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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., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Drs. de Vries’ and Heunks’ institutions received funding from Amsterdam Cardiovascular Sciences. Dr. de Vries has received speaker fees from the Dutch Ultrasound Center (the Netherlands) and travel and speaker fees from the Chinese Organization of Rehabilitation Medicine (China). Dr. Jonkman has received personal fees from Liberate Medical (United States). Dr. Heunks received research support from Liberate Medical (United States), Fisher and Paykel, and Orion Pharma (Finland), and speakers fee from Getinge (Sweden). Dr. de Man disclosed the off-label product use of oxidation-reduction potential measurement with the RedoxSYS System from Aytu Biosciences. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

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.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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, η 2  = 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, η 2  = 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, η 2  = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F[3,440] = 8.4, p < 0.05, η 2  = 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, η 2  = 0.11). SuHx mice exhibit a modest compensation in diaphragm contractility and mitochondrial dysfunction during coupled respiration; the latter partially regulated through ST2 signaling., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

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.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 (P Imax )., Methods: Patients with COPD and a P Imax lower than 60 cmH 2 O 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% P Imax 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

What Is Known and Objective: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose?, Comment: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism., What Is New and Conclusion: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous., (© 2021 John Wiley & Sons Ltd.)

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% O 2 , 7% CO 2 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.

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.

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., (Published by Elsevier Ltd.)

Background: In patients with chronic obstructive pulmonary disease (COPD), the maximum level of diaphragm excursion (DE max ) is correlated with dynamic lung hyperinflation and exercise tolerance. This study aimed to elucidate the utility of DE max 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 DE max . 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 DE max to predict responses to PR., Results: Baseline levels of forced expiratory volume in 1 s, 6MWD, maximum inspiratory pressure, DE max 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, DE max was significantly correlated with an increase of > 30 m in 6MWD. The area under the ROC curve of DE max 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 DE max ., Conclusion: DE max could adequately predict the improvement in exercise tolerance after PR in patients with COPD., (© 2021. The Author(s).)

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 )., (© 2021. The Author(s).)

Diaphragm muscle blood flow (BF) and vascular conductance (VC) are elevated with chronic heart failure (HF) during exercise. Exercise training (ExT) elicits beneficial respiratory muscle and pulmonary system adaptations in HF. We hypothesized that diaphragm BF and VC would be lower in HF rats following ExT than their sedentary counterparts (Sed). Respiratory muscle BFs and mean arterial pressure were measured via radiolabeled microspheres and carotid artery catheter, respectively, during submaximal treadmill exercise (20 m/min, 5 % grade). During exercise, no differences were present between HF + ExT and HF + Sed in diaphragm BFs (201 ± 36 vs. 227 ± 44 mL/min/100 g) or VCs (both, p > 0.05). HF + ExT compared to HF + Sed had lower intercostal BF (27 ± 3 vs. 41 ± 5 mL/min/100 g) and VC (0.21 ± 0.02 vs. 0.31 ± 0.04 mL/min/mmHg/100 g) during exercise (both, p < 0.05). Further, HF + ExT compared to HF + Sed had lower transversus abdominis BF (20 ± 1 vs. 35 ± 6 mL/min/100 g) and VC (0.14 ± 0.02 vs. 0.27 ± 0.05 mL/min/mmHg/100 g) during exercise (both, p < 0.05). These data suggest that exercise training lowers the intercostal and transversus abdominis BF responses in HF rats during submaximal treadmill exercise., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rationale: Prolonged mechanical ventilation is often associated with either a decrease (known atrophy) or an increase (supposed injury) in diaphragmatic thickness. Shear wave elastography is a noninvasive technique that measures shear modulus, a surrogate of tissue stiffness and mechanical properties. Objectives: To describe changes in shear modulus (SM) during the ICU stay and the relationship with alterations in muscle thickness. To perform a comprehensive ultrasound-based characterization of histological and force production changes occurring in the diaphragm. Methods: Translational study using critically ill patients and mechanically ventilated piglets. Serial ultrasound examination of the diaphragm collecting thickness and SM was performed in both patients and piglets. Transdiaphragmatic pressure and diaphragmatic biopsies were collected in piglets. Measurements and Main Results: We enrolled 102 patients, 88 of whom were invasively mechanically ventilated. At baseline, SM was 14.3 ± 4.3 kPa and diaphragm end-expiratory thickness was 2.0 ± 0.5 mm. Decrease or increase by more than 10% from baseline was reported in 86% of the patients for thickness and in 92% of the patients for SM. An increase in diaphragmatic thickness during the stay was associated with a decrease in SM (β = -9.34 ± 4.41; P  = 0.03) after multivariable analysis. In the piglet sample, a decrease in SM over 3 days of mechanical ventilation was associated with loss of force production, slow and fast fiber atrophy, and increased lipid droplets accumulation. Conclusions: Increases in diaphragm thickness during critical illness is associated with decreased tissue stiffness as demonstrated by shear wave ultrasound elastography, consistent with the development of muscle injury and weakness. Clinical trial registered with www.clinicaltrials.gov (NCT03550222).

