Pediatric Acute Respiratory distress syndrome MAnagement (PARMA) - PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. ARDS affects nearly 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 20%. There are no specific pharmacological therapies for ARDS, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Lung-protective ventilation with lower tidal volumes and driving pressures (defined as plateau pressure minus positive end-expiratory pressure) is the backbone of ventilation strategies in adults, with variable adoption in pediatrics. However, pre-clinical and observational clinical data suggest that the tidal volume and driving pressure limits extrapolated from adults are too restrictive for children. As lower tidal volumes and driving pressures are associated with worse oxygenation and ventilation, overly restrictive lung-protective ventilation may contribute to prolonged ventilation via worse gas exchange in pediatrics with no improvement in outcomes. In a re-analysis of adult ARDS cohorts, our group demonstrated that driving pressure is the most significant causal effector of mortality. By contrast, oxygenation (measured as PaO2/FIO2) was primarily implicated in children. Unfortunately, observational studies are intrinsically confounded, as higher tidal volumes and pressures are used in sicker children with greater baseline risk for poor outcomes. Furthermore, as pediatrics uses different ventilator modes, plateau pressures are rarely measured and ΔP (peak pressure minus positive end-expiratory pressure, a close approximate of driving pressure in pediatric modes) is substituted. Thus, a randomized trial comparing specific ventilation strategies is sorely needed in pediatric ARDS, with post-randomization ventilator protocols congruent with current pediatric practice. Herein we propose the Pediatric ARDS MAnagement (PARMA) trial, a phase 2A trial of high versus low ΔP ventilation in pediatric ARDS conducted at the Children’s Hospital of Philadelphia (CHOP). Additionally, we will use electrical impedance tomography (EIT) to quantify lung aeration. Given the low prevalence of pediatric ARDS and low mortality rates, PARMA will be analyzed in a Bayesian framework, utilizing a composite primary outcome that combines time to hypoxemia resolution and mortality. We specifically will test the efficacy of a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) ventilation on time to resolution of ARDS (alive and PaO2/FIO2 > 300), hypothesizing faster hypoxemia resolution (Aim 1), and improved lung aeration (Aim 2) with high ΔP. PARMA addresses a critical knowledge gap in pediatric mechanical ventilation, and will directly inform the design of a subsequent definitive trial of different ΔP strategies in pediatric ARDS.
