Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice.

Oxidative stress caused by mechanical ventilation contributes to the pathophysiology of ventilator-induced lung injury (VILI). A key mechanism maintaining redox balance is the upregulation of nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant gene expression. We tested whether pretreatment with an Nrf2-antioxidant response element (ARE) pathway activator tert-butylhydroquinone (tBHQ) protects against VILI. Male C57BL/6J mice were pretreated with an intraperitoneal injection of tBHQ (n = 10), an equivalent volume of 3% ethanol (EtOH3%, vehicle, n = 13), or phosphate-buffered saline (controls, n = 10) and were then subjected to high tidal volume (HVT) ventilation for a maximum of 4 h. HVT ventilation severely impaired arterial oxygenation ([Formula: see text] = 49 ± 7 mmHg, means ± SD) and respiratory system compliance, resulting in a 100% mortality among controls. Compared with controls, tBHQ improved arterial oxygenation ([Formula: see text] = 90 ± 41 mmHg) and respiratory system compliance after HVT ventilation. In addition, tBHQ attenuated the HVT ventilation-induced development of lung edema and proinflammatory response, evidenced by lower concentrations of protein and proinflammatory cytokines (IL-1ß and TNF-α) in the bronchoalveolar lavage fluid, respectively. Moreover, tBHQ enhanced the pulmonary redox capacity, indicated by enhanced Nrf2-depentent gene expression at baseline and by the highest total glutathione concentration after HVT ventilation among all groups. Overall, tBHQ pretreatment resulted in 60% survival (P < 0.001 vs. controls). Interestingly, compared with controls, EtOH3% reduced the proinflammatory response to HVT ventilation in the lung, resulting in 38.5% survival (P = 0.0054 vs. controls). In this murine model of VILI, tBHQ increases the pulmonary redox capacity by activating the Nrf2-ARE pathway and protects against VILI. These findings support the efficacy of pharmacological Nrf2-ARE pathway activation to increase resilience against oxidative stress during injurious mechanical ventilation.

The epidemiology and clinical outcomes of ventilator-associated events among 20,769 mechanically ventilated patients at intensive care units: an observational study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection (HAI) in intensive care units (ICUs). Ventilator-associated event (VAE), a more objective definition, has replaced traditional VAP surveillance and is now widely used in the USA. However, the adoption outside the USA is limited. This study aims to describe the epidemiology and clinical outcomes of VAEs in China, based on a prospectively maintained registry. METHODS: An observational study was conducted using an ICU-HAI registry in west China. Patients that were admitted to ICUs and underwent mechanical ventilation (MV) between April 1, 2015, and December 31, 2018, were included. The characteristics and outcomes were compared between patients with and without VAEs. The rates of all VAEs dependent on different ICUs were calculated, and the pathogen distribution of patients with possible VAP (PVAP) was described. RESULTS: A total of 20,769 ICU patients received MV, accounting for 21,723 episodes of mechanical ventilators and 112,697 ventilator-days. In all, we identified 1882 episodes of ventilator-associated condition (VAC) events (16.7 per 1000 ventilator-days), 721 episodes of infection-related ventilator-associated complications (IVAC) events (6.4 per 1000 ventilator-days), and 185 episodes of PVAP events (1.64 per 1000 ventilator-days). The rates of VAC varied across ICUs with the highest incidence in surgical ICUs (23.72 per 1000 ventilator-days). The median time from the start of ventilation to the onset of the first VAC, IVAC, and PVAP was 5 (3-8), 5 (3-9), and 6 (4-13) days, respectively. The median length of hospital stays was 28.00 (17.00-43.00), 30.00 (19.00-44.00), and 30.00 (21.00-46.00) days for the three VAE tiers, which were all longer than that of patients without VAEs (16.00 [12.00-23.00]). The hospital mortality among patients with VAEs was more than three times of those with non-VAEs. CONCLUSIONS: VAE was common in ICU patients with ≥ 4 ventilator days. All tiers of VAEs were highly correlated with poor clinical outcomes, including longer ICU and hospital stays and increased risk of mortality. These findings highlight the importance of VAE surveillance and the development of new strategies to prevent VAEs.

High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult patients with acute lung injury and acute respiratory distress syndrome.

