Acetaminophen and Febrile Shinya Murata, MD, PhD,a​ Keisuke Okasora, MD, PhD,a​ Takuya Tanabe, MD, PhD,​b Motoko Ogino, MD,a​ SeizureSatoshi Yamazaki, MD,a​ ChizuRecurrences Oba, MD,​a Kohsuke Syabana, MD, ​c ShouheiDuring Nomura, MD, PhD,a​ a a a c theAkihiko Shirasu, Same MD, PhD,​ Keisuke Fever Inoue, MD, PhD, Episode​ Mitsuru Kashiwagi, MD, PhD,​ Hiroshi Tamai, MD, PhD

OBJECTIVES: abstract

To confirm the safety of using acetaminophen for febrile seizures (FSs) and to METHODS: assess its efficacy in preventing FS recurrence during the same fever episode. – 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 RESULTS: same fever episode. We evaluated 423 patients; of these, 219 were in the rectal acetaminophen group, and 204 were in the no antipyreticsP 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%; < .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: CONCLUSIONS: 2.3 13.3). Acetaminophen is a safe antipyretic against FSs and has the potential to prevent FS recurrence during the same fever episode.

WHAT’S KNOWN ON THIS SUBJECT: Acetaminophen has long been thought to be ineffective for aDepartment of Pediatrics, Hirakata City Hospital, Hirakata, Osaka, Japan; bDepartment of Child Neurology, preventing febrile seizure recurrence both in the Tanabe Children’s Clinic, Hirakata, Osaka, Japan; and cDepartment of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan same and another fever episode(s).

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: [email protected] and Febrile Seizure Recurrences During the Same Fever Episode. Pediatrics. 2018;142(5):e20181009

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 142, number 5, November 2018:e20181009 ARTICLE Febrile seizures (FSs) are the most did not use a placebo in this study. (10 mg/kg) by a pediatrician within common type– of seizure in childhood, Children with FSs who visited the the emergency department. The with a cumulative1 3 incidence of emergency department at Hirakata parents were then instructed to 2% to 5%. ‍‍ In Japan, FSs occur City Hospital between May 1, 2015, administer an acetaminophen 4 ∼ in 7% to 11% of children, and and April 30, 2017, were considered suppository (10 mg/kg) every the risk of recurrence is 15% for inclusion in this study. Our 6 hours until 24 hours after the 5 ° during the same febrile illness. hospital has pediatric emergency onset of the FS, if the fever However, clear evidence is lacking wards that are open 24 hours every remained >38.0 C. Parents in in many issues related to FS, and day and accept many emergency the no antipyretics group were appropriate medical treatment cases. FS was defined according instructed not to administer any “ has not yet been understood. The to the criteria of the Japanese7 antipyretics to their child for 24 relationship between antipyretics Society of Child Neurology as a hours after the FS. As mentioned ≥ ° and FSs is one such issue. Indeed, seizure accompanied by fever (body Procedureearlier, no placebo was used. some pediatricians in Japan still temperature 38.0 C), without counsel families of children with central nervous system infection, ” FS that antipyretics will increase that occurs in infants and children 6 6 Baseline characteristics, including the risk of FS recurrence. On the through 60 months of age. age, sex, past history of FSs, history other hand, the appropriate use of Patients who had already of FSs in a first-degree relative, antipyretics is considered effective in ° experienced 2 or more FSs during the duration between onset of fever alleviating discomfort in the patient. current fever episode were excluded (>38.0 