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Patients with acute respiratory distress syndrome (ARDS) require periods of deep sedation and mechanical ventilation, leading to diaphragm dysfunction. Our study seeks to determine whether the combination of temporary transvenous diaphragm neurostimulation (TTDN) and mechanical ventilation changes the degree of diaphragm injury and cytokines concentration in a preclinical ARDS model. Moderate ARDS was induced in pigs using oleic acid, followed by ventilation for 12 h post-injury with volume-control at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH 2 O, respiratory rate and [Formula: see text] set to achieve normal arterial blood gases. Two groups received TTDN: every second breath (MV + TTDN50%, n = 6) or every breath (MV + TTDN100%, n = 6). One group received ventilation only (MV, n = 6). Full-thickness diaphragm and quadricep muscle biopsies were taken at study end. Samples were fixed and stained with hematoxylin and eosin and a point-counting technique was applied to calculate abnormal muscle area fraction. Cytokine concentrations were measured in homogenized tissue using porcine-specific enzyme-linked immunosorbent assay (ELISA) and compared with serum samples. Percentage of abnormal diaphragm tissue was different between MV [8.1% (6.0-8.8)] versus MV + TTDN50% [3.4% (2.1-4.8)], P = 0.010 and MV versus MV + TTDN100% [3.1% (2.5-4.0)], P = 0.005. Percentage of abnormal quadriceps tissue was not different between groups. Cytokine concentration patterns in diaphragm samples were different between all groups ( P < 0.001) and the interaction between TTDN application and resultant cytokine concentration pattern was significant ( P = 0.025). TTDN, delivered in synchrony with mechanical ventilation, mitigated diaphragm injury, as evidenced by less abnormal tissue in the diaphragm samples, in pigs with oleic acid-induced ARDS and is an exciting tool for lung and diaphragm-protective ventilation. NEW & NOTEWORTHY This study adds to our understanding of applying transvenous diaphragm neurostimulation synchronously with mechanical ventilation by examining its effects on diaphragm muscle injury and cytokine concentration patterns in pigs with acute respiratory distress syndrome (ARDS). We observed that using this therapy for 12 h post lung injury mitigated ventilator-induced diaphragm injury and changed the pattern of cytokine concentration measured in diaphragm tissue. These findings suggest that transvenous diaphragm neurostimulation is an exciting tool for lung and diaphragm protective ventilation.

Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Background: Chronic respiratory failure is a common cause of ventilator dependence in the intensive care unit (ICU). The causes of chronic respiratory failure include primary disease or complications, such as ICU-acquired weakness. Traditional practice requires patients to remain immobile and bedridden; however, recent evidence suggests that early adequate exercise promotes recovery without increasing risks. In this study, we explored the efficacy of planned progressive abdominal sandbag training in promoting the successful withdrawal of patients with chronic respiratory failure from mechanical ventilation., Methods: This study was conducted between April 2019 and November 2020. Patients were recruited and divided into two groups: abdominal sandbag training group and control group (no training). The training group participated in a 3-month daily pulmonary rehabilitation program, which involved a 30-min session of progressive sandbag loading on the upper abdomen as a form of diaphragmatic resistant exercise. The pressure support level of the ventilator was adjusted to maintain a tidal volume of 8 mL/kg. To investigate the effect of abdominal sandbag training on patients with chronic respiratory failure, we compared tidal volume, shallow breathing index, maximum respiratory pressure, and diaphragm characteristics between the training and control groups., Results: This study included 31 patients; of them, 17 (54.8 %) received abdominal sandbag training and 14 (45.2 %) did not. No significant between-group difference was found in baseline characteristics. Compared with the control group, the training group exhibited considerable improvements in ventilation-related parameters (p < 0.001): the tidal volume markedly increased (p = 0.012), rapid shallow breathing index declined (p = 0.016), and maximum respiratory pressure increased (p < 0.001) in the training group. The diaphragm motion value (p = 0.048) and diaphragm thickness (p = 0.041) were greater in the training group than in the control group. Nine patients (52.9 %) in the training group were removed from the ventilator compared with 1 (7.1 %) in the control group (p = 0.008)., Conclusion: Abdominal sandbag training may be beneficial for patients dependent on a ventilator. The training improves the function of the diaphragm muscle, thereby increasing tidal volume and reducing the respiratory rate and rapid shallow breathing index, thus facilitating withdrawal from ventilation. This training approach may also improve the thickness and motion of the diaphragm and the rate of ventilator detachment., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Diaphragmatic dysfunction is a common problem in patients who have been mechanically ventilated., Objectives: The study aimed to evaluate the effectiveness of inspiratory muscle training (IMT) on diaphragm muscle thickness and function in mechanically ventilated patients., Material and Methods: A single-blind trial was conducted. Twenty patients were randomly assigned to either the conventional physiotherapy (CP) group or to the IMT group for 5 days following extubation. The CP group received only CP, while the IMT group received CP in addition to IMT. Ten healthy controls (HCs) underwent IMT. Maximum inspiratory pressure (MIP) and physical function were recorded. Diaphragm excursion (DE), diaphragm thickness at the end of inspiration (Tdi), diaphragm thickness at the end of expiration (Tde), peak contraction velocity (PCV), and peak relaxation velocity (PRV) were evaluated with ultrasonography before and after the intervention., Results: The IMT group and HCs showed significant improvements in DE (p = 0.005; p = 0.005, respectively), PCV (p = 0.028; p = 0.015, respectively) and PRV (p = 0.029; p = 0.020, respectively) after 5 days of IMT. A significant increase in MIP was recorded in all groups after the intervention (CP: p = 0.044; IMT: p = 0.005; HC: p < 0.001). There was a significant improvement in the Medical Research Council (MRC) and the Physical Function in Intensive Care Test (PFIT) scores in both the CP and IMT groups (p < 0.001 and p < 0.001, respectively)., Conclusions: Inspiratory muscle training improves diaphragmatic functions, including MIP, diaphragm excursion, PCV, and PRV. We think that IMT applied after extubation may serve as a tool to prevent and facilitate the recovery of diaphragmatic function.