BACKGROUND: In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), mortality remains high. These patients require mechanical ventilation, which has been associated with ventilator-induced lung injury. High levels of positive end-expiratory pressure (PEEP) could reduce this condition and improve patient survival. This is an updated version of the review first published in 2013. OBJECTIVES: To assess the benefits and harms of high versus low levels of PEEP in adults with ALI and ARDS. SEARCH METHODS: For our previous review, we searched databases from inception until 2013. For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and the Web of Science from inception until May 2020. We also searched for ongoing trials (www.trialscentral.org; www.clinicaltrial.gov; www.controlled-trials.com), and we screened the reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials that compared high versus low levels of PEEP in ALI and ARDS participants who were intubated and mechanically ventilated in intensive care for at least 24 hours. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias and extracted data independently. We contacted investigators to identify additional published and unpublished studies. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included four new studies (1343 participants) in this review update. In total, we included 10 studies (3851 participants). We found evidence of risk of bias in six studies, and the remaining studies fulfilled all criteria for low risk of bias. In eight studies (3703 participants), a comparison was made between high and low levels of PEEP, with the same tidal volume in both groups. In the remaining two studies (148 participants), the tidal volume was different between high- and low-level groups. In the main analysis, we assessed mortality occurring before hospital discharge only in studies that compared high versus low PEEP, with the same tidal volume in both groups. Evidence suggests that high PEEP may result in little to no difference in mortality compared to low PEEP (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.90 to 1.04; I² = 15%; 7 studies, 3640 participants; moderate-certainty evidence). In addition, high PEEP may result in little to no difference in barotrauma (RR 1.00, 95% CI 0.64 to 1.57; I² = 63%; 9 studies, 3791 participants; low-certainty evidence). High PEEP may improve oxygenation in patients up to the first and third days of mechanical ventilation (first day: mean difference (MD) 51.03, 95% CI 35.86 to 66.20; I² = 85%; 6 studies, 2594 participants; low-certainty evidence; third day: MD 50.32, 95% CI 34.92 to 65.72; I² = 83%; 6 studies, 2309 participants; low-certainty evidence) and probably improves oxygenation up to the seventh day (MD 28.52, 95% CI 20.82 to 36.21; I² = 0%; 5 studies, 1611 participants; moderate-certainty evidence). Evidence suggests that high PEEP results in little to no difference in the number of ventilator-free days (MD 0.45, 95% CI -2.02 to 2.92; I² = 81%; 3 studies, 1654 participants; low-certainty evidence). Available data were insufficient to pool the evidence for length of stay in the intensive care unit. AUTHORS' CONCLUSIONS: Moderate-certainty evidence shows that high levels compared to low levels of PEEP do not reduce mortality before hospital discharge. Low-certainty evidence suggests that high levels of PEEP result in little to no difference in the risk of barotrauma. Low-certainty evidence also suggests that high levels of PEEP improve oxygenation up to the first and third days of mechanical ventilation, and moderate-certainty evidence indicates that high levels of PEEP improve oxygenation up to the seventh day of mechanical ventilation. As in our previous review, we found clinical heterogeneity - mainly within participant characteristics and methods of titrating PEEP - that does not allow us to draw definitive conclusions regarding the use of high levels of PEEP in patients with ALI and ARDS. Further studies should aim to determine the appropriate method of using high levels of PEEP and the advantages and disadvantages associated with high levels of PEEP in different ARDS and ALI patient populations.

Lung recruitment manoeuvres for reducing mortality and respiratory morbidity in mechanically ventilated neonates.

