Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial.

BACKGROUND: Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. METHODS: An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. RESULTS: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. CONCLUSION: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. TRIAL REGISTRATION: ISRCTN16022198 . Registered on 14 August 2017.

Establishing and augmenting views on the acceptability of a paediatric critical care randomised controlled trial (the FEVER trial): a mixed methods study.

OBJECTIVE: To explore parent and staff views on the acceptability of a randomised controlled trial investigating temperature thresholds for antipyretic intervention in critically ill children with fever and infection (the FEVER trial) during a multi-phase pilot study. DESIGN: Mixed methods study with data collected at three time points: (1) before, (2) during and (3) after a pilot trial. SETTING: English, Paediatric Intensive Care Units (PICUs). PARTICIPANTS: (1) Pre-pilot trial focus groups with pilot site staff (n=56) and interviews with parents (n=25) whose child had been admitted to PICU in the last 3 years with a fever and suspected infection, (2) Questionnaires with parents of randomised children following pilot trial recruitment (n=48 from 47 families) and (3) post-pilot trial interviews with parents (n=19), focus groups (n=50) and a survey (n=48) with site staff. Analysis drew on Sekhon et al's theoretical framework of acceptability. RESULTS: There was initial support for the trial, yet some held concerns regarding the proposed temperature thresholds and not using paracetamol for pain or discomfort. Pre-trial findings informed protocol changes and training, which influenced views on trial acceptability. Staff trained by the FEVER team found the trial more acceptable than those trained by colleagues. Parents and staff found the trial acceptable. Some concerns about pain or discomfort during weaning from ventilation remained. CONCLUSIONS: Pre-trial findings and pilot trial experience influenced acceptability, providing insight into how challenges may be overcome. We present an adapted theoretical framework of acceptability to inform future trial feasibility studies. TRIAL REGISTRATION NUMBERS: ISRCTN16022198 and NCT03028818.

Different temperature thresholds for antipyretic intervention in critically ill children with fever due to infection: the FEVER feasibility RCT.

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.