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Objective: Prolonged 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. Methods: A 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. Results: Fourteen 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. Conclusions: DP is safe and feasible for patients at high risk of pulmonary insufficiency after extensive aortic reconstructive surgery. more...

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. [ABSTRACT FROM AUTHOR] more...

Objective: This study aims to study the effect of prolonged mechanical ventilation on diaphragmatic functionand to review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology. to study the role of the advantage of early weaning off decisions resulting in improved patientoutcomes. Methods: Polytrauma inpatients in the Department of Surgery, MGMMC, Indore, on mechanical ventilation. These patients were assessed for diaphragmatic thickness and excursion through ultrasonography. Results: A total of 100 patients were included in the study period of 1 year. Out of these, 36 patients were discharged and 64 died due to mechanical ventilation for longer duration. Conclusion: Though ventilator support is lifesaving, it should be used precautionarily, and intermittent ventilator support is much prognostically better in terms of the outcome when compared to controlled ventilation. [ABSTRACT FROM AUTHOR] more...

Introduction: Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability. Methods: Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control. Results: Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin). Conclusions: Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency. more...

Introduction: Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability. Methods: Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control. Results: Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin). Conclusions: Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency. [ABSTRACT FROM AUTHOR] more...

Abstract Background Ventilator-induced diaphragmatic dysfunction (VIDD) is associated with weaning difficulties, intensive care unit hospitalization (ICU), infant mortality, and poor long-term clinical outcomes. The expression patterns of long noncoding RNAs (lncRNAs) and mRNAs in the diaphragm in a rat controlled mechanical ventilation (CMV) model, however, remain to be investigated. Results The diaphragms of five male Wistar rats in a CMV group and five control Wistar rats were used to explore lncRNA and mRNA expression profiles by RNA-sequencing (RNA-seq). Muscle force measurements and immunofluorescence (IF) staining were used to verify the successful establishment of the CMV model. A total of 906 differentially expressed (DE) lncRNAs and 2,139 DE mRNAs were found in the CMV group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions or pathways of these DE mRNAs. Our results revealed that these DE mRNAs were related mainly related to complement and coagulation cascades, the PPAR signaling pathway, cholesterol metabolism, cytokine-cytokine receptor interaction, and the AMPK signaling pathway. Some DE lncRNAs and DE mRNAs determined by RNA-seq were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-sEq. Co-expression network analysis indicated that three selected muscle atrophy-related mRNAs (Myog, Trim63, and Fbxo32) were coexpressed with relatively newly discovered DE lncRNAs. Conclusions This study provides a novel perspective on the molecular mechanism of DE lncRNAs and mRNAs in a CMV model, and indicates that the inflammatory signaling pathway and lipid metabolism may play important roles in the pathophysiological mechanism and progression of VIDD. more...

Rationale: Diaphragm dysfunction is frequently observed in critically ill patients with difficult weaning from mechanical ventilation. Objectives: To evaluate the effects of temporary transvenous diaphragm neurostimulation on weaning outcome and maximal inspiratory pressure. Methods: Multicenter, open-label, randomized, controlled study. Patients aged ⩾18 years on invasive mechanical ventilation for ⩾4 days and having failed at least two weaning attempts received temporary transvenous diaphragm neurostimulation using a multielectrode stimulating central venous catheter (bilateral phrenic stimulation) and standard of care (treatment) (n = 57) or standard of care (control) (n = 55). In seven patients, the catheter could not be inserted, and in seven others, pacing therapy could not be delivered; consequently, data were available for 43 patients. The primary outcome was the proportion of patients successfully weaned. Other endpoints were mechanical ventilation duration, 30-day survival, maximal inspiratory pressure, diaphragm-thickening fraction, adverse events, and stimulation-related pain. Measurements and Main Results: The incidences of successful weaning were 82% (treatment) and 74% (control) (absolute difference [95% confidence interval (CI)], 7% [-10 to 25]), P = 0.59. Mechanical ventilation duration (mean ± SD) was 12.7 ± 9.9 days and 14.1 ± 10.8 days, respectively, P = 0.50; maximal inspiratory pressure increased by 16.6 cm H2O and 4.8 cm H2O, respectively (difference [95% CI], 11.8 [5 to 19]), P = 0.001; and right hemidiaphragm thickening fraction during unassisted spontaneous breathing was +17% and -14%, respectively, P = 0.006, without correlation with changes in maximal inspiratory pressure. Serious adverse event frequency was similar in both groups. Median stimulation-related pain in the treatment group was 0 (no pain). Conclusions: Temporary transvenous diaphragm neurostimulation did not increase the proportion of successful weaning from mechanical ventilation. It was associated with a significant increase in maximal inspiratory pressure, suggesting reversal of the course of diaphragm dysfunction. Clinical trial registered with www.clinicaltrials.gov (NCT03096639) and the European Database on Medical Devices (CIV-17-06-020004). [ABSTRACT FROM AUTHOR] more...

