Title: A Randomised Multiple Centre Trial of Conservative versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU)
Funder: Department of Health and Social Care

Abstract: 20,000 critically ill children are admitted to paediatric intensive care units (PICU) each year in the UK. Of these children, 95% will receive additional oxygen, often in combination with a breathing machine (or ventilator). Oxygen is one of the most common treatments used in emergency situations. Doctors and nurses adjust oxygen treatment based on how much oxygen their patient has in their blood, known as oxygen saturations. Whilst we know very low oxygen saturations are harmful, current research shows that very high saturations may also be dangerous for very ill people. This research will aim to find the optimal levels of oxygen needed for children in intensive care - potentially improving their recovery rates. _x000D_ _x000D_ Recent research in adults has shown that high oxygen saturations can lead to worse outcomes in emergencies, such as heart attacks and strokes. We don't know if this harm is an effect of the oxygen level itself or a side-effect of the more intensive treatments given to keep oxygen levels high. Differences in how children’s bodies function compared with adults mean the results of this research cannot be applied to children._x000D_ _x000D_ Our aim is to find out whether children in intensive care who are receiving oxygen while needing help from a ventilator, should have their oxygen saturations kept at a lower level (88-92%, which is still within recommended guidelines) or at the level currently used (95-100%). We plan to conduct a clinical trial involving 2,000 children from 15 NHS PICUs. They will be randomly assigned to the higher or lower group. This ensures that the two groups are as similar as possible, apart from the level of oxygen they receive. All other medical care will be decided by the doctors and nurses. We will follow-up all the children in the study after 90-days and one year to see how they are after leaving PICU. If critically ill children on intensive care can be managed safely with slightly lower oxygen saturations, they might need less intensive treatment and they may recover more quickly. This is why it is very important we answer this question in children._x000D_ _x000D_ In 2017, we carried out a small version of this trial that showed all the elements of it worked and parents and carers were happy with their child participating. Parents of children who have been in PICU are helping us oversee the study. An independent committee will monitor the study’s progress._x000D_ _x000D_ Once the study is complete, we will publish the results in a widely read and well-regarded medical journal. We will present the results at various national and international conferences. The results of this study will help doctors and nurses make more informed decisions about the best oxygen saturations to use in PICU. We will also make the results available to the public and patients on our website.

Lay abstract: Research Question: In critically-ill children referred as an emergency for paediatric intensive care and commenced on invasive mechanical ventilation and supplemental oxygen [Population], is a conservative oxygen saturation target of 88-92% [Intervention] superior to a liberal oxygen saturation target (95-100%) [Comparator] in terms of a composite of mortality and the number of days free of organ support in the next 30 days [Outcome]?_x000D_ _x000D_ DESIGN: Multiple centre open, parallel group RCT with integrated economic evaluation_x000D_ _x000D_ SETTING: 15 paediatric intensive care units (PICUs) and associated retrieval services_x000D_ _x000D_ TARGET POPULATION: Critically ill children referred as an emergency to a participating PICU commenced on invasive mechanical ventilation and supplemental oxygen._x000D_ _x000D_ INCLUSION CRITERIA: (1) Age >38 weeks corrected gestational age and <16 years; (2) unplanned PICU referral; (3) commenced on invasive mechanical ventilation with supplemental oxygen; and (4) within 6 hours of face-to-face contact with PICU staff or retrieval team._x000D_ _x000D_ EXCLUSION CRITERIA: Death perceived as imminent; brain pathology/injury as primary reason for admission; known pulmonary hypertension; known or suspected uncorrected congenital cardiac disease; known sickle cell disease, end-of-life care plan in place with limitation of resuscitation; receiving long-term mechanical ventilation prior to this admission; or recruited to Oxy-PICU in a previous admission._x000D_ _x000D_ INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve a peripheral oxygen saturation (SpO2) target of 88-92% during invasive mechanical ventilation._x000D_ _x000D_ COMPARATOR: Adjustment of ventilation and inspired oxygen settings to achieve a SpO2 target of =95% during invasive mechanical ventilation. _x000D_ _x000D_ CONSENT: Research without prior consent model where written informed consent will be deferred to after randomisation due to the emergency nature of the treatment._x000D_ _x000D_ PRIMARY OUTCOME: Composite outcome of death and days of organ support at 30 days (clinical effectiveness) and incremental costs, quality-adjusted life years (QALYs) and net monetary benefit at 12 months (cost effectiveness)._x000D_ _x000D_ OTHER OUTCOMES: -_x000D_ -Incremental costs at 30 days_x000D_ -Mortality at PICU discharge, 30 days, 90 days and 12 months_x000D_ -Time to liberation from ventilation_x000D_ -Duration of organ support_x000D_ -Length of PICU and hospital stay_x000D_ -Functional status at PICU discharge_x000D_ -Health-related quality of life (HrQoL) at 12 months _x000D_ _x000D_ SAMPLE SIZE: The primary outcome will be analysed using rank-based methods, with death at 30 days ranked as the worst outcome. To achieve 90% power, using simulations based on data from the Oxy-PICU pilot RCT, to detect a clinically meaningful reduction in the mean duration of organ support of 12 hours from 120 to 108 hours and assuming no impact on 7.5% mortality requires a total sample size of 2040 patients (allowing for withdrawal/refusal of deferred consent of 10%) A single interim analysis will be undertaken. _x000D_ _x000D_ TIMELINE: Total 48 months (HRA approval 1-4; site approvals/initiations 5-12; patient recruitment 7-30; internal pilot 7-12; follow-up 19-42; analysis/dissemination 33-48)._x000D_ _x000D_ ANTICIPATED IMPACT: It is anticipated that if a more permissive oxygen threshold is found to be clinically and cost-effective, implementation of these outputs into clinical guidelines and adoption into the NHS routine practice, will ensure a more efficient use of scarce NHS resources.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE