Ventilator-induced Diaphragmatic Dysfunction Research Articles

Identification of key genes affecting ventilator-induced diaphragmatic dysfunction in diabetic mice.

Mechanical ventilation (MV) is often required in critically ill patients. However, prolonged mechanical ventilation can lead to Ventilator-induced diaphragmatic dysfunction (VIDD), resulting in difficulty in extubation after tracheal intubation, prolonged ICU stay, and increased mortality. At present, the incidence of diabetes is high in the world, and the prognosis of diabetic patients with mechanical ventilation is generally poor. Therefore, the role of diabetes in the development of VIDD needs to be discovered. MV modeling was performed on C57 mice and DB mice, and the control group was set up in each group. After 12h of mechanical ventilation, the muscle strength of the diaphragm was measured, and the muscle fiber immunofluorescence staining was used to verify the successful establishment of the MV model. RNA sequencing (RNA-seq) method was used to detect mRNA expression levels of the diaphragms of each group, and then differential expressed gene analysis, Heatmap analysis, WGCNA analysis, Venn analysis, GO and KEGG enrichment analysis were performed. qRT-PCR was used to verify the expression of the selected mRNAs. Our results showed that, compared with C57 control mice, the muscle strength and muscle fiber cross-sectional area of mice after mechanical ventilation decreased, and DB mice showed more obvious in this respect. RNA-seq showed that these differential expressed (DE) mRNAs were mainly related to genes such as extracellular matrix, collagen, elastic fiber and Fbxo32. GO and KEGG enrichment analysis showed that the signaling pathways associated with diabetes were mainly as follows: extracellular matrix (ECM), protein digestion and absorption, PI3K-Akt signaling pathway, calcium signaling pathway, MAPK signaling pathway and AGE-RAGE signaling pathway in diabetic complications, etc. ECM has the closest relationship with VIDD in diabetic mice. The key genes determined by WGCNA and Venn analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-seq. VIDD can be aggravated in diabetic environment. This study provides new evidence for mRNA changes after mechanical ventilation in diabetic mice, suggesting that ECM and collagen may play an important role in the pathophysiological mechanism and progression of VIDD in diabetic mice, and provides some clues for the research, diagnosis, and treatment of VIDD in diabetic context.

Diaphragm Force and Mitochondrial Function Following Enhanced Nitric Oxide Availability During Mechanical Ventilation

During mechanical ventilation (MV), force developed by the diaphragm decreases over time much faster than locomotor muscles, known as ventilator-induced diaphragm dysfunction (VIDD). VIDD is accompanied by an increase in intramyofiber protein S-nitrosylation, a modification of cysteines by nitric oxide (NO). During the treatment of acute respiratory distress syndrome (ARDS), inhaled NO is commonly used to improve gas exchange, but little is known about the effects of increased NO availability to the diaphragm during MV and the intracellular mechanisms to protect against excessive S-nitrosylation. We hypothesize that the enzyme S-nitrosoglutathione reductase (GSNOR) protects against excessive protein S-nitrosylation in diaphragm myofibers in conditions where NO availability is enhanced during MV, thereby preserving contractile function. We tested this hypothesis by enhancing NO availability and blocking GSNOR activity in mice during MV. Mice were treated with GSNOR inhibitor (SPL-334; GSNORi) or both GSNORi and NO donor isosorbide dinitrate (GSNORi-ISDN) together, and mechanically ventilated for 2h. E x vivo diaphragm force and mitochondrial respiration were measured. Male (C57BL/6J) 3-4 month old mice (n=27) were anesthetized and subjected to MV for 0 (non-MV), 2, 4, or 6h (150 breaths/min, 10 cmH2O PIP, 3.5 cmH2O PEEP. 8 mL/kg VT). Alternatively, mice were treated with PBS/10% DMSO (DMSO, n=6) or 25 μg SPL-334 in PBS/DMSO (GSNORi, n=6) or 25 μg SPL-334 + 1.7 mg ISDN in PBS/DMSO (GSNORi-ISDN; n=6), and then subjected to MV for 2 h. After MV, mice were euthanized, and diaphragm strips were used for force, and permeabilized fiber bundles for mitochondrial oxidative phosphorylation and H2O2 generation measurements. Peak tetanic force was decreased by MV ~23% at 4 h and ~40% at 6 h (P=0.0183 and P=0.0062, respectively, one-way ANOVA, Tukey post-test) vs 0 h. However, peak force was not different between DMSO, GSNORi and GSNORi-ISDN at 2 h MV. Coupled-phosphorylating mitochondrial respiration (Kruskal-Wallis H=2.2, p=0.35) was not different but H2O2 flux was highest in GSNORi-ISDN vs DMSO and GSNORi (Kruskal-Wallis H=6.6, p=0.03). GSNORi and ISDN treatment during MV did not produce any changes to VIDD and to mitochondrial respiration, but increased ROS production. If exogenous NO is not provided, inhibiting GSNOR in vivo alone does not affect diaphragm function ex vivo during short MV. Support: TRDRP (T32IR5221 and T29KT0397CA, to L.N.) and SDSU 2023 SEED Grant (to L.N.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Irisin attenuates ventilator-induced diaphragmatic dysfunction by inhibiting endoplasmic reticulum stress through activation of AMPK.

