Drug interventions

Citation/ElMethodResults
Purssell214

Study Type:
Review.
EL: 1+
Inclusion: Primary studies comparing oral paracetamol and ibuprofen as treatments for fever in children, and included sufficient statistics to extract mean temp and effect size at either or all of 0,1,2,4, and 6 hr. oral paracetamol and ibuprofen as treatments for fever in children,The author found 13 papers and 8 were included. 5 of them used randomization. The age studied ranged from 4 mo to 13 yr.

Differences in temp between ibuprofen and paracetamol
TM. diff (°C)95%CINo.p
1 hr−0.01−0.04:0.025 s
n:448
0.22
4 hr0.630.59: 0.696 s
n:423
<0.001
6 hr0.580.52: 0.645s
n:267
0.005
T: time; S: studies
The differences that exist appear to be unrelated to dosages of the drugs. This is further supported by the high degree of homogeneity across drug dosages at 4 and 6 hr.
Data extraction was done by one person and the potential for bias or error in extraction and interpretation exists.
Lack of uniformity about the dosage of drugs.
Overall, it appears that ibuprofen is more effective than paracetamol, particularly at 4 and 6 hr.
Perrott210

Study Type: SR.
EL: 1+
Number of People: Seventeen blinded, randomized controlled trials with 915 children (<18 years). Inclusion/exclusion: children (<18 years) receiving either drug to treat fever or moderate to severe pain. Single-dose acetaminophen and ibuprofen for treating children's pain or fever.Under a fixed-effects model, outcome measures for an initial single dose of ibuprofen vs acetaminophen were the risk ratio for achieving more than 50% of maximum pain relief, effect size for febrile temperature reduction, and risk ratio for minor and major harm. Data Synthesis: Ibuprofen (4–10 mg/kg) and acetaminophen (7–15 mg/kg) showed comparable efficacy (3 pain relief trials; 186 children). The risk ratio point-estimates was 1.14 (95%confidence interval [CI], 0.82–1.58) at 2 hours after receiving the dose, and 1.11 (95% CI, 0.89–1.38) at 4 hours. Ibuprofen (5–10 mg/kg) reduced temperature more than acetaminophen (10–15 mg/kg) at 2, 4, and 6 hours after treatment (respective weighted-effect sizes: 0.19 [95% CI, 0.05–0.33], 0.31 [95% CI, 0.19–0.44], and 0.33 [95% CI, 0.19–0.47]) (9 fever trials; 1078 children). For ibuprofen 10 mg/kg (acetaminophen, 10–15 mg/kg), corresponding effect sizes were 0.34 (95% CI, 0.12–0.56), 0.81 (95% CI, 0.56–1.03), and 0.66 (95% CI, 0.44–0.87). There was no evidence the drugs cause serious harm.
Wong215

Study Type: RCT
EL: 1+
Multiracial, multinational, multicenter, single, oral dose, prospective, randomised, modified parallel group study.
Ibuprofen vs Acetaminophen vs. Dipyrone.
Number of People: 555 patients completed the study 179 in the dipyrone group191 in the acetaminophen group and 185 in the ibuprofen group.. Inclusion/exclusion: Approached 628 febrile children, 6 mo to 6 yr with body weight ≥5 kg and able to receive oral medication. Recruited from May to December 1998. They were identified either in inpatient ward or emergency clinics.
Exclusion:
Having history of febrile seizures within 6 mo prior to the study, receiving Abx more than 12 hr before study, receiving antipyretics with 4 hr of study, receiving treatment with any investigational drug in the prior 4 weeks, and having a history of hypersensitivity or adverse reaction of the study drugs.
Children were also excluded if they had poor prognosis (tropical disease e.g. dengue fever, malaria, fever, cramps, and/or severe dehydration. Conditions that might interfere with drug absorption; histories of connective tissue disease or AIDS; haematological toxic effects within the past 3 mo; changes in mood or conscious.

Outcome Measures: Definition of fever: TT 38.5–40.5 °C.
TT of the right ear were obtained by a digital otoscopic temperature device (Thermoscan HM2W/C; Braun, Inc). In children < 3yr, 3 successive readings were taken, and the highest temp was recorded.

Patients were randomly assigned 1:1:1 to receive one of the drug in a single dose by syringe. The dosage and manner of administration per manufacturers’ labelling instructions in the packaging insert, exactly as the caregiver would do in the domestic situation.
The dosage of dipyrone (Novalgina) was 15 mg/kg. the dose for acetaminophen (Tylenol) was adjusted according to each pt’s age, averaged 12 mg/kg. Ibuprofen (Ibupirac) was given in initial temperature using dose of 5 mg/kg for <39.2 °C and 10 mg/kg for ≥39.2 °C.

