Inhaled 45–50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia

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 2–26 h 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 < 40 h were randomized to: (i) Cooling (33 °C) from 2–26 h (n = 10); or (ii) Cooling and inhaled 45–50% Argon (Cooling + Argon) from 2–26 h (n = 8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48 h after hypoxia–ischemia. EEG was monitored. At 48 h 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 48 h 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 48 h. 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 2–26 h augmented hypothermic protection at 48 h 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.

Argon attenuates multiorgan failure following experimental aortic cross‐clamping

“…Pigs receiving post-resuscitation treatment with argon also had complete neurological recovery [7]. In a piglet model of perinatal asphyxia, argon administration was shown to be safe [21], and reduced neuronal cell death [9]. It also reduced cerebral infarct size after transient cerebral artery occlusion in rats [4], and the risk of mortality after subarachnoid haemorrhage [5].…”

Expression Changes in Lactate and Glucose Metabolism and Associated Transporters in Basal Ganglia following Hypoxic-Ischemic Reperfusion Injury in Piglets

“…11 After completion of PET/CT and MR spectroscopy at the designated time points, the piglets were immediately injected with anesthetics. After the reaction disappeared (ie, loss of pain reflex because of excessive anesthetic), the skull was opened along the sutura craniun, and the spinal cord was cut at the medulla.…”

DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats

“…TUNEL-positive neurons were counted in left cortex-facing blood clots (3 sections per rat, 4 different areas in 500×500 μm grids per section) by a blinded investigator. Data were expressed as TUNEL+Neurons/mm 2 (Broad et al, 2016; Topkoru et al, 2013). …”