Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial.
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 (<14 days), acute kidney injury, hypoglycaemia, anaemia, and haemoglobinuria was similar between groups (p > 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.


BACKGROUND
ClinicalTrials.gov NCT01255215.
3-588D Edmonton Clinic Health Academy, University of Alberta, 11405 87 Ave NW, Edmonton, AB, T6G 1C9, Canada. mthawkes@utoronto.ca.
Michael T
MT
Hawkes
Sandra Rotman Centre for Global Health, MaRS Centre, University of Toronto, 101 College St TMDT 10-360A, Toronto, ON, M5G 1L7, Canada. andrea.conroy@gmail.com.
Andrea L
AL
Conroy
Global Health Uganda, Upper Paediatrics Office, Mulago Hospital, PO Box 33842, Plot 138, Upper Mawanda Road, Kawempe, Kampala, Uganda. opokabob@yahoo.com.
Robert O
RO
Opoka
Sandra Rotman Centre for Global Health, MaRS Centre, University of Toronto, 101 College St TMDT 10-360A, Toronto, ON, M5G 1L7, Canada. laura.hermann@afrims.org.
Laura
L
Hermann
Applied Health Research Centre, St Michael's Hospital, 250 Yonge St, 6th Floor, Toronto, ON, M5T 3M7, Canada. kevin.thorpe@utoronto.ca.
Kevin E
KE
Thorpe
Sandra Rotman Centre for Global Health, MaRS Centre, University of Toronto, 101 College St TMDT 10-360A, Toronto, ON, M5G 1L7, Canada. chloe.mcdonald@mail.utoronto.ca.
Chloe
C
McDonald
Johns Hopkins School of Public Health, International Vaccine Access Center, 615 N Wolfe St, Baltimore, MD, 21205, USA. hanireally@gmail.com.
Hani
H
Kim
Sandra Rotman Centre for Global Health, MaRS Centre, University of Toronto, 101 College St TMDT 10-360A, Toronto, ON, M5G 1L7, Canada. sarah.higgins@mail.utoronto.ca.
Sarah
S
Higgins
Jinja Regional Referral Hospital, Plot 7, Nalufenya Road, Jinja, Uganda. somnamasopo@yahoo.com.
Sophie
S
Namasopo
Department of Pediatrics, Indiana University, 702 Barnhill Dr, Room 5900, Indianapolis, IN, 46202, USA. chjohn@iu.edu.
Chandy
C
John
Division of Infectious Disease, University of British Columbia, Rm D433, HP East, Vancouver Hospital, 2733 Heather Street, Vancouver, BC, V5Z-3J5, Canada. miller42@mail.ubc.ca.
Chris
C
Miller
Department of Medicine, University of Washington, 1959 NE Pacific Street, HSB RR-511, Box 356420, Seattle, WA, 98195-6420, USA. wcliles@medicine.washington.edu.
W Conrad
WC
Liles
Sandra Rotman Centre for Global Health, MaRS Centre, University of Toronto, 101 College St TMDT 10-360A, Toronto, ON, M5G 1L7, Canada. kevin.kain@uhn.ca.
Kevin C
KC
Kain
D000280:Administration, Inhalation; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage*; D010919:Placebos / Q000008:administration & dosage; D011446:Prospective Studies; D016896:Treatment Outcome; D033921:Vesicular Transport Proteins / Q000097:blood*
D000890:Anti-Infective Agents; D010919:Placebos; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; D009569:Nitric Oxide