C) and initial FS, duration of Although FSs are usually benign, they from the study. Patients with seizure, body temperature on first can be frightening for parents and seizures lasting >15 minutes were arrival at our hospital, and laboratory caregivers. Therefore, understanding considered to have status epilepticus data (white blood cell counts, the relationship between antipyretics and were excluded from the study. hemoglobin, hematocrit, and platelet and FSs is critical for ensuring proper Patients with epilepsy, chromosomal counts as well as the C-reactive treatment. abnormalities, inborn errors of protein, creatinine, albumin, sodium, In clinical practice, the majority metabolism, brain tumor, intracranial potassium, chloride, and blood sugar of pediatricians consider that FS hemorrhage, hydrocephalus, or levels) on first arrival at our hospital recurrence during the same fever a history of intracranial surgery were recorded at study entry. Blood episode will not be increased by were also excluded. Patients who samples were collected from each using acetaminophen, the most had been administered diazepam patient before the administration of common antipyretic administered suppository to prevent FSs and acetaminophen on arrival. Parents to infants and children. However, patients whose parents requested the were instructed to bring the children to the best of our knowledge, no use of diazepam suppository were back to our hospital immediately if researchers have determined excluded. Patients who had taken the FSs recurred. Parents were also whether antipyretics, particularly antihistamines were also excluded instructed to record the number acetaminophen, significantly increase because– antihistamines may increase of acetaminophen administrations the incidence and recurrence of FSs. seizure8 10 susceptibility in patients with and to send us this information on a As such, our aim in this study was StudyFSs. ‍‍ Medication postcard after the fever resolved. If to assess whether acetaminophen we did not receive the postcard, an reduces the recurrence of FSs during investigator contacted the parents to the same fever episode and to obtain the required information. We Patients with FSs were randomly confirm the safety of administering also checked adherence to the study allocated to 2 groups, namely the acetaminophen to children with FSs. protocol through the postcards and rectal acetaminophen group and no METHODS telephone interviews. antipyretics group. The allocation Patients With Diarrhea Study Design and Patient Population sequence was generated by 2 of the authors using random-number tables. The dose of rectal acetaminophen Patients with diarrhea were excluded This study was approved by the was set to be 10 mg/kg because from random assignment because ethics committee at Hirakata City most pediatricians in Japan prescribe of difficulty in administering the Hospital. All parents provided written acetaminophen at this dose. Patients suppositories. In addition, some of informed consent for their child to in the rectal acetaminophen group these patients were considered to be participate in this prospective, open, were immediately administered better categorized into other clinical randomized controlled trial. We an acetaminophen suppository entities such as convulsions with Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 MURATA et al 11 mild gastroenteritis (CwG). For patients with diarrhea, we checked the seizure recurrence rate during the same fever episode and compared it with the rate from patients without diarrhea who were included in our Statisticalrandomized Analysis trial.

