Diaphragmatic Research Articles

Reliability of digital filtering on surface electromyographic activity of respiratory muscles in patients with COVID-19

Introduction: Surface electromyography (sEMG) is valuable for assessing respiratory muscle activity, but the influence of electromagnetic fields can impair the accuracy of the signals. This study aims to compare the Root Mean Square (RMS) values of sEMG signals from respiratory muscles in COVID-19 patients receiving oxygen therapy in the ICU before and after digital filtering. Methods: This exploratory analysis is part of a cross-sectional study registered on ClinicalTrials.gov (NCT05572853). sEMG signals from the sternocleidomastoid, scalenus, diaphragm, and rectus abdominis muscles were recorded in COVID-19 patients receiving low-flow oxygen therapy. The RMS data were analyzed and processed using Scilab 6.1.1 software before and after applying a filter with a 60 Hz notch and a passband between 20-500 Hz. Results: 71 patients with a mean age of 55 ± 14 years, predominantly male (73.2%), were included. Muscle’s activity remained unchanged after signal filtering, showing higher RMS intensity (pre-filter/post-filter) for the scalene (14.0 ± 8.6 / 8.5 ± 6.2), sternocleidomastoid (12.0 ± 8.8 / 6.8 ± 7.8), diaphragm (11.7 ± 8.1 / 5.4 ± 7.1), and rectus abdominis (10.4 ± 4.7 / 3.1 ± 1.9) muscles. RMS attenuation was significant for all muscles (p < 0.001), with no agreement between pre- and post-filtering from Bland-Altman analysis. Conclusions: The applied digital filter attenuated RMS values while maintaining the same respiratory muscle activation, enhancing signal identification by reducing noise.

Functional and Structural Changes in Diaphragm Neuromuscular Junctions in Early Aging.

Age-related impairment of the diaphragm causes respiratory complications. Neuromuscular junction (NMJ) dysfunction can be one of the triggering events in diaphragm weaknesses in old age. Prominent structural and functional alterations in diaphragm NMJs were described in elderly rodents, but NMJ changes in middle age remain unclear. Here, we compared diaphragm muscles from young adult (3 months) and middle-aged (12 months) BALB/c mice. Microelectrode recordings, immunofluorescent staining, electron microscopy, myography, and whole-body plethysmography were used. We revealed presynaptic (i) and postsynaptic (ii) changes. The former (i) included an increase in both action potential propagation velocity and neurotransmitter release evoked by low-, moderate-, and high-frequency activity but a decrease in immunoexpression of synapsin 1 and synaptic vesicle clustering. The latter (ii) consisted of a decrease in currents via nicotinic acetylcholine receptors and the area of their distribution. These NMJ changes correlated with increased contractile responses to moderate- to high-frequency nerve activation. Additionally, we found alterations in the pattern of respiration (an increase in peak inspiratory flow and a tendency of elevation of the tidal volume), which imply increased diaphragm activity in middle-aged mice. We conclude that enhancement of neuromuscular communication (due to presynaptic mechanism) accompanied by improved contractile responses occurs in the diaphragm in early aging.

Characterization of Effect of Enterovirus D68 in 129/Sv Mice Deficient in IFN-α/β and/or IFN-γ Receptors.

Enterovirus D68 (EV-D68), a respiratory RNA virus in the family Picornaviridae, is implicated as a potential etiological agent for acute flaccid myelitis in preteen adolescents. The absence of a specific therapeutic intervention necessitates the development of an effective animal model for EV-D68. The AG129 mouse strain, characterized by the double knockout of IFN-α/β and IFN-γ receptors on the 129 genetic background, has been proposed as a suitable model for EV-D68. The goals of this study were to assess the effect of a nonmouse-adapted EV-D68 strain (US/MO/14-18947, NR-49129) in AG129 (IFN-α/β and IFN-γ receptors null), A129 (IFN-α/β receptor null), G129 (IFN-γ receptor null), and the 129 background strain (129S2/SvPasCrl) when infected intraperitoneally at 10 d of age. Both AG129 and A129 strains demonstrated similar clinical signs (paralysis, paresis, lethargy, dyspnea [characterized by prominent abdominal respiration], and morbidity requiring euthanasia) induced by EV-D68. While G129 and 129S2 strains also exhibited susceptibility to EV-D68, the severity of clinical signs was less than in AG129 and A129 strains, and many survived to the experimental endpoint. Histopathological and immunohistochemical data confirmed EV-D68 tropism for the skeletal muscle and spinal cord and suggest that the dyspnea observed in infected mice could be attributed, in part, to lesions in the diaphragmatic skeletal muscles. These findings contribute valuable insights into the pathogenesis of EV-D68 infection in this mouse model and provide investigators with key information on virus dose and mouse strain selection when using this mouse model to evaluate candidate EV-D68 therapeutics.

