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Combined and alternating paracetamol and ibuprofen therapy for febrile children

  1. Tiffany Wong1,2,*,
  2. Antonia S Stang3,
  3. Heather Ganshorn4,
  4. Lisa Hartling5,
  5. Ian K Maconochie6,
  6. Anna M Thomsen2,
  7. David W Johnson7

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 30 OCT 2013

Assessed as up-to-date: 6 SEP 2013

DOI: 10.1002/14651858.CD009572.pub2


How to Cite

Wong T, Stang AS, Ganshorn H, Hartling L, Maconochie IK, Thomsen AM, Johnson DW. Combined and alternating paracetamol and ibuprofen therapy for febrile children. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009572. DOI: 10.1002/14651858.CD009572.pub2.

Author Information

  1. 1

    University of British Columbia, BC Children's Hospital, Department of Pediatrics, Vancouver, Canada

  2. 2

    Alberta Children's Hospital, Calgary, Canada

  3. 3

    Community Health Services, Department of Pediatrics, Calgary, AB, Canada

  4. 4

    University of Calgary, Libraries and Cultural Resources, Calgary, Alberta, Canada

  5. 5

    University of Alberta, Department of Pediatrics, Edmonton, Alberta, Canada

  6. 6

    St Mary's Hospital, Department of Paediatrics A&E, London, UK

  7. 7

    Faculty of Medicine, University of Calgary, Alberta Children's Hospital, Department of Pediatrics, Calgary, Alberta, Canada

*Tiffany Wong, tiffanywong.mak@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 30 OCT 2013

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Characteristics of included studies [ordered by study ID]
Erlewyn-Lajeunesse 2006

MethodsStudy design: open label, three-arm randomized trial.

Study dates and duration: October 2004 to January 2005.

Method of temperature measurement: tympanometric thermometer.

Time points measured in study: admission, T0 (time medication given), hour 1 and 2 (if patient not discharged).


ParticipantsNumber: 123 randomized.

Number of patients in each intervention: paracetamol n=41, ibuprofen n=42, paracetamol plus ibuprofen n=40.

Inclusion criteria: consecutive children between 6 months and 10 years old with a fever of 38 °C.

Exclusion criteria: paracetamol or ibuprofen given in the previous six hours, severe or life threatening infection, suspected chicken pox, cellulitis or other spreading skin infection, known to be immunosuppressed, allergy to either ibuprofen or paracetamol, medicated with warfarin, heparin or antihypertensives, symptoms of active gastrointestinal bleeding, known coagulopathy, acute jaundice, likely dehydration, defined as more than four episodes of diarrhoea or vomiting in the previous 24 hours, asthma, defined as a need for regular 'preventer' medication, chronic renal, liver or cardiac failure.

Baseline characteristics:

  • Sex distribution not reported
  • Age, years: paracetamol group 1.5(0.6-9.5), ibuprofen group 1.5 (0.5-9.6), paracetamol + ibuprofen group 2.4 (0.6-8.2)
  • Baseline data were similar in all three groups, except that more children were admitted to hospital in the combined group (13/36) compared to the ibuprofen (3/35) and paracetamol groups (5/35).


InterventionsGroup 1: paracetamol 15 mg/kg

Group 2: ibuprofen 5 mg/kg

Group 3: paracetamol 15 mg/kg + ibuprofen 5 mg/kg

Frequency of administration: single dose of each


OutcomesPrimary

  1. Child’s temperature at one hour


Secondary

  1. Temperature at two hours
  2. Time spent in department


NotesLocation: Bristol, UK

Setting: single centre - Children's Emergency Department, Bristol.

Funding: the Anthony Hopkins Memorial Prize, awarded by the Faculty of Accident and Emergency Medicine as an unrestricted award to the Emergency Department.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe allocation sequence was block randomized and generated independently of the research team.

Allocation concealment (selection bias)Low riskAllocations were placed in sequentially numbered sealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen label trial, however temperature is an objective measurement that should not be subject to bias from lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThis was an open label trial, however temperature is an objective measurement that should not be subject to bias from lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo reasons given for missing data or patients withdrawn.

Subjects withdrawn or missing data: combined 9%, ibuprofen 14.7%, paracetamol 9%.

Selective reporting (reporting bias)High risk
  • Study did not report mean temperatures at hour 2 as initially stated: "Too few children had data at two hours to allow meaningful comparison, as they had already been discharged home."
  • "Secondary outcome analysis of the time spent on the unit did not add to our findings and is not reported."
  • Mean fall from T0 to T1 was reported but not stated as an outcome measure.

