Developing a framework for designing the next generation of pediatric ARDS trials

Advancements in the evidence-based care of critically ill children have been limited by recent clinical trials failing to show definitive statistical benefits across a variety of outcomes. Clinicians at the bedside, however, often interpret the results of these trials differently, believing the results are not necessarily applicable to their patient, that the results are equivocal, or that results suggest potential benefit. These differences are partly due to the currently used frequentist clinical trial design methodology that hypothesizes unrealistically high treatment efficacy to adequately power trials amongst the limited pool of critically ill children and generate a binary interpretation of definitively beneficial or not based on these factors. Additionally, the heterogeneity of treatment effect amongst the critically ill has often been ignored and subgroup analysis fails to fully address this important consideration. Thus, this proposal aims to compare heterogeneity of treatment effect (HTE) analysis methodologies in a trial of pediatric ARDS ventilator management. Additionally, the proposed study would examine the construct validity of commonly employed 28-day composite outcomes to predict late morbidity and mortality. Finally, Dr. Keim will develop skills necessary to become a clinical trialist through conducting a feasibility trial comparing positive end-expiratory pressure (PEEP) guided by electrical impedance tomography (EIT), a non-ionizing, non-invasive imaging tool highlighting lung aeration, to standardized PEEP/FiO2 table titration. In addition to feasibility data, Bayesian trial simulations will be conducted to enhance Dr. Keim’s methodological expertise and inform the future definitive trial sample size. Successful completion of these Aims will propel Dr. Keim towards his career goals of refining the methodology utilized in clinical trials of critically ill children to (1) improve the assessment of the feasibility of trials, (2) generate more usable and understandable interpretations for the treating clinician, and (3) highlight methods to understand HTE in clinical trials and develop trial planning to generate individualized treatment effect (ITE) estimates. The results of the proposed studies promise to enhance future pediatric ARDS trials by increasing the clinical relevance of trial outcomes and generating clinically usable probabilistic interpretations that are responsive to the heterogeneity omnipresent in critical care trials. The principal investigator of this study, Dr. Garrett Keim, is uniquely positioned to complete the aims of this proposal due to his training in epidemiologic and biostatistical methods and his research experience investigating morbidity in survivors of pediatric acute respiratory failure. Supported by his strong mentorship team and research environment, he will leverage the opportunities presented by this proposal to develop into an independent patient-oriented physician-scientist and clinical trialist to improve the evidence-based care of critically ill children. Project Number: 1K23HL177271-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Garrett Keim | Institution: CHILDREN'S HOSP OF PHILADELPHIA, PHILADELPHIA, PA | Award Amount: $180,174 | Activity Code: K23 | Study Section: NHLBI Mentored Patient-Oriented Research Study Section[MPOR (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL17727101A1