Mechanical ventilation (MV) is an essential life-saving technique, but prolonged MV can cause significant diaphragmatic dysfunction due to atrophy and decreased contractility of the diaphragm fibres, called ventilator-induced diaphragmatic dysfunction (VIDD). It is not clear about the mechanism of occurrence and prevention measures of VIDD. Irisin is a newly discovered muscle factor that regulates energy metabolism. Studies have shown that irisin can exhibit protective effects by downregulating endoplasmic reticulum (ER) stress in a variety of diseases; whether irisin plays a protective role in VIDD has not been reported. Sprague-Dawley rats were mechanically ventilated to construct a VIDD model, and intervention was performed by intravenous administration of irisin. Diaphragm contractility, degree of atrophy, cross-sectional areas (CSAs), ER stress markers, AMPK protein expression, oxidative stress indicators and apoptotic cell levels were measured at the end of the experiment.Our findings showed that as the duration of ventilation increased, the more severe the VIDD was, the degree of ER stress increased, and the expression of irisin decreased.ER stress may be one of the causes of VIDD. Intervention with irisin ameliorated VIDD by reducing the degree of ER stress, attenuating oxidative stress, and decreasing the apoptotic index. MV decreases the expression of phosphorylated AMPK in the diaphragm, whereas the use of irisin increases the expression of phosphorylated AMPK. Irisin may exert its protective effect by activating the phosphorylated AMPK pathway.

Aminophylline Improves Ventilator-Induced Diaphragmatic Dysfunction by Targeting IGF-1-FOXO1-MURF1 Pathway.