Background: A fall of ≥ 20 % in forced expiratory volume in the first second (FEV1) with a cumulative dose of histamine ≤ 7.8 μmol is considered to indicate bronchial hyperactivity, but no method exists for patients who cannot perform spirometry properly. Here we hypothesized that increases in respiratory central output measured by chest wall electromyography of the diaphragm (EMGdi-c) expressed as a function of tidal volume (EMGdi-c/VT) would have discriminative power to detect a 'positive' challenge test., Methods: In a physiological study EMGdi was recorded from esophageal electrode (EMGdi-e) in 16 asthma patients and 16 healthy subjects during a histamine challenge test. In a second study, EMGdi from chest wall surface electrodes (EMGdi-c) was measured during a histamine challenge in 44 asthma patients and 51 healthy subjects. VT was recorded from a digital flowmeter during both studies., Results: With histamine challenge test the change in EMGdi-e/VT in patients with asthma was significantly higher than that in healthy subjects (104.2 % ± 48.6 % vs 0.03 % ± 17.1 %, p < 0.001). Similarly there was a significant difference in the change of EMGdi-c/VT between patients with asthma and healthy subjects (90.5 % ± 75.5 % vs 2.4 % ± 21.7 %, p < 0.001). At the optimal cut-off point (29 % increase in EMGdi-c/VT), the area under the ROC curve (AUC) for detection of a positive test was 0.91 (p < 0.001) with sensitivity 86 % and specificity 92 %., Conclusions: We conclude that EMGdi-c/VT may be used as an alternative for the assessment of bronchial hypersensitivity and airway reversibility to differentiate patients with asthma from healthy subjects., (Copyright © 2021. Published by Elsevier B.V.)

Diaphragm weakness affects up to 60% of ventilated patients leading to muscle atrophy, reduction of muscle fiber force via muscle fiber injuries and prolonged weaning from mechanical ventilation. Electromagnetic stimulation of the phrenic nerve can induce contractions of the diaphragm and potentially prevent and treat loss of muscular function. Recommended safety distance of electromagnetic coils is 1 m. The aim of this study was to investigate the magnetic flux density in a typical intensive care unit (ICU) setting. Simulation of magnetic flux density generated by a butterfly coil was performed in a Berlin ICU training center with testing of potential disturbance and heating of medical equipment. Approximate safety distances to surrounding medical ICU equipment were additionally measured in an ICU training center in Bern. Magnetic flux density declined exponentially with advancing distance from the stimulation coil. Above a coil distance of 300 mm with stimulation of 100% power the signal could not be distinguished from the surrounding magnetic background noise. Electromagnetic stimulation of the phrenic nerve for diaphragm contraction in an intensive care unit setting seems to be safe and feasible from a technical point of view with a distance above 300 mm to ICU equipment from the stimulation coil., (© 2021. The Author(s).)

Many survivors from severe coronavirus disease 2019 (COVID-19) suffer from persistent dyspnea and fatigue long after resolution of the active infection. In a cohort of 21 consecutive severe post-COVID-19 survivors admitted to an inpatient rehabilitation hospital, 16 (76%) of them had at least one sonographic abnormality of diaphragm muscle structure or function. This corresponded to a significant reduction in diaphragm muscle contractility as represented by thickening ratio (muscle thickness at maximal inspiration/end-expiration) for the post-COVID-19 compared to non-COVID-19 cohorts. These findings may shed new light on neuromuscular respiratory dysfunction as a contributor to prolonged functional impairments after hospitalization for post-COVID-19., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm 2 ) and cervical motoneurons (soma size: 487 ± 189 µm 2 ) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm 2 ) and sacral motoneurons (soma size: 1,411 ± 633 µm 2 ) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle. NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.

Cervical spinal injury is typically associated with respiratory impairments due to damage to bulbospinal respiratory pathways and phrenic motoneurons. Magnetic stimulation is a non-invasive approach for the evaluation and modulation of the nervous system. The present study was designed to examine whether cervical magnetic stimulation can be applied to evaluate diaphragmatic motor outputs in a pre-clinical rat model of cervical spinal injury. The bilateral diaphragm was monitored in anesthetized rats using electromyogram at the acute, subchronic, and chronic stages following left mid-cervical contusion. The center of a figure-of-eight coil was placed 20 mm caudal to bregma to stimulate the cervical spinal cord. The results demonstrated that a single magnetic stimulation can evoke significant motor-evoked potentials in the diaphragms of uninjured animals when the animal's head was placed 30 mm right or left from the center of the coil. The spontaneous bursting of the diaphragm was significantly attenuated by contusion injury at all-time-points post-injury. However, the threshold of the diaphragmatic motor-evoked potential was reduced, and the amplitude of the diaphragmatic motor-evoked potential was enhanced in response to cervical magnetic stimulation at the acute injury stage. Moreover, the motor-evoked potentials of the bilateral diaphragm in animals with contusions were generally larger when the coil was placed at the left spinal cord at the subchronic and chronic injury stages. These results suggested that cervical magnetic stimulation can be used to examine the excitability of phrenic motor outputs post-injury, and magnetic stimulation applied more laterally may be more effective for triggering diaphragmatic motor-evoked potentials.

