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