164 Archives ofDisease in Childhood 1996; 74: 164-167 Comparing efficacy and tolerability of ibuprofen Arch Dis Child: first published as 10.1136/adc.74.2.164 on 1 February 1996. Downloaded from and paracetamol in fever John McIntyre, David Hull Abstract in infants and young children a lot lower than The purpose ofthis study was to compare previously appreciated.3 antipyretic activity and evaluate tolera- Ibuprofen is recommended in treatment of bility of ibuprofen and paracetamol sus- juvenile arthritis and is well tolerated. It is also pension in the treatment of febrile an effective antipyretic.4 It is therefore a poten- children. It was designed as a double tial alternative to paracetamol. Previous studies blind, parallel group, multiple dose study have indicated an appropriate dose range for comparing ibuprofen (20 mg/kg/24 hours) ibuprofen.5 In many studies that have compared with paracetamol (50 mg/kg/24 hours) ibuprofen and paracetamol, young children and given at six hourly intervals for a maxi- those with wheezing and asthma have been mum of 12 doses. Children on paediatric excluded. The objectives of this study were to wards between the ages of 0-2 and 12 compare the antipyretic activity and evaluate years, with fever as defined by an axillary the tolerability of ibuprofen suspension and temperature ¢ 37 5°C, were included. paracetamol suspension used in treating febrile The main outcome measures were: children, including young infants and those change in axillary temperature; palat- with common paediatric illnesses. ability of medication; changes in irrit- ability and clinical condition; overall efficacy at the end of treatment; and Methods number and nature of adverse events. STUDY DESIGN AND PATIENTS The mean temperature change from This was a double blind, parallel group, baseline at four hours was -1-8°C and multiple dose study and was given approval by -1 60C in ibuprofen and paracetamol the local ethics committee. Written informed groups respectively. In both groups: consent was obtained from the parent or legal median palatability score was 'no reac- guardian and from the child when able to give tion'; median irritability score at end consent. Those entering the study were in- point was 'not irritable'; median score patients at a single hospital, between two for change in clinical condition was months and 12 years of age, of either sex, and http://adc.bmj.com/ 'improved'; and median score for overall with an axillary temperature of 37 5°C or above. efficacy was 'good effect'. The proportion Patients were excluded iftheir weight was below of patients experiencing adverse events the third centile for age, they were receiving was similar in both groups, the majority anticoagulant treatment, had a history of of events having doubtful or no relation- intolerance to ibuprofen, paracetamol or similar ship to therapy and being mild in compounds, had previous occurrence or current severity. symptoms of peptic ulceration or gastrointes- In conclusion, ibuprofen suspension tinal bleeding, or had severe liver, heart, kidney, on September 29, 2021 by guest. Protected copyright. was as effective and well tolerated as or systemic disease including malignancy. paracetamol in treatment of fever in Medication that could interfere with the study young children. was not permitted during nor in the six hours (Arch Dis Child 1996; 74: 164-167) before entry to the study. The following were recorded at entry to the Keywords: ibuprofen, fever, paracetamol. study: age, sex, weight, primary diagnosis, treatment received during the previous month, and any history such as asthma, wheezing, or Antipyretic agents have an established place in convulsions. managing febrile children. As fever is common The study medication was prepared by in childhood illnesses, antipyretic drug use is Boots Pharmaceuticals, as orange flavoured widespread.' It is therefore important to be saccharin free suspension. Randomisation was confident that the drugs given are safe and effi- in blocks of four to allow for equal numbers in Department of Child cacious in children with a fever from a variety each treatment group. The dose of medication Health, University Hospital, Nottingham of causes. was determined by age and ibuprofen at J McIntyre In 1986 the Committee on Safety of approximately 20 mg/kg/24 hours or para- D Hull Medicines advised doctors not to prescribe cetamol at 50 mg/kg/24 hours was given in Correspondence to: aspirin routinely for children under 12 years of divided doses. Medication was administered Dr J McIntyre, Jenny Lind age because of a possible association with orally six hourly if required, up to four doses in Children's Department, Norfolk and Norwich Health Reye's syndrome.2 This left paracetamol as the each 24 hour period, for a maximum of three Care NHS Trust, Brunswick only readily available antipyretic. Although days (12 doses). Road, Norwich, Norfolk NR1 3SR. extensively used and with a good safety record