Ventilator-induced Diaphragmatic Dysfunction Research Articles

Prolonged Mechanical Ventilation: Outcomes and Management.

The number of patients requiring prolonged mechanical ventilation (PMV) is increasing worldwide, placing a burden on healthcare systems. Therefore, investigating the pathophysiology, risk factors, and treatment for PMV is crucial. Various underlying comorbidities have been associated with PMV. The pathophysiology of PMV includes the presence of an abnormal respiratory drive or ventilator-induced diaphragm dysfunction. Numerous studies have demonstrated that ventilator-induced diaphragm dysfunction is related to increases in in-hospital deaths, nosocomial pneumonia, oxidative stress, lung tissue hypoxia, ventilator dependence, and costs. Thus far, the pathophysiologic evidence for PMV has been derived from clinical human studies and experimental studies in animals. Moreover, recent studies have demonstrated the outcome benefits of pharmacological agents and rehabilitative programs for patients requiring PMV. However, methodological limitations affected these studies. Controlled prospective studies with an adequate number of participants are necessary to provide evidence of the mechanism, prognosis, and treatment of PMV. The great epidemiologic impact of PMV and the potential development of treatment make this a key research field.

Non-invasive phrenic nerve stimulation to avoid ventilator-induced diaphragm dysfunction in critical care.

Diaphragm muscle atrophy during mechanical ventilation begins within 24h and progresses rapidly with significant clinical consequences. Electrical stimulation of the phrenic nerves using invasive electrodes has shown promise in maintaining diaphragm condition by inducing intermittent diaphragm muscle contraction. However, the widespread application of these methods may be limited by their risks as well as the technical and environmental requirements of placement and care. Non-invasive stimulation would offer a valuable alternative method to maintain diaphragm health while overcoming these limitations. We applied non-invasive electrical stimulation to the phrenic nerve in the neck in healthy volunteers. Respiratory pressure and flow, diaphragm electromyography and mechanomyography, and ultrasound visualization were used to assess the diaphragmatic response to stimulation. The electrode positions and stimulation parameters were systematically varied in order to investigate the influence of these parameters on the ability to induce diaphragm contraction with non-invasive stimulation. We demonstrate that non-invasive capture of the phrenic nerve is feasible using surface electrodes without the application of pressure, and characterize the stimulation parameters required to achieve therapeutic diaphragm contractions in healthy volunteers. We show that an optimal electrode position for phrenic nerve capture can be identified and that this position does not vary as head orientation is changed. The stimulation parameters required to produce a diaphragm response at this site are characterized and we show that burst stimulation above the activation threshold reliably produces diaphragm contractions sufficient to drive an inspired volume of over 600 ml, indicating the ability to produce significant diaphragmatic work using non-invasive stimulation. This opens the possibility of non-invasive systems, requiring minimal specialist skills to set up, for maintaining diaphragm function in the intensive care setting.

Aldh1a1 and Scl25a30 in diaphragmatic dysfunction.

New methods to prevent ventilator-induced diaphragmatic dysfunction (VIDD) are urgently needed, and the cellular basis of VIDD is poorly understood. This study evaluated whether transvenous phrenic nerve stimulation (PNS) could prevent VIDD in rabbits undergoing mechanical ventilation (MV) and explored whether oxidative stress-related genes might be candidate molecular markers for VIDD. Twenty-four adult male New Zealand white rabbits were allocated to control, MV, and PNS groups (n = 8 in each group). Rabbits in the MV and PNS groups underwent MV for 24 h. Intermittent bilateral transvenous PNS was performed in rabbits in the PNS group. Transdiaphragmatic pressure was recorded using balloon catheters. The diameters and cross-sectional areas (CSAs) of types I and II diaphragmatic fibers were measured using immunohistochemistry (IHC) techniques. Genes associated with VIDD were identified by RNA sequencing (RNA-seq), differentially expressed gene (DEG) analysis, and weighted gene co-expression network analysis (WGCNA). Reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and IHC analyses were carried out to verify the transcriptome profile. Pdi60Hz, Pdi80Hz, and Pdi100Hz were significantly higher in the PNS group than in the MV group at 12 and 24 h (P < 0.05 at both time points). The diameters and CSAs of types I (slow-twitch) and II (fast-twitch) fibers were significantly larger in the PNS group than in the MV group (P < 0.05). RNA-seq, RT-PCR, Western blotting, and IHC experiments identified two candidate genes associated with VIDD: Aldh1a1 and Scl25a30. The MV group had significantly higher mRNA and protein expressions of Aldh1a1/ALDH1A1 and significantly lower mRNA and protein expressions of Scl25a30/SCL25A30 than the control or PNS groups (P < 0.05). We have identified two candidate genes involved in the prevention of VIDD by transvenous PNS. These two key genes may provide a theoretical basis for targeted therapy against VIDD.