BACKGROUND: Preterm infants and neonates with respiratory conditions commonly require intubation and conventional mechanical ventilation (CMV) to maintain airway patency and support their respiration. Whilst this therapy is often lifesaving, it simultaneously carries the risk of lung injury. The use of lung recruitment manoeuvres (LRMs) has been found to reduce the incidence of lung injury, and improve oxygenation and lung compliance in ventilated adults. However, evidence pertaining to their use in neonates is limited, and there is no consensus of opinion as to whether LRMs are appropriate or effective in this population. OBJECTIVES: To determine the effects of LRMs on mortality and respiratory outcomes in mechanically ventilated neonates, when compared to no recruitment (routine care).  SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 4) in the Cochrane Library, MEDLINE via Ovid (1946 to 13 April 2020), and CINAHL via EBSCOhost (1989 to 13 April 2020). We also handsearched the reference lists of retrieved studies to source additional articles.  SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over studies that compared the effect of LRMs to no recruitment (routine care) in mechanically ventilated neonates. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data and evaluated risk of bias in the included studies. When studies were sufficiently similar, we performed a meta-analysis using mean difference (MD) for continuous data and risk ratio (RR) for dichotomous data, with their respective 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of the evidence for key (clinically important) outcomes. MAIN RESULTS: We included four studies (152 participants in total) in this review. Three of these studies, enrolling 56 participants, contributed data to our prespecified outcomes. Two studies enrolling 44 participants on CMV for respiratory distress syndrome compared a stepwise LRM with positive end-expiratory pressure (PEEP) to routine care. Meta-analysis demonstrated no evidence of a difference between the LRM and routine care on mortality by hospital discharge (RR 1.00, 95% CI 0.17 to 5.77; low-certainty evidence), incidence of bronchopulmonary dysplasia (RR 0.25, 95% CI 0.03 to 2.07; low-certainty evidence), duration of supplemental oxygen (MD -7.52 days, 95% CI -20.83 to 5.78; very low-certainty evidence), and duration of ventilatory support (MD -3.59 days, 95% CI -12.97 to 5.79; very low-certainty evidence). The certainty of the evidence for these outcomes was downgraded due to risk of bias, imprecision, and inconsistency. Whilst these studies contributed data to four of our primary outcomes, we were unable to identify any studies that reported our other primary outcomes: duration of continuous positive airway pressure therapy, duration of neonatal intensive care unit stay, and duration of hospital stay.  The third study that contributed data to the review enrolled 12 participants on CMV for respiratory and non-respiratory causes, and compared two different LRMs applied after endotracheal tube suctioning to routine care. It was determined that both LRMs may slightly improve end-expiratory lung volume at 120 minutes' post-suctioning, when compared to routine care (incremental PEEP LRM versus routine care: MD -0.21, 95% CI -0.37 to -0.06; double PEEP LRM versus routine care: MD -0.18, 95% CI -0.35 to -0.02). It was also demonstrated that a double PEEP LRM may slightly reduce mean arterial pressure at 30 minutes' post-suctioning, when compared with routine care (MD -16.00, 95% CI -29.35 to -2.65).  AUTHORS' CONCLUSIONS: There is insufficient evidence to guide the use of LRMs in mechanically ventilated neonates. Well-designed randomised trials with larger sample sizes are needed to further evaluate the potential benefits and risks of LRM application in this population.

Association of Intraoperative Ventilator Management With Postoperative Oxygenation, Pulmonary Complications, and Mortality.

BACKGROUND: "Lung-protective ventilation" describes a ventilation strategy involving low tidal volumes (VTs) and/or low driving pressure/plateau pressure and has been associated with improved outcomes after mechanical ventilation. We evaluated the association between intraoperative ventilation parameters (including positive end-expiratory pressure [PEEP], driving pressure, and VT) and 3 postoperative outcomes: (1) PaO2/fractional inspired oxygen tension (FIO2), (2) postoperative pulmonary complications, and (3) 30-day mortality. METHODS: We retrospectively analyzed adult patients who underwent major noncardiac surgery and remained intubated postoperatively from 2006 to 2015 at a single US center. Using multivariable regressions, we studied associations between intraoperative ventilator settings and lowest postoperative PaO2/FIO2 while intubated, pulmonary complications identified from discharge diagnoses, and in-hospital 30-day mortality. RESULTS: Among a cohort of 2096 cases, the median PEEP was 5 cm H2O (interquartile range = 4-6), median delivered VT was 520 mL (interquartile range = 460-580), and median driving pressure was 15 cm H2O (13-19). After multivariable adjustment, intraoperative median PEEP (linear regression estimate [B] = -6.04; 95% CI, -8.22 to -3.87; P < .001), median FIO2 (B = -0.30; 95% CI, -0.50 to -0.10; P = .003), and hours with driving pressure >16 cm H2O (B = -5.40; 95% CI, -7.2 to -4.2; P < .001) were associated with decreased postoperative PaO2/FIO2. Higher postoperative PaO2/FIO2 ratios were associated with a decreased risk of pulmonary complications (adjusted odds ratio for each 100 mm Hg = 0.495; 95% CI, 0.331-0.740; P = .001, model C-statistic of 0.852) and mortality (adjusted odds ratio = 0.495; 95% CI, 0.366-0.606; P < .001, model C-statistic of 0.820). Intraoperative time with VT >500 mL was also associated with an increased likelihood of developing a postoperative pulmonary complication (adjusted odds ratio = 1.06/hour; 95% CI, 1.00-1.20; P = .042). CONCLUSIONS: In patients requiring postoperative intubation after noncardiac surgery, increased median FIO2, increased median PEEP, and increased time duration with elevated driving pressure predict lower postoperative PaO2/FIO2. Intraoperative duration of VT >500 mL was independently associated with increased postoperative pulmonary complications. Lower postoperative PaO2/FIO2 ratios were independently associated with pulmonary complications and mortality. Our findings suggest that postoperative PaO2/FIO2 may be a potential target for future prospective trials investigating the impact of specific ventilation strategies for reducing ventilator-induced pulmonary injury.

Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials.

RATIONALE: Previous trials of higher positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) failed to demonstrate mortality benefit, possibly because of differences in lung recruitability among patients with ARDS. OBJECTIVES: To determine whether the physiological response to increased PEEP is associated with mortality. METHODS: In a secondary analysis of the Lung Open Ventilation Study (LOVS, n = 983), we examined the relationship between the initial response to changes in PEEP after randomization and mortality. We sought to corroborate our findings using data from a different trial of higher PEEP (ExPress, n = 749). MEASUREMENTS AND MAIN RESULTS: The oxygenation response (change in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen: P/F) after the initial change in PEEP after randomization varied widely (median, 9.5 mm Hg; interquartile range, -16 to 47) and was only weakly related to baseline P/F or the magnitude of PEEP change. Among patients in whom PEEP was increased after randomization, an increase in P/F was associated with reduced mortality (multivariable logistic regression; adjusted odds ratio, 0.80 [95% confidence interval, 0.72-0.89] per 25-mm Hg increase in P/F), particularly in patients with severe disease (baseline P/F [less-than-or-equal-to] 150 mm Hg). Changes in compliance and dead space were not associated with mortality. These findings were confirmed by a similar analysis of data from the ExPress trial. CONCLUSIONS: Patients with ARDS who respond to increased PEEP by improved oxygenation have a lower risk of death. The oxygenation response to PEEP might be used to predict whether patients will benefit from higher versus lower PEEP.

Spontaneous breathing in mild and moderate versus severe acute respiratory distress syndrome.

PURPOSE OF REVIEW: This review summarizes the most recent clinical and experimental data on the impact of spontaneous breathing in acute respiratory distress syndrome (ARDS). RECENT FINDINGS: Spontaneous breathing during assisted as well as nonassisted modes of mechanical ventilation improves lung function and reduces lung damage in mild and moderate ARDS. New modes of assisted mechanical ventilation with improved patient ventilator interaction and enhanced variability of the respiratory pattern offer additional benefit on lung function and damage. However, data supporting an outcome benefit of spontaneous breathing in ARDS, even in its mild and moderate forms, are missing. In contrast, controlled mechanical ventilation with muscle paralysis in the first 48 h of severe ARDS has been shown to improve survival, as compared with placebo. Currently, it is unclear whether ventilator settings, rather than the severity of lung injury, determine the potential of spontaneous breathing for benefit or harm. SUMMARY: Clinical and experimental studies show that controlled mechanical ventilation with muscle paralysis in the early phase of severe ARDS reduces lung injury and even mortality. At present, spontaneous breathing should be avoided in the early phase of severe ARDS, but considered in mild-to-moderate ARDS.

The acute respiratory distress syndrome: incidence and mortality, has it changed?

PURPOSE OF REVIEW: The purpose of this review is to examine and discuss the incidence and outcome of patients with the acute respiratory distress syndrome (ARDS). This is a challenging task, as there is no specific clinical sign or diagnostic test that accurately identifies and adequately defines this syndrome. RECENT FINDINGS: This review will focus on published epidemiological studies reporting population-based incidence of ARDS, as defined by the American-European Consensus Conference criteria. In addition, the current outcome figures for ARDS patients reported in observational and randomized controlled trials will be reviewed. The focus will be on studies published since 2000, when the ARDSnet study on protective mechanical ventilation was published, although particular emphasis will be on those articles published in the last 24 months. SUMMARY: On the basis of current evidence, and despite the order of magnitude of reported European and USA incidence figures, it seems that the incidence and overall mortality of ARDS has not changed substantially since the original ARDSnet study. The current mortality of adult ARDS is still greater than 40%.

