Effect of dexmedetomidine on propofol requirements in healthy subjects.
Dexmedetomidine-propofol pharmacodynamic interaction was evaluated in nine healthy subjects in a crossover design. Dexmedetomidine/placebo was infused using a computer-controlled infusion pump (CCIP) to maintain a pseudo-steady-state plasma concentration of 0.66 +/- 0.080 or 0 ng/mL, respectively. Forty-five minutes after the dexmedetomidine/placebo infusion was started, propofol was infused using a second CCIP to achieve a stepwise logarithmically ascending propofol concentration (1.00 to 13.8 microg/mL) profile. Each propofol step lasted 10 min. Blood was sampled for plasma concentration determination, and pharmacodynamic endpoint assessments were made during the study. Propofol and dexmedetomidine/placebo infusions were terminated when three endpoints (subjects were too sedated to hold a syringe, followed by loss of eyelash reflex, followed by loss of motor response to electrical stimulation) were achieved sequentially. The concentration of propofol associated with 50% probability of achieving a pharmacodynamic endpoint in the absence of dexmedetomidine (EC50; placebo treatment) was 6.63 microg/mL for motor response to electrical stimulation and ranged from 1.14 to 1.98 microg/mL for the ability to hold a syringe, eyelash reflex, and sedation scores. The apparent EC50 values of propofol (EC50APP; concentration of propofol at which the probability of achieving a pharmacodynamic endpoint is 50% in the presence of dexmedetomidine concentrations observed in the current study; dexmedetomidine treatment) were 0.273, 0.544-0.643, and 3.89 microg/mL for the ability to hold a syringe, sedation scores, and motor response, respectively. Dexmedetomidine reduced propofol concentrations required for sedation and suppression of motor response. Therefore, the propofol dose required for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine.
Dutta
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Clinical Pharmacokinetics Department, Abbott Laboratories, 100 Abbott Park Road, Department 4PK, AP13A-3, Abbott Park, Illinois 60064-6104, USA. Sandeep.Dutta@Abbott.com
Karol
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Cohen
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Jones
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Mant
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D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D020927:Dexmedetomidine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D016015:Logistic Models; D008297:Male; D010919:Placebos; D015742:Propofol / Q000008:administration & dosage*; D012016:Reference Values
D006993:Hypnotics and Sedatives; D010919:Placebos; D020927:Dexmedetomidine; D015742:Propofol