Deventilation syndrome in patients with chronic obstructive pulmonary disease using nocturnal non-invasive ventilation: what are the underlying mechanisms?

Introduction Patients with chronic obstructive pulmonary disease (COPD) commonly experience severe dyspnea after discontinuation of nocturnal non-invasive ventilation (NIV), known as deventilation syndrome (DVS), which negatively affects quality of life. Despite various hypotheses, the precise mechanisms of DVS remain unknown. Methods An observational pilot study was performed monitoring 16 stable COPD patients, before, during and after an afternoon nap on NIV. Seven patients experienced DVS (Borge dyspnea scale ≥ 5), while nine served as controls (Borg Dyspnea Scale ≤ 2). Hyperinflation was evaluated through inspiratory capacity (IC) measurements and end-expiratory lung impedance (EELI) via electrical impedance tomography. Respiratory muscle activity was assessed by diaphragmatic surface electromyography (sEMG). Results Post-NIV dyspnea scores were significantly higher in the DVS group (5[3-7] vs. 0[0-1.5], p<0.001). IC values were lower in the DVS group compared to controls, both pre- (54[41-63] vs. 88[72-94] %pred., p=0.006) and post-NIV (45[40-59] vs. 76[65-82] %pred., p=0.005), while no intergroup difference was seen in IC changes pre- and post-NIV. EELI values after NIV indicated a tendency towards lower values in controls and higher values in DVS patients. sEMG amplitudes were higher in the DVS group within the first 5 minutes post-NIV (221[112-294] vs. 100[58-177]% of baseline, p=0.030). Conclusion This study suggests that it is unlikely that DVS originates from the inability to create diaphragmatic muscle activity after NIV. Instead, NIV-induced hyperinflation in individuals with static hyperinflation may play a significant role. Addressing hyperinflation holds promise in preventing DVS symptoms in COPD patients.

Positioning in pelvic robotic surgery and its repercussions on patient safety

Objectives: To describe the positions used in robotic pelvic surgery, observe the impact of these positions on patient safety and evaluate precautions for the patient's surgical positioning during the intraoperative period. Methods: A Systematic Literature Review (RSL) was carried out over the last 5 years. Results: 184 articles were located, of which 13 were selected according to PRISMA recommendations. Result: It was found that the main type of positioning used in robotic surgeries of the pelvic region is the trendelenburg associated with the lithotomy position, in addition to the pneumopritoneus. The main complications are: bradycardia, thromboembolisms, increased ocular, intra-abdominal and intra-thoracic pressure, neuropraxia, compartment syndrome, increased ICP, facial edema, injuries to pressure points. Prevention measures include the use of special anti-skid padding and mattresses, buttock padding, adequate positioning of the limbs. The use of fastening straps is recommended to avoid the risk of slips and falls and repositioning to the supine position for 10 minutes every 3 hours.

Understanding Secondary Sarcopenia Development in Young Adults Using Pig Model with Chronic Pancreatitis.

Chronic pancreatitis (CP) in young individuals may lead to disease-related secondary sarcopenia (SSARC), characterized by muscle loss and systemic inflammation. In this study, CP was induced in young pigs, and serum levels of key hormones, muscle fiber diameters in various muscles, and the mRNA expression of genes related to oxidative stress and programmed cell death were assessed. A decrease in muscle fiber diameters was observed in SSARC pigs, particularly in the longissimus and diaphragm muscles. Hormonal analysis revealed alterations in dehydroepiandrosterone, testosterone, oxytocin, myostatin, and cortisol levels, indicating a distinct hormonal response in SSARC pigs compared to controls. Oxytocin levels in SSARC pigs were significantly lower and myostatin levels higher. Additionally, changes in the expression of catalase (CAT), caspase 8 (CASP8), B-cell lymphoma 2 (BCL2), and BCL2-associated X protein (BAX) mRNA suggested a downregulation of oxidative stress response and apoptosis regulation. A reduced BAX/BCL2 ratio in SSARC pigs implied potential caspase-independent cell death pathways. The findings highlight the complex interplay between hormonal changes and muscle degradation in SSARC, underscoring the need for further research into the apoptotic and inflammatory pathways involved in muscle changes due to chronic organ inflammation in young individuals.

