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

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Diaphragmatic ultrasound evaluation in acute heart failure: clinical and functional associations.

Heart failure patients often experience respiratory symptoms due to diaphragmatic involvement, but the diaphragmatic motion in heart failure remains understudied. This research aimed to investigate the correlation between ultrasonographically assessed diaphragmatic motion and thickness with cardiac performance indexes in an emergency setting. Seventy-two acutely decompensated heart failure patients and 100 non-heart failure individuals were enrolled. Diaphragmatic motion and thickness were assessed via ultrasound. Cardiac and respiratory parameters were recorded, and regression analysis was performed. Heart failure patients exhibited reduced diaphragmatic motion at total lung capacity compared to controls, and an inverse association was found between motion and heart failure severity (NYHA stage). Diaphragmatic thickness was also higher in heart failure patients at tidal volume and total lung capacity. Notably, diaphragmatic motion inversely correlated with systolic pulmonary artery pressure. The study highlights diaphragmatic dysfunction in acutely decompensated heart failure, with reduced motion and increased thickness. These changes were associated with cardio-respiratory parameters, specifically systolic pulmonary artery pressure. Monitoring diaphragmatic motion via ultrasound may aid in evaluating heart failure severity and prognosis in emergency settings. Additionally, interventions targeting diaphragmatic function could improve heart failure management. Further research is warranted to enhance heart failure management and patient outcomes.

Diaphragmatic Dysfunction due to Neuralgic Amyotrophy After SARS-CoV-2 Vaccination: A Case Report.

Neuralgic amyotrophy is an idiopathic neuropathy characterized by acute-onset pain, typically in the upper extremity or shoulder, followed by weakness of the associated muscles. Phrenic nerve involvement is rare. We report a 63-year-old man who presented with dyspnea and right shoulder pain after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. His chest radiograph showed an elevated right hemidiaphragm that was absent before vaccination. A pulmonary function test showed a restrictive pattern with a significant reduction (40%) in forced vital capacity in the supine position. Diaphragm ultrasonography revealed a reduction in both diaphragmatic excursion and a thickening fraction of the right hemidiaphragm. Electrophysiological studies suggested a right upper brachial plexopathy. Considering the temporal relationship between the vaccination and absence of other causes, SARS-CoV-2 vaccination was thought to be the reason for neuralgic amyotrophy with diaphragmatic dysfunction. As there was no evidence of hypoventilation or sleep disturbance that may require noninvasive ventilation, the patient was followed with conservative treatment with analgesics. During 8 months of follow-up, his shoulder pain was relieved significantly but dyspnea improved only slightly. Neuralgic amyotrophy is an under-diagnosed etiology of diaphragmatic dysfunction and should be considered in patients with dyspnea and shoulder pain.

Reduction in Ventilation-Induced Diaphragmatic Mitochondrial Injury through Hypoxia-Inducible Factor 1α in a Murine Endotoxemia Model.

Mechanical ventilation (MV) is essential for patients with sepsis-related respiratory failure but can cause ventilator-induced diaphragm dysfunction (VIDD), which involves diaphragmatic myofiber atrophy and contractile inactivity. Mitochondrial DNA, oxidative stress, mitochondrial dynamics, and biogenesis are associated with VIDD. Hypoxia-inducible factor 1α (HIF-1α) is crucial in the modulation of diaphragm immune responses. The mechanism through which HIF-1α and mitochondria affect sepsis-related diaphragm injury is unknown. We hypothesized that MV with or without endotoxin administration would aggravate diaphragmatic and mitochondrial injuries through HIF-1α. C57BL/6 mice, either wild-type or HIF-1α-deficient, were exposed to MV with or without endotoxemia for 8 h. MV with endotoxemia augmented VIDD and mitochondrial damage, which presented as increased oxidative loads, dynamin-related protein 1 level, mitochondrial DNA level, and the expressions of HIF-1α and light chain 3-II. Furthermore, disarrayed myofibrils; disorganized mitochondria; increased autophagosome numbers; and substantially decreased diaphragm contractility, electron transport chain activities, mitofusin 2, mitochondrial transcription factor A, peroxisome proliferator activated receptor-γ coactivator-1α, and prolyl hydroxylase domain 2 were observed (p < 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1α-deficient mice (p < 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1α signaling pathway.