Background: Respiratory failure resulting from diaphragmatic muscle weakness is a major cause of long-term hospitalization in children with cerebral palsy (CP). Manual diaphragmatic stretching technique (MDST) can be directly applied to stretch diaphragmatic muscle and has been reported to improve respiratory function in patients with asthma and COPD. However, there have been no studies among CP. This study aimed to examine the effects of a six-week MDST course on respiratory function among CP., Methods: Fifty-three children with spastic CP were randomly assigned to experimental (n = 27) and control (n = 26) groups. The experimental group received MDST on non-consecutive days, three days per week for six weeks alongside standard physiotherapy (SDPT), while the control group received only SDPT. The outcome variables were diaphragmatic mobility, pulmonary function and chest wall expansion., Results: MDST significantly improved diaphragmatic mobility on both sides of the body, with a between-group difference of 0.97 cm (95% CI 0.55-1.39 cm, p < 0.001) for the right side and 0.82 cm (95% CI 0.35-1.29 cm, p = 0.001) for the left side. MDST significantly improved chest wall expansion at the xiphoid process and umbilical levels, with between-group differences of 0.57 cm (95% CI 0.12-1.20 cm, p = 0.013) and 0.87 cm (95% CI 0.31-1.43 cm, p = 0.003), respectively. There was no significant difference in pulmonary function testing between the groups., Conclusion: MDST could significantly improve diaphragmatic mobility, and lower and abdominal chest wall expansion, among children with CP. Therefore, MDST could be considered as an additional technique for physiotherapy programmes, to improve diaphragmatic function in spastic CP., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: With the increased ageing of society, more and more elderly people are admitted to the intensive care unit, How to accurately predict whether elderly patients can successfully wean from the ventilator is more complicated. Diaphragmatic excursion (DE) and diaphragm thickening fraction (DTF) were measured by bedside ultrasound to assess diaphragm function. The lung ultrasound score (LUS) and the rapid shallow breathing index (RBSI) were used as indices of diaphragm function to predict the outcome of weaning from mechanical ventilation. The aim of this study was to examine the clinical utility of these parameters in predicting extubation success., Methods: This prospective study included 101 consecutive elderly patients undergoing a trial of extubation in the ICU of Haidian Hospital between June 2017 and July 2020. Patients were divided into the successful weaning group (n = 69) and the failed weaning group (n = 32). Baseline characteristics, including RSBI, were recorded. Measurements of DE, DTF and LUS were made using ultrasound within 24 h before extubation., Results: Median DE was greater in patients with extubation success than in those with extubation failure (1.64 cm vs. 0.78 cm, p = 0.001). Patients with extubation success had a greater DTF than those with extubation failure (49.48% vs. 27.85%, p = 0.001). The areas under the receiver operating curves for the RSBI, LUS, DE and DFT were 0.680, 0.764, 0.831 and 0.881, respectively. The best cut-off values for predicting successful weaning were DTF ≥ 30%, DE ≥ 1.3 cm, LUS ≤ 11, and RSBI ≤ 102. The specificity of DTF (84%) in predicting weaning outcome was higher than that of RBSI (53%), that of LUS (55%), and that of DE (62%). The sensitivity of DTF (94%) was greater than that of RBSI (85%), that of LUS (71%), and that of DE (65%). The combination of RSBI, LUS, DE, and DTF showed the highest AUC (AUC = 0.919), with a sensitivity of 96% and a specificity of 89%., Conclusions: DTF has higher sensitivity and specificity for the prediction of successful weaning in elderly patients than the other parameters examined. The combination of RSBI, LUS, DE and DFT performed well in predicting weaning outcome. This has potentially important clinical application and merits further evaluation., (© 2021. The Author(s).)