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia. Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e., 21% O2) diminishes diaphragm perfusion and O2 delivery in the quiescent diaphragm, the effect of MV with 100% O2 is unknown. We tested the hypothesis that MV supplemented with hyperoxic gas (100% O2) would increase diaphragm vascular resistance and reduce diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (4-6 mo) were randomly divided into two groups: 1) MV þ 100% O2 followed by MV þ 21% O2 (n = 9) or 2) MV þ 21% O2 followed by MV þ 100% O2 (n = 10). Diaphragmatic blood flow (mL/min/100 g) and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV þ 100% O2, and MV þ 21% O2. Compared with SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV þ 100% O2 and MV þ 21% O2 (all P < 0.05). Medial costal diaphragmatic blood flow was lower with MV þ 100% O2 (26 ± 6 mL/min/100 g) versus MV þ 21% O2 (51 ± 15 mL/min/100 g; P < 0.05). Second, the addition of 100% O2 during normoxic MV exacerbated the MVinduced reductions in medial costal diaphragm perfusion (23 ± 7 vs. 51 ± 15 mL/min/100 g; P < 0.05) and O2 delivery (3.4 ± 0.2 vs. 6.4 ± 0.3 mL O2/min/100 g; P < 0.05). These data demonstrate that administration of supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a significantly greater degree than normoxic MV. This suggests that prolonged bouts of MV (i.e., 6 h) with hyperoxia may accelerate MV-induced vascular dysfunction in the quiescent diaphragm and potentially exacerbate downstream contractile dysfunction. [ABSTRACT FROM AUTHOR] more...

Background: Ventilator-induced diaphragmatic dysfunction (VIDD) is associated with weaning difficulties, intensive care unit hospitalization (ICU), infant mortality, and poor long-term clinical outcomes. The expression patterns of long noncoding RNAs (lncRNAs) and mRNAs in the diaphragm in a rat controlled mechanical ventilation (CMV) model, however, remain to be investigated. Results: The diaphragms of five male Wistar rats in a CMV group and five control Wistar rats were used to explore lncRNA and mRNA expression profiles by RNA-sequencing (RNA-seq). Muscle force measurements and immunofluorescence (IF) staining were used to verify the successful establishment of the CMV model. A total of 906 differentially expressed (DE) lncRNAs and 2,139 DE mRNAs were found in the CMV group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions or pathways of these DE mRNAs. Our results revealed that these DE mRNAs were related mainly related to complement and coagulation cascades, the PPAR signaling pathway, cholesterol metabolism, cytokine-cytokine receptor interaction, and the AMPK signaling pathway. Some DE lncRNAs and DE mRNAs determined by RNA-seq were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-sEq. Co-expression network analysis indicated that three selected muscle atrophy-related mRNAs (Myog, Trim63, and Fbxo32) were coexpressed with relatively newly discovered DE lncRNAs. Conclusions: This study provides a novel perspective on the molecular mechanism of DE lncRNAs and mRNAs in a CMV model, and indicates that the inflammatory signaling pathway and lipid metabolism may play important roles in the pathophysiological mechanism and progression of VIDD. [ABSTRACT FROM AUTHOR] more...

