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Dexmedetomidine pharmacokineticpharmacodynamic modelling in healthy volunteers, 1 : influence of arousal on bispectral index and sedation

(2017) BRITISH JOURNAL OF ANAESTHESIA. 119(2). p.200-210
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Abstract
Background. Dexmedetomidine, a selective alpha(2)-adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. Methods. In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokineticpharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. Results. We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. Conclusions. The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation.
Keywords
CONTROLLED INFUSION, PROPOFOL, PHARMACODYNAMICS, CONSCIOUSNESS, REMIFENTANIL, SEVOFLURANE, AGE, dexmedetomidine, healthy volunteers, hypnotics and sedatives, noise, pharmacology

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Chicago
Colin, Pieter, LN Hannivoort, DJ Eleveld, KMEM Reyntjens, AR Absalom, HEM Vereecke, and Michel Struys. 2017. “Dexmedetomidine Pharmacokineticpharmacodynamic Modelling in Healthy Volunteers, 1 : Influence of Arousal on Bispectral Index and Sedation.” British Journal of Anaesthesia 119 (2): 200–210.
APA
Colin, P., Hannivoort, L., Eleveld, D., Reyntjens, K., Absalom, A., Vereecke, H., & Struys, M. (2017). Dexmedetomidine pharmacokineticpharmacodynamic modelling in healthy volunteers, 1 : influence of arousal on bispectral index and sedation. BRITISH JOURNAL OF ANAESTHESIA, 119(2), 200–210.
Vancouver
1.
Colin P, Hannivoort L, Eleveld D, Reyntjens K, Absalom A, Vereecke H, et al. Dexmedetomidine pharmacokineticpharmacodynamic modelling in healthy volunteers, 1 : influence of arousal on bispectral index and sedation. BRITISH JOURNAL OF ANAESTHESIA. 2017;119(2):200–10.
MLA
Colin, Pieter et al. “Dexmedetomidine Pharmacokineticpharmacodynamic Modelling in Healthy Volunteers, 1 : Influence of Arousal on Bispectral Index and Sedation.” BRITISH JOURNAL OF ANAESTHESIA 119.2 (2017): 200–210. Print.
@article{8532512,
  abstract     = {Background. Dexmedetomidine, a selective alpha(2)-adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. 
Methods. In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokineticpharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. 
Results. We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. 
Conclusions. The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation.},
  author       = {Colin, Pieter and Hannivoort, LN and Eleveld, DJ and Reyntjens, KMEM and Absalom, AR and Vereecke, HEM and Struys, Michel},
  issn         = {0007-0912},
  journal      = {BRITISH JOURNAL OF ANAESTHESIA},
  keywords     = {CONTROLLED INFUSION,PROPOFOL,PHARMACODYNAMICS,CONSCIOUSNESS,REMIFENTANIL,SEVOFLURANE,AGE,dexmedetomidine,healthy volunteers,hypnotics and sedatives,noise,pharmacology},
  language     = {eng},
  number       = {2},
  pages        = {200--210},
  title        = {Dexmedetomidine pharmacokineticpharmacodynamic modelling in healthy volunteers, 1 : influence of arousal on bispectral index and sedation},
  url          = {http://dx.doi.org/10.1093/bja/aex085},
  volume       = {119},
  year         = {2017},
}

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