Diaphragmatic Dysfunction Research Articles

Temporary diaphragm pacing for patients at risk of prolonged mechanical ventilation after extensive aortic repair

ObjectiveProlonged mechanical ventilation (MV) after extensive aortic reconstructive surgery is common. Studies have demonstrated that diaphragm pacing (DP) improves lung function in patients with unilateral diaphragm paralysis. The goal of this study is to determine whether this technology can be applied to complex aortic repair to reduce prolonged MV and other respiratory sequelae. MethodsA retrospective review was performed of patients who underwent temporary DP after extensive aortic reconstructive surgery between 2019 and 2022. The primary end point was prolonged MV incidence. Other measured end points included diaphragm electromyography improvement, length of hospitalization, duration of intensive care unit stay, and reintubation rates. ResultsFourteen patients deemed at high risk of prolonged MV based on their smoking and respiratory history underwent DP after extensive aortic repair. The mean age was 70.2 years. The indications for aortic repair were a thoracoabdominal aortic aneurysm (n = 8, including 2 ruptured, 2 symptomatic, and 1 mycotic), a perivisceral aneurysm (n = 4), and a perivisceral coral reef aorta (n = 2). All patients had a significant smoking history (active or former) or other risk factors for ventilator-induced diaphragmatic dysfunction and prolonged MV. The mean total duration of MV postoperatively was 31.9 hours (range, 8.1-76.5 hours). The total average pacing duration was 4.4 days. Two patients required prolonged MV, with an average of 75.4 hours. Two patients required reintubation. No complications related to DP wire placement or removal occurred. ConclusionsDP is safe and feasible for patients at high risk of pulmonary insufficiency after extensive aortic reconstructive surgery.

Conservative rehabilitation therapy for respiratory dysfunction due to phrenic nerve sacrifice during resection of massive mediastinal tumor: A case series study.

Cases of respiratory dysfunction due to phrenic nerve sacrifice during resection of massive mediastinal tumor have rarely been studied in detail. Diaphragmatic dysfunction in such cases can lead to potentially fatal respiratory and circulatory disturbances. Therefore, timely diagnosis and intervention are important. Conservative rehabilitation therapy is the first choice for respiratory dysfunction due to diaphragmatic dysfunction. We present 3 patients with respiratory dysfunction due to phrenic nerve sacrifice during resection of massive mediastinal tumor. The diagnostic methods and therapeutic procedures for diaphragmatic dysfunction for each patient are described in detail. This study highlights the role of ventilator support combined with physical therapy in the treatment of respiratory dysfunction in such cases. The diagnosis of diaphragmatic dysfunction as well as the risk assessment of phrenic nerve involvement are also discussed. The modalities of ventilator support, including modes and parameters, are listed. This study provides experiences of diagnosis and treatment of respiratory dysfunction due to phrenic nerve sacrifice during resection of massive mediastinal tumor. Timely diagnosis of diaphragmatic dysfunction primarily relies on clinical manifestations and radiography. Conservative rehabilitation therapy can improve or restore diaphragmatic function in majority of patients, and avert or delay the need for surgical intervention. Preoperative assessment of the risk of phrenic nerve involvement is important in such cases.

Ventilator-induced Diaphragmatic Dysfunction in Patients with Traumatic Brain Injury

Ventilator-induced Diaphragmatic Dysfunction in Patients with Traumatic Brain Injury

Ultrasound Assessment of Diaphragm Function in Traumatic Brain Injury: A Prospective Observational Study

