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.

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.

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.

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.

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.

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.

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.

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.

The Impact of Ventilator-Associated Events in Critically Ill Subjects With Prolonged Mechanical Ventilation.

BACKGROUND: The Centers for Disease Control and Prevention recently released a surveillance definition for respiratory complications in ventilated patients, ventilator-associated events (VAEs), to replace ventilator-associated pneumonia (VAP). VAEs consist of ventilator-associated conditions (VAC), infection-related ventilator-associated complications (IVAC), and possible VAP. A duration of mechanical ventilation of at least 4 d is required to diagnose VAE. However, the observed duration of mechanical ventilation was < 4 d in many previous studies. We evaluated the impact of VAEs on clinical outcomes in critically ill subjects who required mechanical ventilation for ≥ 4 d. METHODS: This single-center retrospective cohort study was conducted in the general ICU of an academic hospital. We included 407 adult subjects who were admitted to the ICU and required mechanical ventilation for at least 4 d. VAC and IVAC were identified from the electronic medical records. VAP was defined according to the Centers for Disease Control and Prevention 2008 criteria and was identified from the surveillance data of the infection control team of our hospital. Clinical outcomes were studied in the VAC, IVAC, and VAP groups. Possible VAP was not investigated. RESULTS: Higher mortality was seen in VAC and IVAC subjects, but not in VAP subjects, compared with those without VAEs and VAP. By multivariable hazard analysis for hospital mortality, IVAC was independently associated with hospital mortality (hazard ratio 2.42, 95% CI 1.39-4.20, P = .002). VAC also tended to show a similar association with hospital mortality (hazard ratio 1.45, 95% CI 0.97-2.18, P = .07). On the other hand, VAP did not increase a hazard of hospital death (hazard ratio 1.08, 95% CI 0.44-2.66, P = .87). CONCLUSIONS: We found that a VAE was related to hospital mortality in critically ill subjects with prolonged mechanical ventilation, and that VAP was not.

A multi-faceted strategy to reduce ventilation-associated mortality in brain-injured patients. The BI-VILI project: a nationwide quality improvement project.

PURPOSE: We assessed outcomes in brain-injured patients after implementation of a multi-faceted approach to reduce respiratory complications in intensive care units. METHODS: Prospective nationwide before-after trial. Consecutive adults with acute brain injury requiring mechanical ventilation for ≥24 h in 20 French intensive care units (ICUs) were included. The management of invasive ventilation in brain-injured patients admitted between 1 July 2013 and 31 October 2013 (4 months) was monitored and analysed. After the baseline period (1 November 2013-31 December 2013), ventilator settings and decision to extubate were selected as targets to hasten weaning from invasive ventilation. During the intervention period, low tidal volume (≤7 ml/kg), moderate positive end-expiratory pressure (PEEP, 6-8 cm H2O) and an early extubation protocol were recommended. The primary endpoint was the number of days free of invasive ventilation at day 90. Comparisons were performed between the two periods and between the compliant and non-compliant groups. RESULTS: A total of 744 patients from 20 ICUs were included (391 pre-intervention; 353 intervention). No difference in the number of invasive ventilation-free days at day 90 was observed between the two periods [71 (0-80) vs. 67 (0-80) days; P = 0.746]. Compliance with the complete set of recommendations increased from 8 (2%) to 52 (15%) patients after the intervention (P < 0.001). At day 90, the number of invasive ventilation-free days was higher in the 60 (8%) patients whose care complied with recommendations than in the 684 (92%) patients whose care deviated from recommendations [77 (66-82) and 71 (0-80) days, respectively; P = 0.03]. The mortality rate was 10% in the compliant group and 26% in the non-compliant group (P = 0.023). Both multivariate analysis [hazard ratio (HR) 1.78, 95% confidence interval (95% CI) 1.41-2.26; P < 0.001] and propensity score-adjusted analysis (HR 2.25, 95% CI 1.56-3.26, P < 0.001) revealed that compliance was an independent factor associated with the reduction in the duration of mechanical ventilation. CONCLUSIONS: Adherence to recommendations for low tidal volume, moderate PEEP and early extubation seemed to increase the number of ventilator-free days in brain-injured patients, but inconsistent adoption limited their impact. Trail registration number: NCT01885507.

Evaluation of the New Centers for Disease Control and Prevention Ventilator-Associated Event Module and Criteria in Critically Ill Children in Greece.

OBJECTIVE To evaluate the new adult Centers for Disease Control and Prevention (CDC) ventilator-associated event (VAE) module in critically ill children and compare with the traditionally used CDC definition for ventilator-associated pneumonia (VAP). DESIGN Retrospective observational study of mechanically ventilated children in a pediatric intensive care unit in Greece January 1-December 31, 2011. METHODS Assessment of new adult CDC VAE module including 3 definition tiers: ventilator-associated condition (VAC), infection-related VAC, and possible/probable ventilator-associated pneumonia (VAE-VAP); comparison with traditional CDC criteria for clinically defined pneumonia in mechanically ventilated children (PNEU-VAP). We recorded Pediatric Risk of Mortality score at admission (PRISM III), number of ventilator-days, and outcome. RESULTS Among 119 patients with mechanical ventilation (median [range] number of ventilator-days, 7 [1-183]), 19 patients experienced VAC. Criteria for VAE-VAP were fulfilled in 12 of 19 patients with VAC (63%). Children with either VAC or VAE-VAP were on ventilation more days than patients without these conditions (16.5 vs 5 d, P=.0006 and 18 vs 5 d, P<.001, respectively), whereas PRISM-III score was similar between them. Mortality was significant higher in patients with new VAE-VAP definition (50%), but not in patients with VAC (31.6%), than the patients without new VAE-VAP (14%, P=.007) or VAC (15%, P=.1), respectively. No significant association was found between PNEU-VAP and death. Incidences of PNEU-VAP and VAE-VAP were similar, but the agreement was poor. CONCLUSIONS VAE-VAP and PNEU-VAP found similar prevalence in critically ill children but with poor agreement. However, excess of death was significantly associated only with VAE-VAP. Infect Control Hosp Epidemiol 2016:1-5.

Conservative fluid management prevents age-associated ventilator induced mortality.

BACKGROUND: Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hospital mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. METHODS: 2month old and 20month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4h with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. RESULTS: At 4h, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1h in advanced age HVT subjects. In 4h ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in older subjects. CONCLUSION: Our study demonstrates that conservative fluid alone can attenuate the age associated increase in ventilator associated mortality.

PReVENT--protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial.

BACKGROUND: It is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS. METHODS/DESIGN: PReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space. DISCUSSION: PReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoint. TRIAL REGISTRATION: The trial is registered at www.clinicaltrials.gov under reference number NCT02153294 on 23 May 2014.

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.

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.

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.

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.

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.