Lung- and Diaphragm-Protective Ventilation by Titrating Inspiratory Support to Diaphragm Effort: A Randomized Clinical Trial.

OBJECTIVES: Lung- and diaphragm-protective ventilation is a novel concept that aims to limit the detrimental effects of mechanical ventilation on the diaphragm while remaining within limits of lung-protective ventilation. The premise is that low breathing effort under mechanical ventilation causes diaphragm atrophy, whereas excessive breathing effort induces diaphragm and lung injury. In a proof-of-concept study, we aimed to assess whether titration of inspiratory support based on diaphragm effort increases the time that patients have effort in a predefined "diaphragm-protective" range, without compromising lung-protective ventilation. DESIGN: Randomized clinical trial. SETTING: Mixed medical-surgical ICU in a tertiary academic hospital in the Netherlands. PATIENTS: Patients (n = 40) with respiratory failure ventilated in a partially-supported mode. INTERVENTIONS: In the intervention group, inspiratory support was titrated hourly to obtain transdiaphragmatic pressure swings in the predefined "diaphragm-protective" range (3-12 cm H2O). The control group received standard-of-care. MEASUREMENTS AND MAIN RESULTS: Transdiaphragmatic pressure, transpulmonary pressure, and tidal volume were monitored continuously for 24 hours in both groups. In the intervention group, more breaths were within "diaphragm-protective" range compared with the control group (median 81%; interquartile range [64-86%] vs 35% [16-60%], respectively; p < 0.001). Dynamic transpulmonary pressures (20.5 ± 7.1 vs 18.5 ± 7.0 cm H2O; p = 0.321) and tidal volumes (7.56 ± 1.47 vs 7.54 ± 1.22 mL/kg; p = 0.961) were not different in the intervention and control group, respectively. CONCLUSIONS: Titration of inspiratory support based on patient breathing effort greatly increased the time that patients had diaphragm effort in the predefined "diaphragm-protective" range without compromising tidal volumes and transpulmonary pressures. This study provides a strong rationale for further studies powered on patient-centered outcomes.

Effect of superior trunk block on diaphragm function and respiratory parameters after shoulder surgery.

BACKGROUND: The interscalene brachial plexus block has been used effectively for intraoperative and postoperative analgesia in patients undergoing shoulder surgery, but it is associated with high rates of diaphragmatic dysfunction. Performing the block more distally, at the level of the superior trunk, may reduce the incidence of phrenic nerve palsy. We hypothesized that superior trunk block would result in diaphragmatic paralysis rate of less than 20%. METHODS: 30 patients undergoing arthroscopic shoulder surgery received superior trunk block under ultrasound guidance. Measurements of diaphragm excursion were determined with ultrasound prior to the block, 15 min after the block, and postoperatively in phase II of postanesthesia care unit, in conjunction with clinical parameters of respiratory function. RESULTS: 10 patients (33.3%, 95% CI 17.3% to 52.8%) developed complete hemidiaphragmatic paralysis at the postoperative assessment. An additional eight patients (26.7%) developed paresis without paralysis. Of the 18 patients with diaphragm effects, seven (38.9%) reported dyspnea. 83.3% of patients with abnormal diaphragm motion (56.7% of the total sample) had audibly reduced breath sounds on auscultation. Oxygen saturation measurements did not correlate with diaphragm effect and were not significantly reduced by the postoperative assessment. CONCLUSION: Although injection of local anesthetic at the superior trunk level is associated with less diaphragmatic paralysis compared with traditional interscalene block, a significant portion of patients will continue to have ultrasonographic and clinical evidence of diaphragmatic weakness or paralysis.

Magnetic twitch assessment of diaphragm and quadriceps weakness in critically ill mechanically ventilated patients.

