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Purpose of Review: The optimal strategy for assessing and preventing ventilator-induced lung injury in the acute respiratory distress syndrome (ARDS) is controversial. Recent investigative efforts have focused on personalizing ventilator settings to individual respiratory mechanics. This review examines the strengths and weaknesses of using transpulmonary pressure measurements to guide ventilator management in ARDS., Recent Findings: Recent clinical studies suggest that adjusting ventilator settings based on transpulmonary pressure measurements is feasible, may improve oxygenation, and reduce ventilator-induced lung injury., Summary: The measurement of transpulmonary pressure relies upon esophageal manometry, which requires the acceptance of several assumptions and potential errors. Notably, this includes the ability of localized esophageal pressures to represent global pleural pressure. Recent investigations demonstrated improved oxygenation in ARDS patients when positive end-expiratory pressure was adjusted to target specific end-inspiratory or end-expiratory transpulmonary pressures. However, there are different methods for estimating transpulmonary pressure and different goals for positive end-expiratory pressure titration among recent studies. More research is needed to refine techniques for the estimation and utilization of transpulmonary pressure to guide ventilator settings in ARDS patients.

Objective: Deep sedation and delirium are common in the ICU. Mechanically ventilated patients with acute lung injury are at especially high risk for deep sedation, delirium, and associated long-term physical and neuropsychiatric impairments. We undertook an ICU-wide structured quality improvement project to decrease sedation and delirium., Design: Prospective quality improvement project in comparison with a retrospective acute lung injury control group., Setting: Sixteen-bed medical ICU in an academic teaching hospital with pre-existing use of goal-directed sedation with daily interruption of sedative infusions., Patients: Consecutive acute lung injury patients., Intervention: A "4Es" framework (engage, educate, execute, evaluate) was used as part of the quality improvement process. A new sedation protocol was created and implemented, which recommends a target Richmond Agitation Sedation Scale score of 0 (alert and calm) and requires failure of intermittent sedative dosing prior to starting continuous infusions. In addition, twice-daily delirium screening using the Confusion Assessment Method for the ICU was introduced into routine practice., Measurements and Main Results: Sedative use and delirium status in acute lung injury patients after implementation of the quality improvement project (n = 82) were compared with a historical control group (n = 120). During the quality improvement vs. control periods, use of narcotic and benzodiazepine infusions were substantially lower (median proportion of medical ICU days per patient: 33% vs. 74%, and 22% vs. 70%, respectively, both p < 0.001). Further, wakefulness increased (median Richmond Agitation Sedation Scale score per patient: -1.5 vs. -4.0, p < 0.001), and days awake and not delirious increased (median proportion of medical ICU days per patient: 19% vs. 0%, p < 0.001)., Conclusion: Through a structured quality improvement process, use of sedative infusions can be substantially decreased and days awake without delirium significantly increased, even in severely ill, mechanically ventilated patients with acute lung injury.

Objectives: Lung-protective ventilation with lower tidal volume and lower plateau pressure improves mortality in patients with acute lung injury and acute respiratory distress syndrome. We sought to determine the incidence of elevated plateau pressure in acute lung injury /acute respiratory distress syndrome patients receiving lower tidal volume ventilation and to determine the factors that predict elevated plateau pressure in these patients., Patients: We used data from 1398 participants in Acute Respiratory Distress Syndrome Network trials, who received lower tidal volume ventilation (≤ 6.5mL/kg predicted body weight)., Design: We considered patients with a plateau pressure greater than 30cm H2O and/or a tidal volume less than 5.5mL/kg predicted body weight on study day 1 to have "elevated plateau pressure." We used logistic regression to identify baseline clinical variables associated with elevated plateau pressure and to develop a model to predict elevated plateau pressure using a subset of 1,188 patients. We validated the model in the 210 patients not used for model development., Setting: Medical centers participating in Acute Respiratory Distress Syndrome Network clinical trials., Interventions: None., Measurements and Main Results: Of the 1,398 patients in our study, 288 (20.6%) had elevated plateau pressure on day 1. Severity of illness indices and demographic factors (younger age, greater body mass index, and non-white race) were independently associated with elevated plateau pressure. The multivariable logistic regression model for predicting elevated plateau pressure had an area under the receiving operator characteristic curve of 0.71 for both the developmental and the validation subsets., Conclusions: acute lung injury patients receiving lower tidal volume ventilation often have a plateau pressure that exceeds Acute Respiratory Distress Syndrome Network goals. Race, body mass index, and severity of lung injury are each independently associated with elevated plateau pressure. Selecting a smaller initial tidal volume for non-white patients and patients with higher severity of illness may decrease the incidence of elevated plateau pressure. Prospective studies are needed to evaluate this approach.

