Respiratory Distress Syndrome Network Trials Research Articles

Declining Mortality in Patients With Acute Respiratory Distress Syndrome: An Analysis of the Acute Respiratory Distress Syndrome Network Trials

There has been multiple advances in the management of acute respiratory distress syndrome, but the temporal trends in acute respiratory distress syndrome-related mortality are not well known. This study aimed to investigate the trends in mortality in acute respiratory distress syndrome patients over time and to explore the roles of daily fluid balance and ventilation variables in those patients. Secondary analysis of randomized controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2013. Multicenter study involving Acute Respiratory Distress Syndrome Network trials. Patients with acute respiratory distress syndrome. None. Individual patient data from 5,159 acute respiratory distress syndrome patients (excluding the Late Steroid Rescue Study trial) were enrolled in this study. The crude mortality rate decreased from 35.4% (95% CI, 29.9-40.8%) in 1996 to 28.3% (95% CI, 22.0-34.7%) in 2013. By adjusting for the baseline Acute Physiology and Chronic Health Evaluation III, age, ICU type, and admission resource, patients enrolled from 2005 to 2010 (odds ratio, 0.61; 95% CI, 0.50-0.74) and those enrolled after 2010 (odds ratio, 0.73; 95% CI, 0.58-0.92) were associated with lower risk of death as compared to those enrolled before 2000. The effect of year on mortality decline disappeared after adjustment for daily fluid balance, positive end-expiratory pressure, tidal volume, and plateau pressure. There were significant trends of declines in daily fluid balance, tidal volume, and plateau pressure and an increase in positive end-expiratory pressure over the 17 years. Our study shows an improvement in the acute respiratory distress syndrome-related mortality rate in the critically ill patients enrolled in the Acute Respiratory Distress Syndrome Network trials. The effect was probably mediated via decreased tidal volume, plateau pressure, and daily fluid balance and increased positive end-expiratory pressure.

Oxygen Exposure Resulting in Arterial Oxygen Tensions Above the Protocol Goal Was Associated With Worse Clinical Outcomes in Acute Respiratory Distress Syndrome.

High fractions of inspired oxygen may augment lung damage to exacerbate lung injury in patients with acute respiratory distress syndrome. Participants enrolled in Acute Respiratory Distress Syndrome Network trials had a goal partial pressure of oxygen in arterial blood range of 55-80 mm Hg, yet the effect of oxygen exposure above this arterial oxygen tension range on clinical outcomes is unknown. We sought to determine if oxygen exposure that resulted in a partial pressure of oxygen in arterial blood above goal (> 80 mm Hg) was associated with worse outcomes in patients with acute respiratory distress syndrome. Longitudinal analysis of data collected in these trials. Ten clinical trials conducted at Acute Respiratory Distress Syndrome Network hospitals between 1996 and 2013. Critically ill patients with acute respiratory distress syndrome. None. We defined above goal oxygen exposure as the difference between the fraction of inspired oxygen and 0.5 whenever the fraction of inspired oxygen was above 0.5 and when the partial pressure of oxygen in arterial blood was above 80 mm Hg. We then summed above goal oxygen exposures in the first five days to calculate a cumulative above goal oxygen exposure. We determined the effect of a cumulative 5-day above goal oxygen exposure on mortality prior to discharge home at 90 days. Among 2,994 participants (mean age, 51.3 yr; 54% male) with a study-entry partial pressure of oxygen in arterial blood/fraction of inspired oxygen that met acute respiratory distress syndrome criteria, average cumulative above goal oxygen exposure was 0.24 fraction of inspired oxygen-days (interquartile range, 0-0.38). Participants with above goal oxygen exposure were more likely to die (adjusted interquartile range odds ratio, 1.20; 95% CI, 1.11-1.31) and have lower ventilator-free days (adjusted interquartile range mean difference of -0.83; 95% CI, -1.18 to -0.48) and lower hospital-free days (adjusted interquartile range mean difference of -1.38; 95% CI, -2.09 to -0.68). We observed a dose-response relationship between the cumulative above goal oxygen exposure and worsened clinical outcomes for participants with mild, moderate, or severe acute respiratory distress syndrome, suggesting that the observed relationship is not primarily influenced by severity of illness. Oxygen exposure resulting in arterial oxygen tensions above the protocol goal occurred frequently and was associated with worse clinical outcomes at all levels of acute respiratory distress syndrome severity.

Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality

BackgroundAnaesthetists have traditionally ventilated patients’ lungs with tidal volumes (TVs) between 10 and 15 ml kg−1 of ideal body weight (IBW), without the use of PEEP. Over the past decade, influenced by the results of the Acute Respiratory Distress Syndrome Network trial, many anaesthetists have begun using lower TVs during surgery. It is unclear whether the benefits of low TV ventilation can be extended into the perioperative period.MethodsWe reviewed the records of 29 343 patients who underwent general anaesthesia with mechanical ventilation between January 1, 2008 and December 31, 2011. We calculated TV kg−1 IBW, PEEP, peak inspiratory pressure (PIP), and dynamic compliance. Cox regression analysis with propensity score matching was performed to examine the association between TV and 30-day mortality.ResultsMedian TV was 8.6 [7.7–9.6] ml kg−1 IBW with minimal PEEP [4.0 (2.2–5.0) cm H2O]. A significant reduction in TV occurred over the study period, from 9 ml kg−1 IBW in 2008 to 8.3 ml kg−1 IBW in 2011 (P=0.01). Low TV 6–8 ml kg−1 IBW was associated with a significant increase in 30-day mortality vs TV 8–10 ml kg−1 IBW: hazard ratio (HR) 1.6 [95% confidence interval (CI) [1.25–2.08], P=0.0002]. The association remained significant after matching: HR 1.63 [95% CI (1.22–2.18), P<0.001]. There was only a weak correlation between TV kg−1 IBW and dynamic compliance (r=−0.006, P=0.31) and a weak-to-moderate correlation between TV kg−1 IBW and PIP (r=0.32 P<0.0001).ConclusionsUse of low intraoperative TV with minimal PEEP is associated with an increased risk of 30-day mortality.

Factors Associated With Elevated Plateau Pressure in Patients With Acute Lung Injury Receiving Lower Tidal Volume Ventilation

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. 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). 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. Medical centers participating in Acute Respiratory Distress Syndrome Network clinical trials. None. 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. 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.

The need for and feasibility of a pediatric ventilation trial

To explore what design would be reasonable, acceptable, and feasible for a pediatric trial investigating the effect of low tidal volume ventilation. A two-round modified Delphi approach among pediatric intensivists with a visible special interest in mechanical ventilation. None. Pediatric intensivists. None. In the first questionnaire "experts" classified 64 items as "important," "not so important" or "not important" (June 2010). The second questionnaire included the 29 items having been classified by more than 50% of the experts as being "important" in the first questionnaire that needed to be ranked in order of importance (August 2010). Twenty-nine of 50 (64%) experts responded to the first questionnaire, and 28 of the 29 initial responders (96.6%) to the second questionnaire. Actual expert opinion favored the following: age of study population 0 yrs to 2 yrs, expected duration of ventilation ≥ 48 hrs, and stratification by the severity of hypoxemia (cutoff PaO(2)/FIO(2) < 200). The two study arms should compare the effect of 6 mL/kg vs. 10 mL/kg on mortality. However, these views of the experts face two major issues. First, 10 mL/kg does not represent standard of care. Second, numerous uncertainties render mortality unsuitable as primary measure of outcome including a large sample size (>1500). Actual expert opinion favored investigating the effect of 6 mL/kg vs.10 mL/kg on mortality. Such a design suffers from various serious criticisms. Therefore, and in our opinion, a pediatric Acute Respiratory Distress Syndrome Network trial is not realistic.

A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation*

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. 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. 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. 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. 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.

The value of positive end-expiratory pressure and Fio2 criteria in the definition of the acute respiratory distress syndrome*

