Controlled Mechanical Ventilation Research Articles

Placement of the feline V-gel Advanced supraglottic airway device and tracheal selectivity during controlled mechanical ventilation: a clinical and tomodensitometric evaluation.

The aims of the study was to assess the placement of the V-gel Advanced (V-gel-A) and to evaluate tracheal selectivity during controlled mechanical ventilation, using CT. In this prospective clinical study, 20 healthy cats undergoing general anaesthesia for an elective procedure underwent four successive CT scans from the nose to the mid-abdomen: at baseline (no device); after the placement of the V-gel-A, after a controlled mechanical ventilation (CMV) period of 5 mins; and after the placement of an endotracheal tube (ETT). Using both a purpose designed position score and a gas score estimating the quantity of gas in different digestive regions, the position of the V-gel-A and presence of gas in the digestive tract at each step were evaluated. Number of attempts and times required to place the V-gel-A and ETT were recorded and compared. The V-gel-A was found to be correctly placed, with position scores of 3/5 in six cats, 4/5 in 13 cats and 5/5 in one cat. Imperfect positioning was due to minor axial rotation or incomplete occlusion of the oesophagus by the tip of the device. The gas scores significantly increased after placement of the V-gel-A compared with baseline and after CMV was initiated. Correct positioning of the device was mostly achieved at the first attempt; no significant difference was found in the time required to place V-gel-A vs ETT, nor in the number of attempts (P >0.05). The V-gel-A was clinically easy to place and use in both spontaneous and controlled ventilation. The device properly fitted the larynx and was never observed to occlude the airway. However, incomplete occlusion of the oesophagus was frequently observed and may lead to a lack of complete tracheal selectivity.

A novel positive end-expiratory pressure titration using electrical impedance tomography in spontaneously breathing acute respiratory distress syndrome patients on mechanical ventilation: an observational study from the MaastrICCht cohort.

There is no universally accepted method for positive end expiratory pressure (PEEP) titration approach for patients on spontaneous mechanical ventilation (SMV). Electrical impedance tomography (EIT) guided PEEP-titration has shown promising results in controlled mechanical ventilation (CMV), current implemented algorithm for PEEP titration (based on regional compliance measurements) is not applicable in SMV. Regional peak flow (RPF, defined as the highest inspiratory flow rate based on EIT at a certain PEEP level) is a new method for quantifying regional lung mechanics designed for SMV. The objective is to study whether RPF by EIT is a feasible method for PEEP titration during SMV. Single EIT measurements were performed in COVID-19 ARDS patients on SMV. Clinical (i.e., tidal volume, airway occlusion pressure, end-tidal CO2) and mechanical (cyclic alveolar recruitment, recruitment, cumulative overdistension (OD), cumulative collapse (CL), pendelluft, and PEEP) outcomes were determined by EIT at several pre-defined PEEP thresholds (1-10% CL and the intersection of the OD and CL curves) and outcomes at all thresholds were compared to the outcomes at baseline PEEP. In total, 25 patients were included. No significant and clinically relevant differences were found between thresholds for tidal volume, end-tidal CO2, and P0.1 compared to baseline PEEP; cyclic alveolar recruitment rates changed by -3.9% to -37.9% across thresholds; recruitment rates ranged from - 49.4% to + 79.2%; cumulative overdistension changed from - 75.9% to + 373.4% across thresholds; cumulative collapse changed from 0% to -94.3%; PEEP levels from 10 up to 14 cmH2O were observed across thresholds compared to baseline PEEP of 10 cmH2O. A threshold of approximately 5% cumulative collapse yields the optimum compromise between all clinical and mechanical outcomes. EIT-guided PEEP titration by the RPF approach is feasible and is linked to improved overall lung mechanics) during SMV using a threshold of approximately 5% CL. However, the long-term clinical safety and effect of this approach remain to be determined.

Mechanically ventilated classrooms in central Italy's heritage school buildings: Proposal of archetypes and CO2 prediction models

This study proposed a typological analysis to identify the archetypes of classrooms equipped with controlled mechanical ventilation (CMV) in Italy and an experimental campaign on 58 typical classrooms to identify the main indoor microclimatic characteristics and CO2 concentrations. From the analyses carried out, general information was gathered on the heating systems and the main energy and acoustic improvements carried out in the schools. The typological analysis identified four different types of mechanical ventilation systems installed in three different classroom archetypes: wide, square and deep, with percentages of window area of 25 %, 30 % and 40 % respectively.The field measurement campaign showed that, in terms of CO2 concentration, mechanical ventilation was effective in the winter period, while in the mid-season and summer periods, natural ventilation was predominant due to the opening of windows by the occupants. Furthermore, in the case of manual control, incorrect use of the machine by the occupants, who reported noise-related problems or insufficient user training, resulted in CO2 levels above the recommended limits.Multivariate regressions developed for schools equipped with CMVs predicted maximum and average CO2 concentrations as a function of minimum and maximum indoor and outdoor temperatures with a significance (R2, correct) of 76 % and 83 % respectively.

Pressure Support Ventilation During Extracorporeal Membrane Oxygenation Support in Patients With Acute Respiratory Distress Syndrome.

In the initial phases of veno-venous extracorporeal membrane oxygenation (VV ECMO) support for severe acute respiratory distress syndrome (ARDS), ultraprotective controlled mechanical ventilation (CMV) is typically employed to limit the progression of lung injury. As patients recover, transitioning to assisted mechanical ventilation can be considered to reduce the need for prolonged sedation and paralysis. This study aimed to evaluate the feasibility of transitioning to pressure support ventilation (PSV) during VV ECMO and to explore variations in respiratory mechanics and oxygenation parameters following the transition to PSV. This retrospective monocentric study included 191 adult ARDS patients treated with VV ECMO between 2009 and 2022. Within this population, 131 (69%) patients were successfully switched to PSV during ECMO. Pressure support ventilation was associated with an increase in respiratory system compliance (p = 0.02) and a reduction in pulmonary shunt fraction (p < 0.001). Additionally, improvements in the cardiovascular Sequential Organ Failure Assessment score and a reduction in pulmonary arterial pressures (p < 0.05) were recorded. Ninety-four percent of patients who successfully transitioned to PSV were weaned from ECMO, and 118 (90%) were discharged alive from the intensive care unit (ICU). Of those who did not reach PSV, 74% died on ECMO, whereas the remaining patients were successfully weaned from extracorporeal support. In conclusion, PSV is feasible during VV ECMO and potentially correlates with improvements in respiratory function and hemodynamics.

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.

Improving the ventilation of a classroom to achieve heating energy savings and better indoor air quality

Indoor air quality and heating energy consumption are closely linked, especially in densely occupied spaces, as classrooms. In a classroom of Rennes University, a transient thermal simulation highlights the impact of ventilation on heating consumptions for different cases: (1) without controlled mechanical ventilation (CMV), (2) with a single flow CMV (SF CMV) of a regulatory flow of 18 m3.h−1. person−1 during periods of occupancy, and (3) a double flow CMV (DF CMV) whose flow is during periods of occupancy either equal to 18 m3.h−1. person−1 or (4) to 35 m3.h−1.person−1. The infiltration flowrate was evaluated experimentally using CO2 concentration measurements in the first case, which corresponds to the actual situation. In the normal use of the classroom with 30 persons inside, CO2 concentration exceeds 5000 ppm and the heating energy consumption is equal to 52 kWh.m−2.year−1. In case (2) and (3), CO2 concentration has a maximum level of 1350 ppm and the energy consumption is equal to 65 and 53 kWh.m−2.year−1, respectively. In case (4), the maximum CO2 concentration stays in the range 800-900 ppm without excessive heating consumption (58 kWh.m−2.year−1). Finally, by limiting the fresh air flowrate to 18 m3.h−1.person−1 in DF CMV and coupling it to a façade insulation (extra Case 5), the heating consumption is reduced to 32 kWh.m−2.year−1. These results are valuable within the context of the upcoming energy renovation strategy of the campus. Practical application In most schools, in France and elsewhere, insufficient ventilation flowrates are often observed compared to regulatory requirements. If compliance with ventilation standards and the subsequent revision of CMV installations are necessary to ensure the health of users, it is important to evaluate the energy cost of these renovations, and to identify the best choice to reduce heating consumptions. Our contribution is to compare different renovation choices in terms of two indicators: energy consumption and indoor air quality evaluated using CO2 concentration.