Long‐term mechanical ventilation (MV) is defined as the use of MV for more than 6 hours per day for at least 3 weeks. Children requiring long‐term MV include those with neuromuscular disease, central dysregulation, or lung dysfunction. Such children with medical complexity may be at risk for ventilator‐induced diaphragmatic dysfunction. Ventilator‐induced diaphragmatic dysfunction has been described in adult patients requiring acute MV with ultrasound (US). At this time, diaphragmatic US has not been evaluated in the pediatric post–acute care setting or incorporated into weaning strategies. We present 24 cases of children requiring long‐term MV who underwent diaphragmatic US examinations to evaluate for ventilator‐induced diaphragmatic dysfunction. [ABSTRACT FROM AUTHOR] more...

Abstract Background Mechanical ventilation (MV) is a life-saving technology that restores or assists breathing. Like any treatment, MV has side effects. In some patients it can cause diaphragmatic atrophy, injury, and dysfunction (ventilator-induced diaphragmatic dysfunction, VIDD). Accumulating evidence suggests that VIDD makes weaning from MV difficult, which involves increased morbidity and mortality. Methods and analysis This paper describes the protocol of a randomized, controlled, open-label, multicenter trial that is designed to investigate the safety and effectiveness of a novel therapy, temporary transvenous diaphragm pacing (TTVDP), to improve weaning from MV in up to 88 mechanically ventilated adult patients who have failed at least two spontaneous breathing trials over at least 7 days. Patients will be randomized (1:1) to TTVDP (treatment) or standard of care (control) groups. The primary efficacy endpoint is time to successful extubation with no reintubation within 48 h. Secondary endpoints include maximal inspiratory pressure and ultrasound-measured changes in diaphragm thickness and diaphragm thickening fraction over time. In addition, observational data will be collected and analyzed, including 30-day mortality and time to discharge from the intensive care unit and from the hospital. The hypothesis to be tested postulates that more TTVDP patients than control patients will be successfully weaned from MV within the 30 days following randomization. Discussion This study is the first large-scale clinical trial of a novel technology (TTVDP) aimed at accelerating difficult weaning from MV. The technology tested provides the first therapy directed specifically at VIDD, an important cause of delayed weaning from MV. Its results will help delineate the place of this therapeutic approach in clinical practice and help design future studies aimed at defining the indications and benefits of TTVDP. Trial registration ClinicalTrials.gov, NCT03096639. Registered on 30 March 2017. more...

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Background: 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., Methods: 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 (H 2 O 2 ), 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., Results: 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., Conclusions: 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. more...

Background: 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 ., Methods: 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)., Results: 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)., Conclusions: 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. more...

Background: Mechanical ventilation (MV) is a life-saving technology that restores or assists breathing. Like any treatment, MV has side effects. In some patients it can cause diaphragmatic atrophy, injury, and dysfunction (ventilator-induced diaphragmatic dysfunction, VIDD). Accumulating evidence suggests that VIDD makes weaning from MV difficult, which involves increased morbidity and mortality.Methods and Analysis: This paper describes the protocol of a randomized, controlled, open-label, multicenter trial that is designed to investigate the safety and effectiveness of a novel therapy, temporary transvenous diaphragm pacing (TTVDP), to improve weaning from MV in up to 88 mechanically ventilated adult patients who have failed at least two spontaneous breathing trials over at least 7 days. Patients will be randomized (1:1) to TTVDP (treatment) or standard of care (control) groups. The primary efficacy endpoint is time to successful extubation with no reintubation within 48 h. Secondary endpoints include maximal inspiratory pressure and ultrasound-measured changes in diaphragm thickness and diaphragm thickening fraction over time. In addition, observational data will be collected and analyzed, including 30-day mortality and time to discharge from the intensive care unit and from the hospital. The hypothesis to be tested postulates that more TTVDP patients than control patients will be successfully weaned from MV within the 30 days following randomization.Discussion: This study is the first large-scale clinical trial of a novel technology (TTVDP) aimed at accelerating difficult weaning from MV. The technology tested provides the first therapy directed specifically at VIDD, an important cause of delayed weaning from MV. Its results will help delineate the place of this therapeutic approach in clinical practice and help design future studies aimed at defining the indications and benefits of TTVDP.Trial Registration: ClinicalTrials.gov, NCT03096639 . Registered on 30 March 2017. [ABSTRACT FROM AUTHOR] more...