The criteria that define acute lung injury and the acute respiratory distress syndrome include PaO₂/Fio₂ but not positive end-expiratory pressure or Fio2. PaO2/Fio2 ratios of some patients increase substantially after mechanical ventilation with positive end-expiratory pressure of 5-10 cm H₂O, and the mortality of these patients may be lower than those whose PaO₂/Fio₂ratios remain <200. Also, PaO₂/Fio₂ may increase when Fio2 is raised from moderate to high levels, suggesting that patients with similar PaO₂/Fio₂ ratios but different Fio₂ levels have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline positive end-expiratory pressure and Fio₂ to PaO₂/Fio₂ for predicting mortality of acute lung injury/acute respiratory distress syndrome patients enrolled in Acute Respiratory Distress Syndrome Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO₂/Fio₂. Analysis of baseline physiologic data and outcomes of patients previously enrolled in clinical trials conducted by the National Institutes of Health Acute Respiratory Distress Syndrome Network. Intensive care units of 40 hospitals in North America. Two thousand three hundred and twelve patients with acute lung injury/acute respiratory distress syndrome. None. Only 1.3% of patients enrolled in Acute Respiratory Distress Syndrome Network trials had baseline positive end-expiratory pressure < 5 cm H₂O, and 50% had baseline positive end-expiratory pressure ≥10 cm H₂O. Baseline PaO₂/Fio₂ predicted mortality, but after controlling for PaO₂/Fio₂, baseline positive end-expiratory pressure did not predict mortality. In contrast, after controlling for baseline PaO₂/Fio₂, baseline Fio₂ did predict mortality. Effects of two study interventions (lower tidal volumes and fluid-conservative hemodynamic management) were similar in mild and severe hypoxemia subsets as defined by PaO₂/Fio₂ ratios. At Acute Respiratory Distress Syndrome Network hospitals, the addition of baseline positive end-expiratory pressure would not have increased the value of PaO₂/Fio₂ for predicting mortality of acute lung injury/acute respiratory distress syndrome patients. In contrast, the addition of baseline Fio2 to PaO₂/Fio₂ could be used to identify subsets of patients with low or high mortality.

Adaptive Support Ventilation: An Inappropriate Mechanical Ventilation Strategy for Acute Respiratory Distress Syndrome?

We thank Drs. Dongelmans and Schultz for their letter expressing interest in our recent publication on adaptive support ventilation (ASV).1They correctly describe how ASV works but indicate that the ability of ASV to vary tidal volume in response to a changing clinical presentation is of concern especially if the tidal volume is allowed to exceed 6 ml/kg.First, it is important to remember that the tidal volumes used by the Acute Respiratory Distress Syndrome Network2in its landmark study varied between 4 and 8 ml/kg. Indeed, as we showed in our study, even though the average tidal volume delivered to patients in the low-tidal volume arm was about 6 ml/kg, tidal volume did vary between 4 and 8 ml/kg in many patients.We believe that allowing tidal volume to increase while keeping plateau pressure at a minimum setting (&lt;28 cm H2O in our study) is the major concern of Drs. Dongelmans and Schultz, and they reference Hager et al. 3to demonstrate their point. However, they failed to acknowledge the subsequent letter from Shiu and Rozen4who determined from Hager's data that no significant change in mortality was observed regardless of tidal volume once plateau pressure was less than 28 cm H2O. Drs. Dongelmans and Schultz also referred to the article by Gajic et al .,5which was a retrospective review with plateau pressures available on only a few patients to illustrate the potential of large tidal volumes causing acute lung injury. The tidal volume range applied by ASV is essentially within the range of the lowest risk group (≤9 ml/kg) in the article by Gajic et al .5In addition, there are numerous articles in the surgical literature that indicate that at least short-term application of large tidal volume does not result in lung injury6–10in patients without existing lung injury. As we noted in our discussion, the upper and lower limits on ASV may need to be adjusted, and we believe that the upper limit should be set for patients with acute lung injury or acute respiratory distress syndrome at 8 ml/kg. However, the concept of ASV is sound because if practitioners are left on their own to adjust tidal volume, even centers who participated in the Acute Respiratory Distress Syndrome Network trial do not always appropriately select low tidal volumes and plateau pressures.11Where we believe the concept of ASV is most critical is in the patient where in spite of tidal volume being set at 6 ml/kg, plateau pressure exceeds 28 cm H2O. It is very clear that in these patients, the risk of increased mortality is real.3,12ASV does in these patients what the clinician should do and that is to reduce the tidal volume to avoid overdistension. ASV may not have the absolute limits correct, but the concept of closed loop control of ventilation is the future!*Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. rkacmarek@partners.org

