Abstract
BackgroundSevere malaria remains a major cause of childhood mortality globally. Decreased endothelial nitric oxide is associated with severe and fatal malaria. The hypothesis was that adjunctive inhaled nitric oxide (iNO) would improve outcomes in African children with severe malaria.MethodsA randomized, blinded, placebo-controlled trial of iNO at 80 ppm by non-rebreather mask versus room air placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. The primary outcome was the longitudinal course of angiopoietin-2 (Ang-2), an endothelial biomarker of malaria severity and clinical outcome.ResultsOne hundred and eighty children were enrolled; 88 were assigned to iNO and 92 to placebo (all received IV artesunate). Ang-2 levels measured over the first 72 h of hospitalization were not significantly different between groups. The mortality at 48 h was similar between groups [6/87 (6.9 %) in the iNO group vs 8/92 (8.7 %) in the placebo group; OR 0.78, 95 % CI 0.26–2.3; p = 0.65]. Clinical recovery times and parasite clearance kinetics were similar (p > 0.05). Methaemoglobinaemia >7 % occurred in 25 % of patients receiving iNO and resolved without sequelae. The incidence of neurologic deficits (<14 days), acute kidney injury, hypoglycaemia, anaemia, and haemoglobinuria was similar between groups (p > 0.05).ConclusionsiNO at 80 ppm administered by non-rebreather mask was safe but did not affect circulating levels of Ang-2. Alternative methods of enhancing endothelial NO bioavailability may be necessary to achieve a biological effect and improve clinical outcome.Trial Registration: ClinicalTrials.gov NCT01255215Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0946-2) contains supplementary material, which is available to authorized users.
Highlights
Severe malaria remains a major cause of childhood mortality globally
The primary objective was to determine if inhaled nitric oxide (iNO) at 80 ppm, relative to placebo room air, would improve endothelial function as determined by an accelerated rate of decline of Ang-2 in peripheral blood among African children with severe malaria receiving artesunate. Trial design This was a prospective, parallel arm, randomized, placebo-controlled, blinded trial of iNO versus placebo (1:1 ratio), among children with severe malaria, all of whom were treated with artesunate
Ten patients were positive for both histidine rich protein 2 (HRP2) and pLDH bands on screening rapid diagnostic test but negative on microscopy of the admission sample
Summary
Severe malaria remains a major cause of childhood mortality globally. Decreased endothelial nitric oxide is associated with severe and fatal malaria. The hypothesis was that adjunctive inhaled nitric oxide (iNO) would improve outcomes in African children with severe malaria. Severe malaria due to Plasmodium falciparum claims 0.6–1.2 million lives annually, 86 % of whom are children in sub-Saharan Africa [1, 2]. Despite the use of highly effective anti-malarial medications, 10–30 % patients with severe malaria will die [3], highlighting the need for new adjunctive therapy. NO regulates a broad range of physiologic and pathologic processes, including vasodilation, platelet aggregation, apoptosis, inflammation, chemotaxis, neurotransmission, antimicrobial defence, and endothelial activation [6]. The vascular endothelium plays a central role in the pathogenesis of severe malaria.
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