The ultrasound study of diaphragm function represents a valid method that has been extensively studied in recent decades in various fields, especially in intensive care, emergency, and pulmonology settings. Diaphragmatic function is pivotal in these contexts due to its crucial role in respiratory mechanics, ventilation support strategies, and overall patient respiratory outcomes. Dysfunction or weakness of the diaphragm can lead to respiratory failure, ventilatory insufficiency, and prolonged mechanical ventilation, making its assessment essential for patient management and prognosis in critical care and emergency medicine. While several studies have focused on diaphragmatic functionality in the context of intensive care, there has been limited attention within the field of anesthesia. The ultrasound aids in assessing diaphragmatic dysfunction (DD) by measuring muscle mass and contractility and their potential variations over time. Recent advancements in ultrasound imaging allow clinicians to evaluate diaphragm function and monitor it during mechanical ventilation more easily. In the context of anesthesia, early studies have shed light on the patho-physiological mechanisms of diaphragm function during general anesthesia. In contrast, more recent research has centered on evaluating diaphragmatic functionality at various phases of general anesthesia and by comparing diverse types of procedures or anatomical position during surgery. The objectives of this current review are to highlight the use of diaphragm ultrasound for the evaluation of diaphragmatic function during perioperative anesthesia and surgery. Specifically, we aim to examine the effects of anesthetic agents, surgical techniques, and anatomical positioning on diaphragmatic function. We explore how ultrasound aids in assessing DD by measuring muscle mass and contractility, as well as their potential variations over time. Additionally, we will discuss recent advancements in ultrasound imaging that allow clinicians to evaluate diaphragm function and monitor it during mechanical ventilation more easily., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mechanical ventilation (MV) can cause diaphragmatic injury and ventilator induced diaphragmatic dysfunction (VIDD). Diaphragm ultrasonography (DU) is increasingly used to assess diaphragmatic anatomy, function and pathology of patients receiving MV in the pediatric intensive care unit (PICU). We report the poor contractile ability of diaphragm during ventilation of critically ill patients in our PICU and the association to prolonged length of MV and PICU stay., Methods: Patients who received MV within 24 h of admission to the PICU, expected to undergo continuous MV for more than 48 h and succeeded to extubate were included in the study. DU monitoring was performed daily after the initiation of MV until extubation. Diaphragm thickening fraction (DTF) measured by DU was used as an indicator of diaphragmatic contractile activity. Patients with bilateral DTF = 0% during DU assessment were allocated into the severe VIDD group (n = 26) and the rest were into non-severe VIDD group (n = 29). The association of severe VIDD with individual length of MV, hospitalization and PICU stay were analyzed., Results: With daily DU assessment, severe VIDD occurred on 2.9 ± 1.2 days after the initiation of MV, and lasted for 1.9 ± 1.7 days. Values of DTF of all patients recovered to > 10% before extubation. The severe VIDD group had a significantly longer duration (days) of MV [12.0 (8.0-19.3) vs. 5.0 (3.5-7.5), p < 0.001] and PICU stay (days) [30.5 (14.9-44.5) vs. 13.0 (7.0-24.5), p < 0.001]. The occurrence of severe VIDD, first day of severe VIDD and length of severe VIDD were significantly positively associated with the duration of MV and PICU stay. The occurrence of severe VIDD on the second and third days after initiation of MV significantly associated to longer PICU stay (days) [43.0 (9.0-70.0) vs. 13.0 (3.0-40.0), p = 0.009; 36.0 (17.0-208.0) vs. 13.0 (3.0-40.0), p = 0.005, respectively], and the length of MV (days) was significantly longer in those with severe VIDD on the third day after initiation of MV [16.5 (7.0-29.0) vs. 5.0 (2.0-22.0), p = 0.003]., Conclusions: Daily monitoring of diaphragmatic function with bedside ultrasonography after initiation of MV is necessary in critically ill patients in PICU and the influences and risk factors of severe VIDD need to be further studied. (355 words)., (© 2024. The Author(s).)

Background: During mechanical ventilation, post-insufflation diaphragm contractions (PIDCs) are non-physiologic and could be injurious. PIDCs could be frequent during reverse-triggering, where diaphragm contractions follow the ventilator rhythm. Whether PIDCs happens with different modes of assisted ventilation is unknown. In mechanically ventilated patients with hypoxemic respiratory failure, we aimed to examine whether PIDCs are associated with ventilator settings, patients' characteristics or both., Methods: One-hour recordings of diaphragm electromyography (EAdi), airway pressure and flow were collected once per day for up to five days from intubation until full recovery of diaphragm activity or death. Each breath was classified as mandatory (without-reverse-triggering), reverse-triggering, or patient triggered. Reverse triggering was further subclassified according to EAdi timing relative to ventilator cycle or reverse triggering leading to breath-stacking. EAdi timing (onset, offset), peak and neural inspiratory time (Ti neuro ) were measured breath-by-breath and compared to the ventilator expiratory time. A multivariable logistic regression model was used to investigate factors independently associated with PIDCs, including EAdi timing, amplitude, Ti neuro , ventilator settings and APACHE II., Results: Forty-seven patients (median[25%-75%IQR] age: 63[52-77] years, BMI: 24.9[22.9-33.7] kg/m 2 , 49% male, APACHE II: 21[19-28]) contributed 2 ± 1 recordings each, totaling 183,962 breaths. PIDCs occurred in 74% of reverse-triggering, 27% of pressure support breaths, 21% of assist-control breaths, 5% of Neurally Adjusted Ventilatory Assist (NAVA) breaths. PIDCs were associated with higher EAdi peak (odds ratio [OR][95%CI] 1.01[1.01;1.01], longer Ti neuro (OR 37.59[34.50;40.98]), shorter ventilator inspiratory time (OR 0.27[0.24;0.30]), high peak inspiratory flow (OR 0.22[0.20;0.26]), and small tidal volumes (OR 0.31[0.25;0.37]) (all P ≤ 0.008). NAVA was associated with absence of PIDCs (OR 0.03[0.02;0.03]; P < 0.001). Reverse triggering was characterized by lower EAdi peak than breaths triggered under pressure support and associated with small tidal volume and shorter set inspiratory time than breaths triggered under assist-control (all P < 0.05). Reverse triggering leading to breath stacking was characterized by higher peak EAdi and longer Ti neuro and associated with small tidal volumes compared to all other reverse-triggering phenotypes (all P < 0.05)., Conclusions: In critically ill mechanically ventilated patients, PIDCs and reverse triggering phenotypes were associated with potentially modifiable factors, including ventilator settings. Proportional modes like NAVA represent a solution abolishing PIDCs., (© 2024. The Author(s).)