Other biasUnclear riskPotential baseline imbalance: higher proportion of patients in combined group were admitted to hospital compared with other groups.

Hay 2008

MethodsStudy design: individually-randomized, blinded three-arm trial.

Study dates and duration: January 2005 to May 2007.

Method of temperature measurement: axillary continuous probe for 24 hours, then standard digital axillary thermometer for home measurements.

Time points measured in study: temperature taken every 30 seconds using axillary temperature probe for first 24 hours, then as needed with standard axillary thermometer at home.


ParticipantsNumber: 156 randomized.

Number of patients in each intervention: paracetamol n=52, ibuprofen n=52, paracetamol plus Ibuprofen n=52.

Inclusion criteria: children aged 6 months to 6 years in the primary care setting and households in England.

Required axillary temperatures of at least 37.8 °C and up to 41 °C.

Exclusion criteria: if patients required hospital admission, clinically dehydrated; had recently participated in another trial; had previously participated in PITCH; had a known intolerance, allergy or contraindication to a trial drug; had a chronic neurological, cardiac, pulmonary (except asthma), liver or renal disease; or had parents who could not read or write in English.

Baseline characteristics:

  • Sex, N(%): paracetamol (n=52) – boy = 26 (50), girl = 26 (50), ibuprofen (n=52) – boy = 37 (71), girl = 15 (29), both (n=52) – boy = 25 (48), girl = 27 (52).
  • Diagnoses included otitis media, respiratory tract infections, non-specific viral illnesses etc.


InterventionsGroup A: paracetamol 15 mg/kg every 4-6 hours

Group B: ibuprofen 10 mg/kg every 6-8 hours

Group C: paracetamol + ibuprofen alternating

Advice was given to parents to give the study drugs for up to 48 hours


OutcomesPrimary:

  1. Number of minutes without fever (<37.2 °C) in the first 4 hours
  2. The proportion of children reported as being normal on the discomfort scale at 48 hours


Secondary:

  1. Time to temperature first falling below 37.2 °C in the first 24 hours (fever clearance)
  2. The time spent without fever over 24 hours
  3. Proportion of children without fever associated symptoms: discomfort, reduced activity, reduced appetite and disturbed sleep at 48 hours and day 5
  4. Adverse effects


NotesLocation: England

Setting: multi-centre – 35 primary care sites (NHS Direct, one walk-in centre, 30 general practices, two general practitioner out of hours cooperatives, and the emergency department of the Bristol Royal Hospital for Children) and households.

Funding: National Institute for Health Research Health Technology Programme.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization sequence was generated via a remote, automated telephone service provided by the Health Services Research Unit at the University of Aberdeen.

Allocation concealment (selection bias)Low riskAfter written informed consent had been obtained and the baseline questionnaire completed, the research nurse telephoned a remote, automated randomization service.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy medication identity was concealed.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskResearch nurse was blinded to process.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskArticle did not address why three patients (one from ibuprofen and two from ibuprofen plus paracetamol group) had missing data for time without fever. "Attrition was minimal."

"Thus, children were omitted from analyses only if none of the data required were available, and as these were so few in number the influence of missing data on the intention-to-treat analyses was negligible."

Selective reporting (reporting bias)Low riskAll assessed outcomes were reported.

Other biasLow riskThe possibility of receiving either or both drugs combined and the severity of the child's illness may have influenced parental decision to participate.

Kramer 2008

MethodsStudy design: prospective, randomized double-blind placebo control study.

Study dates and duration: January 2004 to January 2006.

Method of temperature measurement: children > 2 years oral, Children < 2 years rectal. Parents given thermometers for home use.

Time points measured in study:temperature measurements at hours 0, 3, 4, 5, 6.


ParticipantsNumber: 40 randomized.

Number of patients in each intervention: paracetamol n=19, paracetamol alternating with ibuprofen n=19.

Inclusion criteria: healthy children presenting to the out patient clinic with chief complaint of fever. Fever in clinic > 38 °C

Exclusion criteria: history of any antipyretic use in the preceding 4 hours or if they had an allergy or other medical contraindication to the medications.

Baseline characteristics:

  • Sex, N(%): Aal (n=38), males = 18 (47.4), females = 20 (52.6)
  • Diagnoses, N(%) bacterial illness 13 (34.2), viral illness 25 (65.8).