Abstract Background Prolonged mechanical ventilation is associated with weaning failure in severe TBI patients. Ultrasound is a noninvasive modality for evaluating diaphragm function. On ultrasonography (USG), diaphragm thickness is observed to decrease over time in mechanically ventilated patients. However, little literature exists on the severity of diaphragmatic dysfunction in traumatic brain injury (TBI) patients. This study aimed to observe the changes occurring in diaphragmatic function in mechanically ventilated TBI patients. Methods TBI patients aged 18 to 65 years, requiring mechanical ventilation, were included. USG assessment of diaphragm function was done on days 0, 3, 5 and 7 of neurotrauma intensive care unit (NICU) admission in the supine position, during sedation holiday and spontaneous breathing trial. Measurements were done at end expiration (TE) and at maximal inspiration (TI) using 7- to 13-MHz linear array probe for three consecutive times and then averaged. Thickness fraction was calculated as (TI – TE/TE) × 100. Diaphragmatic excursion (DE) was measured in the M mode using 1- to 5-MHz phased array probe, as maximal height of inspiration. Results Forty patients were evaluated. The mean diaphragmatic thickness fraction (DTF) at days 0, 3, 5, and 7 was 33.58 ± 10.08, 33.4 ± 9.76, 32.32 ± 8.36, and 31.65 ± 8.23, respectively. Change in DTF was statistically significant on day 7 (p = 0.040). The mean DE at days 0, 3, 5, and 7 was 9.61 ± 3.99, 9.02 ± 3.46, 8.87 ± 2.63, 8.56 ± 2.74, respectively. Changes in DE over days 3, 5, and 7 were statistically significant (p < 0.001). The mean DTF was lower on day 3 in patients who were admitted for less than 20 days than those who required hospital admission for more than 20 days (p = 0.044). Conclusion Decrease in DTF and DE over the period of 7 days was observed with a significant decrease occurring on the 7th day following TBI.

Transcutaneous electrical diaphragmatic stimulation in mechanically ventilated patients: a randomised study

BackgroundFew specific methods are available to reduce the risk of diaphragmatic dysfunction for patients under mechanical ventilation. The number of studies involving transcutaneous electrical stimulation of the diaphragm (TEDS) is increasing but none report results for diaphragmatic measurements, and they lack power. We hypothesised that the use of TEDS would decrease diaphragmatic dysfunction and improve respiratory muscle strength in patients in ICU.MethodsWe conducted a controlled trial to assess the impact of daily active electrical stimulation versus sham stimulation on the prevention of diaphragm dysfunction during the weaning process from mechanical ventilation. The evaluation was based on ultrasound measurements of diaphragm thickening fraction during spontaneous breathing trials. We also measured maximal inspiratory muscle pressure (MIP), peak cough flow (PEF) and extubation failure.ResultsSixty-six patients were included and randomised using a 1:1 ratio. The mean number of days of mechanical ventilation was 10 ± 6.8. Diaphragm thickening fraction was > 30% at the SBT for 67% of participants in the TEDS group and 54% of the Sham group (OR1.55, 95% CI 0.47–5.1; p = 0.47). MIP and PEF were similar in the TEDS and Sham groups (respectively 35.5 ± 11.9 vs 29.7 ± 11.7 cmH20; p = 0.469 and 83.2 ± 39.5 vs. 75.3 ± 34.08 L/min; p = 0.83). Rate of extubation failure was not different between groups.ConclusionTEDS did not prevent diaphragm dysfunction or improve inspiratory muscle strength in mechanically ventilated patients.Trial registration: Prospectively registered on the 20th November 2019 on ClinicalTrials.gov Identifier NCT04171024.

Neuralgic amyotrophy: a common cause of unilateral and bilateral diaphragmatic pareses

There are several causes for unilateral or bilateral diaphragmatic paresis. The most common cause is an (intraoperative) injury to the phrenic nerve.However, in up to 20% of cases, no explanation can be found despite extensive workup. Neuralgic amyotrophy (NA, also known as Parsonage-Turner syndrome) is a common underdiagnosed multifocal autoimmune-inflammatory disease that predominantly affects proximal nerve segments of the upper extremities. Classic symptoms include acute onset of severe pain in the shoulder girdle with delayed onset of paresis of the shoulder and arm muscles. In at least 7% of cases, the phrenic nerve is also affected. Based on the annual incidence of NA of 1:1000, the entity as a cause of diaphragmatic dysfunction is probably not as uncommon as previously thought. However, clinical experience shows that this diagnosis is often not considered, and diaphragmatic paresis gets wrongly classified as idiopathic.This is particularly disastrous because in the early stage of NA, medical therapy with corticosteroids is mostly not considered and the possibility that surgical repair of the diaphragm may be performed prematurely, given that the condition may resolve spontaneously many months after symptom onset.The aim of the present article is to raise awareness of the entity of NA as a cause of diaphragmatic paresis and to establish a standardized approach to diagnosis and treatment.