Controlled Mechanical Ventilation in Critically Ill Patients and the Potential Role of Venous Bagging in Acute Kidney Injury.

A very low incidence of acute kidney injury (AKI) has been observed in COVID-19 patients purposefully treated with early pressure support ventilation (PSV) compared to those receiving mainly controlled ventilation. The prevention of subdiaphragmatic venous congestion through limited fluid intake and the lowering of intrathoracic pressure is a possible and attractive explanation for this observed phenomenon. Both venous congestion, or "venous bagging", and a positive fluid balance correlate with the occurrence of AKI. The impact of PSV on venous return, in addition to the effects of limiting intravenous fluids, may, at least in part, explain this even more clearly when there is no primary kidney disease or the presence of nephrotoxins. Optimizing the patient-ventilator interaction in PSV is challenging, in part because of the need for the ongoing titration of sedatives and opioids. The known benefits include improved ventilation/perfusion matching and reduced ventilator time. Furthermore, conservative fluid management positively influences cognitive and psychiatric morbidities in ICU patients and survivors. Here, it is hypothesized that cranial lymphatic congestion in relation to a more positive intrathoracic pressure, i.e., in patients predominantly treated with controlled mechanical ventilation (CMV), is a contributing risk factor for ICU delirium. No studies have addressed the question of how PSV can limit AKI, nor are there studies providing high-level evidence relating controlled mechanical ventilation to AKI. For this perspective article, we discuss studies in the literature demonstrating the effects of venous congestion leading to AKI. We aim to shed light on early PSV as a preventive measure, especially for the development of AKI and ICU delirium and emphasize the need for further research in this domain.

Effect of end-inspiratory pause duration on respiratory system compliance calculation in mechanically ventilated dogs with healthy lungs

ObjectiveTo compare respiratory system compliance (CRS), expressed per kilogram of bodyweight (CRSBW), calculated without end-inspiratory pause (EIP) and after three EIP times (0.2, 0.5 and 1 seconds) with that after 3 second EIP (considered the reference EIP for static CRS) and to determine the EIP times that provided CRSBW values in acceptable agreement with static CRSBW during controlled mechanical ventilation (CMV) in anaesthetized dogs. Study designProspective, randomized, nonblinded, crossover clinical study. AnimalsA group of 24 client-owned dogs with healthy lungs undergoing surgery in lateral recumbency. MethodsDuring CMV in dogs undergoing general anaesthesia, five EIPs [0 (no EIP), 0.2, 0.5, 1 and 3 seconds] were consecutively applied in random order. Tidal volume (Vt) was set at 10 mL kg–1 and positive end-expiratory pressure (PEEP) was not applied. Respiratory rate and inspiratory time were established according to each EIP time, setting EIP between 0 and 50% of the inspiratory time. The CRSBW was calculated as [expired Vt/(plateau pressure – PEEP)]/bodyweight and recorded every 15 seconds for 2 minutes after a 5 minute equilibration period with each EIP. One-way anova for repeated measures and the Bland–Altman analysis were used to compare CRSBW and evaluate agreement between EIP times, respectively. ResultsThe CRSBW was significantly greater as the EIP time increased up to 1 second (p < 0.05). In the Bland–Altman analysis, none of the tested EIPs (0, 0.2, 0.5 and 1 seconds) provided 95% confidence intervals for limits of agreement within the maximum allowed difference considered for acceptable agreement with 3 second EIP. Conclusionsand clinical relevance An EIP ≤ to 1 second does not provide a CRSBW value in acceptable agreement with static CRSBW in healthy dogs. Besides, the application of an EIP ≤ to 0.5 seconds underestimates the static CRSBW to an increasing extent as the EIP time decreases.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. Retrospective observational cohort study. Twenty-four Italian ICUs from February 2020 to May 2020. Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Estimation of transpulmonary driving pressure during synchronized mechanical ventilation using a single lower assist maneuver (LAM) in rabbits: a comparison to measurements made with an esophageal balloon

BackgroundMechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath (“lower assist maneuver”, LAM).MethodsIn 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL (“PL_LAM”) using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath.ResultsAll animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland–Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist.ConclusionDuring synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.

Regional peak flow as a novel approach to assess regional pulmonary mechanics by electrical impedance tomography: an observational validation study.

Spontaneous breathing efforts during mechanical ventilation are a widely accepted weaning approach for acute respiratory distress syndrome (ARDS) patients. These efforts can be too vigorous, possibly inflicting lung and diaphragm damage. Higher positive end expiratory pressure (PEEP) levels can be used to lower the magnitude of vigorous breathing efforts. Nevertheless, PEEP titrating tools are lacking in spontaneous mechanical ventilation (SMV). Therefore, the aim is to develop an electrical impedance tomography (EIT) algorithm for quantifying regional lung mechanics independent from a stable plateau pressure phase based on regional peak flow (RPF) by EIT, which is hypothetically applicable in SMV and to validate this algorithm in patients on controlled mechanical ventilation (CMV). The RPF algorithm quantifies a cumulative overdistension (ODRPF) and collapse (CLRPF) rate and is validated in a prospective cohort of mechanically ventilated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients on CMV. ODRPF and CLRPF are compared with compliance-based cumulative overdistension (ODP500) and collapse (CLP500) rates from the Pulmovista 500 EIT device at multiple PEEP levels (PEEP 10 cmH2O to PEEP 24 cmH2O) in EIT measurements from CMV patients by linear mixed models, Bland-Altman analysis and intraclass correlation coefficient (ICC). Seventy-eight patients were included. Linear mixed models revealed an association between ODRPF and ODP500 of 1.02 (0.98-1.07, P<0.001) and between CLRPF and CLP500 of 0.93 (0.80-1.05, P<0.001). ICC values ranged from 0.78 to 0.86 (P<0.001) for ODRPF and ODP500 and from 0.70 to 0.85 (P<0.001) for CLRPF and CLP500 (PEEP 10 to PEEP 24). The mean bias between ODRPF and ODP500 in these PEEP levels ranged from 0.80% to 4.19% and from -1.31% to 0.13% between CLRPF and CLP500. A RPF approach for quantifying regional lung mechanics showed a moderate to good agreement in coronavirus disease 2019 (COVID-19) related ARDS patients on CMV compared to the compliance-based approach. This, in addition to being independent of a plateau pressure phase, indicates that the RPF approach is a valid method to explore for quantifying regional lung mechanics in SMV.

Improved understanding of the respiratory drive pathophysiology could lead to earlier spontaneous breathing in severe acute respiratory distress syndrome