Patients with acute respiratory distress syndrome often require mechanical ventilation to maintain adequate gas exchange and to reduce the workload of the respiratory muscles. Although lifesaving, positive pressure mechanical ventilation can potentially injure the lungs and diaphragm, further worsening patient outcomes. While the effect of mechanical ventilation on the risk of developing lung injury is widely appreciated, its potentially deleterious effects on the diaphragm have only recently come to be considered by the broader intensive care unit community. Importantly, both ventilator-induced lung injury and ventilator-induced diaphragm dysfunction are associated with worse patient-centered outcomes., Competing Interests: Disclosure Dr Goligher reports receiving personal fees for consulting and/or advisory board activities from Getinge, Lungpacer, Zoll, Baxter, Bioage, Stimit, Vyaire, Drager, and Heecap., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Invasive mechanical ventilation (MV) is one of the most practiced interventions in the intensive care unit (ICU) and is unmistakably lifesaving for children with acute respiratory failure (ARF). However, if delivered inappropriately (i.e. ignoring the respiratory system mechanics and not targeted to the need of the individual patient at a specific time point in the disease trajectory), the side effects will outweigh the benefits. Decades of experimental and clinical investigations have resulted in a better understanding of three important detrimental effects of MV. These are ventilation-induced lung injury (VILI), patient self-inflicted lung injury (P-SILI), and ventilation-induced diaphragmatic injury (VIDD). VILI, P-SILI, and VIDD have in common that they occur when there is either too much or too little ventilatory assistance.Conclusion: The purpose of this review is to give the paediatrician an overview of the challenges to prevent these detrimental effects and titrate MV to the individual patient needs., (© 2024. The Author(s).)

Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients ( N = 54) to those of non-ICU patients undergoing thoracic surgery ( N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.

Objective: This study was performed to explore the predictive value of the diaphragmatic thickness fraction (DTF) combined with the integrated pulmonary index (IPI) for the extubation outcome in patients with severe acute pancreatitis (SAP)., Methods: This prospective study involved 93 patients diagnosed with SAP and treated with mechanical ventilation in our hospital from October 2020 to September 2023. The patients were divided into a successful extubation group (61 patients) and an extubation failure group (32 patients) based on the extubation outcomes. The predictive value of the DTF, IPI, and their combination for extubation failure was analyzed., Results: The DTF and IPI were independent risk factors for extubation failure in patients with SAP undergoing mechanical ventilation. In addition, the combination of the DTF and IPI showed predictive value for extubation failure in these patients., Conclusion: The DTF and IPI hold predictive value for extubation failure in patients with SAP undergoing mechanical ventilation, and their combined use may improve the predictive efficiency.

Backgrounds: Increased respiratory drive has been demonstrated to correlate with weaning failure, which could be quantified by electrical activity of the diaphragm (EAdi). We described the physiological process of EAdi-based parameters during the spontaneous breathing trial (SBT) and evaluated the change of EAdi-based parameters as potential predictors of weaning failure., Methods: We conducted a prospective study in 35 mechanically ventilated patients who underwent a 2-hour SBT. EAdi and ventilatory parameters were continuously measured during the SBT. Diaphragm ultrasound was performed before the SBT and at the 30 min of the SBT. Three EAdi-based parameters were calculated: neuro-ventilatory efficiency, neuro-excursion efficiency and neuro-discharge per min., Results: Of the thirty 35 patients studied, 25 patients were defined as SBT success, including 22 patients weaning successfully and 3 patients reintubated. Before the SBT, neuro-excursion efficiency differed significantly between two groups and had the highest predictive value for SBT failure (AUROC 0.875, p < 0.01). Early increases in EAdi were observed in SBT, which are more prominent in SBT failure group. One minute, changes in EAdi and neuro-discharge per min also predicted weaning outcome (AUROCs 0.944 and 0.918, respectively)., Conclusions: EAdi-based parameters, especially neuro-excursion efficiency and changes in neuro-discharge per min, may detect impending weaning failure earlier than conventional indices. EAdi monitoring provides physiological insights and a more tailored approach to facilitate successful weaning. Further research should validate these findings and explore the utility of combined EAdi and diaphragm ultrasound assessment in weaning ICU patients from mechanical ventilation., Trial Registration: Registered at ClinicalTrials.gov on 20 September 2022 (Identifier: NCT05632822)., (© 2024. The Author(s).)

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., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

This review addresses the phenomenon of "reverse triggering", an asynchrony that occurs in deeply sedated patients or patients in transition from deep to light sedation. Reverse triggering has been reported to occur in 30-90% of all ventilated patients. The underlying pathophysiological mechanisms remain unclear, but "entrainment" is proposed as one of them. Detecting this asynchrony is crucial, and methods such as visual inspection, esophageal pressure, diaphragmatic ultrasound and automated methods have been used. Reverse triggering may have effects on lung and diaphragm function, probably mediated by the level of breathing effort and eccentric activation of the diaphragm. The optimal management of reverse triggering has not been established, but may include the adjustment of ventilatory parameters as well as of sedation level, and in extreme cases, neuromuscular block. It is important to understand the significance of this condition and its detection, but also to conduct dedicated research to improve its clinical management and potential effects in critically ill patients., (Copyright © 2023 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.)

