Methemoglobin and nitric oxide therapy in Ugandan children hospitalized for febrile illness: results from a prospective cohort study and randomized double-blind placebo-controlled trial.
Exposure of red blood cells to oxidants increases production of methemoglobin (MHb) resulting in impaired oxygen delivery to tissues. There are no reliable estimates of methemoglobinemia in low resource clinical settings. Our objectives were to: i) evaluate risk factors for methemoglobinemia in Ugandan children hospitalized with fever (study 1); and ii) investigate MHb responses in critically ill Ugandan children with severe malaria treated with inhaled nitric oxide (iNO), an oxidant that induces MHb in a dose-dependent manner (study 2).



Two prospective studies were conducted at Jinja Regional Referral Hospital in Uganda between 2011 and 2013. Study 1, a prospective cohort study of children admitted to hospital with fever (fever cohort, n = 2089 children 2 months to 5 years). Study 2, a randomized double-blind placebo-controlled parallel arm trial of room air placebo vs. 80 ppm iNO as an adjunctive therapy for children with severe malaria (RCT, n = 180 children 1-10 years receiving intravenous artesunate and 72 h of study gas). The primary outcomes were: i) masimo pulse co-oximetry elevated MHb levels at admission (>2 %, fever cohort); ii) four hourly MHb levels in the RCT.



In the fever cohort, 34 % of children admitted with fever had elevated MHb at admission. Children with a history of vomiting, delayed capillary refill, elevated lactate, severe anemia, malaria, or hemoglobinopathies had increased odds of methemoglobinemia (p < 0.05 in a multivariate model). MHb levels at admission were higher in children who died (n = 89) compared to those who survived (n = 1964), p = 0.008. Among children enrolled in the iNO RCT, MHb levels typically plateaued within 12-24 h of starting study gas. MHb levels were higher in children receiving iNO compared to placebo, and MHb > 10 % occurred in 5.7 % of children receiving iNO. There were no differences in rates of study gas discontinuation between trial arms.



Hospitalized children with evidence of impaired oxygen delivery, metabolic acidosis, anemia, or malaria were at risk of methemoglobinemia. However, we demonstrated high-dose iNO could be safely administered to critically ill children with severe malaria with appropriate MHb monitoring.



ClinicalTrials.gov Identifier: NCT01255215 (Date registered: December 5, 2010).
Depatment of Medicine, University of Toronto, Toronto, Canada.|Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.
Andrea L
AL
Conroy
Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada.
Michael
M
Hawkes
Depatment of Medicine, University of Toronto, Toronto, Canada.|Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.
Kyla
K
Hayford
Depatment of Medicine, University of Toronto, Toronto, Canada.
Laura
L
Hermann
Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Canada.
Chloe R
CR
McDonald
Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.
Suparna
S
Sharma
Department of Pediatrics, Jinja Regional Referral Hospital, Jinja, Uganda.
Sophie
S
Namasopo
Department of Paediatrics and Child Health, Mulago Hospital, Makerere University, Kampala, Uganda.
Robert O
RO
Opoka
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Chandy C
CC
John
Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
W Conrad
WC
Liles
Department of Respiratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Christopher
C
Miller
Depatment of Medicine, University of Toronto, Toronto, Canada. kevin.kain@uhn.ca.|Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada. kevin.kain@uhn.ca.|Institute of Medical Sciences, University of Toronto, Toronto, Canada. kevin.kain@uhn.ca.|Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada. kevin.kain@uhn.ca.|MaRS Centre, TMDT, 10th floor 10-351, Toronto, ON, M5G1L7, Canada. kevin.kain@uhn.ca.
Kevin C
KC
Kain
D000280:Administration, Inhalation; D002675:Child, Preschool; D016638:Critical Illness; D004311:Double-Blind Method; D045462:Endothelium-Dependent Relaxing Factors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005334:Fever / Q000209:etiology*; D006760:Hospitalization; D006801:Humans; D007223:Infant; D008288:Malaria / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008708:Methemoglobinemia / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control; D009569:Nitric Oxide / Q000009:adverse effects* / Q000627:therapeutic use; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014454:Uganda
D045462:Endothelium-Dependent Relaxing Factors; D009569:Nitric Oxide
Anemia; Fever; Inhaled nitric oxide; Malaria; Metabolic acidosis; Methemoglobin; Oxygen delivery; Pediatrics; Uganda