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OBJECTIVES: To confirm the safety of using acetaminophen for febrile seizures (FSs) and to abstract
assess its efficacy in preventing FS recurrence during the same fever episode.
METHODS: In this single-center, prospective, open, randomized controlled study, we included
children and infants (age range: 6–60 months) with FSs who visited our hospital between
May 1, 2015, and April 30, 2017. The effectiveness of acetaminophen was examined by
comparing the recurrence rates of patients in whom rectal acetaminophen (10 mg/kg) was
administered every 6 hours until 24 hours after the first convulsion (if the fever remained
>38.0°C) to the rates of patients in whom no antipyretics were administered. No placebo
was administered to controls. The primary outcome measure was FS recurrence during the
same fever episode.
RESULTS: We evaluated 423 patients; of these, 219 were in the rectal acetaminophen group,
and 204 were in the no antipyretics group. In the univariate analysis, the FS recurrence
rate was significantly lower in the rectal acetaminophen group (9.1%) than in the no
antipyretics group (23.5%; P < .001). Among the variables in the final multiple logistic
regression analysis, rectal acetaminophen use was the largest contributor to the prevention
of FS recurrence during the same fever episode (odds ratio: 5.6; 95% confidence interval:
2.3–13.3).
CONCLUSIONS: Acetaminophen is a safe antipyretic against FSs and has the potential to prevent
FS recurrence during the same fever episode.
Drs Murata, Okasora, and Tanabe conceptualized and designed the study, drafted the initial WHAT THIS STUDY ADDS: The current study is the
manuscript, and reviewed and revised the manuscript; Drs Ogino, Yamasaki, Oba, Syabana, first randomized controlled trial to assess the
Nomura, Shirasu, and Inoue created the sampling and analysis protocols, supervised the data ability of acetaminophen to prevent febrile seizure
collection, were involved in the data interpretation and discussion, and critically reviewed and recurrence during the same fever episode with
edited the manuscript; Drs Kashiwagi and Tamai were involved in the study design and data bivariate and multiple logistic regression analyses.
acquisition and contributed to the writing of the manuscript; and all authors approved the
manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered with the UMIN Clinical Trials Registry (https://upload.umin.ac.jp/cgi-
open-bin/ctr/ctr_view.cgi?recptno=R000032366) (identifier UMIN000028272).
DOI: https://doi.org/10.1542/peds.2018-1009
Accepted for publication Aug 20, 2018
Address correspondence to Shinya Murata, MD, PhD, Department of Pediatrics, Hirakata City
To cite: Murata S, Okasora K, Tanabe T, et al. Acetaminophen
Hospital, 2-14-1 Kinya-honmachi, Hirakata, Osaka 573-1013, Japan. E-mail: wildwind1980@live.jp
and Febrile Seizure Recurrences During the Same Fever
Episode. Pediatrics. 2018;142(5):e20181009
Statistical Analysis
We used JMP version 13 software
(SAS Institute, Inc, Cary, NC) for
the statistical analyses. Statistical
significance was set at P < .05.
The primary outcome was seizure
recurrence during the same fever
episode. We estimated the sample
size for the multiple logistic
regression analysis using standard
methods; at least 10 cases were
presumed to be necessary for each FIGURE 1
independent variable. As the FS Study enrollment.
recurrence rate within the same
fever episode was estimated to be logistic regression analysis was in the no antipyretics group were
15%,5 400 children with FSs were performed with all variables showing excluded from the analysis because
required to perform a multiple P < .05 in the bivariate analysis. We of nonadherence to the protocol or
logistic regression analysis with 5 determined the final multivariate loss to follow-up. Finally, the data
independent variables. logistic regression model by from 423 patients, 219 in the rectal
Patients’ characteristics and hierarchical background elimination. acetaminophen group and 204 in the
laboratory data were compared We also assessed the linearity of no antipyretics group, were analyzed
between the rectal acetaminophen variables in the final multivariate (Fig 1). None of the patients used
and no antipyretics groups. We logistic regression model to verify diazepam suppositories during the
stratified the patient characteristics the validity of the model using the study period.
and laboratory data by age (6–21 and statistical software R (version 3.2.5).
No significant differences in the
22–60 months). Continuous variables
patient characteristics or laboratory
were compared by using Mann–
RESULTS data were identified between
Whitney U test. Binary variables were
the rectal acetaminophen and no
compared by using Pearson’s χ2 test. Patient Characteristics antipyretics groups, regardless of
We first conducted bivariate analyses During the study period, a total of stratification by age (6–21, 22–60
and then used a multiple logistic 794 children visited our hospital months, and all patients). The rate
regression analysis to identify the for FSs. Of these, 279 children were of FS recurrence during the same
factors that contributed to the excluded (188 who used diazepam fever episode was 16.0% (68 out
decrease in FS recurrence within suppository to prevent FSs, 34 who of 423 patients). All FS recurrences
the same fever episode. Bivariate had taken antihistamines, and 57 occurred within 24 hours after the
analyses were performed by others), and the parents of another initial FS. The rate of FS recurrence
comparing the patient characteristics 17 children declined to participate during the same fever episode
and laboratory data according in this study. Sixty children with was significantly lower in the
to the presence or absence of FS diarrhea were not included in the rectal acetaminophen group
recurrence during the same fever study protocol. Therefore, 438 than in the no antipyretics group
episode. Continuous variables were patients were allocated to 1 of for all age groups (Table 1). When
compared by using Mann–Whitney the following 2 groups: the rectal including all patients regardless
U test. Binary variables were acetaminophen group (229 children) of age, the recurrence rate was
compared by using Pearson’s χ2 and the no antipyretics group (209 9.1% in the rectal acetaminophen
test. Thereafter, in consideration children). Ten patients in the rectal group and 23.5% in the no
of potential interactions, a multiple acetaminophen group and 5 patients antipyretics group (P < .001).
In children 6 to 21 months of age, experienced FS recurrence showed 56% of patients with and without FS
the recurrence rate was 13.2% neurologic sequelae. recurrence, respectively, used rectal
in the rectal acetaminophen acetaminophen (P < .001).
group and 24.3% in the no Bivariate Analyses
antipyretics group (P = .0297). In the bivariate analyses, we Multiple Logistic Regression Analysis
In children 22 to 60 months of identified significant relationships A multiple logistic regression
age, the recurrence rate was between FS seizure recurrence and analysis was performed with the
4.1% in the rectal acetaminophen rectal acetaminophen use, age, and following 3 variables, which showed
group and 22.6% in the no duration of seizure (Supplemental significant differences in the bivariate
antipyretics group (P < .001). Table 3). Age was significantly lower analyses, with consideration of
No serious complications related to and the duration of seizure was interactions: rectal acetaminophen
acetaminophen, such as hypotension, significantly shorter in children with use, age, and duration of seizure.
hypothermia, or anaphylaxis, were versus without FS recurrence (P < We selected the variables for
observed. None of the patients who .05 for both). We found that 29% and the final multivariate logistic
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