Abstract 222: Role of Pathologic Calpain Activity in Post-Cardiac Arrest Hypothermic Targeted Temperature Management

Abstract

Objective: Optimization of post-cardiac arrest hypothermic-targeted temperature management (HTTM) is limited by an inadequate understanding of the fundamental mechanisms of action. This study tested the hypothesis that post-cardiac arrest HTTM reduces delayed secondary neuronal cytosolic Ca 2+ overload that causes pathologic calpain activity and neuronal death after cardiac arrest (CA) Methods: Male Long Evens rats were subjected to 8-minute asphyxial CA (ACA) followed by CPR. Rats that achieved return of spontaneous circulation (ROSC) were block randomized to normothermic- targeted temperature management (NTTM; n=13), hypothermic-TTM at 36 o C (HTTM-36;n=13) or 33 o C (HTTM-33;n=10). HTTM was initiated 1h after ROSC and maintained for 24h. Neurologic function score was assessed daily. Rats were euthanized at 48h post-ROSC. Regional brain homogenates were generated in a subset of animals for Western blot analysis of calpain-cleaved alpha-spectrin as a measure of pathologic calpain activity (n=6/group). Sham rats were used as uninjured controls (n=9) Results: Survival at 48h post-ROSC was 69%, 69%, and 90% in the NTTM, HTTM-36 and HTTM-33 groups respectively (p>0.05: chi-squared). Survival with good neurologic function (GNF: defined as NFS > 450 out of 500) was 0%, 15%, and 60% in the NTTM, HTTM-36 and HTTM-33 groups respectively (p<0.05 for HTTM-33 vs. HTTM-36 and NTTM: chi-squared). Compared to NTTM, pathologic calpain activity in the hippocampus, cortex, caudoputamen, and cerebellum was decreased by 23±20%, 38±56%, 40±55%, 62±20% in the HTTM-36 groups and 33±13%, 55±72%, 66±89%, 69±17% in the HTTM-33 group respectively (p <0.05 for HTTM-33 and HTTM-36 cerebellum, p> 0.05 for all other regions: ANOVA, Tukey’s post-hoc) Conclusion: In this rat model of asphyxial cardiac arrest, HTTM with a target temperature of 33°C improved 48-hour survival with GNF compared to HTTM with a target temperature of 36°C and NTTM. Post-cardiac arrest regional brain calpain activity was significantly reduced with HTTM at 33°C and 36°C compared to NTTM in the cerebellum, but not other brain regions. Further work is needed to explore the potential causal link between the reduction of pathologic calpain activity and the neuroprotective effect of post-cardiac arrest HTTM