Evaluating the clinical and cost effectiveness of using a more permissive blood pressure target to guide careful titration of vasoactive agents in critically ill children with hypotension: PRotocolised Evaluation of permiSSive blood pressure targets versus Usual caRE (PRESSURE)

Research question In critically ill children with hypotension [Population], is a strategy of permissive blood pressure targets (MAP target of 5th centile for age/gender/height), [Intervention] in order to minimise dose and duration of therapy (e.g. vasoactive drugs), superior to usual care [Comparator] in terms of a composite outcome of mortality and days of ventilator support at 30 days (clinical effectiveness) and incremental costs, QALYs and net monetary benefit at 12 months (cost-effectiveness) [Outcome]? Background Low blood pressure (hypotension) is a key feature of shock, which occurs in a number of disease states commonly encountered in PICU. Untreated, hypotension impairs tissue perfusion and organ function, with increased risk of death and organ failure and poor neurological outcome in survivors. Treatment is by the administration of fluid boluses and infusions of vasoactive drugs. Though these interventions may be lifesaving, they also carry potential for harm. Excessive fluids are associated with prolonged PICU stay and increased mortality. Vasoactive drugs induce vasoconstriction and may reduce blood flow, causing secondary effects on cardiac, mesenteric, metabolic, microbiome and immune function. Hypotension is a major trigger for treatment, with most current guidelines recommending targeting 50th centile BP for age; whereas in adults 5th centile is now routinely targeted. Unfortunately, current guidelines for blood pressure targets in children are based on low quality evidence consisting mainly of single centre retrospective observational studies. There have been no randomised controlled trials. The purpose of PRESSURE is to evaluate the clinical and cost-effectiveness of permissive hypotension (MAP target 5th centile for age and gender whilst receiving vasoactive drugs) in critically ill children with hypotension. Aims and objectives To evaluate the clinical and cost-effectiveness of permissive blood pressure targets (MAP target 5th centile for age and gender whilst receiving vasoactive drugs) in critically ill children with hypotension on: composite outcome of mortality and duration of organ support at 30 days (rank- based analysis with death ranked as worse than 30 days of organ support); incremental costs, quality-adjusted life years (QALYs) and net monetary benefit at 12 months; incremental costs at 30 days; mortality at PICU discharge, 30 days, 90 days and 12 months; duration of survival to 12 months; time to liberation from invasive ventilation; duration of organ support; length of PICU and hospital stay; functional status at PICU discharge and at 12 months; and health-related quality of life (HrQoL) at 12 months. Methods Pragmatic data-enabled multi-centre, open randomised clinical trial with internal pilot phase and integrated economic evaluation. Timelines for delivery 01/08/2020 to 31/01/2025 (54 months). Anticipated impact and dissemination The results will be disseminated actively and extensively, both in terms of progress during the trial period and results at the end of the study. The outputs for PRESSURE will include meeting and conference presentations (international and national) of study progress and results; publication of the study; and incorporation into clinical guidelines. These separate outputs will be targeted at relevant stakeholders in formats suitable for the target audience. This will ensure that the potential benefit and impact of the PRESSURE trial is maximised.