Critically ill mechanically ventilated (MV) patients develop significant muscle weakness, which has major clinical consequences. There remains uncertainty, however, regarding the severity of leg weakness, the precise relationship between muscle strength and thickness, and the risk factors for weakness in MV patients. We therefore measured both diaphragm (PdiTw) and quadriceps (QuadTw) strength in MV patients using magnetic stimulation and compared strength to muscle thickness. Both PdiTw and QuadTw were profoundly reduced for MV patients, with PdiTw 19 % of normal and QuadTw 6% of normal values. There was a poor correlation between strength and thickness for both muscles, with thickness often remaining in the normal range when strength was severely reduced. Regression analysis revealed reductions in PdiTw correlated with presence of infection (p = 0.006) and age (p = 0.007). QuadTw best correlated with duration of MV (p = 0.036). Limb muscles are profoundly weak in critically ill patients, with a severity that mirrors the level of weakness observed in the diaphragm.

Diaphragmatic weakness after transcatheter arterial chemoembolization of the right inferior phrenic artery for treatment of hepatocellular carcinoma: a comparison of outcomes after N-butyl cyanoacrylate versus gelatin sponge embolization.

BACKGROUND: The inferior phrenic artery (IPA) is the most common extrahepatic feeder for hepatocellular carcinoma (HCC) during transhepatic arterial chemoembolization (TACE). PURPOSE: To compare the incidence of diaphragmatic weakness in patients with HCC after TACE of the right IPA conducted using either N-butyl cyanoacrylate (NBCA) or gelatin sponge particles. MATERIAL AND METHODS: Medical records of 111 patients who underwent TACE of the right IPA using NBCA were retrospectively reviewed and compared with data from 135 patients with IPA embolization using gelatin sponge particles. RESULTS: The incidence of diaphragmatic weakness after the initial TACE procedure did not significantly differ between the groups (NBCA group 16.2%; gelatin sponge group 20.7%; P = 0.458). Five patients in the NBCA group and 11 in the gelatin sponge group showed spontaneous resolution of diaphragmatic weakness after a mean period of 3.5 months. Diaphragmatic weakness developed after the initial follow-up visit in 17 patients from the gelatin sponge group due to repeated TACE of the right IPA (mean 2.4 sessions; range 2-4 sessions), while it spontaneously developed without additional TACE procedures in one patient from the NBCA group. Permanent diaphragmatic weakness was less common in the NBCA than in the gelatin sponge group (12.6% and 25.2%, respectively; P = 0.017). The complete response rate did not significantly differ between the groups (NBCA group 16.2%; gelatin sponge group 25.9%; P = 0.065). CONCLUSION: Use of NBCA rather than gelatin sponge particles for TACE of the right IPA resulted in a lower incidence of permanent diaphragmatic weakness.

Respiratory Characteristics in Patients With Major Burn Injury and Smoke Inhalation.

This study aimed to evaluate pulmonary function measurements and respiratory muscle parameters in patients with major burn injury and smoke inhalation. The inclusion criteria included patients who were diagnosed with a smoke inhalation burn or a major burn of more than 20% of total body surface area (TBSA). All subjects underwent a pulmonary function test, respiratory muscle strength test, peak cough flow and fluoroscopic diaphragmatic movement measurement, and 6-minute walk test before starting pulmonary rehabilitation. Evaluations were conducted on the 88th day after the injury, the average time of admission to the Department of the Rehabilitation Medicine for burn rehabilitation after the completion of the acute treatment. The average degree of burns of the total 67 patients was 34.6% TBSA. All parameters in the patient group were significantly lower than the healthy controls, and a mild restrictive pattern of impairment with a reduction in diffusing capacity and more reduced expiratory muscle, than inspiratory muscle strength were observed. Peak cough flow, respiratory muscle strength, and forced vital capacity in the patient group with inhalation burn were significantly lower than in those without inhalation burn. The conditions of the majority of patients with major burn and inhalation injury were consistent with restrictive impairment and significant reduction in diffusion capacity. The patients had expiratory muscle weakness, decreased diaphragmatic movement, and exercise capacity impairment.

Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms.

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar-capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas-liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.

