Combined and alternating paracetamol and ibuprofen therapy for febrile children

Tiffany Wong; Antonia S Stang; Heather Ganshorn; Lisa Hartling; Ian K Maconochie; Anna M Thomsen; David W Johnson

doi:10.1002/14651858.CD009572.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Combined versus single agent, Outcome 1 Mean temperature (°C).

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Analysis 1.2

Comparison 1 Combined versus single agent, Outcome 2 Proportion remaining febrile.

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Analysis 2.1

Comparison 2 Alternating versus single agent, Outcome 1 Non‐communicating Children's Pain Checklist (NCCPC) score.

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Analysis 2.2

Comparison 2 Alternating versus single agent, Outcome 2 Absent from daycare, days.

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Analysis 2.3

Comparison 2 Alternating versus single agent, Outcome 3 Doses of medication per child.

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Analysis 2.4

Comparison 2 Alternating versus single agent, Outcome 4 Mean temperature (°C).

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Analysis 2.5

Comparison 2 Alternating versus single agent, Outcome 5 Proportion remaining febrile.

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Analysis 3.1

Comparison 3 Combined versus alternating therapy, Outcome 1 Temperature (°C).

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Analysis 3.2

Comparison 3 Combined versus alternating therapy, Outcome 2 Proportion Febrile.

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Table 1. Dosing regimens and timing

Study ID	Time after administration (hours)
Study ID	0	1	2	3	4	5	6	7	8
Erlewyn‐Lajeunesse 2006	P (15 mg/kg)	Ⓣ	Ⓣ
	I (5 mg/kg)	Ⓣ	Ⓣ
	P (15 mg/kg) + I (5 mg/kg)	Ⓣ	Ⓣ
Hay 2008	P (15 mg/kg)		Ⓣ		Ⓣ P		Ⓣ		Ⓣ
	I (10 mg/kg)		Ⓣ		Ⓣ		Ⓣ I		Ⓣ
	P (15 mg/kg) + I (10 mg/kg)		Ⓣ		Ⓣ P		Ⓣ I		Ⓣ
Kramer 2008	P (15 mg/kg)			Ⓣ	Ⓣ P	Ⓣ	Ⓣ
Kramer 2008	P (15 mg/kg)			Ⓣ I (10 mg/kg)	Ⓣ	Ⓣ	Ⓣ
Nabulsi 2006	I (10 mg/kg)				Ⓣ	Ⓣ	Ⓣ	Ⓣ	Ⓣ
Nabulsi 2006	I (10 mg/kg)				Ⓣ P (15 mg/kg)	Ⓣ	Ⓣ	Ⓣ	Ⓣ
Paul 2010	I (10 mg/kg)	Ⓣ	Ⓣ	Ⓣ	Ⓣ	Ⓣ	Ⓣ
	I (10 mg/kg)	Ⓣ	Ⓣ	Ⓣ P	Ⓣ	Ⓣ	Ⓣ
	I (10 mg/kg) + P (15 mg/kg)	Ⓣ	Ⓣ	Ⓣ	Ⓣ	Ⓣ	Ⓣ
Sarrell 2006¹	P or I						P
	P or I								I
	P or I				P				I
Ⓣ = Temperature reported; P = paracetamol; I = ibuprofen ¹Sarrell 2006 asked caretakers to record rectal temperatures three times per day.

Table 1. Dosing regimens and timing

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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
Outcomes	Timepoint	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Single agent	Alternating regimen
NCCPC score Standardized stress score for non‐verbal children. A score of 7 or more indicates pain.	Day 1	The 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)	⊕⊕⊝⊝ low^1,2
	Day 2	The 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)	⊕⊕⊝⊝ low^1,2
	Day 3	The 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)	⊕⊕⊝⊝ low^1,2
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 2. Summary of findings: Alternating versus single agent for fever in children

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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
Outcomes	Timepoint	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Single agent	Alternating regimen
Mean Temperature	1 hour	The 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 low^1,2,3,4	Children in the alternating regimen group received a second dose of antipyretic at 3‐4 hours
	4 hours	The 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)	⊕⊕⊝⊝ low^5,6,7
	6 hours	The 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 low^1,3,4
Proportion febrile	1 hour	20 per 100	20 per 100 (6 to 69)	RR 1 (0.29 to 3.45)	40 (1 study)	⊕⊝⊝⊝ very low^1,2,3,4	Children in the alternating regimen group received a second dose of antipyretic at 3‐4 hours
	4 hours	30 per 100	2 per 100 (0 to 39)	RR 0.08 (0.00 to 1.29)	40 (1 study)	⊕⊝⊝⊝ very low^1,3,4
	6 hours	45 per 100	11 per 100 (5 to 25)	RR 0.25 (0.11 to 0.55)	109 (2 studies)	⊕⊕⊝⊝ low^8,6,7
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. ⁵Paul 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. ⁸Paul 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 3. Summary of findings: Alternating versus single agent for fever in children

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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
Outcomes	Timepoint	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Single agent	Combined regimen
Mean Temperature	1 hour	The 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 hours	The 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 hours	The 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 low^5,6,7
Proportion Febrile	1 hour	20 per 100	10 per 100 (2 to 49)	RR 0.5 (0.1 to 2.43)	40 (1 study)	⊕⊝⊝⊝ very low^5,6,7
	4 hours	23 per 100	2 per 100 (1 to 10)	RR 0.08 (0.02 to 0.43)	196 (2 studies)	⊕⊝⊝⊝ moderate ^4,2,3
	6 hours	50 per 100	5 per 100 (1 to 35)	RR 0.10 (0.01 to 0.71)	40 participants (1 study)	⊕⊝⊝⊝ very low^5,6,7
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 4. Summary of findings: Combined versus single agent for fever in children

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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
Outcomes	Timepoint	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Alternating therapy	Combinedtherapy
Mean Temperature	1 hour	The 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 low^1,2,3
	4 hours	The 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 low^1,2,3
	6 hours	The 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 low^1,2,3
Proportion Febrile	1 hour	200 per 1000	100 per 1000 (20 to 486)	RR 0.5 (0.1 to 2.43)	40 (1 study)	⊕⊝⊝⊝ very low^1,2,3
	4 hours	‐	‐	Not estimable	40 (1 study)	⊕⊝⊝⊝ very low^1,2,3
	6 hours	0 per 1000	0 per 1000 (0 to 0)	RR 3 (0.13 to 69.52)	40 (1 study)	⊕⊝⊝⊝ very low^1,2,3
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 5. Summary of findings: Combined versus alternating therapy for fever in children

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Table 6. Adverse Effects

Comparison	Studies	N	Duration of follow up	Serious adverse events	Comments
Combined versus single agent	Erlewyn‐Lajeunesse 2006	123	2 hours	Not reported
	Hay 2008	156	5 days	Five serious AE occurred (Admission to hospital ‐ reasons not reported) with no difference between groups	Non‐severe adverse events (mainly diarrhoea and vomiting) were evenly distributed between groups²
	Paul 2010	46	6 hours	Not reported
Alternating versus single agent	Paul 2010	46	6 hours	Not reported
	Kramer 2008	40	6 hours	None observed	Non‐severe adverse effects reported in 8/38 (21%) of patients with no difference between groups¹
	Nabulsi 2009	70	8 hours	None observed	Rectal temperature < 36.5 °C (range 35.0 °C to 36.2 °C) 5 (13.9%) combined group 6 (18.2%) ibuprofen group
	Sarrell 2006	480	14 days	None observed	Mild elevated liver enzymes, n=8, mild abnormal renal function, n=14, all normalized by 14 day follow up
Alternating versus combined therapy	Paul 2010	46	6 hours	Not 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.

Table 6. Adverse Effects

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Comparison 1. Combined versus single agent

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean temperature (°C) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Hour 1	2	163	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.45, ‐0.08]
1.2 Hour 4	2	173	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐1.05, ‐0.35]
1.3 Hour 6	1	40	Mean Difference (IV, Fixed, 95% CI)	‐1.30 [‐2.01, ‐0.59]
2 Proportion remaining febrile Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Hour 1	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.43]
2.2 Hour 4	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.02, 0.42]
2.3 Hour 6	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.01, 0.71]

Comparison 1. Combined versus single agent

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Comparison 2. Alternating versus single agent

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐communicating Children's Pain Checklist (NCCPC) score Show forest plot	1	1857	Mean Difference (IV, Random, 95% CI)	‐3.24 [‐3.82, ‐2.67]

1.1 Day 1	1	619	Mean Difference (IV, Random, 95% CI)	‐2.36 [‐2.76, ‐1.96]
1.2 Day 2	1	619	Mean Difference (IV, Random, 95% CI)	‐3.76 [‐4.18, ‐3.34]
1.3 Day 3	1	619	Mean Difference (IV, Random, 95% CI)	‐3.64 [‐4.08, ‐3.20]
2 Absent from daycare, days Show forest plot	1	619	Mean Difference (IV, Fixed, 95% CI)	‐0.85 [‐0.95, ‐0.75]

3 Doses of medication per child Show forest plot	1	2166	Mean Difference (IV, Random, 95% CI)	‐1.29 [‐1.69, ‐0.88]

3.1 Day 1	1	619	Mean Difference (IV, Random, 95% CI)	‐1.09 [‐2.40, 0.22]
3.2 Day 2	1	619	Mean Difference (IV, Random, 95% CI)	‐1.39 [‐2.29, ‐0.49]
3.3 Day 3	1	928	Mean Difference (IV, Random, 95% CI)	‐1.39 [‐1.48, ‐1.30]
4 Mean temperature (°C) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Hour 1	1	40	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.28, 0.28]
4.2 Hour 4	2	78	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.94, ‐0.26]
4.3 Hour 6	1	40	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐2.27, ‐0.93]
5 Proportion remaining febrile Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Hour 1	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.29, 3.45]
5.2 Hour 4	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.00, 1.28]
5.3 Hour 6	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.11, 0.55]

Comparison 2. Alternating versus single agent

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Comparison 3. Combined versus alternating therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Temperature (°C) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Hour 1	1	40	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.48, 0.08]
1.2 Hour 4	1	40	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.19, 0.19]
1.3 Hour 6	1	40	Mean Difference (IV, Fixed, 95% CI)	0.30 [0.01, 0.59]
2 Proportion Febrile Show forest plot	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.21, 2.91]

2.1 Hour 1	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.10, 2.43]
2.2 Hour 4	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Hour 6	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 69.52]

Comparison 3. Combined versus alternating therapy

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