Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial

Paul Bangirana; Andrea L. Conroy; Robert Opoka; Michael T. Hawkes; Laura Hermann; Christopher Miller; Sophie Namasopo; W. Conrad Liles; Chandy C. John; Kevin C. Kain

doi:10.1371/journal.pone.0191550

Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial

Paul Bangirana, Andrea L. Conroy, Robert Opoka, Michael T. Hawkes, Laura Hermann, Christopher Miller, Sophie Namasopo, W. Conrad Liles, Chandy C. John, Kevin C. Kain

Medical College, East Africa

Research output: Contribution to journal › Article

20 Citations (Scopus)

Abstract

Background

Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age.

Methods

A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on childrenResults

Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14–0.96) by log binomial regression following adjustment for anticonvulsant use.

Conclusions

Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.

Original language	Undefined/Unknown
Journal	Paediatrics and Child Health, East Africa
DOIs	https://doi.org/10.1371/journal.pone.0191550
Publication status	Published - 1 Jan 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pone.0191550Licence: Unspecified

http://ecommons.aku.edu/eastafrica_fhs_mc_paediatr_child_health/451

Cite this

@article{9953663372234303aab3c668ca206566,

title = "Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial",

abstract = "Background Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age. Methods A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on childrenResults Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14–0.96) by log binomial regression following adjustment for anticonvulsant use. Conclusions Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.",

author = "Paul Bangirana and Conroy, {Andrea L.} and Robert Opoka and Hawkes, {Michael T.} and Laura Hermann and Christopher Miller and Sophie Namasopo and Liles, {W. Conrad} and John, {Chandy C.} and Kain, {Kevin C.}",

year = "2018",

month = jan,

day = "1",

doi = "10.1371/journal.pone.0191550",

language = "Undefined/Unknown",

journal = "Paediatrics and Child Health, East Africa",

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TY - JOUR

T1 - Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial

AU - Bangirana, Paul

AU - Conroy, Andrea L.

AU - Opoka, Robert

AU - Hawkes, Michael T.

AU - Hermann, Laura

AU - Miller, Christopher

AU - Namasopo, Sophie

AU - Liles, W. Conrad

AU - John, Chandy C.

AU - Kain, Kevin C.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age. Methods A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on childrenResults Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14–0.96) by log binomial regression following adjustment for anticonvulsant use. Conclusions Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.

AB - Background Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age. Methods A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on childrenResults Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14–0.96) by log binomial regression following adjustment for anticonvulsant use. Conclusions Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.

U2 - 10.1371/journal.pone.0191550

DO - 10.1371/journal.pone.0191550

M3 - Article

JO - Paediatrics and Child Health, East Africa

JF - Paediatrics and Child Health, East Africa

ER -