• Benjamin Kasenda, Willi Sauerbrei, Patrick Royston, Alain Mercat, Arthur S Slutsky, Deborah Cook, Gordon H Guyatt, Laurent Brochard, Jean-Christophe M Richard, Thomas E Stewart, Maureen Meade, and Matthias Briel.
• Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland.
• BMJ Open. 2016 Sep 8; 6 (9): e011148.

ObjectivesA recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes.SettingPooled data from three randomised trials in intensive care identified by a systematic review.Participants2299 patients with acute lung injury requiring mechanical ventilation.InterventionsHigher (N=1136) versus lower PEEP (N=1163) ventilation strategy.Outcome MeasuresPrespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure-PEEP)) and body mass index (BMI).ResultsWe found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m(2), we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings.ConclusionsMFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS.Study Registration NumberCRD42012003129.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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