Objective: To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury., Design: Prospective cohort study., Setting: 13 intensive care units at four hospitals in Baltimore, Maryland, USA., Participants: 485 consecutive mechanically ventilated patients with acute lung injury., Main Outcome Measure: Two year survival after onset of acute lung injury., Results: 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011)., Conclusions: Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury., Trial Registration: Clinicaltrials.gov NCT00300248.

Objective: Despite improvements in the care of critically ill patients, hospital mortality rate for acute lung injury remains high at approximately 40%. We developed a classification rule to stratify mechanically ventilated patients with acute lung injury according to hospital mortality and compared this rule with the Acute Physiology and Chronic Health Evaluation III prediction., Patients: We used data of 2,022 participants in Acute Respiratory Distress Syndrome Network trials to build a classification rule based on 54 variables collected before randomization., Design: We used a classification tree approach to stratify patients according to hospital mortality using a training subset of 1800 participants and estimated expected prediction errors using tenfold crossvalidation. We validated our classification tree using a subset of 222 participants not included in model building and calculated areas under the receiver operating characteristic curves., Measurements and Main Results: We identified combinations of age (>63 yrs), blood urea nitrogen (>15 mg/dL), shock, respiratory rate (>21 breaths/min), and minute ventilation (>13.9 L/min) as important predictors of hospital mortality at 90 days. The classification tree had a similar expected prediction error in the training set (28% vs. 26%; p = .18) and areas under the receiver operating characteristic curve in the validation set (0.71 vs. 0.73; p = .71) as did a model based on Acute Physiology and Chronic Health Evaluation III., Conclusions: Our tree-based classification rule performed similarly to Acute Physiology and Chronic Health Evaluation III in stratifying patients according to hospital mortality, is simpler to use, contains risk factors that may be specific to acute lung injury, and identified minute ventilation as a potential novel predictor of death in patients with acute lung injury.

Rationale: β₂-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies., Objectives: This clinical trial was designed to test the hypothesis that an aerosolized β₂-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI)., Methods: We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days., Measurements and Main Results: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P = 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95%confidence interval for the difference,-4.0 to 14.7%;P = 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different., Conclusions: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of β₂-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).

Background: Studies of ventilation strategies that included higher PEEP in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have yielded conflicting results., Objective: To determine whether higher PEEP during volume-limited and pressure-limited ventilation is associated with 28-day mortality or barotrauma rates in patients with ALI/ARDS., Methods: We searched MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and the bibliographies of retrieved papers to identify randomized controlled trials that compared higher and lower PEEP in adult patients with ALI/ARDS who were already receiving volume-limited or pressure-limited ventilation. Two of us independently abstracted study-level data, including study design, patient characteristics, study methods, intervention, and main results. We pooled the study-level data with a random-effects model, unless heterogeneity was low (I(2) < 50%), in which case we used a fixed-effects model. The primary outcome was 28-day mortality., Results: Four randomized trials (2,360 participants) were evaluated. Higher PEEP had a nonsignificant trend toward lower 28-day mortality (pooled relative risk 0.90, 95% CI 0.79-1.02). There was no difference in barotrauma between the 2 groups (pooled relative risk 1.17, 95% CI 0.90-1.52). Two studies reported an adjusted hospital death rate, and the pooled results of sensitivity analysis with those adjusted rates were identical to those of the unadjusted analysis., Conclusions: In 4 recent studies that used volume-limited or pressure-limited ventilation in ALI/ARDS patients, higher PEEP was not associated with significantly different short-term mortality or barotrauma. This study does not support the routine use of higher PEEP in patients with ALI/ARDS.

Context: Trials comparing higher vs lower levels of positive end-expiratory pressure (PEEP) in adults with acute lung injury or acute respiratory distress syndrome (ARDS) have been underpowered to detect small but potentially important effects on mortality or to explore subgroup differences., Objectives: To evaluate the association of higher vs lower PEEP with patient-important outcomes in adults with acute lung injury or ARDS who are receiving ventilation with low tidal volumes and to investigate whether these associations differ across prespecified subgroups., Data Sources: Search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) plus a hand search of conference proceedings (2004-January 2010)., Study Selection: Two reviewers independently screened articles to identify studies randomly assigning adults with acute lung injury or ARDS to treatment with higher vs lower PEEP (with low tidal volume ventilation) and also reporting mortality., Data Extraction: Data from 2299 individual patients in 3 trials were analyzed using uniform outcome definitions. Prespecified effect modifiers were tested using multivariable hierarchical regression, adjusting for important prognostic factors and clustering effects., Results: There were 374 hospital deaths in 1136 patients (32.9%) assigned to treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%) assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval [CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of ARDS, defined by a value of 200 mm Hg or less for the ratio of partial pressure of oxygen to fraction of inspired oxygen concentration (P = .02 for interaction). In patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90; 95% CI, 0.81-1.00; P = .049); in patients without ARDS (n = 404), there were 50 hospital deaths (27.2%) in the higher PEEP group and 44 (19.4%) in the lower PEEP group (adjusted RR, 1.37; 95% CI, 0.98-1.92; P = .07). Rates of pneumothorax and vasopressor use were similar., Conclusions: Treatment with higher vs lower levels of PEEP was not associated with improved hospital survival. However, higher levels were associated with improved survival among the subgroup of patients with ARDS.

