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

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WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Patients sedated with standard clinical doses of dexmedetomidine can be readily arousedDexmedetomidine doses producing mild to deep sedation lack significant analgesic effectRemifentanil is an opioid analgesic with only modest sedative propertiesAddition of remifentanil to propofol sedation reduces the propofol concentration required to reach tolerance of shaking the patient while shouting their name and tolerance of laryngoscopy WHAT THIS ARTICLE TELLS US THAT IS NEW: This three-phase crossover trial to study the pharmacodynamic interaction between remifentanil and dexmedetomidine in 30 age- and sex-stratified healthy volunteers found that, despite falling asleep, most subjects remained arousable by calling their name, shaking the subject while shouting their name, or a trapezius squeeze, even after reaching supraclinical concentrationsAdding remifentanil to dexmedetomidine sedation did not affect the likelihood of response to graded stimuliDexmedetomidine potency increased with increasing age 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 EC50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC50 of 1.6 [0.87 to 2.7] ng/ml.

CONCLUSIONS: Low 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.

Original languageEnglish
Pages (from-to)1004-1017
Number of pages14
Issue number5
Publication statusPublished - Nov-2019

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