A Slightly Different Tune: The Multipart Harmony of Noisy Life Support

University of Manitoba, Winnipeg, Manitoba, Canada. amutch@cc.umanitoba.caI would like to bring to the attention of readers of Anesthesiology some inaccuracies in the Editorial View “Noisy Mechanical Ventilation: Listen to the Melody” by Drs. Shimabukuro and Gropper.1This article provided an overview of the research published in the journal by Spieth et al., 2“Effects of different levels of pressure support variability in experimental lung injury.” As stated by the editorialists, “Using variability in breathing patterns is not a completely new concept. It was probably first elucidated by Suki et al. 3in Nature in 1998.” In fact such an approach, subsequently called biologically variable ventilation, was first elucidated in 1996 in work done in my laboratory by Lefevre et al .4Careful reading of the article in Nature indicates that stochastic resonance was advanced as an explanation for the improvement in compliance and oxygenation with a noisy end-inspiratory pressure based on analysis of data from our publication. We have since extended these observations to more generally indicate where noisy ventilation will be efficacious and where it may be detrimental.5This analysis is based on Jensen’s inequality–a mathematical proof stating that a variable input will enhance an output when a smoothly continuous curvilinear function is convex.6In contrast, if the function describing a relationship is concave, the addition of noise can diminish output and potentially be detrimental. Noisy ventilation is especially advantageous with tidal volume protocols according to the Acute Respiratory Distress Syndrome Network trial because the volume-pressure curve is convex curvilinear in the range of low tidal volumes.7The lone negative animal study examining noisy ventilation in an acute respiratory distress syndrome model may be a consequence of large tidal volumes administered over the concave region of the sigmoidal volume-pressure curve—the portion of the static compliance curve where it may be deleterious to provide positive pressure ventilation based on modeling using Jensen’s inequality.8The editorial further raises the question of the use of noisy ventilation in normal lungs. My laboratory has examined the use of noisy ventilation in the experimental setting of baseline anesthesia without lung injury9and during ventilation of the dependent lung during one-lung anesthesia (an article published in Anesthesiology).10Colleagues published, again in Anesthesiology, the first clinical trial examining the application of variable ventilation during abdominal aneurysmectomy.11In each of these studies better gas exchange and respiratory mechanics were seen with noisy ventilation, as compared with conventional monotonous control mode ventilation, similar to the findings by Spieth et al. I do concur with the editorialists that “The importance of variability, whether referring to the respiratory system or DNA, in biologic systems should not be underestimated.” Based on the nonlinear amplification of output in convex curvilinear systems as outlined above, we have shown that noisy perfusion can improve cerebral oxygenation,12diminish renal injury,13and enhance delivery of cardioplegia14during cardiopulmonary bypass. These improvements are likely a consequence of better flow with noisy perfusion pressure over the convex curvilinear flow-pressure curve manifest by the microvasculature. An overview of some of these issues is discussed in a short review.15I also concur that “the time is here to translate these studies to the bedside.” The article by Spieth et al. reinforces prior work by this European group, the group in Boston, and the group in Canada, all demonstrating the advantage of adding noise to life support systems.University of Manitoba, Winnipeg, Manitoba, Canada. amutch@cc.umanitoba.ca

Racial and ethnic disparities in mortality from acute lung injury.

Little is known about the influence of race and ethnicity on mortality from acute lung injury (ALI). We sought to determine whether black race or Hispanic ethnicity is independently associated with mortality among patients with ALI. Retrospective cohort study of patients enrolled in the Acute Respiratory Distress Syndrome Network randomized controlled trials. Adult intensive care units participating in the Acute Respiratory Distress Syndrome Network trials. A total of 2362 mechanically ventilated patients (1715 white, 449 black, and 198 Hispanic) with ALI. The primary outcome was 60-day mortality. A secondary outcome was number of ventilator-free days. Crude mortality was 33% for both blacks and Hispanics compared with 27% for whites (p = 0.02). After adjusting for demographic and clinical covariates, the association between race/ethnicity and mortality persisted (odds ratio [OR] = 1.42; 95% confidence interval [CI] 1.10-1.84 for blacks; OR = 1.94; 95% CI, 1.36-2.77 for Hispanics; OR = 1.00 for whites). After adjustment for severity of illness (Acute Physiology Score), black race was no longer significantly associated with mortality (OR = 1.25; 95% CI, 0.95-1.66), whereas the association with Hispanic ethnicity persisted (OR = 2.00; 95% CI, 1.37-2.90). Hispanics had significantly fewer ventilator-free days compared with whites after adjustment for demographic and clinical covariates (mean difference in days = -2.3; 95% CI -3.90 to -0.70). Black and Hispanic patients with ALI have a significantly higher risk of death compared with white patients. This increased risk seemed to be mediated by increased severity of illness at presentation for blacks, but was unexplained among Hispanics.