Lung and diaphragm protective ventilation: a synthesis of recent data

ABSTRACT Introduction : To adhere to the Hippocratic Oath, to ‘first, do no harm’, we need to make every effort to minimize the adverse effects of mechanical ventilation. Our understanding of the mechanisms of ventilator-induced lung injury (VILI) and ventilator-induced diaphragm dysfunction (VIDD) has increased in recent years. Research focuses now on methods to monitor lung stress and inhomogeneity and targets we should aim for when setting the ventilator. In parallel, efforts to promote early assisted ventilation to prevent VIDD have revealed new challenges, such as titrating inspiratory effort and synchronizing the mechanical with the patients’ spontaneous breaths, while at the same time adhering to lung-protective targets. Areas covered This is a narrative review of the key mechanisms contributing to VILI and VIDD and the methods currently available to evaluate and mitigate the risk of lung and diaphragm injury. Expert opinion Implementing lung and diaphragm protective ventilation requires individualizing the ventilator settings, and this can only be accomplished by exploiting in everyday clinical practice the tools available to monitor lung stress and inhomogeneity, inspiratory effort, and patient–ventilator interaction.

Addressing Diaphragm Dysfunction in Lung Transplant Recipients: The Expanding Role of Diaphragm Pacing

<h3>Purpose</h3> Diaphragmatic dysfunction is documented after lung transplantation and can affect up to 62% patients. Diaphragm pacing (DP) prevents ventilator induced diaphragm dysfunction (VIDD) while on mechanical ventilation (MV) and has been shown via functional electrical stimulation to improve phrenic nerve recovery. We report the largest experience of DP in lung transplantation recipients. <h3>Methods</h3> This is a retrospective analysis of an IRB approved prospective, non-randomized interventional experience at a single institution with two DP systems. A chronic DP system [NeuRx, Synapse Biomedical] was implanted laparoscopically in those with phrenic nerve injury or difficulty with weaning from MV remotely after their transplant. A temporary DP system [TransAeris, Synapse Biomedical] was implanted at the time of transplantation or laparoscopically. In both types of implantation, diaphragm stimulation ensued if needed to wean from MV or for nerve recovery. Results evaluated radiographically and with diaphragm electromyography (dEMG). <h3>Results</h3> DP was utilized in16 patients with no device adverse events. Of those, 5 patients had chronic DP system: a) 1 patient one year post transplant shows no recovery of phrenic nerve injury, still pacing; b) 3 patients showed recovery of phrenic nerve/diaphragm function through pacing; c) 1 patient 2 years post-transplant sustained hip fracture requiring surgery, developed pneumonia and became tracheostomy MV dependent; DP allowed complete diaphragm recovery, decanullation of tracheostomy and removal of DP wires. 11 patients had temporary DP electrodes placed: a) 1 recipient(two months post-transplant) had DP use during ECMO for COVID- 19 sepsis and respiratory failure and subsequently expired when family withdrew therapy; b) 10 implanted at time of lung transplant. Of those 10, 3 patients had bilateral dEMG identified post-operatively with uneventful recovery and removal of electrodes; 7 patients had diaphragm abnormalities identified post-operatively and underwent DP. Of those 7, 5 showed recovery and DP electrodes removed and 2 are still pacing 1 and 9 months post-transplant. <h3>Conclusion</h3> DP was safely used in lung transplantation to identify and improve recovery of phrenic nerve injuries, wean from MV and prevent VIDD. DP shows promise in addressing diaphragm dysfunction after lung transplantation and improving outcomes.

Metabolomic Profiling of Respiratory Muscles and Lung in Response to Long-Term Controlled Mechanical Ventilation.