Arrhythmia in sleep apnea

Sleep apnea is awidespread and yet still underdiagnosed condition. Various studies from the past have provided evidence that there is alink between sleep apnea and various cardiovascular diseases, including arrhythmias. The aim of this article is to provide an overview of the current study situation and to point out possible consequences relevant to everyday life. Asystematic search was carried out in various databases using the keywords sleep apnea (OSAS/SA) and arrhythmias/dysrhythmias. There are several pathophysiological links between sleep-related breathing disorders and cardiac arrhythmias, the most important of which appear to be intrathoracic pressure, increased adrenergic tone as well as recurrent hypoxia and hypercapnia. This results in an increased occurrence of clinically relevant arrhythmias, such as atrial fibrillation, symptomatic bradycardia, high-grade atrioventricular (AV) blocks as well as ventricular arrhythmias in patients with untreated sleep apnea. These pathologies also appear to be positively influenced by the treatment of sleep apnea. Aclose correlation between sleep apnea and cardiac arrhythmias is undisputed. Large randomized studies in this respect are so far rare but it is undisputed that a thorough search should be carried out for sleep apnea and consistently treated in patients with ahistory of cardiac disease as this can have arelevant influence on the treatment and ultimately the prognosis of the patient.

Physiological analyses of swallowing changes due to chronic obstructive pulmonary disease in anesthetized male rats.

Chronic obstructive pulmonary disease (COPD) was previously known as chronic bronchitis and emphysema. It has various main symptoms, such as dyspnea, chronic cough, and sputum, and is often accompanied by dysphagia. Although many published clinical reports have described COPD-related dysphagia, the physiological mechanisms underlying swallowing changes due to COPD remain unclear. Therefore, we analyzed how COPD affects the swallowing reflex using COPD model rats. We performed an electrophysiological study of respiration and swallowing using COPD model induced by intratracheal administration of porcine pancreatic elastase and lipopolysaccharide in Sprague-Dawley male rats. To identify the respiration and swallowing responses, electromyographic activity was recorded from the diaphragm, digastric (Dig), and thyrohyoid (TH) muscles. We confirmed COPD using micro-computed tomography analysis and hematoxylin and eosin staining of the lungs. The duty cycle was defined as the ratio of the inspiration duration to the total respiratory duration. In COPD model rats, the duty cycle was significantly higher than that in control rats. The frequency of the swallowing reflex evoked by electrical stimulation of the superior laryngeal nerve during the inspiration phase was higher in COPD model rats than in control rats. Furthermore, long-term COPD altered Dig and TH muscle activity without pathological muscle change. Our results suggest that COPD increases the frequency of swallowing initiation during the inspiration phase. Furthermore, long-term COPD affects swallowing-related muscle activity without pathological muscle changes. These physiological changes may increase the risk of developing dysphagia. Further studies are necessary to clarify the mechanisms contributing to the functional changes in respiration and swallowing in COPD.

Functional involvement of the sternohyoid muscle during breathing and swallowing in rats.

The sternohyoid muscle depresses the hyoid bone, but it is unclear whether the muscle contributes to respiratory and swallowing mechanisms. This study aimed to clarify whether the sternohyoid muscle participates in the respiration and swallowing reflex and how the activity is modulated in two conditions: with airway stenosis and with a fixed sternohyoid muscle length. Electromyographic activity in the sternohyoid, digastric, thyrohyoid, and diaphragm muscles was recorded in anesthetized rats. The sternohyoid muscle activity was observed in the inspiratory phase and during swallowing, and was well coordinated with digastric and thyrohyoid muscle activity. With airway stenosis, the respiratory activity per respiratory cycle was facilitated in all assessed muscles but the facilitation of activity per second occurred only in the digastric, thyrohyoid, and sternohyoid muscles. With airway stenosis, the swallowing activity was facilitated only in the digastric muscle but not in the thyrohyoid and sternohyoid muscles. Swallowing activity was not observed in the sternohyoid muscle in the condition with the sternohyoid muscle length fixed, although increased inspiratory activity remained. The current results suggest that 1) the sternohyoid muscle is slightly activated in the inspiratory phase, 2) the effect of airway stenosis on respiratory function may differ between the upper airway muscles and diaphragm, and 3) swallowing activity in the sternohyoid muscle is not dominantly controlled by the swallowing central pattern generator but instead occurs as a myotatic reflex.NEW & NOTEWORTHY We found that the sternohyoid muscle was activated in the inspiratory phase. However, increased airway resistance had different effects on the extrathoracic muscles than on the diaphragm. The swallowing activity of the sternohyoid disappeared when the muscle length was fixed. These findings suggest that the sternohyoid muscle may be activated not by the swallowing central pattern generator but as a myotatic reflex.