Role of IL-33 receptor (ST2) deletion in diaphragm contractile and mitochondrial function in the Sugen5416/hypoxia model of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right ventricular failure. Skeletal muscle maladaptations limit physical activity and may contribute to disease progression. The role of alarmin/inflammatory signaling in PAH respiratory muscle dysfunction is unknown. We hypothesized that diaphragm mitochondrial and contractile functions are impaired in SU5416/hypoxia-induced pulmonary hypertension due to increased systemic IL-33 signaling. We induced pulmonary hypertension in adult C57Bl/6 J (WT) and ST2 (IL1RL1) gene ablated mice by SU5416/hypoxia (SuHx). We measured diaphragm fiber mitochondrial respiration, inflammatory markers, and contractile function ex vivo. SuHx reduced coupled and uncoupled permeabilized myofiber respiration by ∼40 %. During coupled respiration with complex I substrates, ST2-/- attenuated SuHx inhibition of mitochondrial respiration (genotype × treatment interaction F[1,67] = 3.3, p = 0.07, η2 = 0.04). Flux control ratio and coupling efficiency were not affected by SuHx or genotype. A higher substrate control ratio for succinate was observed in SuHx fibers and attenuated in ST2-/- fibers (F[1,67] = 5.3, p < 0.05, η2 = 0.07). Diaphragm TNFα, but not IL-33 or NFkB, was increased in SuHx vs. DMSO in both genotypes (F[1,43] = 4.7, p < 0.05, η2 = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F[3,440] = 8.4, p < 0.05, η2 = 0.0025). There was no effect of ST2-/- on the force-frequency relationship. Force decay during a fatigue protocol at 100 Hz, but not at 40 Hz, was attenuated by SuHx vs. DMSO in both genotypes (F[1,41] = 5.6, p < 0.05, η2 = 0.11). SuHx mice exhibit a modest compensation in diaphragm contractility and mitochondrial dysfunction during coupled respiration; the latter partially regulated through ST2 signaling.

Feasibility and Efficacy of Inspiratory Muscle Training in Patients with Head and Neck Cancer receiving Concurrent Chemoradiotherapy.

OBJECTIVES: Patients with head and neck cancer (HNC) undergoing concurrent chemoradiotherapy (CCRT) often experience pulmonary symptoms. This study evaluated if a 7-week inspiratory muscle training (IMT) program during CCRT is feasible, adherent, and safe in patients with HNC. This study also evaluated the effect of IMT on diaphragm thickness, mobility, and cardiorespiratory parameters in patients with HNC receiving CCRT. METHODS: Ten participants with advanced stage HNC receiving CCRT were recruited for the study. Feasibility, adherence, and safety of the intervention were the primary outcomes. Changes in diaphragm thickness and mobility, maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity, forced expiratory volume in first second and functional capacity using 6-MWT were measured at baseline and post 7 weeks of CCRT. IMT was performed at one session per day for 5 days a week for 7 weeks. Eight sets of two minutes of inspiratory manoeuvres with one minute rest period between them with intensity of 40% MIP were given. RESULTS: Ten participants  were included in this study out of the 13 patients screened, indicating the feasibility to be 76.9%. Participants completed a total of 260 training sessions out of the 350 planned sessions denoting the adherence level as 74%. Diaphragm thickness and MEP remained significantly unchanged while significant decline was seen in diaphragm mobility, MIP,FVC, FEV1 and 6-MWD at the end of 7 weeks. No adverse events were reported following the intervention. CONCLUSION: Inspiratory muscle training did not show significant effect on the diaphragm thickness, mobility, and cardiorespiratory parameters; however, it was feasible, adherent, and safe in patients with HNC receiving CCRT.

Inspiratory muscle activation during inspiratory muscle training in patients with COPD.

