Pharmacokinetic-Pharmacodynamic Model for Propofol for Broad Application in Anaesthesia and Sedation
Summary by Michelle Adamczyk, MD 10.28.24
https://www.bjanaesthesia.org/article/S0007-0912(18)30051-5/fulltext
Clinical Hypothesis: Can we develop a combined pharmacokinetic-pharmacodynamic model for propofol target-controlled-infusion (TCI), achieving a desired target concentration predictive of BIS in a diverse population?
Take Home Message:
● TIVA and MAC cases often primarily rely on propofol to target an appropriate level of sedation
● A new pharmacokinetic-pharmacodynamic model for propofol target-controlled-infusion was created, using BIS as a targeted endpoint
● The model accurately predicts propofol concentration and BIS for a wide variety of patients, including neonates, elderly, and high BMI
Summary: This research team created a new model for propofol TCI, combining both pharmacodynamic and pharmacokinetic properties. These models are aimed to help clinicians estimate appropriate infusions for desired levels of sedation over time in a diverse group of patients, including neonates, pediatrics, elderly, and individuals with a wide range of BMI (who all have different factors influencing the concentration of propofol in the targeted organ) based on research.
Background:
Previous researchers have created different models to predict the plasma concentration and effect of propofol over time for different populations of patients. These models can be used in infusion pumps or as suggestions to help more accurately dose propofol to desired effect. These techniques have the goal of more accurately optimizing dosing propofol for a stable concentration, such as in TIVA or MAC cases. However, previous models were primarily either based on pharmacokinetics OR pharmacodynamics.
Study Design:
Combined data from previously published data using PK models for propofol, and added data from studies using propofol and BIS, combining 30 studies together overall.
Methods:
Inclusion criteria: Data from 30 available studies was combined. For the PK component data, 1033 individuals- made up of males, females, age ranging from 27 weeks to 88 years, weight from 0.68 kg to 160 kg and using covariates including (postnatal) age, weight, height, sex, BMI, use of concomitant opioids or local anesthetic drugs, and blood sampling site. For PD data, 122 individuals with age from 3-74 years old and weight 15-141 kg.To be included, parameters had to have a corrected Akaike information criterion to decrease at least 20, and had to improve predictive performance of the model.
Exclusion criteria: Parameters which did not improve predictive performance of the model were excluded
Primary outcome: To create a PK-PD model for propofol TCI
Secondary outcome: None
Results:
The created PK model was compared to previously published PK models with better or equivalent performance. The created PD model was also modified to best fit, and then the models were combined. The combined model was ran with TCI simulations and was compared to published recommendations for induction and maintenance dosing of general anesthesia as well as MAC sedation across the various age ranges included in the study.
Discussion/conclusion:
The final model produces recommendations for propofol administration close to previous recommendations for anesthesia in children, adults, and an elderly population and targeting a BIS value of 47 (within the commonly recommended range of BIS 40-60 for GA). However, the model does not account for variable dosing of concomitant opioids, just presence or absence of opioids. Additionally, the model is weaker for young children and adolescents since while the PK model has more of that age group included in their data, the PD model does not have support for those groups.