Diaphragmatic Dysfunction Research Articles

The Relationship of Diaphragmatic Ultrasound-Based and Manometric Indices With Difficult Weaning in Tracheostomized Patients.

Patients with a tracheostomy and difficult weaning from invasive mechanical ventilation constitute a challenging problem in critical care. An increased duration of ventilation may lead to diaphragmatic dysfunction and a noninvasive assessment of the diaphragm, such as ultrasound, attracts interest in the clinical practice. We evaluated the relationship of ultrasound-derived indices with weaning outcome and with established indices of respiratory strength and load in subjects who are tracheostomized and undergoing weaning. This prospective study was conducted at an academic ICU in Greece. Twenty subjects with tracheostomy and difficult weaning, during a spontaneous breathing trial, underwent time synchronous diaphragmatic sonography and esophageal manometry, to assess diaphragmatic excursion and thickening fraction, esophageal and transdiaphragmatic pressures, pressure-time product of the esophageal pressure, and maximum inspiratory pressure. The primary outcome was liberation from mechanical ventilation at 48 h. The relationship of diaphragmatic ultrasound with esophageal pressure-derived indices was also evaluated. Weaning from invasive ventilation failed in 10 subjects. Diaphragmatic excursion exhibited a significant difference between weaning success and failure (1.34 ± 0.56 versus 0.79 ± 0.44; P = .044), a strong correlation with transdiaphragmatic pressure (r = 0.7, P = .02), and a moderate correlation with the pressure-time product of the esophageal pressure (r = 0.65, P = .02) and the maximum inspiratory pressure (r = 0.66, P = .02). Transdiaphragmatic pressure presented the highest area under the curve (0.97). However, when transdiaphragmatic pressure was compared with diaphragmatic excursion (area under the curve, 0.84) for predictive accuracy, no significant difference was found. Diaphragmatic excursion is a valuable tool for the assessment of diaphragmatic strength, respiratory load, and weaning prediction.

Diaphragm dysfunction is found in patients with chronic painful temporomandibular disorder: A case-control study

AimTo determine whether patients with chronic painful temporomandibular disorder (TMD) had abnormal diaphragm function compared to healthy controls and to explore the correlation between diaphragm contractility, psychological status, and pain characteristics. MethodsA single-blinded, case-control study was conducted involving 23 chronic painful TMD patients and 22 healthy volunteers. The examination and diagnosis were performed according to the Diagnostic Criteria for Temporomandibular Disorders, and questionnaires were used to evaluate pain, depression, anxiety, and physical symptoms status. B-mode ultrasound was used to measure diaphragm thickness and contractility. The sonographer responsible for measuring the diaphragm was blinded to group membership. Results1. Depression, anxiety, and physical symptoms scores were significantly higher in the patients than in the controls (p < 0.05). 2. The Interference Score of pain was significantly correlated with depression and physical symptoms (p < 0.01). 3. Bilateral diaphragm contractility was significantly smaller in the patients than in the controls (right: P = 0.003; left: P = 0.001). 3. There was no correlation between diaphragm contractility on the left and right sides in the patients (r = −0.112, P = 0.611), while there was a positive correlation in the control group (r = 0.638, P = 0.001). 4. No correlation was found between the degree of diaphragm contractility, psychological status, and pain scores. Conclusions1. Patients with chronic painful TMD have worse psychological status, including depression, anxiety, and physical symptoms. 2. Patients with chronic painful TMD have a smaller degree of bilateral diaphragm contractility and more significant left-right incongruity, which indicated that diaphragm dysfunction may be correlated with chronic painful temporomandibular disorder.

Dynamic changes of diaphragm and limb skeletal muscle in patients with sepsis assessed by bedside ultrasound and their correlation with blood urea/creatinine ratio

To investigate the dynamic changes of diaphragm and limb skeletal muscle in patients with sepsis by bedside ultrasound and their correlation with the ratio of blood urea/creatinine ratio (UCR) in 7 days after intensive care unit (ICU) admission. A prospective observational study was conducted. A total of 55 patients with sepsis admitted to ICU of General Hospital of Ningxia Medical University from June 2022 to February 2023 were selected as the research objects. General information, laboratory indicators [urea, serum creatinine (SCr), and UCR] on days 1, 4, and 7 of ICU admission, and prognostic indicators were observed. Bedside ultrasound was used to assess the dynamic changes of diaphragm morphology [including diaphragmatic excursion (DE), end-inspiratory diaphragm thickness (DTei), and end-expiratory diaphragm thickness (DTee)] on days 1, 4, and 7 of ICU admission, as well as limb skeletal muscle (quadriceps femoris) morphology [including rectus femoris-muscle layer thickness (RF-MLT), vastus intermedius-muscle layer thickness (VI-MLT), and rectus femoris-cross sectional area (RF-CSA)]. Diaphragm thickening fraction (DTF) and RF-CSA atrophy rate were calculated, and the incidence of diaphragm and limb skeletal muscle dysfunction was recorded. The correlation between ultrasound morphological parameters of diaphragm and quadriceps and UCR at each time points in 7 days after ICU admission was analyzed by Pearson correlation. A total of 55 patients with sepsis were included, of which 29 were in septic shock. As the duration of ICU admission increased, the incidence of diaphragm dysfunction in patients with sepsis increased first and then decreased (63.6%, 69.6%, and 58.6% on days 1, 4, and 7 of ICU admission, respectively), while the incidence of limb skeletal muscle dysfunction showed an increasing trend (54.3% and 62.1% on days 4 and 7 of ICU admission, respectively), with a probability of simultaneous occurrence on days 4 and 7 of ICU admission were 32.6% and 34.5%, respectively. The UCR on day 7 of ICU admission was significantly higher than that on day 1 [121.77 (95.46, 164.55) vs. 97.00 (70.26, 130.50)], and RF-CSA atrophy rate on day 7 was significantly higher than that on day 4 [%: -39.7 (-52.4, -22.1) vs. -26.5 (-40.2, -16.4)]. RF-CSA was significantly lower on day 7 compared to day 1 [cm2: 1.3 (1.0, 2.5) vs. 2.1 (1.7, 2.9)], with all differences being statistically significant (all P < 0.05). Pearson correlation analysis showed that RF-CSA on day 7 of ICU admission was negatively associated with the UCR on the same day (r = -0.407, P = 0.029). Diaphragmatic dysfunction in patients with sepsis occurred early and can be improved. Limb skeletal muscle dysfunction occurred relatively later and progresses progressively. The RF-CSA on day 7 of ICU admission may be a reliable measure of limb skeletal muscle dysfunction in patients with sepsis, can be an indicator of early identification and diagnosis of ICU-acquired weakness (ICU-AW). Continuous loss of muscle mass occurring in septic patients is mainly associated with persistent organismal catabolism, and undergoes significant changes around a week in ICU.

Diaphragm Ultrasound in Different Clinical Scenarios: A Review with a Focus on Older Patients.

Diaphragm muscle dysfunction is increasingly recognized as a fundamental marker of several age-related diseases and conditions including chronic obstructive pulmonary disease, heart failure and critical illness with respiratory failure. In older individuals with physical frailty and sarcopenia, the loss of muscle mass and function may also involve the diaphragm, contributing to respiratory dysfunction. Ultrasound has recently emerged as a feasible and reliable strategy to visualize diaphragm structure and function. In particular, it can help to predict the timing of extubation in patients undergoing mechanical ventilation in intensive care units (ICUs). Ultrasonographic evaluation of diaphragmatic function is relatively cheap, safe and quick and can provide useful information for real-time monitoring of respiratory function. In this review, we aim to present the current state of scientific evidence on the usefulness of ultrasound in the assessment of diaphragm dysfunction in different clinical settings, with a particular focus on older patients. We highlight the importance of the qualitative information gathered by ultrasound to assess the integrity, excursion, thickness and thickening of the diaphragm. The implementation of bedside diaphragm ultrasound could be useful for improving the quality and appropriateness of care, especially in older subjects with sarcopenia who experience acute respiratory failure, not only in the ICU setting.

Identification of key genes affecting ventilator-induced diaphragmatic dysfunction in diabetic mice.

