Abstract
Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia–ischemia we assessed whether inhaled 45–50% Argon from 2–26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia–ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2–26h (n=10); or (ii) Cooling and inhaled 45–50% Argon (Cooling+Argon) from 2–26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia–ischemia. EEG was monitored. At 48h after hypoxia–ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia–ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia–ischemia (p<0.001 for both) and lower 1H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm2 were 23.9 points lower (95% C.I. 7.3–40.5) for the Cooling+Argon versus Cooling. Inhaled 45–50% Argon from 2–26h augmented hypothermic protection at 48h after hypoxia–ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy.
Highlights
Neonatal Encephalopathy (NE) consequent on perinatal hypoxia–ischemia is the third leading cause of child death and one of the main causes of preventable child neurodisability worldwide (Lawn et al, 2014)
Previous work with our model suggested that the change in lactate/N acetyl aspartate (NAA) during 48 h varied between normo- and hypothermic groups by 1.0 U, with a standard deviation of 0.65 U
One piglet (Cooling + Argon) was lost prior to 48 h due to cardiac arrest. Another piglet (Cooling + Argon) was excluded because the cooling mattress malfunctioned and the piglet was normothermic between 7–9 h; in addition a fault was noted in the ventilator and Argon delivery was not assured for a period of several hours
Summary
Neonatal Encephalopathy (NE) consequent on perinatal hypoxia–ischemia is the third leading cause of child death and one of the main causes of preventable child neurodisability worldwide (Lawn et al, 2014). In neonatal rat (Ma et al, 2005) and piglet (Chakkarapani et al, 2010; Faulkner et al, 2011) studies, the combination of Xenon with cooling provided neuroprotection while neither intervention alone was as effective. Argon does not produce demonstrable anesthetic effects at atmospheric pressure and provides potent neuroprotection, at least equivalent to Xenon, in animal models of hypoxic–ischemic brain injury and in vitro using murine organotypic hippocampal slice cultures (Loetscher et al, 2009) and neuronal cultures (Jawad et al, 2009). In vitro models of cerebral ischemia and traumatic brain injury suggest that the optimum concentration of Argon for protection is 50% and the therapeutic window lasts up to 3 h (Loetscher et al, 2009). Protection has been observed in neonatal rodent models where 70% argon at 2 h after hypoxia–ischemia improved cell survival to naive levels and reduced infarct volume (Zhuang et al, 2012)
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