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Do Higher PEEP and Lung Recruitment Improve Outcomes in ARDs?
By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.
Introduction: The Rationale for higher PEEP And Lung Recruitment
It is now well established that ventilating patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) using a strategy that limits alveolar distending volume and end-inspiratory static airway pressure results in improved survival, as compared to larger-volume, higher-pressure ventilation.1,2 The decreased mortality is believed to be at least in part related to a reduction in ventilator-induced lung injury (VILI) from excessive alveolar stretch. Both animal and human studies support the concept that insufficient lung inflation, resulting in repetitive opening and closing of collapsed airways and alveoli with tidal ventilation, is an additional cause of VILI. To prevent this second form of VILI, it makes sense to open atelectatic areas using large initial inflation volumes, and to use sufficient positive end-expiratory pressure (PEEP) to keep them from collapsing again at end-exhalation. Ever since the advent of lung-protective ventilation using lower tidal volumes and end-inspiratory plateau pressures, some clinicians have advocated the use of such an "open-lung" approach,3 using higher levels of PEEP than those employed in the original ARDS Network low-tidal-volume study,2 along with intermittent "recruitment maneuvers" to maximally open atelectatic areas of lung.
Using the ARDS Network low-tidal-volume approach as a starting point, 3 large multicenter clinical trials have investigated the hypothesis that the use of higher levels of PEEP would further improve outcomes in patients with ALI and ARDS.4,5,6 Two of these appeared just in the last few weeks, in the same issue of JAMA,5,6 along with a pair of accompanying editorials.7,8 In this article I will summarize these two new studies and the rather different takes on their results by the editorialists. Before addressing them, however, I will briefly discuss the ALVEOLI study, the ARDS Network's own trial of higher vs lower PEEP, published in 2004.4
The ARDS Network ALVEOLI Study4
In this clinical trial carried out in 23 US centers, the ARDSnet investigators sought to randomize 750 patients with ALI or ARDS (defined according to internationally accepted standards) to be ventilated using 2 different versions of the PEEP-FIO2 titration ladder used in the earlier tidal volume study.2 All patients received volume assist-control ventilation. Target tidal volume and plateau pressure were 6 mL/kg predicted body weight and a maximum of 30 cm H2O, respectively, as used in the low-tidal-volume arm of the earlier trial. The PEEP-FIO2 ladders were designed to produce substantially higher PEEP levels in the intervention group while still avoiding plateau pressures over 30 cm H2O. Recruitment maneuvers, consisting of 30-second sustained inflations to 35-40 cm H2O, were carried out in the first 80 high-PEEP patients, but this aspect of the protocol was dropped when an interim analysis showed no sustained effects on oxygenation.9 Although measures of oxygenation and other physiologic variables were recorded, the primary outcomes sought were mortality and ventilator-free days.
The study was stopped by the data and safety monitoring board after 549 patients had been enrolled, according to the investigators' a priori futility criteria, when it was apparent that no differences in primary outcome were emerging. Physiologically, however, there were distinct differences between the groups. On the first study day, mean tidal volumes and plateau pressures were 6.0 mL/kg PBW and 27 cm H2O, respectively, in the high-PEEP patients, and 6.1 mL/kg PBW and 24 cm H2O, respectively, in the low-PEEP patients. The corresponding values for PEEP were 14.7 and 8.9 cm H2O, in the two groups, with all these differences being statistically significant. Arterial oxygenation was significantly greater in the high-PEEP than in the low-PEEP patients, with mean PaO2/FIO2 ratios of 220 vs 168 mm Hg (p < 0.01), and corresponding mean FIO2 values of 0.44 and 0.54 (p <0.05), respectively.
Mortality was 24.9% in the lower-PEEP group and 27.5% in the higher-PEEP group (p = 0.48; 95% confidence interval for the difference between groups, -10.0 to 4.7%). Ventilator-free days during the initial 28 days from randomization were 14.5 vs 13.8 in the lower- and higher-PEEP groups, respectively (p = 0.50). There were no differences in the numbers of days without circulatory, coagulation, hepatic, or renal failure, and also no differences in clinically-evident barotrauma.
Thus, the higher-PEEP strategy improved oxygenation but did not affect mortality or any of the other a priori outcomes.
