Maintaining a patient within a specific range of consciousness via precisely controlled anesthetic drug concentrations is critical to safe and efficacious anesthesia. Level of consciousness can assessed by the bispectral index (BIS), an electroencephalographic parameter derived from a proprietary algorithm that converts recordings from a single channel of a frontal EEG into an index of hypnotic level ¹. The short-acting anesthetic propofol can generally be well-titrated to maintain this BIS within a set range by target-controlled infusion (TCI). Indeed, precise propofol TCI allows anesthesia providers to stabilize blood concentrations and swiftly respond to any signs of inadequate anesthetic depth ². 

While a number of studies in various clinical contexts have confirmed that propofol sedation using TCI is a safe and effective anesthetic technique ^3–5, incurring minor rates of adverse events, a certain degree of variability in propofol concentrations remains nonetheless.

One 2005 study assessed the accuracy of the method in human volunteers with two different sedative concentrations, comparing via a regression analysis the plasma propofol concentrations predicted by target-controlled infusion, supported by a pharmacokinetic model and infusion pump, with actual plasma concentrations ⁶. Results demonstrated little systematic bias, but poor precision, as the actual plasma concentration could be predicted with 95% confidence only within a certain limited range of concentrations (0.44-1.38 µg/ml).

Another 2005 study developed a mathematical model to predict the variability of any arbitrary drug delivery method, comparing their simulation with the experimental data of 1,000 patients receiving propofol by bolus injection, conventional infusion, or TCI ⁷. Results revealed the greatest amount of variability with a bolus injection, both in their simulation and experimental data. In addition, they concluded that TCI devices neither create nor eliminate biological variability, which is an intrinsic property of the drug rather than the TCI delivery system. However, TCI devices can be programmed to minimize biological variability by integrating patient-specific covariates into advanced pharmacokinetic models aimed at precise individual drug dosing.

Finally, a recent 2021 study sought to better understand this variability. To this end, an intraoperative database consisting of propofol target concentrations and BIS values 30 minutes after incision and vital signs from over 10,000 patients was mined to identify patients who underwent general endotracheal anesthesia using propofol (titrated to BIS), fentanyl, remifentanil, and rocuronium ⁸, after which data were analyzed by descriptive statistics. Results revealed that higher BIS values were correlated with higher propofol concentrations. In addition, only about 10% of the variability in propofol concentrations was accounted for by patient age and weight. These findings demonstrated substantial residual variability in covariate-adjusted propofol concentrations titrated to BIS, only a small portion of which is clearly linked to patient demographic factors.

Findings from these studies, highlighting a certain degree of pharmacokinetic variability inherent to TCI drug delivery systems, help explain the differences in responses to propofol sedation. This said, further research on the factors contributing to this variability, including patient demographic information, is warranted. This research has key implications for the development of new pharmacokinetic models for propofol target-controlled infusion.

References 

1. Pillai, A. Bispectral Index. in Understanding Anesthetic Equipment and Procedures: A Practical Approach (2015). doi:10.5005/jp/books/12503_30 

2. Gale, T., Leslie, K. & Kluger, M. Propofol anaesthesia via target controlled infusion or manually controlled infusion: Effects on the bispectral index as a measure of anaesthetic depth. Anaesth. Intensive Care (2001). doi:10.1177/0310057×0102900602 

3. García Guzzo, M. E. et al. Deep sedation using propofol target-controlled infusion for gastrointestinal endoscopic procedures: A retrospective cohort study. BMC Anesthesiol. (2020). doi:10.1186/s12871-020-01103-w 

4. Ogawa, T. et al. Propofol sedation with a target-controlled infusion pump in elderly patients undergoing ERCP. Gastrointest. Endosc. (2020). doi:10.1016/j.gie.2020.03.002 

5. Burton, F. M. et al. Propofol Target-Controlled Infusion in Emergency Department Sedation (ProTEDS): A multicentre, single-arm feasibility study. Emerg. Med. J. (2021). doi:10.1136/emermed-2020-209686 

6. Frölich, M. A., Dennis, D. M., Shuster, J. A. & Melker, R. J. Precision and bias of target controlled propofol infusion for sedation. Br. J. Anaesth. (2005). doi:10.1093/bja/aei081 

7. Hu, C., Horstman, D. J. & Shafer, S. L. Variability of target-controlled infusion is less than the variability after bolus injection. in Anesthesiology (2005). doi:10.1097/00000542-200503000-00024 

8. Schnider, T. W., Minto, C. F., Egan, T. D. & Filipovic, M. Relationship between Propofol Target Concentrations, Bispectral Index, and Patient Covariates during Anesthesia. Anesth. Analg. (2021). doi:10.1213/ANE.0000000000005125