Different temperature thresholds for antipyretic intervention in critically ill children with fever due to infection: the FEVER feasibility RCT
Authors: Peters Mark J , Khan Imran , Woolfall Kerry , Deja Elizabeth , Mouncey Paul R , Wulff Jerome , Mason Alexina , Agbeko Rachel , Draper Elizabeth S , Fenn Blaise , Gould Doug W , Koelewyn Abby , Klein Nigel , Mackerness Christine , Martin Sian , O’Neill Lauran , Ramnarayan Padmanabhan , Tibby Shane , Tume Lyvonne , Watkins Jason , Thorburn Kent , Wellman Paul , Harrison David A , Rowan Kathryn M 
Published: February 2019

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.