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

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

Research output: Contribution to journalArticle

4 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 children<5 years at 6 month followup. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability. Results Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Fortytwo 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 (ß (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 languageEnglish (US)
Article numbere0191550
JournalPLoS One
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2018

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Pediatrics
cognition
malaria
Cognition
Malaria
placebos
nitric oxide
Nitric Oxide
Placebos
relative risk
Data storage equipment
Language
anticonvulsants
Intention to Treat Analysis
Aptitude
Uganda
Composite materials
distress
Linear regression
Anticonvulsants

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Bangirana, P., Conroy, A. L., Opoka, R. O., Hawkes, M. T., Hermann, L., Miller, C., ... Kain, K. C. (2018). Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial. PLoS One, 13(1), [e0191550]. https://doi.org/10.1371/journal.pone.0191550

Inhaled nitric oxide and cognition in pediatric severe malaria : A randomized double-blind placebo controlled trial. / Bangirana, Paul; Conroy, Andrea L.; Opoka, Robert O.; Hawkes, Michael T.; Hermann, Laura; Miller, Christopher; Namasopo, Sophie; Liles, W. Conrad; John, Chandy; Kain, Kevin C.

In: PLoS One, Vol. 13, No. 1, e0191550, 01.01.2018.

Research output: Contribution to journalArticle

Bangirana, P, Conroy, AL, Opoka, RO, Hawkes, MT, Hermann, L, Miller, C, Namasopo, S, Liles, WC, John, C & Kain, KC 2018, 'Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial', PLoS One, vol. 13, no. 1, e0191550. https://doi.org/10.1371/journal.pone.0191550
Bangirana, Paul ; Conroy, Andrea L. ; Opoka, Robert O. ; Hawkes, Michael T. ; Hermann, Laura ; Miller, Christopher ; Namasopo, Sophie ; Liles, W. Conrad ; John, Chandy ; Kain, Kevin C. / Inhaled nitric oxide and cognition in pediatric severe malaria : A randomized double-blind placebo controlled trial. In: PLoS One. 2018 ; Vol. 13, No. 1.
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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 children<5 years at 6 month followup. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability. Results Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Fortytwo 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 ({\ss} (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.",
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AU - Hawkes, Michael T.

AU - Hermann, Laura

AU - Miller, Christopher

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AU - Liles, W. Conrad

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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 children<5 years at 6 month followup. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability. Results Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Fortytwo 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 (ß (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 children<5 years at 6 month followup. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability. Results Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Fortytwo 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 (ß (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.

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