What is the future of acute respiratory distress syndrome after the Berlin definition?

PURPOSE OF REVIEW: To analyze recently published articles in the medical literature that studied distinct aspects of adult patients with acute respiratory distress syndrome (ARDS) after the new Berlin definition introduced in 2012. RECENT FINDINGS: The degree of ARDS severity according to this new classification correlated well with extravascular lung water index, pulmonary vascular permeability index and the finding of diffuse alveolar damage on autopsy. The new possibility of bedside echocardiographic evaluation of biventricular cardiac function is indicating the necessity of including a subgroup of severity of patients with right ventricular dysfunction. High-resolution CT evaluation showed that signs of pulmonary fibroproliferation in early ARDS predict increased ventilator dependency, multiple organ failure and mortality. The median development of ARDS 1 or 2 days after hospital admission emphasizes the need for ARDS intrahospital prevention, especially protective ventilation in non-ARDS patients. The better outcome with the use of prone position in patients with PaO2/FIO2 below 150 recently observed questioned the Berlin definition thresholds to decide the future best treatment strategies according to the proposed degree of severity of the syndrome. SUMMARY: The impact of the Berlin definition of ARDS on the incidence, better treatment stratification and mortality ratio of ARDS is still to be determined.

The effect of the pressure-volume curve for positive end-expiratory pressure titration on clinical outcomes in acute respiratory distress syndrome: a systematic review.

PURPOSE: Methods to optimize positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS) remain controversial despite decades of research. The pressure-volume curve (PVC), a graphical ventilator relationship, has been proposed for prescription of PEEP in ARDS. Whether the use of PVC's improves survival remains unclear. METHODS: In this systematic review, we assessed randomized controlled trials (RCTs) comparing PVC-guided treatment with conventional PEEP management on survival in ARDS based on the search of the National Library of Medicine from January 1, 1960, to January 1, 2010, and the Cochrane Central Register of Controlled Trials. Three RCTs were identified with a total of 185 patients, 97 with PVC-guided treatment and 88 with conventional PEEP management. RESULTS: The PVC-guided PEEP was associated with an increased probability of 28-day or hospital survival (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.5, 4.9) using a random-effects model without significant heterogeneity (I (2) test: P = .75). The PVC-guided ventilator support was associated with reduced cumulative risk of mortality (-0.24 (95% CI -0.38, -0.11). The PVC-managed patients received greater PEEP (standardized mean difference [SMD] 5.7 cm H2O, 95% CI 2.4, 9.0) and lower plateau pressures (SMD -1.2 cm H2O, 95% CI -2.2, -0.2), albeit with greater hypercapnia with increased arterial pCO2 (SMD 8 mm Hg, 95% CI 2, 14). Weight-adjusted tidal volumes were significantly lower in PVC-guided than conventional ventilator management (SMD 2.6 mL/kg, 95% CI -3.3, -2.0). CONCLUSION: This analysis supports an association that ventilator management guided by the PVC for PEEP management may augment survival in ARDS. Nonetheless, only 3 randomized trials have addressed the question, and the total number of patients remains low. Further outcomes studies appear required for the validation of this methodology.

Histone deacetylase inhibitors trichostatin A and suberoylanilide hydroxamic acid attenuate ventilator-induced lung injury.