Diaphragm Dysfunction and ICU-Acquired Weakness in Septic Shock Patients with or without Mechanical Ventilation: A Pilot Prospective Observational Study.

Sepsis is a risk factor for diaphragm dysfunction and ICU-acquired weakness (ICU-AW); however, the impact of mechanical ventilation (MV) on these relationships has not been thoroughly investigated. This study aimed to compare the incidence of diaphragm dysfunction and ICU-AW in patients with septic shock, with and without MV. We conducted a single-center prospective observational study that included consecutive patients diagnosed with septic shock admitted to the ICU between March 2021 and February 2022. Ultrasound measurements of diaphragm thickness and manual measurements of limb muscle strength were repeated after ICU admission. The incidences of diaphragm dysfunction and ICU-AW, as well as their associations with clinical outcomes, were compared between patients with MV and without MV (non-MV). Twenty-four patients (11 in the MV group and 13 in the non-MV group) were analyzed. At the final measurements in the MV group, eight patients (72.7%) had diaphragm dysfunction, and six patients (54.5%) had ICU-AW. In the non-MV group, 10 patients (76.9%) had diaphragm dysfunction, and three (23.1%) had ICU-AW. No association was found between diaphragm dysfunction and clinical outcomes. Patients with ICU-AW in the MV group had longer ICU and hospital stays. Among patients with septic shock, the incidence of diaphragm dysfunction was higher than that of ICU-AW, irrespective of the use of MV. Further studies are warranted to examine the association between diaphragm dysfunction and clinical outcomes.

Diaphragm dysfunction predicts weaning outcome after bilateral lung transplant.

Diaphragm dysfunction and its effects on outcomes of ventilator weaning have been evaluated in mixed critical care populations using diaphragm thickening fraction (TFdi; the ratio of the difference between ultrasound diaphragm thickness at end-inspiration and end-expiration to diaphragm thickness at end-expiration) or neuro-ventilatory efficiency (NVE; the ratio of tidal volume and peak electrical activity of the diaphragm). Such data are not available in bilateral-lung transplant recipients. We hypothesized that: i) diaphragm dysfunction, as defined by a TFdi<29%, is more likely to occur in difficult weaning; ii) TFdi and NVE predict weaning outcome; iii) and duration of mechanical ventilation before the first spontaneous breathing trial (SBT) is associated with diaphragm dysfunction. Adult bilateral-lung transplant patients admitted to our ICU were screened at the time of the first SBT (pressure-support of 5cmH2O and zero positive end-expiratory pressure). At the fifth minute, TFdi and NVE were measured over three respiratory cycles. Weaning was classified as simple, difficult or prolonged (successful extubation at the first SBT, within three or after three SBTs, respectively). Forty-four subjects were enrolled. Diaphragm dysfunction occurred in 14 subjects (32%); all of whom had difficult weaning (78% of the subgroup of 18 patients experiencing difficult weaning). Both TFdi (24[20-29] vs 39[35-45]%) and NVE (34[26-45] vs 55[43-62]ml/µV) were lower in difficult weaning (both p<0.001). The areas under the receiver operator curve predicting difficult weaning were 0.88 [95%CI 0.73-0.99] for TFdi, and 0.85 [95%CI 0.71-0.95] for NVE. Duration of ventilation demonstrated a linear inverse correlation with both TFdi and NVE. Diaphragm dysfunction is common following bilateral-lung transplantation and associated with difficult weaning. In such patients, average values for TFdi and NVE were reduced compared to patients with simple weaning. Both parameters showed similar accuracy for predicting success of ventilator weaning, demonstrating an inverse relationship with duration of ventilation.