We used JMP version 13 software (SAS Institute, Inc, Cary,P NC) for the statistical analyses. Statistical significance was set at < .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 FIGURE 1 methods; at least 10 cases were Study enrollment. presumed to be necessary for each independent variable. As the FS recurrence rate within the same fever episode was estimated to be 5 Plogistic regression analysis was in the no antipyretics group were 15%,​ 400 children with FSs were performed with all variables showing excluded from the analysis because required to perform a multiple < .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 modelR 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 (version 3.2.5). – No significant differences in the 22 60 months). Continuous variables RESULTS U patient characteristics or laboratory were compared by using Mann ’ χ Patient Characteristics data were identified between Whitney test. Binary variables were 2 the rectal acetaminophen and no compared by using Pearson s test. – – 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 – Uepisode. 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 ’ χ test. Binary variables were 2 acetaminophen group (229 children) of age, the recurrence rate was compared by using Pearson s and the no antipyretics group (209 9.1% in the rectal acetaminophenP 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 ( < .001). Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 142, number 5, November 2018 3 TABLE 1 Patient Characteristics, Recurrence of FSs, and Laboratory Data All Patients Age 6–21 mo Age 22–60 mo Rectal No Antipyretics, Rectal No Antipyretics, Rectal No Antipyretics, Acetaminophen, n = 204 Acetaminophen, n = 111 Acetaminophen, n = 93 n = 219 n = 121 n = 98 Age in mo, median (IQR) 20 (16–31) 21 (16–30) 17 (13–19) 16 (13–19) 33 (26–44) 31 (25–42.5) Sex, n Male 118 111 55 56 63 55 Female 101 93 66 55 35 38 Past history of FS, n Yes 57 55 27 14 30 41 No 162 149 94 97 68 52 Familial history of FS, n Yes 54 43 31 20 23 23 No 165 161 90 91 75 70 Interval between fever and 9 (3.5–17.3) 7.5 (2.5–17.4) 11 (4–24) 9 (2.5–19) 7 (3–13) 6 (2.8–13) FS in h, median (IQR) Duration of seizure in min, 3 (1–4) 3 (1–5) 3 (2–5) 3 (1–5) 2 (1–4) 2 (1–5) median (IQR) BT on arrival in °C, median 39.7 (39.1–40.1) 39.5 (39.1–39.9) 39.7 (39.3–40.2) 39.4 (38.8–40.0) 39.5 (38.7–40.0) 39.4 (38.9–39.9) (IQR) Recurrence of FS, n (%) 20 yes, 199 no (9.1) 48 yes, 156 no 16 yes, 105 no 27 yes, 84 no (24.3) 4 yes, 94 no (4.1) 21 yes, 72 no (22.6) (23.5) (13.2) Laboratory data WBC count per µL, median 10 990 (8400– 11 390 (8460– 10 440 (7750– 11 330 (8450– 11 910 (8730– 11 560 (8310– (IQR) 14 930) 16 370) 13 680) 17 500) 15 960) 15 330) Hemoglobin, g/dL, median 12.1 (11.5–12.5) 12.0 (11.4–12.5) 11.9 (11.3–12.4) 11.7 (11.2–12.4) 12.3 (11.8–12.7) 12.3 (11.7–12.7) (IQR) Hematocrit, %, median 35.2 (33.9–36.5) 35.1 (33.7–36.6) 34.9 (33.9–36.4) 34.5 (33.1–35.9) 35.6 (34.4–36.8) 35.9 (34.4–37.4) (IQR) PLT, ×104/µL, median (IQR) 27.7 (23.0–35.7) 29.5 (23.5–34.5) 29.2 (22.7–36.8) 29.7 (23.6–35.4) 27.2 (23.6–32.3) 27.8 (23.1–32.8) C-reactive protein, mg/dL, 0.5 (0.2–1.2) 0.5 (0.2–1.1) 0.4 (0.2–1.2) 0.5 (0.2–1.1) 0.6 (0.3–1.2) 0.5 (0.1–1.4) median (IQR) Creatinine, mg/dL, median 0.27 (0.24–0.30) 0.27 (0.24–0.30) 0.26 (0.23–0.29) 0.26 (0.23–0.28) 0.29 (0.25–0.34) 0.29 (0.26–0.33) (IQR) Albumin, g/dL, median 4.4 (4.2–4.6) 4.4 (4.2–4.6) 4.3 (4.1–4.5) 4.4 (4.1–4.5) 4.5 (4.3–4.6) 4.4 (4.2–4.6) (IQR) Sodium, mEq/L, median 136 (134–137) 136 (134–137) 136 (134–137) 136 (134–137) 136 (135–138) 136 (135–137) (IQR) Potassium, mEq/L, median 4.1 (3.9–4.4) 4.1 (3.9–4.4) 4.2 (4.0–4.4) 4.3 (4.0–4.4) 4.0 (3.7–4.29) 4 (3.8–4.2) (IQR) Chloride, mEq/L, median 101 (100–102) 101 (99–103) 101 (100–103) 101 (100–103) 101 (99–102) 101 (99–102) (IQR) Blood sugar, mg/dL, 120 (107–135) 116 (107–130) 118 (106–136) 117 (108–132) 121 (109–134) 115 (106–129) median (IQR) BT, body temperature; IQR, interquartile range; PLT, platelet count; WBC, white blood cell.

