Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial
Gretchen L Birbeck1,2,3, Karl B Seydel4,5, Suzanna Mwanza6
1Epilepsy Division, Department of Neurology, University of Rochester, Rochester, New York.
Insights
Aggressive antipyretic therapy using acetaminophen and ibuprofen reduced maximum temperature and seizures in children with central nervous system malaria. This approach improved outcomes without prolonging parasite clearance.
Area of Science:
- Pediatrics
- Infectious Diseases
- Neurology
Background:
- Central nervous system (CNS) malaria affects children, with a third developing long-term neurological sequelae.
- Higher maximum temperatures and seizures are identified risk factors for these sequelae.
Purpose of the Study:
- To compare aggressive antipyretic therapy (scheduled acetaminophen and ibuprofen) with usual care (acetaminophen alone) in children with CNS malaria.
- To evaluate the impact of aggressive fever reduction on temperature, seizures, and parasite clearance.
Main Methods:
- A randomized clinical trial involving children aged 2-11 years with CNS malaria in Zambia and Malawi.
- Participants received either aggressive antipyretic therapy for 72 hours or usual care.
- Primary outcome was maximum temperature (Tmax); secondary outcomes included seizures and parasite clearance.
Main Results:
- Aggressive antipyretic therapy significantly reduced Tmax (38.6°C vs 39.2°C) compared to usual care.
- Children receiving aggressive therapy had significantly lower odds of multiple or prolonged seizures (8% vs 27%).
- No significant difference in parasite clearance time was observed between groups.
Conclusions:
- Aggressive antipyretic therapy effectively lowers fever in children with CNS malaria to levels seen in non-neurologically impaired children.
- This therapeutic approach improves acute seizure outcomes without negatively impacting parasite clearance.
- Findings suggest a potential strategy to mitigate neurological sequelae in CNS malaria survivors.
Importance:
A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae.
Objective:
To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher.
Design, Setting, And Participants:
This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023.
Intervention:
The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher.
Main Outcomes And Measures:
The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance.
Results:
Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07).
Conclusions And Relevance:
This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03399318.
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