Optimisation of the respiratory drive, as early as possible in the setting of severe acute respiratory distress syndrome (ARDS) and not its suppression, could be a new paradigm in the management of severe forms of ARDS. Severe ARDS is characterised by tachypnoea and hyperpnoea, a consequence of a high respiratory drive. Some patients require endotracheal intubation, controlled mechanical ventilation (CMV) and paralysis to prevent overt ventilatory failure and self-inflicted lung injury. Nevertheless, intubation, CMV and paralysis do not address per se the high respiratory drive, they only suppress it. Optimisation of the respiratory drive could be obtained by a multimodal approach that targets attenuation of fever, agitation, systemic and peripheral acidosis, inflammation, extravascular lung water and changes in carbon dioxide levels. The paradigm we present, based on pathophysiological considerations, is that as soon as these factors have been controlled, spontaneous breathing could resume because hypoxaemia is the least important input to the respiratory drive. Hypoxaemia could be handled by combining positive end-expiratory pressure (PEEP) to prevent early expiratory closure and low pressure support to minimise the work of breathing (WOB). ‘Cooperative’ sedation with alpha-2 agonists, supplemented with neuroleptics if required, is the pharmacological adjunct, administered immediately after intubation as the first-line sedation regimen during the multimodal approach. Given relative contraindications (hypovolaemia, auriculoventricular block, sick sinus syndrome), alpha-2 agonists can help attenuate or moderate fever, increased oxygen consumption VO2, agitation, high cardiac output, inflammation and acidosis. They may also help to preserve microcirculation, cognition and respiratory rhythm generation, thus promoting spontaneous breathing. Returning the physiology of respiratory, ventilatory, circulatory and autonomic systems to normal will support the paradigm of optimised respiratory drive favouring early spontaneous ventilation, at variance with deep sedation, extended paralysis, CMV and use of the prone position as therapeutic strategies in severe ARDS. GLOSSARY Glossary and Abbreviations_SDC, http://links.lww.com/EJAIC/A55

A prospective clinical study on the mechanisms underlying critical illness myopathy-A time-course approach.

Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P<0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P<0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P<0.007] and 50% [P<0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR<0.1), as well as a redistribution of zinc ions from plasma. The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Spontaneous breathing promotes lung injury in an experimental model of alveolar collapse

Vigorous spontaneous breathing has emerged as a promotor of lung damage in acute lung injury, an entity known as “patient self-inflicted lung injury”. Mechanical ventilation may prevent this second injury by decreasing intrathoracic pressure swings and improving regional air distribution. Therefore, we aimed to determine the effects of spontaneous breathing during the early stage of acute respiratory failure on lung injury and determine whether early and late controlled mechanical ventilation may avoid or revert these harmful effects. A model of partial surfactant depletion and lung collapse was induced in eighteen intubated pigs of 32 ±4 kg. Then, animals were randomized to (1) SB‐group: spontaneous breathing with very low levels of pressure support for the whole experiment (eight hours), (2) Early MV-group: controlled mechanical ventilation for eight hours, or (3) Late MV-group: first half of the experiment on spontaneous breathing (four hours) and the second half on controlled mechanical ventilation (four hours). Respiratory, hemodynamic, and electric impedance tomography data were collected. After the protocol, animals were euthanized, and lungs were extracted for histologic tissue analysis and cytokines quantification. SB-group presented larger esophageal pressure swings, progressive hypoxemia, lung injury, and more dorsal and inhomogeneous ventilation compared to the early MV-group. In the late MV-group switch to controlled mechanical ventilation improved the lung inhomogeneity and esophageal pressure swings but failed to prevent hypoxemia and lung injury. In a lung collapse model, spontaneous breathing is associated to large esophageal pressure swings and lung inhomogeneity, resulting in progressive hypoxemia and lung injury. Mechanical ventilation prevents these mechanisms of patient self-inflicted lung injury if applied early, before spontaneous breathing occurs, but not when applied late.

Age‐dependent differences in the ventilator‐induced diaphragm dysfunction (VIDD): A multi‐omics study