The Canadian LOVS Trial5
This clinical trial, the Lung-Open Ventilation Study (LOVS), was carried out in 26 Canadian hospitals plus 3 in Australia and 1 in Saudi Arabia. It compared the effects of 2 different protocols—1 of them designed to achieve greater lung recruitment—for the ventilatory management of patients with ALI or ARDS. The control group was managed according to the ARDSnet low-tidal-volume protocol, using volume assist-control, tidal volumes 6 mL/kg PBW, and plateau pressures less than 30 cm H2O. The intervention group was ventilated using pressure-control ventilation with tidal volume 4-8 mL/kg PBW and maximum plateau pressures 40 cm H2O; a recruitment maneuver consisting of a 40-sec inspiratory hold at 40 cm H2O was performed on each patient in this group on study entry. PEEP and FIO2 were adjusted according to ladders similar to those in the ARDSnet protocols, with PEEP substantially higher at all FIO2 points in the intervention group. Physiological variables were measured, but the primary outcome measure was all-cause hospital mortality.
There were 983 consecutive patients enrolled. On Day 1 of the study, mean tidal volumes in the intervention and control groups were each 6.8 mL/kg PBW. Mean plateau pressures were 30.2 and 24.9 cm H2O, respectively (p < 0.001). PEEP in the 2 groups on Day 1 was 15.6 and 10.1 cm H2O, respectively (p < 0.001). Corresponding mean values for PaO2/FIO2 were 187.4 and 149.1 mm Hg, respectively (p < 0.001).
All-cause hospital mortality was 36.4% in the open-lung, higher-PEEP group, and 40.4% in the control group (relative risk 0.90; 95% CI, 0.77-1.05; p = 0.19). There were no differences in ventilator days or ICU days in the two groups. Barotrauma occurred in 11.2% of the higher-PEEP patients and 9.1% of those in the control group (RR 1.21; 95% CI, 0.83-1.75; p = 0.33). The experimental protocol allowed for use of rescue therapies such as prone positioning, inhaled nitric oxide, and high-frequency oscillatory ventilation, in the event of refractory hypoxemia (defined as PaO2 < 60 mm Hg on FIO2 = 1.0 for at least 1 hr). Refractory hypoxemia occurred more often in the control patients than in the higher-PEEP, "open-lung" patients: 10.2% vs 4.6%, p = 0.01. More patients died with refractory hypoxemia in the control group: 8.9% vs 4.2%, p = 0.03. Rescue therapies were used more often in the control group: 9.3% vs 5.1%, p = 0.045.
Thus, the higher-PEEP, open-lung strategy improved oxygenation and was associated with less use of rescue therapies for severe hypoxemia, but had no significant effect on survival or the other outcomes examined.
The French "Express" Study6
This trial compared a ventilator strategy designed to maximize lung recruitment to a second strategy aimed at limiting lung distension, primarily using different approaches to the application of PEEP. Tidal volume was 6 mL/kg PBW in both protocols. In the minimum-distension group, PEEP and plateau pressure were kept as low as possible while maintaining PaO2 55-80 mm Hg (SpO2 88-95%); target PEEP was 5-9 cm H2O. In the increased recruitment group, PEEP was maintained as high as possible without increasing plateau pressure above 30 cm H2O, regardless of PaO2. Recruitment maneuvers were allowed but not encouraged. As in the LOVS trial, rescue therapies could be used in the event of critical hypoxemia. The primary endpoint was 28-day mortality. Secondary endpoints were 60-day hospital mortality, ventilator-free days, and organ-failure-free days at 28 days.
There were 767 patients in 37 French ICUs enrolled. On Day 1, tidal volume was 6.1 mL/kg PBW in each group. Mean PEEP levels were 14.6 and 7.1 cm H2O in the maximum-recruitment and minimum-distension groups, respectively (p < 0.001), with corresponding mean plateau pressures 27.5 and 21.1 cm H2O (p < 0.001). Oxygenation was greater in the maximum-recruitment patients, with mean FIO2 and PaO2/FIO2 ratios of 0.55 vs 0.66 and 218 vs 150 mm Hg, respectively (p < 0.001 for both).
Twenty-eight day mortality in the maximum-recruitment group was 27.8%, as compared to 31.2% in the minimum-distension group (relative risk, 1.12; 95% CI 0.90-1.40; p = 0.31). Corresponding overall hospital mortality rates in the 2 groups were 35.4% and 39.0%, respectively (p = 0.30). The increased recruitment group compared to the minimal distension group had a higher median number of ventilator-free days at 28 days (7 vs 3, p = 0.04), and also a higher median number of organ-failure-free days (6 vs 2, p = 0.04).