BACKGROUND AND OBJECTIVES: The main target of inspiratory muscle training (IMT) is to improve diaphragm function in patients with COPD who have inspiratory muscle weakness. Ventilatory demand is already increased during quiet breathing in patients with COPD, and whether threshold load imposed by IMT would active more accessory muscle remained to be determined. The purpose of this study was to examine diaphragm and sternocleidomastoid (SCM) activation during IMT with intensities of 30% and 50% maximal inspiratory pressure (PImax). METHODS: Patients with COPD and a PImax lower than 60 cmH2O were recruited for the study. Surface electromyography (EMG) was used to measure diaphragm and SCM activation, and group-based trajectory modeling (GBTM) was used to identify activation patterns during IMT. The generalized estimating equation (GEE) was then used to detect differences of variables between various breathing tasks. Statistical significance was established at p < 0.05. RESULTS: A total of 30 patients with COPD participated in this study. All patients demonstrated significant increases in diaphragm and SCM activation during 30% and 50% PImax of IMT than during quiet breathing (all p < 0.001). Diaphragm demonstrated two distinct patterns in response to IMT: low activation (n = 8) and high activation (n = 22) group using GBTM analysis. CONCLUSION: Diaphragm and SCM were substantially activated during IMT in patients with COPD who had inspiratory muscle weakness. Regardless of whether diaphragm activation was high or low, SCM was activated to a greater extent in response to IMT.

Ampakines Stimulate Diaphragm Activity after Spinal Cord Injury.

Respiratory compromise after cervical spinal cord injury (SCI) is a leading cause of mortality and morbidity. Most SCIs are incomplete, and spinal respiratory motoneurons as well as proprio- and bulbospinal synaptic pathways provide a neurological substrate to enhance respiratory output. Ampakines are allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are prevalent on respiratory neurons. We hypothesized that low dose ampakine treatment could safely and effectively increase diaphragm electromyography (EMG) activity that has been impaired as a result of acute- or sub-acute cervical SCI. Diaphragm EMG was recorded using chronic indwelling electrodes in unanesthetized, freely moving rats. A spinal hemi-lesion was induced at C2 (C2Hx), and rats were studied at 4 and 14 days post-injury during room air breathing and acute respiratory challenge accomplished by inspiring a 10% O2, 7% CO2 gas mixture. Once a stable baseline recording was established, one of two different ampakines (CX717 or CX1739, 5 mg/kg, intravenous) or a vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was delivered. At 4 days post-injury, both ampakines increased diaphragm EMG output ipsilateral to C2Hx during both baseline breathing and acute respiratory challenge. Only CX1739 treatment also led to a sustained (15 min) increase in ipsilateral EMG output. At 14 days post-injury, both ampakines produced sustained increases in ipsilateral diaphragm EMG output and enabled increased output during the respiratory challenge. We conclude that low dose ampakine treatment can increase diaphragm EMG activity after cervical SCI, and therefore may provide a pharmacological strategy that could be useful in the context of respiratory rehabilitation.

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

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

Diaphragmatic excursion is correlated with the improvement in exercise tolerance after pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the maximum level of diaphragm excursion (DEmax) is correlated with dynamic lung hyperinflation and exercise tolerance. This study aimed to elucidate the utility of DEmax to predict the improvement in exercise tolerance after pulmonary rehabilitation (PR) in patients with COPD. METHODS: This was a prospective cohort study. Of the 62 patients with stable COPD who participated in the outpatient PR programme from April 2018 to February 2021, 50 completed the programme. Six-minute walk distance (6MWD) was performed to evaluate exercise tolerance, and ultrasonography was performed to measure DEmax. Responders to PR in exercise capacity were defined as patients who demonstrated an increase of > 30 m in 6MWD. The receiver operating characteristic (ROC) curve was used to determine the cut-off point of DEmax to predict responses to PR. RESULTS: Baseline levels of forced expiratory volume in 1 s, 6MWD, maximum inspiratory pressure, DEmax and quadriceps muscle strength were significantly higher, and peak dyspnoea of modified Borg (mBorg) scale score was lower in responders (n = 30) than in non-responders (n = 20) to PR (p < 0.01). In multivariate analysis, DEmax was significantly correlated with an increase of > 30 m in 6MWD. The area under the ROC curve of DEmax to predict responders was 0.915, with a sensitivity and specificity of 83% and 95%, respectively, at a cut-off value of 44.9 mm of DEmax. CONCLUSION: DEmax could adequately predict the improvement in exercise tolerance after PR in patients with COPD.

Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction.

INTRODUCTION: Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure. MATERIALS AND METHODS: The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV. DISCUSSION: This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.