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As the old joke goes, statistics are like a bikini Ð what they reveal is suggestive, but what they conceal is vital. Three recent randomized controlled trials (RCTs) evaluating the effects of positive end-expiratory pressure (PEEP) on outcome from the acute respiratory distress syndrome (ARDS)1-3 tend to be more bathing suit than bikini: they are a bit outdated and hide as much as they reveal.
In a recent issue of JAMA, Meade at al.2 and Mercat et al.3 report the results of two large RCTs comparing alternative strategies for setting PEEP in patients with acute lung injury (ALI) and ARDS who were ventilated with a targeted tidal volume of 6 ml.kg-1 of predicted body weight. In the Lung Open Ventilation (LOV) trial2, the level of PEEP was selected according to an oxygenation scale similar to that used by the ARDSNet group in the ALVEOLI study1. In the Expiratory Pressure (Express) trial by Mercat et al.3, PEEP selection in the treatment group (higher PEEP) was based on the level needed to achieve a plateau pressure of 28 cm H2O following ventilation with the targeted tidal volume instead of gas exchange and the control group identified as a minimal distension strategy (lower PEEP) set PEEP based on oxygenation response. Despite the different criteria used for PEEP selection, the PEEP levels were similar in both trials (15.6 cm H2O vs. 15.8 cm H2O in the higher PEEP groups; 10.1 cm H2O vs. 8.4 cm H2O in the lower PEEP groups). In both RCTs, the hospital mortality rates were not significantly different (36.4% and 40.4% in the LOV trial vs. 35.4% and 39% in the Express trial). Taken together, these two studies enrolled a total of 1750 patients and the pooled hospital mortality were 35.9% (for the higher PEEP levels) and 39.8% (for the lower PEEP levels) (p=0.10).
At first sight, these results suggest that the application of low or high PEEP levels in patients with ALI and ARDS does not influence outcome. However, this is not what the data shows. A critical review of these two RCTs leads to an alternate interpretation. On the one hand, in both trials patients who received higher PEEP were less likely to require rescue therapy. In addition, a lower PEEP was associated significantly with fewer ventilator-free and organ failure-free days which may be the reason for the 4% mortality difference in favour of the high PEEP groups.
With these two trials, there are a total of five published RCTs examining the effects of higher levels of PEEP in patients with ALI and/or ARDS1-5. The speculation of many clinicians regarding the lack of expected benefit from higher PEEP in the ALVEOLI, LOV and Express trials is that in a substantial proportion of patients in these trials the severity of lung injury was modest. Amato et al.4 and Villar et al.5 enrolled only patients with severe, established ARDS and they both found that the application of higher levels of PEEP was associated with a better outcome. By contrast, in the ALVEOLI, LOV and Express trials, the investigators studied an unselected, mixed population of ALI and ARDS, and as a result, missed the opportunity to test whether the use of higher levels of PEEP is beneficial in patients with persistent ARDS. Patients in the ALVEOLI, LOV and Express trials had a similar PaO2/FiO2 ratio at study entry (about 140 ± 50 mm Hg). However, it is conceivable that a disproportionate number of patients meeting ALI criteria on standard ventilatory settings ended up in the control arm, negating the beneficial effect of the treatment because of a lower mortality (#20% in most series).
Since the ALI/ARDS population was not homogeneous in the LOV and Express trials, the benefit
of higher levels of PEEP could not be appropriately evaluated. In the LOV trial, a PEEP level of
5 cm H2O was a permissible setting in the higher PEEP group. Therefore, a patient with a PaO2 of 60 mm Hg on a FiO2 of 0.3 and 5 cm H2O of PEEP satisfied the AECC inclusion criteria. It is difficult to accept that in these patients there is a need to test the effects of high levels of PEEP and recruitment manoeuvres. In the Express trial patients with ALI (without ARDS) did not benefit and had more adverse effects from higher levels of PEEP, which suggest that both trials failed to focus on the highest risk patients. If the subjects in a trial have a very low risk of the condition that the intervention is hypothesized to prevent, the trial Ð regardless of sample size- will not verify the value of the experimental intervention under study6. Villar et al.7 have recently reported that a systematic method of assessing severity of lung injury is required to identify the best theoretical ARDS candidates for enrolment into RCTs. They found that the response to standard ventilatory setting, 24 hours after meeting American-European Consensus Conference criteria for ARDS, separated patients with an overall mortality of 34% into 3 subgroups with different degrees of lung injury and mortality rates (varying from 6.3% to 45.5%).
The bottom line is that due to misconceptions about which patients would benefit from higher levels of PEEP, the optimal PEEP strategy in patients with persistent ARDS remains unresolved.
Jesœs Villar, MD, PhD, FCCM
Multidisciplinary Organ Dysfunction Evaluation Research Network
Hospital Universitario Dr. Negrin
Las Palmas de Gran Canaria, Spain.
References:
1. 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; 351:327-336. (See also Intensive Care Monitor 2004;11:115).
2. 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. JAMA 2008; 299:637-645. (See this issue p. 52)
3. Mercat A, Richard JCM, Vielle B et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome. JAMA 2008; 299:637-645. (See this issue p. 52)
4. Amato MB, Barbas CS, Medeiros DM eet al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347-354. (See also Intensive Care Monitor 1998;IV:32).
5. Villar J, Kacmarek RM, PŽrez-MŽndez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume strategy improves outcome in persistent acute respiratory distress syndrome. A randomized controlled trial. Crit Care Med 2006; 34:1311-1318.
6. Villar J, PŽrez-MŽndez L, Aguirre-Jaime A, Kacmarek R. Why are physicians so sceptical about positive randomized controlled clinical trials in critical care medicine? Intensive Care Med 2005; 31:196-204.
7. Villar J, PŽrez-MŽndez L, L—pez J eet al. An early PEEP/FiO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2007; 176:795-804.
Postscript
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