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Date: September 29th, 2014

Guest Skeptic: Dr. Anthony Crocco. Associate Professor, McMaster University, Medical Director and Division Head McMaster Children’s Hospital Emergency Department. RANThony#1: Fever Fear.

Case: 2-year-old presents with flu-like symptoms and a fever.

Questions:

Should parent’s combine/alternate acetaminophen and ibuprofen? Will treating the fever make her sicker, longer? Will treating with antipyretics prevent a febrile seizure?

Background: Parent’s are often very concerned about fever in their children. They can develop a real “fever fear” and come into the emergency department for evaluation and reassurance. However, we need to help educate them that fever alone is not dangerous.

Here is what the American Academy of Pediatrics Guides say about fever “…fever, in and of itself, is not known to endanger a generally healthy child. In contrast, fever may actually be of benefit; thus, the real goal of antipyretic therapy is not simply to normalize body temperature but to improve the overall comfort and well-being of the child.”

Questions #1: Should parent’s combine/alternate acetaminophen and ibuprofen?

Reference: Wong T, Stang AS et al. Combined and alternating paracetamol and ibuprofen therapy for febrile children. Cochrane Database of Systematic Reviews 2013.

Population: Randomized controlled trials examining children (<18yrs) with new fever

Randomized controlled trials examining children (<18yrs) with new fever Intervention: Combined or alternating therapy of paracetamol and ibuprofen

Combined or alternating therapy of paracetamol and ibuprofen Comparison: Isolated therapy of either paracetamol or ibuprofen. Alternating therapy as a comparison to combined therapy

Isolated therapy of either paracetamol or ibuprofen. Alternating therapy as a comparison to combined therapy Outcome: Primary: Child discomfort; number of doses of medications given; absences from daycare/school; proportion of febrile children at 1/4/6 hrs post treatment. Secondary: Adverse events



Authors’ Conclusions: “There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to know which of combined or alternating therapy might be more beneficial.”

Quality Checklist for Systematic Review:

The clinical question is sensible and answerable. Unsure The search for studies was detailed and exhaustive. Yes The primary studies were of high methodological quality. Yes The assessments of studies were reproducible. Yes The outcomes were clinically relevant. Unsure There was low statistical heterogeneity for the primary outcome. Yes The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: Temperature was lower after combined treatment.

1 hour (MD -0.27, 95%CI -0.45 to -0.08)

4 hours (MD -0.70, 95%CI -1.05 to -0.35)

6 hours (MD -1.30, 95%CI -2.01 to -0.59)

Alternating therapy improved comfort compared to single therapy (Analysis 2.1) as well as decreased absent days from daycare by -0.88 (95%CI -1.02 to -0.74).

This is a reasonably well-performed systematic review and meta-analysis. Cochrane usually does a good job. There were no restrictions on language/publication type and the authors did a reasonable search of the grey literature. A few issues arise:

Why was the unpublished research on this topic discovered through ClinicalTrials.gov not included in the meta-analysis.

Why did the authors insist on having several primary outcomes (Just like in the movie Highlander – there can be only ONE!)

Why did the authors not present the data on a research paper that adressed fever-associated symptoms at 24/48/120 hrs. (Hay 2008).

It is not surprising that using more antipyretic medications results in tighter control of fever in febrile children. The greater question is “who cares?” There has been a progressive shift away from focusing on normalization of temperature in febrile children towards focusing on patient comfort. This is in keeping with the AAP guidelines we mentioned previously.

The limited data presented in this paper suggests that combined/alternating therapy can be beneficial for comfort, but more studies on this outcome measure are required.

Comment on Authors’ Conclusion Compared to Our Conclusion: Agree that further research is required and that parents should focus on patient comfort instead of normalizing a temperature. There is, in fact, some evidence from this systematic review that alternating therapy has a benefit on comfort.

SGEM Bottom Line: Parents and caregivers should focus on patient comfort instead of normalizing a temperature in febrile children. Alternating therapy may be beneficial for comfort, but more research is required to address this specific question.

Clinical Application In febrile children, alternating or combining antipyretics may be helpful in controlling temperature, but this is of limited usefulness. Comfort may also benefit, but this requires more research.

What Do I Tell My Patient Treat comfort not fever. If one medication is not working try the other. Be careful if using both as not to accidentally overdose on one or the other.

Question #2: Will treating the fever make her sicker, longer?

Reference: Purssell E & While AE. Does the use of antipyretics in children who have acute infections prolong febrile illness? A systematic review and meta-analysis. J Pediatr 2013; 163: 822-7.

Population: RCT or quasi-randomized trials including children with febrile illeness

RCT or quasi-randomized trials including children with febrile illeness Intervention: Use of antipyretics

Use of antipyretics Comparison: No antipyretics

No antipyretics Outcome: Time to recovery

Authors’ Conclusions: “There is no evidence from these studies that the use of antipyretics slows the resolution of fever in children.”

