidiaphragmatic top point, change in intrathoracic area and diaphragmatic thickening fraction. Ultrasonographic measurements were recorded during a standardized respiration cycle. Endpoints for phrenic nerve conductance included baseline-to-peak amplitude, peak-to-peak amplitude and transmission delay of the diaphragmatic compound muscle action potential (CMAP). Measurements for both diaphragmatic- and phrenic nerve recordings were assessed for both the surgical side and the non-surgical side of the thorax and thus measured over time. <h3>Results</h3> We included 40 patients of which 13 had pulmonary lobectomies and 27 had esophageal resections performed. Significant reductions in diaphragmatic excursion were seen on the surgical side of the thorax for all excursion measures (posterior part of the right hemidiaphragm, p < 0.001; hemidiaphragmatic top point, p < 0.001; change in intrathoracic area, p < 0.001) (Figure 1). Conversely, all ultrasound excursion measures did not change significantly on the non-surgical side. Diaphragmatic thickening fraction did not change significantly on either side. For phrenic nerve measures, significant reductions were seen for both CMAP amplitude measures on the surgical side (baseline-to-peak, p < 0.001; peak-to-peak, p < 0.001) and non-surgical side (baseline-to-peak, p < 0.001; peak-to-peak, p < 0.001). Transmission delay also changed significantly between assessments on both the surgical (p =0.041) and the non-surgical side (p =0.021) (Figure 2). <h3>Conclusion</h3> Thoracic surgery caused a significant unilateral reduction in diaphragmatic excursion on the surgical side of the thorax, whereas the contralateral hemidiaphragm's excursion did not decrease significantly. Diaphragmatic compound muscle action potential amplitude was reduced significantly bilaterally. Therefore, our findings show that a postoperative reduction in diaphragmatic excursion is accompanied by partial phrenic nerve palsy, which may be a contributing factor in the pathogenesis of postoperative pulmonary complications.

MRI-assessed diaphragmatic function can predict frequent acute exacerbation of COPD: a prospective observational study based on telehealth-based monitoring system

BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) have considerably high mortality and re-hospitalisation rate. Diaphragmatic dysfunction (DD) is common in COPD patients. However, whether diaphragmatic dysfunction is related to acute exacerbation is yet to be elucidated. This study aimed to evaluate the diaphragm function by magnetic resonance imaging (MRI) in COPD patients and assess whether the impact of DD may help predict AECOPD.Methods20 healthy adult volunteers and 80 COPD patients were enrolled. The diaphragms function parameters were accessed by MRI. Patients were guided to start self-management by the Telehealth-based monitoring system following the enrolment. Events of acute exacerbation of COPD were recorded by the system and confirmed by healthcare providers. Binary univariate and multivariate logistic regression analyses were performed to investigate the factors associated with the frequency of AECOPD. Receiver operating characteristic (ROC) curves were further used to assess the value of prediction indexes.ResultsFifty-nine COPD patients completed a one-year follow-up based on the Telehealth-based monitoring system. The clinical outcomes showed that the diaphragm function parameters at the end of maximal breathing were lower in the COPD group than in the healthy control group (P < 0.05). ANOVA showed significant differences among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages for diaphragm function parameters, including chest wall motion, lung area, upper-lower diameter, and the diaphragm thickening fraction at the end of maximal breathing (P < 0.05). Moreover, significant differences in diaphragm function parameters were observed between patients with infrequent AECOPD (n = 28) and frequent AECOPD (n = 31) based on the frequency of AECOPD (P < 0.05). The diaphragm thickening fraction and the chest wall motion were associated with AECOPD after adjusting for age, sex, BMI, and lung functions, and the combination of predictions showed better accuracy in predicting the frequency of AECOPD.ConclusionsIn COPD patients, diaphragm function parameters correlate with the severity of airflow limitation. The diaphragm thickening fraction and the chest wall motion were associated with the frequency of AECOPD and can predict it.

Temporary phrenic nerve stimulated patients: What is the role of ultrasound examination?

Prolonged mechanical ventilation caused by ventilator-induced diaphragm dysfunction (VIDD) is a serious problem in critically ill patients. Identification of patients who will have difficulty weaning from ventilation along with attempts to reduce total time on mechanical ventilation is some of the aims of intensive care medicine. This article briefly summarizes current options for temporary phrenic nerve stimulation therapy in an effort to keep the diaphragm active as direct prevention and treatment of ventilator-associated diaphragmatic dysfunction in patients on mechanical ventilation. The results of feasibility studies using different approaches are promising but so far, the clinical relevance is low. One important question is which tool would reliably identify early signs of diaphragmatic dysfunction and also be useful in guiding therapy. The authors present a brief overview of the current options considering the advantages and disadvantages of the available examination modalities. Despite the fact that current data point out some limitations of ultrasound examination, we believe that it still has a unique position in the bedside examination of critically ill patients on mechanical ventilation. Temporary phrenic nerve stimulation, regardless of the specific approach used, has the potential to directly treat or reverse VIDD, and ultrasound examination plays an important role in the comprehensive care of critically ill patients.