Patient-ventilator synchrony has been the focus of attention in the field of mechanical ventilation for quite some time now. Toward that end, the modern ventilators are equipped with very sensitive pneumatic triggering mechanisms, which allow for minimal wasting of patient effort. The increasingly sensitive pneumatic triggers have the potential to cause autotriggering, where stimuli other than neural signals (eg, cardiac oscillations) can trigger the mechanical breath. Although autotriggering has been well documented in brain-dead patients, its existence is difficult to prove in patients who have the ability to trigger breath through neural diaphragmatic activity. The only way to be sure that the triggered breath is indeed from the neural diaphragmatic activity rather than a spurious change in pressure or flow is to monitor neural signals during triggered mechanical breaths. Autotriggering can have deleterious effects including diaphragmatic atrophy, increased duration on the mechanical ventilator, and increased stay in the intensive care unit. Esophageal catheters, with the ability to measure phrenic nerve and diaphragmatic activity, allow for the detection of the extent of autotriggering. This article demonstrates the hitherto unknown but potentially common occurrence of autotriggering through nonneural stimuli and their amelioration by making the pneumatic autotriggering less sensitive. The full extent of the phenomenon and its deleterious effects remain to be explored in larger patient populations. [ABSTRACT FROM AUTHOR] more...

Background: Mechanical ventilation (MV) is associated with diaphragm weakness, a phenomenon termed ventilator-induced diaphragmatic dysfunction. Weaning should balance diaphragmatic loading as well as prevention of overload after MV. The weaning methods pressure support ventilation (PSV) and spontaneous breathing trials (SBT) lead to gradual or intermittent reloading of a weak diaphragm, respectively. This study investigated which weaning method allows more efficient restoration of diaphragm homeostasis.Methods: Rats (n = 8 per group) received 12 h of MV followed by either 12 h of pressure support ventilation (PSV) or intermittent spontaneous breathing trials (SBT) and were compared to rats euthanized after 12 h MV (CMV) and to acutely euthanized rats (CON). Force generation, activity of calpain-1 and caspase-3, oxidative stress, and markers of protein synthesis (phosphorylated AKT to total AKT) were measured in the diaphragm.Results: Reduction of diaphragmatic force caused by CMV compared to CON was worsened with PSV and SBT (both p < 0.05 vs. CON and CMV). Both PSV and SBT reversed oxidative stress and calpain-1 activation caused by CMV. Reduced pAKT/AKT was observed after CMV and both weaning procedures.Conclusions: MV resulted in a loss of diaphragmatic contractility, which was aggravated in SBT and PSV despite reversal of oxidative stress and proteolysis. [ABSTRACT FROM AUTHOR] more...

The diaphragm is a unique skeletal muscle designed to be rhythmically active throughout life, such that its sustained inactivation by the medical intervention of mechanical ventilation (MV) represents an unanticipated physiological state in evolutionary terms. Within a short period after initiating MV, the diaphragm develops muscle atrophy, damage, and diminished strength, and many of these features appear to arise from mitochondrial dysfunction. Notably, in response to metabolic perturbations, mitochondria fuse, divide, and interact with neighboring organelles to remodel their shape and functional properties--a process collectively known as mitochondrial dynamics. Using a quantitative electron microscopy approach, here we show that diaphragm contractile inactivity induced by 6 h of MV in mice leads to fragmentation of intermyofibrillar (IMF) but not subsarcolemmal (SS) mitochondria. Furthermore, physical interactions between adjacent organellar membranes were less abundant in IMF mitochondria during MV. The profusion proteins Mfn2 and OPA1 were unchanged, whereas abundance and activation status of the profission protein Drp1 were increased in the diaphragm following MV. Overall, our results suggest that mitochondrial morphological abnormalities characterized by excessive fission-fragmentation represent early events during MV, which could potentially contribute to the rapid onset of mitochondrial dysfunction, maladaptive signaling, and associated contractile dysfunction of the diaphragm. [ABSTRACT FROM AUTHOR] more...

