Abstract 213: Physiogenomic Response to Prolonged Cardiac Arrest and Resuscitation: Hyporesponders Fail to Upregulate Certain Genes

Abstract

Background: In our porcine laboratory studies of prolonged cardiac arrest and resuscitation we have observed that approximately one out of every four animals appears to be hyporesponsive to vasopressor drug therapy during CPR. These hyporesponsive animals fail to generate an increase in coronary perfusion pressure (CPP) sufficient to attain a return of spontaneous circulation (ROSC) and cannot be resuscitated. Some humans unexplainably fail resuscitation despite promising conditions (age, witnessed arrest, bystander CPR, rapid EMS response). We conducted this natural experiment in order to compare the physiogenomic responses of animals that were hyporesponsive, to those that responded as expected to vasopressor therapy. Hypothesis: We hypothesized that we would identify genes that were differentially expressed between the two groups (hyporesponders and normal responders). Methods: We sedated, anesthetized, and instrumented 14 female swine (mean mass 28.6 kgs). Micro-manometer tipped catheters were placed to measure CPP for determination of response status. Ventricular fibrillation (VF) was induced and untreated for 10 minutes, then CPR was begun. Two minutes later pressors were given (epinephrine 0.1 mg/kg and vasopressin 0.6 U/kg). At minute 15 the first rescue shock was delivered. Twenty-eight minutes after the induction of VF, femoral artery samples were harvested and snap-frozen. Gene expression was assessed on the Affymetrix Porcine Genome Array, and affected pathways were ordered with Pathway Express (with Impact Analysis of p<0.05 considered significant). Results: We compared 4 hyporesponsive pigs to a sample of 5 normal responders. There were 213 differentially expressed genes affecting 10 pathways shown in the Table (with the apoptosis pathway at p=0.056). Conclusion: Hyporesponders differentially express genes that affect vasoregulation, myocardial contractility, calcium regulation and 7 other pathways.