Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy

Abstract

Background: Dexmedetomidine 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. Methods: After 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. results: The 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 EC 50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC 50 of 1.6 [0.87 to 2.7] ng/ml. conclusions: Low dexmedetomidine concentrations (EC 50 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.

Novel drug-independent sedation level estimation based on machine learning of quantitative frontal electroencephalogram features in healthy volunteers

“…13 EEG data for propofol and sevoflurane were recorded using a 16-channel Neuroscan® EEG monitor (Compumedics Limited, Charlotte, NC, USA) in healthy volunteers with sampling frequency of 5 kHz, and were later reduced to 1 kHz during transition to extraction file. For dexmedetomidine, 14 a BrainAmp DC32 amplifier with a BrainVision recorder (Brain Vision Solutions, Montreal, Canada) was used to record the 17-channel EEG at a sampling rate of 5 kHz. In all groups, the volunteers were asked to keep their eyes closed for the entire study duration.…”

Postoperative Effects of Continuous Dexmedetomidine Infusion During Gynecological Laparoscopy: A Randomized, Placebo-Controlled, Double-Blind, Single Center Clinical Trial

“…Remifentanil undergoes very high clearance independent of organ function and infusion duration [23], and this also explains why respiratory depression was not observed in this study. A recent study also concluded that the co-administration of remifentanil and DEX infusion did not influence the arousability during general anesthesia [24]. NRS scores at the first postoperative hour were lower in group D both at rest and at movement.…”

Modelling the PSI response in general anesthesia

“…Research on the effects of remifentanil on PSI are scarce in the literature but it seems that remifentanil alone has a slight effect on the PSI [32]. They observed that PSI values decreased below the PSI baseline predicted by the model with no clear relationship between PSI and measured remifentanil concentrations.…”