Mechanical ventilation (MV) is often required in critically ill patients. However, prolonged mechanical ventilation can lead to Ventilator-induced diaphragmatic dysfunction (VIDD), resulting in difficulty in extubation after tracheal intubation, prolonged ICU stay, and increased mortality. At present, the incidence of diabetes is high in the world, and the prognosis of diabetic patients with mechanical ventilation is generally poor. Therefore, the role of diabetes in the development of VIDD needs to be discovered. MV modeling was performed on C57 mice and DB mice, and the control group was set up in each group. After 12h of mechanical ventilation, the muscle strength of the diaphragm was measured, and the muscle fiber immunofluorescence staining was used to verify the successful establishment of the MV model. RNA sequencing (RNA-seq) method was used to detect mRNA expression levels of the diaphragms of each group, and then differential expressed gene analysis, Heatmap analysis, WGCNA analysis, Venn analysis, GO and KEGG enrichment analysis were performed. qRT-PCR was used to verify the expression of the selected mRNAs. Our results showed that, compared with C57 control mice, the muscle strength and muscle fiber cross-sectional area of mice after mechanical ventilation decreased, and DB mice showed more obvious in this respect. RNA-seq showed that these differential expressed (DE) mRNAs were mainly related to genes such as extracellular matrix, collagen, elastic fiber and Fbxo32. GO and KEGG enrichment analysis showed that the signaling pathways associated with diabetes were mainly as follows: extracellular matrix (ECM), protein digestion and absorption, PI3K-Akt signaling pathway, calcium signaling pathway, MAPK signaling pathway and AGE-RAGE signaling pathway in diabetic complications, etc. ECM has the closest relationship with VIDD in diabetic mice. The key genes determined by WGCNA and Venn analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-seq. VIDD can be aggravated in diabetic environment. This study provides new evidence for mRNA changes after mechanical ventilation in diabetic mice, suggesting that ECM and collagen may play an important role in the pathophysiological mechanism and progression of VIDD in diabetic mice, and provides some clues for the research, diagnosis, and treatment of VIDD in diabetic context.

The Impact of Aging and Biological Sex on Diaphragm Hyperemia and Blood Flow Distribution

INTRODUCTION: Age-related respiratory muscle dysfunction (i.e., the diaphragm) diminishes physical capacity and increases the susceptibility to respiratory failure. The diaphragm dysfunction associated with old age is characterized by decreased diaphragm muscle mass and strength, and increased fatiguability. While inadequate perfusion and diminished microvascular function are well recognized to play a central role in age-related peripheral skeletal muscle dysfunction, the impact of aging on diaphragm hyperemia and blood flow distribution, and whether sex differences exist, has not been investigated. METHODS: Young (Y; 4-6 months) and Old (O; 22-24 months) Fischer 344 rats (n=34) were divided into four groups: 1) Young female (YF; n=8), 2) Young male (YM; n=8), 3) Old female (OF; n=9), and 4) Old male (OM; n=9). Fluorescent microspheres were used to assess bulk and regional diaphragm blood flow at rest and during electrically-induced 1Hz contractions. RESULTS: There were no age-related or sex differences in quiescent diaphragm blood flow (BF) or vascular conductance (VC) ( P&gt;0.05). Age-related differences during 1Hz contractions: The increase in total diaphragm BF was significantly lower in OM (98 ± 11 ml/min/100g) compared to YM (141 ± 7 ml/min/100g; p&lt;0.05). Total and regional diaphragm BF was not different in F rats ( P&gt;0.05); however, medial costal diaphragm VC was decreased in OF (1.2 ± 0.1 ml/mmHg/min/100g) compared to YF (1.8 ± 0.2 ml/mmHg/min/100g; p&lt;0.05). Sex differences during 1Hz contractions: Total diaphragm BF and VC were similar in YF and YM ( P &gt; 0.05). While both ventral and medial costal diaphragm BF responses were not different between YF and YM, dorsal costal diaphragm BF was higher in YF (144 ± 27 ml/min/100g) versus YM (84 ± 11 ml/min/100g; p&lt;0.05). Total and regional (ventral, medial, and dorsal costal) diaphragm BF was significantly higher in OF compared to OM ( p&lt;0.05). CONCLUSION: These data demonstrate that aging impaired the ability of the diaphragm to augment BF in response to contractile activity in M rats and decreased medial costal diaphragm VC during contractions in F rats with no significant effect on diaphragmatic hyperemia. In regards to sex differences, these data suggest that both YF and OF may have a greater regional recruitment of the diaphragm compared to YM and OM. The data herein provide a putative mechanism for age-related diaphragm contractile dysfunction and future studies are needed to investigate the impact of aging and biological sex on diaphragm vascular function. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01 and 1F31HL170643-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Myocardial Infarction-induced Heart Failure on Diaphragm Arteriolar Vasorelaxation

