Effects of higher PEEP and recruitment manoeuvres on mortality in patients with ARDS: a systematic review, meta-analysis, meta-regression and trial sequential analysis of randomized controlled trials

Abstract

Purpose: In patients with acute respiratory distress syndrome (ARDS), lung recruitment could be maximised with the use of recruitment manoeuvres (RM) or applying a positive end-expiratory pressure (PEEP) higher than what is necessary to maintain minimal adequate oxygenation. We aimed to determine whether ventilation strategies using higher PEEP and/or RMs could decrease mortality in patients with ARDS.

Methods: We searched MEDLINE, EMBASE and CENTRAL from 1996 to December 2019, included randomized controlled trials comparing ventilation with higher PEEP and/or RMs to strategies with lower PEEP and no RMs in patients with ARDS. We computed pooled estimates with a DerSimonian-Laird mixed-effects model, assessing mortality and incidence of barotrauma, population characteristics, physiologic variables and ventilator settings. We performed a trial sequential analysis (TSA) and a meta-regression.

Results: Excluding two studies that used tidal volume (V_T) reduction as co-intervention, we included 3870 patients from 10 trials using higher PEEP alone (n = 3), combined with RMs (n = 6) or RMs alone (n = 1). We did not observe differences in mortality (relative risk, RR 0.96, 95% confidence interval, CI [0.84-1.09], p = 0.50) nor in incidence of barotrauma (RR 1.22, 95% CI [0.93-1.61], p = 0.16). In the meta-regression, the PEEP difference between intervention and control group at day 1 and the use of RMs were not associated with increased risk of barotrauma. The TSA reached the required information size for mortality (n = 2928), and the z-line surpassed the futility boundary.

Conclusions: At low V_T, the routine use of higher PEEP and/or RMs did not reduce mortality in unselected patients with ARDS.

Trial registration: PROSPERO CRD42017082035 .

Keywords: Acute respiratory distress syndrome; Mechanical ventilation; Positive end-expiratory pressure.

Fig. 1

Study inclusion flowchart

Fig. 2

Forest plot for mortality (collapsed at 28 days, ICU discharge, hospital discharge or 60–days). Studies are stratified according to whether higher PEEP and recruitment manoeuvres were used separately or as a bundle of interventions. ICU, intensive care unit; PEEP, positive end-expiratory pressure

Fig. 3

Funnel plot for mortality (collapsed at 28 days, ICU discharge, hospital discharge or 60 days). Shapes represent different interventions: higher PEEP alone (circle), recruitment manoeuvres alone (cross) or both (triangle). Dotted lines represent the 90%, 95% and 99% pseudo confidence interval regions. ICU, intensive care unit; PEEP, positive end-expiratory pressure

Fig. 4

Trial sequential analysis assessing the effects of PEEP and/or recruitment manoeuvres on mortality (collapsed at 28 days, ICU discharge, hospital discharge). Required information size of 2487 patients (dotted line) is calculated for a relative risk reduction of 25%, α = 5%, power (1-β) = 80%. The Z-line (blue line) of the cumulative meta-analysis of 3757 patients did not cross the efficacy monitoring boundaries for benefit or harm (grey area) but entered the futility wedge (light blue area). Horizontal dashed lines represent the conventional level of significance (p = 0.05)