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

BACKGROUND: 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. METHODS: 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 12 days. 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. RESULTS: (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 12 day 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. CONCLUSIONS: 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.

The Modulation of Interferon Regulatory Factor-1 via Caspase-1-Mediated Alveolar Macrophage Pyroptosis in Ventilator-Induced Lung Injury.

Background: To examine the role of interferon regulatory factor-1 (IRF-1) and to explore the potential molecular mechanism in ventilator-induced lung injury. Methods: Wild-type C57BL/6 mice and IRF-1 gene knockout mice/caspase-1 knockout mice were mechanically ventilated with a high tidal volume to establish a ventilator-related lung injury model. The supernatant of the alveolar lavage solution and the lung tissues of these mice were collected. The degree of lung injury was examined by hematoxylin and eosin staining. The protein and mRNA expression levels of IRF-1, caspase-1 (p10), and interleukin (IL)-1ß (p17) in lung tissues were measured by western blot and quantitative real-time polymerase chain reaction, respectively. Pyroptosis of alveolar macrophages was detected by flow cytometry and western blotting for active caspase-1 and cleaved GSDMD. An enzyme-linked immunosorbent assay was used to measure the levels of IL-1ß, IL-18, IL-6, TNF-α, and high mobility group box protein 1 (HMGB-1) in alveolar lavage fluid. Results: IRF-1 expression and caspase-1-dependent pyroptosis in lung tissues of wild-type mice were significantly upregulated after mechanical ventilation with a high tidal volume. The degree of ventilator-related lung injury in IRF-1 gene knockout mice and caspase-1 knockout mice was significantly improved compared to that in wild-type mice, and the levels of GSDMD, IL-1ß, IL-18, IL-6, and HMGB-1 in alveolar lavage solution were significantly reduced (P < 0.05). The expression levels of caspase-1 (p10), cleaved GSDMD, and IL-1ß (p17) proteins in lung tissues of IRF-1 knockout mice with ventilator-related lung injury were significantly lower than those of wild-type mice, and the level of pyroptosis of macrophages in alveolar lavage solution was significantly reduced. Conclusions: IRF-1 may aggravate ventilator-induced lung injury by regulating the activation of caspase-1 and the focal death of alveolar macrophages.

c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury.

BACKGROUND: As one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis. METHODS: The SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected. RESULTS: c-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway. CONCLUSIONS: c-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

Constant Vt Ventilation and Surfactant Dysfunction: An Overlooked Cause of Ventilator-induced Lung Injury.

Ventilator-induced lung injury (VILI) is currently ascribed to volutrauma and/or atelectrauma, but the effect of constant Vt ventilation (CVtV) has received little attention. This Perspective summarizes the literature documenting that CVtV causes VILI and reviews the mechanisms by which it occurs. Surfactant is continuously inactivated, depleted, displaced, or desorbed as a function of the duration of ventilation, the Vt, the level of positive end-expiratory pressure (PEEP), and possibly the respiratory rate. Accordingly, surfactant must be continuously replenished, and secretion primarily depends on intermittent delivery of large ventilatory excursions. The surfactant abnormalities resulting from CVtV result in atelectasis and VILI. Although surfactant secretion is reduced by the absence of intermittent deep breaths, continuous administration of large Vts depletes surfactant and impairs subsequent secretion. Low or normal lung volumes result in desorption of surfactant. PEEP can be protective by reducing surface film collapse and subsequent film rupture on reexpansion, and/or by reducing surfactant displacement into the airways, but PEEP can also downregulate surfactant release. The effect of CVtV on surfactant is complex. If attention is not paid to facilitating surfactant secretion and limiting its inactivation, depletion, desorption, or displacement, surface tension will increase and atelectasis and VILI will occur.

mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.

Secreted Extracellular Cyclophilin A Is a Novel Mediator of Ventilator-induced Lung Injury.

Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator-induced lung injury. eCypA (extracellular CypA [cyclophilin A]) is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to coronavirus disease (COVID-19). Objectives: To explore the involvement of eCypA in the pathophysiology of ventilator-induced lung injury. Methods: Mice were ventilated with a low or high Vt for up to 3 hours, with or without blockade of eCypA signaling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretching to explore the cellular source of eCypA, and CypA concentrations were measured in BAL fluid from patients with acute respiratory distress syndrome to evaluate the clinical relevance. Measurements and Main Results: High-Vt ventilation in mice provoked a rapid increase in soluble CypA concentration in the alveolar space but not in plasma. In vivo ventilation and in vitro stretching experiments indicated the alveolar epithelium as the likely major source. In vivo blockade of eCypA signaling substantially attenuated physiological dysfunction, macrophage activation, and MMPs (matrix metalloproteinases). Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated concentrations of eCypA within BAL fluid. Conclusions: CypA is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. eCypA represents an exciting novel target for pharmacological intervention.