Critical illness myopathy (CIM) and ventilator-induced diaphragm dysfunction (VIDD) are characterized by severe muscle wasting, muscle paresis, and extubation failure with subsequent increased medical costs and mortality/morbidity rates in intensive care unit (ICU) patients. These negative effects in response to modern critical care have received increasing attention, especially during the current COVID-19 pandemic. Based on experimental and clinical studies from our group, it has been hypothesized that the ventilator-induced lung injury (VILI) and the release of factors systemically play a significant role in the pathogenesis of CIM and VIDD. Our previous experimental/clinical studies have focused on gene/protein expression and the effects on muscle structure and regulation of muscle contraction at the cell and motor protein levels. In the present study, we have extended our interest to alterations at the metabolomic level. An untargeted metabolomics approach was undertaken to study two respiratory muscles (diaphragm and intercostal muscle) and lung tissue in rats exposed to five days controlled mechanical ventilation (CMV). Metabolomic profiles in diaphragm, intercostal muscles and lung tissue were dramatically altered in response to CMV, most metabolites of which belongs to lipids and amino acids. Some metabolites may possess important biofunctions and play essential roles in the metabolic alterations, such as pyruvate, citrate, S-adenosylhomocysteine, alpha-ketoglutarate, glycerol, and cysteine. Metabolic pathway enrichment analysis identified pathway signatures of each tissue, such as decreased metabolites of dipeptides in diaphragm, increased metabolites of branch-chain amino acid metabolism and purine metabolism in intercostals, and increased metabolites of fatty acid metabolism in lung tissue. These metabolite alterations may be associated with an accelerated myofibrillar protein degradation in the two respiratory muscles, an active inflammatory response in all tissues, an attenuated energy production in two respiratory muscles, and enhanced energy production in lung. These results will lay the basis for future clinical studies in ICU patients and hopefully the discovery of biomarkers in early diagnosis and monitoring, as well as the identification of future therapeutic targets.

Reduction in Ventilation-Induced Diaphragmatic Mitochondrial Injury through Hypoxia-Inducible Factor 1α in a Murine Endotoxemia Model.

Mechanical ventilation (MV) is essential for patients with sepsis-related respiratory failure but can cause ventilator-induced diaphragm dysfunction (VIDD), which involves diaphragmatic myofiber atrophy and contractile inactivity. Mitochondrial DNA, oxidative stress, mitochondrial dynamics, and biogenesis are associated with VIDD. Hypoxia-inducible factor 1α (HIF-1α) is crucial in the modulation of diaphragm immune responses. The mechanism through which HIF-1α and mitochondria affect sepsis-related diaphragm injury is unknown. We hypothesized that MV with or without endotoxin administration would aggravate diaphragmatic and mitochondrial injuries through HIF-1α. C57BL/6 mice, either wild-type or HIF-1α-deficient, were exposed to MV with or without endotoxemia for 8 h. MV with endotoxemia augmented VIDD and mitochondrial damage, which presented as increased oxidative loads, dynamin-related protein 1 level, mitochondrial DNA level, and the expressions of HIF-1α and light chain 3-II. Furthermore, disarrayed myofibrils; disorganized mitochondria; increased autophagosome numbers; and substantially decreased diaphragm contractility, electron transport chain activities, mitofusin 2, mitochondrial transcription factor A, peroxisome proliferator activated receptor-γ coactivator-1α, and prolyl hydroxylase domain 2 were observed (p < 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1α-deficient mice (p < 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1α signaling pathway.

Treatment option for diaphragm dysfunction after cardiac surgery: a review and a clinical case

INTRODUCTION. Dysfunction of diaphragm postoperatively is associated with worsened quality of life and increased health care costs due to prolonged respiratory support and morbidity. After cardiac operations, dysfunction of diaphragm can take place in up to 10 % of patients but often remains underdiagnosed. At the same time, histologically revealed changes, such as muscle atrophy in the diaphragm, start within 12 hours of mechanical ventilation. The therapy of diaphragm weakness is not well established and has a limited efficacy. Current analytic review describes therapeutic option for treatment ventilator-induced diaphragm dysfunction with emphasis on electric neuromodulation of phrenic nerve. OBJECTIVE. To optimize respiratory function by bilateral electrostimulation of phrenic nerves on the neck level in patient with diaphragm dysfunction after cardiac operation. MATERIALS AND METHODS. 82-year-old female patient after elective aortic valve replacement was diagnosed with dysfunction of diaphragm and respiratory failure. These changes caused the weaning failure from respirator and led to prolonged ventilator support. On the 20, 22, 24 and 26 days of postoperative period we performed invasive bilateral phrenic nerve stimulation on the neck level for 10 minutes with ultrasound navigation. RESULTS. After electrical modulation of phrenic nerves, diaphragm excursion, detected by ultrasound, was improved. After four procedures, duration of spontaneous breathing trial increased from 1 to 12 hours. On postoperative day 30, the patient was successfully weaned from respiratory support and decannulated without recurrent respiratory failure. There were no any complications during procedure, it was well-tolerated and associated with emotional improvement. CONCLUSIONS. Phrenic nerve stimulation on the neck level can be a valuable option in selected patients with respiratory failure and difficulties with ventilator weaning.

Diaphragm-protective mechanical ventilation in acute respiratory failure.

