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.

• Authors: Xinli Ni, Zeng-Jin Yang, Bing Wang, Erin L Carter, Abby C Larson, Lee J Martin, Raymond C Koehler
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 115 Issue 3 Pg. 627-37 (Sep 2012) ISSN: 1526-7598 [Electronic] United States
• PMID: 22745113 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• EUK-134
• Neuroprotective Agents
• Organometallic Compounds
• Salicylates

Topics

• Animals
• Animals, Newborn
• Antioxidants (therapeutic use)
• Hypothermia, Induced
• Hypoxia-Ischemia, Brain (metabolism, pathology, therapy)
• Male
• Neuroprotective Agents (therapeutic use)
• Organometallic Compounds (therapeutic use)
• Salicylates (therapeutic use)
• Swine