Imaging atelectrauma in Ventilator-Induced Lung Injury using 4D X-ray microscopy.

Mechanical ventilation can damage the lungs, a condition called Ventilator-Induced Lung Injury (VILI). However, the mechanisms leading to VILI at the microscopic scale remain poorly understood. Here we investigated the within-tidal dynamics of cyclic recruitment/derecruitment (R/D) using synchrotron radiation phase-contrast imaging (PCI), and the relation between R/D and cell infiltration, in a model of Acute Respiratory Distress Syndrome in 6 anaesthetized and mechanically ventilated New-Zealand White rabbits. Dynamic PCI was performed at 22.6 µm voxel size, under protective mechanical ventilation [tidal volume: 6 ml/kg; positive end-expiratory pressure (PEEP): 5 cmH2O]. Videos and quantitative maps of within-tidal R/D showed that injury propagated outwards from non-aerated regions towards adjacent regions where cyclic R/D was present. R/D of peripheral airspaces was both pressure and time-dependent, occurring throughout the respiratory cycle with significant scatter of opening/closing pressures. There was a significant association between R/D and regional lung cellular infiltration (p = 0.04) suggesting that tidal R/D of the lung parenchyma may contribute to regional lung inflammation or capillary-alveolar barrier dysfunction and to the progression of lung injury. PEEP may not fully mitigate this phenomenon even at high levels. Ventilation strategies utilizing the time-dependence of R/D may be helpful in reducing R/D and associated injury.

Strain-specific differences in lung tissue viscoelasticity of mechanically ventilated infant Sprague-Dawley and Wistar rats.

Rats are often used in ventilator-induced lung injury (VILI) models. However, strain-specific susceptibility for VILI has not been elucidated yet. The aim of this study was to demonstrate strain-specific differences in VILI in infant Sprague-Dawley and Wistar rats. VILI was compared in 2-wk-old pups after 8 h of protective or injurious ventilation. Pups were ventilated with tidal volumes (VT) of ∼7 mL/kg and positive end-expiratory pressures (PEEP) of 6 cmH2O (VT7 PEEP6) or with VT of ∼21 mL/kg and PEEP 2 cmH2O (VT21 PEEP2). Interleukin-6, macrophage inflammatory protein-2 (MIP-2), inflammatory cells, and albumin in bronchoalveolar lavage fluid (BALF); histology; and low-frequency forced oscillation technique (LFOT) and pressure-volume (PV) maneuvers were assessed. Alveolar macrophages, neutrophils, and MIP-2 derived from BALF revealed more pronounced VILI after VT21 PEEP2 in both strains. LFOT and PV analyses demonstrated rat strain-specific differences both at baseline and particularly in response to VT21 PEEP2 ventilation. Sprague-Dawley rats showed higher airway and tissue resistance and elastance values with no difference in hysteresivity between ventilation strategies. Wister rats challenged by VT21 PEEP2 experienced significantly more energy dissipation when compared with VT7 PEEP6 ventilation. In conclusion, both rat strains are useful for VILI models. The degree of VILI severity depends on ventilation strategy and selected strain. However, fundamental and time-dependent differences in respiratory system mechanics exist and reflect different lung tissue viscoelasticity. Hence, strain-specific characteristics of the respiratory system need to be considered when planning and interpreting VILI studies with infant rats.

Five novel clinical phenotypes for critically ill patients with mechanical ventilation in intensive care units: a retrospective and multi database study.

