Adjunctive Mechanical Ventilation or Intravenous Hypertonic Saline in Malawian Children with Cerebral Malaria and Highly Increased Brain Volume: A Randomized, Phase 3 Clinical Trial.

BACKGROUND

Cerebral malaria (CM) impacts hundreds of thousands of African children and causes significant morbidity and mortality. Beyond supportive care and antimalarials, treatments that improve outcomes have not been identified.

METHODS

We conducted a randomized, open-label, phase 3 clinical trial in Blantyre, Malawi (2018-2023). Children aged 6 months to 12 years with CM (Blantyre Coma Score ≤ 2, Plasmodium falciparum parasitemia, and no alternative coma etiology) underwent magnetic resonance imaging (MRI) screening. Participants with severe brain swelling [brain volume score (BVS) 6-8] were randomized to early intubation and mechanical ventilation, 3% hypertonic saline (HTS), or usual care. The primary outcome was 7-day mortality. Secondary outcomes included neurologic morbidity in survivors, serious adverse events, and changes in transcranial Doppler (TCD)-measured cerebral blood flow velocities (CBFVs).

RESULTS

Of 206 children screened with MRI, 57 met criteria for randomization (23 mechanical ventilation, 17 HTS, and 17 usual care). Neither mechanical ventilation nor HTS reduced 7-day mortality compared with usual care (risk difference - 0.075, 95% CI - 0.27 to 0.17, p = 0.59 for ventilation; 0.002, 95% CI - 0.22 to 0.28, p = 1.0 for HTS). Neurologic morbidity at hospital discharge did not differ between intervention groups and controls. HTS administration resulted in rapid and sustained increases in CBFVs in all major cerebral vessels. Among children with baseline cerebral hyperemia, those treated with HTS had significantly worse outcomes (combined neurologic morbidity or death) than hyperemic children receiving usual care (relative risk 3.0, 95% CI 1.02 to 10.9, p = 0.04).

CONCLUSIONS

In children with CM and severe brain swelling, adjunctive early mechanical ventilation or hypertonic saline does not improve survival or neurologic outcomes. Hypertonic saline increases cerebral blood flow and is associated with harm in children with baseline cerebral hyperemia. These findings demonstrate that non-phenotype-guided neuroprotective strategies are ineffective in CM and highlight the need for cerebrovascular endotype-informed therapeutic approaches.