Use of Ultrasound to Check Diaphragmatic Thickness to Assist in Weaning

Dysfunction of the respiratory muscles is now considered to be a serious complication of critical health issues. Diaphragm dysfunction has been associated to higher mortality and complications weaning with mechanical ventilation in patients getting invasive mechanical ventilation treating acute respiratory failure. Diaphragm dysfunction can occur in mechanically ventilated patients for a variety of factors, involving disuse atrophy with mechanical ventilation. Therefore, it is becoming increasingly essential for clinical and research priorities to measure and track diaphragm contractile activity, structural dimensions, as well as strength during mechanical ventilation. It is generally accepted that ultrasound may be used to visualize the diaphragm. The key indicators of diaphragm function have been developed over the past 15 years for mechanically ventilated patients to monitor changes in diaphragm size as well as function over time, to evaluate and diagnose diaphragmatic dysfunction, and to determine whether these indices can predict successfully exiting mechanical ventilation. These indices include diaphragm thickness, thickening fraction, as well as excursion. Keywords: Diaphragm, Diaphragm thickening fraction, Diaphragmatic excursion, Ultrasound, Weaning.

Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network.

Theophylline is an oral methylxanthine bronchodilator recommended as alternate therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, it is not generally recommended for the treatment of other respiratory disorders such as obstructive sleep apnea (OSA) or hypoxia. Most clinical practice guidelines rely on evidence published prior to the year 2000 to make these recommendations. This scoping review aimed to gather and characterize evidence describing theophylline for the management of respiratory disorders in adults between January 1, 2000 and December 31, 2020. Databases searched included Ovid MEDLINE, Embase, CINAHL Complete, Scopus, and International Pharmaceutical Abstracts. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Studies were included if they were published in English, theophylline was used for any respiratory disorder, and the study outcomes were disease- or patient-oriented. After removal of duplicates, 841 studies were screened and 55 studies were included. Results aligned with current clinical guideline recommendations relegating theophylline as an alternative therapy for the treatment of respiratory disorders, in favor of inhaled corticosteroids and inhaled bronchodilators. This scoping review identified the need for future research including: theophylline versus other medications deemed alternative therapies for asthma and COPD, meta-analyses of low-dose theophylline, and studies evaluating evidence-based patient-oriented outcomes for OSA, hypoxia, ventilator-induced diaphragmatic dysfunction, and spinal cord injury-related pulmonary function.

LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study.

LAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness. We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry. Twenty-seven patients with genetically confirmed LAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients. LAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed. This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

Asynchrony Injures Lung and Diaphragm in Acute Respiratory Distress Syndrome.

Patient-ventilator asynchrony is often observed during mechanical ventilation and is associated with higher mortality. We hypothesized that patient-ventilator asynchrony causes lung and diaphragm injury and dysfunction. Prospective randomized animal study. University research laboratory. Eighteen New Zealand White rabbits. Acute respiratory distress syndrome (ARDS) model was established by depleting surfactants. Each group (assist control, breath stacking, and reverse triggering) was simulated by phrenic nerve stimulation. The effects of each group on lung function, lung injury (wet-to-dry lung weight ratio, total protein, and interleukin-6 in bronchoalveolar lavage), diaphragm function (diaphragm force generation curve), and diaphragm injury (cross-sectional area of diaphragm muscle fibers, histology) were measured. Diaphragm RNA sequencing was performed using breath stacking and assist control (n = 2 each). Inspiratory effort generated by phrenic nerve stimulation was small and similar among groups (esophageal pressure swing ≈ -2.5 cm H2O). Breath stacking resulted in the largest tidal volume (>10 mL/kg) and highest inspiratory transpulmonary pressure, leading to worse oxygenation, worse lung compliance, and lung injury. Reverse triggering did not cause lung injury. No asynchrony events were observed in assist control, whereas eccentric contractions occurred in breath stacking and reverse triggering, but more frequently in breath stacking. Breath stacking and reverse triggering significantly reduced diaphragm force generation. Diaphragmatic histology revealed that the area fraction of abnormal muscle was ×2.5 higher in breath stacking (vs assist control) and ×2.1 higher in reverse triggering (vs assist control). Diaphragm RNA sequencing analysis revealed that genes associated with muscle differentiation and contraction were suppressed, whereas cytokine- and chemokine-mediated proinflammatory responses were activated in breath stacking versus assist control. Breath stacking caused lung and diaphragm injury, whereas reverse triggering caused diaphragm injury. Thus, careful monitoring and management of patient-ventilator asynchrony may be important to minimize lung and diaphragm injury from spontaneous breathing in ARDS.

