Suppression of Shivering during Hypothermia Using a Novel Drug Combination in Healthy Volunteers

Abstract

Background Hypothermia may be beneficial in stroke victims; however, it provokes vigorous shivering. Buspirone and dexmedetomidine each linearly reduce the shivering threshold with minimal sedation and no respiratory depression. This study tested the hypotheses that the combination of buspirone and dexmedetomidine would (1) synergistically reduce the shivering threshold, (2) synergistically reduce the gain and maximum intensity of shivering, and (3) produce sufficient inhibition to permit cooling to 34 degrees C without excessive hypotension or sedation. Methods Eight healthy men were randomly assigned on 4 days to (1) no drug, (2) buspirone (60 mg orally), (3) dexmedetomidine (intravenous infusion to target plasma concentration of 0.6 ng/ml), or (4) combination of buspirone and dexmedetomidine at same doses. Lactated Ringer's solution (approximately 3 degrees C) was infused intravenously to decrease tympanic membrane temperature by 1.5 degrees C/h. Shivering threshold was defined as an increase in oxygen consumption greater than 20%. Sedation was evaluated using the Observer's Assessment of Sedation/Alertness scale. Results Mean arterial pressure and heart rate were slightly lower on dexmedetomidine and combination days. Likewise, the level of sedation was statistically different on these 2 days but clinically unimportant. Buspirone reduced the shivering threshold from 36.6 degrees C +/- 0.4 degrees C to 35.9 degrees C +/- 0.4 degrees C, dexmedetomidine reduced it to 34.7 degrees C +/- 0.5 degrees C, and the combination to 34.1 +/- 0.4 degrees C. The interaction effect of 0.04 degrees C was not significant. The gain of shivering and maximum shivering intensity were similar on each day. Conclusions The combination of buspirone and dexmedetomidine additively reduced the shivering threshold. Thus, supplementing dexmedetomidine with buspirone blocks shivering and causes only minimal sedation.