Background: No single clinical or biologic marker reliably predicts clinical outcomes in acute lung injury (ALI)/ARDS. We hypothesized that a combination of biologic and clinical markers would be superior to either biomarkers or clinical factors alone in predicting ALI/ARDS mortality and would provide insight into the pathogenesis of clinical ALI/ARDS., Methods: Eight biologic markers that reflect endothelial and epithelial injury, inflammation, and coagulation (von Willebrand factor antigen, surfactant protein D [SP-D]), tumor necrosis factor receptor-1, interleukin [IL]-6, IL-8, intercellular adhesion molecule-1, protein C, plasminogen activator inhibitor-1) were measured in baseline plasma from 549 patients in the ARDSNet trial of low vs high positive end-expiratory pressure. Mortality was modeled with multivariable logistic regression. Predictors were selected using backward elimination. Comparisons between candidate models were based on the receiver operating characteristics (ROC) and tests of integrated discrimination improvement., Results: Clinical predictors (Acute Physiology And Chronic Health Evaluation III [APACHE III], organ failures, age, underlying cause, alveolar-arterial oxygen gradient, plateau pressure) predicted mortality with an area under the ROC curve (AUC) of 0.82; a combination of eight biomarkers and the clinical predictors had an AUC of 0.85. The best performing biomarkers were the neutrophil chemotactic factor, IL-8, and SP-D, a product of alveolar type 2 cells, supporting the concept that acute inflammation and alveolar epithelial injury are important pathogenetic pathways in human ALI/ARDS., Conclusions: A combination of biomarkers and clinical predictors is superior to clinical predictors or biomarkers alone for predicting mortality in ALI/ARDS and may be useful for stratifying patients in clinical trials. From a pathogenesis perspective, the degree of acute inflammation and alveolar epithelial injury are highly associated with the outcome of human ALI/ARDS.

Acute lung injury (ALI) is characterized by rapid alveolar injury, inflammation, cytokine induction, and neutrophil accumulation. Although early events in the pathogenesis of ALI have been defined, the mechanisms underlying resolution are unknown. As a model of ALI, we administered intratracheal (i.t.) LPS to mice and observed peak lung injury 4 days after the challenge, with resolution by day 10. Numbers of alveolar lymphocytes increased as injury resolved. To examine the role of lymphocytes in this response, lymphocyte-deficient Rag-1-/- and C57BL/6 WT mice were exposed to i.t. LPS. The extent of injury was similar between the groups of mice through day 4, but recovery was markedly impaired in the Rag-1-/- mice. Adoptive transfer studies revealed that infusion of CD4+CD25+Foxp3+ Tregs as late as 24 hours after i.t. LPS normalized resolution in Rag-1-/- mice. Similarly, Treg depletion in WT mice delayed recovery. Treg transfer into i.t. LPS-exposed Rag-1-/- mice also corrected the elevated levels of alveolar proinflammatory cytokines and increased the diminished levels of alveolar TGF-beta and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-beta inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3+CD4+CD25hiCD127loFoxp3+ cells. These results indicate that Tregs modify innate immune responses during resolution of lung injury and suggest potential targets for treating ALI, for which there are no specific therapies currently available.

Rationale: There are conflicting data regarding the safety and efficacy of recruitment maneuvers (RMs) in patients with acute lung injury (ALI)., Objectives: To summarize the physiologic effects and adverse events in adult patients with ALI receiving RMs., Methods: Systematic review of case series, observational studies, and randomized clinical trials with pooling of study-level data., Measurements and Main Results: Forty studies (1,185 patients) met inclusion criteria. Oxygenation (31 studies; 636 patients) was significantly increased after an RM (PaO2): 106 versus 193 mm Hg, P = 0.001; and PaO2/FiO2 ratio: 139 versus 251 mm Hg, P < 0.001). There were no persistent, clinically significant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P = 0.02). Hypotension (12%) and desaturation (9%) were the most common adverse events (31 studies; 985 patients). Serious adverse events (e.g., barotrauma [1%] and arrhythmias [1%]) were infrequent. Only 10 (1%) patients had their RMs terminated prematurely due to adverse events., Conclusions: Adult patients with ALI receiving RMs experienced a significant increase in oxygenation, with few serious adverse events. Transient hypotension and desaturation during RMs is common but is self-limited without serious short-term sequelae. Given the uncertain benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence on clinical outcomes, the routine use of RMs cannot be recommended or discouraged at this time. RMs should be considered for use on an individualized basis in patients with ALI who have life-threatening hypoxemia.