Diaphragmatic muscle dysfunction associated with artificial mechanical ventilation: a narrative review of the literature

Mechanical ventilation is a respiratory support therapy that can cause diaphragm muscle injury and induce dysfunction, which is associated with prolonged ventilation, weaning failure and mortality. Protecting the diaphragm during ventilation requires the use of tools to monitor diaphragmatic effort. The aim of this review was to address current and relevant elements about the pathophysiology of diaphragmatic function in ventilated patients. For this purpose, a narrative review of the literature available in Google Scholar, Pumed/Medline, regional SciELO, and academic Google was carried out under the terms: diaphragmatic function-diaphragmatic function in ventilated patients/diaphragmatic ultrasound in ventilated patients pathophysiology/ diaphragmatic function and others. Fundamental theoretical contents on the clinic of diaphragmatic muscle dysfunction, its relationship with artificial ventilation and related structures, such as the lung, are addressed. It is concluded that the diaphragm represents the main muscle involved in respiration and diaphragmatic muscle dysfunction represents a frequent complication in critically ill patients. Diaphragmatic ultrasound is a tool that aids decision making on artificial ventilation, potentially reduces the duration of respiratory support and associated complications

Multi-modal evaluation of respiratory diaphragm motion in chronic obstructive pulmonary disease using MRI series and CT images.

Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation and breathing difficulty, is usually caused by prolonged inhalation of toxic substances or long-term smoking habits. Some abnormal features of COPD can be observed using medical imaging methods, such as magnetic resonance imaging (MRI) and computed tomography (CT). This study aimed to conduct a multi-modal analysis of COPD, focusing on assessing respiratory diaphragm motion using MRI series in conjunction with low attenuation volume (LAV) data derived from CT images. This study utilized MRI series from 10 normal subjects and 24 COPD patients, along with thoracic CT images from the same patients. Diaphragm profiles in the sagittal thoracic MRI series were extracted using field segmentation, and diaphragm motion trajectories were generated from estimated diaphragm displacements via registration. Re-sliced sagittal CT images were used to calculate regional LAVs for four distinct lung regions. The similarities among diaphragm motion trajectories at various positions were assessed, and their correlations with regional LAVs were analyzed. Compared with the normal subjects, patients with COPD typically exhibited fewer similarities in diaphragm motion, as indicated by the mean normalized correlation coefficient of the vertical motion component (0.96 for normal subjects vs. 0.76 for severity COPD patients). This reduction was significantly correlated with the LAV% in the two lower lung regions with a regression coefficient of 0.81. Our proposed evaluation method may assist in the diagnosis and therapy planning for patients with COPD.

SCG variability and spectral energy distribution during normal breathing and breath hold at different lung volumes and airway pressures

Seismocardiographic (SCG) signals are chest wall vibrations induced by cardiac activity and are potentially useful for cardiac monitoring and diagnosis. SCG waveform is observed to vary with respiration, but the mechanism of these changes is poorly understood as alterations in autonomic tone, lung volume, heart location and intrathoracic pressure are all varying during the respiratory cycle. Understanding SCG variability and its sources may help reduce variability and increase SCG clinical utility. This study investigated SCG variability during breath holding (BH) at two different lung volumes (i.e., end inspiration and end expiration) and five airway pressures (i.e., 0, ± 2–4, and ± 15–20 cm H2O). Variability during normal breathing was also studied with and without grouping SCG beats into two clusters of similar waveform morphologies (performed using the K-medoid algorithm in an unsupervised machine learning fashion). The study included 15 healthy subjects (11 Females and 4 males, Age: 21 ± 2 y) where SCG, ECG, and spirometry were simultaneously acquired. SCG waveform variability was calculated at each experimental state (i.e., lung volume and airway pressure). Results showed that breath holding was more effective in reducing the intra-state variability of SCG than clustering normal breathing data. For the BH states, the intra-state variability increased as the airway pressure deviated from zero. The subaudible-to-audible energy ratio of the BH states increased as the airway pressure decreased below zero which may be related to the effect of the intrathoracic pressure on cardiac afterload and blood ejection. When combining the BH waveforms at end inspiration and end expiration states (at the same airway pressures) into one group, the intra-state variability increased, which suggests that the lung volume and associated change in heart location were a significant source of variability. The linear trend between airway pressure and waveform changes was found to be statistically significant for BH at end expiration. To confirm these findings, more studies are needed with a larger number of airway pressure levels and larger number of subjects.