Mechanical ventilation injures not only the lungs but also the diaphragm, resulting in dysfunction associated with poor outcomes. The chief mechanisms of ventilator-induced diaphragm dysfunction are : disuse atrophy due to insufficient contraction and excessive ventilatory support ; concentric load-induced injury due to excessive contraction and insufficient ventilatory support ; eccentric load-induced injury due to contraction during the expiratory phase ; and longitudinal atrophy caused by high positive end-expiratory pressure. To protect the diaphragm during mechanical ventilation, maintaining proper levels of diaphragm contraction is paramount ; thus, monitoring of respiratory effort and finely tuned ventilator settings are necessary. Furthermore, maintaining of synchronization between the patient and the ventilator is also important. As diaphragm dysfunction is more likely to occur in critically ill patients, diaphragm-protective mechanical ventilation strategies are essential to reduce the mortality rate of intensive care unit patients. This review outlines clinical evidence of ventilator-induced diaphragm dysfunction and its underlying mechanisms, and strategies to facilitate diaphragm-protective mechanical ventilation. J. Med. Invest. 69 : 165-172, August, 2022.

Phrenic nerve stimulation prevents diaphragm atrophy in patients with respiratory failure on mechanical ventilation

BackgroundDiaphragm atrophy and dysfunction is a major problem among critically ill patients on mechanical ventilation. Ventilator-induced diaphragmatic dysfunction is thought to play a major role, resulting in a failure of weaning. Stimulation of the phrenic nerves and resulting diaphragm contraction could potentially prevent or treat this atrophy. The subject of this study is to determine the effectiveness of diaphragm stimulation in preventing atrophy by measuring changes in its thickness.MethodsA total of 12 patients in the intervention group and 10 patients in the control group were enrolled. Diaphragm thickness was measured by ultrasound in both groups at the beginning of study enrollment (hour 0), after 24 hours, and at study completion (hour 48). The obtained data were then statistically analyzed and both groups were compared.ResultsThe results showed that the baseline diaphragm thickness in the interventional group was (1.98 ± 0.52) mm and after 48 hours of phrenic nerve stimulation increased to (2.20 ± 0.45) mm (p=0.001). The baseline diaphragm thickness of (2.00 ± 0.33) mm decreased in the control group after 48 hours of mechanical ventilation to (1.72 ± 0.20) mm (p<0.001).ConclusionsOur study demonstrates that induced contraction of the diaphragm by pacing the phrenic nerve not only reduces the rate of its atrophy during mechanical ventilation but also leads to an increase in its thickness – the main determinant of the muscle strength required for spontaneous ventilation and successful ventilator weaning.Trial registration: The study was registered with ClinicalTrials.gov (18/06/2018, NCT03559933, https://clinicaltrials.gov/ct2/show/NCT03559933).

PILOT STUDY OF PERCUTANEOUS TEMPORARY DIAPHRAGM PACING WIRES IN CARDIAC SURGERY PATIENTS AT RISK OF PROLONGED MECHANICAL VENTILATION DURING THE COVID-19 PANDEMIC

BACKGROUNDProlonged mechanical ventilation (PMV) after cardiac surgery occurs in 12% of patients, and significantly increases morbidity and mortality. Diaphragm pacing (DP) decreases ventilation times by 64% in other patient groups. We investigated the feasibility and outcomes of DP in urgent cardiac surgeries to decrease ventilator burden during the COVID-19 pandemic.METHODS AND RESULTSThis pilot study is an open-label FDA (IDE# G170294) prospective trial of temporary DP electrode use in high risk cardiac surgery patients (ClinicalTrials.gov Identifier–NCT04309123). Prior to sternotomy closure, the pleural space is opened, two electrodes (Figure 1) are placed in each diaphragm muscle, and the wires are tunneled percutaneously. The electrodes record diaphragm burst electromyography (dEMG) continuously for the first 24 hours and then once daily (Figure 2). In PMV patients (MV>24 hours), DP is initiated to prevent diaphragm atrophy and ventilator induced diaphragm dysfunction. The primary outcome was incidence of serious device related adverse events. The secondary outcome was time on MV. From 4/2/20–6/25/20, 44 patients were consented, 32 were implanted, and 12 were not. PMV was required in 10 patients implanted and 4 not implanted. There were no serious adverse events related to DP electrode implantation, all stimulated patients had improved ventilation and diaphragm function, and all electrodes were removed successfully. Criteria that best predicted PMV were: IABP, history of TIA or CVA, COPD, LVEF < 20%, and prior open-heart surgery. Using these criteria, the median time on mechanical ventilation in the first 120 hours was 35.7% versus 80.0% for the stimulated and non-stimulated groups, respectively.CONCLUSIONTemporary DP electrode placement during cardiac surgery is feasible and safe. DP improved diaphragm function and ventilation, and increased the likelihood of extubation by 48 hours. These results provide a catalyst for a prospective randomized controlled trial to decrease the MV burden in an enhanced recovery after surgery (ERAS) protocol.

