Dexmedetomidine effects on metabolic rate over 5 days in humans

The alpha-2-adrenergic agonist drug dexmedetomidine induces sleep-like sedation and reduces global metabolic rate. Drug-induced metabolic suppression sustained over days in humans could be a strategy for reducing energy expenditure (EE), oxygen consumption (VO2), and carbon dioxide production (VCO2) during prolonged rescue or austere conditions with limited life-support. We tested the feasibility of reducing EE, VO2 and VCO2 measured with intermittent indirect calorimetry using subcutaneous infusion of dexmedetomidine 1 µg/kg/hour for 18 hours per day over five days in healthy adults. Five participants received multiple days of dexmedetomidine in a laboratory setting, and five separate participants received placebo for one or five days. Relative to resting metabolic rate, dexmedetomidine infusion reduced VO2 (effects, 95%CI, at 6-hour time epoch: -0.084 L/min, -0.145 to -0.023), VCO2 (-0.067 L/min, -0.130 to -0.005) and EE (-577 kcal/day, -1016 to -137). Relative to placebo, dexmedetomidine produced light sedation (Richmond Agitation Sedation Score: -1.25; 95%CI -1.70 to -0.80 relative to placebo), with lower heart rate (-15 beats/minute; 95%CI -23 to -7) and core body temperature (-1.3ºC; 95%CI -1.7 to -0.8). Dexmedetomidine effects on all physiological variables decreased over time and were absent after day 2. Maximum and minimum plasma drug levels did not change over days. Participants reported rebound anxiety and insomnia after the study. Administering a sedating level of dexmedetomidine that reduces VO2, VCO2, and EE for 2 days was feasible in healthy adults. However, tolerance to drug effects develops by 3 days, which is a critical limitation for long-term use of this drug regimen.