Background and rationale
Fever is a host response that helps to control infections with a very wide range of pathogens.1 Fever has been very highly conserved throughout evolution for at least 580 million years,1 and is seen across many species including reptiles, birds and mammals.2 Recently, even plants have been shown to raise core temperatures to control fungal infections.3 In humans, fever is known to increase numerous basic immunological processes including neutrophil production, recruitment and killing; monocyte/macrophage/dendritic cell phagocytosis; and antigen presentation, T-cell maturation and lymphocyte recruitment.1
Studies in non-critically ill patients with chickenpox,4 malaria5 and rhinovirus6 infections have led to a rediscovery of the potential beneficial effects of fever. This is recognised by the National Institute for Health and Care Excellence (NICE) in guidance for the management of feverish illness in children,7 which recommends:
Do not use antipyretic agents with the sole aim of reducing body temperature in children with fever.
Reproduced with permission from NICE.
7 © NICE 2013. Fever in Under 5s: Assessment and Initial Management. Available from
www.nice.org.uk/guidance/cg160. All rights reserved. Subject to Notice of rights NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication.
NICE
However, this advice is not aimed at the management of critically ill children.
Observational studies demonstrate that treatment of fever in critically ill children is inconsistent.8 In this population, there is a lack of robust data to guide antipyretic intervention. This frequently leaves the decision of if and when to treat fever at the discretion of the bedside nurse. There is genuine uncertainty as to whether or not the immunological advantages of a fever in defending the body against viruses and bacteria during critical illness outweigh the metabolic costs and cardiorespiratory consequences of a high fever.2 In cases with underlying neurological pathology (e.g. traumatic brain injury, hypoxic–ischaemic encephalopathy and encephalomyelitis), practice is to avoid fever because of consistent associations with worse outcomes, but in the much larger proportion of emergency admissions in whom other organ failures predominate (most commonly respiratory) the optimal approach is unknown. With emerging evidence that fever may be beneficial in critically ill adults, but also cognisant of the physiological differences between adults and children, there is an important need to evaluate whether or not a more permissive approach to fever management in critically ill children improves outcomes.
A recent systematic review9 identified five, small, completed randomised controlled trials (RCTs) of antipyretic interventions in critically ill adults. These trials were small (ranging from 26 to 200 participants) and the results of a meta-analysis on intensive care unit mortality were inconclusive [relative risk for fever control compared with no fever control or a more permissive threshold 0.97, 95% confidence interval (CI) 0.58 to 1.63]. One larger RCT among adults, the HEAT trial10 in Australia and New Zealand, examined the effect of acetaminophen (Perfalgan, Bristol-Myers Squibb) (paracetamol) versus placebo to treat fever in 700 critically ill adults with known or suspected infection. No differences were seen in the primary outcome of the number of paediatric intensive care unit (PICU)-free days to day 28 or in mortality. The CASS trial (NCT01455116)11 found a non-significant increase in 30-day mortality in mechanically ventilated adult patients with septic shock who were actively cooled to hypothermia when compared with normal thermal management. Analysis of the trial’s secondary outcomes revealed that induced hypothermia worsened respiratory failure, circulatory collapse and delayed reduction in serum c-reactive protein. We are not aware of any completed or ongoing RCTs comparing antipyretics or fever thresholds in critically ill children.
A systematic review of observational studies of the association between fever and mortality in critically ill adults found wide variation in the definitions of fever and its association with mortality.12 Two further observational studies in adults, not included in the systematic review, found different relationships between fever and mortality for patients with and without infection, with fever associated with lower mortality among admissions with infection unless the temperature exceeded 40 °C.13,14 Similar results have been found in small cohorts of critically ill children with infection.15
The FEVER feasibility study aimed to establish whether or not it is feasible to conduct a clinical trial to evaluate different temperature thresholds at which clinicians deliver antipyretic intervention in critically ill children with fever owing to infection [i.e. comparing a permissive approach to fever (e.g. treat at ≥ 39.5 °C) with a standard restrictive approach (e.g. treat at ≥ 37.5 °C)].
Clinical trials, such as the proposed FEVER RCT, are expensive and the chances of successful completion are improved if both the feasibility and pilot testing of certain key parameters can be clearly demonstrated. Using a mixed-methods approach comprising three separate studies, the FEVER feasibility study included the FEVER qualitative study, the FEVER observational study and the FEVER pilot RCT with integrated-perspectives study.
Aim
The overarching aim for the FEVER feasibility study was to explore and test important key parameters needed to inform the design and ensure the successful conduct of a definitive FEVER RCT, and to report a clear recommendation for continuation or not to a full trial. Each of the three studies had specific objectives.
Objectives
The FEVER qualitative study
To review, with input from parents/legal representatives:
the acceptability of the selection of temperature thresholds and options for analgesia for a definitive FEVER RCT
potential barriers to recruitment, the proposed process of decision-making and deferred consenting, and co-develop information and documentation for a definitive FEVER RCT
the selection of important, relevant, patient-centred, primary and secondary outcomes for a definitive FEVER RCT.
To review and explore, with input from clinicians:
the acceptability of temperature thresholds and options for analgesia for a definitive FEVER RCT
potential barriers to recruitment, deferred consenting and associated training needs for a definitive FEVER RCT.
The FEVER observational study
Estimate the size of the potentially eligible population for the definitive FEVER RCT.
Confirm, using empirical data, the temperature threshold(s) currently employed for a standard approach for antipyretic intervention in NHS PICUs.
Estimate the characteristics [e.g. mean and standard deviation (SD)] of selected important, relevant, patient-centred primary outcome measure(s).
The FEVER pilot randomised control trial with integrated-perspectives study
Test the willingness of clinicians to screen, recruit and randomise eligible critically ill children.
Estimate the recruitment rate of critically ill children.
Test the acceptability of the deferred consenting procedure and participant information.
Test, following randomisation, the delivery of and adherence to the selected temperature thresholds (intervention and control) for antipyretic intervention and to demonstrate separation between the randomised groups in peak temperature measurement over the first 48 hours following randomisation.
Test follow-up for the identified, potential, patient-centred primary and other important secondary outcome measures and for adverse event (AE) reporting.
Inform the final selection of a patient-centred primary outcome measure.
The FEVER feasibility study management
The FEVER feasibility study was sponsored and co-ordinated by the Intensive Care National Audit and Research Centre (ICNARC) Clinical Trials Unit (CTU) (UK Clinical Research Collaboration ID number 42). A Study Management Group (SMG) was convened, comprising the chief investigator (MJP) and co-investigators (RA, ESD, BF, DAH, NK, PRM, PR, KMR, ST, LT, JW and KW), and was responsible for overseeing day-to-day management of the entire FEVER feasibility study. The SMG met regularly throughout the duration of the study to monitor its conduct and progress. Two parents (CF and JW) and one young adult (BF) (all co-investigators) with experience of a critical illness caused by a severe infection were members of the SMG and provided valuable input into the design and conduct of the FEVER feasibility study, including reviewing documents for parent interviews (e.g. draft FEVER pilot trial participant documentation) and informing study recruitment approaches (i.e. identification of social media groups and charities), in addition to being involved in reviewing study progress and findings.
