Inhaled nitric oxide as adjunctive therapy for severe malaria

a randomized controlled trial

Michael T. Hawkes, Andrea L. Conroy, Robert O. Opoka, Laura Hermann, Kevin E. Thorpe, Chloe McDonald, Hani Kim, Sarah Higgins, Sophie Namasopo, Chandy John, Chris Miller, W. Conrad Liles, Kevin C. Kain

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: 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. Methods: A 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. Results: One 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 ( 0.05). Conclusions: iNO 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 NCT01255215

Original languageEnglish (US)
Article number946
JournalMalaria Journal
Volume14
Issue number1
DOIs
StatePublished - Oct 29 2015

Fingerprint

Malaria
Nitric Oxide
Randomized Controlled Trials
Angiopoietin-2
Placebos
Masks
Therapeutics
Methemoglobinemia
Mortality
Neurologic Manifestations
Biological Availability
Parasites
Hospitalization
Biomarkers
Air
Incidence

Keywords

  • Child
  • Endothelium
  • Nitric oxide
  • Randomized controlled trial
  • Severe malaria

ASJC Scopus subject areas

  • Infectious Diseases
  • Parasitology

Cite this

Hawkes, M. T., Conroy, A. L., Opoka, R. O., Hermann, L., Thorpe, K. E., McDonald, C., ... Kain, K. C. (2015). Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. Malaria Journal, 14(1), [946]. https://doi.org/10.1186/s12936-015-0946-2

Inhaled nitric oxide as adjunctive therapy for severe malaria : a randomized controlled trial. / Hawkes, Michael T.; Conroy, Andrea L.; Opoka, Robert O.; Hermann, Laura; Thorpe, Kevin E.; McDonald, Chloe; Kim, Hani; Higgins, Sarah; Namasopo, Sophie; John, Chandy; Miller, Chris; Liles, W. Conrad; Kain, Kevin C.

In: Malaria Journal, Vol. 14, No. 1, 946, 29.10.2015.

Research output: Contribution to journalArticle

Hawkes, MT, Conroy, AL, Opoka, RO, Hermann, L, Thorpe, KE, McDonald, C, Kim, H, Higgins, S, Namasopo, S, John, C, Miller, C, Liles, WC & Kain, KC 2015, 'Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial', Malaria Journal, vol. 14, no. 1, 946. https://doi.org/10.1186/s12936-015-0946-2
Hawkes MT, Conroy AL, Opoka RO, Hermann L, Thorpe KE, McDonald C et al. Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. Malaria Journal. 2015 Oct 29;14(1). 946. https://doi.org/10.1186/s12936-015-0946-2
Hawkes, Michael T. ; Conroy, Andrea L. ; Opoka, Robert O. ; Hermann, Laura ; Thorpe, Kevin E. ; McDonald, Chloe ; Kim, Hani ; Higgins, Sarah ; Namasopo, Sophie ; John, Chandy ; Miller, Chris ; Liles, W. Conrad ; Kain, Kevin C. / Inhaled nitric oxide as adjunctive therapy for severe malaria : a randomized controlled trial. In: Malaria Journal. 2015 ; Vol. 14, No. 1.
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abstract = "Background: 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. Methods: A 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. Results: One 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 ( 0.05). Conclusions: iNO 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 NCT01255215",
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AU - Thorpe, Kevin E.

AU - McDonald, Chloe

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AU - Higgins, Sarah

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N2 - Background: 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. Methods: A 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. Results: One 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 ( 0.05). Conclusions: iNO 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 NCT01255215

AB - Background: 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. Methods: A 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. Results: One 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 ( 0.05). Conclusions: iNO 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 NCT01255215

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