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Respiratory Medicine (2009) 103, 1174e1181 available at www.sciencedirect.

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journal homepage: www.elsevier.com/locate/rmed

High levels of PEEP may improve survival in acute respiratory distress syndrome: A meta-analysis
Yuji Oba*, Danish M. Thameem, Tareq Zaza
University of MissourieColumbia, Division of Pulmonary, Critical Care and Environmental Medicine, Five Hospital Drive, CE 412, Columbia, MO 65212, USA Received 4 December 2008; accepted 12 February 2009 Available online 9 March 2009

KEYWORDS
Meta-analysis; Positive-pressure respiration; Respiration; Articial; Respiratory distress syndrome; Adult

Summary Objective: Positive end-expiratory pressure (PEEP) has been viewed as an essential component of mechanical ventilation in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). However, clinical trials have not yet convincingly demonstrated that high PEEP levels improve survival. The object of this study was to test a priori hypotheses that a small but clinically important mortality benet of high PEEP did exist, especially in patients with greater overall severity of illness and differences in PEEP protocols might have affected the study results. Methods: Meta-analysis of randomized controlled trials comparing high versus low PEEP in ARDS/ALI. Studies were identied by search of MEDLINE (1950e2008) and other sources. Measurements and main results: Five studies including 2447 patients were identied. A pooled analysis showed a signicant reduction in hospital mortality in favor of high PEEP (RR Z 0.89; 95% CI, 0.80e0.99; p Z 0.03). However, signicant statistical and clinical heterogeneities such as differences in disease severity and ventilator protocols were found. The differences in PEEP protocols were not associated with differences in mortality rates. A logistic analysis suggested that the benecial effect of high PEEP was greater in patients with higher ICU severity scores. Conclusions: The statistical and clinical heterogeneities make proper interpretation of the results difcult. However, a small, but signicant mortality benet of high PEEP may exist. In addition, our analysis suggests the effects of high PEEP are greater in patients with higher ICU severity scores. Published by Elsevier Ltd.

Introduction
Acute respiratory distress syndrome (ARDS) is recognized as the most severe form of acute lung injury (ALI). Despite recent advances in understanding its pathogenesis and treatment, the management of ARDS remains a challenging

* Corresponding author. Tel.: 1 573 882 8583; fax: 1 573 884 4543. E-mail address: obay@health.missouri.edu (Y. Oba). 0954-6111/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.rmed.2009.02.008

PEEP in ARDS problem. The current standard for managing patients with ARDS/ALI is to provide low tidal volume mechanical ventilation and a conservative uid management strategy.1,2 However, mortality from ARDS/ALI remains at 30% or greater.3 Positive end-expiratory pressure (PEEP) improves gas exchange and respiratory compliance. It also reduces inammatory mediators in plasma and bronchoalveolar lavage uid,4 and ventilator-induced lung injury by preventing alveolar derecruitment which might be associated with low tidal volume mechanical ventilation. Despite benecial results in small randomized clinical trials favoring the combination of high PEEP and low tidal volumes,5,6 larger randomized clinical trials have not yet convincingly demonstrated that high PEEP is superior.7,8 We hypothesized that a mortality benet of high PEEP did exist, especially in patients with greater overall severity of illness as measured by composite measures such as an APACHE II or III score, but it was so small that it could be demonstrated only in a much larger trial or a meta-analysis. In addition, we hypothesized that differences in PEEP protocols across the clinical trials might have affected the study results. In the clinical trials which showed a signicant mortality benet, the optimal PEEP levels were determined by using static pressureevolume curves while non-benecial trials used other methods. How to determine the optimal or best PEEP levels in ARDS/ALI is still matter of debate.9,10 The purpose of this study was to test the above hypotheses by conducting an exploratory meta-analysis.

1175 a hospital with ARDS/ALI. The intervention was high versus low PEEP and trials had to have at least one of the following outcome variables: hospital mortality, ventilator weaning and length of hospital stay.