INTRODUCTION: Diaphragm atrophy and contractile dysfunction are prevalent in heart failure (HF), diminishing physical capacity and quality of life. The delivery of blood flow and oxygen necessary to support the metabolic demand of contractions is largely governed by the resistance vasculature (i.e., arterioles) with the endothelium playing a central role in arteriolar vasorelaxation. Adequate perfusion and blood flow distribution, and thus resistance vessel vasodilation, is a major determinate of diaphragm contractile function. While the mechanistic bases of HF-induced diaphragm dysfunction continue to be elucidated, the impact of HF on diaphragm vasomotor control has not been investigated. METHODS: Adult (6 mo) Sprague-Dawley rats (n=7) were divided into two groups: 1) Healthy Control (HC; n=4) and 2) MI-induced heart failure (HF; n=3). First-order arterioles (1A) from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O and allowed to equilibrate for 60 min to develop spontaneous tone. Thereafter, endothelium-dependent and -independent vasorelaxation responses to cumulative doses of acetylcholine (ACh; 10−9 to 10−4M) and sodium nitroprusside (SNP; 10−9 to 10−4M) were determined. RESULTS: There were no differences in spontaneous development (%) or maximal diameter (μm) between HC (20 ± 4%; 178 ± 11 μm) and HF (18 ± 2%; 184 ± 29 μm) diaphragm 1As ( P &gt; 0.05). Maximal ACh-mediated relaxation (%) was significantly reduced in HF rats compared to HC rats (52 ± 2 versus 68 ± 5%; P &lt; 0.05). Maximal endothelial-independent vasorelaxation with SNP, was not different between HC and HF rats (71 ± 3 versus 73 ± 1%; P &gt; 0.05). CONCLUSION: The preliminary data herein demonstrate that HF impaired endothelial function and vasomotor function in the medial costal diaphragm resistance vasculature. This suggests that, in HF, there may be a redistribution of blood flow to less effcient regions of the diaphragm (e.g., ventral costal) to sustain contractile function and compensate for the diminished medial costal vasomotor function demonstrated herein. Studies including a larger sample size are warranted to investigate the impact of HF on regional blood flow distribution and resistance vessel function in the diaphragm. Such investigations would yield novel mechanistic insights into HF-induced diaphragm dysfunction. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diaphragm Force and Mitochondrial Function Following Enhanced Nitric Oxide Availability During Mechanical Ventilation

During mechanical ventilation (MV), force developed by the diaphragm decreases over time much faster than locomotor muscles, known as ventilator-induced diaphragm dysfunction (VIDD). VIDD is accompanied by an increase in intramyofiber protein S-nitrosylation, a modification of cysteines by nitric oxide (NO). During the treatment of acute respiratory distress syndrome (ARDS), inhaled NO is commonly used to improve gas exchange, but little is known about the effects of increased NO availability to the diaphragm during MV and the intracellular mechanisms to protect against excessive S-nitrosylation. We hypothesize that the enzyme S-nitrosoglutathione reductase (GSNOR) protects against excessive protein S-nitrosylation in diaphragm myofibers in conditions where NO availability is enhanced during MV, thereby preserving contractile function. We tested this hypothesis by enhancing NO availability and blocking GSNOR activity in mice during MV. Mice were treated with GSNOR inhibitor (SPL-334; GSNORi) or both GSNORi and NO donor isosorbide dinitrate (GSNORi-ISDN) together, and mechanically ventilated for 2h. E x vivo diaphragm force and mitochondrial respiration were measured. Male (C57BL/6J) 3-4 month old mice (n=27) were anesthetized and subjected to MV for 0 (non-MV), 2, 4, or 6h (150 breaths/min, 10 cmH2O PIP, 3.5 cmH2O PEEP. 8 mL/kg VT). Alternatively, mice were treated with PBS/10% DMSO (DMSO, n=6) or 25 μg SPL-334 in PBS/DMSO (GSNORi, n=6) or 25 μg SPL-334 + 1.7 mg ISDN in PBS/DMSO (GSNORi-ISDN; n=6), and then subjected to MV for 2 h. After MV, mice were euthanized, and diaphragm strips were used for force, and permeabilized fiber bundles for mitochondrial oxidative phosphorylation and H2O2 generation measurements. Peak tetanic force was decreased by MV ~23% at 4 h and ~40% at 6 h (P=0.0183 and P=0.0062, respectively, one-way ANOVA, Tukey post-test) vs 0 h. However, peak force was not different between DMSO, GSNORi and GSNORi-ISDN at 2 h MV. Coupled-phosphorylating mitochondrial respiration (Kruskal-Wallis H=2.2, p=0.35) was not different but H2O2 flux was highest in GSNORi-ISDN vs DMSO and GSNORi (Kruskal-Wallis H=6.6, p=0.03). GSNORi and ISDN treatment during MV did not produce any changes to VIDD and to mitochondrial respiration, but increased ROS production. If exogenous NO is not provided, inhibiting GSNOR in vivo alone does not affect diaphragm function ex vivo during short MV. Support: TRDRP (T32IR5221 and T29KT0397CA, to L.N.) and SDSU 2023 SEED Grant (to L.N.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitral Annular Plane Systolic Excursion (MAPSE) as a Predictor of Weaning Failure in Mechanically Ventilated Patients