Introduction &amp; ObjectiveMechanical ventilation is a life‐saving intervention in patients with respiratory failure. Controlled mechanical ventilation (CMV) is the mode of mechanical ventilation used in patients with an insufficient central respiratory drive and frequently used in COVID‐19 patients ventilated in the prone position. However, CMV is also associated with negative consequences for the major respiratory muscle the diaphragm, i.e., the ventilator induced diaphragm dysfunction (VIDD). VIDD is the major factor underlying the delayed weaning from the ventilator especially in old intensive care unit (ICU) patients. The age‐related difference in mortality rate has become a major concern during the COVID‐19 pandemic. The current experimental study was undertaken to improve our understanding the mechanisms underlying age‐related differences in the response to CMV using a unique experimental ICU model allowing long‐term studies in a rat exposed CMV.Materials and MethodsYoung (7‐8 months) and old (28‐32 months) female F344 BN hybrid rats were exposed to the ICU condition for 5 days (anaesthetized, mechanically ventilated, and pharmacologically paralyzed by post‐synaptic blockade of the neuromuscular transmission). Transcriptomics (RNA‐Seq) and proteomics (Olink) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition.ResultsAccording to multi‐omics analyses, significant differences were observed in the diaphragm between young and old rats in response to ICU condition. In the diaphragm of young rats, CMV resulted in decreases in the biological processes related to energy metabolism and production as indicated by the downregulation of pathway like “glycolysis/gluconeogenesis”, “fatty acid metabolism”, “TCA cycle”, and “oxidative phosphorylation”, etc. On the other hand, in the diaphragm of old rats, dramatic immune and inflammatory responses were observed after CMV, as reflected in the upregulation of “Cytokine‐cytokine receptor interaction”, “TNF signaling pathway”, “IL‐17 signaling pathway”, etc. Transcriptomic results were consistent with plasma proteomics analyses, i.e., CMV induced a higher level of inflammatory factors and cytokines/chemokines in old rats.ConclusionsAfter 5‐days exposure to CMV, our multi‐omics study demonstrated age‐related inflammatory response to long‐term mechanical ventilation.Significance/ImplicationThus, CMV should be cautiously used and restricted to as short duration as possible, especially in the old patients. In the current COVID‐19 pandemic, the dramatically increased mortality in old ICU patients with COVID‐19‐associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the VIDD and hyperinflammatory responses induced by CMV per se.

Ruxolitinib Prevents Ventilator Induced Diaphragm Dysfunction

Mechanical ventilation (MV), however brief results in the loss of diaphragm muscle mass and strength, termed ventilator induced diaphragm dysfunction (VIDD). VIDD increases dependence, complicates and prolongs weaning and significantly increases discharge mortality rate and health care costs worldwide. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway was recently identified as an important signalling pathway implicated in VIDD, upregulated in the diaphragm following MV and limb muslces during critical care. Regulation of STAT3 is imperritve to skeletal muscle mass and function, as STAT3 is required in proper muscle growth and regeneration, while chronic activation of STAT3 is implicated in muscle dysfunction. As JAK/STAT pathway inhibition can restrict the development of chronic muscle wasting conditons, this study aimed to explore the therapeutic potential of Ruxolitinib, an approved JAK1/2 inhibitor for myelofibrosis, for treatment of CIM. We hypothesised Ruxolitinib would reduce loss of muscle mass and function associated with VIDD. Here, rats were subjected to five days controlled MV (CMV) with and without daily Ruxolitinib gavage. Five‐days CMV significantly reduced diaphragm muscle size and impaired specific force, which was associated with 2‐fold upregulation of P‐STAT3, disrupted mitochondrial structure and respiratory function. Expression of the motor protein myosin was not affected, however CMV may alter myosin function through deamidation post translational modification. Ruxolitinib increases five‐day survival rate, restored P‐STAT3 expression and preserved diaphragm muscle size and specific force. These functional improvements were associated with improved mitochondrial structure, augmented mitochondrial respiratory function and reversal or augmentation of myosin deamidations. These results provide evidence of the preclinical potential of repurposing Ruxolitinib for the treatment of VIDD.