The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity. Aminophylline (AP) has the potential to enhance the contractility of animal skeletal muscle fibers and improve the activity of human respiratory muscles, and the insulin-like growth factor-1 (IGF-1)- forkhead box protein O1 (FOXO1)-muscle RING finger-1 (MURF1) pathway plays a crucial role in skeletal muscle dysfunction. This study aimed to investigate the impact of AP on VIDD and to elucidate the role of the IGF-1-FOXO1-MURF1 pathway as an underlying mechanism. Rat models of VIDD were established through MV treatment. IGF-1 lentiviral (LV) interference (LV-IGF-1-shRNA; controlled by lentiviral negative control LV-NC) was employed to inhibit IGF-1 expression and thereby block the IGF-1-FOXO1-MURF1 pathway. Protein and mRNA levels of IGF-1, FOXO1, and MURF1 were assessed using western blot and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), respectively. Diaphragm contractility and morphometry were examined through measurement of compound muscle action potentials (CMAPs) and hematoxylin and eosin (H&E) staining. Oxidative stress was evaluated by levels of hydrogen peroxide (H2O2), superoxide dismutase (SOD), antioxidant glutathione (GSH), and carbonylated protein. Mitochondrial stability was assessed by measuring the mitochondrial membrane potential (MMP), and mitochondrial fission and mitophagy were examined through protein levels of dynamin-related protein 1 (DRP1), mitofusin 2 protein (MFN2), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), and Parkin (western blot). Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay and levels of Bax, B-cell lymphoma 2 (BCL-2), and Caspase-3. Levels of Atrogin-1, neuronally expressed developmentally downregulated 4 (NEDD4), and muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1) mRNA, as well as ubiquitinated protein, were utilized to determine protein degradation. Furthermore, the SUnSET (surface sensing of translation) method was employed to determine rates of protein synthesis. MV treatment upregulated IGF-1 while downregulated FOXO1 and MURF1 (p < 0.05). AP administration reversed IGF-1, FOXO1 and MURF1 (p < 0.05), which was suppressed again by IGF-1 inhibition (p < 0.05), demonstrating the blockage of the IGF-1-FOXO1-MURF1 pathway. MV treatment caused decreased CMAP and cross-sectional areas of diaphragm muscle fibers, and increased time course of CMAP (p < 0.05). Additionally, oxidative stress, cell apoptosis, and protein degradation were increased and mitochondrial stability was decreased by MV treatment (p < 0.05). Conversely, AP administration reversed all these changes induced by MV, but this reversal was disrupted by the blockage of the IGF-1-FOXO1-MURF1 pathway. In this study, MV treatment induced symptoms of VIDD in rats, which were all effectively reversed by AP regulating the IGF-1-FOXO1-MURF1 pathway, demonstrating the potential of AP in ameliorating VIDD.

Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Ultrasonographic evaluation of diaphragm thickness and excursion: correlation with weaning success in trauma patients: prospective cohort study.

Prolonged mechanical ventilation (MV) subjects multiple trauma patients to ventilator-induced diaphragmatic dysfunction. There is limited evidence on the predictive role of diaphragm ultrasound (DUS) for weaning success in multiple trauma patients. Therefore, we evaluated Ultrasound of the diaphragm as a valuable indicator of weaning outcomes, in trauma patients. This prospective cohort study included 50 trauma patients from September 2018 to February 2019. DUS was performed twice: upon ICU admission and the first weaning attempt. The diagnostic accuracy of indexes was evaluated by ROC curves. The study included patients with a mean age of 35.4 ± 17.37, and 78% being male. The median injury severity score was 75 (42-75). The failure group exhibited significantly lower right diaphragmatic excursion (DE) compared to the success group (P = 0.006). In addition, the failure group experienced a significant decrease in both right and left DE from admission to the first attempt of weaning from MV (P < 0.001). Both groups showed a significant decrease in inspiratory and expiratory thickness on both sides during weaning from MV compared to the admission time (P < 0.001). The findings from the ROC analysis indicated that the Rapid shallow breathing index (RSBI) (Sensitivity = 91.67, Specificity = 100), respiratory rate (RR)/DE (Right: Sensitivity = 87.5, Specificity = 92.31), and RR/TF (Thickening Fraction) (Right: Sensitivity = 83.33, Specificity = 80.77) demonstrated high sensitivity and specificity in predicting weaning outcome. In the context of patients with multiple trauma, employing DUC and assessing diaphragmatic excursion, thickness, RR/DE index, RR/TF index, and RSBI can aid in determining successful ventilator weaning.

Diaphragm atrophy during invasive mechanical ventilation is related to extubation failure in preterm infants: An ultrasound study.

