Do epoch lengths of hypnotic depth indicators affect estimated of blood-brain equilibration rate constants of propofol?

Abstract

This study aimed to investigate the effect of epoch length of hypnotic depth indicators on the blood–brain equilibration rate constant (k_e0) estimates of propofol. Propofol was administered by zero-order infusion (1.5, 3.0, 6, and 12 mg·kg⁻¹·h⁻¹) for one hour in 63 healthy volunteers. The k_e0 of propofol was estimated using an effect-compartment model linking pharmacokinetics and pharmacodynamics, in which response variables were electroencephalographic approximate entropy (ApEn) or bispectral index (BIS) (n = 32 each for propofol infusion rates of 6 and 12 mg·kg⁻¹·h⁻¹). Epoch lengths of ApEn were 2, 10, 30, and 60 seconds (s). The correlations between plasma propofol concentrations (Cp) and BIS and ApEn 2, 10, 30, and 60 s were determined, as was the Ce associated with 50% probability of unconsciousness (Ce_50,LOC). The pharmacokinetics of propofol were well described by a three-compartment model. The correlation coefficient between Cp and ApEn 2, 10, 30, and 60 s were −0.64, −0.54, −0.39, and −0.26, respectively, whereas correlation coefficient between Cp and BIS was −0.74. The blood-brain equilibration half-life based on the k_e0 estimates for ApEn at 2, 10, 30, 60 s and BIS were 4.31, 3.96, 5.78. 6.54, 5.09 min, respectively, whereas the Ce_50,LOC for ApEn at 2, 10, 30, 60 s and BIS were 1.55, 1.47, 1.28, 1.04, and 1.55 μg·ml⁻¹, respectively. Since k_e0, which determines the onset of drug action, varies according to the epoch length, it is necessary to consider the epoch length together when estimating k_e0.