Because the diaphragm is essential for survival, we wondered if it might be less vulnerable to the long-lasting effects of fatigue than limb muscles. Using a recently introduced magnetic probe to activate the phrenic nerves, we followed the evolution of twitch transdiaphragmatic pressure after inducing fatigue in healthy volunteers. Twenty-four hours after its induction, diaphragmatic fatigue had not fully recovered. Findings from this study later served as the foundation for incorporating a once-daily, T-tube-trial arm into a randomized controlled trial of techniques for ventilator weaning in intensive care unit patients and also influenced the design of a controlled trial of the weaning of tracheostomy patients who required prolonged ventilation. The research methodology was later employed to determine whether low-frequency fatigue is responsible for weaning failure. Employing a further modification of the technique-twitch airway pressure-it became evident that respiratory muscle weakness is a greater problem than fatigue in ventilated patients. Twitch airway pressure is now being used to document the prevalence and consequences of ventilator-induced respiratory muscle weakness. Our study-which began with a circumscribed, simple question-has yielded dividends in unforeseen directions, illustrating the fruitfulness of research into basic physiological mechanisms. [ABSTRACT FROM AUTHOR] more...

Question: Does inspiratory muscle training accelerate weaning from mechanical ventilation? Does it improve respiratory muscle strength, tidal volume, and the rapid shallow breathing index? Design: Randomised trial with concealed allocation and intention-to-treat analysis. Participants: 92 patients receiving pressure support ventilation were included in the study and followed up until extubation, tracheostomy, or death. Intervention: The experimental group received usual care and inspiratory muscle training using a threshold device, with a load of 40% of their maximal inspiratory pressure with a regimen of 5 sets of 10 breaths, twice a day, 7 days a week. The control group received usual care only. Outcome measures: The primary outcome was the duration of the weaning period. The secondary outcomes were the changes in respiratory muscle strength, tidal volume, and the rapid shallow breathing index. Results: Although the weaning period was a mean of 8 hours shorter in the experimental group, this difference was not statistically significant (95% CI –16 to 32). Maximal inspiratory and expiratory pressures increased in the experimental group and decreased in the control group, with significant mean differences of 10cmH2O (95% CI 5 to 15) and 8cmH2O (95% CI 2 to 13), respectively. The tidal volume also increased in the experimental group and decreased in the control group (mean difference 72 ml, 95% CI 17 to 128). The rapid shallow breathing index did not differ significantly between the groups. Conclusion: Inspiratory muscle training did not shorten the weaning period significantly but it increased respiratory muscle strength and tidal volume. [Copyright &y& Elsevier] more...

Since the early 1970s there has been an ongoing debate regarding the wisdom of promoting unassisted spontaneous breathing throughout the course of critical illness in patients with severe respiratory failure. The basis of this debate has focused on the clinical relevance of opposite problems. Historically, the term "disuse atrophy" has described a situation wherein sustained inactivity of the respiratory muscles (ie, passive ventilation) results in deconditioning and weakness. More recently it has been referred to as "ventilator-induced diaphragmatic dysfunction." In contrast, "use atrophy" describes a situation where chronic high-tension inspiratory work causes structural damage to the diaphragm and weakness. Both laboratory and clinical studies demonstrated that relatively brief periods of complete respiratory muscle inactivity, as well as intense muscle loading, result in acute inflammation, loss of muscle mass, and weakness. Yet in critical illness other factors also affect respiratory muscle function, including prolonged use of neuromuscular blocking agents, administration of corticosteroids, and sepsis. This makes the attribution of acquired respiratory muscle weakness and ventilator-dependence to either ventilator-induced diaphragmatic dysfunction or loaded breathing extremely difficult. Regardless, the clinical implications of this research strongly suggest that passive mechanical ventilation should be avoided whenever possible. However, promotion of unassisted spontaneous breathing in the acute phase of critical illness also may carry a substantial risk of respiratory muscle injury and weakness. Use of mechanical ventilation modes in a manner that induces spontaneous breathing effort, while simultaneously reducing the work load on the respiratory muscles, is probably sufficient to minimize both problems. [ABSTRACT FROM AUTHOR] more...