Diaphragm dysfunction is associated with poor outcomes in critically ill patients. Ventilator-induced diaphragmatic dysfunction (VIDD), including diaphragm atrophy (DA), is poorly studied in newborns. We aimed to assess VIDD and its associations in newborns. Single-center prospective study. Diaphragm thickness was measured at end-inspiration (TDI) and end-expiration (TDE) on the right midaxillary line. DA was defined as decrease in TDE ≥ 10%. Daily measurements were recorded in preterm newborns on invasive mechanical ventilation (IMV) for ≥2 days. Clinical characteristics of patients and extubation failure were recorded. Univariate analysis, logistic regression, and mixed models were performed to describe VIDD and associated factors. We studied 17 patients (median gestational age 270/7 weeks) and 22 IMV cycles (median duration 9 days). Median TDE decreased from 0.118 cm (interquartile range [IQR]0.094-0.165) on the first IMV day to 0.104 cm (IQR 0.083-0.120) on the last IMV day (p = .092). DA occurred in 11 IMV cycles (50%) from 10 infants early during IMV (median: second IMV day). Mean airway pressure (MAP) and lung ultrasound score (LUS) on the first IMV day were significantly higher in patients who developed DA. DA was more frequent in patients with extubation failure than in those with extubation success within 7 days (83.3 vs. 33.3%, p = .038). DA, significantly associated with extubation failure, occurred in 58.8% of the study infants on IMV. Higher MAP and LUS at IMV start were associated with DA. Our results suggest a potential role of diaphragm ultrasound to assess DA and predict extubation failure in clinical practice.

IGF-1 Regulates Skeletal Muscle Degradation and Remolding in Ventilator-Induced Diaphragmatic Dysfunction by Mediating FOXO1 Expression.

Mechanical ventilation (MV) sustains life in critically ill patients by providing adequate alveolar ventilation. However, prolonged MV could induce inspiratory muscle atrophy known as ventilator-induced diaphragmatic dysfunction (VIDD). Insulin-like growth factor (IGF)-1 has been proven to play crucial roles in regulating skeletal muscle size and function. Meanwhile, the forkhead box protein O1 (FOXO1) has been linked to muscle atrophy. This study aimed to explore the effect of IGF-1 on muscle degradation and remodeling in VIDD and delved into the association of the underlying mechanism involving FOXO1. VIDD models were established by treating rats with MV. Adeno-associated virus (AAV) was used for transfection to construct IGF-1 and/or FOXO1 overexpressed rats. There were four groups in this study: normal rats (NC), normal rats with MV treatment (MV), IGF-1-overexpressed rats with MV treatment (MV+IGF-1), and rats overexpressing both IGF-1 and FOXO1 with MV treatment (MV+IGF-1+FOXO1). Protein levels were measured by western blot or enzyme-linked immunosorbent assay (ELISA), and mRNA levels were detected by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). IGF-1 and FOXO1 expression were validated by detecting mRNA and protein levels. Diaphragmatic muscle contractility and morphometry were tested using stimulating electrodes in conjunction with hematoxylin and eosin (H&E) staining. Interleukin (IL)-6 and carbonylated protein were used for evaluating muscle atrophy and oxidation, respectively. Protein degradation was determined by troponin-I level and tyrosine release. Apoptosis was assessed using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay, alongside markers like Bax, B-cell lymphoma 2 (BCL-2), and Cleaved Caspase-3. Atrogin-1, muscle RING finger 1 (MURF1), neuronally expressed developmentally downregulated 4 (NEDD4), muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1), and ubiquitinated protein was used to determine proteolysis. Additionally, protein synthesis was measured by assessing the rates of mixed muscle protein (MMP) and myosin heavy chain (MHC). MV treatment caused IGF-1 downregulation (p < 0.01) and FOXO1 upregulation (p < 0.01). The IGF-1 upregulation downregulated FOXO1 in the MV+IGF-1 group (p < 0.001) while IGF-1 and FOXO1 were both upregulated in the MV+IGF-1+FOXO1 group (p < 0.001). The treatment of MV decreased muscle contractility and cross-sectional areas of diaphragm muscle fibers (p < 0.01). Additionally, IL-6, troponin-1, tyrosine release, carbonylated protein, TUNEL positive nuclei, Bax, Cleaved Caspase-3, Atrogin-1, MURF1, neuronally expressed developmentally downregulated 4 (NEDD4), MUSA1, and ubiquitinated protein levels increased significantly in MV group (p < 0.001) while levels of BCL-2, fractional synthetic rate of MMP and MHC, and type I and type II MHC protein mRNA expression decreased in MV group (p < 0.001). All of these alterations were reversed in the MV+IGF-1 group (p < 0.01), while the IGF-1-induced reversion was disrupted in the MV+IGF-1+FOXO1 group (p < 0.01). IGF-1 may protect diaphragmatic muscles from VIDD-induced structural damage and function loss by downregulating FOXO1. This action suppresses muscle breakdown and facilitates muscle remodeling in diaphragmatic muscles affected by VIDD.