BACKGROUND: Although protective mechanical ventilation (MV) has been used in a variety of applications, lung injury may occur in both patients with and without acute respiratory distress syndrome (ARDS). The purpose of this study is to use machine learning to identify clinical phenotypes for critically ill patients with MV in intensive care units (ICUs). METHODS: A retrospective cohort study was conducted with 5013 patients who had undergone MV and treatment in the Department of Critical Care Medicine, Peking Union Medical College Hospital. Statistical and machine learning methods were used. All the data used in this study, including demographics, vital signs, circulation parameters and mechanical ventilator parameters, etc., were automatically extracted from the electronic health record (EHR) system. An external database, Medical Information Mart for Intensive Care III (MIMIC III), was used for validation. RESULTS: Phenotypes were derived from a total of 4009 patients who underwent MV using a latent profile analysis of 22 variables. The associations between the phenotypes and disease severity and clinical outcomes were assessed. Another 1004 patients in the database were enrolled for validation. Of the five derived phenotypes, phenotype I was the most common subgroup (n = 2174; 54.2%) and was mostly composed of the postoperative population. Phenotype II (n = 480; 12.0%) led to the most severe conditions. Phenotype III (n = 241; 6.01%) was associated with high positive end-expiratory pressure (PEEP) and low mean airway pressure. Phenotype IV (n = 368; 9.18%) was associated with high driving pressure, and younger patients comprised a large proportion of the phenotype V group (n = 746; 18.6%). In addition, we found that the mortality rate of Phenotype IV was significantly higher than that of the other phenotypes. In this subgroup, the number of patients in the sequential organ failure assessment (SOFA) score segment (9,22] was 198, the number of deaths was 88, and the mortality rate was higher than 44%. However, the cumulative 28-day mortality of Phenotypes IV and II, which were 101 of 368 (27.4%) and 87 of 480 (18.1%) unique patients, respectively, was significantly higher than those of the other phenotypes. There were consistent phenotype distributions and differences in biomarker patterns by phenotype in the validation cohort, and external verification with MIMIC III further generated supportive results. CONCLUSIONS: Five clinical phenotypes were correlated with different disease severities and clinical outcomes, which suggested that these phenotypes may help in understanding heterogeneity in MV treatment effects.

Perioperative Lung Protection: Clinical Implications.

In the past, it was common practice to use a high tidal volume (VT) during intraoperative ventilation, because this reduced the need for high oxygen fractions to compensate for the ventilation-perfusion mismatches due to atelectasis in a time when it was uncommon to use positive end-expiratory pressure (PEEP) in the operating room. Convincing and increasing evidence for harm induced by ventilation with a high VT has emerged over recent decades, also in the operating room, and by now intraoperative ventilation with a low VT is a well-adopted approach. There is less certainty about the level of PEEP during intraoperative ventilation. Evidence for benefit and harm of higher PEEP during intraoperative ventilation is at least contradicting. While some PEEP may prevent lung injury through reduction of atelectasis, higher PEEP is undeniably associated with an increased risk of intraoperative hypotension that frequently requires administration of vasoactive drugs. The optimal level of inspired oxygen fraction (FIO2) during surgery is even more uncertain. The suggestion that hyperoxemia prevents against surgical site infections has not been confirmed in recent research. In addition, gas absorption-induced atelectasis and its association with adverse outcomes like postoperative pulmonary complications actually makes use of a high FIO2 less attractive. Based on the available evidence, we recommend the use of a low VT of 6-8 mL/kg predicted body weight in all surgery patients, and to restrict use of a high PEEP and high FIO2 during intraoperative ventilation to cases in which hypoxemia develops. Here, we prefer to first increase FIO2 before using high PEEP.

Monitoring lung impedance changes during long-term ventilator-induced lung injury ventilation using electrical impedance tomography.

OBJECTIVE: The target of this methodological evaluation was the feasibility of long-term monitoring of changes in lung conditions by time-difference electrical impedance tomography (tdEIT). In contrast to ventilation monitoring by tdEIT, the monitoring of end-expiratory (EELIC) or end-inspiratory (EILIC) lung impedance change always requires a reference measurement. APPROACH: To determine the stability of the used Pulmovista 500® EIT system, as a prerequisite it was initially secured on a resistive phantom for 50 h. By comparing the slopes of EELIC for the whole lung area up to 48 h from 36 pigs ventilated at six positive end-expiratory pressure (PEEP) levels from 0 to 18 cmH2O we found a good agreement (range of r 2 = 0.93-1.0) between absolute EIT (aEIT) and tdEIT values. This justified the usage of tdEIT with its superior local resolution compared to aEIT for long-term determination of EELIC. MAIN RESULTS: The EELIC was between -0.07 Ωm day-1 at PEEP 4 and -1.04 Ωm day-1 at PEEP 18 cmH2O. The complex local time pattern for EELIC was roughly quantified by the new parameter, centre of end-expiratory change (CoEEC), in equivalence to the established centre of ventilation (CoV). The ventrally located mean of the CoV was fairly constant in the range of 42%-46% of thorax diameter; however, on the contrary, the CoEEC shifted from about 40% to about 75% in the dorsal direction for PEEP levels of 14 and 18 cmH2O. SIGNIFICANCE: The observed shifts started earlier for higher PEEP levels. Changes of EELI could be precisely monitored over a period of 48 h by tdEIT on pigs.