Evaluation:
After medication, TT was measured 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, and 6 hours later. Adverse events were assessed during the 6 hr study period and for an additional 14 days after drug ingestion.
All three drugs were effective in reducing TT. Time reach this reduction was statistically comparable for all three groups.
The number of pt who achieved normalisation was significantly greater in the dipyrone and ibuprofen group than in the acetaminophen group (p=0.004).
Temperature reductions of at least until the end of 6 hr observation only with dipyrone. Reductions in a similar range were maintained with acetaminophen and ibuprofen for up to 3 hr.
Absolute reduction of temp over time: similar during the first 2 hr. At 4–5–6 hr, mean temp in dipyrone is significantly lower (p=0.004).

Tolerability:
Drug related adverse effects: 17% in dipyrone; 15% in acetaminophen and 27 in ibuprofen (ns, p value not reported).
BP and pulse rate tended to decrease uniformly.
Total of 9 pt (3 in the dipyrone; 2 in acetaminophen and 4 in ibuprofen ) had temp < 36.0 °C.
During the study periods, anticonvulsants, antacids, corticosteroids, or non steroidal anti-inflammatory drugs were prohibited.

Baseline characteristics
Dipyrone (n=209)Acetaminophen (n=210)Ibuprofen (n=209)
Age (mo)
Mean ±SD28±1831±2129±19
Range6–806–916–83
Weight
Mean ±SD13±413±513±4
Range6–266–306–28
TT (°C)39.3±0.639.2±0.639.2±0.6
Diagnosis
URI135 (64%)145 (69%)134 (64%)
LRI37 (18%)44 (21%)40 (19%)
UTI6 (3%)1 (0.5%)10 (5%)
GI infection26 (12%)25 (12%)26 (12%)
Other44 (21%)37 (18%)39 (19%)
Temperature reduction:
Dipyrone (n=179)Acetaminophen (n=191)Ibuprofen (n=185)
Pt (N[%]) with TT reduction ≥ 1.5 °C154 (86)148 (77)153 (83)
Time to temp reduction
Mean (min ±SD)103±68109±77120±83
Range15–36015–36015–360
Pt (N[%]) with normalised temp (TT≤37.5 °C)147(82)130 (68)145 (78)
Time to temperature normalisation
Mean (min ±SD)123±71118±80130±87
Range15–36015–36015–360
Figueras216

Study Type: RCT
EL: 1+
Number of People: Population: 6 mo-12 yr. A total of 200 paediatric inpatients were randomly allocated to either intervention or control group.
Inclusion/exclusion: Age (Y):Mean (SD) 3.48 (2.7) in the ibuprofen and 3.78 (3.0) paracetamol.
Inclusion:
Body weigh > 3rd centile and absence of CNS infection symptoms, bilateral otitis or any other condition which the investigator’s judgment would make it inadvisable for the enrolment.
Exclusion:
Had history of malabsorption, febrile crisis over the past 6 mo, hypersensitivity to NASIDs or paracetamol, GI bleeding, significant renal, hepatic, pulmonary, endocrine, haematological, cardiac, neurological or CNS dysfunction. Uncontrolled DM, clotting alterations, or current diagnosis of epilepsy.
Had been treated with t1/2>12 h Abx within 24 hr admission. A min 4-hr washout periods was mandatory before inclusion for pt who had received antipyretics within 4 hr. A period of 6 h should have elapsed for those who had been given non-betalactamic Abx 6 hr.
Intervention: 1 drop of ibuprofen-arginine kg/body weight ( 6.67 ibuprofen mg/kg) or 4 drops of paracetamol (10.65mg/kg) together with a matching placebo.
Temperature measurement:
Fever was defined as 38.5 °C the max normal TT measured by “ Thermo Scan Pro I Braun Instant Thermometer” in the oral mode”.
After administration, TT were taken at 20, 40 min, 1,1.5,2,3,4,5,6, and 8 hr. Adverse events were assessed.
Efficacy:
The evolution of temp over time was not significantly different between ibuprofen and paracetamol groups (p=0.22).
The reduction of TT between both treatments did not differ significantly at the 4-hr control (p=0.527), with a mean decrease difference in ibuprofen group of 1.3 °C (SD 1.1) against 1.2 °C (0.96) in the paracetamol group. This reduction did not reach significance over the study period (p=0.697). The percentage reduction calculated at the 4-h point was not statistically significant between groups (65.9% for ibuprofen and 66.8% for paracetamol, p=0.96). Other antipyretic analyses such as max decrease in TT, percentage of pt with reductions in TT equal or superior than 1.5 °C were similar between groups with a better trend of ibuprofen group without reaching statistical significance. Only the percentage of pt that achieved a reduction in TT of 2 °C or more was higher in the ibuprofen group compared with the paracetamol group (22.1% against 15.6%, p=0.043) following multi-variant analysis.
CharacteristicsIbuprofen (n=100)Paracetamol (n=99)p-value
Age (Y)Mean (SD)3.48 (2.7)3.78 (3.0)0.451
Weight (kg)Mean (SD)16.59 (8.14)18.59 (11.32)0.798
Diagnosis at admissionN
URI4150ns
LRI1216ns
GI infection93ns
Soft tissue infection57ns
Otitis10ns
Other2520ns
TTMean (SD) °C39.14 (0.6)39.13 (0.56)0.743
Antipyretic activity
CharacteristicsIbuprofen (n=94)Paracetamol (n=93)p-value
Mean change in TT at 4 hr ( °C)Mean (SD)1.3 (1.1)120 (0.96)0.527
Reduction of TT at 4 hr ( °C)Mean (SD)65.9(53.9)66.81(50.2)0.96
Max TT change( °C)Mean (SD)1.91 (0.96)1.76 (0.89)0.205
Time become apyrexial (min)Mean (SD)75.1 (5.2)77.0(5.81)0.515
Pt with temp reduction of ≥ 1.5 °C%33.228.60.260
Pt with temp reduction of ≥2 °C%22.115.90.043
Pt with reduction of temp to normal range%43.240.70.422
Walson217