The role of Point of Care Ultrasound (POCUS) and focused echocardiography in optimization of non-invasive mechanical ventilation: from diaphragmatic functionality to hemodynamic monitoring

Abstract This case shows the use of ultrasound guidance to optimize non-invasive mechanical ventilation for a 62-year-old patient with a complex medical history. Point-of-care ultrasound (POCUS) was used to assess diaphragmatic function and hemodynamics, leading to adjustments in ventilator setting. The approach improved gas exchange, resolved respiratory acidosis, and enhanced hemodynamics, providing a promising strategy for ventilator management in complex clinical cases. Keywords: Non-Invasive Mechanical Ventilation, Point-of-Care Ultrasound, Diaphragmatic Ultrasound, Focused Echocardiography, Ventilator-Induced Diaphragmatic Dysfunction, Hemodynamics.

Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways

BackgroundMechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the role of cellular senescence in VIDD.MethodsA total of twelve New Zealand rabbits were randomly divided into 2 groups: (1) spontaneously breathing anaesthetized animals (the CON group) and (2) mechanically ventilated animals (for 48 h) in V-ACV mode (the MV group). Respiratory parameters were collected during ventilation. Diaphragm were collected for further analyses.ResultsCompared to those in the CON group, the percentage and density of sarcomere disruption in the MV group were much higher (p < 0.001, both). The mRNA expression of MAFbx and MuRF1 was upregulated in the MV group (p = 0.003 and p = 0.006, respectively). Compared to that in the CON group, the expression of MAFbx and MuRF1 detected by western blotting was also upregulated (p = 0.02 and p = 0.03, respectively). Moreover, RNA-seq showed that genes associated with senescence were remarkably enriched in the MV group. The mRNA expression of related genes was further verified by q-PCR (Pai1: p = 0.009; MMP9: p = 0.008). Transverse cross-sections of diaphragm myofibrils in the MV group showed more intensive positive staining of SA-βGal than those in the CON group. p53-p21 axis signalling was elevated in the MV group. The mRNA expression of p53 and p21 was significantly upregulated (p = 0.02 and p = 0.05, respectively). The western blot results also showed upregulation of p53 and p21 protein expression (p = 0.03 and p = 0.05, respectively). Moreover, the p21-positive staining in immunofluorescence and immunohistochemistry in the MV group was much more intense than that in the CON group (p < 0.001, both).ConclusionsIn a rabbit model, we demonstrated that mechanical ventilation in A/C mode for 48 h can still significantly induce ultrastructural damage and atrophy of the diaphragm. Moreover, p53-dependent senescence might play a role in mechanical ventilation-induced dysfunction. These findings might provide novel therapeutic targets for VIDD.

Electrical stimulation mitigates muscle degradation shift in gene expressions during 12-h mechanical ventilation

Ventilator-induced diaphragm dysfunction (VIDD), a dysfunction of the diaphragm muscle caused by prolonged mechanical ventilation (MV), is an important factor that hinders successful weaning from ventilation. We evaluated the effects of electrical stimulation of the diaphragm muscle (pulsed current with off-time intervals) on genetic changes during 12 h of MV (E-V12). Rats were divided into four groups: control, 12-h MV, sham operation, and E-V12 groups. Transcriptome analysis using an RNA microarray revealed that 12-h MV caused upregulation of genes promoting muscle atrophy and downregulation of genes facilitating muscle synthesis, suggesting that 12-h MV is a reasonable method for establishing a VIDD rat model. Of the genes upregulated by 12-h MV, 18 genes were not affected by the sham operation but were downregulated by E-V12. These included genes related to catabolic processes, inflammatory cytokines, and skeletal muscle homeostasis. Of the genes downregulated by 12-h MV, 6 genes were not affected by the sham operation but were upregulated by E-V12. These included genes related to oxygen transport and mitochondrial respiration. These results suggested that 12-h MV shifted gene expression in the diaphragm muscle toward muscle degradation and that electrical stimulation counteracted this shift by suppressing catabolic processes and increasing mitochondrial respiration.

