N6‐Cyclohexyladenosine, an A1 Adenosine Receptor Agonist, as a Novel Thermolytic Adjunctive Pharmacotherapy for Targeted Temperature Management

Abstract

Targeted temperature management (TTM) previously known as therapeutic hypothermia, the lowering of core body temperature (Tb) over a 24h period, is a lifesaving and neuroprotective standard of care intervention for cardiac arrest and neonatal hypoxic ischemic encephalopathy. Prior work shows that the A1 Adenosine receptor (A1AR) agonist N6‐Cyclohexyladenosine (CHA), inhibits shivering and nonshivering thermogenesis and lowers core body temperature. However, an optimal delivery protocol has not been developed. Here our purpose is to optimize a CHA delivery protocol to achieve and maintain a predictable and consistent target Tb of 32°C over a 24h period and also to quantify and characterize physiological responses to CHA assisted cooling at a temperature range and cooling interval consistent with current evidence based guidelines for targeted temperature management in cardiac arrest.Sprague‐Dawley rats (n = 22) were instrumented with CTA‐F40 transmitters (DSI International) for continuous recording of Tb and ECG, arterial and venous cannulas and in some cases, brain cannula for monitoring brain temperature. Rats were administered CHA via continuous IV infusion or intraperitoneal injections to inhibit thermogenesis. In the first experiment ambient temperature was modulated to lower Tb with increasing doses of CHA to optimize cooling. In the second experiment cage surface temperature was modulated to control Tb with the CHA dose determined from the first experiment. Core body and brain temperatures, heart rate and rhythm, blood gas and electrolytes were monitored throughout the experimentsResults indicate a pronounced individual variation in response to CHA and the development of tolerance, necessitating a higher starting dose and use of dynamic conductive temperature modulation to prevent overcooling. We show that core body temperature predicts brain temperature during CHA induced cooling. CHA inhibits thermoregulatory shivering and core body temperature of 32°C can be safely maintained and modulated with surface cooling and continuous IV infusion of CHA over a 24h period. Acid‐base, electrolyte and blood gas analysis indicated acute hyperglycemia and a mild respiratory acidosis during the initiation of cooling. The hyperglycemia was transient and all rats were normoglycemic at the end of cooling and arterial pH normalized via metabolic compensation.Support or Funding InformationNIH R15 NS070779