Abstract 2: Orexin-A Improves Arousal from Post--Cardiac Arrest Coma in a Rodent Model

Abstract

Introduction: Coma after cardiac arrest (CA) is common and leads to suffering for patients while being an emotional and financial burden to families and society. Other than hypothermia, there is currently no therapy to improve neurological outcome after CA. The hypothalamic Orexin pathway provides a potential pharmacologic target towards improving arousal after coma. Hypothesis: Post-resuscitaion, Orexin-A intracerebroventricular (icv) infusion after bolus injection will provide immediate and long term term arousal after CA which can be assessed by quantitative EEG (qEEG) and behavioral testing (neurologic deficit scale; NDS). Methods: Rats (N=17; Adult Male Wistar; 300-350gms) were implanted with icv cannula attached to an osmotic pump. One week later, rats underwent baseline EEG followed by intubation, mechanical ventilation, cannulation of the femoral vessels, followed by 7 minutes of asphyxial cardiac arrest. Forty-five minutes after the resuscitation, rats were randomized to either Orexin-A (n=8) or saline (n=9) icv bolus and infusion. EEG was monitored continuously for 4 hours after CA, and for 30 minutes at 24hrs, 48hrs, 72hrs, and 12 days post-CA. NDS was also conducted at these times. EEG was analyzed using a custom algorithm to analyze the information quantity (IQ), an entropy based nonlinear measure for the entire frequency domain and clinical sub-bands. Results: Orexin-A treated rats demonstrated higher normalized IQ immediately after receiving the Orexin-A in comparison to saline (0.731±0.028[AM1] vs. 0.613±0.021; p<0.01). This acute improvement in IQ sustained for 4hrs Post-CA. Moreover, the band-specific analysis [RG2] showed that Orexin-A improved the IQ in β-band at 72hrs (1.160±0.039 vs. 1.052±0.029; p<0.05). Behaviorally, Orexin-A allows rats to perform significantly better on the NDS at 4hrs (38.3±3.2 vs. 30.1±1.9; p<0.05); 24hrs (67.1±4.1 vs. 49.8±3.8; p<0.01); 48hrs (73.4±4.3 vs. 61.0±3.6; p<0.05), and 72hrs (75.0±3.3 vs. 65.2±2.9; p<0.05). Conclusions: Rats receiving icv Orexin-A post-CA showed better arousal on both qEEG and behavioral (NDS) testing. Orexin-A may have therapeutic potential in disorders of arousal and coma after CA.