Objective: This study aimed to examine the use of point-of-care ultrasonography (POCUS) in detecting diaphragmatic dysfunction (DD) and evaluate its ability to predict noninvasive mechanical ventilation (NIV) failure in patients presented to the emergency department with acute exacerbation of chronic obstructive pulmonary disease (AECOPD)., Methods: In this prospective cohort study, the diaphragm was examined using POCUS in patients with AECOPD. DD was defined as a diaphragm thickening fraction of less than 20% during spontaneous breathing. NIV failure was the primary outcome of the study, and duration of hospital stay and in-hospital mortality were the secondary outcomes. Specificity, sensitivity, positive predictive value, and negative predictive value were estimated for predicting NIV failure in DD and evaluating the diagnostic performance of POCUS., Results: 60 patients were enrolled the study. NIV failure was found in 11 (73.3%) of 15 patients with DD and in 2 (4.4%) of 45 patients without DD. In predicting NIV failure, DD had a sensitivity of 84.6% (95% confidence interval [CI]:54.6-98.1), specificity of 91.5% (95% CI:79.6-97.6), positive predictive value of 73.3% (95% CI:51.2-87.8), and negative predictive value of 95.6% (95% CI:85.7-98.7). The duration of hospital stay was not different between groups (p = .065). No in-hospital mortality was seen in patients without DD., Conclusions: DD has high sensitivity and specificity in predicting NIV failure in patients admitted to the emergency department with AECOPD. DD can be assessed by an experienced clinician noninvasively using POCUS in emergency departments., Competing Interests: Declaration of Competing Interest Each author certifies that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with this article. This study has been presented as an oral presentation and awarded the best oral presentation in the 15th Turkish Emergency Medicine Congress at November 21–24, 2019., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: Sitting-to-supine fall in vital capacity (ΔVC) can be used to help identify diaphragm dysfunction (DD), but its optimal predictive threshold value is uncertain. Our aim was to evaluate the diagnostic performance of ΔVC in identifying the presence of unilateral or bilateral DD., Methods: Patients referred to the diaphragm dysfunction clinic of our center (2017-2018) were included. All subjects had lung function testing (including measurement of ΔVC) and an ultrasound assessment of diaphragm thickening fraction (TFdi). Unilateral DD was defined as a single hemidiaphragm with TFdi ≤30 % and bilateral DD as a mean TFdi value of both hemidiaphragms ≤30 %. Clinical and physiological characteristics were compared across groups, and sensitivity/specificity analyses of ΔVC to identify DD were performed., Results: 84 patients were included (31 unilateral DD, 17 bilateral DD and 36 without significant DD). DD groups had similar age, gender and BMI (all p > 0.05), but patients with bilateral DD had lower FVC, FEV1, MIP, TLC, ΔVC and more frequent orthopnea than patients with unilateral DD (all p < 0.05). There was a significant correlation between TFdi and ΔVC (rho=-0.56, p < 0.001). The optimal ΔVC value to identify bilateral DD was ≤-15 % [AUC 0.97 (95 %CI 0.89-1.00), p < 0.001, with sensitivity and specificity of 100 % and 89 %, respectively]. No single threshold of ΔVC could accurately predict unilateral DD [AUC 0.58 (95 %CI 0.45-0.72), p = 0.24]., Conclusion: ΔVC performs poorly in identifying patients with unilateral DD. However, a ΔVC value ≤-15 % is strongly associated with the presence of bilateral DD. These findings should be taken into account when using ΔVC in the evaluation of patients with suspected DD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mechanical ventilation (MV) is a life-saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator-induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin-angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1-7 (Ang1-7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1-7 protects the diaphragm against MV-induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1-7 shielded diaphragm fibers against MV-induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1-7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1-7 has the therapeutic potential to protect against VIDD by preventing MV-induced contractile dysfunction and atrophy of both slow and fast muscle fibers., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society forClinical Pharmacology and Therapeutics.)

Background: There is no universally accepted method to assess the pressure-generating capacity of inspiratory muscles in children on mechanical ventilation (MV), and no study describing its evolution over time in this population., Methods: In this prospective observational study, we have assessed the function of the inspiratory muscles in children on various modes of MV. During brief airway occlusion maneuvers, we simultaneously recorded airway pressure depression at the endotracheal tube (ΔPaw, force generation) and electrical activity of the diaphragm (EAdi, central respiratory drive) over five consecutive inspiratory efforts. The neuro-mechanical efficiency ratio (NME, ΔPaw/EAdi max ) was also computed. The evolution over time of these indices in a group of children in the pediatric intensive care unit (PICU) was primarily described. As a secondary objective, we compared these values to those measured in a group of children in the operating room (OR)., Results: In the PICU group, although median NME occl decreased over time during MV (regression coefficient - 0.016, p = 0.03), maximum ΔPaw max remained unchanged (regression coefficient 0.109, p = 0.50). Median NME occl at the first measurement in the PICU group (after 21 h of MV) was significantly lower than at the only measurement in the OR group (1.8 cmH 2 O/µV, Q 1 -Q 3 1.3-2.4 vs. 3.7 cmH 2 O/µV, Q 1 -Q 3 3.5-4.2; p = 0.015). Maximum ΔPaw max in the PICU group was, however, not significantly different from the OR group (35.1 cmH 2 O, Q 1 -Q 3 21-58 vs. 31.3 cmH 2 O, Q 1 -Q 3 28.5-35.5; p = 0.982)., Conclusions: The function of inspiratory muscles can be monitored at the bedside of children on MV using brief airway occlusions. Inspiratory muscle efficiency was significantly lower in critically ill children than in children undergoing elective surgery, and it decreased over time during MV in critically ill children. This suggests that both critical illness and MV may have an impact on inspiratory muscle efficiency.

Background: Robot-assisted laparoscopic prostatectomy (RALP) frequently entails postoperative pulmonary complications (PPCs) due to the Trendelenburg position and pneumoperitoneum. Diaphragm thickening fraction (TF) as an imaging marker can offer the advantage of predicting respiratory outcomes. Therefore, we evaluated the effect of diaphragm TF on the occurrence of PPCs in RALP., Methods: We measured the preoperative thickness of the diaphragm at peak inspiration ( T pi ) and end expiration ( T ee ) using ultrasonography. Diaphragm TF was calculated as TF = ( T pi - T ee )/ T ee . A receiver operating characteristic (ROC) curve analysis of TF was performed. After dividing patients into two groups according to the optimal TF cut-off value, we compared the occurrence of PPCs between the groups. The predictivity of diaphragm TF for the occurrence of PPCs was evaluated., Results: Of 145 patients, 40 patients (27.6%) developed PPCs. Patients with PPCs had a significantly lower TF than those without PPCs (0.31 ± 0.09 vs. 0.39 ± 0.11, P < 0.001). In the ROC curve analysis, the optimal TF cut-off value was 0.28. The patients were divided into TF ≥ 0.28 group ( n = 114) and TF < 0.28 group ( n = 31). The incidence of PPCs was significantly higher in the TF < 0.28 group than in the TF ≥ 0.28 group (51.6% vs. 21.1%, P = 0.001). Diaphragm TF < 0.28 was associated with a higher incidence of PPCs than diaphragm TF ≥ 0.28 (odds ratio = 4.534, 95% confidence interval [1.763-11.658], P = 0.002)., Conclusion: Preoperative diaphragm TF < 0.28 was associated with an increased incidence of PPCs, suggesting that diaphragm TF as a prognostic imaging marker provides useful information on PPCs in RALP requiring the Trendelenburg position and pneumoperitoneum. Trial Registry Number . This trial is registered with KCT0005028., Competing Interests: All authors declared no competing interests., (Copyright © 2021 Jihion Yu et al.)

