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Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children: a phase II randomized open-label clinical trial

Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children: a phase II randomized open-label clinical trial
Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children: a phase II randomized open-label clinical trial
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-?, interferon-?, interleukin [IL]-1?, 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.
cerebral malaria, methemoglobin, nitric oxide, plasmodium falciparum
1-9
Mwanga-Amumpaire, Juliet
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Carroll, Ryan W.
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Baudin, Elisabeth
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Kemigisha, Elisabeth
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Nampijja, Dorah
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Mworozi, Kenneth
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Santorino, Data
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Nyehangane, Dan
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Nathan, Daniel I.
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De Beaudrap, Pierre
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Etard, Jean-François
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Feelisch, Martin
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Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Berssenbrugge, Annie
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Bangsberg, David
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Bloch, Kenneth D.
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Boum, Yap
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Zapol, Warren M.
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Mwanga-Amumpaire, Juliet
6cda067d-5796-4a59-aca9-ea3c26422eb6
Carroll, Ryan W.
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Baudin, Elisabeth
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Kemigisha, Elisabeth
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Nampijja, Dorah
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Mworozi, Kenneth
3cf042c9-70f1-4892-84d8-e3f5e592c7c0
Santorino, Data
20fc5e23-07f7-4a57-8d7c-71ac04a344d2
Nyehangane, Dan
eb74a151-a319-435e-81de-50e92c889492
Nathan, Daniel I.
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De Beaudrap, Pierre
edc96c1b-f034-4c49-be32-3b9c1d9fd59b
Etard, Jean-François
ac035d6e-795f-401a-8d61-c380b7d9ac07
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Fernandez, Bernadette O.
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Berssenbrugge, Annie
edff649f-8143-40a6-8e2d-9f0e1c068484
Bangsberg, David
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Bloch, Kenneth D.
25d43ddf-77d4-448b-b618-079a0492aba1
Boum, Yap
59579b35-abae-4b0d-9e68-eb87637d7ef3
Zapol, Warren M.
84efe66d-166f-4b1d-8db2-b48586aea27e

Mwanga-Amumpaire, Juliet, Carroll, Ryan W. and Baudin, Elisabeth et al. (2015) Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children: a phase II randomized open-label clinical trial. Open Forum Infectious Diseases, 2 (3), 1-9. (doi:10.1093/ofid/ofv111). (PMID:26309894)

Record type: Article

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-?, interferon-?, interleukin [IL]-1?, 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.

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More information

Accepted/In Press date: 21 July 2015
Published date: 24 July 2015
Additional Information: Erratum http://dx.doi.org/10.1093/ofid/ofv132
Keywords: cerebral malaria, methemoglobin, nitric oxide, plasmodium falciparum
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 381156
URI: https://eprints.soton.ac.uk/id/eprint/381156
PURE UUID: 4eb5d0be-cd4f-4594-8b9b-c7776fe15e50
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381

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Date deposited: 05 Oct 2015 11:46
Last modified: 25 Apr 2019 00:31

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Contributors

Author: Juliet Mwanga-Amumpaire
Author: Ryan W. Carroll
Author: Elisabeth Baudin
Author: Elisabeth Kemigisha
Author: Dorah Nampijja
Author: Kenneth Mworozi
Author: Data Santorino
Author: Dan Nyehangane
Author: Daniel I. Nathan
Author: Pierre De Beaudrap
Author: Jean-François Etard
Author: Martin Feelisch ORCID iD
Author: Bernadette O. Fernandez ORCID iD
Author: Annie Berssenbrugge
Author: David Bangsberg
Author: Kenneth D. Bloch
Author: Yap Boum
Author: Warren M. Zapol

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