Increased diaphragm echodensity correlates with postoperative pulmonary complications in patients after major abdominal surgery: a prospective observational study

BackgroundAssociated with increased morbidity and mortality, postoperative pulmonary complications (PPCs) often occur after major abdominal surgery. Diaphragmatic dysfunction is suggested to play an important role in the development of PPCs and diaphragm echodensity can be used as an indicator of diaphragm function. This study aimed to determine whether diaphragm echodensity could predict the occurrence of PPCs in patients after major abdominal surgery.MethodsDiaphragm ultrasound images of patients after major abdominal surgery were collected during spontaneous breathing trials. Echodensity was quantified based on the right-skewed distribution of grayscale values (50th percentile, ED50; 85th percentile, ED85; mean, EDmean). Intra- and inter-analyzer measurement reproducibility was determined. Outcomes including occurrence of PPCs, reintubation rate, duration of ventilation, and length of ICU stay were recorded.ResultsDiaphragm echodensity was measured serially in 117 patients. Patients who developed PPCs exhibited a higher ED50 (35.00 vs. 26.00, p < 0.001), higher ED85 (64.00 vs. 55.00, p < 0.001) and higher EDmean (39.32 vs. 33.98, p < 0.001). In ROC curve analysis, the area under the curve of ED50 for predicting PPCs was 0.611. The optimal ED50 cutoff value for predicting the occurrence of PPCs was 36. According to this optimal ED50 cutoff value, patients were further divided into a high-risk group (ED50 > 36, n = 35) and low-risk group (ED50 ≤ 36, n = 82). Compared with the low-risk group, the high-risk group had a higher incidence of PPCs (unadjusted p = 0.003; multivariate-adjusted p < 0.001).ConclusionDiaphragm echodensity can be feasibly and reproducibly measured in mechanically ventilated patients. The increase in diaphragm echodensity during spontaneous breathing trials was related to an increased risk of PPCs in patients after major abdominal surgery.

YAP1 silencing attenuated lung injury/fibrosis but worsened diaphragmatic function by regulating oxidative stress and inflammation response in mice.

Oxidative stress is a crucial mechanism in the pathophysiology of lung injury/fibrosis and diaphragmatic dysfunction. Yes-associated protein 1 (YAP1) is a key oxidative stress response regulator. However, how lung injury/fibrosis and the subsequent YAP1 silencing treatment affect diaphragmatic function remains largely uncharacterized. In this study, mice models of acute lipopolysaccharide (LPS) and paraquat exposure were used to establish acute lung injury and chronic pulmonary fibrosis. AT2 and C2C12cells were co-cultured under LPS and paraquat challenge. YAP1 was interfered with shRNA given in vivo and verteporfin administration in vitro. Pulmonary histology, contractile properties, and cross-sectional areas (CSAs) of the diaphragm and gastrocnemius were evaluated. Histological and biochemical analyses were performed for targeted biomarker determination. We found that LPS and paraquat caused significant lung injury/fibrosis and significantly reduced the diaphragmatic-specific force and CSAs compared with the control. YAP1 silencing alleviated inflammatory cell infiltration or collagen deposition in the lungs yet worsened the already impaired diaphragmatic function by increasing inflammatory cytokines (IL-6 and TNF-α), mitochondrial reactive oxidative species (ROS) emission, protein degradation (Murf-1, atrogin-1, and calpain), and decreasing antioxidant capabilities (superoxide dismutase 2 and glutathione peroxidase). No significant improvements were observed in diaphragmatic function by transient YAP1 knockdown in the gastrocnemius. In vitro, LPS- or paraquat-caused cytotoxicity in AT2 cells was mostly alleviated by verteporfin in a concentration that was 20-fold higher than that in C2C12cells (20 and 1μg/mL, respectively). Finally, 0.5μg/mL of verteporfin significantly ameliorated hydrogen peroxide-induced proteolytic activity and antioxidant enzyme suppression in C2C12cells, whereas 2μg/mL of verteporfin deteriorated the same. Collectively, lung injury/fibrosis adversely affects the diaphragm. YAP1 inhibition alleviates lung injury/fibrosis but worsens diaphragmatic function potentially by enhancing inflammatory cytokines and ROS-mediated protein degradation. This disparity might be attributed to differences in susceptibility to YAP1 inhibition between muscles and the lungs.

Quantification of diaphragmatic dynamic dysfunction in septic patients by bedside ultrasound