InterventionsGroup A: paracetamol (15 mg/kg) alternated with placebo

Group B: paracetamol (15 mg/kg) alternating with Ibuprofen (10 mg/kg)

Administration regime:

Time                     Group A                             Group B

0                           APAP                                 APAP

3                           placebo                              ibuprofen

4                           APAP                                 placebo


OutcomesPrimary:

  1. Temperature at enrolment and hours 3, 4, 5, 6


Secondary:

  1. Symptom checklist at hours 3 and 4
  2. Parental perception of efficacy at hours 3 and 4


NotesLocation: Washington, USA

Setting: single centre: pediatric clinic at Madigan Army Medical centre in Tacoma, Washington.

Funding: Resident Research Grant from the American Academy of Pediatrics.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskChildren were assigned to treatment group A or B using previously generated computer based randomization blocks performed by the Department of Clinical investigation.

Allocation concealment (selection bias)Unclear riskEach caretaker received a sealed envelope containing their randomization sequence. No mention of the envelope being opaque.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParents and investigators remained blinded to the regimen each child had received. Pharmacist was unblinded, but did not assess patients.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskParents and investigators who measured temperature remained blinded to the regimen each child received.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll subjects were accounted for.

Loss to follow up: alternating group 0.5%, paracetamol 0.5%.

Selective reporting (reporting bias)Low riskAll assessed outcomes were reported.

Other biasLow risk

Nabulsi 2006

MethodsStudy design: randomized, double-blind and placebo-controlled clinical trial.

Study dates and duration: November 2002 to April 2005.

Method of temperature measurement: rectal. Each patient used the same thermometer for the whole duration of study (SureTemp 679, Welch Allyn).

Time points measured in study: baseline rectal temperature at T0 then at hours 4, 5, 6, 7, 8.


ParticipantsNumber: 70 randomized

Number of patients in each intervention: combined ibuprofen & paracetamol n=37, ibuprofen & placebo n=33.

Inclusion criteria: febrile inpatients aged 6 months – 14 years, with rectal temp ≥ 38.8 °C.

Exclusion criteria: vomiting, any medical or surgical condition that precluded oral drug administration, acute or chronic hepatic disease, malabsorption syndromes, acute or chronic renal disease with the exception of UTI, chronic metabolic disease, bleeding disorders, asthma, chronic neurological disease that may affect central thermoregulation, cancer, immune suppression, sepsis, critical medical status or known allergy to paracetamol or ibuprofen.

Baseline characteristics:

  • Age, mean years (SD): combined ibuprofen & paracetamol 3.7 (3.3), ibuprofen & placebo 3.6 (2.9)
  • Sex, male gender, n(%): combined ibuprofen & paracetamol 26 (70.3), Ibuprofen & placebo 19 (57.6)
  • Diagnoses: viral 62.9%, bacteria 27.1%, other 10%.


InterventionsControl: ibuprofen 10 mg/kg followed by placebo 4 hours later

Treatment group: single oral dose ibuprofen 10 mg/kg followed by single oral dose paracetamol 15 mg/kg 4 hours later  


OutcomesPrimary:

  1. Proportion of children with normal body temperature at 6 hours (normal = rectal temp 36.5 °C to 37.9 °C)


Secondary:

  1. Proportions of afebrile children in each group at 7 and 8 hours from baseline
  2. Maximum decline in temperature during study period
  3. Time to recurrence of fever
  4. Mean temp changes from baseline at t= 4, 5, 6, 7 and 8h
  5. The proportion of patients in each group with any adverse effect that may be related to either drug such as hypothermia, chilliness or gastrointestinal bleeding


NotesLocation: Lebanon

Setting: multi-centre. This study was conducted in the paediatric inpatient services of two hospitals in Beirut: the American University of Beirut Medical Centre (AUBMC), which is a tertiary care facility; and Najjar Hospital, a secondary care facility.

Funding: this study was funded by the Medical Practice Plan of the Faculty of Medicine at the American University of Beirut, Grant number 686056. Gulf Pharmaceutical Industries, United Arab Emirates, donated all the drugs investigated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskChildren enrolled in the study were assigned a random number by the hospital pharmacist according to a computer-generated random-number list, which was kept with the pharmacist until the end of the study.

Allocation concealment (selection bias)Low riskThe allocation sequence was generated by one of the co-investigators who was not involved in subject recruitment, drug administration or outcome assessment.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSubjects, parents and research assistant were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNurses responsible for drug administration and outcome assessment, treating physicians were blinded to patients' assignment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntent-to-treat analysis was planned.