Aberrant mitochondrial dynamics contributes to diaphragmatic weakness induced by mechanical ventilation.

In critical care patients, the ""temporary inactivity of the diaphragm caused by mechanical ventilation (MV) triggers a series of events leading to diaphragmatic dysfunction and atrophy, commonly known as ventilator-induced diaphragm dysfunction (VIDD). While mitochondrial dysfunction related to oxidative stress is recognized as a crucial factor in VIDD, the exact molecular mechanism remains poorly understood. In this study, we observe that 6 h of MV triggers aberrant mitochondrial dynamics, resulting in a reduction in mitochondrial size and interaction, associated with increased expression of dynamin-related protein 1 (DRP1). This effect can be prevented by P110, a molecule that inhibits the recruitment of DRP1 to the mitochondrial membrane. Furthermore, isolated mitochondria from the diaphragms of ventilated patients exhibited increased production of reactive oxygen species (ROS). These mitochondrial changes were associated with the rapid oxidation of type 1 ryanodine receptor (RyR1) and a decrease in the stabilizing subunit calstabin 1. Subsequently, we observed that the sarcoplasmic reticulum (SR) in the ventilated diaphragms showed increased calcium leakage and reduced contractile function. Importantly, the mitochondrial fission inhibitor P110 effectively prevented all of these alterations. Taken together, the results of our study illustrate that MV leads, in the diaphragm, to both mitochondrial fragmentation and dysfunction, linked to the up-/down-regulation of 320 proteins, as assessed through global comprehensive quantitative proteomics analysis, primarily associated with mitochondrial function. These outcomes underscore the significance of developing compounds aimed at modulating the balance between mitochondrial fission and fusion as potential interventions to mitigate VIDD in human patients.

Temporary diaphragm pacing for patients at risk of prolonged mechanical ventilation after extensive aortic repair

ObjectiveProlonged mechanical ventilation (MV) after extensive aortic reconstructive surgery is common. Studies have demonstrated that diaphragm pacing (DP) improves lung function in patients with unilateral diaphragm paralysis. The goal of this study is to determine whether this technology can be applied to complex aortic repair to reduce prolonged MV and other respiratory sequelae. MethodsA retrospective review was performed of patients who underwent temporary DP after extensive aortic reconstructive surgery between 2019 and 2022. The primary end point was prolonged MV incidence. Other measured end points included diaphragm electromyography improvement, length of hospitalization, duration of intensive care unit stay, and reintubation rates. ResultsFourteen patients deemed at high risk of prolonged MV based on their smoking and respiratory history underwent DP after extensive aortic repair. The mean age was 70.2 years. The indications for aortic repair were a thoracoabdominal aortic aneurysm (n = 8, including 2 ruptured, 2 symptomatic, and 1 mycotic), a perivisceral aneurysm (n = 4), and a perivisceral coral reef aorta (n = 2). All patients had a significant smoking history (active or former) or other risk factors for ventilator-induced diaphragmatic dysfunction and prolonged MV. The mean total duration of MV postoperatively was 31.9 hours (range, 8.1-76.5 hours). The total average pacing duration was 4.4 days. Two patients required prolonged MV, with an average of 75.4 hours. Two patients required reintubation. No complications related to DP wire placement or removal occurred. ConclusionsDP is safe and feasible for patients at high risk of pulmonary insufficiency after extensive aortic reconstructive surgery.

Ventilator-induced Diaphragmatic Dysfunction in Patients with Traumatic Brain Injury

Ventilator-induced Diaphragmatic Dysfunction in Patients with Traumatic Brain Injury

Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network.

