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Meta-analysis: Ventilation Strategies and Outcomes of the Acute Respiratory Distress Syndrome and Acute Lung Injury

Christian Putensen, MD, PhD; Nils Theuerkauf, MD; Jörg Zinserling, PhD; Hermann Wrigge, MD, PhD; and Paolo Pelosi, MD
[+] Article, Author, and Disclosure Information

From University Hospital Bonn, Bonn, Germany, and the University of Insubria, Varese, Italy.

Potential Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Zinserling (e-mail, joerg.zinserling@ukb.uni-bonn.de).

Requests for Single Reprints: Christian Putensen, MD, PhD, Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany; e-mail, putensen@buni-bonn.de.

Current Author Addresses: Drs. Putensen, Theuerkauf, Zinserling, and Wrigge: Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

Dr. Pelosi: Department of Ambient, Health, and Safety, University of Insubria, Servizio di Anestesia B, Ospedale di Circolo e Fondazione Macchi viale Borri 57, 21100 Varese, Italy.

Author Contributions: Conception and design: C. Putensen, P. Pelosi.

Analysis and interpretation of the data: C. Putensen, N. Theuerkauf, J. Zinserling, H. Wrigge, P. Pelosi.

Drafting of the article: C. Putensen, P. Pelosi.

Critical revision of the article for important intellectual content: C. Putensen, P. Pelosi.

Final approval of the article: C. Putensen, P. Pelosi.

Provision of study materials or patients: C. Putensen.

Statistical expertise: J. Zinserling.

Obtaining of funding: C. Putensen.

Administrative, technical, or logistic support: C. Putensen.

Collection and assembly of data: C. Putensen, N. Theuerkauf, J. Zinserling, H. Wrigge, P. Pelosi.

Ann Intern Med. 2009;151(8):566-576. doi:10.7326/0003-4819-151-8-200910200-00011
Text Size: A A A

Background: Trials have provided conflicting results regarding the effect of different ventilatory strategies on the outcomes of patients with the acute respiratory distress syndrome (ARDS) and acute lung injury.

Purpose: To determine whether ventilation with low tidal volume (Vt) and limited airway pressure or higher positive end-expiratory pressure (PEEP) improves outcomes for patients with ARDS or acute lung injury.

Data Sources: Multiple computerized databases (through March 2009), reference lists of identified articles, and queries of principal investigators. No language restrictions were applied.

Study Selection: Randomized, controlled trials (RCTs) reporting mortality and comparing lower versus higher Vt ventilation, lower versus higher PEEP, or a combination of both in adults with ARDS or acute lung injury.

Data Extraction: Using a standard protocol, 2 reviewer teams assessed trial eligibility and abstracted data on quality of study design and conduct, population characteristics, intervention, co-interventions, and confounding variables.

Data Synthesis: 4 RCTs tested lower versus higher Vt ventilation at similar PEEP in 1149 patients, 3 RCTs compared lower versus higher PEEP at low Vt ventilation in 2299 patients, and 2 RCTs compared a combination of higher Vt and lower PEEP ventilation versus lower Vt and higher PEEP ventilation in 148 patients. Lower Vt ventilation reduced hospital mortality (odds ratio, 0.75 [95% CI, 0.58 to 0.96]; P = 0.02) compared with higher Vt ventilation at similar PEEP. Higher PEEP did not reduce hospital mortality (odds ratio, 0.86 [CI, 0.72 to 1.02]; P = 0.08) compared with lower PEEP using low Vt ventilation. Higher PEEP reduced the need for rescue therapy to prevent life-threatening hypoxemia (odds ratio, 0.51 [CI, 0.36 to 0.71]; P < 0.001) and death (odds ratio, 0.51 [CI, 0.36 to 0.71]; P < 0.001) in patients receiving rescue therapies.

Limitations: Pooling according to similar ventilatory strategies resulted in few RCTs analyzed in each group. The benefit of low Vt is derived from only 1 study.

Conclusion: Available evidence from a limited number of RCTs shows better outcomes with routine use of low Vt but not high PEEP ventilation in unselected patients with ARDS or acute lung injury. High PEEP may help to prevent life-threatening hypoxemia in selected patients.

Primary Funding Source: None.


Grahic Jump Location
Literature search and selection.

ALI = acute lung injury; ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure; RCT = randomized, controlled trial; Vt = tidal volume.

Grahic Jump Location




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Submit a Comment/Letter
Posted on October 26, 2009
Federico Gordo-Vidal
Hospital del Henares
Conflict of Interest: None Declared

We read with great interest the meta-analysis published by Putensen et al (1). We agree with its conclusions, however we would like to add some suggestions.

Our group conducted previously a meta-analysis (2) on the effect of higher vs. lower PEEP levels in patients with ARDS. Four articles evaluated the effect of PEEP levels on mortality, not showing significant differences (RR 0.73, 95% CI 0.49 to 1.10). However, an analysis of the three studies in which PEEP level was individualized according to pulmonary mechanics (pressure-volume curve) found a significant decrease in mortality (RR 0.59, 95% CI: 0.43 to 0.82).