Data extraction
We independently abstracted data from all studies using standardized forms. Data were abstracted on study design, setting, and population; severity of illness; the exact methods of applying PEEP; and the outcome variables listed above. In calculating each outcome variable, we used intention to treat data (including all patients randomized). Disagreements regarding values or analysis were resolved by discussion. The methodological quality of the studies included in the meta-analysis was scored with the Jadad composite scale.11 This is a 5-point quality scale, with low quality studies having a score of 2 and high quality studies a score of 3.11,12

Data analysis
Barotrauma and mortality were dichotomous variables, and ICU, ventilator, and organ failure-free days were continuous variables. The data analysis was performed using meta-analysis software (RevMan 4.2, Cochrane Collaboration, Oxford, and NCSS 2004, Kaysville, UT, USA and StatsDirect 2.6, StatsDirect Ltd, Sale, Cheshire, UK). The results were expressed as relative risk (RR) or odds ratio (OR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, along with their 95% condence intervals (CIs). A Z-test was performed to examine the overall effect. We tested heterogeneity between trials with c2 tests, with p  0.05 indicating signicant heterogeneity.13 A random effects model was used if signicant heterogeneity was detected. A xed effects model was used otherwise.

Methods
Identication of trials
We aimed to identify all relevant randomized controlled trials which compared the effects of high versus low PEEP levels in patients with ARDS/ALI. Two authors independently searched the National Library of Medicines Medline database for relevant studies in any language published from 1950 to May 2008 using the MeSH headings and keywords: Respiratory Distress Syndrome, Adult AND Positive-Pressure Respiration or PEEP, AND Survival Analysis or Survival Rate or Hospital Mortality or Treatment Outcome or Length of Stay or Ventilator Weaning AND randomized controlled trials (publication type) or controlled clinical trials or clinical trials, randomized. In addition, we searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and CINAHL. Bibliographies of all selected articles and review articles that included information on PEEP in ARDS/ALI were reviewed for other relevant articles. In addition, we reviewed our personal les and contacted experts in the specialty. This search strategy was done iteratively until we did not nd any new potential citations on review of the reference lists of retrieved articles.

Results
The search strategy generated 54 studies. From these, we identied 5 randomized clinical trials,5e8,14 including a total of 2447 patients, which compared the effects of high versus low PEEP and met our inclusion criteria. Demographic data and overall quality ratings of the included studies are presented in Table 1a. Three studies examined the effects of high versus low PEEP levels in patients receiving low tidal volumes.7,8,14 The remaining 2 studies examined the combined effects of low tidal volume and high PEEP versus conventional tidal volume and low PEEP (Table 1b).5,6 The mortality rates from these 2 studies were adjusted for the mortality reduction due to low tidal volume ventilation since it is now widely accepted that low tidal volume ventilation improves survival in ARDS/ALI.1,15 To accomplish this, we created a hypothetical group in which patients were treated with low tidal volumes, instead of conventional tidal volumes, and low PEEP to match the tidal volumes between 2 groups studied in each trial.5,6 The mortality rate for the hypothetical group was calculated as follows. The relative risk reduction (RRR) of

Study selection and data extraction


To be included in the analysis trials had to be randomized clinical trials in all which all patients were admitted to

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Table 1a Characteristics of studies included in meta-analysis. No. of patients Amato 1998 High PEEP Low PEEP ALVEOLI 2004 High PEEP Low PEEP Villar 2006 High PEEP Low PEEP EXPRESS 2008 High PEEP Low PEEP LOV 2008 High PEEP Low PEEP 29 24 276 273 50 45 385 382 475 508 Female (%) NR Age 33(13) 36(14) 54(17) 49(17) 48 52 60(16) 60(15) 55(17) 57(17) Severity score 28(7)a 27(6)a 96(33)b 91(30)b 32(6)a 32(6)a 50(16)c 49(16)c 25(8)a 26(8)a PaO2: FiO2 112(51) 134(67) 151(67) 165(77) 111 109 144(58) 143(57) 145(48) 145(49) Pulmonary ARDS (%) 66 46 58 53 40 36 70 75 69 76

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Jadad score 2

43 47 60 40 32 33 41 40

Values are given as means (SDs). NR Z not reported. a APACHE II score. b APACHE III score. c SAPS II score.