Study Type: RCT
EL: 1+
Number of People: 64 pt aged from 6 mo to 11 yr 7 mo, 15 in 3 of the ibuprofen dose groups and 16 in the acetaminophen group. Inclusion/exclusion: 64 pt aged from 6 mo to 11 yr 7 mo, weighing 6.8–56.1 kg who had been febrile for less than 48 hr and who had initial OT or RT of 39.0 0C to 40.50C.
Patients receiving any temp relating drugs, within 6 hr before study or requiring antibiotics from 12 hr before the initial dose to 24 hr after the first dose. Pt with significant GI, renal, hepatic, cardiac, haematologic, bronchospastic, malignant or CNS disease. Pt with vomiting, severe diarrhoea, dehydration, and pt who received investigational drugs within 1 mo of the beginning of the study. Every 6 hr, each pt had 2 liquids, one of which contained placebo and one contained active drug.
By 6 hr after initiation of drug, the mean temp decreases for ibuprofen administered in doses of 2.5 mg/kg and 5 mg/kg were less prominent than for both 10 mg/kg ibuprofen and acetaminophen. The differences were less obvious in the 12-hr measurement. Mean percentage reduction of fever in the group receiving 2.5 mg/kg ibuprofen (76.0%) was significant lower than that of the group receiving 10 mg/kg ibuprofen.

In 61 of the 64 evaluable patients, treatments were effective and well tolerated during the entire study. While the rates of temperature reduction and maximal reduction of fever after administration of the initial dose were equal for patients receiving 10-mg/kg ibuprofen therapy and 15-mg/kg acetaminophen therapy, and both regimens were more effective than smaller doses of ibuprofen in reducing fever, after the second dose (and continuing to the end of the study) there were no statistically significant differences in temperature response among the treatment groups. Six children were withdrawn from
Autret218

Study Type: RCT.
EL: 1+
Number of People: Children aged 6 mo to 5 yr with fever presumed infectious origin treated with antibiotics.
A double blind RCT.

Fever was defined as RT ≥38.0 °C measured by mercury thermometer.

Intervention
7.5 mg/kg ibuprofen syrup (n=77).
Control:
10 mg/kg acetaminophen syrup (n=77).

Outcome Measures: Area under reduction in temp and temp evolution over time and tolerability.
RT measured at 1,2,4,6,8,12,24,36,48,60, and 72 hr after the first dose. The first dose was followed 6 hr later by the second dose regardless of the degree of degree of hyperthermia. The following doses were given at regular intervals of 6 hr if the temp was > 37.8 C, up to max of 30 mg/kg for ibuprofen and 40 mg/kg/24 hr for acetaminophen.
Temp evolution over time was not significantly different between two groups ( p not reported). The temp reduction over the first 4 hr was significantly higher after ibuprofen (60%) than acetaminophen (45%). Both drugs were well tolerated.
Children < 2y and more did not show any significant difference between treatments for any of the assessment criteria.
Source of funding: All drugs were supplied by Boots Pharmaceuticals.

From: Evidence tables

Cover of Feverish Illness in Children
Feverish Illness in Children: Assessment and Initial Management in Children Younger than 5 Years.
NICE Clinical Guidelines, No. 47.
National Collaborating Centre for Women’s and Children’s Health (UK).
London (UK): RCOG Press; 2007 May.
Copyright © 2007, National Collaborating Centre for Women’s and Children’s Health.

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