In children 6 to 21 months of age, experienced FS recurrence showed 56% of patients withP and without FS the recurrence rate was 13.2% Bivariateneurologic Analyses sequelae. recurrence, respectively, used rectal in the rectal acetaminophenP Multipleacetaminophen Logistic ( Regression < .001). Analysis group and 24.3% in the no antipyretics group ( = .0297). In the bivariate analyses, we 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 acetaminophenP 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 ( < .001). Table 3). Age was significantly lower analyses, with consideration of No serious complications related to and the duration of seizure wasP 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 ( < We selected the variables for observed. None of the patients who .05 for both). We found that 29% and the final multivariate logistic Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 MURATA et al TABLE 2 Multiple Logistic Regression Analysis Odds Ratio (95% Confidence Interval) P regression model using hierarchical background elimination starting Rectal acetaminophen Yes Reference <.001 from the following 6 variables: rectal No 5.6 (2.3–13.3) — acetaminophen use, age, duration Age, mo of seizure, rectal acetaminophen 1 mo decrement 1.08 (1.03–1.11) <.001 use and age, rectal acetaminophen Duration of seizure, min use and duration of seizure, and age 1 min decrement 1.15 (0.99–1.32) .0481 Rectal acetaminophen and age — .0026 and duration of seizure. As a result , not applicable. of this selection, the 4 variables — of rectal acetaminophen use, age, duration of seizure, and rectal acetaminophen use and age were regression analysis also revealed that of antipyretics. Therefore, the retained. The continuous variables, a younger age and shorter duration effectiveness of acetaminophen namely duration of convulsion as of seizure were associated with was likely underestimated in the well as age, satisfied the criteria for higher FS recurrence rates during the previous study. linearity. We reanalyzed the final same fever episode. model with the 4 variables of rectal The results of the current study acetaminophen use, age, duration of In our comparison of the support that acetaminophen can seizure, and rectal acetaminophen recurrence rates between the rectal effectively prevent FS recurrence use and age using a multivariate acetaminophen and no antipyretics within the same fever episode, logistic regression test (Table 2). groups, it was demonstrated that despite the fact that acetaminophen All 4 variables were independently acetaminophen has the potential has long been considered ineffective and significantly associated with FS to prevent FS recurrence during for preventing FS recurrence both recurrence. Among these variables, the same fever episode. This in the same and different fever rectal acetaminophen use had the – is in contrast to the12 findings of episode(s). Indeed, in the randomized highest odds ratio of 5.6 (95% Schnaiderman et al who examined controlled 13trials performed by 14 confidencePatients With interval: Diarrhea 2.3 13.3). the effectiveness of acetaminophen Uhari et al and Strengell et al during the same febrile illness by to evaluate the effectiveness of comparing the FS recurrencen rates acetaminophen during separate between a regular usage group The FS recurrence rate during the n fever episodes, no significant (4-hour intervals; = 53) and a same fever episode was 35% in the differences in the FS recurrence sporadic usage group ( = 51; 60 children with diarrhea, which was ° rates were observed between sporadic use contingent on a body significantly higher than the rates in the acetaminophen and placebo temperature >37.9 C) in 104 children the rectal acetaminophen group and groups in either trial.15 In addition, presenting with simple FS. In that no antipyretics group (Supplemental Rosenbloom et al concluded that study, 4 children in the regular Fig 2). acetaminophen was ineffective usage group (7.5%) and 4 children for preventing FS recurrence in a DISCUSSION in the sporadic usage group (7.8%) meta-analysis of 13,these14​ randomized experienced a second FS. The authors controlled trials. As such, our concluded that the prophylactic data should be interpreted with This is the first randomized administration of acetaminophen caution, particularly because the controlled trial to indicate that in children with FS was ineffective included patients were children acetaminophen could prevent the for preventing FS recurrence given who visited our hospital after FS recurrence of FSs during the same the lack of a significant difference in had already occurred. Therefore, fever episode. In this study, the FS the FS recurrence rate between the in the current study, we could not recurrence rate was significantly 2 groups, although a larger amount determine the preventive effects lower in the rectal acetaminophen of acetaminophen was administered of acetaminophen in children who group than in the no antipyretics to the regular usage group. The had not yet had a FS during a fever group. In our multiple logistic different findings between our study12 episode. regression analysis it was suggested and the study by Schnaiderman et al that, among the variables in the final can be explained by the inclusion of There may be several explanations model, rectal acetaminophen was the different control groups; whereas of the mechanisms by which largest contributor to the prevention no antipyretics were used in our acetaminophen reduces the of FS recurrence during the same study,12 the study by Schnaiderman recurrence of FS. First, fever episode. The multiple logistic et al permitted the sporadic use acetaminophen may reduce FS Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 142, number 5, November 2018 5 CONCLUSIONS recurrence by lowering body features: (1) clustered