8.1. Introduction
Fever is an increase in temperature that occurs as the result of the action of substances known as pyrogens upon the hypothalamus, the part of the brain that controls body temperature. These pyrogens have the effect of increasing the temperature set-point of the hypothalamus, which causes it to increase the temperature of the body.205 The hypothalamus is sometimes likened to a thermostat, instigating heat promotion or loss procedures to achieve the desired set-point temperature. It is important to differentiate fever, which is regulated by the body, from hyperthermia, which is caused by external factors and is not regulated by the hypothalamus.
Fever is a normal physiological response to infection and a number of other conditions. Although it is a normal response, some people, including many doctors, nurses and parents, believe that fever should be treated to reduce temperature. This is usually either because of concerns about the damaging effect of fever or because it is thought to be a distressing symptom.205,206 However, opinions differ about this, with others believing that fever should be allowed to run its course.207
If it is thought necessary to reduce fever, there are a number of interventions that are or have been used, either alone or in combination. Pharmacological treatments differ fundamentally from physical treatments, as they aim to lower the hypothalamic set-point rather than simply cool the body. If it is thought necessary to reduce fever, the safest, most clinically and cost-effective treatments and those most acceptable to the child should be used. The first question that the GDG considered was what, if any, antipyretic interventions should be used. A variety of interventions were considered, specifically drugs, such as paracetamol and ibuprofen, and physical methods such as tepid sponging.
8.2. Physical and drug interventions
Clinical question
What if any, antipyretic interventions are effective in reducing body temperature in children with fever?
There are a number of interventions that can be undertaken to reduce temperature, both pharmacological and physical; however, it is not clear whether these treatments are either beneficial or necessary, or what the indications for the treatment of fever should be. Consequently, there is wide variation in practice, both with the use of interventions, and the outcomes that are aimed for. Some healthcare professionals aim to reduce temperature to what they consider to be normal, while others aim simply to reduce temperature. Although the circumstances under which interventions are used will vary, it is important that the possible benefits and harms of treating fever are understood. This includes any adverse effects from the interventions.
Elevations in body temperature result from rising levels of substances such as prostaglandins in the hypothalamus. This has the effect of resetting the hypothalamic temperature set-point and increasing temperature. Paracetamol and nonsteroidal anti-inflammatory agents such as ibuprofen inhibit the action of the cyclooxygenase enzyme involved in the production of this prostaglandin and others and this is the basis of their antipyretic activity, although inflammatory mediators other than prostaglandins may also be potential drug targets. Peripherally, the production of pyrogenic cytokines is also suppressed and the production of endogenous anti-inflammatory compounds is promoted.
Physical treatments such as tepid sponging cool the part of the body being sponged but do not reduce the levels of prostaglandins and so the temperature of the whole body is not reduced. Furthermore, because the hypothalamus is still set at a higher temperature level, physical treatments may cause shivering and other adverse effects as the body aims to meet the hypothalamic set-point temperature, which continues to be raised. Shivering with a high temperature is sometimes referred to as a rigor.
8.2.1. Physical interventions
There are a number of physical interventions that can be used to reduce body temperature, including undressing, fanning and sponging with cool or cold water. These take advantage of heat loss through convection and evaporation but do not treat the underlying causes of the fever; either the disease or the alteration in hypothalamic set-point.
Narrative evidence
Two reviews208,209 with EL 1+ and EL 2+ ratings, respectively, due to the nature of the included studies, were found. These compared tepid sponging with antipyretic drugs. One SR210 which evaluated the benefits and harms of sponging techniques was also found. One further study compared undressing with paracetamol and tepid sponging.211 There is a lack of evidence regarding opening windows or fanning as methods of reducing temperature. Tepid sponging offers no significant benefit over antipyretic agents alone.209 In studies looking at combinations of sponging techniques and drugs, sponging seemed to have no or only short-lived additive effects on the reduction in temperature. Adverse effects in some children included crying and shivering in those treated with sponging. Undressing alone had little effect on temperature. A small study in adult volunteers with artificially induced fever showed that, during active external cooling, shivering was common, and both heat production and blood pressure were raised.212 Discomfort was also significant, a finding that is supported by some studies of tepid sponging in children.213
GDG translation
Physical methods of temperature reduction do not treat the cause of fever, which is circulating pyrogens occurring as the result of the underlying condition. Tepid sponging is time consuming, may cause distress, and has minimal medium- to long-term effects on temperature. Undressing appears to have little, if any, effect on temperature. There was no evidence regarding other physical methods of temperature control, for example fanning, although this shares the above limitation. Physical methods may also cause shivering if the cooling is too much or too quick.213 This may cause vasoconstriction and an increase in temperature and metabolism.