VENTILATOR-INDUCED DIAPHRAGMATIC DYSFUNCTION: MODIFIABLE CAUSES OF INJURY AND CORRELATED OUTCOMES

TOPIC: Critical Care TYPE: Late Breaking PURPOSE: The purposes of this study are to correlate the incidence of ventilator-induced diaphragmatic injury in the MICU to patient outcomes, and to assess for associations between diaphragmatic dysfunction and modifiable variables in mechanical ventilator management or sedation strategy. METHODS: Adult critically-ill patients admitted to Yale New Haven Hospital MICU were enrolled if intubated, mechanically ventilated, and qualified for a breathing trial. Diaphragm thickness, thickening fraction, and excursion were measured by bedside ultrasound, alongside an airway occlusion maneuver and maximum inspiratory pressure. These measurements were correlated with patient outcome variables, including duration of mechanical ventilation, re-intubation within 7 days of extubation, NIV following extubation, tracheostomy, and death during hospitalization, as well as modifiable ventilator settings and level of sedation. RESULTS: In an analysis of our first 13 patients, we found that there was a non-statistical difference in length of hospital stay between those with a reduced diaphragm thickening fraction (TF) ≤ 20% vs those with a normal TF (49.75 vs 32.22 days, p=0.087), although there was no difference in days on mechanical ventilation or length of ICU stay. When dividing patient subsets into categories of reduced or excessive effort (TF ≤ 20% or TF > 30%) vs normal effort (20% < TF ≤ 30%), we found that only those with abnormal effort had re-intubation within 7 days of extubation (3 vs 0) or required tracheostomy (3 vs 0). Those with a diaphragm thickening fraction ≤ 20% had near-statistically significant differences in admission APACHE II score (20.5 in low TF vs 15 in normal TF, p=0.063), as well as lower ventilatory pressure support (inspiratory pressure 17.78 cmH2O in low TF vs 22.39 cmH2O in normal TF, p=0.099). CONCLUSIONS: Although underpowered given a small initial dataset, our study may indicate that a reduced thickening fraction at time of breathing trial may correlate with a prolonged hospital stay, although is not a marker for prolonged mechanical ventilation. Reduced or increased effort may also suggest increased risk of re-intubation or need for tracheostomy. It is also important to note that those who had a higher severity of critical illness at time of intubation, and those who received less inspiratory support while on mechanical ventilation, had a reduced thickening fraction relative to those less ill or receiving greater pressure support. CLINICAL IMPLICATIONS: Only recently has diaphragmatic myotrauma been characterized as a potential mediator for prolonged mechanical ventilation and poor patient outcomes. However, the assessment of its presence by simple, reproducible, and non-invasive means has remained elusive, and its clinical utility dubious at best. This study illustrates the potential use of ultrasound-based diaphragmatic thickening fraction at time of spontaneous breathing trial as a measure of normal, decreased, or increased respiratory muscle effort, and how this may correlate to length of hospital stay, risk of re-intubation, and need for tracheostomy. It also suggests that the level of critical illness may correspond with a higher incidence of diaphragmatic injury, and that increased mechanical support, while maintaining lung protective strategy, may help maintain normal respiratory muscle function. Further studies will be necessary in the future to corroborate these results. DISCLOSURES: No relevant relationships by Jan Fouad, source=Web Response No relevant relationships by Lauren Killingsworth, source=Web Response No relevant relationships by Margaret Pisani, source=Web Response

Inspiratory Muscle Training Prevents Diaphragmatic Atrophy in Mechanically Ventilated COVID-19 Patients

Background: Unloading the diaphragm by mechanical ventilation results in diaphragmatic dysfunction and atrophy, a condition recognized in critical care settings as ventilator-induced diaphragmatic dysfunction (VIDD). This condition contributes to prolonged mechanical ventilation, extubation failure and higher risk of mortality.The aim of The Study: The current study aimed to investigate the effectiveness of inspiratory muscle training in preventing or reversing diaphragmatic atrophy in mechanically ventilated COVID-19 patients.Materials and Methods: 55 intubated, mechanically ventilated patients with hypoxic respiratory failure due to COVID-19 were randomly assigned into study (n = 32) and control (n = 23) groups. The former received inspiratory muscle training with the routine physiotherapy programme and the latter received routine physiotherapy only. Diaphragmatic thickness was measured and compared in both groups using ultrasonography.Results: In the study group, diaphragmatic thickness at end of inspiration and expiration significantly increased by 14% and 8% respectively (p 0.05). In the control group, there was a significant decrease in all three parameters (p < 0.001).Conclusion: Inspiratory muscle training by adjusting the ventilator’s trigger sensitivity is a safe, effective and feasible method that can successfully prevent diaphragmatic atrophy in mechanically ventilated, COVID-19 patients.