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.

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.)

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: 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).)

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).

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: 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.

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: Mechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction., Methods: Sprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure., Results: MV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H 2 O 2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified., Conclusion: These results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction. The reviews of this paper are available via the supplemental material section.

Objectives: Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model., Design: Experimental randomized study., Setting: Research laboratory., Subjects: C57/BL6 mice., Interventions: Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls., Measurements and Main Results: For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas., Conclusions: We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.

Rationale: The extent of diaphragmatic atrophy and dysfunction in critically ill children from developing countries is not established., Objectives: To estimate changes in ultrasound measurements of diaphragmatic thickness over the first week of mechanical ventilation. To assess magnitude and risk factors of diaphragmatic atrophy., Methods: In an observational cohort study, children aged 1-18 years, requiring mechanical ventilation were included. Ultrasound measurements of diaphragmatic thickness at end-expiration (DTe) and end-inspiration (DTi), and diaphragmatic thickening fraction (DTF) were performed daily during the first week of admission, and pre- and post-extubation. Diaphragmatic atrophy (%) and atrophy rate (rate of decline in DTe, % per day) were calculated., Measurements and Main Results: Of 55 children (74.6% boys) enrolled, 20 (36.4%) died. Of 35 children with planned extubation, 5 (14.3%) required reintubation. Baseline median (interquartile range [IQR]) DTe, DTi, and DTF were 1.27 mm (1, 1.6), 1.76 mm (1.35, 2.10), and 33.75% (26.90, 44.60), respectively. There was a significant reduction in DTe over the first week of mechanical ventilation (p < .001), median (IQR) diaphragmatic atrophy and atrophy rate of 9.91% (5.26, 17.35) and 2.01% (1.08, 3.04) per day, respectively. Diaphragmatic atrophy rate was lower in pressure targeted ventilation (n = 44; 1.79% [1.03, 2.87]) than volume targeted ventilation (n = 11; 3.10% [1.31, 5.49]), p = .038. There was no difference in diaphragmatic parameters (atrophy rate, and peri-extubation DTe and DTF) in extubation success versus failure., Conclusions: The diaphragm undergoes progressive atrophy during the first week of mechanical ventilation in critically ill children. Future studies should evaluate ventilation strategies to reduce the diaphragmatic atrophy., (© 2020 Wiley Periodicals LLC.)

Introduction: Ultrasound is a feasible and reproducible method for measuring right diaphragmatic excursion (RDE) in ED patients with acute dyspnea (AD). In AD patients, the correlation between the RDE value and the need for mechanical ventilation (MV) is not known., Materials: This was a bicentric, observational prospective study. The RDE measurement was done at admission. The need for MV was defined by the use of MV within 4 h of AD management. An optimal threshold for RDE was determined as the value that minimized the incorrect predictions of the use of MV in the first 4 h as the highest Youden index., Results: We analyzed 102 patients (79 [70; 86] years), 38 (37%) of whom had been ventilated. The RDE value was 1.7 cm [1.4; 2.0] and 2.2 cm [1.8; 2.6] in the ventilated and non-ventilated groups, respectively (p = 0.06). The AUC was 0.68 95% CI [0.57; 0.80]. With a threshold of 2 cm, the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were 76% [60%; 89%], 59% [46%; 71%], 81% [67%; 91%], and 53% [39%; 66%], respectively. In the non-COPD patients, the RDE values were 1.5 cm [1.2; 1.9] and 2.2 cm [1.8; 2.6] (p < 0.01) in the ventilated and not-ventilated groups, respectively. The AUC was 0.77 95% CI [0.64; 0.90]. With a threshold of 2.18 cm, the sensitivity, specificity, NPV, and PPV were 91% [71%; 99%], 51% [36%; 66%], 92% [75%; 99%], and 54% [38%; 69%], respectively., Conclusion: The RDE values at ED admission were unable to define a prognostic threshold value associated with subsequent MV need in the AD patients. In non-COPD patients, the NPV was 92%., Competing Interests: Declaration of competing interest XB, LZ, and LM declare a competing interest as an US teacher for GE (GE Medical Systems Ultrasound) customers. The other authors state that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The diaphragm is vulnerable to injury during mechanical ventilation, and diaphragm dysfunction is both a marker of severity of illness and a predictor of poor patient outcome in the ICU. A combination of factors can result in diaphragm weakness. Both insufficient and excessive diaphragmatic contractile effort can cause atrophy or injury, and recent evidence suggests that targeting an appropriate amount of diaphragm activity during mechanical ventilation has the potential to mitigate diaphragm dysfunction. Several monitoring tools can be used to assess diaphragm activity and function during mechanical ventilation, including pressure-derived parameters, electromyography, and ultrasound. This review details these techniques and presents the rationale for a diaphragm-protective ventilation strategy., Competing Interests: Dr Schepens is supported in part by the European Respiratory Society, Fellowship STRF October 2018. Dr Goligher is supported by an Early Career Investigator Award from the Canadian Institutes of Health Research, and he has disclosed a relationship with Getinge. Ms Fard has disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Background: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors., Methods: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters., Results: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH 2 O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction., Conclusion: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.

