Higher vs Lower Positive End-Expiratory Pressure in Patients With Acute Lung Injury and Acute Respiratory Distress Syndrome
Briel M, Meade, M, Mercat A et al. JAMA 2010; 303 865:875
Reviewers: Carolyn Furuya MD; Haider Warraich MBBS; Robina Matyal MD
Beth Israel Deaconess Medical Center
Harvard Medical School
Prevention of ventilation-induced lung injury in critically ill patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has previously been investigated and it is generally accepted that lung protective strategies such as supplying low tidal volumes and inspiratory pressures are beneficial. However, it is unclear whether high vs low levels of positive end-expiratory pressure (PEEP) in this population is preferable. Randomized controlled trials have failed to demonstrate differences between high and low level PEEP, but these studies may have been underpowered to detect differences in outcomes. Additionally, it is plausible that subgroups of patients may exist that exhibit different morbidity and mortality outcomes when exposed to high vs low PEEP. This meta-analysis of individual-patient data was done to compare outcomes in patients with acute lung injury and ARDS when exposed to high vs low PEEP.
In this meta-analysis of individual patient data, trials selected compared high vs low PEEP and involved critically ill adults (>16 years) with a diagnosis of acute lung injury or ARDS receiving low tidal volume ventilation. Randomized trials that compared high vs low PEEP were identified via an electronic search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) and a hand-search of conference proceedings from 2004-2010. The primary outcome was hospital mortality at 60 days. Secondary outcomes were death prior to discharge from the intensive care unit, pneumothorax requiring chest tube up to 28 days, death resulting from pneumothorax, time to unassisted breathing from day 1 to day 28, requirement of rescue therapy, and the need for neuromuscular blocking agents, vasopressors, or corticosteroids. Individual-patient data were compiled and examined and patients were classified as having ARDS based on a ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2:FIO2) of 200 mm Hg or less. The authors compared various respiratory variables using 2-sided t tests and used a log-binomial regression to calculate relative risks and 95% confidence intervals. Baseline patient characteristics were compared based on Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology II scores. Of the 1426 trials identified via electronic search, 4 trials were identified as potentially eligible. Three trials were included in the primary meta-analysis and one was included in sensitivity analysis only.
Three trials (ALVEOLI 2004, LOVS 2008, and EXPRESS 2008) including 2299 patients met eligibility criteria. In the ALVEOLI and LOVS trials, high vs low PEEP was titrated based on oxygenation. The EXPRESS trial titrated PEEP to plateau pressure and did not take oxygenation into account. The high vs low PEEP groups exhibited similar baseline characteristics and in both groups low tidal volumes (a mean of 6 mL/kg predicted body weight) were used. There was no statistically significant difference in hospital mortality between the high vs low PEEP groups (32.9% vs 35.2%; RR 0.945, 95% CI 0.86-1.04, P=0.25), but there was a significant reduction of intensive care unit mortality for patients in the high PEEP group (28.5% vs 32.8%, RR 0.87, CI 0.78-0.97, P=0.01).
Ventilation strategies in patients with ALI or ARDS has been a topic of great interest. Different investigators have employed different strategies in randomized controlled trials; investigators have tested higher versus lower tidal volume, higher versus lower PEEP and lower tidal volume and PEEP titrated versus higher tidal volume and lower PEEP. However, this important ongoing debate continues in the absence of consensus due to underpowered studies and conflicting results.
While mechanical ventilation remains crucial to support critically ill patients, it can also be harmful in patients due to excessive wall tension and stress resulting in barotrauma further complicating patients’ clinical course and adversely affecting the patients prognosis. In this trial, higher PEEP group maintained higher oxygenation levels, reflected by lower FiO2 levels. Amongst the three trials that passed inclusion criteria, there were no significant differences in baseline characteristics between the two groups. The results of this study, while showing a mortality benefit for patients with ARDS, shows that higher PEEP has no benefit or even harm in patients with ALI but not ARDS. This is supported by previous animal models as well as by studies recognizing that ARDS patients have more recruitable lung volumes, and PEEP reduces atelectasis, recruits collapsed lung alveoli and by maintaining pulmonary airway pressures at a more constant rate, reduces the amount of work the lung has to undergo during ventilation. However, a recent meta-analysis that reviewed RCTs studying different ventilation strategies and outcomes in patients with ARDS/ALI concluded that though high PEEP may prevent hypoxemia in selected patients, it does not seem to confer any benefit otherwise, whereas using low tidal volume but not high PEEP did in fact result in better outcomes.
This paper was limited by the number of RCTs it could include due to differences in designs, end points and data collection. The study remained underpowered to be able to change the null hypothesis; the authors themselves also point out that this is a subgroup analysis. Two of the three trials included were not completed due to futility. Additionally, caregivers were not blinded to the PEEP category of the patient, which might have influenced them to alter rescue strategies for higher PEEP patients.
Overall, this study only emphasizes the need for larger RCTs that have a higher number of patients with standardized definitions of outcomes as well as ‘ARDS’ and ‘ALI’, and should be able to look at different ventilation strategies, so that consensus can be reached as to which strategy has the least adverse effects while maintaining optimum ventilation. Needless to say, this important debate has not yet been concluded.