Weaning failure is multifactorial in nature; it can result from diaphragmatic dysfunction, excess mechanical load, weaning-induced cardiovascular dysfunction, or a reduced ability to clear secretions. To investigate mitral annular plane systolic excursion (MAPSE) by using M-mode echocardiography as a predictor of weaning failure and its relation to length of intensive care unit stay, and to hospital mortality, and correlation of MAPSE with APACHE II and SOFA scores as predictors of outcome. This was a prospective observational cohort study conducted on 50 patients admitted to Critical Care Medicine Department, Cairo University Hospitals (Kasr Al-Aini Hospitals), with a diagnosis of acute respiratory failure who required mechanical ventilation, from January 2019 to December 2020. There was significant relation between weaning from mechanical ventilation and APACHE II score, we found highly significant difference with SOFA score. ROC curve for detection of weaning using MAPSE showed Area Under the Curve of 0.918 with highly statistically significant relation with cut off value is 13.9 with Sensitivity 83.3% and Specificity 92.3%; and thus, MAPSE could be a good indicator for successful weaning. We concluded that; Low Mitral annular plane systolic excursion (MAPSE) could be a good predictor of weaning failure and mortality, The higher MAPSE values are correlated with lower ICU stay duration. We found that RSBI and SOFA score are predictors for successful weaning, also SOFA and APACHE II scores are indicators of mortality.

Irisin attenuates ventilator-induced diaphragmatic dysfunction by inhibiting endoplasmic reticulum stress through activation of AMPK.

Mechanical ventilation (MV) is an essential life-saving technique, but prolonged MV can cause significant diaphragmatic dysfunction due to atrophy and decreased contractility of the diaphragm fibres, called ventilator-induced diaphragmatic dysfunction (VIDD). It is not clear about the mechanism of occurrence and prevention measures of VIDD. Irisin is a newly discovered muscle factor that regulates energy metabolism. Studies have shown that irisin can exhibit protective effects by downregulating endoplasmic reticulum (ER) stress in a variety of diseases; whether irisin plays a protective role in VIDD has not been reported. Sprague-Dawley rats were mechanically ventilated to construct a VIDD model, and intervention was performed by intravenous administration of irisin. Diaphragm contractility, degree of atrophy, cross-sectional areas (CSAs), ER stress markers, AMPK protein expression, oxidative stress indicators and apoptotic cell levels were measured at the end of the experiment.Our findings showed that as the duration of ventilation increased, the more severe the VIDD was, the degree of ER stress increased, and the expression of irisin decreased.ER stress may be one of the causes of VIDD. Intervention with irisin ameliorated VIDD by reducing the degree of ER stress, attenuating oxidative stress, and decreasing the apoptotic index. MV decreases the expression of phosphorylated AMPK in the diaphragm, whereas the use of irisin increases the expression of phosphorylated AMPK. Irisin may exert its protective effect by activating the phosphorylated AMPK pathway.

Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature.

The causes of diaphragmatic paresis are manifold. An association between neuralgic amyotrophy (NA) and hepatitis E virus (HEV) infection has been reported. We wondered about the prevalence of diaphragmatic disfunction and hepatitis E infection in our clinic. From July 1st, 2020 to August 31st, 2023, patients presenting with diaphragmatic dysfunction and simultaneous clinical symptoms of an acute NA, or a history of NA, as well as patients with previously unexplained diaphragmatic dysfunction were examined for HEV infection. By August 31st, 2023, 13 patients with diaphragmatic dysfunction and HEV infection were diagnosed (4 women, 9 men). Mean age was 59 ± 10 years. Liver values were normal in all patients. The median latency to diagnosis was five months (range: 1-48 months); nine patients, 4 of them with typical symptoms of NA, presented with acute onset three patients showed bilateral diaphragmatic dysfunction. All patients had a positive IgG immunoblot. Seven patients, three with NA, had an elevated hepatitis E IgM titer and six of them also a positive IgM immunoblot. In all cases, O2C hepatitis genotype 3 was identified. In eight cases, all those with a high IgG titer >125, the O2 genotype 1 was also detected. NA that shows involvement of the phrenic nerve resulting in diaphragmatic dysfunction and dyspnoea, may be associated with HEV infection. The observation of 13 patients with diaphragmatic dysfunctions and HEV infection within a period of three years indicates a high number of undetected HEV-associated diaphragmatic dysfunction in the population, especially in the absence of NA symptoms. Therefore, even in diaphragmatic dysfunction without NA symptoms and causative damaging event, HEV infection should be considered, as it may represent a subform of NA with only phrenic nerve involvement. Therapy of HEV-associated diaphragmatic dysfunction in the acute phase is an open question. In view of the poor prognosis for recovery, antiviral therapy should be discussed. However, no relevant data are currently available.

