Age progression from vicenarians (20-29year) to nonagenarians (90-99year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography.

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task. Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29year) to nonagenarians (90-99year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (Cp) to gradually reach 3.5μgmL-1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis. Age was significant covariate for baseline BIS effect (E0), inhibitory propofol concentration at 50% BIS decline (IC50) and maximum BIS decline (Emax). First-order rate constant Ke0 of 0.47min-1 in vicenarians (20-29year) gradually increased with age-progression to 1.85min-1 in nonagenarians (90-99year). Simulation modelling showed that clinically recommended Cp of 3.5μgmL-1 for 20-29year BIS 50 should be reduced to 3.0 for 30-49year, 2.5 for 50-69year and 2.0 for 80-89year. We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades' age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5μgmL-1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5μgmL-1 for 20-29year should be gradually decreased to 2.0μgmL-1 for 80-89year. European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.