The POOR Get POORer: A Hypothesis for the Pathogenesis of Ventilator-induced Lung Injury.

Protective ventilation strategies for the injured lung currently revolve around the use of low Vt, ostensibly to avoid volutrauma, together with positive end-expiratory pressure to increase the fraction of open lung and reduce atelectrauma. Protective ventilation is currently applied in a one-size-fits-all manner, and although this practical approach has reduced acute respiratory distress syndrome deaths, mortality is still high and improvements are at a standstill. Furthermore, how to minimize ventilator-induced lung injury (VILI) for any given lung remains controversial and poorly understood. Here we present a hypothesis of VILI pathogenesis that potentially serves as a basis upon which minimally injurious ventilation strategies might be developed. This hypothesis is based on evidence demonstrating that VILI begins in isolated lung regions manifesting a Permeability-Originated Obstruction Response (POOR) in which alveolar leak leads to surfactant dysfunction and increases local tissue stresses. VILI progresses topographically outward from these regions in a POOR-get-POORer fashion unless steps are taken to interrupt it. We propose that interrupting the POOR-get-POORer progression of lung injury relies on two principles: 1) open the lung to minimize the presence of heterogeneity-induced stress concentrators that are focused around the regions of atelectasis, and 2) ventilate in a patient-dependent manner that minimizes the number of lung units that close during each expiration so that they are not forced to rerecruit during the subsequent inspiration. These principles appear to be borne out in both patient and animal studies in which expiration is terminated before derecruitment of lung units has enough time to occur.

Elastic power but not driving power is the key promoter of ventilator-induced lung injury in experimental acute respiratory distress syndrome.

BACKGROUND: We dissected total power into its primary components to resolve its relative contributions to tissue damage (VILI). We hypothesized that driving power or elastic (dynamic) power offers more precise VILI risk indicators than raw total power. The relative correlations of these three measures of power with VILI-induced histologic changes and injury biomarkers were determined using a rodent model of acute respiratory distress syndrome (ARDS). Herein, we have significantly extended the scope of our previous research. METHODS: Data analyses were performed in male Wistar rats that received endotoxin intratracheally to induce ARDS. After 24 h, they were randomized to 1 h of volume-controlled ventilation with low VT = 6 ml/kg and different PEEP levels (3, 5.5, 7.5, 9.5, and 11 cmH2O). Applied levels of driving power, dynamic power inclusive of PEEP, and total power were correlated with VILI indicators [lung histology and biological markers associated with inflammation (interleukin-6), alveolar stretch (amphiregulin), and epithelial (club cell protein (CC)-16) and endothelial (intercellular adhesion molecule-1) cell damage in lung tissue]. RESULTS: Driving power was higher at PEEP-11 than other PEEP levels. Dynamic power and total power increased progressively from PEEP-5.5 and PEEP-7.5, respectively, to PEEP-11. Driving power, dynamic power, and total power each correlated with the majority of VILI indicators. However, when correlations were performed from PEEP-3 to PEEP-9.5, no relationships were observed between driving power and VILI indicators, whereas dynamic power and total power remained well correlated with CC-16 expression, alveolar collapse, and lung hyperinflation. CONCLUSIONS: In this mild-moderate ARDS model, dynamic power, not driving power alone, emerged as the key promoter of VILI. Moreover, hazards from driving power were conditioned by the requirement to pass a tidal stress threshold. When estimating VILI hazard from repeated mechanical strains, PEEP must not be disregarded as a major target for modification.

Males Receive Low-Tidal Volume Component of Lung Protective Ventilation More Frequently than Females in the Emergency Department.