Loss to follow up: combined group 3%, ibuprofen group 0%.

Selective reporting (reporting bias)Low riskAll assessed outcomes were reported.

Other biasUnclear riskForced to stop the trial before achieving the calculated sample size.

Paul 2010

MethodsStudy design: three-arm, randomized, controlled trial.

Study dates and duration: March 2006 to July 2009.

Method of temperature measurement: temporal artery thermometer.

Time points measured in study: hourly for 6 hours.


ParticipantsNumber: 46 patients; among the 46 patients, 8 participated twice, 3 participated 3 times and 35 participated only once, contributing to 60 febrile episodes that were randomly assigned into the 3 treatment groups.

Number of patients in each intervention: 20 episodes per group.

Inclusion criteria: 6 months - 8 years with temperature ≥38 °C. Required to demonstrate an ability to cooperate with serial temporal artery temperature measurements and to take medications by mouth

Exclusion criteria: Received paracetamol within 6 hours of presentation or ibuprofen, aspirin or other NSAIDs within 8 hours of presentation. Other major exclusions included weight > 60kg (to avoid surpassing 600 mg of ibuprofen or 1000 mg of paracetamol in a single dose), a history of adverse reaction to any study medication ingredient, diabetes mellitus, renal dysfunction, hepatic dysfunction, thrombocytopenia, or presence of moderate or severe dehydration. Children were also excluded if medical judgement determined that the severity of the underlying illness prohibited inclusion or if the child had already participated in the trial on 3 previous occasions.

Baseline characteristics:

  • Age: n=46 (60 febrile episodes in 46 children). Aged 6 months to 8 years. Mean (SD) age = 3.4 (2.2) years
  • Sex: 31/60 (51.7%) were girls
  • Diagnoses: most common presenting diagnoses were upper respiratory infection (n=27), fever without a source (n=12), acute otitis media (n=8).


InterventionsTreatment group A: single dose ibuprofen 10 mg/kg (oral suspension 100 mg/5 mL)

Treatment group B: single dose APAP 15 mg/kg (oral solution USP 160 mg/5 mL) plus ibuprofen 10 mg/kg

Treatment group C: ibuprofen 10 mg/kg at the beginning of the study followed by 15 mg/kg of APAP 3 hours later


OutcomesPrimary:

  1. Effect of treatment on temperature over 6 hours


NotesLocation: USA

Setting: one academic medical centre in Hershey, Pennsylvania, USA; patients recruited from outpatient clinics and child day-care facilities.

Funding: this study was supported by a research grant from the George L. Laverty Foundation and in part by a General clinical Research Centre grant from the National Institutes of Health and a CGRC Construction Grant awarded to the Pennsylvania State University College of Medicine.

Disclosure: first author has been a paid consultant for the Consumer Healthcare Products Association, McNeil Consumer Healthcare, Novartis Consumer Health, Inc., Procter & Gamble, and Reckitt Benckiser Healthcare International Ltd., but no industry employees were involved in any aspect of the study.

11 patients participated ≥ 2 times (maximum 3 times).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskEach child was randomly assigned to 1 of 3 treatment groups according to a computer-generated log.

Allocation concealment (selection bias)Unclear riskNot specified.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo attempt was made to blind the participants, however temperature is an objective measurement that should not be subject to bias from lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo attempt was made to blind the research nurses, however temperature is an objective measurement that should not be subject to bias from lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of participants during the study.

Selective reporting (reporting bias)Low riskAll assessed outcomes were reported.

Other biasLow risk

Sarrell 2006

MethodsStudy design: randomized, double-blind, parallel-group trial.

Study dates and duration: September 2003 to March 2004.

Method of temperature measurement: rectal glass and mercury thermometer.

Time points measured in study: daily temperature diary (parents asked to measure rectal temp at least 3 times daily during tx then once daily x 10 days), telephone interview at 24 hours and 48 hours, office visit day 3, 5, 10, and 14 day follow up evaluation.


ParticipantsNumber: 480

Number of patients in each intervention: 160 in each of the 3 groups.

Inclusion criteria: all consecutive children aged 6 - 36 months who had rectal temperature ≥38.4 °C.

Exclusion criteria: not attending daycare centers, had taken temperature-altering drugs or antibiotics within 10 days before presentation, known abnormal liver or renal laboratory values, medical history of renal or hepatic impairment, gastrointestinal bleeding, known allergy to any antipyretic, congenital or acquired immunodeficiency, Reye syndrome, asthma, bronchiolitis or malignancy, and children whose caregivers were unable to apply the NCCPC to measure stress.

