NVD in Hypothermic HIE Neonates

Summary

Neonatal hypoxic ischemic (HI) injury is an unpredictable neurologic injury with devastating, long term consequences for parents who are expecting a normal child. Hypothermia for 72 hr within 6 hrs of birth improves the combined outcome of death or severe disability, and hypothermia is now standard of care in tertiary centers throughout the world. However, approximately 50% of infants with hypoxic ischemic encephalopathy (HIE) treated with hypothermia still have adverse neurologic outcomes, due to ongoing neuroinflammation and oxidative stress in spite of hypothermia. Further, the majority of HIE infants are insufficient or deficient in a critical neurosteroid, 25(OH)vitamin D, which has been shown to adversely affect outcome after adult stroke. By adding vitamin D to N-acetylcysteine (NAC), an antioxidant, the investigators hypothesized that both drugs would increase glutathione (GSH) concentrations in critical brain areas, mitigate continuing oxidative stress after injury during hypothermia and after rewarming, and improve neurodevelopmental outcomes. This is an open-label, non-randomized, escalating dose, pilot trial to evaluate the disposition and safety of NAC in combination with active vitamin D in neonates who present within 6 hrs of hypoxia ischemia/asphyxial event and received moderate hypothermia to 33 degrees C for 72 hours per routine protocol.

Timeline

Start

2015-01-01

Primary completion

2017-04-01

Completion

2020-03-01

Publications

• Background Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.
• Background Nie X, Lowe DW, Rollins LG, Bentzley J, Fraser JL, Martin R, Singh I, Jenkins D. Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res. 2016 Jul;108:24-33. doi: 10.1016/j.neures.2016.01.008. Epub 2016 Feb 3.
• Background Lowe DW, Fraser JL, Rollins LG, Bentzley J, Nie X, Martin R, Singh I, Jenkins D. Vitamin D improves functional outcomes in neonatal hypoxic ischemic male rats treated with N-acetylcysteine and hypothermia. Neuropharmacology. 2017 Sep 1;123:186-200. doi: 10.1016/j.neuropharm.2017.06.004. Epub 2017 Jun 6.
• Background Lowe DW, Hollis BW, Wagner CL, Bass T, Kaufman DA, Horgan MJ, Givelichian LM, Sankaran K, Yager JY, Katikaneni LD, Wiest D, Jenkins D. Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy. Pediatr Res. 2017 Jul;82(1):55-62. doi: 10.1038/pr.2017.13. Epub 2017 Jan 17.
• Background Wiest DB, Chang E, Fanning D, Garner S, Cox T, Jenkins DD. Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection. J Pediatr. 2014 Oct;165(4):672-7.e2. doi: 10.1016/j.jpeds.2014.06.044. Epub 2014 Jul 23.
• Results Moss HG, Brown TR, Wiest DB, Jenkins DD. N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2018 Jun;38(6):950-958. doi: 10.1177/0271678X18765828. Epub 2018 Mar 21.
• Results Sanchez-Illana A, Thayyil S, Montaldo P, Jenkins D, Quintas G, Oger C, Galano JM, Vigor C, Durand T, Vento M, Kuligowski J. Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma. Anal Chim Acta. 2017 Dec 15;996:88-97. doi: 10.1016/j.aca.2017.09.026. Epub 2017 Sep 28.

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