Although diaphragmatic dysfunction is an important indicator of severity of illness and poor prognosis in ICU patients, there is no convenient and practical method to monitor diaphragmatic function. This study was designed to analyze diaphragmatic dynamic dysfunction by bedside ultrasound in septic patients and provide quantitative evidence to assess diaphragm function systematically. This prospective observational study was conducted from October 2019 to January 2021 in the Department of Respiratory and Critical Care Medicine. 74 patients suffered from sepsis were recruited and divided into two groups, sepsis group 1 (2 ≤ SOFA ≤ 5, n = 41) and sepsis group 2 (SOFA > 5, n = 33). 107 healthy volunteers were randomly recruited as the control group. In all participants, the diaphragmatic thickness and excursion were measured directly and the dynamic parameters including thickening fraction (TF), EQB/EDB, Contractile velocity, and area under diaphragmatic movement curve (AUDMC) were calculated by bedside ultrasound during quiet breathing (QB) and deep breathing (DB). Each parameter among three groups was analyzed separately by covariance analysis, which was adjusted by age, sex, body mass index, MAP, hypertension, and diabetes. First, contractile dysfunction occurred before diaphragmatic atrophy both in sepsis group 1 and sepsis group 2. Second, compared with the control group, the dynamic parameters showed significant decrease in sepsis group 1 and more obvious change in sepsis group 2, including TF, EQB/EDB. Third, the maximum contractile velocity decreased in sepsis group 1, reflecting the damage of intrinsic contraction efficiency accurately. Finally, per breathing AUDMC in two septic groups were lower than those in control group. However, per minute AUDMC was compensated by increasing respiratory rate in sepsis group 1, whereas it failed to be compensated which indicated gradual failure of diaphragm in sepsis group 2. Diaphragmatic ultrasound can be used to quantitatively evaluate the severity of sepsis patients whose contractile dysfunction occurred before diaphragmatic atrophy. As dynamic parameters, TF and EQB/EDB are early indicator associated with diaphragmatic injury. Furthermore, maximum contractile velocity can reflect intrinsic contraction efficiency accurately. AUDMC can evaluate diaphragmatic breathing effort and endurance to overcome resistance loads effectively.

Inspiratory muscle strength and function in mechanically ventilated COVID-19 survivors 3 and 6 months after intensive care unit discharge.

BackgroundKnowledge regarding the long-term impact of invasive mechanical ventilation on the inspiratory muscles and functional outcomes in COVID-19 survivors is limited.MethodsIn this single-centre prospective cohort study, we evaluated invasively ventilated patients with COVID-19 pneumonia 3 and 6 months post -ICU discharge. Outcomes included: maximal inspiratory pressure (MIP), ultrasound parameters for diaphragm function, 6-min walk distance (6MWD), dyspnea and quality of life. We evaluated associations between MIP and duration of mechanical ventilation with follow-up outcomes.ResultsFifty COVID-19 survivors discharged from ICU between 15 Oct 2020 and 1 Apr 2021 were enrolled. Overall, survivors showed a recovery trajectory over time. However, impaired MIP remained in 24(48%) and 12 (24%) at 3 and 6 months, respectively. Diaphragm dysfunction was not observed. At 3 months, 23 (46%) had impaired functional capacity versus 10 (20%), at 6 months. Dyspnea persisted in 44 (88%) at 3 months and 38 (76%) at 6 months. Quality of life was slightly decreased at 3 months with further improvements at 6 months. MIP was correlated to 6MWD, 6MWD % predicted, dyspnea across follow-up and quality of life at 3 months. The duration of invasive ventilation was correlated with 6MWD and 6MWD % predicted.ConclusionIn invasively ventilated COVID-19 survivors, inspiratory muscle strength impairments persisted 6 months after ICU discharge, while maintaining normal diaphragm function. Decreased functional capacity, dyspnea and slightly reduced health status were observed. Early screening of survivors is of utmost importance to identify those with impairments and at risk of delayed or incomplete recovery.

Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in hemodialysis patients

Skeletal muscle atrophy is prevalent and remarkably increases the risk of cardiovascular (CV) events and mortality in hemodialysis (HD) patients. However, whether diaphragm dysfunction predicts clinical outcomes in HD patients is unknown. This was a prospective cohort study of 103 HD patients. After assessment of diaphragm function by ultrasonography and collection of other baseline data, a 36-month follow-up was then initiated. Participants were divided into diaphragm dysfunction (DD+) group and normal diaphragm function (DD−) group, according to cutoff value of thickening ratio (i.e. the change ratio of diaphragm thickness) at force respiration. The primary endpoint was the first nonfatal CV event or all-cause mortality. A secondary endpoint was less serious CV events (LSCEs, a composite of heart failure readmission, cardiac arrhythmia or myocardial ischemia needed pharmacological intervention in hospital). 98 patients were eligible to analysis and 57 (58.16%) were men. 28 of 44 patients(63.64%) in DD+ group and 23 of 54 patients (42.59%) in DD− group had at least one nonfatal CV event or death (p = 0.038). Compared to DD− group, DD+ group had significantly higher incidence of LSCEs (21 vs.14, p = 0.025) and shorter survival time (22.02 ± 12.98 months vs. 26.74 ± 12.59 months, p = 0.046). Kaplan–Meier analysis revealed significantly higher risks of primary endpoint (p = 0.039), and LSCEs (p = 0.040) in DD+ group. Multivariate hazard analysis showed that DD+ group had significantly higher risk of primary endpoint [hazard ratio (HR) 1.59; 95% confident interval (CI) 1.54–1.63], and LSCEs (HR 1.47; 95%CI 1.40–1.55). Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in HD patients.Trial registration: This study was registered with Chinese Clinical Trials Registry (www.chictr.org.cn) as ChiCTR1800016500 on Jun 05, 2018.