Because there is limited evidence regarding clothing of the feverish child, the GDG agreed by consensus that children with fever should be clothed appropriately for their surroundings, with the aim of preventing overheating or shivering. The major consideration should be the comfort of the child, and the prevention of over-rapid cooling that may cause shivering which may be distressing for child and parents. Care also needs to be taken not to overdress febrile children. It is not possible to be prescriptive about this because of varying environmental and other conditions, and the provision of information about appropriate clothing is an important role for healthcare professionals. In view of the lack of evidence from clinical studies for or against the use of physical cooling methods, the GDG concluded that research in this area may be beneficial.
Recommendations on physical interventions for reducing temperature
Tepid sponging is not recommended for the treatment of fever.
Children with fever should not be underdressed or over-wrapped.
Research recommendation on physical interventions for reducing temperature
The GDG recommends that studies are conducted on the effectiveness of physical methods of attempting to reduce fever, for example lowering ambient temperature, fanning and cold oral fluids.
8.2.2. Drug interventions
The primary method of temperature control is the use of antipyretic drugs such as paracetamol and ibuprofen. Unlike the physical methods previously discussed, these do treat the proximal cause of fever, the increased hypothalamic set-point, although neither physical nor pharmacological methods treat the ultimate cause, for example an underlying infection. The GDG sought to identify the most appropriate pharmacological treatment for fever (as distinct from the cause of the fever), considering not only antipyretic efficacy but also safety and cost.
Narrative evidence
Two EL 1+ reviews210,214 and four EL 1+ RCTs215–218 comparing paracetamol and ibuprofen were found. Paracetamol and ibuprofen were both shown to be effective at reducing fever in children.210,214,215,217,218 Both reviews210,214 demonstrated that ibuprofen had a more pronounced and/or longer lasting effect on fever compared with paracetamol. However, in many of those studies paracetamol was used in doses below those currently recommended in the UK.
Adverse effects of antipyretic drugs
One EL 1+ meta-analysis210 which compared patients receiving single doses of paracetamol or ibuprofen was found. Despite the widespread use of ibuprofen and paracetamol, adverse events were rare. No evidence was found to suggest a difference in the risk of either minor or major harm between the two drugs. However, there have been reports of serious suspected adverse reactions even at therapeutic doses for both drugs.4,219 There is greater experience with the use of paracetamol but ibuprofen use is increasing and different adverse effect profiles may emerge.
Delphi consensus
There is a lack of evidence regarding indications for when children should be given antipyretic drugs. The GDG therefore decided to use the Delphi survey to provide information for these questions. After two rounds of Delphi the results below were obtained.
Delphi statement 8.1
Antipyretic drugs should be given to all children with fever.
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| 1 to 3 | 4 to 6 | 7 to 9 | Don’t know | Missing | Total | Median |
|---|
| 10 (19%) | 11 (21%) | 29 (56%) | 2 (4%) | | 52 | 7 |
After two rounds of Delphi this question failed to reach consensus and this statement was not therefore included in the draft version of the guideline. The second question to answer was Statement 8.2 of the Delphi consensus.
Delphi statement 8.2
Antipyretic drugs should be offered to children who are miserable with fever because they may make them feel better.
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| 1 to 3 | 4 to 6 | 7 to 9 | Don’t know | Missing | Total | Median |
|---|
| 3 (6%) | 5 (10%) | 43 (83%) | 1 (2%) | | 52 | 8 |
This reached agreement by consensus of 83% of respondents after round 2 and is therefore included as a recommendation in the guideline.
Evidence summary
Paracetamol and ibuprofen are both effective antipyretics. Physical methods of temperature reduction offer little additional benefit and cause crying and shivering in some children. There is no evidence of a significant difference in the incidence of adverse events between the two drugs. On current evidence both drugs are equally effective but paracetamol has a longer established safety record.
There is no evidence for any specific indications for the administration of antipyretics. Care should, however, be taken with all drugs, including antipyretics if given in combination with other drugs, or if the child is suffering other complications or conditions such as dehydration. Delphi consensus provided strong agreement that antipyretic drugs should be offered to children who are miserable with fever because they may make them feel better, but not that they should be given to all children with fever.
Health economics
Since no evidence of difference in the effectiveness of paracetamol and ibuprofen was identified, decisions on which should be used in the NHS should be based on individual prices available to trusts at the time of purchase.
GDG translation
Ibuprofen and paracetamol are widely used as antipyretic drugs. Although adverse effects and toxicities are possible with their use, paediatric formulations are safe in most children. Healthcare professionals and others involved in the supply of these drugs should ensure that parents understand how to administer them safely.