INTRODUCTION: Mechanical ventilation is a commonly performed procedure in the emergency department (ED). Approximately 240,000 patients per year receive mechanical ventilation in the ED representing 0.23% of ED visits. An ED-based trial published in 2017 showed that a bundle of interventions in mechanically ventilated patients, including low tidal volume ventilation, reduced the development of acute respiratory distress syndrome by nearly 50%. Prior literature has shown that as many as 40% of ED patients do not receive lung protective ventilation. Our goal was to determine whether differences exist between the percent of males vs females who are ventilated at ≥ 8 milliliters per kilogram (mL/kg) of predicted body weight. METHODS: We conducted this study at Temple University Hospital, a tertiary care center located in Philadelphia, Pennsylvania. This was a planned subgroup analysis of study looking at interventions to improve adherence to recommended tidal volume settings. We used a convenience sample of mechanically ventilated patients in our ED between September 1, 2017, and September 30, 2018. All adult patient > 18 years old were eligible for inclusion in the study. Our primary outcome measure was the number of patients who had initial tidal volumes set at > 8 mL/kg of predicted body weight. Our secondary outcome was the number of patients who had tidal volumes set at ≥ 8 mL/kg at 60 minutes after initiation of mechanical ventilation. RESULTS: A total of 130 patients were included in the final analysis. We found that significantly more females were initially ventilated with tidal volumes ≥ 8 mL/kg compared to men: 56% of females vs 9% of males (p=<0.001). Data was available for 107 patients (82%) who were in the ED at 60 minutes after initiation of mechanical ventilation. Again, a significantly larger percentage of females were ventilated with tidal volumes ≥ 8 mL/kg at 60 minutes: 56% of females vs 10% of males (p<0.001). CONCLUSION: The vast majority of tidal volumes ≥ 8 mL/kg during mechanical ventilation occurs in females. We suggest that objective measurements, such as a tape measure and tidal volume card, be used when setting tidal volumes for all patients, especially females.

Lung injury in brain ischemia/reperfusion is exacerbated by mechanical ventilation with moderate tidal volume in rats.

Ischemic stroke is one of the most frequent causes of injury in the central nervous system which may lead to multiorgan dysfunction, including in the lung. The aim of this study was to investigate whether brain ischemia/reperfusion with or without mechanical ventilation leads to lung injury. Male Sprague-Dawley rats were assigned to four groups: Sham, 1-h brain ischemia (MCAO)/24-h reperfusion (I/R), mechanical ventilation with moderate tidal volume (MTV), and I/R+MTV. The pulmonary capillary permeability (Kfc) was measured in the isolated perfused lung. Mean arterial blood pressure (MAP), heart rate (HR), blood-gas variables, histopathological parameters, lung glutathione peroxidase, and TNF-α were measured. Kfc in the I/R, MTV, and I/R+MTV groups were higher than that in the Sham group. In the I/R, MTV, and I/R+MTV groups, arterial partial pressures of oxygen and the arterial partial pressure of oxygen/fraction of inspired oxygen ratios were lower, whereas arterial partial pressures of carbon dioxide were higher than those in the Sham group. The histopathological score in the I/R group was more than that in the Sham group, and in the MTV and I/R+MTV groups were higher than those in the Sham and I/R groups. Furthermore, there were stepwise rises in TNF-α in the I/R, MTV, and I/R+MTV groups, respectively. There was no significant difference in MAP between groups. However, HR in the MTV group was higher than that in the Sham group. Brain ischemia/reperfusion leads to pulmonary capillary endothelial damage and the impairment of gas exchange in the alveolar-capillary barrier, which is exacerbated by mechanical ventilation with moderate tidal volume partially linked to inflammatory reactions.

Thyroid Function Modulates Lung Fluid and Alveolar Viscoelasticity in Mechanically Ventilated Rat.

BACKGROUND: Mechanical ventilation (MV) is life saving; yet it may induce severe lung injury and lead to multisystem organ failure and death. Thyroid hormones (THs) promote alveolar fluid clearance and alleviates hypoxia-induced lung injury. Given that the mechanism involved in hypoxia-induced lung injury is different from that of ventilator-induced lung injury, we examined the effects of thyroid function on lung extravascular fluid (LF), aquaporin 5 (AQP 5) expression, and alveolar viscoelasticity (AVE) in mechanically ventilated rat. METHODS: Hypothyroid (hypo) and hyperthyroid (hyper) animals were generated by administration of metimazole and L-thyroxine, respectively. Lung injury was induced by high-tidal volume MV. The LF was estimated by lung wet weight-to-dry weight ratio assessment. Expression of AQP 5 was evaluated by western blotting and in situ immunohistochemistry. The AVE was judged by elastic lung pressure/volume curve recording. RESULTS: Injurious MV significantly reduced lung AQP 5 expression and altered LF and AVE in a thyroid function-dependent manner. Regardless of animals' ventilation mode, hyper state caused significant reductions in LF and lung AQP 5 protein. It also improved AVE irrespective of animals' ventilation mode. The effects of hypo condition on LF, AQP 5 expression, and AVE were in contrast to that of hyper state. CONCLUSIONS: These data indicate that thyroid function has profound effects on LF, AQP 5, and AVE in mechanically ventilated lungs. Given that the effects of thyroidal status were as prominent as that of injurious MV, we suggest that thyroid function should be considered when patients are to be subjected to MV.

