Metabolomic Profiles Indicate Variable Tolerance to Hypoxia in Newborn Piglets: An Experimental Study of Low Dose Nicotine After Global Hypoxia.

INTRODUCTION Treatment of hypoxic-ischemic encephalopathy (HIE) remains incomplete. This study aimed to characterise metabolomic changes induced by severe hypoxia and assess whether low-dose intravenous nicotine could modify these changes. We aimed to explore whether piglets with decreased hypoxia tolerance (DHT) display a pre-existing metabolic signature compared with those with increased hypoxia tolerance (IHT).

Methods

Forty-one piglets were exposed to hypoxia (8 % O2) until predefined endpoints and randomised into three groups; nicotine (18 or 46 µg/kg/h) or saline, for 4 hours. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry (LC-MS) on dried blood spots collected before hypoxia, at the end of hypoxia, and at the end of the experiment. Metabolic features were compared between nicotine treated animals and the controls, and between the DHT and IHT groups.

Results

Hypoxia altered numerous metabolites. Before hypoxia, DHT had higher levels of allantoin, O-phosphoethanolamine, glutamate, glutamylglycine, trimethylamine N-oxide, cytidine and histamine, and lower levels of dimethylarginine. The differences persisted after hypoxia. At the end of the study period, no significant differences were observed between the nicotine and control groups.

Conclusion

Severe hypoxia induced rapid changes in the metabolomic profile. Low doses of nicotine did not significantly modify this response. Differences in metabolomic profiles between the hypoxia tolerance groups before hypoxia may reflect a possible pre-existing susceptibility to hypoxia. Identifying metabolomic markers of susceptibility to hypoxia opens for optimising both standardised and individualised treatment.