Controlled mechanical ventilation (CMV) can cause diaphragmatic motionlessness to induce diaphragmatic dysfunction. Partial maintenance of spontaneous breathing (SB) can reduce ventilation-induced diaphragmatic dysfunction (VIDD). However, to what extent SB is maintained in CMV can attenuate or even prevent VIDD has been rarely reported. The current study aimed to investigate the relationship between SB intensity and VIDD and to identify what intensity of SB maintained in CMV can effectively avoid VIDD. Adult rats were randomly divided according to different SB intensities: SB (0% pressure controlled ventilation (PCV)), high-intensity SB (20% PCV), medium-intensity SB (40% PCV), medium-low intensity SB (60% PCV), low-intensity SB (80% PCV), and PCV (100% PCV). The animals underwent 24-h controlled mechanical ventilation (CMV). The transdiaphragmatic pressure (Pdi), the maximal Pdi (Pdi max) when phrenic nerves were stimulated, Pdi/Pdi max, and the diaphragmatic tonus under different frequencies of electric stimulations were determined. Calpain and caspase-3 were detected using ELISA and the cross-section areas (CSAs) of different types of muscle fibers were measured. The Pdi showed a significant decrease from 20% PCV and the Pdi max showed a significant decrease from 40% PCV (P<0.05). In vivo and vitro diaphragmatic tonus exhibited a significant decrease from 40% PCV and 20% PCV, respectively (P<0.05). From 20% PCV, the CSAs of types I, IIa, and IIb/x muscle fibers showed significant differences, which reached the lowest levels at 100% PCV. SB intensity is negatively associated with the development of VIDD. Maintenance of SB at an intensity of 60%-80% may effectively prevent the occurrence of VIDD., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the condition of the diaphragm in patients with long-term mechanical ventilation using ultrasound technology and to analyze its relationship with ventilation time and muscle atrophy in order to clarify the reasons for diaphragm dysfunction in long-term mechanical ventilation patients. Methods: Patients admitted to the respiratory department at the Chinese PLA General Hospital between June 2018 and April 2019 with mechanical ventilation were included in this study. The enrolled patients were divided into a short-term mechanical ventilation group (7 days ≤ ventilation time<1 month) and a long-term mechanical ventilation group (mechanical ventilation time ≥ 1 month). The diaphragmatic excursion, inspiratory time, contraction rate, E-T index, diaphragm thickness, diaphragm thickness fraction (DTF), and tibialis anterior thickness were compared between the two groups. The correlation between ventilation time and diaphragm thickness was analyzed in all patients. Results: The mean diaphragm thickness and DTF were significantly lower in the long-term mechanical ventilation group than in the short-term mechanical ventilation group [(0.13±0.036) vs (0.17±0.05) cm and (0.22±0.045) vs (0.27±0.075)](all P< 0.05). However, there was no significant difference in diaphragmatic excursion, inspiratory time, contraction rate, E-T index or tibialis anterior thickness between the two groups (all P> 0.05). There was a significant linear correlation between ventilation time and diaphragm thickness ( P< 0.01). Tibialis anterior thickness was not significantly correlated with ventilation time ( P> 0.05). Conclusion: Diaphragm thickness and function were significantly reduced in patients with long-term mechanical ventilation, which was correlated with the duration of ventilation. Nutritional status was not the main factor affecting diaphragm thickness.

Purpose of Review: Diaphragm weakness can impact survival and increases comorbidities in ventilated patients. Mechanical ventilation is linked to diaphragm dysfunction through several mechanisms of injury, referred to as myotrauma. By monitoring diaphragm activity and titrating ventilator settings, the critical care clinician can have a direct impact on diaphragm injury., Recent Findings: Both the absence of diaphragm activity and excessive inspiratory effort can result in diaphragm muscle weakness, and recent evidence demonstrates that a moderate level of diaphragm activity during mechanical ventilation improves ICU outcome. This supports the hypothesis that by avoiding ventilator overassistance and underassistance, the clinician can implement a diaphragm-protective ventilation strategy. Furthermore, eccentric diaphragm contractions and end-expiratory shortening could impact diaphragm strength as well. This review describes these potential targets for diaphragm protective ventilation., Summary: A ventilator strategy that results in appropriate levels of diaphragm activity has the potential to be diaphragm-protective and improve clinical outcome. Monitoring respiratory effort during mechanical ventilation is becoming increasingly important.

Purpose of Review: Extracorporeal support allows ultraprotective controlled and assisted ventilation, which can prevent lung and diaphragm injury. We focused on most recent findings in the application of extracorporeal support to achieve lung protection and diaphragm- protection, as well as on relevant monitoring., Recent Findings: A recent randomized trial comparing the efficacy of extracorporeal support as a rescue therapy to conventional protective mechanical ventilation was stopped for futility but post hoc analyses suggested that extracorporeal support is beneficial for patients with very severe acute respiratory distress syndrome. However, the optimal ventilation settings during extracorporeal support are still debated. It is conceivable that they should enable the highest amount of CO2 removal with lowest mechanical power.Extracorporeal CO2 removal can minimize acidosis and enable the use of ultra-protective lung ventilation strategies when hypoxemia is not a major issue. Moreover, it can protect lung and diaphragm function during assisted ventilation through control of the respiratory effort.Lung mechanics, gas exchange, diaphragm electrical activity, ultrasound, electrical impedance tomography could be integrated into clinical management to define lung and diaphragm protection and guide personalized ventilation settings., Summary: Technological improvement and the latest evidence indicate that extracorporeal support may be an effective tool for lung and diaphragm protection.