Objective: To describe clinical, radiological and treatment characteristics in pediatric patients with SLS., Material and Methods: This is a descriptive and retrospective study in patients under 16 years old with the diagnosis of SLE complicated by SLS at the General Hospital. National Medical Center La Raza. Clinical, radiological and treatment variables were analyzed. Results are shown in frequencies and percentages., Results: Data from 11 patients, 9 females and 2 males were collected. Mean age at diagnosis of SLS was 12.2 years. Age at diagnosis of SLE was 11.1 years. SLEDAI 17.3. Renal desease 72%, hematological 91%, lymphopenia 63%, mucocutaneous 72%, neurological 9%, arthritis 54%, serositis 91%, fever 81%, secondary antiphospholipid syndrome, low C3 72%, low C4 81%, positive ANA 91%, positive anti-DNA 91%. Regarding clinical manifestations of SLE: cough 81%, dyspnea 91%, hipoxemia 81%, pleuritic pain 71%, average oxygen saturation 83%. Chest X-rays findings: right hemidiaphragm affection 18%, left 63%, bilateral 18%. Elevated hemidiaphragm 91%, atelectasis 18%, pleural effusion 91%, over one third of the cardiac silhouette under the diphragm 36%, bulging diaphragm 45%, 5th. anterior rib that crosses over the diaphragm 91%. M-mode ultrasound: diaphragmatic hypomotility 100%, pleural effusion 63%. Pulmonary function tests: restrictive pattern in 45% of the cases. Treatment was with supplementary oxygen 100%, intubation 18%, antibiotics 100%, steroids 100%, intravenous immunoglobulin 54%, plasmapheresis 18%, cyclophosphamide 54% and rituximab 18%. The clinical course was favorable in 81%., Conclusions: SLS should be suspected in patients with SLE and active disease who present hipoxemia, pleuritic pain, cough, dyspnea, pleural effusion and signs of restriction on chest X-rays. Therefore, a diaphragmatic M-mode ultrasound should be performed in order to establish the diagnosis.

Background: Diaphragm plication (DP) improves pulmonary function and quality of life for those with diaphragm paralysis or dysfunction. It is unknown whether differing degrees of diaphragm dysfunction as measured by sniff testing affect results after plication., Methods: Patients who underwent minimally invasive DP from 2008 to 2019 were dichotomized based on sniff test results: paradoxical motion (PM) versus no paradoxical motion (NPM); the latter included normal, decreased, and no motion. Preoperative and postoperative pulmonary function testing (PFT) after DP was compared between groups. The impact of the diaphragm height index, a measure of diaphragm elevation, was also assessed., Results: A total of 26 patients underwent preoperative sniff testing, DP, and postoperative PFT. Including all patients, DP resulted in a 17.8% ± 5.5% improvement in forced expiratory volume in 1 second (P < .001), a 14.4% ± 5.3% improvement in forced vital capacity (P < .001), and a 4.7% ± 4.6% improvement in the diffusing capacity of carbon monoxide (P = .539). There were greater improvements in the PM group (n = 16) compared with the NPM group (n = 10) for forced expiratory volume in 1 second (27.2% ± 6.0% versus 3.9% ± 6.2%; P = .017) and forced vital capacity (28.1% ± 5.3% versus -0.5% ± 3.3%; P = .001). There was no difference in the change in the diffusing capacity of carbon monoxide between groups. There were no differences between patients with PM and NPM in the postoperative course or complications. No value for diaphragm height index predicted improvement in PFT after DP., Conclusions: Patients with PM on sniff test have dramatically greater objective improvements in pulmonary function after plication compared with those without PM. Most patients without PM do not demonstrate improvement in standard PFT. Improvements in dyspnea require additional study., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Unilateral C 2 hemisection (C 2 SH) disrupts descending inspiratory-related drive to phrenic motor neurons and thus, silences rhythmic diaphragm muscle (DIAm) activity. There is gradual recovery of rhythmic DIAm EMG activity over time post-C 2 SH, consistent with neuroplasticity, which is enhanced by chronic (2 wk) intrathecal BDNF treatment. In the present study, we hypothesized that acute (30 min) intrathecal BDNF treatment also enhances recovery of DIAm EMG activity after C 2 SH. Rats were implanted with bilateral DIAm EMG electrodes to verify the absence of ipsilateral eupneic DIAm EMG activity at the time of C 2 SH and at 3 days post-C 2 SH. In those animals displaying no recovery of DIAm EMG activity after 28 days ( n = 7), BDNF was administered intrathecally (450 mcg) at C 4 . DIAm EMG activity was measured continuously both before and for 30 min after BDNF treatment, during eupnea, hypoxia-hypercapnia, and spontaneous sighs. Acute BDNF treatment restored eupneic DIAm EMG activity in all treated animals to an amplitude that was 78% ± 9% of pre-C 2 SH root mean square (RMS) ( P < 0.001). In addition, acute BDNF treatment increased DIAm RMS EMG amplitude during hypoxia-hypercapnia ( P = 0.023) but had no effect on RMS EMG amplitude during sighs. These results support an acute modulatory role of BDNF signaling on excitatory synaptic transmission at phrenic motor neurons after cervical spinal cord injury. NEW & NOTEWORTHY Brain-derived neurotrophic factor (BDNF) plays an important role in promoting neuroplasticity following unilateral C 2 spinal hemisection (C 2 SH). BDNF was administered intrathecally in rats displaying lack of ipsilateral inspiratory-related diaphragm (DIAm) EMG activity after C 2 SH. Acute BDNF treatment (30 min) restored eupneic DIAm EMG activity in all treated animals to 78% ± 9% of pre-C 2 SH level. In addition, acute BDNF treatment increased DIAm EMG amplitude during hypoxia-hypercapnia but had no effect on EMG amplitude during sighs.