New methods to prevent ventilator-induced diaphragmatic dysfunction (VIDD) are urgently needed, and the cellular basis of VIDD is poorly understood. This study evaluated whether transvenous phrenic nerve stimulation (PNS) could prevent VIDD in rabbits undergoing mechanical ventilation (MV) and explored whether oxidative stress-related genes might be candidate molecular markers for VIDD. Twenty-four adult male New Zealand white rabbits were allocated to control, MV, and PNS groups ( n = 8 in each group). Rabbits in the MV and PNS groups underwent MV for 24 h. Intermittent bilateral transvenous PNS was performed in rabbits in the PNS group. Transdiaphragmatic pressure was recorded using balloon catheters. The diameters and cross-sectional areas (CSAs) of types I and II diaphragmatic fibers were measured using immunohistochemistry (IHC) techniques. Genes associated with VIDD were identified by RNA sequencing (RNA-seq), differentially expressed gene (DEG) analysis, and weighted gene co-expression network analysis (WGCNA). Reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and IHC analyses were carried out to verify the transcriptome profile. Pdi 60Hz , Pdi 80Hz , and Pdi 100Hz were significantly higher in the PNS group than in the MV group at 12 and 24 h ( P < 0.05 at both time points). The diameters and CSAs of types I (slow-twitch) and II (fast-twitch) fibers were significantly larger in the PNS group than in the MV group ( P < 0.05). RNA-seq, RT-PCR, Western blotting, and IHC experiments identified two candidate genes associated with VIDD: Aldh1a1 and Scl25a30 . The MV group had significantly higher mRNA and protein expressions of Aldh1a1 /ALDH1A1 and significantly lower mRNA and protein expressions of Scl25a30 /SCL25A30 than the control or PNS groups ( P < 0.05). We have identified two candidate genes involved in the prevention of VIDD by transvenous PNS. These two key genes may provide a theoretical basis for targeted therapy against VIDD. more...

An introduction is presented in which the editor discusses various topics within the issue including spontaneous breathing (SB), acute respiratory distress syndrome (ARDS) and intra-alveolar edema.

Purpose: To evaluate the effect of theophylline in patients with ventilator-induced diaphragmatic dysfunction (VIDD)., Materials and Methods: Patients who required mechanical ventilation at least 72 hours, met the criteria for a spontaneous breathing trial, and had evidence of VIDD by ultrasonography were included in the study., Results: Of the 40 patients, 21 received theophylline and 19 did not. Clinical characteristics were similar in the 2 groups. Assessment of VIDD showed no between-group differences in baseline diaphragmatic excursion (DE) of both hemidiaphragms. Changes in DE from baseline to 72 hours (ΔDE) were significantly higher in the theophylline group than in the nontheophylline group in the right (3.5 ± 4.5 mm vs 0.4 ± 2.1 mm; P = .004) and left (3.2 ± 5.1 mm vs 0.1 ± 4.0 mm; P = .03) hemidiaphragms and in the total DE of both diaphragms (6.9 ± 9.1 mm vs 0.5 ± 5.7 mm; P = .02). In the theophylline group, theophylline was effective for the diaphragms with VIDD, whereas it was not effective for the diaphragms without VIDD. ΔDE in the right (rs = -0.49, P = .006) hemidiaphragm and total Δ DE in both diaphragms (rs = -0.46, P = .01) correlated negatively with weaning time., Conclusions: Theophylline significantly improved diaphragmatic movements in patients with VIDD. Our results warrant a larger study to determine whether theophylline use has benefits during weaning from mechanical ventilation., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...