Dexmedetomidine pharmacodynamics in healthy volunteers: Striking a balance between the hypnotic and sedative properties and the haemodynamic side effects.
Pieter J. Colin (1,2), Laura N. Hannivoort (1), Douglas J. Eleveld (1), Koen M. Reyntjens (1), Anthony R. Absalom (1), Hugo E.M. Vereecke (1), Michel M.R.F. Struys (1,3)
(1) Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands; (2)Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Belgium; (3) Department of Anesthesia, Ghent University, Gent, Belgium.
Objectives: To develop a PKPD model which allows the description of dexmedetomidine (DMED) induced effects on clinical measures of hypnosis and sedation and haemodynamic side effects. A secondary goal was to investigate the effects of stimulation on the sedative properties of DMED. For this, two methods of stimulation were studied: continuous background auditory stimulation and short, sudden verbal/tactile/painful stimulation.
Methods: DMED plasma concentrations, Bispectral index (BIS), Modified Observer’s Assessment of Alertness/Sedation scale (MOAA/S), mean arterial pressure (MAP) and heart rate (HR) were recorded from 18 healthy volunteers on two separate occasions. DMED was dosed using a target-controlled infusion system[1]. Volunteers were isolated from background noise during 1 session and were exposed to looped operating room background noise in another session. In a sequential PKPD modelling approach using NONMEM, we explored the concentration-response relationship between DMED and the different endpoints.
Results: The modelling revealed an increasing delay between plasma concentrations and HR, BIS, MAP and MOAA/S, with half-lives for effect-site equilibration ranging from 1.7 to 14.3 min. Concentration-responses were described by an Emax model (HR), a double Emax model (MAP) and a latent-variable based linear interpolation between two Emax models (BIS). The BIS model adequately described the BIS signal both before and after sudden stimulation. MOAA/S were best described using a proportional odds logistic regression model with different C50s for both sessions. No relevant covariate relationships were detected, apart from those already included in the PK model[2] and the influence of age on the baseline MAP.
Conclusions: Our model provides valuable insight in the phenomenon of DMED mediated arousable sedation and the influence of sudden stimulation on this arousability. Moreover, it shows that by depriving a volunteer from background noise the sensitivity towards the sedative effects decrease. Finally, simulations show that BIS is useful for guiding DMED dosing and that its relationship with the MOAA/S scale is similar to other hypnotics, such as propofol. Also, the haemodynamic side effects and the DMED induced hypnotic and sedative properties go hand in hand, such that the former might serve as a surrogate for the latter when BIS monitoring is not available to guide dosing.
References:
[1] Dyck JB, Maze M, Haack C, Azarnoff DL, Vuorilehto L, Shafer SL: Computer-controlled infusion of intravenous dexmedetomidine hydrochloride in adult human volunteers. Anesthesiology 1993; 78: 821-8
[2] Hannivoort LN, Eleveld DJ, Proost JH, Reyntjens KM, Absalom AR, Vereecke HE, Struys MM: Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers. Anesthesiology 2015; 123: 357-67
