Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs

Xinli Ni, Zeng Jin Yang, Bing Wang, Erin L. Carter, Abby C. Larson, Lee J Martin, Raymond C Koehler

Research output: Contribution to journalArticle

Abstract

Background: The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with 1 day of whole-body hypothermia implemented 4 hours after resuscitation. Methods: Anesthetized piglets were subjected to 40 minutes of hypoxia (10% inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell-counting methods. Results: At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17% ± 6% (±95% confidence interval) of the value in a sham-operated control group (100% ± 15%). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40% ± 12% viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46% ± 15%). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47% ± 18%) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference:-15% to 29%) or delayed hypothermia (-16% to 19%). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. Conclusions: We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.

Original languageEnglish (US)
Pages (from-to)627-637
Number of pages11
JournalAnesthesia and Analgesia
Volume115
Issue number3
DOIs
StatePublished - Sep 2012

Fingerprint

Hypothermia
Swine
Ischemia
Antioxidants
Putamen
Neurons
Therapeutics
Resuscitation
Confidence Intervals
Brain Hypoxia-Ischemia
Neuroprotection
Hypoxia
Caudate Nucleus
Neocortex
Basal Ganglia
Body Temperature
Intravenous Infusions
Catalase
Superoxide Dismutase
Cell Death

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs. / Ni, Xinli; Yang, Zeng Jin; Wang, Bing; Carter, Erin L.; Larson, Abby C.; Martin, Lee J; Koehler, Raymond C.

In: Anesthesia and Analgesia, Vol. 115, No. 3, 09.2012, p. 627-637.

Research output: Contribution to journalArticle

@article{9566c0956a69467da40ea381e7860e7e,
title = "Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs",
abstract = "Background: The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with 1 day of whole-body hypothermia implemented 4 hours after resuscitation. Methods: Anesthetized piglets were subjected to 40 minutes of hypoxia (10{\%} inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell-counting methods. Results: At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17{\%} ± 6{\%} (±95{\%} confidence interval) of the value in a sham-operated control group (100{\%} ± 15{\%}). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40{\%} ± 12{\%} viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46{\%} ± 15{\%}). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47{\%} ± 18{\%}) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference:-15{\%} to 29{\%}) or delayed hypothermia (-16{\%} to 19{\%}). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. Conclusions: We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.",
author = "Xinli Ni and Yang, {Zeng Jin} and Bing Wang and Carter, {Erin L.} and Larson, {Abby C.} and Martin, {Lee J} and Koehler, {Raymond C}",
year = "2012",
month = "9",
doi = "10.1213/ANE.0b013e31825d3600",
language = "English (US)",
volume = "115",
pages = "627--637",
journal = "Anesthesia and Analgesia",
issn = "0003-2999",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs

AU - Ni, Xinli

AU - Yang, Zeng Jin

AU - Wang, Bing

AU - Carter, Erin L.

AU - Larson, Abby C.

AU - Martin, Lee J

AU - Koehler, Raymond C

PY - 2012/9

Y1 - 2012/9

N2 - Background: The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with 1 day of whole-body hypothermia implemented 4 hours after resuscitation. Methods: Anesthetized piglets were subjected to 40 minutes of hypoxia (10% inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell-counting methods. Results: At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17% ± 6% (±95% confidence interval) of the value in a sham-operated control group (100% ± 15%). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40% ± 12% viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46% ± 15%). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47% ± 18%) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference:-15% to 29%) or delayed hypothermia (-16% to 19%). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. Conclusions: We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.

AB - Background: The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with 1 day of whole-body hypothermia implemented 4 hours after resuscitation. Methods: Anesthetized piglets were subjected to 40 minutes of hypoxia (10% inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell-counting methods. Results: At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17% ± 6% (±95% confidence interval) of the value in a sham-operated control group (100% ± 15%). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40% ± 12% viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46% ± 15%). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47% ± 18%) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference:-15% to 29%) or delayed hypothermia (-16% to 19%). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. Conclusions: We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.

UR - http://www.scopus.com/inward/record.url?scp=84865681650&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865681650&partnerID=8YFLogxK

U2 - 10.1213/ANE.0b013e31825d3600

DO - 10.1213/ANE.0b013e31825d3600

M3 - Article

C2 - 22745113

AN - SCOPUS:84865681650

VL - 115

SP - 627

EP - 637

JO - Anesthesia and Analgesia

JF - Anesthesia and Analgesia

SN - 0003-2999

IS - 3

ER -