Outcome issues of mechanical ventilator settings in acute respiratory distress syndrome patients from Québec ICUs after the 2000 Acute Respiratory Distress Syndrome Network trial

Objective. To undertake a retrospective assessment of a knowledge translation of how a low tidal volume setting has affected the overall outcome of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) patients in Quebec ICUs. Material and methods. This was a study of case files from five Quebec ICUs, separated into two groups: those from before and after November 2000 (i.e. 6 months after the publication of the first ARDS Network trial). The primary outcome was changes in tidal volume. Secondary outcomes comprised mortality, number of days without organ dysfunction/failure, positive end-expiratory pressure (PEEP) level, respiratory rate and partial pressure of CO2 (PaCO2). Results. Of 105 patients, 55 were studied before and 50 after the landmark trial. Compared to the situation before November 2000: (i) tidal volume (normalized to predicted ideal body weight) fell; (ii) PEEP, respiratory rate and PaCO2 rose; and (iii) in-hospital mortality decreased and days without organ failure increased ...

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI). We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower VT would reduce urine NO as a result of less stretch injury. Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg VT ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr). Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure-free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg VT group (p = 0.04). Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg VT strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.

Higher urine desmosine levels are associated with mortality in patients with acute lung injury.

Desmosine is a stable breakdown product of elastin that can be reliably measured in urine samples. We tested the hypothesis that higher baseline urine desmosine would be associated with higher mortality in 579 of 861 patients included in the recent Acute Respiratory Distress Syndrome Network trial of lower tidal volume ventilation (1). We also correlated urine desmosine levels with indexes of disease severity. Finally, we assessed whether urine desmosine was lower in patients who received lower tidal volumes. Desmosine was measured by radioimmunoassay in urine samples from days 0, 1, and 3 of the study. The data were expressed as a ratio of urine desmosine to urine creatinine to control for renal dilution. The results show that higher baseline (day 0) urine desmosine-to-creatinine concentration was associated with a higher risk of death on adjusted analysis (odds ratio 1.36, 95% confidence interval 1.02-1.82, P=0.03). Urine desmosine increased in both ventilator groups from day 0 to day 3, but the average rise was higher in the 12-ml/kg predicted body weight group compared with the 6-ml/kg predicted body weight group (P=0.053, repeated-measures model). In conclusion, patients with acute lung injury ventilated with lower tidal volumes have lower urine desmosine levels, a finding that may reflect reduced extracellular matrix breakdown. These results illustrate the value of evaluating urinary biological markers that may have prognostic and pathogenetic significance in acute lung injury.

Defining the standard of care in randomized controlled trials of titrated therapies

To discuss the appropriate standard of care in randomized controlled trials of titrated therapies in critically ill patients. The debate over the appropriate standard of care in randomized controlled trials was sparked by the Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation. In this trial, patients were randomized to either low or traditional tidal volume ventilation, and the investigators reported that low tidal volume ventilation significantly improved survival in patients with acute respiratory distress syndrome. However, it was argued that the control group used in this trial was not reflective of current practice patterns and that the improvement in survival may have been derived from patients in the control group being placed at increased risk. This debate forced intensivists to consider what defines an appropriate standard-of-care control group in randomized controlled trials of titrated therapies. If titrated therapies are to be studied safely, the mechanism behind the titration must be understood and incorporated into the control group. Failure to include a comparator group receiving current practice creates a study design that may jeopardize patient safety because there is no control group representing probable patient outcome outside of the trial. Additionally, randomizing patients to the extremes of a range of care without incorporation of a current practice control group prevents the investigators from making valid recommendations for changing current practice. The incorporation of current practice patterns into randomized controlled trials of titrated therapies is essential for producing generalizable results and safeguarding patients.

Ventilator-induced lung injury.

The clinical relevance of experimental ventilator-induced lung injury has recently received a resounding illustration by the Acute Respiratory Distress Syndrome Network trial that showed a 22% reduction of mortality in patients with acute respiratory disease syndrome when lung mechanical stress was lessened by tidal volume reduction during mechanical ventilation. This clinical confirmation of the concept of ventilator-induced lung injury has also undisputedly substantiated the experimental observation that excessive tidal volume and/or end-inspiratory lung volume is the main determinant of ventilator-induced lung injury. More recently, attention has focused on the roles and implication in the pathogenesis of ventilator-induced lung injury of inflammatory cells and mediators that may be activated and released either in the alveolar space or in the systemic circulation because of the rupture of the alveolar-capillary barrier and on the cellular response to mechanical stress.