Aggressive Antipyretic Therapy Reduces Seizure Risk in Children with CNS Malaria: JAMA

Malaria with neurological involvement often results in long-term complications, with one-third of survivors developing sequelae. Higher maximum temperature (Tmax) and seizures are known risk factors for these outcomes. Effective management of fever in these children is crucial. This study aimed to evaluate whether aggressive antipyretic therapy could improve clinical outcomes compared to usual care.

The study was conducted from 2019 to 2022 across inpatient pediatric services at a tertiary care and a district hospital in Zambia, and a tertiary care center in Malawi. Children aged 2 to 11 years with CNS malaria, excluding those with creatinine levels above 1.2 mg/dL, were included. A total of 256 participants were randomized into two groups: aggressive antipyretic therapy (n=128) and usual care (n=128).

Aggressive Antipyretic Group: Received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen (10 mg/kg) every 6 hours for 72 hours, irrespective of their temperature.

Usual Care Group: Received 15 mg/kg of acetaminophen as needed every 6 hours for temperatures above 38.5°C.

The primary outcome was Tmax over 72 hours, with secondary outcomes including seizure frequency and parasite clearance times. Data analysis was conducted between December 2022 and April 2023.

• The aggressive antipyretic group showed a significantly lower Tmax of 38.6°C compared to 39.2°C in the usual care group (difference, -0.62°C; 95% CI, -0.82 to -0.42; P<.001).

• Additionally, the odds of experiencing multiple or prolonged seizures were markedly lower in the aggressive therapy group, with 10 children (8%) affected compared to 34 children (27%) in the usual care group (OR, 0.26; 95% CI, 0.12 to 0.56).

• Severe adverse events occurred in 40 children (15%), with 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] in usual care vs 3 [2%] in aggressive therapy).

• Increased creatinine led to discontinuation of the study drugs 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).

The aggressive antipyretic therapy not only lowered Tmax to levels comparable to children without neurological impairments in prior studies but also significantly reduced the risk of seizures without extending the duration of parasitemia. This finding highlights the potential benefits of a more proactive approach to fever management in children with CNS malaria.

Aggressive antipyretic therapy reduces the maximum temperature and the risk of multiple or prolonged seizures in children with CNS malaria. This approach offers a significant improvement in clinical outcomes, emphasizing the need for proactive fever management in this vulnerable population.

Reference:

Birbeck, G. L., Seydel, K. B., Mwanza, S., Tembo, D., Chilombe, M., Watts, A., Ume-Ezeoke, I., Mathews, M., Patel, A. A., Mwenechanya, M., Pensulo, P., & McDermott, M. P. (2024). Acetaminophen and ibuprofen in pediatric central nervous system malaria: A randomized clinical trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2024.1677