Objective: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures., Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice., Results: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea., Interpretation: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023-1035., (© 2021 American Neurological Association.)

Introduction: In this study, we aimed to evaluate diaphragmatic dysfunction (DD) by using a practical approach in patients with amyotrophic lateral sclerosis (ALS) at the first visit to a chest diseases outpatient clinic., Methods: Patients with ALS seen in our outpatient clinic for the past 5 y and followed up for at least 1 y, were retrospectively evaluated. Having at least one of the following three criteria was accepted as DD: (a) paradoxical abdominal movement (PAM), (b) sitting-supine forced vital capacity (FVC) difference ≥ 20%, (c) sitting-supine arterial oxygen saturation measured by pulse oximetry (SpO 2 ) difference ≥ 4%. Respiratory symptoms, arterial blood gas analysis, sleep studies, noninvasive mechanical ventilation use, and mortality were recorded., Results: Five-hundred patients with ALS were included (female/male: 220/280, age: 58.9 ± 11.3 y). Of the patients, 22.8% had daytime hypercapnia. DD was observed in 55% of the patients (PAM in 112, sitting-supine FVC difference ≥ 20% in 50, and sitting-supine SpO 2 difference ≥ 4% in 113 patients). Of the patients with DD, 31.6% (n = 87) had no respiratory symptoms, 46.4% had FVC > 70% and 33.5% had FVC <50%. Nocturnal hypoxemia (sleep time spent with SpO 2  < 90% ≥30%) was present in 59.7%, and all patients with nocturnal hypoxemia had DD. Obstructive sleep apnea (8 severe, 14 moderate, 39 mild) was detected in 55% of the patients with polysomnography (n = 61) or polygraphy (n = 50). During follow-up, 52.2% of the patients died. Mean survival time was shorter in patients with DD (P < .001)., Conclusion: Paradoxical abdomimal movement (PAM), sitting-supine SpO 2 difference ≥ 4% and sitting-supine FVC difference ≥ 20% are indicators of DD, which should be routinely evaluated at every outpatient visit., (© 2021 Wiley Periodicals LLC.)

Background: Type 2 diabetes mellitus (T2DM) is usually associated with respiratory manifestations including inspiratory muscle weakness which affects exercise capacity. The present study aimed to determine the effect of inspiratory muscle training (IMT) on inspiratory muscle strength and exercise capacity in patients with Type 2 diabetes mellitus (T2DM)., Methods: This was a randomized controlled trial in patients with type 2 diabetes mellitus with no previous cardiopulmonary or neuromuscular diseases. Patients had no back pain. Patients were randomized into interventional or placebo groups. Sniff nasal inspiratory pressure (SNIP), maximum inspiratory pressure (MIP), and six-minute walking test (6MWT) were measured at baseline and 8 weeks post incremental inspiratory muscle training., Results: At baseline, interventional and placebo groups were similar in age, body mass index, sex inspiratory muscle strength, and exercise capacity. After 8 weeks of incremental inspiratory muscle training at 40% of MIP, the interventional group had a significant increase in the SNIP (mean difference: 18.5 ± 5.30 cm H2O vs 2.8 ± 4.8 cm H2O) and MIP (mean difference: 19.4 ± 4.3 Vs 5.4 ± 3.6 cm H2O) compared to the placebo group, respectively. The interventional group showed improvement in the 6MWT (mean difference: 70 ± 29 m vs 34 ± 24 m) compared to the placebo group, P < .05., Conclusion: Incremental inspiratory muscle training increased the diaphragm strength in patients with T2DM and improved exercise capacity., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