The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation. Histone deacetylase inhibitors have been shown to exert anti-inflammation activity. The purpose of this study was to examine the protecting roles and mechanisms of the histone deacetylase inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) in ventilator-induced lung injury in normal rat lung. Male Sprague-Dawley rats were divided into four groups: lung-protective ventilation (LV), injurious ventilation (HV), HV+TSA and HV+ SAHA groups. Mechanical ventilation (MV) settings were 7 ml/kg VT and 3cm H2O positive end-expiratorypressure [PEEP], 40 breaths/min for LV group and 42 ml/kg VT, zero end-expiratoryvolume [ZEEP], 40 breaths/min for the HV, HV+TSA and HV+ SAHA groups. After 2 h of MV, acute lung injury (ALI) score, wet-to-dry (W/D) weight ratio and the activity of myeloperoxidase (MPO) were determined. The concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-10 (IL-6) in the homogenized lung were measured by ELISA. The expression ICAM-1 was measured by both realtime PCR and Western blot assays. In addition, survival of each group was also assessed. Our results indicated that administration of TSA or SAHA alleviated ventilator-induced lung injury. This was accompanied by reduced neutrophil infiltration, reduced MPO activity, decreased intercellular adhesion molecule-1 (ICAM-1) expression in lung tissue, and lower TNF-alpha, IL-1beta and IL-6 levels. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of ventilator-induced lung injury rats. Our data suggested that TSA and SAHA could significantly alleviate ventilator-induced rat lung injury and prolong the survival time of those rats by attenuate intrapulmonary inflammatory response.

Impact of mechanical power on ICU mortality in ventilated critically ill patients: a retrospective study with continuous real-life data.

BACKGROUND: Over the past decade, numerous studies on potential factors contributing to ventilation-induced lung injury have been carried out. Mechanical power has been pointed out as the parameter that encloses all ventilation-induced lung injury-contributing factors. However, studies conducted to date provide data regarding mechanical power during the early hours of mechanical ventilation that may not accurately reflect the impact of power throughout the period of mechanical ventilatory support on intensive care unit mortality. METHODS: Retrospective observational study conducted at a single center in Spain. Patients admitted to the intensive care unit, > o = 18 years of age, and ventilated for over 24 h were included. We extracted the mechanical power values throughout the entire mechanical ventilation in controlled modes period from the clinical information system every 2 min. First, we calculate the cutoff-point for mechanical power beyond which there was a greater change in the probability of death. After, the sum of time values above the safe cut-off point was calculated to obtain the value in hours. We analyzed if the number of hours the patient was under ventilation with a mechanical power above the safe threshold was associated with intensive care unit mortality, invasive mechanical ventilation days, and intensive care unit length of stay. We repeated the analysis in different subgroups based on the degree of hypoxemia and in patients with SARS CoV-2 pneumonia. RESULTS: The cut-off point of mechanical power at with there is a higher increase in intensive care unit mortality was 18 J/min. The greater the number of hours patients were under mechanical power > 18 J/min the higher the intensive care unit mortality in all the study population, in patients with SARS CoV-2 pneumonia and in mild to moderate hypoxemic respiratory failure. The risk of death in the intensive care unit increases 0.1% for each hour with mechanical power exceeding 18 J/min. The number of hours with mechanical power > 18 J/min also affected the days of invasive mechanical ventilation and intensive care unit length of stay. CONCLUSIONS: The number of hours with mechanical power > 18 J/min is associated with mortality in the intensive care unit in critically ill patients. Continuous monitoring of mechanical power in controlled modes using an automated clinical information system could alert the clinician to this risk.

Mitochondrial-targeted DNA repair enzyme 8-oxoguanine DNA glycosylase 1 protects against ventilator-induced lung injury in intact mice.

This study tested the hypothesis that oxidative mitochondrial-targeted DNA (mtDNA) damage triggered ventilator-induced lung injury (VILI). Control mice and mice infused with a fusion protein targeting the DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 (OGG1) to mitochondria were mechanically ventilated with a range of peak inflation pressures (PIP) for specified durations. In minimal VILI (1 h at 40 cmH(2)O PIP), lung total extravascular albumin space increased 2.8-fold even though neither lung wet/dry (W/D) weight ratios nor bronchoalveolar lavage (BAL) macrophage inflammatory protein (MIP)-2 or IL-6 failed to differ from nonventilated or low PIP controls. This increase in albumin space was attenuated by OGG1. Moderately severe VILI (2 h at 40 cmH(2)O PIP) produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio and marked increases in BAL MIP-2 and IL-6, accompanied by oxidative mitochondrial DNA damage, as well as decreases in the total tissue glutathione (GSH) and GSH/GSSH ratio compared with nonventilated lungs. All of these injury indices were attenuated in OGG1-treated mice. At the highest level of VILI (2 h at 50 cmH(2)O PIP), OGG1 failed to protect against massive lung edema and BAL cytokines or against depletion of the tissue GSH pool. Interestingly, whereas untreated mice died before completing the 2-h protocol, OGG1-treated mice lived for the duration of observation. Thus mitochondrially targeted OGG1 prevented VILI over a range of ventilation times and pressures and enhanced survival in the most severely injured group. These findings support the concept that oxidative mtDNA damage caused by high PIP triggers induction of acute lung inflammation and injury.