A prospective crossover study comparing six current generation supraglottic airway device's ability to seal during CPR in human cadavers.

BackgroundSupraglottic Airway (SGA) devices are frequently used during CPR, but little is known about their ability to consistently seal the airway during CPR. Aim of StudyThe objective of this prospective crossover human cadaver study was a comparison of intrathoracic pressures generated during automated CPR (aCPR) with an ITD (Impedance Threshold Device, Zoll™) with six currently available SGAs to a standard endotracheal tube (ETT). The hypothesis was that current SGAs would vary in their ability to develop intrathoracic pressures compared to the ETT. MethodsAirway pressures (AP) and negative intrathoracic pressures (ITP) were measured in six recently deceased human cadavers of varying body habitus. After placement of an ETT and six different SGAs, we assessed airway and intrathoracic pressures during automated CPR and manual positive pressure ventilation using bag valve mask (BVM). The ETT served as the control for airway seal and was placed first followed by each SGA. Primary outcome compared airway and ITP between all groups. ResultsSGAs varied in their ability to create negative airway pressure and negative ITP. ConclusionIn this human cadaver model, the ability to generate negative ITP varied with different SGAs during aCPR with an ITD.

Airway mechanics alters generation of cough motor pattern.

Effects of sequential increase in airway resistance: no, low (5 kPa.s/l), high (24 kPa.s/l), and complete block in the inspiratory or expiratory phase of mechanically induced cough on the cough motor pattern were studied in 16 anesthetized (pentobarbital) spontaneously breathing cats (3.70±0.15 kg, 11♂, 5♀). Esophageal pressure and electromyographic activities of the diaphragm during inspiration and abdominal muscles during expiration were analyzed. No significant changes in the number of coughs occurred. Inspiratory occlusion caused a prolongation of cough inspiratory phase, cough inspiratory diaphragm activity, and all cough-related activity. Inspiratory occlusion along with high resistance increased inspiratory esophageal pressure amplitude, total cough cycle duration and the time between maximum activity of the diaphragm and abdominal muscles. High expiratory resistance and occlusion resulted in increased cough expiratory esophageal pressure amplitude, a longer active portion of cough expiration, and cough abdominal activity. Expiratory occlusion also prolonged cough expiratory phase, all cough activity, and total cough cycle. Significantly increased airway resistance and occlusion induce secondary, in addition to mechanical, changes in cough by significantly modulating the generated cough motor pattern. A certain level of resistance appears to be successfully compensated, resulting in minimal changes in coughing characteristics, including expiratory airflow and the rising time of the airflow. Afferent feedback from the respiratory tract, particularly volume feedback, represents a significant factor in modulating cough, mainly under various pathological conditions in the respiratory system.

Optimizing Positive End-Expiratory Pressure Based on Intra-Abdominal Pressure in Patients with Acute Respiratory Failure.