Lung Protective Mechanical Ventilation (MV) of critically ill adults and children is lifesaving but it may decrease diaphragm contraction and promote Ventilator Induced Diaphragm Dysfunction (VIDD). An ideal MV strategy would balance lung and diaphragm protection. Building off a Phase I pilot study, we are conducting a Phase II controlled clinical trial that seeks to understand the evolution of VIDD in critically ill children and test whether a novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can balance lung and diaphragm protective ventilation to reduce time on MV. REDvent systematically adjusts PEEP, FiO 2 , inspiratory pressure, tidal volume and rate, and uses real-time measures from esophageal manometry to target normal levels of patient effort of breathing. This trial targets 276 children with pulmonary parenchymal disease. Patients are randomized to REDvent vs. usual care for the acute phase of MV (intubation to first Spontaneous Breathing Trial (SBT)). Patients in either group who fail their first SBT will be randomized to REDvent vs usual care for weaning phase management (interval from first SBT to passing SBT). The primary clinical outcome is length of weaning, with several mechanistic outcomes. Upon completion, this study will provide important information on the pathogenesis and timing of VIDD during MV in children and whether this computerized protocol targeting lung and diaphragm protection can lead to improvement in intermediate clinical outcomes. This will form the basis for a larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day ventilator free days. Clinical Trials Registration: NCT03266016., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mechanical ventilation (MV) is identified as an independent contributor to diaphragmatic atrophy and contractile dysfunction. Appropriate sedation is also essential during MV, and anesthetics may have direct adverse effects on the diaphragm. However, there is a lack of research into the effects of different anesthetics on diaphragm function during MV., Objectives: In the present study, we aim to examine the effect of midazolam, dexmedetomidine, and propofol on diaphragm function during MV., Design: Animal study., Setting: University research laboratory., Subjects: Male Wistar rats., Interventions: Animals were experienced 12 h of MV or spontaneous breathing (SB) with continuous anesthetics infusion. Diaphragm contractile properties, cross-sectional areas, microcirculation, oxidative stress, and proteolysis were examined., Measurements and Main Results: Diaphragmatic specific force was markedly reduced in the midazolam group compared with the dexmedetomidine (-60.4 ± 3.01%, p < 0.001) and propofol group (-58.3 ± 2.60%, p < 0.001) after MV. MV sedated with midazolam induced more atrophy of type II fibers compared with dexmedetomidine (-21.8 ± 2.11%, p = 0.0001) and propofol (-8.2 ± 1.53%, p = 0.003). No significant differences of these indices were found in the midazolam, dexmedetomidine, and propofol groups under SB condition (all p > 0.05, respectively). Twelve hours of MV resulted in a time dependent reduction in diaphragmatic functional capillary density (PB -25.1%, p = 0.0001; MZ -21.6%, p = 0.0003; DD -15.2%, p = 0.022; PP -24.8%, p = 0.0001, respectively), which did not occur in the gastrocnemius muscle. The diaphragmatic lipid peroxidation adducts 4-HNE and HIF-1α levels were significantly lower in dexmedetomidine group and propofol group compared to midazolam group (p < 0.05, respectively). Meanwhile, the catalase and SOD levels were also relatively lower (p < 0.05, respectively) in midazolam group compared to dexmedetomidine group and propofol group., Conclusions: Twelve hours of mechanical ventilation during midazolam sedation led to a more severe diaphragm dysfunction than dexmedetomidine and propofol, possibly caused by its relative weaker antioxidant capacity., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Intensive care unit (ICU)-acquired weakness (ICU-AW) and ICU-acquired diaphragm dysfunction (ICU-DD) occur frequently in mechanically ventilated (MV) patients. It is unknown whether they have different risk factors and different impacts on outcome. This study was designed to (1) describe the respective risk factors associated with ICU-AW and severe ICU-DD and (2) evaluate the respective impact of ICU-AW and severe ICU-DD on outcome., Methods: Post hoc analysis of two prospective cohort studies conducted in two ICUs. In patients mechanically ventilated for at least 24 h undergoing a first spontaneous breathing trial, severe ICU-DD was defined as diaphragm twitch pressure < 7 cmH 2 O and ICU-AW was defined as Medical Research Council Score < 48., Results: One hundred sixteen patients were assessed. Factors independently associated with severe ICU-DD were age, longer duration of MV, and exposure to sufentanil, and those factors associated with ICU-AW were longer duration of MV and exposure to norepinephrine. Severe ICU-DD (OR 3.56, p = 0.008), but not ICU-AW, was independently associated with weaning failure (59%). ICU-AW (OR 4.30, p = 0.033), but not severe ICU-DD, was associated with ICU mortality. Weaning failure and mortality rate were higher in patients with both severe ICU-DD and ICU-AW (86% and 39%, respectively) than in patients with either severe ICU-DD (64% and 0%) or ICU-AW (63% and 13%)., Conclusion: Severe ICU-DD and ICU-AW have different risk factors and different impacts on weaning failure and mortality. The impact of the combination of ICU-DD and ICU-AW is more pronounced than their individual impact.

Background: Humidification is a standard of care during invasive mechanical ventilation. Two types of devices are used for this purpose: heated humidifiers and heat-and-moisture exchangers (HME)., Aim: To compare the short-term physiologic effects of an active HME, with those of heated humidifiers and HMEs in terms of respiratory effort, ventilatory pattern, and arterial blood gases during invasive mechanical ventilation., Methods: We conducted a randomized crossover study with 3 different devices in 15 stable subjects who had a tracheostomy and were ventilator-dependent. Transdiaphragmatic pressure, ventilatory pattern, arterial blood gases, and dyspnea scale were recorded at baseline and at the end of a 20-min period with each device., Results: Compared with heated humidifiers, the active HME was associated with higher diaphragmatic pressure-time product per minute (117.10 [interquartile range {IQR} 34.58-298.60]) versus 80.86 (IQR, 25.46-110.55) cm H 2 O×s/min, P = .01), higher P aCO 2 (48.50 [IQR, 40.65-53.70] vs 39.60 [IQR, 37.50-49.95]) mm Hg, P = .02) and lower pH (7.41 [IQR, 7.36-7.49] vs 7.45 [IQR, 7.40-7.51], P = .030) without any significant difference in ventilatory pattern. A significantly worse dyspnea scale score (active HME, 3 (2-4) vs heated humidifiers: 4 (3-5); P = .009) was also observed. No significant differences were seen between active HME and HME., Conclusions: This study indicated that, compared with the heated humidifiers, the use of the active HME or the HME increased inspiratory effort, P aCO 2 , pH, and dyspnea in stable subjects who were tracheostomized and ventilator-dependent. (ClinicalTrials.gov registration NCT02499796.)., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2019 by Daedalus Enterprises.)