Table 1b Study

PEEP and tidal volumes employed in the clinical studies. Set PEEP Day 1 Day 2e4 16.4 (2.2) 8.7 (2.0) 7.7y 12.9 (4.5) 8.5 (3.7) 4.4y 11.2 (3.1) 8.7 (2.8) 2.5y 13.4 (4.7) 6.7 (1.8) 6.7y 11.8 (4.1) 8.8 (3.0) 3.0y Day 6e7 13.2 (2.2) 9.3 (2.5) 3.9y 12.9 (4.0) 8.4 (4.3) 4.5y 8.2 (3.5) 8.3 (3.7) 0.1 8.9 (5.1) 6.2 (2.1) 2.7y 10.3 (4.3) 8.0 (3.1) 2.3y Tidal volume (mL/kga) Day 1 362 (59)b 763 (127) 401y 6.0 (0.9) 6.1 (0.8) 0.1y 7.3 (0.9) 10.2 (1.2) 2.9y 6.1 (0.3) 6.1 (0.4) 0 6.8 (1.4) 6.8 (1.3) 0 Day 2e4 348 (32)b 768 (64) 420y 5.8 (1.0) 6.1 (1.1) 0.3y 7.1 (0.9) 10.0 (1.0) 2.9y 6.2 (0.5) 6.2 (0.6) 0 6.9 (1.5) 6.7 (1.5) 0.2y Day 6e7 387 (38)b 738 (83) 351y 5.8 (1.2) 6.2 (1.3) 0.4 7.1 (0.9) 9.9 (1.2) 2.8y 6.8 (1.3) 6.4 (0.9) 0.4y 6.9 (1.3) 7.0 (1.6) 0.1

Amato 1998 High PEEP group Low PEEP group Difference ALVEOLI 2004 High PEEP group Low PEEP group Difference Villar 2006 High PEEP group Low PEEP group Difference EXPRESS 2008 High PEEP group Low PEEP group Difference LOV 2008 High PEEP group Low PEEP group Difference

16.3 (3.8) 6.9 (3.9) 9.4y 14.7 (3.5) 8.9 (3.5) 5.8y 14.1 (2.8) 9.0 (2.7) 5.1y 14.6 (3.2) 7.1 (1.8) 7.5y 15.6 (3.9) 10.1 (3.0) 5.5y

Values are given as means (SDs). y p < 0.05. a Predicted body weight. b Actual tidal volume.

PEEP in ARDS hospital mortality secondary to low tidal volumes was estimated to be 13% (95% CI: 1 to 25%). This estimate was obtained by pooling data from previous randomized clinical trials1,16e18 using the same method described by Petrucci and Iacovelli.19 In the Amato study, the hospital mortality rate in the group treated with conventional tidal volume and low PEEP was 71%.5 The mortality rate for the hypothetical group treated with low tidal volume and low PEEP was estimated to be 0.71e0.71 0.13 Z 62% (95% CI: 53e 72%). The same adjustment was made for Villars study6 before pooling the data. A pooled analysis showed a signicant reduction in hospital mortality with the use of high PEEP (RR Z 0.89; 95% CI, 0.80e0.99; p Z 0.03, Fig. 1). Sensitivity analyses using a random effects model, odds ratios, and risk differences did not affect the result. We conducted another sensitivity analysis by varying the RRR of hospital mortality attributed to low tidal volumes within the range of its 95% CI. Even when the highest-end of RRR (25%) was assumed (i.e., the greatest effect of low tidal volumes on hospital mortality; hence a minimum contribution of high PEEP levels on mortality reduction), high PEEP strategy still marginally reduced hospital mortality (RR Z 0.9; 95% CI, 0.81e1.00). We examined the relation between treatment benet and underlying risk. We estimated the predicted mortality rates in the included clinical trials based on reported ICU severity scores (Table 2). The predicted mortality rates in the ALVEOLI study were estimated based on the study by Cooke et al. which demonstrated a relationship between PaO2/FiO2 ratio at onset of acute lung injury and probability of hospital death.20 The studies which showed larger treatment effects5,6 appeared to have involved patients with greater overall severity of illness. We examined correlation, as suggested by Sharp et al.,21 between the

