Lauran O’nEill

Background: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practised but is associated with harm in observational studies. Objectives: To evaluate the clinical and cost-effectiveness of a conservative oxygenation target of peripheral oxygen saturation 88–92% compared with peripheral oxygen saturation > 94% in critically ill children admitted to paediatric intensive care unit as an emergency. Design and setting: A pragmatic, open, multicentre, parallel-group, randomised clinical trial conducted in 15 National Health Service paediatric intensive care units and associated emergency transport services across England and Scotland. Participants: Children aged > 38 weeks corrected gestational age and < 16 years, enrolled within 6 hours of being accepted for admission to paediatric intensive care unit as an emergency; receiving invasive mechanical ventilation with supplemental oxygen; and in face-to-face contact with paediatric intensive care unit or emergency transport services staff. Interventions: Adjustment of ventilator and inspired oxygen settings aiming to achieve peripheral oxygen saturation 88–92% (conservative oxygenation) or peripheral oxygen saturation > 94% (liberal oxygenation) during invasive mechanical ventilation. Main outcome measures: Primary outcomes: duration of organ support at 30 days, with death by day 30 ranked as the worst outcome (clinical effectiveness) and incremental costs, quality-adjusted life-years and net monetary benefit at 12 months (cost-effectiveness). Secondary outcomes: incremental costs at 30 days; mortality at paediatric intensive care unit discharge, 30 days, 90 days and 12 months; time to liberation from ventilation; duration of organ support; length of paediatric intensive care unit and hospital stay; functional status at paediatric intensive care unit discharge; and health-related quality of life at 12 months. Results: Two thousand and forty children were randomised between 1 September 2020 and 15 May 2022. Consent was obtained for 1872 (94%) – 939 to the conservative and 933 to the liberal oxygenation group – who were included in the primary analysis. Duration of organ support or death in the first 30 days was lower in the conservative oxygenation group [probabilistic index 0.53, 95% confidence interval 0.50 to 0.55; p = 0.04 Wilcoxon rank-sum test, adjusted odds ratio 0.84 (95% confidence interval 0.72 to 0.99)]. Both components of the composite primary outcome and secondary outcomes favoured conservative oxygenation. Average costs at 30 days strongly indicated lower costs with conservative oxygenation. Longer-term estimated incremental costs and quality-adjusted life-years were lower and net monetary benefit marginally favoured conservative oxygenation but with wide uncertainty [incremental costs −£879 (95% confidence interval −9036 to 7278); quality-adjusted life-years 0.001 (−0.010 to 0.011); net monetary benefit £894 (95% confidence interval −7290 to 9078)]. Limitations: Exclusion of two large paediatric intensive care unit populations, due to a lack of equipoise and the number of participants excluded because of not being able to obtain deferred consent. Future work: Future work should focus on identification of the mechanisms underlying the observed benefit; trials of intermediate or lower peripheral oxygen saturation values in individuals at higher risk; and identification of individualised treatment effects in relation to oxygen therapy. Conclusions: A conservative oxygenation target resulted in a greater probability of a better outcome in terms of duration of organ support at 30 days or death. Longer-term survival and health-related quality of life were consistent with the primary outcome. While conservative oxygenation is likely to reduce costs in the short term, longer-term cost-effectiveness was surrounded with wide uncertainty. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127547.

OBJECTIVES: A conservative oxygenation strategy, targeting peripheral oxygen saturations (Spo ₂) between 88% and 92% in mechanically ventilated children in PICU, was associated with a shorter duration of organ support and greater survival compared with Spo ₂ greater than 94% in our recent Oxy-PICU trial. Spo ₂ monitors may overestimate arterial oxygen saturation (Sao ₂) in patients with higher levels of skin pigmentation compared with those with less skin pigmentation. We investigated if ethnicity was associated with changes in distributions of Spo ₂ and Fio ₂ and outcome. DESIGN: Post-hoc analysis of a pragmatic, open-label, multicenter randomized controlled trial. SETTING: Fifteen PICUs across the United Kingdom and Scotland. PATIENTS: Children aged 38 weeks corrected gestational age to 15 years accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. METHODS: Hierarchical regression models for Spo ₂ and Fio ₂, and ordinal models for the primary trial outcome of a composite of the duration of organ support at 30 days and death, were used to examine the effects of ethnicity, accounting for baseline Spo ₂, Fio ₂, and mean airway pressure and trial allocation. MEASUREMENTS AND MAIN RESULTS: Ethnicity data were available for 1577 of 1986 eligible children, 1408 (89.3%) of which were White, Asian, or Black. Spo ₂ and Fio ₂ distributions did not vary according to Black or Asian ethnicity compared with White children. The trial primary outcome measure also did not vary significantly with ethnicity. The point estimate for the treatment effect of conservative oxygenation in Black children was 0.64 (95% CI, 0.33–1.25) compared with 0.84 (0.68–1.04) in the overall trial population. CONCLUSIONS: These data do not suggest that the association between improved outcomes and conservative oxygenation strategy in mechanically ventilated children in PICU is modified by ethnicity.