Baseline characteristics:

  • Age months (SD): paracetamol 18.6 (8.72), ibuprofen 19.5 (9.09), paracetamol plus ibuprofen 19.3 (9.29)
  • Sex male (%): paracetamol 71 (46%), ibuprofen 73 (40%), paracetamol plus ibuprofen 62 (38%)
  • Diagnoses: Paracetamol n(%)              Ibuprofen n(%)                Paracetamol plus Ibuprofen n(%)


URI                    66(43)                81(52)                    80(51)

AOM                 16(10)                 13(8)                       17(11)

Pharyngitis         10(7)                  7(5)                           3(2)

Bronchiolitis       8(5)                    7(5)                           9(6)

Gastroenteritis    7(5)                    7(5)                           6(4)

Viral illness        47(30)               40(25)                      40(26)


InterventionsGroup1: paracetamol (12.5 mg/kg) q6h, max 50 mg/kg/day); half of the group received initial loading with paracetamol (25 mg/kg) and the other half received initial loading with ibuprofen (10 mg/kg)

Group 2: ibuprofen (5 mg/kg) q8h, max 20 mg/kg/day; half of the group received initial loading with paracetamol (25 mg/kg) and the other half received initial loading with ibuprofen (10 mg/kg)

Group 3: paracetamol (12.5 mg/kg/dose, max 50 mg/kg/d) alternating with ibuprofen (5 mg/kg/dose, max 20 mg/kg/d) q4h; half of the group received initial loading with paracetamol (25 mg/kg) and the other half received loading with ibuprofen (10 mg/kg)


OutcomesPrimary:

  1. Body temperature
  2. Stress score
  3. Amount of antipyretic used at the 3 day time point (number of doses)


Secondary:

  1. Total days that a primary caretaker had to stay home from work because the infant could not attend daycare because of illness
  2. Recurrence of fever (≥37.8 °C) within 5 and 10 days after initiation of treatment
  3. Number of emergency department visits within 10 days of enrolment
  4. Hepatic and renal function
  5. Appearance of gastrointestinal symptoms or bleeding


NotesLocation: Central Israel

Setting: multi-Centre; three primary paediatric community ambulatory centers.

Funding: None disclosed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computerized random number generator to stratify according to the center in blocks of 60 numbers so that each block comprised 20 patients randomly assigned to each treatment group, with 10 patients assigned to each loading medication."

Allocation concealment (selection bias)Low riskAdmitting nurse used a computerized random-number generator and handed the parent or guardian a sealed opaque folder holding 3 sealed envelopes: 1 containing an advice sheet explaining the physiology of fever and its nonpharmacologic management; 1 containing the prescription for the loading medication; and 1 containing the drug prescription.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParents were described as being blinded, but the differences in drug regimens and lack of placebos in the single agent arms suggest that blinding is unlikely.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All of the children were evaluated and followed up by the same physician (E.M.S.), who was blinded to the group allocations (as were the parents or guardians)."

Incomplete outcome data (attrition bias)
All outcomes
Low riskA total of 480 infants met the eligibility criteria, of whom 464 (96.7%) completed the study. Of the 16 infants (3.3%) who withdrew from the study, 7 (1.5%) failed to return for follow-up visits within the first 10 days, and 9 (1.9%) did not return for laboratory evaluation after symptoms were alleviated.

Selective reporting (reporting bias)Unclear riskNo significant differences found with different loading medications, so patients were grouped according to maintenance medication. Data for outcomes from different loading medication groups were not reported.

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Del Vecchio 2001Letter

Diez Domingo 2001Physician survey

Drucker 2009Comment on PITCH trial

Lal 2000No mean temperature or proportion afebrile data published, despite being measured. Thus, study was at high risk for selective outcome reporting bias. Author was contacted and did not have access to original data. No quality of life indices examined.