Patients were withdrawn from the study if Accepted 20 September there have been recent reports indicating the at any time continued participation could be 1995 margin of safety of frequent therapeutic doses considered detrimental to their well being. Comparing efficacy and tolerability ofibuprofen andparacetamol in fever 165 EVALUATIONS Table 1 Summary ofprimary diagnosis at admission (n= 150) At the first dose, axillary temperature was Arch Dis Child: first published as 10.1136/adc.74.2.164 on 1 February 1996. Downloaded from recorded and then at hourly intervals for six Primary diagnosis Total No ofpatients hours and thereafter every six hours or imme- Febrile convulsion 35 diately before any subsequent doses. After the Viral illness (non-specific) 29 first dose, palatability was recorded by obser- Chest infection 25 Asthma/wheezing 1 5 vation of the child's reaction or by request if Croup 10 the child was aged over 7 years, using a five Gastroenteritis 8 Bronchiolitis 8 point scale (from 0=disliked the taste a lot to Soft tissue infection 6 4=liked the taste a lot). Irritability was Urinary tract infection 4 Otitis media 3 assessed using a three point scale (from 0=very Tonsillitis 3 irritable to 2=not irritable). Before subsequent Herpes stomatitis 1 Septic arthritis 1 doses the change in clinical condition was Tracheitis 1 noted on a five point scale (from 0=much Septicaemia 1 worse to 4=much improved), and after, irri- tability was reassessed and other measures of cooling noted. When the last dose of study (range 0-2-9-4 years), the median weight medication was given, or when the fever had 11-9 kg (range 5-8-34 kg), and 20 were 612 resolved, overall efficacy of the medication was months ofage. At entry, in the ibuprofen group recorded on a four point scale (from O=no there were 11 patients with a primary diagnosis effect to 3=very good effect). Occurrence of of wheezing and 21 with a past history of any adverse events were documented with wheezing and/or asthma; for the paracetamol respect to nature, causality, and severity. group there were four and 12 patients respec- tively. All 150 patients entered into the study took at least one dose of study medication, STATISTICS although one patient did not ingest her med- The planned sample size was 75 patients in each ication. Thirty five patients in the ibuprofen treatment group: with 90% power and a 5% sig- group and 28 in the paracetamol group were nificance level, assuming a variability of 1 07'C receiving concomitant treatment at entry. the detectable difference for the change from baseline in temperature over a four hour period was 0 56°C. The variability observed during the EFFICACY DATA trial was 1.18'C. All statistical tests performed The main results are summarised in table 2. were two tailed with significance determined by The difference between treatments for the reference to the 5% level. The null hypothesis mean change from baseline in body tempera- was always that ibuprofen and paracetamol ture at four hours was -0-20C (95% confi- were equivalent. Change in body temperature at dence interval -0-6 to 0-2; p=0 39). The four hours was compared between treatment largest mean decreases in body temperature groups using an analysis of covariance with a occurred during the first five hours. In the http://adc.bmj.com/ factor for treatment and age as a covariate. ibuprofen group the maximum mean decrease Ordinal measures ofpalatability, change in irrit- from baseline was 2°C at three hours and in ability from baseline to end point, change in the paracetamol group 1 7"C at two, three, and clinical condition at end point, and overall four hours. The changes in actual mean tem- efficacy were compared between treatment perature are shown in the figure. After 36 groups using the Wilcoxon rank sum statistic. hours there was only a small proportion of Withdrawals and the time for the temperature patients remaining in the study so the mean on September 29, 2021 by guest. Protected copyright. to fall below 37-5°C were compared using the decreases beyond this have not been plotted. log rank test. The number ofpatients experienc- During the study, the temperature fell below ing adverse events and the number of patients 37.50 for 73/76 (96%) patients in the ibupro- whose temperature fell by 10C or more at four fen group and 66/74 (89%) patients in the hours were each compared using the x2 test. paracetamol group. There were no statistically significant differences between the treatment groups in: (a) the distribution ofthe times until Results the temperature fell below 37 5°C (median All 150 patients who entered the study pro- times of 2 hours and 1-4 hours for ibuprofen vided at least one valid post-baseline efficacy and paracetamol groups respectively; p=025) assessment and all available efficacy data were and (b) the distribution of the times until the included in the analysis on the basis ofintent to second dose (median times of six hours in both treat.