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Background Ventilator-induced diaphragmatic dysfunction is a serious complication associated with higher ICU mortality, prolonged mechanical ventilation, and unsuccessful withdrawal from mechanical ventilation. Although neurally adjusted ventilatory assist (NAVA) could be associated with lower patient-ventilator asynchrony compared with conventional ventilation, its effects on diaphragmatic dysfunction have not yet been well elucidated. Methods Twenty Japanese white rabbits were randomly divided into four groups, (1) no ventilation, (2) controlled mechanical ventilation (CMV) with continuous neuromuscular blockade, (3) NAVA, and (4) pressure support ventilation (PSV). Ventilated rabbits had lung injury induced, and mechanical ventilation was continued for 12 h. Respiratory waveforms were continuously recorded, and the asynchronous events measured. Subsequently, the animals were euthanized, and diaphragm and lung tissue were removed, and stained with Hematoxylin-Eosin to evaluate the extent of lung injury. The myofiber cross-sectional area of the diaphragm was evaluated under the adenosine triphosphatase staining, sarcomere disruptions by electron microscopy, apoptotic cell numbers by the TUNEL method, and quantitative analysis of Caspase-3 mRNA expression by real-time polymerase chain reaction. Results Physiological index, respiratory parameters, and histologic lung injury were not significantly different among the CMV, NAVA, and PSV. NAVA had lower asynchronous events than PSV (median [interquartile range], NAVA, 1.1 [0–2.2], PSV, 6.8 [3.8–10.0], p  = 0.023). No differences were seen in the cross-sectional areas of myofibers between NAVA and PSV, but those of Type 1, 2A, and 2B fibers were lower in CMV compared with NAVA. The area fraction of sarcomere disruptions was lower in NAVA than PSV (NAVA vs PSV; 1.6 [1.5–2.8] vs 3.6 [2.7–4.3], p  < 0.001). The proportion of apoptotic cells was lower in NAVA group than in PSV (NAVA vs PSV; 3.5 [2.5–6.4] vs 12.1 [8.9–18.1], p  < 0.001). There was a tendency in the decreased expression levels of Caspase-3 mRNA in NAVA groups. Asynchrony Index was a mediator in the relationship between NAVA and sarcomere disruptions. Conclusions Preservation of spontaneous breathing using either PSV or NAVA can preserve the cross sectional area of the diaphragm to prevent atrophy. However, NAVA may be superior to PSV in preventing sarcomere injury and apoptosis of myofibrotic cells of the diaphragm, and this effect may be mediated by patient-ventilator asynchrony.

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.

Respiratory muscle ultrasound is used to evaluate the anatomy and function of the respiratory muscle pump. It is a safe, repeatable, accurate, and non-invasive bedside technique that can be successfully applied in different settings, including general intensive care and the emergency department. Mastery of this technique allows the intensivist to rapidly diagnose and assess respiratory muscle dysfunction in critically ill patients and in patients with unexplained dyspnea. Furthermore, it can be used to assess patient–ventilator interaction and weaning failure in critically ill patients. This paper provides an overview of the basic and advanced principles underlying respiratory muscle ultrasound with an emphasis on the diaphragm. We review different ultrasound techniques useful for monitoring of the respiratory muscle pump and possible therapeutic consequences. Ideally, respiratory muscle ultrasound is used in conjunction with other components of critical care ultrasound to obtain a comprehensive evaluation of the critically ill patient. We propose the ABCDE-ultrasound approach, a systematic ultrasound evaluation of the heart, lungs and respiratory muscle pump, in patients with weaning failure.

Diaphragm weakness is highly prevalent in critically ill patients. It may exist prior to ICU admission and may precipitate the need for mechanical ventilation but it also frequently develops during the ICU stay. Several risk factors for diaphragm weakness have been identified; among them sepsis and mechanical ventilation play central roles. We employ the term critical illness-associated diaphragm weakness to refer to the collective effects of all mechanisms of diaphragm injury and weakness occurring in critically ill patients. Critical illness-associated diaphragm weakness is consistently associated with poor outcomes including increased ICU mortality, difficult weaning, and prolonged duration of mechanical ventilation. Bedside techniques for assessing the respiratory muscles promise to improve detection of diaphragm weakness and enable preventive or curative strategies. Inspiratory muscle training and pharmacological interventions may improve respiratory muscle function but data on clinical outcomes remain limited.

Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear. To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome. In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48. Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45-0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76-0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay. Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

The diaphragm is the main inspiratory muscle, and its dysfunction can lead to significant adverse clinical consequences. The aim of this review is to provide clinicians with an overview of the main causes of uni- and bi-lateral diaphragm dysfunction, explore the clinical and physiological consequences of the disease on lung function, exercise physiology and sleep and review the available diagnostic tools used in the evaluation of diaphragm function. A particular emphasis is placed on the clinical significance of diaphragm weakness in the intensive care unit setting and the use of ultrasound to evaluate diaphragmatic action.