Protective effects of aerosolized pulmonary surfactant powder in a model of ventilator-induced lung injury.

Mechanical ventilation may contribute to the impairment of the pulmonary surfactant system, which is one of the mechanisms leading to the progression of acute lung injury. To investigate the potential protective effects of pulmonary surfactant in a rat model of ventilator-induced lung injury, the surfactant powder was aerosolized using an in-house made device designed to deliver the aerosolized powder to the inspiratory line of a rodent ventilator circuit. Rats were randomized to (i) administration of aerosolized recombinant surfactant protein C based pulmonary surfactant, (ii) intratracheally instillation of the same surfactant re-constituted in saline, and (iii) no treatment. Animals were monitored during 2 h of high-tidal volume mechanical ventilation, after which rats were sacrificed, and further analysis of lung mechanics and surfactant function were completed. Blood gas measurements during ventilation showed extended maintenance of oxygen levels above 400 mmHg in aerosol treated animals over non-treated and instilled groups, while total protein analysis showed reduced levels in the aerosol compared to non-treated groups. Dynamic captive bubble surface tension measurements showed the activity of surfactant recovered from aerosol treated animals is maintained below 1 mN/m. The prophylactic treatment of aerosolized surfactant powder reduced the severity of lung injury in this model.

Extracorporeal Membrane Oxygenation for Respiratory Failure.

This review focuses on the use of veno-venous extracorporeal membrane oxygenation for respiratory failure across all blood flow ranges. Starting with a short overview of historical development, aspects of the physiology of gas exchange (i.e., oxygenation and decarboxylation) during extracorporeal circulation are discussed. The mechanisms of phenomena such as recirculation and shunt playing an important role in daily clinical practice are explained.Treatment of refractory and symptomatic hypoxemic respiratory failure (e.g., acute respiratory distress syndrome [ARDS]) currently represents the main indication for high-flow veno-venous-extracorporeal membrane oxygenation. On the other hand, lower-flow extracorporeal carbon dioxide removal might potentially help to avoid or attenuate ventilator-induced lung injury by allowing reduction of the energy load (i.e., driving pressure, mechanical power) transmitted to the lungs during mechanical ventilation or spontaneous ventilation. In the latter context, extracorporeal carbon dioxide removal plays an emerging role in the treatment of chronic obstructive pulmonary disease patients during acute exacerbations. Both applications of extracorporeal lung support raise important ethical considerations, such as likelihood of ultimate futility and end-of-life decision-making. The review concludes with a brief overview of potential technical developments and persistent challenges.

Protective ventilation from ICU to operating room: state of art and new horizons.

The prevention of ventilator-associated lung injury (VALI) and postoperative pulmonary complications (PPC) is of paramount importance for improving outcomes both in the operating room and in the intensive care unit (ICU). Protective respiratory support includes a wide spectrum of interventions to decrease pulmonary stress-strain injuries. The motto 'low tidal volume for all' should become routine, both during major surgery and in the ICU, while application of a high positive end-expiratory pressure (PEEP) strategy and of alveolar recruitment maneuvers requires a personalized approach and requires further investigation. Patient self-inflicted lung injury is an important type of VALI, which should be diagnosed and mitigated at the early stage, during restoration of spontaneous breathing. This narrative review highlights the strategies used for protective positive pressure ventilation. The emerging concepts of damaging energy and power, as well as pathways to personalization of the respiratory settings, are discussed in detail. In the future, individualized approaches to protective ventilation may involve multiple respiratory settings extending beyond low tidal volume and PEEP, implemented in parallel with quantifying the risk of VALI and PPC.

Does Iso-mechanical Power Lead to Iso-lung Damage?: An Experimental Study in a Porcine Model.

BACKGROUND: Excessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury. METHODS: Three ventilatory strategies-high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)-were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD). RESULTS: At iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups. CONCLUSIONS: Different ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.