Thus, a ventilation strategy designed to maximize lung recruitment without causing overdistension improved oxygenation and was associated with more ventilator- and organ-failure-free days in the first 28 days after enrollment, but did not affect survival.
The Editorials: Same Data, Different Takes
In the hierarchy of evidence, concordant results in multiple randomized controlled trials examining a given therapy in similar patients rank pretty high when it comes to demonstrating the efficacy (or lack thereof) of that therapy. It is pretty tempting to conclude that, added to the findings of the earlier ARDSnet ALVEOLI trial, these 2 new reports demonstrate that higher levels of PEEP, with or without recruitment maneuvers, do not further improve outcomes in patients with ALI or ARDS beyond what can be attained using low-tidal-volume, low-plateau-pressure ventilation. However, in the same issue of JAMA as the reports of the LOVS and Express trials, there are 2 editorials, each commenting on both studies, and they offer very different interpretations.
Gattinoni and Caironi7 argue that because experimental studies (short-term studies of physiologic and pathologic changes in animal models, and physiologic and imaging studies of patients) show better results with higher PEEP and greater lung recruitment, the latter should be used in managing patients with ALI and ARDS despite the overall negative findings of these clinical trials. The authors postulate that the LOVS trial and the Express study enrolled heterogeneous groups of patients with varying responses to PEEP and lung recruitment, and that better characterization of the extent of edema and atelectasis present at enrollment would have permitted demonstration of the beneficial effects of these interventions. They point to the greater numbers of rescue interventions triggered by severe hypoxemia in the lower-PEEP groups in both studies as evidence for the efficacy of higher PEEP and greater lung recruitment. Until better techniques are available for identifying patients with prominent pulmonary edema and therefore greater recruitability, they make the following conclusion: "Thus, strategies with higher levels of PEEP, as tested in these 2 clinical trials, appear safe and probably beneficial, especially in patients with ALI and ARDS who are most sick, whereas strategies with lower levels of PEEP may worsen outcomes."7
In contrast, in their editorial, Chiche and Angus8 emphasize that both the LOVS trial and the Express study were negative studies, finding no differences between the approaches studied. They point out the challenges and pitfalls in assessing the implications of large-scale clinical trials such as these in complex, critically ill patients. For example, with respect to the greater use of rescue therapies for severe hypoxemia in the control groups of both studies, they raise the possibility that differences in clinician behavior may be involved. Physicians managing patients on higher PEEP used rescue interventions less often. Chiche and Angus note that this could have been because higher levels of PEEP actually protected the patients' lungs and facilitated recovery, rendering alternative interventions such as prone positioning or inhaled nitric oxide less necessary. However, it could also have been because higher PEEP simply made the patients appear less sick by improving oxygenation without changing the underlying disease process, or that "clinicians had greater trust in higher PEEP and therefore felt less need to take additional measures."8
Conclusion: How Should We Use This Information?
The available evidence is clear that lung-protective ventilation incorporating small tidal volumes and limited plateau pressure in the management of ALI and ARDS saves lives. The onus is clearly on any intensivist who chooses not to use such an overall lung-protective strategy. Some clinicians feel strongly that pressure-targeted ventilation is better than volume-targeted ventilation in patients with ARDS, and similarly strong feelings exist about whether patients should be relaxed or made to breathe actively during ventilatory support. For these aspects of management, definitive evidence—evidence the patient would care about, such as will it increase my chances of survival or reduce complications or get me out of the ICU faster—is not available. I think the same thing may be said for high-vs-low PEEP, and whether to add recruitment maneuvers to the ventilatory regimen. Strong feelings abound, but there is insufficient objective evidence to sway clinicians who do not have their own biases on the issues.
While it would be hard to defend the use of high-pressure, large-tidal-volume mechanical ventilation in 2008, in my opinion maintaining a rigid, dogmatic stance on how much PEEP to use or whether to do recruitment maneuvers is not justifiable. We know that the plateau pressure should be kept below 30 cm H2O, and we know that we should adjust the tidal volume for predicted body weight and keep it lower than those we used to use. However, we simply don't "know" enough about PEEP or lung recruitment to say that they "must" be approached a certain way, and that clinicians who do not choose to do it the way we do are wrong.