• Maud A S Weerink, BarendsClemens R MCRM, Ernesto R R Muskiet, ReyntjensKoen M E MKMEM, Froukje H Knotnerus, Martine Oostra, Jan F P van Bocxlaer, StruysMichel M R FMMRF, and Pieter J Colin.
• From the Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.A.S.W., C.R.M.B., E.R.R.M., K.M.E.M.R., F.H.K., M.O., M.M.R.F.S., P.J.C.) the Departments of Basic and Applied Medical Sciences (M.M.R.F.S.) Bioanalysis (P.J.C., J.F.P.v.B.), Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
• Anesthesiology. 2019 Nov 1; 131 (5): 100410171004-1017.

BackgroundDexmedetomidine is a sedative with modest analgesic efficacy, whereas remifentanil is an opioid analgesic with modest sedative potency. Synergy is often observed when sedative-hypnotics are combined with opioid analgesics in anesthetic practice. A three-phase crossover trial was conducted to study the pharmacodynamic interaction between remifentanil and dexmedetomidine.MethodsAfter institutional review board approval, 30 age- and sex- stratified healthy volunteers were studied. The subjects received consecutive stepwise increasing target-controlled infusions of dexmedetomidine, remifentanil, and remifentanil with a fixed dexmedetomidine background concentration. Drug effects were measured using binary (yes or no) endpoints: no response to calling the subject by name, tolerance of shaking the patient while shouting the name ("shake and shout"), tolerance of deep trapezius squeeze, and tolerance of laryngoscopy. The drug effect was measured using the electroencephalogram-derived "Patient State Index." Pharmacokinetic-pharmacodynamic modeling related the administered dexmedetomidine and remifentanil concentration to these observed effects.ResultsThe binary endpoints were correlated with dexmedetomidine concentrations, with increasing concentrations required for increasing stimulus intensity. Estimated model parameters for the dexmedetomidine EC50 were 2.1 [90% CI, 1.6 to 2.8], 9.2 [6.8 to 13], 24 [16 to 35], and 35 [23 to 56] ng/ml, respectively. Age was inversely correlated with dexmedetomidine EC50 for all four stimuli. Adding remifentanil did not increase the probability of tolerance of any of the stimuli. The cerebral drug effect as measured by the Patient State Index was best described by the Hierarchical interaction model with an estimated dexmedetomidine EC50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC50 of 1.6 [0.87 to 2.7] ng/ml.ConclusionsLow dexmedetomidine concentrations (EC50 of 0.49 ng/ml) are required to induce sedation as measured by the Patient State Index. Sensitivity to dexmedetomidine increases with age. Despite falling asleep, the majority of subjects remained arousable by calling the subject's name, "shake and shout," or a trapezius squeeze, even when reaching supraclinical concentrations. Adding remifentanil does not alter the likelihood of response to graded stimuli.

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