Electrostimulation as a method of correction of respiratory disorders in patients with cervical spinal cord injury: A review

BACKGROUND:Patients with cervical spinal cord injury have the highest risk of developing respiratory dysfunction and associated complications such as pneumonia, atelectasis, and respiratory failure. Respiratory dysfunction is the leading cause of comorbid, somatic, and infectious pathology, and mortality following traumatic cervical spinal cord injuries. Mechanical ventilation of the lungs is the standard treatment for such patients; however, it is associated with atrophy and diaphragm dysfunction.&#x0D; AIM:To analyze literature data on the use of electrical stimulation techniques of the spinal cord, nerves, and muscles for the correction of respiratory disorders in patients with cervical spinal cord trauma.&#x0D; MATERIALS AND METHODS:This study presented the results of the search and analysis of peer-reviewed articles that examined the effects of various electrical stimulation techniques on respiratory function in patients with cervical spinal cord injury. ScienceDirect, Google Scholar, and PubMed were searched from 2000 to 2022.&#x0D; RESULTS:Currently, new treatment options are available for patients with tetraplegia, with reduced ventilatory function. Many studies have shown the positive effect of electrostimulation techniques on ventilatory function such as reduced time spent on mechanical ventilation and reduced incidence of infections and other lung complications.&#x0D; CONCLUSIONS:Electrical stimulation promotes neuromuscular plasticity and results in improved spontaneous activation of the diaphragm and respiratory muscles. Electrostimulation inacomprehensive rehabilitation program of patients with traumatic spinal cord injuries at the cervical level is currently employed to promote weaning from mechanical ventilation and prevent accompanying complications such as respiratory failure, pneumonia, and atelectasis. In addition to invasive electrical stimulation of the diaphragmatic nerve and/or spinal cord, existing less invasive electrostimulation techniques require further investigation in patients with spinal cord injury and respiratory dysfunction.

Eccentric Contractions of the Diaphragm During Mechanical Ventilation.

Diaphragm dysfunction is a highly prevalent phenomenon in patients receiving mechanical ventilation, mainly due to ventilatory over-assistance and the development of diaphragm disuse atrophy. Promoting diaphragm activation whenever possible and facilitating an adequate interaction between the patient and the ventilator is encouraged at the bedside to avoid myotrauma and further lung injury. Eccentric contractions of the diaphragm are defined as muscle activation while muscle fibers are lengthening within the exhalation phase. There is recent evidence that suggests that eccentric activation of the diaphragm is very frequent and may occur during post-inspiratory activity or under different types of patient-ventilator asynchronies, which include ineffective efforts, premature cycling, and reverse triggering. The consequences of this eccentric contraction of the diaphragm may have opposite effects, depending on the level of breathing effort. For instance, during high or excessive effort, eccentric contractions can result in diaphragm dysfunction and injured muscle fibers. Conversely, when eccentric contractions of the diaphragm occur along with low breathing effort, a preserved diaphragm function, better oxygenation, and more aerated lung tissue are observed. Despite this controversial evidence, evaluating the level of breathing effort at the bedside seems crucial and is highly recommended to optimize ventilatory therapy. The impact of eccentric contractions of the diaphragm on the patient's outcome remains to be elucidated.

Pulmonary recovery directly after COVID-19 and in Long-COVID

Permanent impairment in patients after SARS-CoV-2 infection is frequent, but neither pathophysiology nor mechanisms of the so-called Post-COVID-Syndrome (Long-COVID) are well understood. We present data on pulmonary impairment, pulmonary recovery and outcome comparing patients admitted to a specific COVID-19 rehabilitation program directly after COVID-19 infection with patients long after COVID-19 infection. Diagnostic work up included echocardiography, cardiopulmonary exercise testing and pleural sonography. The rehabilitation program included multimodal respiratory therapy, endurance and resistance muscular training, psychological assistance, and educational measures. Patients in both groups showed similar pulmonary problems. Diaphragm dysfunction was common in both groups. Cardiopulmonary exercise testing showed dysfunctional breathing in most patients of both groups. The specific rehabilitation program applied yielded marked improvements with satisfying pulmonary recovery in both groups. Return to work was possible or expected in most patients. In conclusion, directly after COVID-19 infection as well as in long Covid 4–20 months after COVID-19 dysfunctional breathing patterns in cardiopulmonary exercise testing and diaphragm dysfunction on ultrasound are common and need diagnostic awareness and therapy measures. Specialized rehabilitation programs directly after COVID-19 as well as for Long-COVID patients are effective therapeutic options.

