SGEM#239: Febrile Seizure Recurrence – With or Without You Acetaminophen?

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Date: December 13th , 2018

Reference: Murata et al. Acetaminophen and febrile seizure recurrences during the same fever episode. Pediatrics. 2018

Guest Skeptic: Dr. Damian Roland is a Consultant at the University of Leicester NHS Trust and Honorary Associate Professor for the University of Leicester’s SAPPHIRE group. He specialises in Paediatric Emergency Medicine and is a passionate believer that education exists to be shared (#foamed).

Damian is part of the Don’t Forget the Bubbles (DFTB) team. They published an epic paper to determine the transit time of a Lego head (Tagg et al). The primary outcome was the FART (Found and Retrieved Time) score. Bowel habit were standardized before the trial started using the SHAT (Stool Hardness and Transit) score. The story was picked up by the BBC, Forbes and even talked about by James Corden on the Late, Late Show.

Case: An 18-month-old presents having had a febrile convulsion (febrile seizure) at home. The seizure lasted no more than a minute and now having been in the department for a couple of hours the infant is back to their normal selves. Observations are normal except a low-grade fever and there is a clear focus in a right otitis media for an infection. You start to counsel the parents with likely outcomes for the future and immediate safety netting advice. You tell the parents that regular antipyretics won’t stop another febrile convulsion occurring and they should really only be used to help their child when they are distressed with a fever. After you leave the room a student who had witnessed the consultation asks you why you said you couldn’t stop febrile convulsions when a recent publication from Japan has clearly shown that regular rectal acetaminophen significantly reduces the risk of recurrence?

Background: Febrile seizures are very common and very, very scare for care-givers and parents. During winter periods a typical emergency department may well see a child a day presenting with a febrile seizure

There was a SRMA by Rosenbloom et al. (Eur J Paediatr Neurol 2013) that concluded antipyretics were ineffective in reducing the recurrence of febrile seizures in children.

SGEM#95 covered this paper with Pediatric Super Hero Anthony Crocco. Our bottom line was that antipyretics appear to offer no significant improvement in the recurrence rates of febrile seizures in children.

Fever fear is a real concern for parents and they often come to the emergency department for evaluation and reassurance.

The American Academy of Pediatrics guidelines say “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.”

Standard advice has always been that the regular administration of an antipyretic won’t reduce the risk of recurrence but a recent publication in Pediatrics has challenged this position.

Clinical Question: Does the regular administration of acetaminophen reduce the risk of immediate recurrence of a febrile seizure in children?

Reference: Murata et al. Acetaminophen and febrile seizure recurrences during the same fever episode. Pediatrics. 2018

Population: Infants and Children 6 to 60 months old attending an Emergency Department at a single Japanese City Hospital
- Exclusions: Patients with 2 or more FSs during the current fever episode, seizures lasting >15 minutes, patients with epilepsy, chromosomal abnormalities, inborn errors of metabolism, brain tumor, intracranial hemorrhage, hydrocephalus, or a history of intracranial surgery, patients who had been administered diazepam suppository, patients whose parents requested the use of diazepam suppository, patients who had taken antihistamines or patients with diarrhea.
Intervention: Rectal acetaminophen (10mg/kg) at presentation and every six hours until 24 hours after the onset of the febrile seizure
Comparison: No treatment for 24 hours after the onset of the febrile seizure
Outcome:
- Primary: Seizure recurrence during the same fever episode
- Secondary: Variables associated with febrile seizures recurrence (acetaminophen use, age, and duration of seizure).

Authors’ Conclusions: “Acetaminophen is a safe antipyretic against FSs (Febrile Seizures) and has the potential to prevent FS recurrence during the same fever episode”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized. Yes
The randomization process was concealed. Unsure
The patients were analyzed in the groups to which they were randomized. No
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Unsure
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: There were 438 children randomize in this trial to rectal acetaminophen or no antipyretics. The median age was about 20 months, a quarter had a history of a febrile seizure and 16% had a febrile seizure in this study.

Febrile seizure recurrence rate was significantly lower with rectal acetaminophen compared to no antipyretic treatment.

Primary Outcome: Febrile seizure recurrence
- 9.1% in the intervention group vs. 23.5% in the control group (p <0.001)
- Absolute difference of 14.4% and NNT 7 to prevent one recurrence
Secondary Outcomes: Four variables (rectal acetaminophen use, age of patient, duration of seizure and rectal acetaminophen and age) were independently associated with FS recurrence.

1) Exclusions: They excluded 1/3 of potential patients for a variety of reasons. The vast majority of the exclusions were because the patient had been given a diazepam suppository to prevent a febrile seizure or the parents requested the use of diazepam suppository. We always like to see consecutive inclusions and some of these exclusions could have introduced some selection bias into the trial.

2) Blinding, No Placebo Group and Prognostic Factors: The trial was not blinded and there was no placebo group. This could have biased the self-reporting of parents to favor acetaminophen. We are also unsure if both groups were similar with regards to prognostic factors because no confidence intervals were provided around the point estimates.

3) Intention-to-Treat (ITT) Analysis: It appeared they did not perform an intention-to-treat analysis which would again bias the results towards intervention/treatment group (rectal acetaminophen).

4) External Validity: Another issue with this study is the external validity. Many patients were excluded from inclusion because they had already received a rectal suppository of diazepam. I do not use a rectal benzodiazepines to prophylactically prevent a febrile seizures. While it may be the standard to give acetaminophen rectally in Japan this has not been my experience. It is rare parents prefer the rectal route and most often give antipyretics orally. This means this Japanese population may not be the same as the patients we see in the UK or elsewhere.

5) Ethics: One last point is the ethical consideration of withholding antipyretics from a febrile child. We have already discussed that the AAP recommends treating for comfort not to lower the temperature. Withholding antipyretic therapy in a sick febrile child could be considered unethical because it could withhold comfort for some children.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We disagree with the authors’ conclusions given the methodologic limitations of the trial.

SGEM Bottom Line: Treat a febrile child with antipyretics for comfort not to normalize the temperature or prevent a recurrent febrile seizure.

Case Resolution: The child is given acetaminophen orally not to bring down the fever or prevent a febrile seizure but to ameliorate the pain of acute otitis media.

Dr. Damian Roland

Clinical Application: This is a chance to remind people again that fever is not the enemy but pain, distress and serious bacterial illness are the real concern. A chance to debate external validity and cultural validity. I think it would be possible to replicate this study elsewhere and possibly come up with similar results but culturally per rectum is considered unacceptable/inappropriate for this purpose. There is debate hear about the social context of care (as opposed to the evidence-based context of care)

However uncomfortable it may appear, while I would not change my practice based on this, I think it does hint that you can probably reduce the recurrence rate through this method. Whether you should is the key question.

What Do I Tell My Patient? Your child had a febrile seizure and are common in children. They are at a low risk of developing epilepsy. The evidence is not clear on whether or not keeping the fever down will prevent another seizure. The best advice is to use acetaminophen to help keep your child comfortable and not focus as much on the temperature.

Keener Kontest: We had a number of people with the correct answer last week. The first correct answer came from Dr. Ally Hynes an EM resident from Mercy St. Vincent in Toledo, Ohio. She knew Henry Dale was the researcher working in the Wellcome Physiological Research laboratories in 1906 that insisted on using the name adrenaline in all his publications?

Listen to the SGEM podcast on iTunes or your favourite podcast app to hear the new keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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