Theophylline is an oral methylxanthine bronchodilator recommended as alternate therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, it is not generally recommended for the treatment of other respiratory disorders such as obstructive sleep apnea (OSA) or hypoxia. Most clinical practice guidelines rely on evidence published prior to the year 2000 to make these recommendations. This scoping review aimed to gather and characterize evidence describing theophylline for the management of respiratory disorders in adults between January 1, 2000 and December 31, 2020. Databases searched included Ovid MEDLINE, Embase, CINAHL Complete, Scopus, and International Pharmaceutical Abstracts. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Studies were included if they were published in English, theophylline was used for any respiratory disorder, and the study outcomes were disease- or patient-oriented. After removal of duplicates, 841 studies were screened and 55 studies were included. Results aligned with current clinical guideline recommendations relegating theophylline as an alternative therapy for the treatment of respiratory disorders, in favor of inhaled corticosteroids and inhaled bronchodilators. This scoping review identified the need for future research including: theophylline versus other medications deemed alternative therapies for asthma and COPD, meta-analyses of low-dose theophylline, and studies evaluating evidence-based patient-oriented outcomes for OSA, hypoxia, ventilator-induced diaphragmatic dysfunction, and spinal cord injury-related pulmonary function.

Clinical utility of diaphragmatic ultrasonography for mechanical ventilator weaning in adults: A study protocol for systematic review and meta-analysis.

Mechanical ventilation is associated with several risks, including barotrauma, ventilator-associated pneumonia, and ventilator-induced diaphragmatic dysfunction. A delay in weaning from mechanical ventilation increases these risks, and prolonged weaning has been shown to increase hospital mortality. Various tools have been used in clinical practice to predict successful weaning from mechanical ventilation; however, they have a low prognostic accuracy. The use of ultrasonography in intensive care units is an area of growing interest since it is a noninvasive, convenient, and safe modality. Since ultrasonography can provide real-time assessment of diaphragmatic morphology and function, it may have clinical utility in predicting successful mechanical ventilator weaning. This study aimed to describe a protocol to assess the effectiveness of diaphragmatic ultrasonography in the decision-making process for ventilator weaning in terms of its impact on clinical outcomes. This systematic review of published analytical research will use an aggregative thematic approach according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocolsguidelines. We will perform a comprehensive search for studies on the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases. Two authors will independently perform abstract and full-text screening and data extraction. Additionally, a meta-analysis and the risk of bias evaluation will be conducted, as appropriate. Systematic reviews on the effectiveness of diaphragmatic ultrasonography in the decision-making process for ventilator weaning in terms of its impact on clinical outcomes are lacking. The results of this systematic review may serve as a basis for future clinical trials. Systematic review registration: This protocol was registered with the Open Science Framework: https://osf.io/cn8xf.

Single fibre cytoarchitecture in ventilator-induced diaphragm dysfunction (VIDD) assessed by quantitative morphometry second harmonic generation imaging: Positive effects of BGP-15 chaperone co-inducer and VBP-15 dissociative corticosteroid treatment.

Ventilator-induced diaphragm dysfunction (VIDD) is a common sequela of intensive care unit (ICU) treatment requiring mechanical ventilation (MV) and neuromuscular blockade (NMBA). It is characterised by diaphragm weakness, prolonged respirator weaning and adverse outcomes. Dissociative glucocorticoids (e.g., vamorolone, VBP-15) and chaperone co-inducers (e.g., BGP-15) previously showed positive effects in an ICU-rat model. In limb muscle critical illness myopathy, preferential myosin loss prevails, while myofibrillar protein post-translational modifications are more dominant in VIDD. It is not known whether the marked decline in specific force (force normalised to cross-sectional area) is a pure consequence of altered contractility signaling or whether diaphragm weakness also has a structural correlate through sterical remodeling of myofibrillar cytoarchitecture, how quickly it develops, and to which extent VBP-15 or BGP-15 may specifically recover myofibrillar geometry. To address these questions, we performed label-free multiphoton Second Harmonic Generation (SHG) imaging followed by quantitative morphometry in single diaphragm muscle fibres from healthy rats subjected to five or 10days of MV + NMBA to simulate ICU treatment without underlying confounding pathology (like sepsis). Rats received daily treatment of either Prednisolone, VBP-15, BGP-15 or none. Myosin-II SHG signal intensities, fibre diameters (FD) as well as the parameters of myofibrillar angular parallelism (cosine angle sum, CAS) and in-register of adjacent myofibrils (Vernier density, VD) were computed from SHG images. ICU treatment caused a decline in FD at day 10 as well as a significant decline in CAS and VD from day 5. Vamorolone effectively recovered FD at day 10, while BGP-15 was more effective at day 5. BGP-15 was more effective than VBP-15 in recovering CAS at day 10 although not to control levels. In-register VD levels were restored at day 10 by both compounds. Our study is the first to provide quantitative insights into VIDD-related myofibrillar remodeling unravelled by SHG imaging, suggesting that both VBP-15 and BGP-15 can effectively ameliorate the structure-related dysfunction in VIDD.