Неинвазивная вентиляция легких (лекция)

В лекции освещены вопросы step by step респираторной терапии у больных с острой дыхательной дисфункцией (ОДД). Первым шагом в лечении больных с ОДД (при отсутствии показаний к инвазивной механической вентиляции легких) является использование высокопоточной оксигенации (ВПО) и неинвазивной вентиляции легких (НИВЛ). По сравнению с инвазивной механической вентиляцией легких эти технологии имеют определенные преимущества. Они не приводят к вентилятор-ассоциированному повреждению легких, вентилятор-ассоциированной диафрагмальной дисфункции и не вызывают вентилятор-ассоциированной пневмонии. НИВЛ обеспечивает определенная концентрация кислорода на вдохе (FiO2) в сочетании с умеренным давлением в конце выдоха (РЕЕР)/постоянным положительным давлением в дыхательных путях (СРАР) и инспираторным давлением. В отличие от оксигенации через лицевую маску или носовые канюли она уменьшает возможность экспираторного закрытия мелких дыхательных путей, предупреждает коллапс альвеол и возможность возникновения ателектазов. Преимуществом НИВЛ в сравнении со стандартной оксигенотерапией через лицевую маску/носовые канюли можно считать то, что она обеспечивает умеренный уровень РЕЕР/СРАР, который уменьшает пред- и постнагрузку левого желудочка. Это имеет особенное значение у больных с острой левожелудочковой недостаточностью или отеком легких. Главным условием успешного проведения НИВЛ является наличие адекватного сознания у больного. В основе клинической эффективности ВПО лежит возможность создания большой скорости потока газа (до 60 л/мин). Такая скорость потока (которая равна или даже больше скорости потока при вдохе больного) минимизирует «примешивание» комнатного воздуха и разрешает поддерживать на вдохе высокую FiO2. Принципиально важно наличие возможности методом step by step регулировать скорость потока и температуры, точное измерение FiO2. Современные системы ВПО имеют специальные контуры из полупроницаемых материалов, которые не допускают образования конденсата и имеют оригинальные носовые или трахеостомические канюли.

Диафрагмальная дисфункция среди детей на искусственной вентиляции легких: проспективное обсервационное когортное исследование

Актуальность. Искусственная вентиляция легких (ИВЛ) может приводить к повреждению диафрагмы, которое называют вентилятор-индуцированной диафрагмальной дисфункцией и связывают с неблагоприятными результатами лечения, длительным отлучением от респираторной терапии и длительным пребыванием в отделении интенсивной терапии. Целью нашего исследования было установить распространенность диафрагмальной дисфункции среди детей в зависимости от стратегии ИВЛ. Рабочей была гипотеза, что возникновение диафрагмальной дисфункции не зависит от стратегии проведения ИВЛ. Материалы и методы. Нами проведено проспективное когортное одноцентровое исследование в отделении анестезиологии с койками интенсивной терапии КНП «Львовская областная детская клиническая больница «ОХМАТДЕТ». В исследование включали пациентов с острой дыхательной недостаточностью, требующих ИВЛ более 3 суток. Критериями исключения из исследования были: отказ законных представителей пациента от участия в исследовании на любом из его этапов, агональное состояние пациента при поступлении на лечение. В исследование были включены 89 пациентов в возрасте от 1 мес. до 18 лет. Все пациенты были разделены случайным образом на 2 группы (с помощью сервиса random.org). В I группу вошли пациенты, у которых применяли легочно-протективную стратегию ИВЛ, во II группу — пациенты, у которых применяли легочно-протективную и диафрагм-протективную стратегии ИВЛ. В анализ данных включены 82 пациента. Для оценки показателей, зависящих от возраста, пациенты были разделены на возрастные подгруппы: 1-я подгруппа — дети в возрасте 1 мес. — 1 год; 2-я подгруппа — дети 1–3 лет; 3-я подгруппа — дети 3–6 лет; 4-я подгруппа — дети 6–13 лет; 5-я подгруппа — дети 13–18 лет. Этапы исследования: 1-е сутки (d1), 3-и сутки (d3), 5-е сутки (d5), 7-е сутки (d7), 9-е сутки (d9), 14-е сутки (d14), 28-е сутки (d28). В обеих группах пациентов изучали: изменения амплитуды движений диафрагмы в ходе исследования; контрактильные свойства диафрагмы с помощью определения фракции ее истончения и динамику в ходе исследования; рассматривали снижение данного показателя менее 15 % как маркер диафрагмальной слабости; повышение его более 35 % как маркер высокой работы дыхания и потенциально повреждающий фактор для диафрагмы; время вдоха по ультразвуковым данным; мониторировали показатели кислотно-щелочного равновесия крови и параметры искусственной вентиляции легких. Результаты. Нами выявлены специфические возрастные особенности: среди пациентов 1-й возрастной подгруппы в І группе мы регистрировали слабость правого купола диафрагмы с компенсаторным чрезмерным сокращением левого купола в начале отлучения и на этапе d9, тогда как во II группе эпизод чрезмерной работы диафрагмы был зарегистрирован только на этапе d5. Среди пациентов 2-й возрастной подгруппы I группы изменения были диаметрально противоположными по сравнению с 1-й возрастной подгруппой — преобладала чрезмерная работа правого купола с низкими показателями сокращения левого купола на всех этапах исследования, тогда как во II группе был зарегистрирован эпизод диафрагмальной слабости на этапе d3. В 3-й возрастной подгруппе достоверно позже восстанавливалась надлежащая диафрагмальная активность в І группе пациентов по сравнению со II группой. В 4-й возрастной подгруппе среди пациентов I группы отмечен эпизод высокой работы диафрагмы на этапе d5, тогда как во II группе все показатели были в пределах, рекомендованных диафрагм-протективной стратегией. В 5-й возрастной подгруппе в І группе достоверно чаще регистрировали чрезмерную работу как правого, так и левого куполов диафрагмы, во II группе были эпизоды как диафрагмальной слабости, так и чрезмерной ее работы. Использование в комплексе интенсивной терапии диафрагм-протективной стратегии при проведении отлучения от ИВЛ позволило снизить продолжительность ИВЛ: у пациентов 1-й возрастной подгруппы — в 1,5 раза (p = 0,08); у пациентов 2-й возрастной подгруппы — в 2,4 раза (p = 0,18); в 4-й возрастной подгруппе — в 1,75 раза (p = 0,1); в 5-й возрастной подгруппе — в 4,25 раза (p = 0,009). У пациентов 3-й возрастной подгруппы продолжительность ИВЛ возросла в 1,1 раза (p = 0,68). Выводы. Распространенность и разнообразие проявлений диафрагмальной дисфункции зависят от стратегии проведения механической вентиляции легких. Комплексный подход на этапе отлучения от респираторной терапии, включающей проведение диафрагм-протективной стратегии ИВЛ, позволяет уменьшить инцидентность возникновения дисфункции диафрагмы и снизить продолжительность отлучения от ИВЛ.

Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction

IntroductionVentilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure. Materials and methodsThe NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV. DiscussionThis trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

Altered expression of microRNAs in the rat diaphragm in a model of ventilator-induced diaphragm dysfunction after controlled mechanical ventilation

BackgroundVentilator-induced diaphragm dysfunction (VIDD) is a common complication of life support by mechanical ventilation observed in critical patients in clinical practice and may predispose patients to severe complications such as ventilator-associated pneumonia or ventilator discontinuation failure. To date, the alterations in microRNA (miRNA) expression in the rat diaphragm in a VIDD model have not been elucidated. This study was designed to identify these alterations in expression.ResultsAdult male Wistar rats received conventional controlled mechanical ventilation (CMV) or breathed spontaneously for 12 h. Then, their diaphragm tissues were collected for RNA extraction. The miRNA expression alterations in diaphragm tissue were investigated by high-throughput microRNA-sequencing (miRNA-seq). For targeted mRNA functional analysis, gene ontology (GO) analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were subsequently conducted. qRT-PCR validation and luciferase reporter assays were performed. We successfully constructed a model of ventilator-induced diaphragm dysfunction and identified 38 significantly differentially expressed (DE) miRNAs, among which 22 miRNAs were upregulated and 16 were downregulated. GO analyses identified functional genes, and KEGG pathway analyses revealed the signaling pathways that were most highly correlated, which were the MAPK pathway, FoxO pathway and Autophagy–animal. Luciferase reporter assays showed that STAT3 was a direct target of both miR-92a-1-5p and miR-874-3p and that Trim63 was a direct target of miR-3571.ConclusionsThe current research supplied novel perspectives on miRNAs in the diaphragm, which may not only be implicated in diaphragm dysfunction pathogenesis but could also be considered as therapeutic targets in diaphragm dysfunction.