High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult patients with acute lung injury and acute respiratory distress syndrome.

BACKGROUND: Mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remains high. These patients require mechanical ventilation, but this modality has been associated with ventilator-induced lung injury. High levels of positive end-expiratory pressure (PEEP) could reduce this condition and improve patient survival. OBJECTIVES: To assess the benefits and harms of high versus low levels of PEEP in patients with ALI and ARDS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 4), MEDLINE (1950 to May 2013), EMBASE (1982 to May 2013), LILACS (1982 to May 2013) and SCI (Science Citation Index). We used the Science Citation Index to find references that have cited the identified trials. We did not specifically conduct manual searches of abstracts of conference proceedings for this review. We also searched for ongoing trials (www.trialscentral.org; www.clinicaltrial.gov and www.controlled-trials.com).     SELECTION CRITERIA: We included randomized controlled trials that compared the effects of two levels of PEEP in ALI and ARDS participants who were intubated and mechanically ventilated in intensive care for at least 24 hours. DATA COLLECTION AND ANALYSIS: Two review authors assessed the trial quality and extracted data independently. We contacted investigators to identify additional published and unpublished studies.  MAIN RESULTS: We included seven studies that compared high versus low levels of PEEP (2565 participants). In five of the studies (2417 participants), a comparison was made between high and low levels of PEEP with the same tidal volume in both groups, but in the remaining two studies (148 participants), the tidal volume was different between high- and low-level groups. We saw evidence of risk of bias in three studies, and the remaining studies fulfilled all criteria for adequate trial quality.In the main analysis, we assessed mortality occurring before hospital discharge only in those studies that compared high versus low PEEP with the same tidal volume in both groups. With the three studies that were included, the meta-analysis revealed no statistically significant differences between the two groups (relative risk (RR) 0.90, 95% confidence interval (CI) 0.81 to 1.01), nor was any statistically significant difference seen in the risk of barotrauma (RR 0.97, 95% CI 0.66 to 1.42). Oxygenation was improved in the high-PEEP group, although data derived from the studies showed a considerable degree of statistical heterogeneity. The number of ventilator-free days showed no significant difference between the two groups. Available data were insufficient to allow pooling of length of stay in the intensive care unit (ICU). The subgroup of participants with ARDS showed decreased mortality in the ICU, although it must be noted that in two of the three included studies, the authors used a protective ventilatory strategy involving a low tidal volume and high levels of PEEP. AUTHORS' CONCLUSIONS: Available evidence indicates that high levels of PEEP, as compared with low levels, did not reduce mortality before hospital discharge. The data also show that high levels of PEEP produced no significant difference in the risk of barotrauma, but rather improved participants' oxygenation to the first, third, and seventh days. This review indicates that the included studies were characterized by clinical heterogeneity.  

Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism.

OBJECTIVES: Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-κB, a key transcriptional regulator in inflammation, injury, and repair. DESIGN: Prospective randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-κB pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-κB pathway in hypercapnic acidosis-mediated protection from stretch injury was then determined. MEASUREMENTS AND MAIN RESULTS: Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-κB inhibitor IκBα and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-κB activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. CONCLUSIONS: Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-κB-dependent mechanism.

Stress and strain within the lung.

PURPOSE OF REVIEW: To describe the physiological meaning and the clinical application of the lung stress and strain concepts. RECENT FINDINGS: The end-inspiratory plateau pressure and ratio of tidal volume/ideal body weight are inadequate surrogates for the end-inspiratory stress (equal to the transpulmonary pressure) and the end-inspiratory strain (change in lung volume relative to the resting volume). For a given plateau pressure or tidal volume/ideal body weight, stress and strain may vary largely due to the variability of chest wall elastance and the resting lung volume. The injurious limits of stress and strain in healthy lungs are reached when stress and strain reach the total lung capacity. This occurs when the resting lung volume (the baby lung in case of acute respiratory distress syndrome) is increased by two-fold to three-fold. As these limits are rarely reached in clinical practice and damage has been reported with stress and strain well below this upper limit, this implies the presence in the lung parenchyma of regions which act as stress raisers or pressure multipliers. These are primarily linked to the inhomogeneous distribution of local stress and strain. SUMMARY: End-inspiratory stress and strain, as well as the lung inhomogeneity and the stress raisers, must be taken in account when setting mechanical ventilation.