A prospective clinical study on the mechanisms underlying Critical Illness Myopathy – A time‐course approach

BackgroundCritical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, and prolonged weaning from the ventilator. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences which has become increasingly evident during the current COVID‐19 pandemic, but underlying mechanisms remain elusive.MethodsTen neuro‐ICU patients exposed to long‐term controlled mechanical ventilation (CMV) were followed with repeated muscle biopsies 3times/week for up to 12 days. Single muscle fiber contractile recordings were conducted on the first and final biopsy. A multiomics approach was taken to analyze gene and protein expression in muscle and plasma at all six timepoints.Findingsi) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro‐ICU patients during the observation period. The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins and activation of protein degradation pathways, resulting in significant muscle fiber atrophy and loss in force generation capacity which declined &gt;65% during the 12‐day observation period, ii) membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves, and iii), analyses of plasma revealed early activation of inflammatory and proinflammatory pathways, as well as a redistribution of zinc ions from plasma in parallel with the activation of zinc transporters.InterpretationThe mechanical ventilation induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM. It is therefore suggested that future intervention strategies should target the lung injury and the mechanical silencing in critical ill ICU patients.

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.

Unusual pericuff leak around proseal-laryngeal mask airway corrected by clamping gastric drain port: A case report

ProSealTM-Laryngeal Mask Airway (PLMA) (Laryngeal Mask Company, Henley-on Thames, UK) is commonly used for securing the airway with an added advantage over classic LMA as its gastric drain tube allows the insertion of Ryle’s tube and suctioning of gastric contents. The ProSeal LMA is designed in such a way that it allows controlled mechanical ventilation. During controlled mechanical ventilation, air leaks can occur because of positive airway pressures. Air leaks from the gastric drain port are almost always due to the malposition of PLMA. Here, we report a case of air leak from gastric drain port despite correctly placed PLMA and its successful management without removing the device.

Individualized positive end-expiratory pressure following alveolar recruitment manoeuvres in lung-healthy anaesthetized dogs: a randomized clinical trial on early postoperative arterial oxygenation

ObjectiveTo assess and compare the effect of intraoperative stepwise alveolar recruitment manoeuvres (ARMs), followed by individualized positive end-expiratory pressure (PEEP), defined as PEEP at maximal respiratory system compliance + 2 cmH2O (PEEPmaxCrs+2), with that of spontaneous ventilation (SV) and controlled mechanical ventilation (CMV) without ARM or PEEP on early postoperative arterial oxygenation in anaesthetized healthy dogs. Study designProspective, randomized, nonblinded clinical study. AnimalsA total of 32 healthy client-owned dogs undergoing surgery in dorsal recumbency. MethodsDogs were ventilated intraoperatively (inspired oxygen fraction: 0.5) with one of the following strategies: SV, CMV alone, and CMV with PEEPmaxCrs+2 following a single ARM (ARM1) or two ARMs (ARM2, the second ARM at the end of surgery). Arterial blood gas analyses were performed before starting the ventilatory strategy, at the end of surgery, and at 5, 10, 15, 30 and 60 minutes after extubation while breathing room air. Data were analysed using Kruskal-Wallis and Friedman tests (p < 0.050). ResultsAt any time point after extubation, PaO2 was not significantly different between groups. At 5 minutes after extubation, PaO2 was 95.1 (78.1–104.0), 93.8 (88.3–104.0), 96.9 (86.6–115.0) and 89.1 (87.6–102.0) mmHg in the SV, CMV, ARM1 and ARM2 groups, respectively. PaO2 decreased at 30 minutes after extubation in the CMV, ARM1 and ARM2 groups (p < 0.050), but it did not decrease after 30 minutes in the SV group. Moderate hypoxaemia (PaO2, 60–80 mmHg) was observed in one dog in the ARM1 group and two dogs each in the SV and ARM2 groups. Conclusions and clinical relevanceIntraoperative ARMs, followed by PEEPmaxCrs+2, did not improve early postoperative arterial oxygenation compared with SV or CMV alone in healthy anaesthetized dogs. Therefore, this ventilatory strategy might not be clinically advantageous for improving postoperative arterial oxygenation in healthy dogs undergoing surgery when positioned in dorsal recumbency.