seizures temperature. However, in the current occurring within 24 to 48 hours as In our study, it was shown that study, no significant difference in the most distinctive clinical feature, acetaminophen may reduce the body temperature was observed 2 (2) occurrence in previously healthy recurrence of FSs during the hours after the first acetaminophen 6-month- to 3-year-old infants and ° same fever episode and thus administration between children children, (3) at least 1 convulsive can be considered safe for use with and without FS recurrence. episode occurring at 38 C– or less, (4) in children with FSs. Nevertheless, That said, the monitoring of body association with mild gastroenteritis,18 24 the constant use of acetaminophen temperature was insufficient in and (5) good prognosis. ‍‍ The rate in children with FSs is not our study; thus, the difference in of seizure recurrence was significantly recommended because the body temperature during the study higher in children with diarrhea than outcome of FS is usually favorable. period was unclear. Additional in those without diarrhea. Therefore, The most important aspect of studies in which researchers use seizures with pyrexia associated with clinical practice against FS is close or continuous monitoring of diarrhea are presumed to have strong providing appropriate explanations body temperature are necessary to susceptibility to seizure recurrence. to parents to relieve anxiety and elucidate the relationship between Exclusion of children with diarrhea to ensure appropriate use of FS recurrence and the antipyretic from randomized trial may have acetaminophen on the basis of effects of acetaminophen. Second, resulted in reduction of FS recurrence the individual conditions. acetaminophen may reduce FS in our study. This may be related ACKNOWLEDGMENTS recurrence through effects other than to the difference in the efficacy of antipyretic effects, although these acetaminophen from that in previous effects currently remain unknown. An studies. Further investigation of FS in We thank former Professor extensive exploration of biomarkers children with diarrhea is necessary. Nishimura Yasuichiro (Department such as metabolites and humoral Our study has some limitations. First, of Mathematics, Osaka Medical factors may be useful in solving this as mentioned above, the information College) for the assistance with problem. Comparisons between on body temperature was insufficient the statistical analysis. We also acetaminophen and other antipyretics because close monitoring of body thank Dr Takuya Matsuda, such as ibuprofen may also help to temperature was not performed in Ishikawa Showichi, and Okuhira clarify the association between FS our study; thus, evaluating the exact Takeru (Department of Pediatrics, recurrence and the nonantipyretic antipyretic effects of acetaminophen Osaka Medical College) for the effects of acetaminophen. was difficult. Second, patients who helpful discussions and support. In our study, patients with diarrhea used diazepam suppositories were We thank Dr Tomoki Aomatsu and were excluded from the randomized excluded from the study. In clinical Atsushi Yoden (Department of controlled trial because we considered settings, clinicians occasionally use Pediatrics, Osaka Medical College) that such patients were not suitable both diazepam and antipyretics. for the special advice and suggestions. In addition, we for direct comparison with children Therefore, the combined effects ’ with FSs without diarrhea. First, of diazepam and acetaminophen thank Dr Takehiko Hirasawa suppositories may be difficult to use should be assessed in future studies. (Hirasawa Children s Clinic) for in children with diarrhea because they Finally, the causative pathogens and teaching us the importance of stimulate defecation. Second, some origins of fever were not considered physical examination. of these11,16,​ patients17​ met the criteria for in our study. Because it is possible ABBREVIATIONS CwG,​ ‍ ‍ which is characterized by that the rate of FS recurrence is frequent seizure clusters. CwG was16 influenced by these factors, future first described in Japan in 1982 researchers investigating the effects CwG: convulsions with mild and is now recognized worldwide of acetaminophen should consider gastroenteritis as a distinct clinical entity. CwG the causative pathogens and origins FS: febrile seizure is characterized by the following of fever. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 142, number 5, November 2018 7 Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode Shinya Murata, Keisuke Okasora, Takuya Tanabe, Motoko Ogino, Satoshi Yamazaki, Chizu Oba, Kohsuke Syabana, Shouhei Nomura, Akihiko Shirasu, Keisuke Inoue, Mitsuru Kashiwagi and Hiroshi Tamai Pediatrics 2018;142; DOI: 10.1542/peds.2018-1009 originally published online October 8, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/142/5/e20181009 References This article cites 24 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/142/5/e20181009#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Emergency Medicine http://www.aappublications.org/cgi/collection/emergency_medicine_ sub Neurology http://www.aappublications.org/cgi/collection/neurology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode Shinya Murata, Keisuke Okasora, Takuya Tanabe, Motoko Ogino, Satoshi Yamazaki, Chizu Oba, Kohsuke Syabana, Shouhei Nomura, Akihiko Shirasu, Keisuke Inoue, Mitsuru Kashiwagi and Hiroshi Tamai Pediatrics 2018;142; DOI: 10.1542/peds.2018-1009 originally published online October 8, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/142/5/e20181009

Data Supplement at: http://pediatrics.aappublications.org/content/suppl/2018/10/04/peds.2018-1009.DCSupplemental

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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