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 Pre-clinical studies suggest that dyssynchronous diaphragm contractions during mechanical ventilation may cause acute diaphragm dysfunction. We aimed to describe the variability in diaphragm contractile loading conditions during mechanical ventilation and to establish whether dyssynchronous diaphragm contractions are associated with the development of impaired diaphragm dysfunction. Methods In patients receiving invasive mechanical ventilation for pneumonia, septic shock, acute respiratory distress syndrome, or acute brain injury, airway flow and pressure and diaphragm electrical activity (Edi) were recorded hourly around the clock for up to 7 days. Dyssynchronous post-inspiratory diaphragm loading was defined based on the duration of neural inspiration after expiratory cycling of the ventilator. Diaphragm function was assessed on a daily basis by neuromuscular coupling (NMC, the ratio of transdiaphragmatic pressure to diaphragm electrical activity). Results A total of 4508 hourly recordings were collected in 45 patients. Edi was low or absent (≤ 5 µV) in 51% of study hours (median 71 h per patient, interquartile range 39–101 h). Dyssynchronous post-inspiratory loading was present in 13% of study hours (median 7 h per patient, interquartile range 2–22 h). The probability of dyssynchronous post-inspiratory loading was increased with reverse triggering (odds ratio 15, 95% CI 8–35) and premature cycling (odds ratio 8, 95% CI 6–10). The duration and magnitude of dyssynchronous post-inspiratory loading were associated with a progressive decline in diaphragm NMC ( p  < 0.01 for interaction with time). Conclusions Dyssynchronous diaphragm contractions may impair diaphragm function during mechanical ventilation. Trial registration MYOTRAUMA, ClinicalTrials.gov NCT03108118. Registered 04 April 2017 (retrospectively registered).

Rationale Diaphragm neurostimulation-assisted ventilation (DNAV) can improve cardiopulmonary function during passive mechanical ventilation. However, this technique requires a reliable method to monitor and titrate diaphragmatic loading to avoid both insufficient and excessive diaphragmatic stimulation. Objective To establish whether the reduction in airway pressure-time product (ΔPTPaw) obtained during diaphragm neurostimulation in assist control volume-controlled mode accurately quantifies the magnitude of respiratory muscle effort elicited by neurostimulation. Methods This was a secondary analysis of the STIMULUS trial. Diaphragm neurostimulation was titrated across four levels targeting progressive occlusion pressures of 0, − 5, − 10, and − 15 cm H₂O at two PEEP levels. At each level, airway, esophageal, and gastric pressures were recorded to compute transdiaphragmatic pressure-time product (PTPdi), respiratory muscles pressure-time product (PTPmus), and ΔPTPaw, defined as the difference in airway pressure-time product between non-stimulated and stimulated breaths. Linear mixed-effects models, Bland–Altman analyses, and receiver operating characteristic (ROC) curves were used to assess agreement and discriminative ability. Measurements and main results Twelve patients contributed 494 high-quality respiratory cycles (63% of recorded cycles). Valid Pdi data were available in nine patients. Increasing neurostimulation was associated with higher PTPdi and PTPmus and a corresponding reduction in PTPaw. ΔPTPaw was correlated with both PTPdi (R² = 0.82) and PTPmus (R² = 0.92), with good agreement observed (limits: − 4 to 44 cm H₂O·s/min for PTPdi, and − 5 to 39 cm H₂O·s/min for PTPmus). ΔPTPaw demonstrated excellent discrimination for inadequate (area under receiver operating characteristic curve, AUROC ≥ 0.94) and excessive (AUROC ≥ 0.86) diaphragmatic effort. Conclusions ΔPTPaw is a reliable, non-invasive surrogate for monitoring diaphragm loading during DNAV under assist-controlled volume-controlled mode and may guide neurostimulation titration in mechanically ventilated patients.

Monitoring inspiratory drive and effort may aid proper selection and setting of respiratory support in patients with acute respiratory failure (ARF), whether they are intubated or not. Although diaphragmatic electrical activity (EAdi) and esophageal manometry can be considered the reference methods for assessing respiratory drive and inspiratory effort, respectively, various alternative techniques exist, each with distinct advantages and limitations. This narrative review provides a comprehensive overview of bedside methods to assess respiratory drive and effort, with a primary focus on patients with ARF. First, EAdi and esophageal manometry are described and discussed as reference techniques. Then, alternative methods are categorized along the neuromechanical pathway from inspiratory drive to muscular effort into three groups: (1) techniques assessing the respiratory drive: airway occlusion pressure (P0.1), mean inspiratory flow (Vt/Ti) and respiratory muscle surface electromyography (sEMG); (2) techniques assessing the respiratory muscle effort: whole-breath occlusion pressure (ΔPocc), pressure-muscle index (PMI), nasal pressure swing (ΔPnose), diaphragm ultrasonography (USdi), central venous pressure swing (ΔCVP), breathing effort (BREF) models, and flow index; (3) techniques and clinical parameters assessing the consequences of effort: tidal volume (Vt), electrical impedance tomography (EIT), dyspnea. For each, we summarize the physiological rationale, measurement methodology, interpretation of results, and key limitations.