Comparison of Early Postoperative Diaphragm Muscle Function after Lobectomy via VATS and Open Thoracotomy: A Sonographic Study.

Although a growing body of evidence emphasizes the superiority of VATS over conventional thoracotomy, little is still known about early postoperative diaphragm muscle function after lobectomy via these two approaches. To fill the gap in existing literature, we conducted a comparative study between VATS and conventional thoracotomy in terms of postoperative diaphragm muscle function, assessing its contractility, strength, the magnitude of effort and potential risk of dysfunction such as atrophy and paralysis. A total of 59 patients (30 after VATS), who underwent anatomical pulmonary resection at our institution, were enrolled in this study. The control group consisted of 28 health subjects without medical conditions that could contribute to diaphragm dysfunction. Diaphragm muscle was assessed before and after surgery using ultrasonography. We found that both surgical approaches were associated with postoperative impairment of diaphragm muscle function-compared to baseline data. Postoperative reduction in diaphragm contraction was demonstrated in most of the 59 patients. In the case of the control group, the differences between measurements were not observed. We noted that lobectomy via thoracotomy was linked with a greater percentage of patients with diaphragm paralysis and/or atrophy than VATS. Similar findings were observed in referring to diaphragm magnitude effort, as well as diaphragm contraction strength, where minimally invasive surgery was associated with better diaphragm function parameters-in comparison to thoracotomy. Disturbance of diaphragm work was reported both at the operated and non-operated side. Upper-right and left lobectomy were connected with greater diaphragm function impairment than other segments. In conclusion, the VATS technique seems to be less invasive than conventional thoracotomy providing a better postoperative function of the main respiratory muscle.

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS.

Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 μg/kg for 10 min, followed by a continuous infusion at 0.2 μg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

(514) - Diaphragm Dysfunction from Phrenic Nerve Injuries During LVAD or Heart Transplants: Positive Role of Diaphragm Pacing

(514) - Diaphragm Dysfunction from Phrenic Nerve Injuries During LVAD or Heart Transplants: Positive Role of Diaphragm Pacing

Aminophylline Improves Ventilator-Induced Diaphragmatic Dysfunction by Targeting IGF-1-FOXO1-MURF1 Pathway.