Malik 2007Review article

Mayoral 2000Survey

Miller 2007Discussion

Nabulsi 2010Systematic review

Pashapour 2009Comparison not relevant to this review

Pereira 2012Systematic review

Purssell 2011Systematic review

Ruiz Lazaro 2009Review of PITCH trial

Uhl 2008Review article

 
Comparison 1. Combined versus single agent

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean temperature (°C)3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Hour 1
2163Mean Difference (IV, Fixed, 95% CI)-0.27 [-0.45, -0.08]

    1.2 Hour 4
2173Mean Difference (IV, Fixed, 95% CI)-0.70 [-1.05, -0.35]

    1.3 Hour 6
140Mean Difference (IV, Fixed, 95% CI)-1.30 [-2.01, -0.59]

 2 Proportion remaining febrile2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Hour 1
140Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.43]

    2.2 Hour 4
2196Risk Ratio (M-H, Random, 95% CI)0.08 [0.02, 0.42]

    2.3 Hour 6
140Risk Ratio (M-H, Random, 95% CI)0.10 [0.01, 0.71]

 
Comparison 2. Alternating versus single agent

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Non-communicating Children's Pain Checklist (NCCPC) score11857Mean Difference (IV, Random, 95% CI)-3.24 [-3.82, -2.67]

    1.1 Day 1
1619Mean Difference (IV, Random, 95% CI)-2.36 [-2.76, -1.96]

    1.2 Day 2
1619Mean Difference (IV, Random, 95% CI)-3.76 [-4.18, -3.34]

    1.3 Day 3
1619Mean Difference (IV, Random, 95% CI)-3.64 [-4.08, -3.20]

 2 Absent from daycare, days1619Mean Difference (IV, Fixed, 95% CI)-0.85 [-0.95, -0.75]

 3 Doses of medication per child12166Mean Difference (IV, Random, 95% CI)-1.29 [-1.69, -0.88]

    3.1 Day 1
1619Mean Difference (IV, Random, 95% CI)-1.09 [-2.40, 0.22]

    3.2 Day 2
1619Mean Difference (IV, Random, 95% CI)-1.39 [-2.29, -0.49]

    3.3 Day 3
1928Mean Difference (IV, Random, 95% CI)-1.39 [-1.48, -1.30]

 4 Mean temperature (°C)2Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Hour 1
140Mean Difference (IV, Random, 95% CI)0.0 [-0.28, 0.28]

    4.2 Hour 4
278Mean Difference (IV, Random, 95% CI)-0.60 [-0.94, -0.26]

    4.3 Hour 6
140Mean Difference (IV, Random, 95% CI)-1.60 [-2.27, -0.93]

 5 Proportion remaining febrile2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Hour 1
140Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.29, 3.45]

    5.2 Hour 4
140Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.00, 1.28]

    5.3 Hour 6
2109Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.11, 0.55]

 
Comparison 3. Combined versus alternating therapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Temperature (°C)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Hour 1
140Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.48, 0.08]

    1.2 Hour 4
140Mean Difference (IV, Fixed, 95% CI)0.0 [-0.19, 0.19]

    1.3 Hour 6
140Mean Difference (IV, Fixed, 95% CI)0.30 [0.01, 0.59]

 2 Proportion Febrile1120Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.21, 2.91]

    2.1 Hour 1
140Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.10, 2.43]

    2.2 Hour 4
140Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Hour 6
140Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 69.52]

 
Table 1. Dosing regimens and timing

Study IDTime after administration (hours)


012345678

Erlewyn-Lajeunesse 2006P (15 mg/kg)

I (5 mg/kg)

P (15 mg/kg) + I (5 mg/kg)

Hay 2008P (15 mg/kg)P

I (10 mg/kg)I

P (15 mg/kg) + I (10 mg/kg)PI

Kramer 2008P (15 mg/kg)P

P (15 mg/kg)I (10 mg/kg)

Nabulsi 2006I (10 mg/kg)

I (10 mg/kg)P (15 mg/kg)

Paul 2010I (10 mg/kg)

I (10 mg/kg)P

I (10 mg/kg) + P (15 mg/kg)

Sarrell 20061P or IP

P or II

P or IPI

 Ⓣ = Temperature reported; P = paracetamol; I = ibuprofen
1 Sarrell 2006 asked caretakers to record rectal temperatures three times per day.
 
Table 2. Summary of findings: Alternating versus single agent for fever in children

Alternating versus single agent for fever in children

Patient or population: children with fever
Intervention: alternating versus single agent

OutcomesTimepointIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Single agentAlternating regimen

NCCPC score
Standardized stress score for non-verbal children.

