The Heterogeneous Effect of High PEEP strategies on Survival in Acute Respiratory Distress Syndrome: preliminary results of a data-driven analysis of randomized trials

Background Mixed trial results suggest that some ventilated patients with acute respiratory distress syndrome (ARDS) benefit from high PEEP while others may be harmed, indicating heterogeneity of treatment effect (HTE). This study applies data-driven predictive approaches to uncover HTE and re-examines previously hypothesized HTE. This manuscript serves as a pre-registration of planned external validation of our trained models.

We identified eight randomized trials, and obtained individual patient data (IPD) from three of them (ALVEOLI, LOVS, EXPRESS), as our train cohort. We used effect modelling to predict individualized treatment effects (predicted 28-day mortality risk difference between PEEP strategies) across patient subgroups stratified by observed tertiles (≤8 cmH2O, 9–11 cmH2O, ≥12 cmH2O). Candidate effect modelling methods included meta-learners and technique-specific methods. Optimal methods were selected through ‘leave-one-trial-out’ cross-validation, evaluating the methods’ performances in each PEEP tertile using AUC-benefit. We trained final models using the best performing methods implemented with or without forward selection (which yielded sufficient AUC-benefit), and additional final models by selecting the variables that yielded consistency in the forward selections performed in the cross validation, if any. We further evaluated earlier hypothesized HTE comparing (1) patients with baseline PaO2/FiO2 ≤ 200 versus > 200 mmHg, and (2) patients with hypoinflammatory versus hyperinflammatory subphenotypes. Preliminary findings In the lower PEEP tertile (≤8 cmH2O), an X-learner implemented without, and an S-learner implemented with forward selection (both with flexible base learners), yielded the highest AUC benefits and were used to train final models. In the high PEEP tertile (≥12 cmH2O), only the causal forest implemented with forward selection yielded an AUC benefit exceeding zero. Respiratory-system compliance (CRS) was consistently selected in the forward selections of cross validation, and was used to train an extra final causal forest model, with predicted effects shifting from harm to benefit for CRS 26.5 mL/cmH2O or higher. Higher PEEP benefited patients with baseline PaO2/FiO2 ≤200 mmHg (OR 0.80, 95% CI 0.66–0.98), incurred harm among those with PaO2/FiO2 >200 mmHg (OR 1.74, 95% CI 1.02–2.98; interaction P=0.01). This HTE was strongest when PaO2/FiO2 was measured at low PEEP (≤8 cmH2O), reduced at mid-level PEEP (9–11 cmH2O), and negligible at high PEEP (≥12 cmH2O). A second-order interaction showed significant heterogeneity of HTE (ie, second-order heterogeneity) across PEEP tertiles (P=0.03). Preliminary Conclusions Our preliminary findings indicated that baseline CRS ≥ 26.5 mL/cmH2O predicts benefit, while CRS 200 mmHg predicts harm from high PEEP when PaO2/FiO2 is measured at a low baseline PEEP (≤8 cmH2O). Using data from the LOVS trial, we investigated HTE for high PEEP between hypo- and hyperinflammatory subphenotypes but found none, despite significant HTE observed earlier in the ALVEOLI trial. Competing Interest Statement A.H. Jonkman declares research funding paid to the institution by Pulmotech B.V., for validation of new esophageal pressure sensor. D. Talmor declares support from the National Institutes of Health and lecture honoraria from Mindray. J. Villar was funded by Instituto de Salud Carlos III, Madrid, Sapin (CB06/06/1088, PI19/00141, AC-21_2/00039), ERAPerMed(JTC_2021), ERAPerMed(JTC_2021), The European Regional Development Funds, Fundacion Canaria Intituto de Investigacipn Sanitaria de Canarias, and Asociacion Cientifica Pulmon y Ventilacion Mecanica. C.S. Calfee declares grants from National Institute of Health, Roche Genentech, and Quantum Leap Healthcare Collaborative to her institution, consulting fees from Vasomune, Gen1e Life Sciences, NGM Bio, Cellenkos, Calcimedica, Arrowhead, EnliTISA, Novartis, and Merck, being speaker at a symposium on ESICM guidelines supported by Fisher-Paykel, a Patent on metagenomic sequencing for sepsis diagnosis (co-recipient) issued to Regents of University of California and Chan Zuckerberg BioHub, and being council member of the International Sepsis Forum (unpaid). L. Brochard declares past grants to hist institution from Medtronic, Vitalaire and Stimit, symposium fees (as principal investigator of a trial) from Fisher-Paykel and Stimit, and received equipment from Sentec, Cerebra Health and Fisher-Paykel. P. Sinha declares support from the National Institutes of Health (R35-GM142992) and consulting fees from AstraZeneca and Prenosis Inc. Funding Statement This study did not receive any funding. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study included individual patient data from three randomized controlled trials. The trial by Mercat et al. enrolled patinets at 37 intensive care units in France, and their study protocol was approved for all centers by the ethics committee of the Angers University Hospital (Comite Consultatif de Protection des Personnes dans la Recherche Biomedicale), according to French law. The trial by Brower et al. enrolled patients at 23 hospitals of the National HeartLung, and Blood Institute (NHLBI) ARDS Clinical Trials Network, and was approved by the institutional review board of each hospital. The trial by Meade et al. enrolled patients in 30 hospitals in Canada, Australia, and Saudi Arabia, and the research ethics board of each hospital approved the trial. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes The Competing Interest Statement (declarations added for L. Brochard and for P. Sinha). Data Availability All data produced in the present study are available upon reasonable request to the authors