The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity. Aminophylline (AP) has the potential to enhance the contractility of animal skeletal muscle fibers and improve the activity of human respiratory muscles, and the insulin-like growth factor-1 (IGF-1)- forkhead box protein O1 (FOXO1)-muscle RING finger-1 (MURF1) pathway plays a crucial role in skeletal muscle dysfunction. This study aimed to investigate the impact of AP on VIDD and to elucidate the role of the IGF-1-FOXO1-MURF1 pathway as an underlying mechanism. Rat models of VIDD were established through MV treatment. IGF-1 lentiviral (LV) interference (LV-IGF-1-shRNA; controlled by lentiviral negative control LV-NC) was employed to inhibit IGF-1 expression and thereby block the IGF-1-FOXO1-MURF1 pathway. Protein and mRNA levels of IGF-1, FOXO1, and MURF1 were assessed using western blot and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), respectively. Diaphragm contractility and morphometry were examined through measurement of compound muscle action potentials (CMAPs) and hematoxylin and eosin (H&E) staining. Oxidative stress was evaluated by levels of hydrogen peroxide (H2O2), superoxide dismutase (SOD), antioxidant glutathione (GSH), and carbonylated protein. Mitochondrial stability was assessed by measuring the mitochondrial membrane potential (MMP), and mitochondrial fission and mitophagy were examined through protein levels of dynamin-related protein 1 (DRP1), mitofusin 2 protein (MFN2), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), and Parkin (western blot). Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay and levels of Bax, B-cell lymphoma 2 (BCL-2), and Caspase-3. Levels of Atrogin-1, neuronally expressed developmentally downregulated 4 (NEDD4), and muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1) mRNA, as well as ubiquitinated protein, were utilized to determine protein degradation. Furthermore, the SUnSET (surface sensing of translation) method was employed to determine rates of protein synthesis. MV treatment upregulated IGF-1 while downregulated FOXO1 and MURF1 (p < 0.05). AP administration reversed IGF-1, FOXO1 and MURF1 (p < 0.05), which was suppressed again by IGF-1 inhibition (p < 0.05), demonstrating the blockage of the IGF-1-FOXO1-MURF1 pathway. MV treatment caused decreased CMAP and cross-sectional areas of diaphragm muscle fibers, and increased time course of CMAP (p < 0.05). Additionally, oxidative stress, cell apoptosis, and protein degradation were increased and mitochondrial stability was decreased by MV treatment (p < 0.05). Conversely, AP administration reversed all these changes induced by MV, but this reversal was disrupted by the blockage of the IGF-1-FOXO1-MURF1 pathway. In this study, MV treatment induced symptoms of VIDD in rats, which were all effectively reversed by AP regulating the IGF-1-FOXO1-MURF1 pathway, demonstrating the potential of AP in ameliorating VIDD.

Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction.

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. 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. 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. 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.

Diaphragmatic dysfunction is associated with postoperative pulmonary complications and phrenic nerve paresis in patients undergoing thoracic surgery

PurposeWe aimed to quantify perioperative changes in diaphragmatic function and phrenic nerve conduction in patients undergoing routine thoracic surgery.MethodsA prospective observational study was performed in patients undergoing esophageal resection or pulmonary lobectomy. Examinations were carried out the day prior to surgery, 3 days and 10–14 days after surgery. Endpoints for diaphragmatic function included ultrasonographic measurements of diaphragmatic excursion and thickening fraction. Endpoints for phrenic nerve conduction included baseline-to-peak amplitude, peak-to-peak amplitude, and transmission delay. Measurements were assessed on both the surgical side and the non-surgical side of the thorax.ResultsForty patients were included in the study. Significant reductions in diaphragmatic excursion were seen on the surgical side of the thorax for all excursion measures (posterior part of the right hemidiaphragm, p < 0.001; hemidiaphragmatic top point, p < 0.001; change in intrathoracic area, p < 0.001). Significant changes were seen for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.041) on the surgical side. However, significant changes were also seen on the non-surgical side for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.022). A postoperative reduction in posterior diaphragmatic excursion of more than 50% was significantly associated with postoperative pulmonary complications (coefficient: 2.69 (95% CI [1.38, 4.01], p < 0.001).ConclusionThoracic surgery caused a significant unilateral reduction in diaphragmatic excursion on the surgical side of the thorax, which was accompanied by significant changes in phrenic nerve conduction. However, phrenic nerve conduction was also significantly affected on the non-surgical side to a lesser extent, which was not mirrored in diaphragmatic excursion. Our findings suggest that phrenic nerve paresis plays a role in postoperative diaphragmatic dysfunction, which may be a contributing factor in the pathogenesis of postoperative pulmonary complications.Clinical trials registration numberNCT04507594.

Relationship Between Diaphragm Thickness, Thickening Fraction, Dome Excursion, and Respiratory Pressures in Healthy Subjects: An Ultrasound Study

PurposeDiaphragm ultrasonography is used to identify causes of diaphragm dysfunction. However, its correlation with pulmonary function tests, including maximal inspiratory (MIP) and expiratory pressures (MEP), remains unclear. This study investigated this relationship by measuring diaphragm thickness, thickening fraction (TF), and excursion (DE) using ultrasonography, and their relationship to MIP and MEP. It also examined the influence of age, sex, height, and BMI on these measures.MethodsWe recruited healthy Japanese volunteers and conducted pulmonary function tests and diaphragm ultrasonography in a seated position. Diaphragm ultrasonography was performed during quiet breathing (QB) and deep breathing (DB) to measure the diaphragm thickness, TF, and DE. A multivariate analysis was conducted, adjusting for age, sex, height, and BMI.ResultsBetween March 2022 and January 2023, 109 individuals (56 males) were included from three facilities. The mean (standard deviation) MIP and MEP [cmH2O] were 72.2 (24.6) and 96.9 (35.8), respectively. Thickness [mm] at the end of expiration was 1.7 (0.4), TF [%] was 50.0 (25.9) during QB and 110.7 (44.3) during DB, and DE [cm] was 1.7 (0.6) during QB and 4.4 (1.4) during DB. Multivariate analysis revealed that only DE (DB) had a statistically significant relationship with MIP and MEP (p = 0.021, p = 0.008). Sex, age, and BMI had a statistically significant influence on relationships between DE (DB) and MIP (p = 0.008, 0.048, and < 0.001, respectively).ConclusionIn healthy adults, DE (DB) has a relationship with MIP and MEP. Sex, age, and BMI, but not height, are influencing factors on this relationship.