Positive end-expiratory pressure (PEEP) is a crucial component of mechanical ventilation to improve oxygenation in critically ill patients with respiratory failure. The interaction between abdominal and thoracic compartment pressures is known well. Especially in intra-abdominal hypertension, lower PEEP may cause atelectotrauma by repetitive opening and closing of alveoli. In this study, it was aimed to investigate the effect of PEEP adjustment according to the intra-abdominal pressure (IAP) on oxygenation and clarify possible harms. Patients older than 18 were mechanically ventilated due to hypoxemic respiratory failure and had normal IAP (<15 mmHg) included in the study. Patients with severe cardiovascular dysfunction were excluded. The following PEEP levels were applied: PEEPzero of 0 cmH2O, PEEPIAP/2 = 50% of IAP, and PEEPIAP = 100% of IAP. After a 30-minute equilibration period, arterial blood gases and mean arterial pressures were measured. One hundred thirty-eight patients (mean age 66.5 ± 15.9, 56.5% male) enrolled on the study. The mean IAP was 9.8 ± 3.4. Seventy-nine percent of the patients' PaO2/FiO2 ratio was under 300 mmHg. Figure 1 shows the change in PaO2/FiO2 ratio, PaCO2, PPlato, and MAP of the patients according to the PEEP levels. Overall increases were detected in the PaO2/FiO2 ratio (P < 0.001) and Pplato (P < 0.001), while PaCO2 and MAP did not change after increasing PEEP gradually. Pairwise analyses revealed differences in PaO2/FiO2 between PEEPzero (186.4 [85.7-265.8]) and PEEPIAP/2 (207.7 [101.7-292.9]) (t = -0.77, P < 0.001), between baseline and PEEPIAP (236.1 [121.4-351.0]) (t = -1.7, P < 0.001), and between PEEPIAP/2 and PEEPIAP (t = -1.0, P < 0.001). Plato pressures were in the safe range (<30 cmH2O) at all three PEEP levels (PEEPzero = 12 [10-15], PEEPIAP/2 = 15 [13-18], PEEPIAP = 17 [14-22]). In patients with acute hypoxemic respiratory failure and mechanically ventilated, PEEP adjustment according to the IAB improves oxygenation, especially in the settings of the limited source where other PEEP titration methods are absent.

Application of the Valsalva maneuver in medicine and sport

The Valsalva maneuver, named after Antonio Maria Valsalva, is one of the vagal maneuvers. It is defined as a forced expiration against a closed glottis, leading to an increase in intrathoracic and intra-abdominal pressure. Over the years it has become a subject of interest to many clinical researchers who have comprehensively studied its physiology and clinical significance. As a result, the application of the Valsalva maneuver has expanded to become a versatile technique applied across a wide range of medical specialties as a diagnostic and therapeutic tool. Additionally, it has found its use in sport among athletes. The aim of this article is to present the current state of knowledge about the clinical significance of the Valsalva maneuver and show that this simple physiological technique described in the 18th century remains a valuable tool in modern clinical practice and has found its use in sport. The review was based on chosen literature obtained from the PubMed electronic database, Google Scholar electronic database, and other scientific articles. Search terms included keywords listed below. Keywords: Valsalva maneuver; vagal maneuver; respiratory maneuver; autonomic system

Design and optimisation of soft robotic actuators for augmented lung-ventilation

Pulmonary rehabilitation through invasive ventilation involves the insertion of an endotracheal tube into the trachea of a sedated patient to control breathing via a ventilating machine. Invasive ventilation offers benefits such as greater control over oxygen supply, higher efficiency in supporting patient respiration, and the ability to manage airway secretions. However, this method also poses treatment challenges like ventilator-induced pneumonia, airway injury, long recovery times, and ventilator dependence. Here, we explore an alternative invasive ventilation technique using soft robotic actuators to mimic the biological function of the diaphragm for augmenting and assisting ventilation. We investigated two actuator geometries, each at two locations superior to the diaphragm. These actuators were tested on a bespoke ex vivo testbed that accurately simulated key diaphragmatic characteristics throughout the respiratory cycle. From this, we have been able to drive intrathoracic pressures greater than the 5 cmH2O required for ventilation in a human male. Additionally, by optimising the placement and geometry of these soft robotic actuators we have been able to generate maximum intrathoracic pressures of (6.81 ± 0.39) cmH2O.

Diaphragmatic Myopathy Associated with Dual Immune Checkpoint Inhibitors in a Patient with Renal Cell Carcinoma