A score of 7 or more indicates pain.
Day 1The mean NCCPC score in the control group was
11.38
The mean NCCPC score in the intervention groups was
2.01 lower
(2.58 to 1.44 lower)
-309
(1 study)
⊕⊕⊝⊝
low1,2

Day 2The mean NCCPC score in the control group was
8.85
The mean NCCPC score in the intervention groups was
3.76 lower
(4.27 to 3.25 lower)
-475
(1 study)
⊕⊕⊝⊝
low1,2

Day 3The mean NCCPC score in the control group was
7.81
The mean NCCPC score in the intervention groups was
3.63 lower
(4.17 to 3.09 lower)
-464
(1 study)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

 1 Downgraded by 2 for risk of bias: in this study mothers collected the data on NCCPC scores and were unblinded to allocation. In addition, in this study the mean number of doses of medication was actually lower in the group allocated to alternating treatment. The reasons for this are unclear as logically they should receive more doses.
 
Table 3. Summary of findings: Alternating versus single agent for fever in children

Alternating versus single agent for fever in children

Patient or population: children with fever
Intervention: alternating versus single agent

OutcomesTimepointIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Single agentAlternating regimen

Mean Temperature1 hourThe mean temperature in the control group was
37.6 °C
The mean temperature in the intervention groups was
0 °C higher
(0.28 °C lower to 0.28 °C higher)
-40
(1 study)
⊕⊝⊝⊝
very low1,2,3,4
Children in the alternating regimen group received a second dose of antipyretic at 3-4 hours

4 hoursThe mean temperature in the control groups ranged from
37.5 °C to 38.0 °C
The mean temperature in the intervention groups was
0.60 °C lower
(0.94 °C to 0.26 °C lower)
-78
(2 studies)
⊕⊕⊝⊝
low5,6,7

6 hoursThe mean temperature in the control group was
38.5 °C
The mean temperature in the intervention groups was
1.60°C lower
(2.27 °C to 0.93 °C lower)
-40
(1 study)
⊕⊝⊝⊝
very low1,3,4

Proportion febrile1 hour20 per 10020 per 100
(6 to 69)
RR 1
(0.29 to 3.45)
40
(1 study)
⊕⊝⊝⊝
very low1,2,3,4
Children in the alternating regimen group received a second dose of antipyretic at 3-4 hours

4 hours30 per 1002 per 100
(0 to 39)
RR 0.08
(0.00 to 1.29)
40
(1 study)
⊕⊝⊝⊝
very low1,3,4

6 hours45 per 10011 per 100
(5 to 25)
RR 0.25
(0.11 to 0.55)
109
(2 studies)
⊕⊕⊝⊝
low8,6,7

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

 1 This single study compared a single dose of ibuprofen with ibuprofen plus paracetamol 3 hours later.
2 At this time point both treatment arms had received the same medication so differences would not be expected.
3 Downgraded by 1 for risk of bias: this study was at unclear risk of selection bias as allocation concealment was not described.
4 Downgraded by 2 for very serious imprecision due to the very small sample size.
5 Paul 2010 compared ibuprofen at baseline plus paracetamol at 3 hours in the intervention group. Kramer 2008 compared paracetamol at baseline plus ibuprofen at 3 hours in the intervention group.
6 Downgraded by 1 for serious risk of bias: both studies are at unclear risk of selection bias as allocation concealment was not described.
7 Downgraded by 1 for imprecision due to the small sample size.
8 Paul 2010 compared ibuprofen at baseline plus paracetamol at 3 hours in the intervention group. Nabulsi 2006 compared ibuprofen at baseline plus paracetamol at 4 hours in the intervention group.
 
Table 4. Summary of findings: Combined versus single agent for fever in children

Combined versus single agent for fever in children

Patient or population: children with fever
Intervention: combined ibuprofen and paracetamol at baseline

Control: a single agent alone at baseline

OutcomesTimepointIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Single agentCombined regimen

Mean Temperature1 hourThe mean temperature in the control groups ranged from
37.6 °C to 37.9 °C
The mean temperature in the intervention groups was
0.27 °C lower
(0.45 °C to 0.08 °C lower)
-163
(2 studies)
⊕⊝⊝⊝

moderate

1,2,3

4 hoursThe mean temperature in the control groups ranged from
36.5 °C to 37.5 °C
The mean temperature in the intervention groups was
0.7 °C lower
(1.05 °C to 0.35 °C lower)
-173
(2 studies)
⊕⊝⊝⊝

moderate

4,2,3

6 hoursThe mean temperature in the control group was
38.5 °C
The mean temperature in the intervention groups was
1.30 °C lower
(2.01 °C to 0.59 °C lower)
-40
(1 study)
⊕⊝⊝⊝
very low5,6,7