Clinical correlates of respiratory disorders in patients with severe multiple sclerosis: A cross-sectional cohort

Background: Respiratory disorders remain incompletely described in multiple sclerosis (MS), even though they are a frequent cause of death. Methods: The objective was to describe respiratory disorders in MS patients with Expanded Disability Status Score (EDSS) ⩾ 6.5. Diaphragm dysfunction was defined by at least two of the seven criteria: clinical signs, inspiratory recruitment of neck muscles during wakefulness, reduced upright vital capacity (VC) < 80%, upright-to-supine VC ⩾ 15% of upright VC, decrease in Maximal Inspiratory Pressure < 60%, phasic activation of inspiratory neck muscles during sleep, and opposition of thoracic and abdominal movements during sleep. Cough weakness was defined by a peak cough flow < 270 L/min and/or need for cough assist. Sleep apnea syndrome was defined by an apnea–hypopnea index ⩾ 15. Results: Notably, 71 MS patients were included: median age 54 [48, 61] years; median disease duration 21.4 [16.0, 31.4] years. Of these, 52 patients had one or more respiratory disorders; diaphragm dysfunction was the most frequent (n = 34). Patients with diaphragm dysfunction and cough weakness were more disabled. The fatigue score and the cognitive evaluations did not differ between the groups. Five patients required non-invasive ventilation. Conclusion: Respiratory disorders are frequent in severe MS, mostly diaphragm dysfunction. Of interest, instrumental interventions are available to address these disorders.

Evaluation of computed tomography in the diagnosis of ultrasound-proven diaphragm dysfunction.

Computed tomography (CT) is routinely employed on the evaluation of dyspnea, yet limited data exist on its assessment of diaphragmatic muscle. This study aimed to determine the capability of CT in identifying structural changes in the diaphragm among patients with ultrasound-confirmed diaphragmatic dysfunction. Diaphragmatic ultrasounds conducted between 2018 and 2021 at our center in Marseille, France, were retrospectively collected. Diaphragmatic pillars were measured on CT scans at the L1 level and the celiac artery. Additionally, the difference in height between the two diaphragmatic domes in both diaphragmatic dysfunction cases and controls was measured and compared. A total of 65 patients were included, comprising 24 with diaphragmatic paralysis, 13 with diaphragmatic weakness, and 28 controls. In the case group (paralysis and weakness) with left dysfunctions (n = 24), the CT thickness of the pillars at the level of L1 and the celiac artery was significantly thinner compared with controls (2.0mm vs. 7.4mm and 1.8mm vs. 3.1mm, p < 0.001 respectively). Significantly different values were observed for paralysis (but not weakness) in the right dysfunction subgroup (n = 15) (2.6mm vs. 7.4mm and 2.2mm vs. 3.8mm, p < 0.001 respectively, for paralysis vs. controls). Regardless of the side of dysfunction, a significant difference in diaphragmatic height was observed between cases and controls (7.70cm vs. 1.16cm and 5.51cm vs. 1.16cm, p < 0.001 for right and left dysfunctions, respectively). Threshold values determined through ROC curve analyses for height differences between the two diaphragmatic domes, indicative of paralysis or weakness in the right dysfunctions, were 4.44cm and 3.51cm, respectively. Similarly for left dysfunctions, the thresholds were 2.70cm and 2.48cm, respectively, demonstrating good performance (aera under the curve of 1.00, 1.00, 0.98, and 0.79, respectively). In cases of left diaphragmatic dysfunction, as well as in paralysis associated with right diaphragmatic dysfunction, CT revealed thinner pillars. Additionally, a notable increase in the difference in diaphragmatic height demonstrated a strong potential to identify diaphragmatic dysfunction, with specific threshold values.