The aim of this study was to assess diaphragm thickness (DT) and mobility (DM) and to investigate their relationship to clinical parameters in patients with non-cystic fibrosis (non-CF) bronchiectasis. Thirty-eight patients with non-CF bronchiectasis were enrolled in this cross-sectional study. DT was measured using ultrasound at different lung volumes (at residual volume [DT RV ], functional residual capacity [DT FRC ] and total lung capacity [DT TLC ]). DM was measured using ultrasound during quiet breathing (DM QB ) and deep breathing (DM DB ). Disease severity, pulmonary function, respiratory muscle strength, exercise capacity and physical activity were assessed. DT RV correlated with disease severity (ρ = 0.332, p = 0.042), FEV1% (r = 0.387, p = 0.016) and FVC% (r = 0.405, p = 0.012). DT FRC correlated with FVC% (r = 0.331, p = 0.042). DT TLC correlated with disease severity (r = 0.430, p = 0.007) and total physical activity time (r = 0.379, p = 0.019). DM DB correlated with disease severity (ρ = -0.380, p = 0.019), FEV1% (r = 0.369, p = 0.023) and FVC% (r = 0.405, p = 0.012). DT is related to disease severity, pulmonary function and physical activity, while DM is related to disease severity and pulmonary function in patients with non-CF bronchiectasis., Competing Interests: Conflict of interest disclosure The authors declare no competing interests., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Prolonged mechanical ventilation (MV) induces diaphragm dysfunction in patients in the intensive care units (ICUs). Our study aimed to explore the therapeutic efficacy of early rehabilitation therapy in patients with prolonged MV in the ICU., Methods: Eighty eligible patients who underwent MV for > 72 h in the ICU from June 2019 to March 2020 were enrolled in this prospective randomised controlled trial. The patients were randomly divided into a rehabilitation group (n = 39) and a control group (n = 41). Rehabilitation therapy included six levels of rehabilitation exercises. Diaphragm function was determined using ultrasound (US)., Results: Diaphragmatic excursion (DE) and diaphragm thickening fraction (DTF) were significantly decreased in all patients in both groups after prolonged MV (p < 0.001). The rehabilitation group had significantly higher DTF (p = 0.008) and a smaller decrease in DTF (p = 0.026) than the control group after 3 days of rehabilitation training. The ventilator duration and intubation duration were significantly shorter in the rehabilitation group than in the control group (p = 0.045 and p = 0.037, respectively). There were no significant differences in the duration of ICU stay, proportion of patients undergoing tracheotomy, and proportion of recovered patients between the two groups., Conclusions: Early rehabilitation is feasible and beneficial to ameliorate diaphragm dysfunction induced by prolonged MV and advance withdrawal from the ventilator and extubation in patients with MV. Diaphragm US is suggested for mechanically ventilated patients in the ICU. Trial registration Chinese Clinical Trial Registry, ID: ChiCTR1900024046, registered on 2019/06/23.

[Figure: see text].

Diaphragm muscle dysfunction is increasingly recognized as an important element of several diseases including neuromuscular disease, chronic obstructive pulmonary disease and diaphragm dysfunction in critically ill patients. Functional evaluation of the diaphragm is challenging. Use of volitional maneuvers to test the diaphragm can be limited by patient effort. Non-volitional tests such as those using neuromuscular stimulation are technically complex, since the muscle itself is relatively inaccessible. As such, there is a growing interest in using imaging techniques to characterize diaphragm muscle dysfunction. Selecting the appropriate imaging technique for a given clinical scenario is a critical step in the evaluation of patients suspected of having diaphragm dysfunction. In this review, we aim to present a detailed analysis of evidence for the use of ultrasound and non-ultrasound imaging techniques in the assessment of diaphragm dysfunction. We highlight the utility of the qualitative information gathered by ultrasound imaging as a means to assess integrity, excursion, thickness, and thickening of the diaphragm. In contrast, quantitative ultrasound analysis of the diaphragm is marred by inherent limitations of this technique, and we provide a detailed examination of these limitations. We evaluate non-ultrasound imaging modalities that apply static techniques (chest radiograph, computerized tomography and magnetic resonance imaging), used to assess muscle position, shape and dimension. We also evaluate non-ultrasound imaging modalities that apply dynamic imaging (fluoroscopy and dynamic magnetic resonance imaging) to assess diaphragm motion. Finally, we critically review the application of each of these techniques in the clinical setting when diaphragm dysfunction is suspected.

A 65-year-old man was admitted to the ICU for septic shock due to pneumonia. He remained on mechanical ventilation for 96 hours. His shock resolved, and he no longer required IV vasopressor therapy. His vital signs included a BP of 105/70 mm Hg, heart rate 85 beats/min, respiratory rate 22 breaths/min, and oxygen saturation 95%. His ventilator settings were volume control/assist control with a positive end-expiratory pressure of 5 and an Fio 2 set to 40%. On these setting his blood gas showed an Pao 2 of 75 mm Hg. He was following simple commands and had minimal tracheobronchial secretions. He was placed on a spontaneous breathing trial with a spontaneous mode of ventilation and pressure support of 7/5. He remained hemodynamically stable and showed no distress through the procedure, so he was extubated to 6 L oxygen by nasal cannula. Eighteen hours later, the patient was found to have increased work of breathing, with use of accessory respiratory muscles. A blood gas showed an elevated level of CO 2 , so the patient was reintubated. After intubation, the patient again appeared comfortable on minimal ventilator settings. Chest radiography before reintubation showed no new parenchymal process, but an elevated left diaphragm. After a thorough workup, it was determined that diaphragmatic weakness was the most likely reason for respiratory failure. The team questioned whether there was a way to have detected this before extubation., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Postprandial objective abdominal distention is frequently associated with a subjective sensation of abdominal bloating, but the relation between both complaints is unknown. While the bloating sensation has a visceral origin, abdominal distention is a behavioral somatic response, involving contraction and descent of the diaphragm with protrusion of the anterior abdominal wall. Our aim was to determine whether abdominal distention influences digestive sensations. In 16 healthy women we investigated the effect of intentional abdominal distention on experimentally induced bloating sensation (by a meal overload). Participants were first taught to produce diaphragmatic contraction and visible abdominal distention. After a meal overload, sensations of bloating (0 to 10) and digestive well-being (-5 to + 5) were measured during 30-s. maneuvers alternating diaphragmatic contraction and diaphragmatic relaxation. Compared to diaphragmatic relaxation, diaphragmatic contraction was associated with diaphragmatic descent (by 21 + 3 mm; p < 0.001), objective abdominal distension (32 + 5 mm girth increase; p = 0.001), more intense sensation of bloating (7.3 + 0.4 vs. 8.0 + 0.4 score; p = 0.010) and lower digestive well-being (-0.9 + 0.5 vs. -1.9 + 0.5 score; p = 0.028). These results indicate that somatic postural tone underlying abdominal distention worsens the perception of visceral sensations (ClinicalTrials.gov ID: NCT04691882).

