title: Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial.
abstract: Background.  Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods.  This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate. We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results.  Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels-blood methemoglobin and plasma nitrate-increased in patients treated with NO (both P < .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions.  Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours.
authors: Epicentre Mbarara Research Centre ; Mbarara University of Science and Technology , Uganda.
authors: Juliet
authors: J
authors: Mwanga-Amumpaire
authors: Department of Anesthesia, Critical Care, and Pain Medicine ; Center for Global Health ; Pediatric Critical Care Medicine , MassGen Hospital for Children , Boston, Massachusetts ; Harvard Medical School , Cambridge, Massachusetts.
authors: Ryan W
authors: RW
authors: Carroll
authors: Epicentre , Paris , France.
authors: Elisabeth
authors: E
authors: Baudin
authors: Epicentre Mbarara Research Centre.
authors: Elisabeth
authors: E
authors: Kemigisha
authors: Mbarara University of Science and Technology , Uganda.
authors: Dorah
authors: D
authors: Nampijja
authors: Epicentre Mbarara Research Centre.
authors: Kenneth
authors: K
authors: Mworozi
authors: Mbarara University of Science and Technology , Uganda.
authors: Data
authors: D
authors: Santorino
authors: Epicentre Mbarara Research Centre.
authors: Dan
authors: D
authors: Nyehangane
authors: Department of Anesthesia, Critical Care, and Pain Medicine.
authors: Daniel I
authors: DI
authors: Nathan
authors: UMI 233, Institut de Recherche Pour le Développement, Université Montpellier 1 , France.
authors: Pierre
authors: P
authors: De Beaudrap
authors: Epicentre , Paris , France ; UMI 233, Institut de Recherche Pour le Développement, Université Montpellier 1 , France.
authors: Jean-François
authors: JF
authors: Etard
authors: University of Southampton , United Kingdom.
authors: Martin
authors: M
authors: Feelisch
authors: University of Southampton , United Kingdom.
authors: Bernadette O
authors: BO
authors: Fernandez
authors: Ikaria , Clinton, New Jersey.
authors: Annie
authors: A
authors: Berssenbrugge
authors: Center for Global Health ; Harvard Medical School , Cambridge, Massachusetts.
authors: David
authors: D
authors: Bangsberg
authors: Department of Anesthesia, Critical Care, and Pain Medicine ; Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital.
authors: Kenneth D
authors: KD
authors: Bloch
authors: Epicentre Mbarara Research Centre ; Mbarara University of Science and Technology , Uganda.
authors: Yap
authors: Y
authors: Boum
authors: Department of Anesthesia, Critical Care, and Pain Medicine ; Harvard Medical School , Cambridge, Massachusetts.
authors: Warren M
authors: WM
authors: Zapol
keywords: Plasmodium falciparum; cerebral malaria; methemoglobin; nitric oxide