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

Abstract

Background: 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.

Methods: Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29 year) to nonagenarians (90-99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (C_p) to gradually reach 3.5 μg mL^-1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis.

Results: Age was significant covariate for baseline BIS effect (E₀), inhibitory propofol concentration at 50% BIS decline (IC₅₀) and maximum BIS decline (E_max). First-order rate constant K_e0 of 0.47 min^-1 in vicenarians (20-29 year) gradually increased with age-progression to 1.85 min^-1 in nonagenarians (90-99 year). Simulation modelling showed that clinically recommended C_p of 3.5 μg mL^-1 for 20-29 year BIS 50 should be reduced to 3.0 for 30-49 year, 2.5 for 50-69 year and 2.0 for 80-89 year.

Conclusion: 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 C_p of 3.5 μg mL^-1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of C_p 3.5 μg mL^-1 for 20-29 year should be gradually decreased to 2.0 μg mL^-1 for 80-89 year.

Clinical trial registry numbers: 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.

Keywords: Age; Bispectral index; Diagnostic accuracy; Electroencephalography; Pharmacokinetic–pharmacodynamic; Statistical model.