Background: Acute increases in muscle sonographic echodensity reflect muscle injury. Diaphragm echodensity has not been measured in mechanically ventilated patients. We undertook to develop a technique to characterize changes in diaphragm echodensity during mechanical ventilation and to assess whether these changes are correlated with prolonged mechanical ventilation., Methods: Diaphragm ultrasound images were prospectively collected in mechanically ventilated patients and in 10 young healthy subjects. Echodensity was quantified based on the right-skewed distribution of grayscale values (50th percentile, ED50; 85 th percentile, ED85). Intra- and inter-analyzer measurement reproducibility was determined. Outcomes recorded included duration of ventilation and ICU complications (including reintubation, tracheostomy, prolonged ventilation, or death)., Results: Echodensity measurements were obtained serially in 34 patients comprising a total of 104 images. Baseline (admission) diaphragm ED85 was increased in mechanically ventilated patients compared to younger healthy subjects (median 56, interquartile range (IQR) 42-84, vs. 39, IQR 36-52, p = 0.04). Patients with an initial increase in median echodensity over time (≥ + 10 in ED50 from baseline) had fewer ventilator-free days to day 60 (n = 13, median 46, IQR 0-52) compared to patients without this increase (n = 21, median 53 days, IQR 49-56, unadjusted p = 0.03). Both decreases and increases in diaphragm thickness during mechanical ventilation were associated with increases in ED50 over time (adjusted p = 0.03, conditional R 2  = 0.80) and the association between increase in ED50 and outcomes persisted after adjusting for changes in diaphragm thickness., Conclusions: Many patients exhibit increased diaphragm echodensity at the outset of mechanical ventilation. Increases in diaphragm echodensity during the early course of mechanical ventilation are associated with prolonged mechanical ventilation. Both decreases and increases in diaphragm thickness during mechanical ventilation are associated with increased echodensity.

Background: Among discharged COVID-19 patients, the health-related quality of life is poor, and patients suffer from significant physical and psychological impairment. This study was designed to investigate the effects of Liuzijue exercise on the rehabilitation of COVID-19 patients., Methods: Thirty three eligible patients with COVID-19 were enrolled in the study after discharge. All the participants practiced Liuzijue exercise once per day for 20 minutes over 4 weeks. Data were collected at baseline and the end of the intervention. Primary outcomes involved functional capacity and secondary outcomes involved quality of life., Results: The maximal inspiratory pressure (MIP), peak inspiratory flow (PIF), and diaphragm movement in deep breathing (DM-DB) of patients increased significantly after 4 weeks of intervention. The dyspnea was also alleviated and exercise capacity was significantly improved. In terms of quality of life, physical functioning and role-physical scores were significantly increased. Moreover, Liuzijue could significantly alleviate the depression and anxiety status of the patients., Conclusion: Liuzijue exercise is a viable alternative home exercise program that produced better functional capacity and quality of life in discharged patients with COVID-19. These findings also showed the necessity of rehabilitation intervention for cured COVID-19 patients., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

High spinal cord injuries (SCI) lead to permanent respiratory insufficiency, and the search for new therapeutics to restore this function is essential. To date, the most documented preclinical model for high SCI is the rat cervical C2 hemisection. However, molecular studies with this SCI model are limited due to the poor availability of genetically modified specimens. The aim of this work was to evaluate the pathophysiology of respiratory activity following a cervical C2 injury at different times post-injury in a C57BL/6 mouse model. No significant spontaneous recovery of diaphragmatic activity was observed up to 30 days post-injury in eupneic condition. However, during a respiratory challenge, i.e. mild asphyxia, a partial restoration of the injured diaphragm was observed at 7 days post-injury, corresponding to the crossed phrenic phenomenon. Interestingly, the diaphragmatic recording between 2 respiratory bursts on the injured side showed an amplitude increase between 1-7 days post-injury, reflecting a change in phrenic motoneuronal excitability. This increase in inter-burst excitability returned to pre-injured values when the crossed phrenic phenomenon started to be effective at 7 days post-injury. Taken together, these results demonstrate the ability of the mouse respiratory system to express long-lasting plasticity following a C2 cervical hemisection and genetically modified animals can be used to study the pathophysiological effects on these plasticity phenomena., (Copyright © 2020 Elsevier B.V. All rights reserved.)