What We Already Know About This Topic: Diaphragm dysfunction and atrophy develop during controlled mechanical ventilation. Although oxidative stress injures muscle during controlled mechanical ventilation, it is unclear whether it causes autophagy or fiber atrophy., What This Article Tells Us That Is New: Pretreatment of rats undergoing 24 h of mechanical ventilation with N-acetylcysteine prevents decreases in diaphragm contractility, inhibits the autophagy and proteasome pathways, but has no influence on the development of diaphragm fiber atrophy., Background: Diaphragm dysfunction and atrophy develop during prolonged controlled mechanical ventilation. Fiber atrophy has been attributed to activation of the proteasome and autophagy proteolytic pathways. Oxidative stress activates the proteasome during controlled mechanical ventilation, but it is unclear whether it also activates autophagy. This study investigated whether pretreatment with the antioxidant N-acetylcysteine affects controlled mechanical ventilation-induced diaphragm contractile dysfunction, fiber atrophy, and proteasomal and autophagic pathway activation. The study also explored whether proteolytic pathway activity during controlled mechanical ventilation is mediated by microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes., Methods: Three groups of adult male rats were studied (n = 10 per group). The animals in the first group were anesthetized and allowed to spontaneously breathe. Animals in the second group were pretreated with saline before undergoing controlled mechanical ventilation for 24 h. The animals in the third group were pretreated with N-acetylcysteine (150 mg/kg) before undergoing controlled mechanical ventilation for 24 h. Diaphragm contractility and activation of the proteasome and autophagy pathways were measured. Expressions of microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes were measured with quantitative polymerase chain reaction., Results: Controlled mechanical ventilation decreased diaphragm twitch force from 428 ± 104 g/cm (mean ± SD) to 313 ± 50 g/cm and tetanic force from 2,491 ± 411 g/cm to 1,618 ± 177 g/cm. Controlled mechanical ventilation also decreased diaphragm fiber size, increased expression of several autophagy genes, and augmented Atrogin-1, MuRF1, and Nedd4 expressions by 36-, 41-, and 8-fold, respectively. Controlled mechanical ventilation decreased the expressions of six microRNAs (miR-20a, miR-106b, miR-376, miR-101a, miR-204, and miR-93) that regulate autophagy genes. Pretreatment with N-acetylcysteine prevented diaphragm contractile dysfunction, attenuated protein ubiquitination, and downregulated E3 ligase and autophagy gene expression. It also reversed controlled mechanical ventilation-induced microRNA expression decreases. N-Acetylcysteine pretreatment had no affect on fiber atrophy., Conclusions: Prolonged controlled mechanical ventilation activates the proteasome and autophagy pathways in the diaphragm through oxidative stress. Pathway activation is accomplished, in part, through inhibition of microRNAs that negatively regulate autophagy-related genes.

Introduction: Invasive mechanical ventilation contributes to ventilator-induced diaphragmatic dysfunction, delaying extubation and increasing mortality in adults. Despite the possibility of having a higher impact in paediatrics, this dysfunction is not routinely monitored. Diaphragm ultrasound has been proposed as a safe and non-invasive technique for this purpose. The aim of this study was to describe the evolution of diaphragmatic morphology and functional measurements by ultrasound in ventilated children., Material and Methods: Prospective exploratory study. Children admitted to Paediatric Intensive Care Unit requiring mechanical ventilation > 48 hours were included. The diaphragmatic thickness, excursion and the thickening fraction were assessed by ultrasound., Results: Seventeen cases were included, with a median age of 42 months. Ten were male, seven had comorbidities and three in seventeen had malnutrition at admission. The median time under mechanical ventilation was seven days. The median of the initial and minimum diaphragmatic thickness was 2.3 mm and 1.9 mm, respectively, with a median decrease in thickness of 13% under pressure-regulated volume control. Diaphragmatic atrophy was observed in 14/17 cases. Differences in the median thickness variation were found between patients with sepsis and without (0.70 vs 0.25 mm; p = 0.019). During pressure support ventilation there was a tendency to increase diaphragmatic thickness and excursion. Extubation failure occurred for diaphragmatic thickening fraction ≤ 35%., Discussion: Under pressure-regulated volume control there was a tendency for a decrease in diaphragmatic thickness. In the pre-extubation stage under pressure support, there was a tendency for it to increase. These results suggest that, by titrating ventilation using physiological levels of inspiratory effort, we can reduce the diaphragmatic morphological changes associated with ventilation., Conclusion: The early recognition of diaphragmatic changes may encourage a targeted approach, namely titration of ventilation, in order to reduce ventilator-induced diaphragmatic dysfunction and its clinical repercussions.

