Elisa Giallongo

Background: Target trial emulations (TTE) offer a framework for assessing comparative effectiveness to complement randomised controlled trials (RCT). However, little attention has been given to challenges that arise in emulating a published RCT from routine data. Methods: We aimed to evaluate the validity of a TTE by benchmarking it against the published RCT and assessing potential biases arising from limitations in the emulation. We followed methodological guidance in emulating the FIRST-ABC step-up RCT from PICANet data. This TTE compared two modes of non-invasive respiratory support in children admitted to paediatric intensive care according to the primary outcome, the time to liberation from respiratory support. The complete-case analysis included 5,405 children. To reduce the risk of confounding we applied doubly robust methods. A structured risk of bias assessment using the ROBINS-I framework was conducted to evaluate potential biases arising from departures of the TTE from the benchmark RCT, with the ROBINS-I domains applied across each component of the target trial framework. Results: The estimated risk ratio for liberation from respiratory support at the median follow-up was 1.33 (95% CI 1.27–1.40) from the TTE versus 1.03 (95% CI 0.90–1.18) from the RCT. The risk of bias assessment identified important limitations in the emulation, including inability to fully replicate the RCT eligibility criteria and outcome measurement, and the potential for residual unmeasured confounding. Conclusions: These findings highlight key challenges in replicating an ideal trial from routine data and offer practical insights to improve the conduct and interpretation of TTEs. Clinical trial number: Not applicable

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.

Oxygen supplementation is a recommended treatment for children with severe pneumonia or hypoxaemia. The open, fractional-factorial Children’s Oxygen Administration Strategies Trial (COAST) recruited Kenyan and Ugandan children with severe pneumonia and hypoxaemia. Participants in the severe hypoxaemia stratum (SpO ₂ < 80%) were randomised to high-flow nasal therapy (HFNT) or low-flow oxygen (LFO), and in the hypoxaemia stratum (SpO ₂ 80–91%) to HFNT, LFO or permissive hypoxaemia (ratio 1:1:2). The trial stopped early and there is ongoing uncertainty about the clinical benefits of the alternative strategies. There is a lack of evidence about the relative costs, of alternative oxygen delivery for critically-ill children in low- and middle- income countries. We used data from COAST to conduct a cost-consequence analysis of the treatment strategies. We measured resource use for 28 days post-randomisation (n = 1,842). Resources included oxygen delivery, medications, blood and fluid products, diagnostic tests, point of care tests, hospital admission and length of stay. We calculated the total costs and reported the incremental costs as the difference in the mean total costs between groups, adjusting for baseline differences. In the severe hypoxaemia stratum, the mean total cost was $393.04 for HFNT and $218.73 for LFO. In the hypoxemia stratum, the mean total costs were $391.95 (HFNT), $198.26 (LFO) and $167.80 (permissive). The adjusted cost difference between HFNT versus LFO and liberal versus permissive was $184.43 (95% CI l: $127.90, $240.95), and $124.01 (95% CI: $99.53, $148.49), respectively. The differences of HFNT and LFO versus permissive were $216.22 (95% CI: $160.77, $271.68) and $31.80 (95% CI: $11.49, $52.11), respectively. For children with severe hypoxaemia, HFNT is more costly than LFO. For children with hypoxaemia, either of HFNT or LFO were more costly than permissive hypoxaemia. The main driver of costs for HFNT is the high cost of equipment and consumables; other costs were similar across treatment groups in both strata, as were health outcomes.

Introduction The development of the target trial emulation (TTE) methodology has enhanced the conduct of non-randomised studies. By leveraging readily available routinely collected data, TTEs offer opportunities for complementing randomised controlled trials (RCTs), providing more precise estimates and improving the external validity of RCTs. To explore this potential, we selected a successfully completed RCT as a case study. In the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) step-up RCT, high flow nasal cannula (HFNC) was found to be non-inferior to continuous positive airway pressure (CPAP) in terms of time to liberation from respiratory support in the paediatric critical care setting. We will emulate the FIRST-ABC step-up trial using routinely collected data from the Paediatric Intensive Care Audit Network (PICANet) database. Methods and analysis This is a protocol for a TTE that will use longitudinally collected data from the PICANet database. The study aims to emulate the FIRST-ABC step-up RCT using an observational study design in a frequentist framework. We will benchmark the results against the published trial. The study will apply a new-user design by selecting children admitted to paediatric intensive care units that started HFNC or non-invasive ventilatory support (as a surrogate for CPAP). The eligibility criteria and selected outcomes will reflect those of FIRST-ABC within the constraints of the available routinely collected data. We will use advanced quantitative doubly robust methods to minimise the impact of confounding by indication and allow for heterogeneity according to child characteristics. The analysis will be repeated using a Bayesian approach for follow-up research. Ethics and dissemination The research received ethics approval from the London School of Hygiene & Tropical Medicine Research Ethics Committee. This study will expand the findings from the FIRST-ABC step-up RCT, providing additional insight from a large representative sample using real-world data. The frequentist and Bayesian approaches will enable a discussion about the advantages and drawbacks of the two strategies. The results will be disseminated to the research and clinical community and made accessible to the public. In addition, the study results will be used in future research, which aims to supplement RCTs with additional evidence from a TTE.

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.