Acetaminophen + Ibuprofen for fever and seizure management in pediatric CNS malaria

In children (aged 2-11 years) with central nervous system malaria, preemptive treatment with a combination of two accessible and affordable oral antipyretics (Acetaminophen and Ibuprofen) decreases both fever and acute symptomatic seizures.

The study compared aggressive antipyretic therapy with scheduled Acetaminophen and Ibuprofen versus usual care with Acetaminophen alone for temperatures 38.5°C or higher for pediatric central nervous system (CNS) malaria.

At tertiary care centers, a randomized clinical trial was conducted, involving children diagnosed with CNS malaria, from 2019 to 2022, with data evaluation done from December 2022 to April 2023. Out of 553 patients screened, 226 (40.9%) were ineligible and 57 (10.3%) declined participation. This left 256 volunteers (128 per group), with a mean age of 4.3 (Standard deviation [SD] 2.1) years;  141 (55%) were male and 115 (45%) were female.

Regardless of clinical temperature, the aggressive antipyretic group was treated with Ibuprofen (10 mg/kg) in combination with Acetaminophen (30 mg/kg load, then 15 mg/kg) every 6 hours for 72 hours. For a fever of 38.5 °C or greater, the usual care group was given 15 mg/kg of Acetaminophen every 6 hours as required. The key endpoint was maximum temperature (Tmax) over 72 hours, the total follow-up duration. Secondary endpoints included seizures and parasite clearance.

The aggressive antipyretic group displayed a lower Tmax (difference, −0.62 °C; 95% confidence interval [CI], −0.82 to −0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures when compared to the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56), as shown in Table 1:

The study found no significant difference in parasite clearance time between the groups. However, serious adverse events emerged in 40 kids (15%), 25 (20%) in the usual care arm, and 12 kids (12%) in the aggressive antipyretic arm, including 13 fatalities. Raised levels of creatinine elicited medication withdrawal in 8 kids (6%) in the usual care arm and 13 kids (10%) in the aggressive antipyretic arm (OR 1.74; 95% CI 0.63 to 5.07).

Compared with usual care (Acetaminophen alone for temperatures of 38.5°C or higher), aggressive antipyretic therapy decreased Tmax to levels similar to those observed in children with good neurological outcomes (without neurological impairments) in prior studies. Furthermore, it also led to improved acute seizure outcomes without prolonging parasitemia.