Abstract 223: Kynurenine Pathway Activation Following Resuscitation from Cardiac Arrest: An Experimental and Clinical Investigation---from a Rat and a Pig Model to a Preliminary Clinical Validation

Abstract

Background. Kynurenine pathway (KP) is a major route of the tryptophan catabolism, mainly activated upon several inflammatory stimulation and involved in the pathogenesis of numerous cerebral disorders shock states. In the present study, tryptophan and KP metabolites concentrations were measured in plasma from rats, pigs, and humans resuscitated from cardiac arrest (CA). We hypothesized that the KP would be markedly activated following CA. Methods. Plasma was obtained from: A: 18 rats, subjected to 6 min CA and 6 min CPR; B: 10 pigs, subjected to 10 min CA and 5 min CPR with post-arrest normo- (n=5) or hypothermia treatment (n=5); and C: 3 healthy human volunteers and 5 patients resuscitated from CA, with or without hypothermia. Metabolites were extracted and levels analyzed by mass spectrometry with high performance liquid chromatography. Assessements were available at baseline and hrs and days post-arrest (Figure). The specific KP metabolites were subsequently correlated with specific functional measurements and survival. Results. KP activaction after CA was observed in rats, pigs, and humans. More specifically decreases in tryptophan occurred after resuscitation period and were accompanied by significant increases in its major metabolites, 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid in each species, that persisted up to 3-5 days post-arrest (p<0.01, Figure). In rats, changes in KP metabolites reflected changes in post-resuscitation myocardial dysfunction. In pigs, decreases in tryptophan (r=-0.728, p=0.017) and increases in 3-HAA (r=0.792, p<0.01) were significanlty related to the severity of hippocampal injuries. In humans, post-arrest increases in 3-HAA were inversly related with 72 hr survival (r=-0.94, p=0.18). Conclusions. In this fully translational investigation, the KP was activated early following resuscitation from CA. KP activation might account for the severity of post resuscitation syndrome and ultimately to survival.