1177 predicted mortality rates and RRs of hospital mortality associated with the use of high PEEP. A linear regression analysis conrmed that there was a strong negative association (correlation coefcient Z 0.89, p < 0.05) between the predicted mortality and the RRs of hospital mortality e that is, higher the predicted mortality, the greater the mortality reduction associated with the use of high PEEP (Fig. 2). We also conducted a logistic regression analysis as suggested by Thompson22 to examine if different PEEP strategies affected the hospital mortality rates. We hypothesized that the use of pressureevolume curves for the titration of PEEP enhanced the mortality benets. However, the analysis failed to show a signicant association between the use of pressureevolume curves and mortality rates (OR Z 0.90; 95% CI: 0.57e1.44; p Z 0.67). We found a signicant funnel plot asymmetry both on visual inspection (Fig. 3) and by Eggers23 (p Z 0.05) and BeggeMazumdars tests24 (p Z 0.02), suggesting underpublication of negative results. Three studies reported on 28-day mortality.6e8 The 28day mortality rate of low PEEP strategy in Amatos study5 was adjusted for the mortality reduction due to low tidal volume ventilation using the same method as described above. There was a trend toward decreased 28-day mortality (RR Z 0.88; 95% CI, 0.76e1.01; p Z 0.06) with the use of high PEEP (Fig. 1). The study results revealed no statistically signicant difference in ICU-free days (WMD Z 0.04 days; 95% CI: 1.03 to 1.10; p Z 0.94), ventilator-free days (WMD Z 1.03 days; 95% CI: 1.44 to 3.51; p Z 0.41), or organ failure-free days (WMD Z 2.01 days; 95% CI: 1.91 to 5.93; p Z 0.32) between the high and low PEEP strategies (Fig. 4). The ventilator-free days of the low PEEP strategy in Villars study6 were also adjusted for the reduction attributed to

Figure 1

Forest plot examining the effect of high versus low PEEP on hospital and 28-day mortality. RR Z relative risk.

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Table 2 Potential source for clinical and methodological heterogeneities. Strategy used in the high PEEP group Amato 1998 Villar 2006 ALVEOLI 2004 EXPRESS 2008 LOV 2008 2 cm H2O above PFlex 2 cm H2O above PFlex PEEPeFiO2 table Titrated to Pplat of 28e30 cm H2O PEEPeFiO2 table Observed mortality % (High/Low PEEP group) 45/71 34/56 25/27 35/39 36/40

Y. Oba et al.

Predicted mortality % (High/Low PEEP group) 64/60 76/76 37/36a 46/44 53/56

PFlex Z lower inection point. a Estimated from PaO2/FiO2 ratios.20

low tidal volumes using the same method described above. The incidence of barotrauma was also similar in the both strategies (OR Z 1.19; 95% CI: 0.89e1.58; p Z 0.25, Fig. 5).

