Title: 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)
Funder: Department of Health and Social Care

Abstract: When children are critically ill in intensive care, their blood pressure can fall. A very low blood pressure, known as hypotension, can be dangerous, even life threatening. It can cause damage to the brain and other body systems in survivors. _x000D_ _x000D_ Many intensive care treatments are used to increase blood pressure. These include intravenous fluids and drugs, called vasoactive agents, to make the heart pump harder. However, these treatments also carry risks of side-effects and complications. Currently to guide these invasive treatments, most doctors aim to achieve a blood pressure in the normal range for age. _x000D_ _x000D_ However, recent research shows that it may be safer not to push blood pressure all the way back up to normal, but simply to avoid very low pressures. If children on intensive care can be managed safely with lower blood pressures, they might need less intensive treatment and they may recover more quickly. Some clinical trials in adults with severe infection and low blood pressure support this approach. Unfortunately, no clinical trials have been done in children, so there is no clear evidence on which to base practice._x000D_ _x000D_ The Paediatric Intensive Care Society and the Intensive Care National Audit & Research Centre (ICNARC), have done many studies in critically ill children. We have come together to propose the PRotocolised Evaluation of permiSSive hypotension versus Usual caRE (PRESSURE) study, which aims to find out the best blood pressure target to use for children in Paediatric Intensive Care Units (PICUs) across the UK. We plan to conduct a clinical trial testing a lower blood pressure target (depending upon age, gender and height) in children with hypotension in intensive care (group one) against current usual NHS practice (group two). To find out which treatment is best - at the end of the study, we will compare the amount of time children need support for their breathing (mechanical ventilation) and survival in intensive care between the two groups. We will also look at survival and child development after leaving PICU, as well as the total costs of the treatments._x000D_ _x000D_ We, with parents and ex-patients, have experience of designing and performing studies in emergency situations in children. Very low blood pressure is an emergency. Hence, it can only be studied effectively with a ‘deferred consent’ approach where permission to continue with the study is sought from parents as soon as possible after the emergency care has been provided. We have used this approach in a number of recent emergency clinical trials. Families have been strongly supportive. _x000D_ _x000D_ Our team includes members from each of the key groups needed, including those who care for children in PICU and parents of children who have been in PICU. ICNARC has extensive experience of carrying out trials in PICU and will act as the “clinical trials unit” co-ordinating all of the hospitals taking part, ensuring that the study is conducted to a high standard._x000D_ _x000D_ PRESSURE will help us determine the better blood pressure target to use for children with low blood pressure in PICU. The results will have an impact on the treatment of very sick children in the NHS and worldwide.

Lay abstract: Research question_x000D_ 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]?_x000D_ _x000D_ Background_x000D_ 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._x000D_ _x000D_ Aims and objectives_x000D_ 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._x000D_ _x000D_ Methods_x000D_ Pragmatic data-enabled multi-centre, open randomised clinical trial with internal pilot phase and integrated economic evaluation._x000D_ _x000D_ Timelines for delivery_x000D_ 01/08/2020 to 31/01/2025 (54 months)._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ 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.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR