Acetaminophen, one of the routine medicines used for temperature reduction in febrile children, is available in multiple routes of administration, including oral and rectal routes. Our objective is to compare the antipyretic effectiveness of oral acetaminophen versus rectal acetaminophen in pediatric patients with fever in terms of temperature reduction.
Medline and Embase databases were searched from inception to August 2021. Cohort studies, case-control studies, experimental studies, and randomized controlled trial studies comparing oral and rectal administered acetaminophen in pediatric patients were included. Two reviewers independently extracted data.
A total of 5 randomized studies (n = 362) were included in the meta-analysis. No significant difference was found between oral and rectal acetaminophen in temperature reduction at 1 hour (weighted mean difference [WMD], 0.04°C; 95% confidence interval [CI], −0.10°C to 0.19°C; P = .501) or 3 hours (WMD, −0.14°C; 95% CI, −0.37°C to 0.10°C; P = .212) after administration (WMD, −0.14°C; 95% CI, −0.37°C to 0.10°C; P = .212).
Oral and rectal acetaminophen have no significant difference in antipyretic effectiveness at 1 and 3 hours after administration. If both options are available, oral acetaminophen would be preferred because of a more predictable drug level after administration. However, for febrile children with specific circumstances for whom oral acetaminophen could not be administered, rectal acetaminophen may be an alternative option for a short period of time (<48 hours).
Fever in children is one of the most common clinical symptoms managed by pediatricians and other health care providers. It is also a frequent cause of parental concern. Under normal circumstances, acetaminophen is one of the routine medicines used to relieve pain and reduce fever in children because its safety and efficacy are well established.1,2 Currently, acetaminophen is available in multiple routes of administration, including oral and rectal routes. According to the American Academy of Pediatrics’ suggestion, rectal acetaminophen therapy should be avoided because of possible toxicity because peak drug levels may vary and often do not achieve therapeutic targets after the recommended doses are administered.2 However, rectal suppository form is still necessary for treating febrile children with specific circumstances, for example, unconscious state, vomiting, or patients who were kept nil per os. The previous studies on antipyretic efficacies revealed conflicting results; 1 favored the use of oral acetaminophen, whereas others found no significant difference in the antipyretic effect between oral and rectal acetaminophen.3–8 In addition, from the search of literature up to August 2021, the only meta-analysis was published in November 2008 and included a total of 158 children and 83 adults in 4 studies.9 To the best of our knowledge, no meta-analysis with pediatric patients alone has been conducted. Thus, the aim of this study was to compare the antipyretic effectiveness of oral acetaminophen versus rectal acetaminophen in pediatric patients with fever in terms of temperature reduction.
Methods
Search Strategy
Two investigators (N.T. and S.T.) independently performed a systematic search of the Medline, and Embase databases from inception to August 2021 using a search strategy including the terms “acetaminophen,” “paracetamol,” “Tylenol,” “oral,” “rectal,” “fever,” “temperature,” “antipyretic,” and “pediatric,” as described in Supplemental Table 2.
Inclusion Criteria
The eligible criteria included the following:
Cohort studies (prospective or retrospective), case-control studies, experimental studies, or randomized controlled trials (RCTs) that compared the antipyretic effectiveness between oral and rectal routes among patients aged ≤18 years.
Relative risk, odds ratio, hazard ratio, incidence ratio with 95% confidence intervals (CI), or sufficient raw data to calculate effect size must be provided.
Exclusion Criteria
Reviews, letters, and studies on adults were excluded from the study.
Data Extraction and Quality Assessment Tool
Two authors (N.T. and S.T.) independently extracted the data from the included studies, with disputes resolved by consensus after discussion with a third author (A.T.). A revised Cochrane risk-of-bias tool (RoB2) was used to evaluate the quality of each randomized controlled trial by assessing a judgment (high, low, or unclear) for individual elements from 5 domains (randomization process, deviation from intended intervention, missing outcome data, measurement of the outcome, and selection of the reported result).
Outcomes
The primary outcome was the reduction in temperature at 1 hour and 3 hours after administration of acetaminophen.
Statistical Analysis
This meta-analysis was performed by using a random-effects model. The extracted studies were excluded from the analysis if they did not justify an outcome in each cohort. Weighted mean difference (WMD) was used to determine the difference in outcomes between the 2 groups. Q statistic and I2 statistic were used to assess evidence of heterogeneity.10 The I2 statistic ranges in value from 0% to 100% (I2 <25%, low heterogeneity; I2 =25% to 50%, moderate heterogeneity; and I2≥50%, substantial heterogeneity).11 Publication bias was assessed by using a funnel plot. Sensitivity analysis was performed by excluding 1 study at a time to assess the influence of individual studies on the overall meta-analysis, as described by Patsopoulos et al.10,12 All analyses were conducted by using Stata software (version 14 Stata Corp, College Station, TX, USA).
Results
Literature Search
The initial literature search identified 137 studies from the Medline and Embase databases. We excluded 50 studies because of duplication. We excluded 78 studies because they were not cohort studies, case-control studies, experimental trials, or RCTs, did not study the population of interest, or were the same author group with the same database. Nine studies were relevant for evaluation. Four studies were excluded because of reasons given in the PRISMA flow diagram in Fig 1. Therefore, 5 studies were included in this meta-analysis.
Description of Included Studies
A total of 5 randomized studies were included in this meta-analysis (Table 1), and included 289 patients aged 3 months to 12 years with fever who were managed in the hospital. Studies were done in Finland, the United Kingdom, Canada, Lebanon, and Iran. The oldest study included was published in 1977 and the most recent study included was published in 2017.
Included Studies
| Oral Acetaminophen | Rectal Acetaminophen | ||||||
|---|---|---|---|---|---|---|---|
| Source | Age | Inclusion Temperature | Design | Dose | No. of Subjects | Dose | No. of Subjects |
| Keinänen et al3 (1977) | 4mo to 12y | >38.5 (rectal) | Randomized | 10 mg/kg | 15 | 10 mg/kg | 15 |
| Vernon et al4 (1979) | 3mo to 2y | >38.5 (rectal) | Randomized | 15–20 mg/kg | 10 | 15–20 mg/kg | 12 |
| 2y to 6y | >38.5 (rectal) | 15–20 mg/kg | 8 | 15–20 mg/kg | 7 | ||
| Scolnik et al5 (2002) | 6mo to 6y | >39 (rectal) | Randomized, controlled | 15 mg/kg | 23 | 15 mg/kg | 24 |
| Karbasi et al6 (2010) | 6mo to 6y | >39 (rectal) | Randomized, double-blind, double dummy | 15 mg/kg | 26 | 15 mg/kg | 27 |
| Bastola et al7 (2017) | 6mo to 6y | >38 (axillary) | Randomized, controlled, prospective, interventional | 15 mg/kg | 63 | 15 mg/kg | 59 |
| Oral Acetaminophen | Rectal Acetaminophen | ||||||
|---|---|---|---|---|---|---|---|
| Source | Age | Inclusion Temperature | Design | Dose | No. of Subjects | Dose | No. of Subjects |
| Keinänen et al3 (1977) | 4mo to 12y | >38.5 (rectal) | Randomized | 10 mg/kg | 15 | 10 mg/kg | 15 |
| Vernon et al4 (1979) | 3mo to 2y | >38.5 (rectal) | Randomized | 15–20 mg/kg | 10 | 15–20 mg/kg | 12 |
| 2y to 6y | >38.5 (rectal) | 15–20 mg/kg | 8 | 15–20 mg/kg | 7 | ||
| Scolnik et al5 (2002) | 6mo to 6y | >39 (rectal) | Randomized, controlled | 15 mg/kg | 23 | 15 mg/kg | 24 |
| Karbasi et al6 (2010) | 6mo to 6y | >39 (rectal) | Randomized, double-blind, double dummy | 15 mg/kg | 26 | 15 mg/kg | 27 |
| Bastola et al7 (2017) | 6mo to 6y | >38 (axillary) | Randomized, controlled, prospective, interventional | 15 mg/kg | 63 | 15 mg/kg | 59 |
Quality Assessment Tool
The RoB2 tool, shown in Fig 2, was used for all RCTs included in the study. All studies did not clearly state that the assessors of the participants’ temperature were not aware of the participants' intervention.
Meta-analysis
Of the total 289 patients included in this study, 145 (50.17%) were given oral acetaminophen and 144 (49.83%) were given rectal acetaminophen. There was no crossover of the treatment groups. We analyzed the reduction in temperature at 1 hour and 3 hours after administration of acetaminophen.
There was no significant difference between oral and rectalacetaminophen in temperature reduction at 1 hour after administration (WMD, 0.04°C; 95% CI, −0.10°C to 0.19°C; P = .501) (Fig 3).
There was no significant difference between oral and rectal acetaminophen in temperature reduction at 3 hours after administration (WMD, −0.14°C; 95% CI, −0.37°C to 0.10°C; P = .212) (Fig 4).
Sensitivity Analysis
None of the studies included in the meta-analysis had a significant effect on heterogeneity or the weighted mean difference.
Publication Bias
Discussion
This study found no significant difference between oral and rectal acetaminophen in temperature reduction at 1 and 3 hours after administration.
At least 2 new studies6,7 have been produced since the last publication of meta-analysis on the effect of oral compared with rectal acetaminophen in pediatric patients with fever since a meta-analysis performed in 2008.8 The quality assessment of the included studies revealed high-quality data with only minor concern about the outcome assessors that were not blinded to the treatment group. However, most studies did clearly state that how to measure the temperature and the outcomes are objective data, which lessen concern for bias. This study chose the outcome of temperature reduction at 1 and 3 hours after acetaminophen administration for the reason that acetaminophen plasma concentrations usually peaked at 30 to 60 minutes after oral administration and 3 hours after rectal administration.15,16 The previous meta-analysis, which included the data analysis of both adults and children, revealed that the decrease in temperature at 1 hour after administration had no significant difference between rectal and oral administration (WMD, −0.14°C; 95% CI, −0.36°C to 0.08°C; P = .49). There was also no difference of the decline in temperature at 3 hours after administration of acetaminophen (WMD, −0.10°C; 95% CI, −0.41°C to 0.21°C; P = .84).9 In addition, this previous meta-analysis study had done the comparison of the maximum decline in temperature between rectal and oral administration, which also indicated no difference (WMD, −0.10°C; 95% CI, −0.24°C to 0.04°C; P > .99), and, apparently, there was no difference in the average time to a temperature reduction of 1°C (WMD, −0.06°C; 95% CI, −1.34°C to 1.23°C; P < .001).17 Unfortunately, these 2 new studies published did not touch on these issues.7,8
The major distinction between our study and the previous meta-analysis was the target population; whereas the latter was performed on adults and children, we focused solely on the pediatric population. The result from the current study revealed that there was no significant difference between the effectiveness of oral and rectal acetaminophen in terms of treating fever in pediatric patients. This was broadly in line with the primary recommendations of many previous studies and meta-analyses for the mode of delivery of acetaminophen to most pediatric patients with fever. Even so, we acknowledge some limitations in our study; the form of rectal suppository used was somehow different. According to the previous study, the dissolution of acetaminophen from lipophilic suppositories was longer than from hydrophilic suppositories.18 Keinänen et al3 used acetaminophen in a hydrophilic base suppository, which revealed that temperature reduction in 2 hours was significantly greater in oral compared with rectal acetaminophen whereas Vernon et al,4 Scolnik et al,5 and Karbasi et al6 used acetaminophen in a lipophilic base suppository, which revealed no difference in temperature reduction. Another limitation was that the toxicity effects were subject to the accumulation of acetaminophen after multiple rectal doses. As a result, they could not be reviewed because all studies were entirely on a single dose of rectal acetaminophen. However, a study done by Chen et al19 which was about the safety of rectal acetaminophen in neonates who received multiple doses of rectal acetaminophen for 24 hours or more, by assessing the changes in liver enzymes and serum creatinine, revealed that multiple doses of rectal acetaminophen over a short period (<48 hours) appeared to be well-tolerated by these populations. Although there was no study done on children in other age groups, it was known that neonates were the most sensitive group to acetaminophen toxicity, particularly after multiple doses.20 It could, therefore, be considered that for febrile children with specific circumstances, for example, unconscious state, vomiting, or patients who were kept nil per os, rectal acetaminophen would be an appropriate alternative to oral acetaminophen for a short period of time.
Finally, we recommend that additional studies with larger samples and standardized dose and form of acetaminophen, together with the study of toxic effects should be done.
Conclusions
Oral and rectal acetaminophen have no significant difference in antipyretic effectiveness at 1 and 3 hours after administration. If both options are available, oral acetaminophen would be preferred because of a more predictable drug level after administration. However, for febrile children with specific circumstances for whom oral acetaminophen could not be administered, rectal acetaminophen may be an alternative option for a short period of time.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.
Dr Tantivit determined the research question, designed the study, established criteria for inclusion and exclusion studies, searched relevant studies, selected studies on the basis of abstract review, selected studies on the basis of on full-text review, extracted information from studies, and drafted the initial manuscript; Dr Thangjui searched relevant studies, selected studies on the basis of full-text review, extracted information from studies, conducted statistical analysis, and reviewed and revised the manuscript; Dr Trongtorsak developed a search strategy for the identification of relevant studies, drafted the initial manuscript, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Comments