Closed-loop parameter optimization for patient-specific phrenic nerve stimulation.

Ventilator-induced diaphragm dysfunction occurs rapidly following the onset of mechanical ventilation and has significant clinical consequences. Phrenic nerve stimulation has shown promise in maintaining diaphragm function by inducing diaphragm contractions. Non-invasive stimulation is an attractive option as it minimizes the procedural risks associated with invasive approaches. However, this method is limited by sensitivity to electrode position and inter-individual variability in stimulation thresholds. This makes clinical application challenging due to potentially time-consuming calibration processes to achieve reliable stimulation. We applied non-invasive electrical stimulation to the phrenic nerve in the neck in healthy volunteers. A closed-loop system recorded the respiratory flow produced by stimulation and automatically adjusted the electrode position and stimulation amplitude based on the respiratory response. By iterating over electrodes, the optimal electrode was selected. A binary search method over stimulation amplitudes was then employed to determine an individualized stimulation threshold. Pulse trains above this threshold were delivered to produce diaphragm contraction. Nine healthy volunteers were recruited. Mean threshold stimulation amplitude was 36.17 ± 14.34 mA (range 19.38-59.06 mA). The threshold amplitude for reliable nerve capture was moderately correlated with BMI (Pearson's r = 0.66, p = 0.049). Repeating threshold measurements within subjects demonstrated low intra-subject variability of 2.15 ± 1.61 mA between maximum and minimum thresholds on repeated trials. Bilateral stimulation with individually optimized parameters generated reliable diaphragm contraction, resulting in significant inhaled volumes following stimulation. We demonstrate the feasibility of a system for automatic optimization of electrode position and stimulation parameters using a closed-loop system. This opens the possibility of easily deployable individualized stimulation in the intensive care setting to reduce ventilator-induced diaphragm dysfunction.

A Trend towards Diaphragmatic Muscle Waste after Invasive Mechanical Ventilation in Multiple Trauma Patients-What to Expect?

Considering the prioritization of life-threatening injuries in trauma care, secondary dysfunctions such as ventilator-induced diaphragmatic dysfunction (VIDD) are often overlooked. VIDD is an entity induced by muscle inactivity during invasive mechanical ventilation, associated with a profound loss of diaphragm muscle mass. In order to assess the incidence of VIDD in polytrauma patients, we performed an observational, retrospective, longitudinal study that included 24 polytraumatized patients. All included patients were mechanically ventilated for at least 48 h and underwent two chest CT scans during their ICU stay. Diaphragmatic thickness was measured by two independent radiologists on coronal and axial images at the level of celiac plexus. The thickness of the diaphragm was significantly decreased on both the left and right sides (left side: -0.82 mm axial p = 0.034; -0.79 mm coronal p = 0.05; right side: -0.94 mm axial p = 0.016; -0.91 coronal p = 0.013). In addition, we obtained a positive correlation between the number of days of mechanical ventilation and the difference between the two measurements of the diaphragm thickness on both sides (r =0.5; p = 0.02). There was no statistically significant correlation between the body mass indexes on admission, the use of vitamin C or N-acetyl cysteine, and the differences in diaphragmatic thickness.

Intraoperative Hemi-Diaphragm Electrical Stimulation Demonstrates Attenuated Mitochondrial Function without Change in Oxidative Stress in Cardiothoracic Surgery Patients.

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries (n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.