Discussion
Our analysis showed high PEEP levels decreased hospital mortality when all relevant studies were combined. However, this should be interpreted with caution for the following reasons. First, the inspection of funnel plot and the statistical tests suggested a possibility of publication bias and/or small study effects. Actually, when 2 outliers5,6 were removed from the analysis, the effect of high PEEP levels on hospital mortality became no longer statistically signicant (RR Z 0.9; 95% CI, 0.81e1.01; p Z 0.08). The small studies which showed larger treatment effects used pressureevolume curves for the titration of PEEP (Table 2). Therefore, we examined if differences in the PEEP strategies contributed to this heterogeneity. However, the use of static pressureevolume curves was not associated with the hospital mortality rates. We also found that neither the differences of PEEP levels, plateau pressures nor the static compliance between high versus low PEEP strategies were associated with the hospital mortality rates. The method to reliably obtain optimal PEEP levels for each individual patient remains elusive despite years of extensive clinical and laboratory research15 and the use of

FiO2ePEEP table employed in the large clinical studies has been criticized.9,10 The ARDSnet protocol14 lacks a solid physiologic basis and may increase the risk of alveolar overination. Therefore, titration of PEEP based on respiratory mechanics may be more advantageous to avoid ventilator-induced lung injury.9,10 Our nding suggests that the use of pressureevolume curve may not be the best way of nding an optimal PEEP setting as previously criticized.25,26 A practical method of identifying the optimal or best PEEP remains to be established.25,27,28 On the other hand, the logistic analysis suggested that the benecial effect of high PEEP was greater in patients with higher ICU severity scores. This nding suggests that the difference in underlying risk of death across the included trials is a signicant source of heterogeneity. In other words, the difference in case mix across the included trials could explain the funnel plot asymmetry. If all the included studies had recruited patients with much higher ICU severity scores, the mortality benet might have been easier to detect. Second, we incorporated 2 studies which examined the combined effect of low tidal volumes and high PEEP levels. Although, hospital mortality rates from those studies were adjusted for the mortality reduction due to low tidal volumes to estimate the isolated benet of high PEEP on hospital mortality, the accuracy of those estimates would need further validation. However, the sensitivity analyses supported the robustness of the pooled analysis. Third, clinical heterogeneity described above raises a question if it is appropriate to estimate the effects of high PEEP from a pooled analysis. The patient characteristics among the included studies also varied widely. Predicted

Figure 2 Linear regression and 95% condence interval of relative risk of hospital mortality associated with the use of high PEEP against predicted hospital mortality. Risk of death with high PEEE relative to low PEEP decreases as predicted mortality increases. RR Z relative risk.

Figure 3

Funnel plot inspection on hospital mortality.

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Figure 4 Forest plot examining the effect of high versus low PEEP on ventilator, ICU, and organ failure-free days. WMD Z weighted mean difference.

mortality rates ranged from 37 to 72%. The mean age ranged from 33 to 60. The proportion of pulmonary causes of acute lung injury ranged from 36 to 70% (Table 1a). Clinical heterogeneity may render pooling of the data unreliable or inappropriate but the direction of benet is consistently in support of the high PEEP strategy. It should still be kept in mind that the magnitude of its benet might not be generalizable because of the clinical heterogeneity. We examined the relationship between plateau pressures and hospital mortality rates since a recent international observational study suggested that many clinicians were limiting tidal volumes only when plateau pressure was high,29 probably reecting the data which showed an association between high plateau pressures and increased hospital mortality.3,30 Actually, a plot of plateau pressures

versus hospital mortality including all 5 studies showed an upward inection at lower plateau pressures (Fig. 6). The higher mortality rates associated with higher plateau pressures are likely due to conventional tidal volumes used in Amato and Villars studies7,8 causing overextension of the alveoli and further lung injury. On the other hand, the higher mortality rates associated with lower plateau pressures could be attributed to the use of low PEEP levels. Conventional PEEP levels as those employed in the control groups of included trials are probably safe but lower than conventional PEEP levels may not be safe given possible increase in hospital mortality as reported by Ferguson et al.29 In conclusion, although the clinical and methodological heterogeneities such as differences in disease severity and

Figure 5

Forest plot examining the effect of high versus low PEEP on the incidence of barotrauma. RR Z relative risk.