Background: Mechanical ventilation (MV) is a life-saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator-induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity-induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF-κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise-induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise-induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD., Methods: Cause and effect was determined by inhibiting the endurance exercise-induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV-HSP72) or pharmacological (BGP-15) overexpression is sufficient to prevent VIDD., Results: Our results demonstrate that the exercise-induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV-HSP72 and BGP-15-induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF-κB and FoxO target genes., Conclusions: HSP72 overexpression in the diaphragm is an effective intervention to prevent MV-induced oxidative stress and the transcriptional activity of NF-κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD., (© 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator-induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high-mobility group box-1 (HMGB1) levels are associated with patients requiring long-term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti-HMGB1 antibody could attenuate sepsis-exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti-HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor-1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti-HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin-enhanced VIDD by inhibiting HMGB1 signalling pathway., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Purpose: To assess alteration of diaphragmatic function by ultrasonography in a population of mechanically ventilated patients with or without sepsis., Methods: We performed a prospective, 6-month, single-center, observational cohort study. Mechanically ventilated septic and nonseptic patients were studied within 24 hours following intubation and before the moment of ventilator liberation. Diaphragm thickness and contractile activity (quantified by diaphragmatic thickening fraction, DTF) were measured by ultrasonography at the zone of apposition. Intraobserver and interobserver reproducibility were measured., Results: Fifty-two critically ill patients were included, 28 with sepsis and 24 without sepsis. Upon initiation of ventilation, DTF was lower in septic than that in nonseptic patients (P = 0.03). No difference was observed between septic and nonseptic patients for diaphragm thickness. Mean 188 ± 111 hours after the first measurement, both diaphragm thickness and DTF decreased significantly compared with first measurements in septic and nonseptic patients, all P < 0.001. Diaphragm thickness decreased by 9.1 ± 10.7% in nonseptic and by 16.0 ± 13.5% in septic patients, P = 0.049. DTF decreased by 15.2 ± 21.3% in nonseptic and by 30.7 ± 22.0% in septic patients, P = 0.013., Conclusions: Mechanically ventilated patients with sepsis were associated with an earlier and more severe diaphragm dysfunction compared with patients without sepsis., (© 2019 Wiley Periodicals, Inc.)

Cytosolic phospholipase A2 (cPLA2) has been reported to be critical for infection-induced mitochondrial reactive oxygen species (ROS) production and diaphragm dysfunction (DD). In the present study, we aim to investigate whether cPLA2 was involved in ventilator-induced diaphragm dysfunction (VIDD). Our results showed that mechanical ventilation (MV) induced cPLA2 activation in the diaphragm with excessive mitochondrial ROS generation and muscle weakness. Specific inhibition of cPLA2 with CDIBA resulted in decreased mitochondrial ROS levels and improved diaphragm forces. In addition, mitochondria-targeted antioxidant MitoTEMPO attenuated ventilator-induced mitochondrial oxidative stress and downregulated cPLA2 activation in vivo . Both CDIBA and MitoTEMPO were able to attenuate protein degradation, muscle atrophy, and weakness following prolonged MV. Furthermore, laser Doppler imaging showed that MV decreased diaphragm tissue perfusion and induced subsequent hypoxia. An in vitro study also demonstrated a positive association between cPLA2 activation and mitochondrial ROS generation in C2C12 cells cultured under hypoxic condition. Collectively, our study showed that cPLA2 activation positively interacts with mitochondrial ROS generation in the development of VIDD, and ventilator-induced diaphragm hypoxia serves as a possible contributor to this positive feedback loop.

Background: Diaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined. Furthermore, it is unknown whether co-existent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). We investigated the impact of MV (mean duration = 7.65 h), either with or without co-existent respiratory failure caused by surfactant deficiency, on the development of VIDD in newborn lambs., Methods: Newborn lambs (1-4 days) were assigned to control (CTL, non-ventilated), mechanically ventilated (MV), and MV + experimentally induced surfactant deficiency (MV+SD) groups. Immunoblotting and quantitative PCR assessed inflammatory signaling, the ubiquitin-proteasome system, autophagy, and oxidative stress. Immunostaining for myosin heavy chain (MyHC) isoforms and quantitative morphometry evaluated diaphragm atrophy. Contractile function of the diaphragm was determined in isolated myofibrils ex vivo., Results: Equal decreases (25-30%) in myofibrillar force generation were found in MV and MV+SD diaphragms compared to CTL. In comparison to CTL, both MV and MV+SD diaphragms also demonstrated increased STAT3 transcription factor phosphorylation. Ubiquitin-proteasome system (Atrogin1 and MuRF1) transcripts and autophagy indices (Gabarapl1 transcripts and the ratio of LC3B-II/LC3B-I protein) were greater in MV+SD relative to MV alone, but fiber type atrophy was not observed in any group. Protein carbonylation and 4-hydroxynonenal levels (indices of oxidative stress) also did not differ among groups., Conclusions: In newborn lambs undergoing controlled MV, there is a rapid onset of diaphragm dysfunction consistent with VIDD. Superimposed lung injury caused by surfactant deficiency did not influence the severity of early diaphragm weakness.

Purpose: Ventilator-induced diaphragm dysfunction or damage (VIDD) is highly prevalent in patients under mechanical ventilation (MV), but its analysis is limited by the difficulty of obtaining histological samples. In this study we compared diaphragm histological characteristics in Maastricht III (MSIII) and brain-dead (BD) organ donors and in control subjects undergoing thoracic surgery (CTL) after a period of either controlled or spontaneous MV (CMV or SMV)., Methods: In this prospective study, biopsies were obtained from diaphragm and quadriceps. Demographic variables, comorbidities, severity on admission, treatment, and ventilatory variables were evaluated. Immunohistochemical analysis (fiber size and type percentages) and quantification of abnormal fibers (a surrogate of muscle damage) were performed., Results: Muscle samples were obtained from 35 patients. MSIII (n = 16) had more hours on MV (either CMV or SMV) than BD (n = 14) and also spent more hours and a greater percentage of time with diaphragm stimuli (time in assisted and spontaneous modalities). Cross-sectional area (CSA) was significantly reduced in the diaphragm and quadriceps in both groups in comparison with CTL (n = 5). Quadriceps CSA was significantly decreased in MSIII compared to BD but there were no differences in the diaphragm CSA between the two groups. Those MSIII who spent 100 h or more without diaphragm stimuli presented reduced diaphragm CSA without changes in their quadriceps CSA. The proportion of internal nuclei in MSIII diaphragms tended to be higher than in BD diaphragms, and their proportion of lipofuscin deposits tended to be lower, though there were no differences in the quadriceps fiber evaluation., Conclusions: This study provides the first evidence in humans regarding the effects of different modes of MV (controlled, assisted, and spontaneous) on diaphragm myofiber damage, and shows that diaphragm inactivity during mechanical ventilation is associated with the development of VIDD.