Clinical utility of diaphragmatic ultrasonography for mechanical ventilator weaning in adults: A study protocol for systematic review and meta-analysis.

Mechanical ventilation is associated with several risks, including barotrauma, ventilator-associated pneumonia, and ventilator-induced diaphragmatic dysfunction. A delay in weaning from mechanical ventilation increases these risks, and prolonged weaning has been shown to increase hospital mortality. Various tools have been used in clinical practice to predict successful weaning from mechanical ventilation; however, they have a low prognostic accuracy. The use of ultrasonography in intensive care units is an area of growing interest since it is a noninvasive, convenient, and safe modality. Since ultrasonography can provide real-time assessment of diaphragmatic morphology and function, it may have clinical utility in predicting successful mechanical ventilator weaning. This study aimed to describe a protocol to assess the effectiveness of diaphragmatic ultrasonography in the decision-making process for ventilator weaning in terms of its impact on clinical outcomes. This systematic review of published analytical research will use an aggregative thematic approach according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocolsguidelines. We will perform a comprehensive search for studies on the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases. Two authors will independently perform abstract and full-text screening and data extraction. Additionally, a meta-analysis and the risk of bias evaluation will be conducted, as appropriate. Systematic reviews on the effectiveness of diaphragmatic ultrasonography in the decision-making process for ventilator weaning in terms of its impact on clinical outcomes are lacking. The results of this systematic review may serve as a basis for future clinical trials. Systematic review registration: This protocol was registered with the Open Science Framework: https://osf.io/cn8xf.

Effects of inspiratory muscle training on exertional breathlessness in patients with unilateral diaphragm dysfunction: a randomised trial.

Unilateral diaphragm dysfunction (UDD) is an underdiagnosed cause of dyspnoea. Inspiratory muscle training (IMT) is the only conservative treatment for UDD, but the mechanisms of improvement are unknown. We characterised the effects of IMT on dyspnoea, exercise tolerance and respiratory muscle function in people with UDD. 15 people with UDD (73% male, 61±8 years) were randomised to 6 months of IMT (50% maximal inspiratory mouth pressure (PI,max), n=10) or sham training (10% PI,max, n=5) (30 breaths twice per day). UDD was confirmed by phrenic nerve stimulation and persisted throughout the training period. Symptoms were assessed by the transitional dyspnoea index (TDI) and exercise tolerance by constant-load cycle tests performed pre- and post-training. Oesophageal (Pes) and gastric (Pga) pressures were measured with a dual-balloon catheter. Electromyography (EMG) and oxygenation (near-infrared spectroscopy) of respiratory muscles were assessed continuously during exercise. The IMT group (from 45±6 to 62±23% PI,max) and sham group (no progression) completed 92 and 86% of prescribed sessions, respectively. PI,max, TDI scores and cycle endurance time improved significantly more after IMT versus sham (mean between-group differences: 28 (95% CI 13-28) cmH2O, 3.0 (95% CI 0.9-5.1) points and 6.0 (95% CI 0.4-11.5) min, respectively). During exercise at iso-time, Pes, Pga and EMG of the scalene muscles were reduced and the oxygen saturation indices of the scalene and abdominal muscles were higher post- versus pre-training only in the IMT group (all p<0.05). The effects of IMT on dyspnoea and exercise tolerance in UDD were not mediated by an improvement in isolated diaphragm function, but may reflect improvements in strength, coordination and/or oxygenation of the extra-diaphragmatic respiratory muscles.

Single fibre cytoarchitecture in ventilator-induced diaphragm dysfunction (VIDD) assessed by quantitative morphometry second harmonic generation imaging: Positive effects of BGP-15 chaperone co-inducer and VBP-15 dissociative corticosteroid treatment.