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8. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008 Feb 13;299(6):646e55. 9. Grasso S, Fanelli V, Cafarelli A, et al. Effects of high versus low positive end-expiratory pressures in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005 May 1;171(9): 1002e8. 10. Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilatory protocol and alveolar hyperination: role of positive endexpiratory pressure. Am J Respir Crit Care Med 2007 Oct 15; 176(8):761e7. 11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996 Feb;17(1):1e12. 12. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001 Dec 4;135(11): 982e9. 13. Oxman AD, Cook DJ, Guyatt GH. Users guides to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA 1994 Nov 2;272(17):1367e71. 14. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004 Jul 22; 351(4):327e36. 15. Girard TD, Bernard GR. Mechanical ventilation in ARDS: a stateof-the-art review. Chest 2007 Mar;131(3):921e9. 16. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and VolumeLimited Ventilation Strategy Group. N Engl J Med 1998 Feb 5; 338(6):355e61. 17. Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999 Aug;27(8): 1492e8. 18. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume Reduction in ARDS. Am J Respir Crit Care Med 1998 Dec;158(6):1831e8. 19. Petrucci N, Iacovelli W. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev 2007;(3):CD003844. 20. Cooke CR, Kahn JM, Caldwell E, et al. Predictors of hospital mortality in a population-based cohort of patients with acute lung injury. Crit Care Med 2008 May;36(5):1412e20. 21. Sharp SJ, Thompson SG, Altman DG. The relation between treatment benet and underlying risk in meta-analysis. BMJ 1996 Sep 21;313(7059):735e8. 22. Thompson SG. Controversies in meta-analysis: the case of the trials of serum cholesterol reduction. Stat Methods Med Res 1993;2(2):173e92. 23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997 Sep 13; 315(7109):629e34. 24. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994 Dec; 50(4):1088e101. 25. Wilson TA, Ana RC, Hubmayr RD. Mechanics of edematous lungs. J Appl Physiol 2001 Jun;90(6):2088e93. 26. Hickling KG. Reinterpreting the pressureevolume curve in patients with acute respiratory distress syndrome. Curr Opin Crit Care 2002 Feb;8(1):32e8. 27. Grasso S, Terragni P, Mascia L, et al. Airway pressureetime curve prole (stress index) detects tidal recruitment/hyperination in

Figure 6 Polynomial regression and 95% condence interval of hospital mortality against plateau pressure.

ventilator protocols make proper interpretation of the results difcult, a small but signicant mortality benet of high PEEP cannot be excluded. Our analysis suggests that benecial effects of high PEEP are greater in patients with higher ICU severity scores.

Conict of interest
None of the authors have any nancial or conict of interests that are related to this study.

Funding
None.

References
1. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000 May 4;342(18):1301e8. 2. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two uid-management strategies in acute lung injury. N Engl J Med 2006 Jun 15;354(24):2564e75. 3. Checkley W, Brower R, Korpak A, Thompson BT. Effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury. Am J Respir Crit Care Med 2008 Jun 1; 177(11):1215e22. 4. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999 Jul 7;282(1):54e61. 5. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998 Feb 5;338(6):347e54. 6. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006 May;34(5):1311e8. 7. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008 Feb 13;299(6):637e45.

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experimental acute lung injury. Crit Care Med 2004 Apr;32(4): 1018e27. 28. Downie JM, Nam AJ, Simon BA. Pressureevolume curve does not predict steady-state lung volume in canine lavage lung injury. Am J Respir Crit Care Med 2004 Apr 15;169(8): 957e62.

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29. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome. Crit Care Med 2005 Jan;33(1):21e30. 30. Brower RG, Matthay M, Schoenfeld D. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials. Am J Respir Crit Care Med 2002 Dec 1;166(11):1515e7.

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