When the definitive results of two new studies were known, we updated our meta-analysis (3). Pooling the results of the four previous studies and the two recent ones, the use of higher PEEP levels, regardless of PEEP selection mode, did'n reached a statistically significant mortality reduction in a random effects model (RR 0.85, 95% CI 0.71 to 1.01) (p = 0.06).

The favorable effect of the use of the high PEEP (individualized based on the findings of pulmonary mechanics), can be overestimated, it should be noted that in the 3 studies analyzed in the meta-analysis of Putensen et al (1), control groups (low PEEP groups) used PEEP levels well above those used in clinical practice (4).

We conclude that higher PEEP levels are probably beneficial in ARDS, especially in the most severe ones, however PEEP should not be set to fixed levels, but tailored to individual pulmonary mechanics.


1. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Meta- analysis: Ventilation Strategies and Outcomes of the Acute Respiratory Distress Syndrome and Acute Lung Injury. Ann Intern Med. 2009;151(8):566- 76.

2. Gordo-Vidal F, Gomez-Tello V, Palencia-Herrejon E, Latour-Perez J, Sanchez-Artola B, Diaz-Alersi R. High PEEP vs. conventional PEEP in the acute respiratory distress syndrome: a systematic review and meta- analysis. Med Intensiva. 2007;31(9):491-501.

3. Gordo-Vidal F, Gomez-Tello V, Palencia-Herrejon E, Latour-Perez J. Impact of two new studies on the results of a meta-analysis on the application of high PEEP in patients with acute respiratory distress syndrome. Med Intensiva. 2008;32(6):316-7.

4. Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, et al. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med. 2008;177(2):170-7.

Conflict of Interest:

None declared

Error in Table 2?
Posted on October 30, 2009
Duncan Chambers
CRD, University of York, UK
Conflict of Interest: None Declared

I believe there is an error in Table 2 that could cause confusion. Under the outcomes 'Use of rescue therapy' and 'Mortality in patients with rescue therapy', the data in the 'Low PEEP' column refer to the 'High PEEP' group and vice versa.

Conflict of Interest:

None declared

Use of Adjusted Data in a Meta-Analysis
Posted on December 23, 2009
Elliott C Dasenbrook, MD MHS
Case Western Reserve University School of Medicine and University Hospitals Case Medical Center
Conflict of Interest: None Declared

We read with interest the meta-analysis by Putensen and colleagues (1) on ventilation strategies and outcomes in patients with acute lung injury because, as they stated, their meta-analysis "should better separate the effects of tidal volume and PEEP on mortality". In the synthesis of the three randomized controlled trials evaluating the effect of higher versus lower positive end-expiratory pressure (PEEP) in patients receiving protective lung ventilation, we believe the authors used the adjusted hospital mortality from the ALVEOLI study (2) in addition to mislabeling the low and high PEEP at low tidal volume columns. In the ALVEOLI study, the investigators report higher rates of death before hospital discharge in the higher PEEP group as compared to the lower PEEP group (27.5% vs. 24.9%, respectively), which should result in an odds ratio for mortality from a higher PEEP strategy that is greater than one (the author's Table 2 reports an OR of 0.88) . However, in the adjusted analysis, the ALVEOLI investigators report a lower mortality rate in the higher PEEP group (69 vs. 75 deaths, higher vs. lower PEEP, respectively) - the same number of deaths used by the authors in their meta-analysis (Table 2). The authors did not explicitly state the use of adjusted hospital mortality in their methods. Furthermore, the study by Meade and colleagues (3) also reported adjusted hospital mortality that demonstrated a greater hospital mortality from the higher PEEP strategy than in the unadjusted analysis. However, the authors did not include the adjusted hospital mortality from this study in their meta-analysis.

Using the unadjusted hospital mortality from ALVEOLI, we calculated a pooled relative risk (RR) of 0.94 [95% confidence interval (CI) 0.84 to 1.05; p=0.25; I^2=0%] for these three studies (2-4). Furthermore, when using the adjusted hospital mortality data from both aforementioned studies, the pooled results are identical to our unadjusted analysis (pooled RR 0.94; 95% CI 0.84 to 1.05; p=0.25; I^2=0%). Finally, another recently published meta-analysis examining higher versus lower PEEP also used the adjusted hospital mortality from ALVEOLI, but not from Meade and colleagues (5).

Meta-analyses are often considered the highest level of evidence and are frequently utilized by clinicians and professional societies making guideline recommendations. Therefore, it is imperative that authors of all meta-analyses are explicit in the type of data being used for analysis and reported to consumers so that bias in the interpretation of the results can be avoided.


(1) Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Meta -analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009; 151(8):566- 576.

(2) Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351(4):327-336.

(3) Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ 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; 299(6):637-645.

(4) Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299(6):646-655.

(5) Phoenix SI, Paravastu S, Columb M, Vincent JL, Nirmalan M. Does a higher positive end expiratory pressure decrease mortality in acute respiratory distress syndrome? A systematic review and meta-analysis. Anesthesiology 2009; 110(5):1098-1105.

Conflict of Interest:

None declared

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