6N‐Cyclohexyladenosine Suppresses Shivering in Anesthetized Swine

Shivering compromises post‐operative recovery and patient comfort. Shivering is also an impediment to targeted temperature management (TTM), now standard of care for cardiac arrest. Without an effective drug to suppress shivering (referred to here as a thermolytic) high cost and difficulty of temperature management is restricting access to TTM outside of large hospitals and for conditions such as stroke. A more efficacious thermolytic is needed for post‐operative control of shivering and to improve patient comfort during TTM. Our prior work in rats, based on strong scientific premise from the study of hibernating animals, suggests that stimulating CNS A 1 adenosine receptors (A 1 AR) by combining the A 1 AR agonist 6 N cyclohexyladenosine (CHA) with the peripherally acting adenosine receptor antagonist 8‐(p‐sulphophenyl)theophylline (8‐SPT) will provide an effective means to control shivering. This approach works in rodents however, thermolytic efficacy has not been demonstrated in a larger mammal that, like humans, depends primarily on shivering thermogenesis to maintain body temperature. To assess the thermolytic efficacy of CHA in 50–55 kg swine, a species that lacks brown adipose tissue, three pigs were anesthetized with Telazol/Xylazine, propofol, or isoflurane and cooled to a target body temperature of 32 to 34°C with a water blanket set to 4°C. Probes measured core body temperature at the tympanum, lower esophagus, rectum and bladder. Electrocardiography, pulse oximetery and arterial blood pressure were monitored. Shivering was measured by respirometry and by a qualitative visual scale. When shivering was noted, CHA was administered (bolus, 4.2mg; infusion,113μg/kg/h). 8‐SPT (bolus, 186mg), atropine (bolus, 0.5mg) or epinephrine (bolus, 100μg) was then given IV to reverse bradycardia and hypotension. At completion, animals were euthanized and tissues collected for histopathology. Results show that CHA inhibits shivering and that 8‐SPT restores blood pressure and heart rate without reversing the thermolytic effect of CHA. No histopathology was noted. In conclusion, CHA is an effective thermolytic in swine. Support or Funding Information This work was supported by Be Cool Pharmaceutics LLC and the Mayo Clinic