Project Grant R21DA061073

CARDIORESPIRATORY PHARMACODYNAMICS OF FENTANYL-XYLAZINE - PROJECT SUMMARY XYLAZINE HAS BECOME AN INCREASINGLY COMMON ADULTERANT THAT IS OFTEN UNKNOWN TO THE USER. THE COMBINATION OF XYLAZINE WITH FENTANYL IS PARTICULARLY PROMINENT WITH XYLAZINE NOW RECOGNIZED AS AN ESCALATING FACTOR IN FENTANYL OVERDOSE DEATHS. HOW XYLAZINE POTENTIATES FENTANYL TOXICITY INCLUDING THE BASIC DOSE/RESPONSE, HOWEVER, REMAINS UNCLEAR. BOTH FENTANYL AND XYLAZINE PRODUCE RESPIRATORY DEPRESSION AND IT IS GENERALLY ACCEPTED THAT CO- ADMINISTRATION INCREASES POTENCY FOR BOTH, THEREBY ENHANCING THE POTENTIAL FOR PROFOUND HYPOVENTILATION THAT IF LEFT UNTREATED CAN LEAD TO HYPOXIC ORGAN DAMAGE AND DEATH. LESS WELL APPRECIATED IS THAT UNLIKE FENTANYL, INTRAVENOUS XYLAZINE HAS SIGNIFICANT DIRECT ADVERSE CARDIOVASCULAR EFFECTS THAT CAN LEAD TO SUBSTANTIAL REDUCTIONS IN BLOOD PRESSURE AND CARDIAC OUTPUT (WHOLE BODY BLOOD FLOW). IMPLICATIONS OF THIS IN THE CONTEXT OF CO-ADMINISTRATION ARE TWO-FOLD. FIRST, WHILE THE BRAIN AND OTHER VITAL ORGANS EXHIBIT INTRINSIC AUTOREGULATORY RESPONSES TO MAINTAIN BLOOD PERFUSION AND OXYGEN DELIVERY OVER A RANGE OF BLOOD PRESSURE AND BLOOD FLOW, THIS AUTOREGULATION HAS LIMITS WHEN THE BLOOD PRESSURE IS VERY LOW AND/OR METABOLIC DISTURBANCES SUCH AS ACIDOSIS ARE SUPERIMPOSED. RECENTLY PUBLISHED DATA INDICATE THAT, AT LEAST FOR THE BRAIN, XYLAZINE ALSO BLOCKS SOME ASPECTS OF CEREBRAL AUTOREGULATION THAT ARE NOT SIGNIFICANTLY ALTERED BY FENTANYL ALONE. SECOND, SINCE OXYGEN DELIVERY TO TISSUES IS THE PRODUCT OF BOTH THE OXYGEN CONTENT OF ARTERIAL BLOOD AND BLOOD FLOW, XYLAZINE MAY ENHANCE FENTANYL TOXICITY BY NOT ONLY POTENTIATING RESPIRATORY DEPRESSION TO PRODUCE HYPOXEMIA BUT ALSO BY REDUCING ORGAN PERFUSION. ADDITIONALLY, IN THAT FENTANYL IS METABOLIZED IN THE LIVER AND CLEARANCE IS LARGELY DEPENDENT UPON HEPATIC BLOOD FLOW, IT IS POSSIBLE THAT XYLAZINE-INDUCED REDUCTIONS IN CARDIAC OUTPUT MAY ALSO ENHANCE FENTANYL TOXICITY BY IMPAIRING ITS CLEARANCE. CURRENTLY, THERE ARE NO CONTROLLED ROBUST DATA SPECIFICALLY DEFINING HOW THE DOSE/RESPIRATORY RESPONSE FOR FENTANYL IS ALTERED BY XYLAZINE (OR VICE VERSA), HOW XYLAZINE MAY ENHANCE FENTANYL TOXICITY BY FURTHER IMPAIRING OXYGEN DELIVERY, OR WHETHER XYLAZINE ALTERS FENTANYL CLEARANCE. THE PROPOSED STUDIES WILL ADDRESS THESE FUNDAMENTAL KNOWLEDGE GAPS USING ANESTHETIZED SWINE EXTENSIVELY MONITORED TO PROVIDE ASSESSMENT OF A WIDE RANGE OF RESPIRATORY, CARDIOVASCULAR, AND METABOLIC ENDPOINTS AS WELL AS BIOCHEMICAL MAKERS OF END-ORGAN DAMAGE. IMPORTANTLY, SINCE THE DOSES ASSOCIATED WITH CLINICAL TOXICITY MANIFEST AS RESPIRATORY DEPRESSION ARE UNKNOW, WE WILL FIRST DEFINE WITHIN THE EXPERIMENTAL MODEL OF THIS EXPLORATORY STUDY THE DOSE/RESPIRATORY DEPRESSION RESPONSE RELATIONSHIP FOR FENTANYL AND XYLAZINE INDIVIDUALLY AND USE THESE DATA TO GUIDE SUBSEQUENT CO-ADMINISTRATION STUDIES.