Ventilator-induced diaphragm dysfunction (VIDD) is a common sequela of intensive care unit (ICU) treatment requiring mechanical ventilation (MV) and neuromuscular blockade (NMBA). It is characterised by diaphragm weakness, prolonged respirator weaning and adverse outcomes. Dissociative glucocorticoids (e.g., vamorolone, VBP-15) and chaperone co-inducers (e.g., BGP-15) previously showed positive effects in an ICU-rat model. In limb muscle critical illness myopathy, preferential myosin loss prevails, while myofibrillar protein post-translational modifications are more dominant in VIDD. It is not known whether the marked decline in specific force (force normalised to cross-sectional area) is a pure consequence of altered contractility signaling or whether diaphragm weakness also has a structural correlate through sterical remodeling of myofibrillar cytoarchitecture, how quickly it develops, and to which extent VBP-15 or BGP-15 may specifically recover myofibrillar geometry. To address these questions, we performed label-free multiphoton Second Harmonic Generation (SHG) imaging followed by quantitative morphometry in single diaphragm muscle fibres from healthy rats subjected to five or 10days of MV + NMBA to simulate ICU treatment without underlying confounding pathology (like sepsis). Rats received daily treatment of either Prednisolone, VBP-15, BGP-15 or none. Myosin-II SHG signal intensities, fibre diameters (FD) as well as the parameters of myofibrillar angular parallelism (cosine angle sum, CAS) and in-register of adjacent myofibrils (Vernier density, VD) were computed from SHG images. ICU treatment caused a decline in FD at day 10 as well as a significant decline in CAS and VD from day 5. Vamorolone effectively recovered FD at day 10, while BGP-15 was more effective at day 5. BGP-15 was more effective than VBP-15 in recovering CAS at day 10 although not to control levels. In-register VD levels were restored at day 10 by both compounds. Our study is the first to provide quantitative insights into VIDD-related myofibrillar remodeling unravelled by SHG imaging, suggesting that both VBP-15 and BGP-15 can effectively ameliorate the structure-related dysfunction in VIDD.

Imaging of the Diaphragm Following Cardiac Surgery: Focus on Ultrasonographic Assessment.

Diaphragm dysfunction is a common complication following cardiac surgery. Its clinical impact is variable, ranging from the absence of symptoms to the acute respiratory failure. Post-operative diaphragm dysfunction may negatively affect patients' prognosis delaying the weaning from the mechanical ventilation (MV), extending the time of hospitalization and increasing mortality. Ultrasonography is a valid tool to evaluate diaphragmatic impairment in different settings, like the Intensive Care Unit, to predict successful weaning from the MV, and the Cardiovascular Rehabilitation Unit, to stratify patients in terms of risk of functional recovery failure. The aim of this review is to describe the pathophysiology of post-cardiac surgery diaphragm dysfunction, the techniques used for its diagnosis and the potential applications of diaphragm ultrasound.

1686-P: ER Stress Aggravates Diaphragmatic Weakness through Activating PERK/JNK Signaling in Obesity Hypoventilation Syndrome

Obesity hypoventilation syndrome (OHS) is associated with reduced quality of life and increased risk of death. Diaphragmatic dysfunction has been implicated in the pathogenesis of OHS. We found that significant diaphragmatic weakness and lipid accumulation in people with obesity as well as mouse models of obesity, which was associated with activated endoplasmic reticulum (ER) stress indicated by increased PERK signaling and activation of JNK pathway. In cultured myotubes, inhibition of PERK and JNK signaling abrogated the lipids deposition and ameliorated insulin resistance, and inhibition of JNK signaling reversed the impaired elasticity of myotubes induced by lipotoxicity. Collectively, our data suggest that activation of PERK/JNK signaling is an important pathophysiological factor contributing to diaphragmatic contractile dysfunction in OHS. Disclosure X.Xiang: None. Y.Zhu: None. X.Pan: None. W.Xin: None. W.Tang: None. X.He: None. G.Shi: None. Y.Chen: None. Funding National Key R&amp;D Program of China (2017YFA0105803); National Natural Science Foundation of China (82270886, 82070811); 5010 Clinical Research Projects of Sun Yat-sen University (2015015); Science and Technology Plan Project of Guangzhou City (202007040003, 202201020497); Key Area R&amp;D Program of Guangdong Province (2019B020227003); Science and Technology Research Development Program of Guangzhou City (202007040003, 202201020497)