Proportion Febrile 1 hour20 per 10010 per 100
(2 to 49)
RR 0.5
(0.1 to 2.43)
40
(1 study)
⊕⊝⊝⊝
very low5,6,7

4 hours23 per 1002 per 100
(1 to 10)
RR 0.08
(0.02 to 0.43)
196
(2 studies)
⊕⊝⊝⊝

moderate

4,2,3

6 hours50 per 1005 per 100
(1 to 35)
RR 0.10
(0.01 to 0.71)
40 participants
(1 study)
⊕⊝⊝⊝
very low5,6,7

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 These two studies compared ibuprofen plus paracetamol at baseline with ibuprofen alone (Paul 2010) or ibuprofen or paracetamol alone (Erlewyn-Lajeunesse 2006).
2 No serious indirectness: these studies were conducted in the UK and the USA in children with mild febrile illness. The studies excluded children with signs of severe illness or contra-indications to the study drugs.
3 Downgraded by 1 for imprecision due to the small sample size of the studies.
4 These two studies compared ibuprofen plus paracetamol at baseline with ibuprofen alone (Paul 2010 and Hay 2008).
5 This single study was conducted in the USA and compared ibuprofen plus paracetamol at baseline with ibuprofen alone (Paul 2010).
6 Downgraded by 1 for risk of selection bias as allocation concealment was not described.
7 Downgraded by 2 for very serious imprecision: only one very small study.
 
Table 5. Summary of findings: Combined versus alternating therapy for fever in children

Combined versus alternating therapy for fever in children

Patient or population: children with fever
Intervention: alternating versus combined therapy

OutcomesTimepointIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Alternating therapyCombinedtherapy

Mean Temperature 1 hourThe mean temperature in the control group was
37.6 °C
The mean temperature in the intervention groups was
0.2 °C lower
(0.48 °C lower to 0.08 °C higher)
-40
(1 study)
⊕⊝⊝⊝
very low1,2,3

4 hoursThe mean temperature in the control group was
36.9 °C
The mean temperature in the intervention groups was
0 °C higher
(0.19 °C lower to 0.19 °C higher)
-40
(1 study)
⊕⊝⊝⊝
very low1,2,3

6 hoursThe mean temperature in the control group was
36.9 °C
The mean temperature in the intervention groups was
0.3 °C higher
(0.01 °C to 0.59 °C higher)
-40
(1 study)
⊕⊝⊝⊝
very low1,2,3

Proportion Febrile 1 hour200 per 1000100 per 1000
(20 to 486)
RR 0.5
(0.1 to 2.43)
40
(1 study)
⊕⊝⊝⊝
very low1,2,3

4 hours--Not estimable40
(1 study)
⊕⊝⊝⊝
very low1,2,3

6 hours0 per 10000 per 1000
(0 to 0)
RR 3
(0.13 to 69.52)
40
(1 study)
⊕⊝⊝⊝
very low1,2,3

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

 1 This single study was conducted in the USA.
2 Downgraded by 1 for risk of bias: this study was at unclear risk of selection bias as allocation concealment was not described.
3 Downgraded by 2 for very serious imprecision due to the very small sample size.
 
Table 6. Adverse Effects

ComparisonStudiesN

 
Duration of follow upSerious adverse eventsComments

Combined versus single agentErlewyn-Lajeunesse 20061232 hoursNot reported 

Hay 20081565 daysFive serious AE occurred (Admission to hospital - reasons not reported) with no difference between groupsNon-severe adverse events (mainly diarrhoea and vomiting) were evenly distributed between groups2

Paul 2010466 hoursNot reported 

Alternating versus single agent

 
Paul 2010466 hoursNot reported

Kramer 2008

 
406 hours

 
None observed

 
Non-severe adverse effects reported in 8/38 (21%) of patients with no difference between groups1

 

 

Nabulsi 2009

 
708 hoursNone observedRectal temperature < 36.5 °C (range 35.0 °C to 36.2 °C)

5 (13.9%) combined group

6 (18.2%) ibuprofen group

 

Sarrell 200648014 daysNone observedMild elevated liver enzymes, n=8, mild abnormal renal function, n=14, all normalized by 14 day follow up

Alternating versus combined therapyPaul 2010466 hoursNot reported 

 1 Non-severe AE stated as: diarrhoea, flatulence, emesis, decreased appetite, epigastric pain, nausea, headache, insomnia. Symptoms did not prevent any patients from taking study medications.