Positive end-expiratory pressure affects geometry and function of the human diaphragm

Positive end-expiratory pressure (PEEP) is routinely applied in mechanically ventilated patients to improve gas exchange and respiratory mechanics by increasing end-expiratory lung volume (EELV). In a recent experimental study in rats, we demonstrated that prolonged application of PEEP causes diaphragm remodeling, especially longitudinal muscle fiber atrophy. This is of potential clinical importance, as the acute withdrawal of PEEP during ventilator weaning decreases EELV and thereby stretches the adapted, longitudinally atrophied diaphragm fibers to excessive sarcomere lengths, having a detrimental effect on force generation. Whether this series of events occurs in the human diaphragm is unknown. In the current study, we investigated if short-term application of PEEP affects diaphragm geometry and function, which are prerequisites for the development of longitudinal atrophy with prolonged PEEP application. Nineteen healthy volunteers were noninvasively ventilated with PEEP levels of 2, 5, 10, and 15 cmH2O. Magnetic resonance imaging was performed to investigate PEEP-induced changes in diaphragm geometry. Subjects were instrumented with nasogastric catheters to measure diaphragm neuromechanical efficiency (i.e., diaphragm pressure normalized to its electrical activity) during tidal breathing with different PEEP levels. We found that increasing PEEP from 2 to 15 cmH2O resulted in a caudal diaphragm displacement (19 [14-26] mm, P < 0.001), muscle shortening in the zones of apposition (20.6% anterior and 32.7% posterior, P < 0.001), increase in diaphragm thickness (36.4% [0.9%-44.1%], P < 0.001) and reduction in neuromechanical efficiency (48% [37.6%-56.6%], P < 0.001). These findings demonstrate that conditions required to develop longitudinal atrophy in the human diaphragm are present with the application of PEEP.NEW & NOTEWORTHY We demonstrate that PEEP causes changes in diaphragm geometry, especially muscle shortening, and decreases in vivo diaphragm contractile function. Thus, prerequisites for the development of diaphragm longitudinal muscle atrophy are present with the acute application of PEEP. Once confirmed in ventilated critically ill patients, this could provide a new mechanism for ventilator-induced diaphragm dysfunction and ventilator weaning failure in the intensive care unit (ICU).

Transcriptome profiling of the diaphragm in a controlled mechanical ventilation model reveals key genes involved in ventilator-induced diaphragmatic dysfunction

BackgroundVentilator-induced diaphragmatic dysfunction (VIDD) is associated with weaning difficulties, intensive care unit hospitalization (ICU), infant mortality, and poor long-term clinical outcomes. The expression patterns of long noncoding RNAs (lncRNAs) and mRNAs in the diaphragm in a rat controlled mechanical ventilation (CMV) model, however, remain to be investigated.ResultsThe diaphragms of five male Wistar rats in a CMV group and five control Wistar rats were used to explore lncRNA and mRNA expression profiles by RNA-sequencing (RNA-seq). Muscle force measurements and immunofluorescence (IF) staining were used to verify the successful establishment of the CMV model. A total of 906 differentially expressed (DE) lncRNAs and 2,139 DE mRNAs were found in the CMV group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions or pathways of these DE mRNAs. Our results revealed that these DE mRNAs were related mainly related to complement and coagulation cascades, the PPAR signaling pathway, cholesterol metabolism, cytokine-cytokine receptor interaction, and the AMPK signaling pathway. Some DE lncRNAs and DE mRNAs determined by RNA-seq were validated by quantitative real-time polymerase chain reaction (qRT-PCR), which exhibited trends similar to those observed by RNA-sEq. Co-expression network analysis indicated that three selected muscle atrophy-related mRNAs (Myog, Trim63, and Fbxo32) were coexpressed with relatively newly discovered DE lncRNAs.ConclusionsThis study provides a novel perspective on the molecular mechanism of DE lncRNAs and mRNAs in a CMV model, and indicates that the inflammatory signaling pathway and lipid metabolism may play important roles in the pathophysiological mechanism and progression of VIDD.

Point-of-Care Ultrasound Measurement of Diaphragm Thickening Fraction as a Predictor of Successful Extubation in Critically Ill Children.

Ventilation-induced diaphragm dysfunction can delay weaning from mechanical ventilation. Identifying the optimal time for extubation has always been a challenge for intensivists. Diaphragm ultrasound is gaining immense popularity as a surrogate to measure diaphragm function. We attempted to assess the utility of diaphragm function in predicting extubation success using point-of-care ultrasound examination. We conducted a prospective observational study in a single-center tertiary care pediatric intensive care unit (PICU). All children aged between 1 month and 16 years admitted to the PICU and who underwent invasive mechanical ventilation for more than 24 hours were included in the study. Children who died during mechanical ventilation and those with conditions affecting diaphragm function like neuromuscular disorders, pneumothorax, chronic respiratory diseases, and intraabdominal hypertension were excluded from the study. Diaphragm thickening fraction (DTf) was measured during spontaneous breathing trial and correlated to predict extubation success. We found that DTf is an independent predictor of extubation success. DTf more than or equal to 20% was associated with extubation success with a positive predictive value of 85%. The area under the curve for DTf showed good accuracy.