Evaluation of pharmacokinetic models of intravenous dexmedetomidine in sedated patients under spinal anesthesia

Obara, Shinju; Imaizumi, Tsuyoshi; Hakozaki, Takahiro; Hosono, Atsuyuki; Iseki, Yuzo; Sanbe, Norie; Murakawa, Masahiro

doi:10.1007/s00540-017-2424-1

Cited by 6 publications

(5 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, 11 dexmedetomidine pharmacokinetic (PK) models for adults have been published since Dyck et al demonstrated the first PK model in 1993 . Obara et al evaluated the predictive ability of nine PK models of dexmedetomidine and found that the model of Hannivoort et al most accurately predicted the dexmedetomidine plasma concentration in patients undergoing spinal anaesthesia. Recently, Colin et al reported a pharmacokinetic‐pharmacodynamic (PKPD) model for sedation scale and bispectral index (BIS) that was developed in the same subjects used in Hannivoort's PK model .…”

Section: What Is Known and Objectivementioning

confidence: 99%

“…To date, 11 dexmedetomidine pharmacokinetic (PK) models for adults have been published since Dyck et al 4 demonstrated the first PK model in 1993. 5 Obara et al 6 that was developed in the same subjects used in Hannivoort's PK model. 7 This PKPD model enables prediction of the dexmedetomidine effect-site concentration (Ce) and target-controlled infusion (TCI).…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

See 1 more Smart Citation

Target‐controlled infusion of dexmedetomidine effect‐site concentration for sedation in patients undergoing spinal anaesthesia

et al. 2019

View full text Add to dashboard Cite

What is known and objective Dexmedetomidine has been a preferred sedative for patients undergoing regional anaesthesia and is mostly administered via conventional zero‐order infusion. Recently, a pharmacokinetic‐pharmacodynamic (PKPD) model of dexmedetomidine has been published, but no external validation has been reported in clinical trials. We aimed to administer target‐controlled infusion (TCI) of dexmedetomidine at the effect‐site concentration (Ce) to patients undergoing spinal anaesthesia and investigate the relationship between dexmedetomidine Ce and the sedative effects. Methods Forty‐five patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. After confirmation of sensory block level, we initiated effect‐site TCI of dexmedetomidine using Colin's model and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS) with each stepwise increase in the dexmedetomidine Ce. We used a non‐linear mixed‐effects model to determine the PD relationships between the dexmedetomidine Ce and sedation level. Results The dexmedetomidine Ce associated with 50% probability (Ce50) of the MOAA/S scale ≤4, 3 and 2 was 0.57, 0.89 and 1.19 ng/mL, respectively. Mean dexmedetomidine Ce when BIS decreased ≤70 was 0.99 ± 0.15 ng/mL. As dexmedetomidine Ce increased, the MOAA/S scale decreased significantly (correlation coefficient [r] = −.832, P < .0001). BIS decreased significantly with increasing dexmedetomidine Ce (r = −.811, P < .0001) and decreasing MOAA/S scale (r = .838, P < .0001). The most common side effects were hypertension (26.67%) and bradycardia (20%). What is new and conclusion We applied effect‐site TCI of dexmedetomidine in patients undergoing spinal anaesthesia for the first time. Dexmedetomidine Ce correlated significantly with MOAA/S scale and BIS, and was 0.89 and 1.19 ng/mL for moderate and deep sedation, respectively.

show abstract

Section: What Is Known and Objectivementioning

confidence: 99%

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

Target‐controlled infusion of dexmedetomidine effect‐site concentration for sedation in patients undergoing spinal anaesthesia

et al. 2019

View full text Add to dashboard Cite

show abstract

“…38 Absolute values of the performance criteria as published by Varvel et al 33 have to be carefully interpreted in the context of this study, using supraclinical concentrations of dexmedetomidine and taking into account possible drug interactions. Using much lower concentrations of dexmedetomidine, Obara et al 39 validated the Hannivoort model on their data and found also better performance of the Hannivoort model with a median absolute performance error of 18% and median performance error of 5.6%. When evaluating the performance of the Hannivoort model in the lower (clinical) concentration range, we concluded that no adjustments to the model need to be made for use in clinical practice as long as targets do not exceed 3 ng/ml.…”

Section: Interaction Of Remifentanil and Dexmedetomidinementioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

“…Hannivoort found that a three-compartment structural model described the pharmacokinetic data best, but also found that allometric scaling of volumes and clearances resulted in a better fit (Table 3). The Hannivoort PK model performed better than previously published PK models in an initial prospective validation study, where patients received dexmedetomidine during spinal anaesthesia [27]. However, in a subsequent interaction study by Weerink et al, in which healthy volunteers received dexmedetomidine and remifentanil, the Hannivoort PK model performed well only up until targets < 3 ng mL −1 ; but for higher concentrations (which are rarely necessary in clinical practice) non-linear kinetics were suspected and confirmed by Alvarez-Jiminez et al in a closer analysis of both the Hannivoort and Weerink data [35][36][37].…”

Section: The Hannivoort-colin Pkpd Model For Dexmedetomidinementioning

confidence: 84%

General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

Vandemoortele

Hannivoort

Vanhoorebeeck

et al. 2022

JCM

View full text Add to dashboard Cite

Target controlled infusion (TCI) is a clinically-available and widely-used computer-controlled method of drug administration, adjusting the drug titration towards user selected plasma- or effect-site concentrations, calculated according to pharmacokinetic-pharmacodynamic (PKPD) models. Although this technology is clinically available for several anaesthetic drugs, the contemporary commercialised PKPD models suffer from multiple limitations. First, PKPD models for anaesthetic drugs are developed using deliberately selected patient populations, often excluding the more challenging populations, such as children, obese or elderly patients, of whom the body composition or elimination mechanisms may be structurally different compared to the lean adult patient population. Separate PKPD models have been developed for some of these subcategories, but the availability of multiple PKPD models for a single drug increases the risk for invalid model selection by the user. Second, some models are restricted to the prediction of plasma-concentration without enabling effect-site controlled TCI or they identify the effect-site equilibration rate constant using methods other than PKPD modelling. Advances in computing and the emergence of globally collected databases has allowed the development of new “general purpose” PKPD models. These take on the challenging task of identifying the relationships between patient covariates (age, weight, sex, etc) and the volumes and clearances of multi-compartmental pharmacokinetic models applicable across broad populations from neonates to the elderly, from the underweight to the obese. These models address the issues of allometric scaling of body weight and size, body composition, sex differences, changes with advanced age, and for young children, changes with maturation and growth. General purpose models for propofol, remifentanil and dexmedetomidine have appeared and these greatly reduce the risk of invalid model selection. In this narrative review, we discuss the development, characteristics and validation of several described general purpose PKPD models for anaesthetic drugs.

show abstract

Evaluation of pharmacokinetic models of intravenous dexmedetomidine in sedated patients under spinal anesthesia

Abstract: Hannivoort et al.'s pharmacokinetic model, constructed with a dataset obtained from healthy volunteers, can predict dexmedetomidine concentrations best during continuous infusion under spinal anesthesia.

Cited by 6 publications

References 18 publications

Target‐controlled infusion of dexmedetomidine effect‐site concentration for sedation in patients undergoing spinal anaesthesia

Target‐controlled infusion of dexmedetomidine effect‐site concentration for sedation in patients undergoing spinal anaesthesia

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

General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

Contact Info

Product

Resources

About