Quality Checklist for Systematic Review:

The clinical question is sensible and answerable. Yes The search for studies was detailed and exhaustive. Unsure The primary studies were of high methodological quality. No The assessments of studies were reproducible. Yes The outcomes were clinically relevant. Unsure There was low statistical heterogeneity for the primary outcome. Yes The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: Pooled mean difference in fever clearance was -4.16 hours in favour of antipyretics (95%CI -6.35 to -1.96hrs; P=0.002)

This is certainly an interesting question to ask. Will treating a febrile child with antipyretics prolong their illness. This data suggests that treating the fever will NOT prolong their illness.

This study also had significant limitations. Specifically:

There was only a limited attempt at finding data from the ‘grey literature’. The authors should have done more than check reference lists from the published papers. They should have studied conference proceedings, and spoken with experts in the field.

Of the six studies included, three dealt with patients with malaria and one dealt with patients with varicella. None of those studies are generalizable to the patient population and infectious diseases we are likely to encounter.

Two of the six studies did not have blinding.

The primary outcome examined by this study was time to resolution of fever, a surrogate for more important outcomes. In one study (Brandts 1997) there was a signficiant increase in malaria clearance time in the antipyretic group. In another study (Kramer 1991) less than 50% of parents were able to correctly identify that their child had received antipyretic/placebo.

Overall, the ongoing recommendation is that parents focus on treating patient comfort and not treat a specific temperature number. This study does not support the regular use of antipyretics to control temperature.

Comment on Authors’ Conclusion Compared to Our Conclusion: The search yielded studies that are difficult to generalize to our population and the outcome measure is only a surrogate for clinical improvement.

SGEM Bottom Line: Antipyretics should be used to improve comfort during an illness.

Clinical Application: In children with fever due to illness, the current recommendation is that antipyretics are used to improve comfort and less attention should be paid to actual temperature.

What Do I Tell My Patient? We are going to use these drugs to make you (your child) more comfortable.

Question #3: Will treating with antipyretics prevent a febrile seizure?

Reference: Rosenbloom et al. Do antipyretics prevent the recurrence of febrile seizures in children? A systematic review of randomized controlled trials and meta-analysis. Eur J Paediatr Neurol 2013.

Population: Randomized controlled trials including children <18 years old

Randomized controlled trials including children <18 years old Intervention: Antipyretic medications

Antipyretic medications Comparison: Placebo

Placebo Outcome: Rates of febrile seizure recurrence

Authors’ Conclusions: “Antipyretics were ineffective in reducing the recurrence of febrile seizures.”

Quality Checklist for Systematic Reviews:

The clinical question is sensible and answerable. Yes The search for studies was detailed and exhaustive. No The primary studies were of high methodological quality. Unsure The assessments of studies were reproducible. Yes The outcomes were clinically relevant. Yes There was low statistical heterogeneity for the primary outcome. Yes The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: Odds Ratio for recurrence of febrile seizures in the antipyretic group was 0.9 (95% CI: 0.57-1.43).

So treating the fever did not seem to prevent children from having a febrile seizure. This has been a longstanding myth that febrile seizures can be prevented with antipyretics. This study identified three randomized controlled trials and combined their data to show that there is no significant effect in preventing the recurrence of febrile seizures.

Again, there were some major limitations:

There was no attempt to search the grey literature. The authors should have contacted experts in the field to find unpublished data. They should have searched for conference abstracts or commented on searching the reference lists of included articles.

“No language restrictions were applied, but English abstracts required.” This sounds like a language restriction to me – we included all languages, as long as they were English.

There was no risk of bias tool used. We see commonly in Cochrane Systematic Reviews a presentation of the included articles risks of bias. Commonly many of the included articles are found to have significant risks of bias, which then undermines the validity of any conclusion made from the study. Without a similar tool applied, we can only guess as to the risks of bias from the included studies.

The authors use the word “ineffective” to describe the usefulness of antipyretics in preventing febrile seizures. It is a common mistake to equate “no evidence of effect” and ineffective. Failing to prove that one thing is significantly better than another does not prove that they are the same.

Comment on Authors’ Conclusion Compared to Our Conclusion: I would clarify that there is no significant difference in recurrence of febrile seizures when children are treated with antipyretics.

SGEM Bottom Line: Antipyretics appear to offer no significant improvement in the recurrence rates of febrile seizures in children.

Clinical Application: In children with febrile seizures, the regular use of antipyretics appears to have no significant effect on reducing the rates of seizure recurrence.

What Do I Tell My Patient? Treating your child’s fever will not likely have any effect on recurrence rates of febrile seizures.

Summary of All Three Papers:

Antipyretics don’t appear to lengthen duration of fever in ill children

Antipyretics an be combined for effect, but to what end?

Antipyretics don’t appear to decrease risk of febrile seizure recurrence

Fever: Not your enemy!

Keener Kontest: Winner last week was from Canada, Claudia Martin. She guessed without going over the larges ascending aortic aneurysm successfully removed was about 12cm. This is Claudia’s second win so she will be getting the double strength cool skeptical prize.

Listen to the SGEM this week for the Keener Question. If you know the answer than send me an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

More FOAMed Resources on Paediatric Fever:

EM Cases Episode 48 – Pediatric Fever Without A Source