Effect of sustained inflations and intermittent positive pressure ventilation on bronchopulmonary dysplasia or death among neonatal: A protocol for systematic review.

BACKGROUND: Sustained Inflations (SI) and Intermittent Positive Pressure Ventilation (IPPV) are two interventions to prevent Bronchopulmonary dysplasia (BPD). The aim of this study is to assess the effect of these two interventions. METHODS: The databases of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) will be comprehensively searched from inception to September 2019. All RCTs and quasi-RCTs which compare the efficacy of SI vs IPPV among preterm infants are eligible. We will assess the methodological quality using the Cochrane Handbook version 5.1.0. A meta-analysis will be performed using RevMan 5.3 software and the results will be presented using risk ratios (RRs) and 95% confidence intervals (CIs). CONCLUSIONS: This study will provide strong evidence for assessing the effect of SI and IPPV on BPD or death among preterm infants. PROSPERO REGISTRATION NUMBER: CRD42019135816.

Innovative in vitro method to study ventilator induced lung injury.

Mechanical ventilation (MV) is a life-saving therapy for critically ill patients, alleviating the work of breathing and supporting adequate gas exchange. However, MV can cause ventilator induced lung injury (VILI) by baro/volu- and atelectrauma, even lead to acute respiratory distress syndrome (ARDS), and substantially augment mortality. There is a need for specific biomarkers and novel research platforms for VILI/ARDS research to study these detrimental disorders and seek ways to avoid or prevent them. Previous in vitro studies on bronchial epithelium, cultured in air-liquid interface (ALI) conditions, have generally utilized static or constant pressure.  We have developed a Cyclical Pressure ALI Device (CPAD) that enables cyclical stress on ALI cultured human bronchial cells, with the aim of mimicking the effects of MV. Using CPAD we were able to analyze differentially expressed VILI/ARDS and innate immunity associated genes along with increased expression of associated proteins. CPAD provides an easy and accessible way to analyze functional and phenotypic changes that occur during VILI and may provide a platform for future drug testing.

Poder mecánico, variable relacionada a la lesión pulmonar inducida por la ventilación y la mortalidad / Mechanical power, a variable related to ventilation-induced lung injury and mortality

Mechanical power is a variable of interest in lung protection, involving the amount of energy dissipated in the lung parenchyma in each respiratory cycle by means of calculations derived from the respiratory motion equation. The studies consulted associate mechanical power to mortality in patients with acute respiratory distress syndrome. It allows identifying the risk of ventilator-induced damage and pulmonary complications and can be safely used as a marker of improvement in the objectives and goals in artificial mechanical ventilation.

El poder mecánico es una variable de interés en la protección pulmonar, involucra la cantidad de energía que se disipa en el parénquima pulmonar en cada ciclo respiratorio por medio de cálculos derivados de la ecuación del movimiento respiratorio. Los estudios consultados asocian el poder mecánico a la mortalidad en pacientes con síndrome de dificultad respiratoria aguda. Permite identificar el riesgo de daño inducido por la ventilación, complicaciones pulmonares y puede ser usado con seguridad como un marcador de mejoría en los objetivos y metas en ventilación mecánica artificial.

Determinants and Prevention of Ventilator-Induced Lung Injury.

Ventilator-induced lung injury develops from interactions between the lung parenchyma and applied mechanical power. In acute respiratory distress syndrome, the lung is smaller size with an inhomogeneous structure. The same mechanical force applied on a reduced parenchyma would produce volutrauma; the concentration of mechanical forces at inhomogeneous interfaces produces atelectrauma. Higher positive end-expiratory pressures favor volutrauma and reduce atelectrauma; lower values do the opposite. Volutrauma and atelectrauma harms and benefits, however, seem to be equivalent at 5 to 15 cm H2O. At values greater than 15 cm H2O, the risk of damage outweighs the benefits of major atelectrauma prevention.