Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial
Mark J. Peters,
Kerry Woolfall,
Imran Khan,
Elisabeth Deja,
Paul R. Mouncey,
Jerome Wulff,
Alexina Mason,
Rachel S. Agbeko,
Elizabeth S. Draper,
Blaise Fenn,
Doug W. Gould,
Abby Koelewyn,
Nigel Klein,
Christine Mackerness,
Sian Martin,
Lauran O’Neill,
Samiran Ray,
Padmanabhan Ramnarayan,
Shane Tibby,
Kentigern Thorburn,
Lyvonne Tume,
Jason Watkins,
Paul Wellman,
David A. Harrison,
Kathryn M. Rowan,
the FEVER Investigators on behalf of the Paediatric Intensive Care Society Study Group (PICS-SG)
Affiliations
Mark J. Peters
Respiratory, Critical Care and Anaesthesia Unit, Paediatric Intensive Care, UCL Great Ormond Street Institute of Child Health
Kerry Woolfall
Department of Psychological Sciences, North West Hub for Trials Methodology, University of Liverpool
Imran Khan
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Elisabeth Deja
Department of Psychological Sciences, North West Hub for Trials Methodology, University of Liverpool
Paul R. Mouncey
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Jerome Wulff
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Alexina Mason
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Rachel S. Agbeko
NHS Foundation Trust
Elizabeth S. Draper
Department of Health Sciences, University of Leicester
Blaise Fenn
Patient and Parent representative
Doug W. Gould
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Abby Koelewyn
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Nigel Klein
Infection, Inflammation and Rheumatology, UCL Great Ormond Street Institute of Child Health
Christine Mackerness
NHS Foundation Trust
Sian Martin
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Lauran O’Neill
Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children NHS Foundation Trust
Samiran Ray
Respiratory, Critical Care and Anaesthesia Unit, Paediatric Intensive Care, UCL Great Ormond Street Institute of Child Health
Padmanabhan Ramnarayan
Respiratory, Critical Care and Anaesthesia Unit, Paediatric Intensive Care, UCL Great Ormond Street Institute of Child Health
Shane Tibby
Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust
Kentigern Thorburn
Alder Hey Children’s Hospital NHS Foundation Trust
Lyvonne Tume
Faculty of Health and Applied Sciences, University of the West of England
Jason Watkins
Institute of Cellular Medicine, Newcastle University
Paul Wellman
Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust
David A. Harrison
Clinical Trials Unit, Intensive Care National Audit and Research Centre
Kathryn M. Rowan
Clinical Trials Unit, Intensive Care National Audit and Research Centre
the FEVER Investigators on behalf of the Paediatric Intensive Care Society Study Group (PICS-SG)
Abstract 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.