Background: Fever accelerates host immune system control of pathogens but at a high metabolic cost. The optimal approach to fever management and the optimal temperature thresholds used for treatment in critically ill children are unknown. Objectives: To determine the feasibility of conducting a definitive randomised controlled trial (RCT) to evaluate the clinical effectiveness and cost-effectiveness of different temperature thresholds for antipyretic management. Design: A mixed-methods feasibility study comprising three linked studies – (1) a qualitative study exploring parent and clinician views, (2) an observational study of the epidemiology of fever in children with infection in paediatric intensive care units (PICUs) and (3) a pilot RCT with an integrated-perspectives study. Setting: Participants were recruited from (1) four hospitals in England via social media (for the FEVER qualitative study), (2) 22 PICUs in the UK (for the FEVER observational study) and (3) four PICUs in England (for the FEVER pilot RCT). Participants: (1) Parents of children with relevant experience were recruited to the FEVER qualitative study, (2) patients who were unplanned admissions to PICUs were recruited to the FEVER observational study and (3) children admitted with infection requiring mechanical ventilation were recruited to the FEVER pilot RCT. Parents of children and clinicians involved in the pilot RCT. Interventions: The FEVER qualitative study and the FEVER observational study had no interventions. In the FEVER pilot RCT, children were randomly allocated (1 : 1) using research without prior consent (RWPC) to permissive (39.5 °C) or restrictive (37.5 °C) temperature thresholds for antipyretics during their PICU stay while mechanically ventilated. Main outcome measures: (1) The acceptability of FEVER, RWPC and potential outcomes (in the FEVER qualitative study), (2) the size of the potentially eligible population and the temperature thresholds used (in the FEVER observational study) and (3) recruitment and retention rates, protocol adherence and separation between groups and distribution of potential outcomes (in the FEVER pilot RCT). Results: In the FEVER qualitative study, 25 parents were interviewed and 56 clinicians took part in focus groups. Both the parents and the clinicians found the study acceptable. Clinicians raised concerns regarding temperature thresholds and not using paracetamol for pain/discomfort. In the FEVER observational study, 1853 children with unplanned admissions and infection were admitted to 22 PICUs between March and August 2017. The recruitment rate was 10.9 per site per month. The majority of critically ill children with a maximum temperature of > 37.5 °C received antipyretics. In the FEVER pilot RCT, 100 eligible patients were randomised between September and December 2017 at a recruitment rate of 11.1 per site per month. Consent was provided for 49 out of 51 participants in the restrictive temperature group, but only for 38 out of 49 participants in the permissive temperature group. A separation of 0.5 °C (95% confidence interval 0.2 °C to 0.8 °C) between groups was achieved. A high completeness of outcome measures was achieved. Sixty parents of 57 children took part in interviews and/or completed questionnaires and 98 clinicians took part in focus groups or completed a survey. Parents and clinicians found the pilot RCT and RWPC acceptable. Concerns about children being in pain/discomfort were cited as reasons for withdrawal and non-consent by parents and non-adherence to the protocol by clinicians. Limitations: Different recruitment periods for observational and pilot studies may not fully reflect the population that is eligible for a definitive RCT. Conclusions: The results identified barriers to delivering the definitive FEVER RCT, including acceptability of the permissive temperature threshold. The findings also provided insight into how these barriers may be overcome, such as by limiting the patient inclusion criteria to invasive ventilation only and by improved site training. A definitive FEVER RCT using a modified protocol should be conducted, but further work is required to agree important outcome measures for clinical trials among critically ill children. Trial registration: The FEVER observational study is registered as NCT03028818 and the FEVER pilot RCT is registered as Current Controlled Trials ISRCTN16022198. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.