Despite their common use, there is no evidence regarding the indications for the administration of antipyretic drugs. Consequently, the GDG included questions on this in the Delphi survey. The results of this partly confirmed the lack of evidence, with no consensus on the statement that antipyretic drugs should be given to all children with fever. However, there was strong support for the statement that antipyretics should be offered to children who are miserable with fever because they may make them feel better. In response to stakeholder comments that antipyretics should not be given just because a child has a fever, the GDG decided to revisit the question as to whether all children with fever should be given antipyretics. The GDG achieved consensus among themselves that children with fever do not necessarily need to be given antipyretic agents, especially in light of the following recommendation that children who are miserable with fever may benefit from treatment. Because of the uncertainties about the benefits of antipyretic agents and their indications, the GDG recommended that more research should be conducted on the topic.
Because both drugs are safe and effective, no recommendation can be made about which should be used. The health economic analysis suggests that decisions on which should be used in the NHS should be based upon individual prices available to trusts at the time of purchase.
Recommendations on drug interventions for reducing temperature
The use of antipyretic agents should be considered in children with fever who appear distressed or unwell. Antipyretic agents should not routinely be used with the sole aim of reducing body temperature in children with fever who are otherwise well. The views and wishes of parents and carers should be taken into consideration.
Either paracetamol or ibuprofen can be used to reduce temperature in children with fever.
8.2.3. Combining pharmacological treatments
Paracetamol and ibuprofen, the drugs most commonly used to treat fever, are often used together by healthcare professionals, parents and patients, either in combination or alternately.220
Narrative evidence
Two EL 1− RCTs221,222 investigating the combination of antipyretic drug therapies and one EL 1+ RCT223 and one EL 1− RCT222 investigating the alternation of antipyretic drug therapies were found.
Combination treatment
One EL 1− RCT221 from the UK examined the administration of paracetamol, ibuprofen or both. It has to be noted that this study had no blinding and small numbers (n = 37, 35, 36) in each arm. A statistically significant difference between the combination and paracetamol groups was found, but this was only 0.35 °C and was not considered to be clinically significant. Follow-up of the majority of patients was only for 1 hour and therefore failed to detect any delayed differences. A second EL 1− RCT222 from India with small patient numbers (n = 80) showed that ibuprofen combined with paracetamol and nimesulide and paracetamol had almost identical antipyretic effects. No marked adverse effects were detected. Statistical data were not reported.
Neither study was of sufficient methodological quality to provide reliable evidence on the combined use of paracetamol and ibuprofen, which is therefore not recommended.
Alternating treatment
Two RCTs222,223 were found which examined the use of alternating regimens of antipyretic agents.
One EL 1+ RCT223 from Israel assigned children to receive either paracetamol or ibuprofen or to receive alternating paracetamol and ibuprofen for 3 days. The group given the alternating regimen was characterised by a lower mean temperature, more rapid reduction of fever, receiving less antipyretic medication, less stress, and less absenteeism from day care as compared with the other groups; all of the differences were statistically significant (P < 0.05). However, the study involved the use of a double dose loading dose, used low paracetamol maintenance doses and relied on parental temperature measurement and documentation at home. The second EL 1− RCT224 from Lebanon randomly allocated patients into one of two treatment groups: an intervention group where a single oral dose of ibuprofen was administered at baseline followed by a single oral dose of paracetamol 4 hours later; and a control group where a similar dose of ibuprofen was administered initially, followed by placebo 4 hours later. Those in the intervention group were significantly more likely than those in the control group to become afebrile at 6, 7 and 8 hours (P < 0.05). The two groups had similar maximum decline in temperature. No serious adverse reactions were observed. Although these results suggest the superiority of the combined alternating regimen, the findings need to be confirmed in larger trials, since the study had small numbers in each arm and failed to achieve its calculated sample size.
Evidence summary
Current limited evidence from a small number of RCTs suggests that combination treatment offers no advantage over single drug therapy and would not lead to clinically significant further reduction of body temperature. There is also inadequate evidence to demonstrate the safety of combination treatment. An individual case report has highlighted potential interactions between these drugs.225 More methodologically sound studies are therefore required to investigate the use of antipyretic combination treatment before recommendations can be made.
There is some limited evidence to suggest that alternating ibuprofen and paracetamol treatment is superior to monotherapy, although the safety of this treatment has not been studied.
GDG translation
The GDG recognises that combinations of paracetamol and ibuprofen, or regimens alternating the two drugs, are in common use by healthcare professionals and families. There is insufficient evidence to support or refute these practices. The potential for adverse drug reactions of the two used together is not known. Theoretical interactions are recognised and reliable safety data do not exist. Furthermore, each drug is known to be effective as a single agent and the potential for confusion and drug administration errors is increased by using more than one drug.
The studies examining administering paracetamol and ibuprofen at the same time have demonstrated no benefit above giving either agent alone, but these had low patient numbers. The two studies which have claimed benefit from an alternating regimen of ibuprofen and paracetamol do not provide sufficient evidence to support such a recommendation. The GDG is aware that an HTA study is currently examining the use of combined regimens of paracetamol and ibuprofen and will report in 2009.
The GDG noted that, from the evidence, antipyretic agents do not appear to be effective in the prevention of febrile convulsions. There is very limited evidence regarding the effect of paracetamol on activity and other areas contained within the clinical question, which showed inconsistent effects.
Recommendations on combining pharmacological treatment to reduce temperature
Paracetamol and ibuprofen should not be administered at the same time to children with fever.
Paracetamol and ibuprofen should not routinely be given alternately to children with fever. However, use of the alternative drug may be considered if the child does not respond to the first agent.
Research recommendation on combining pharmacological treatment to reduce temperature
The GDG recommends that a study is conducted on the effectiveness and safety of alternating doses of paracetamol and ibuprofen in reducing fever in children who remain febrile after the first antipyretic.
8.3. Effects of body temperature reduction
In addition to the underlying illness, fever may be accompanied by a number of unpleasant symptoms including pain, reduced eating and drinking, and reduced activity. In some cases, for example pain, this is likely to be the result of the illness causing the fever. However, in other cases it is not always clear whether these are the direct result of the fever, or of the underlying illness, or a combination of the two. The GDG therefore considered the use of antipyretic interventions in the treatment of these symptoms.
Because fever is a normal response to infection, some studies have been undertaken to look at the effect of the treatment of fever on specific conditions, including malaria,226 chickenpox227 and various viral infections.228 These showed that antipyresis does appear to slow recovery, and makes little difference to some aspects of wellbeing, although the clinical significance of these findings is marginal. As these studies were undertaken on patients who had a diagnosis, these fell outside of the scope of this guideline, and are not discussed further.
A particular concern of many parents about fever in children is that it may cause fits, or febrile convulsions.206 These are common in young children, and are very rarely associated with epilepsy or other problems in later life.230 Because antipyretics reduce temperature, there is a theoretical rationale for their use in the prevention of febrile convulsions.
Clinical question
Does the use of antipyretic interventions in children with fever serve a benefit or harm in terms of any of the following:
We did not find any evidence against other interventions.
Narrative evidence
Although there are some studies looking at the effect of pharmacological antipyresis on recovery from specific conditions such as chickenpox and malaria, and viral conditions, these fell outside of the scope of this guideline.
Research regarding the use of antipyretics in the prevention and treatment of febrile convulsions is limited. One EL 1+ review231 that was judged to be adequate for inclusion owing to its clinical relevance, after obtaining methodological details from the author, and one EL 1+ SR232 examining the use of antipyretic drugs as prophylaxis against febrile convulsions were found.
The first231 investigated the hypothesis that paracetamol and ibuprofen, used prophylactically, will reduce the incidence of febrile convulsions across a wide variety of conditions. It found no evidence that the prophylactic use of antipyretics has any effect in reducing the incidence of febrile convulsions. The second review232 assessed 12 studies of the effects of paracetamol for treating children in relation to fever clearance time, febrile convulsions and resolution of associated symptoms. It also found no evidence that the use of prophylactic paracetamol influenced the risk of febrile convulsions.
An EL 1+ double-blind RCT228 analysing 225 datasets was also identified, which found that there was no significant difference in mean duration of fever (34.7 hours versus 36.1 hours, P not given) or of other symptoms (72.9 hours versus 71.7 hours). Children treated with paracetamol were more likely to be rated as having at least a 1-category improvement in activity (P = 0.005) and alertness (P = 0.036).
Evidence summary
Limited evidence was found regarding the use of antipyretic medications in the promotion of well-being, activity, eating and drinking, and no evidence of cost-effectiveness. One study suggested that parents could identify some improvement in activity and alertness after the administration of paracetamol, but not in mood, comfort, appetite or fluid intake. There is no evidence that the use of antipyretic agents reduces the incidence of febrile convulsions. (EL 1)
GDG translation
The GDG noted that, from the evidence, antipyretic agents do not appear to be effective in the prevention of febrile convulsions. There is very limited evidence regarding the effect of paracetamol on activity or other areas contained within the clinical question, which showed inconsistent effects.
Recommendation on the role of antipyretics in the prevention of febrile convulsions
Antipyretic agents do not prevent febrile convulsions and should not be used specifically for this purpose.