ABSTRACT Immune-related adverse events (irAEs) have become increasingly prevalent with immune checkpoint inhibitor (ICI) cancer treatment. We present a 79-year-old man with metastatic renal cell carcinoma who developed shortness of breath and hypercapnic respiratory insufficiency after his first cycle of nivolumab and ipilimumab. Laboratory data showed elevated creatinine kinase, troponins, and transaminases. Computed tomography of the chest demonstrated bilateral lower lobe atelectasis. Heart catheterization and endomyocardial biopsy were unremarkable. Electromyogram (EMG) and nerve conduction studies (NCS) of the limb muscles revealed mild diffuse myopathy, normal sensory nerve conductions, and low-amplitude motor responses. Subsequent diaphragmatic EMG and NCS demonstrated severe myopathy. ICI-mediated myopathy predominantly affecting diaphragmatic muscles was diagnosed. Treatment included intravenous methylprednisolone, infliximab, abatacept, rituximab, and plasmapheresis. He underwent tracheostomy placement on hospital day 11 due to minimal improvement. He was discharged to a long-term acute care hospital, but unfortunately, he died less than 1 month later due to recurrent infections. irAEs can affect any organ system, but diaphragmatic dysfunction is uncommon. Use of diaphragmatic EMG, NCS, ultrasound study, or biopsy can support the diagnosis. Treatment includes systemic steroids, plasmapheresis, immunosuppressive medications, respiratory support, and cessation of causative medications. ICI-related diaphragmatic dysfunction should be suspected in those patients at risk with hypoxia, hypercapnia, or prolonged invasive or noninvasive ventilation without a distinct etiology. This case report exemplifies the importance of multidisciplinary workup and management of respiratory symptoms and insufficiency to identify and ameliorate irAEs. Diaphragmatic involvement can be associated with significant morbidity and mortality despite early aggressive multimodal therapy.

Effect of lung volume preservation during spontaneous breathing trial on successful extubation in patients receiving mechanical ventilation: protocol for a multicenter clinical trial

BackgroundIn standard weaning from mechanical ventilation, a successful spontaneous breathing test (SBT) consisting of 30 min 8 cmH2O pressure-support ventilation (PSV8) without positive end-expiratory pressure (PEEP) is followed by extubation with continuous suctioning; however, these practices might promote derecruitment. Evidence supports the feasibility and safety of extubation without suctioning. Ultrasound can assess lung aeration and respiratory muscles. We hypothesize that weaning aiming to preserve lung volume can yield higher rates of successful extubation.MethodsThis multicenter superiority trial will randomly assign eligible patients to receive either standard weaning [SBT: 30-min PSV8 without PEEP followed by extubation with continuous suctioning] or lung-volume-preservation weaning [SBT: 30-min PSV8 + 5 cmH2O PEEP followed by extubation with positive pressure without suctioning]. We will compare the rates of successful extubation and reintubation, ICU and hospital stays, and ultrasound measurements of the volume of aerated lung (modified lung ultrasound score), diaphragm and intercostal muscle thickness, and thickening fraction before and after successful or failed SBT. Patients will be followed for 90 days after randomization.DiscussionWe aim to recruit a large sample of representative patients (N = 1600). Our study cannot elucidate the specific effects of PEEP during SBT and of positive pressure during extubation; the results will show the joint effects derived from the synergy of these two factors. Although universal ultrasound monitoring of lungs, diaphragm, and intercostal muscles throughout weaning is unfeasible, if derecruitment is a major cause of weaning failure, ultrasound may help clinicians decide about extubation in high-risk and borderline patients.Trial registrationThe Research Ethics Committee (CEIm) of the Fundació Unió Catalana d’Hospitals approved the study (CEI 22/67 and 23/26). Registered at ClinicalTrials.gov in August 2023. Identifier: NCT05526053.

Adenine base editing-mediated exon skipping restores dystrophin in humanized Duchenne mouse model

Duchenne muscular dystrophy (DMD) affecting 1 in 3500–5000 live male newborns is the frequently fatal genetic disease resulted from various mutations in DMD gene encoding dystrophin protein. About 70% of DMD-causing mutations are exon deletion leading to frameshift of open reading frame and dystrophin deficiency. To facilitate translating human DMD-targeting CRISPR therapeutics into patients, we herein establish a genetically humanized mouse model of DMD by replacing exon 50 and 51 of mouse Dmd gene with human exon 50 sequence. This humanized mouse model recapitulats patient’s DMD phenotypes of dystrophin deficiency and muscle dysfunction. Furthermore, we target splicing sites in human exon 50 with adenine base editor to induce exon skipping and robustly restored dystrophin expression in heart, tibialis anterior and diaphragm muscles. Importantly, systemic delivery of base editor via adeno-associated virus in the humanized male mouse model improves the muscle function of DMD mice to the similar level of wildtype ones, indicating the therapeutic efficacy of base editing strategy in treating most of DMD types with exon deletion or point mutations via exon-skipping induction.