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Schnider et al. 1999 - The Influence of Age on Propofol Pharmacodynamics

The Influence of Age on Propofol Pharmacodynamics
Schnider, Thomas W. Dr med; Minto, Charles F. MB, ChB; Shafer, Steven L. MD; Gambus, Pedro L. MD; Andresen, Corina MD; Goodale, David B. DDS, PhD; Youngs, Elizabeth J. MD
Anesthesiology 90(6):p 1502-1516, June 1, 1999
Glossary
Biphasic PD model
A pharmacodynamic model that describes a concentration-effect relationship that rises and then falls at very high concentrations. Used here because propofol at high doses causes burst suppression on the EEG, which a simple sigmoid model cannot capture.
Burst suppression
An EEG pattern seen at very deep levels of anesthesia, where periods of normal-looking electrical activity (bursts) alternate with periods of near-silence (suppression). The EEG metric peaks at moderate propofol concentrations and then decreases at very high concentrations as the brain enters burst suppression, producing the biphasic shape.
C50
The effect-site concentration producing 50% of maximum drug effect. Analogous to EC50. In this paper, C50 for loss of consciousness decreases with age, meaning older patients are more sensitive to propofol.
Convolution
A mathematical operation used here to compute the effect-site concentration over time from the plasma concentration time course and the ke0 parameter. Avoids numerically integrating the effect-site ODE at every candidate ke0 during optimization.
EEG
Electroencephalogram. A measure of electrical activity in the brain. Used here as the pharmacodynamic endpoint. The authors derived their own EEG measure from raw frequency components using semilinear canonical correlation.
Effect-site
A hypothetical compartment representing the brain or site of drug action. Drug must transfer from plasma to the effect-site before producing an effect. The rate of transfer is described by ke0.
Hysteresis
The lag between plasma concentration and drug effect. When propofol is infused, the effect rises after the plasma concentration peaks because the drug must first equilibrate with the effect-site.
ke0
The rate constant describing how fast drug equilibrates between plasma and the effect-site. A larger ke0 means faster equilibration and less hysteresis. Estimated in this paper as 0.456 min$^{-1}$, implying a predicted time to peak effect of 1.7 min after bolus.
Pharmacodynamics (PD)
The study of how a drug affects the body.
Pharmacokinetics (PK)
The study of how a drug moves through the body.
Semilinear canonical correlation
A statistical technique used to find the optimal linear combination of EEG frequency components that correlates best with the effect-site concentration. Produces a single scalar EEG measure tailored to the drug being studied, rather than relying on a generic processed index.

Paragraph-by-Paragraph Commentary, but Why?

This writeup is part of an ongoing effort to go through the foundational anesthesia literature in excruciating detail, paragraph by paragraph, to ensure that every concept behind the FluxSim Simulator Library is fully understood (by me, the developer). Each section of the paper is followed by commentary and notes that provide the necessary context for full understanding.

This is the companion paper to Schnider et al. 1998. The PK parameters come from that paper and the PD parameters come from this paper.

Propofol PK Rapid C2, V2 Plasma C1, V1 Slow C3, V3 Cl2 Cl3 Cl1 elimination ke0 PD Effect-site (brain) Ce (virtual)

Three-compartment PK model with virtual effect-site compartment (dashed pink). Propofol enters the plasma compartment and distributes to rapid and slow peripheral compartments via Cl₂ and Cl₃. Metabolic clearance Cl₁ eliminates drug from plasma. ke0 governs equilibration between plasma and the effect-site, which has no volume and does not affect the PK.

Abstract

Background: The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect.

Methods: The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 $ \mu \text{g} \cdot \text{kg}^{-1} \cdot \text{min}^{-1}$) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion.

Results: Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 $\text{min}^{-1}$. The predicted time to peak effect after bolus injection ranging [sic] was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with $\text{C}_{50}$ values for loss of consciousness of 2.35, 1.8, and 1.25 $\mu\text{g/ml}$ in volunteers who were 25, 50, and 75 yr old, respectively.

Conclusions: Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

Commentary and Notes

This paper adds the pharmacodynamic (PD) layer on top of the 1998 PK model. The two key outputs are:

  • Rate Constant $\text{ke}_0$: describes how fast propofol equilibrates between plasma and the effect-site (brain). $$ k_{e0} = 0.456 \left[ \text{min}^{-1} \right] $$
  • Sleep Probability $P_{\text{asleep}}:$ describes the probability of being asleep as a function of effect-site concentration and age. $$ P_{\text{asleep}} = \frac{C^\gamma}{C^\gamma + (x \cdot \text{PREP} + y \cdot (1-\text{PREP}))^\gamma} $$ where $C$ is the effect-site concentration, $x$ and $y$ are age-dependent $C_{50}$ values for patients with and without preoperative medication, and PREP is a variable indicating whether or not the patient took a preoperative drug, such as a benzodiazepine, which can reduce the amount of propofol needed to induce hypnosis. The $\gamma$ parameter controls the steepness of the concentration-response curve. The finding that $C_{50}$ for loss of consciousness decreases with age (2.35, 1.80, and 1.25 µg/ml at ages 25, 50, and 75 yr) means older patients require lower propofol concentrations to achieve the same effect.

Introduction

The dose requirement of many hypnotic and analgesic drugs used in anesthesia is reduced in elderly persons. ${}^{\text{1-3}}$ This can be explained by age-related changes in pharmacokinetics, pharmacodynamics, or both. Recently, we showed that the pharmacokinetics of propofol change with age. ${}^{\text{4}}$ The purpose of this analysis was to study the influence of age on the pharmacodynamics of propofol. Specifically, we wanted to characterize the influence of age on propofol potency and on the time course of plasma effect-site equilibrium. As in previous studies, $^{\text{2,5-7}}$ we used the EEG as a sensitive and continuous measure of drug effect.

There is only one published value for the plasma effect-site equilibrium rate constant ($k_{e0}$) for propofol in the peer-reviewed literature, which was reported by Billard et al. ${}^{\text{8}}$ as an incidental finding in a study comparing different EEG measures of drug effect. Accordingly, one purpose of the current study was to have a carefully developed $k_{e0}$ that can be used to predict effect-site concentrations in the clinical setting when combined with an appropriate pharmacokinetics model.

Commentary and Notes

Prior evidence demonstrates that the dose requirements of hypnotic drugs (like midazolam) and analgesic drugs (like remifentanil) change with age. Additionally, the authors themselves demonstrated that age is a meaningful covariate on propofol pharmacokinetics (PK). This prior literature serves as a strong basis for the following hypothesis: $$ H = \text{Age } \textit{IS } \text{a significant covariate on the pharmaco} \textbf{dynamics} \text{ (PD) of propofol.} $$

Additionally, no high-fidelity $k_{e0}$ existed at the time. The proposed study doubled as an opportunity to carefully develop this value. Schnider et al. tended to design highly efficient studies, targeting numerous hypotheses simultaneously.

Methods

Clinical Protocol

After we received approval for the study protocol from the Stanford Institutional Review Board, we enrolled 25 healthy volunteers into the study. One persons dropped out because of depression. This person was replaced in the age- and dose-stratified design and was not included in the analysis. The study population and the study design are described in a companion article that reports the influence of age on the pharmacokinetics of propofol.${}^4$

For this randomized, double-blinded, two-period, crossover trial, the participants were stratified into three age groups of eight persons each: 18-34 yr, 35-65 yr, and more than 65 yr. Each volunteer was studied twice and received propofol (Zeneca Pharmaceuticals Group, Wilmington, DE) without EDTA (the commercially available formulation of propofol in the United States before July 1996) or propofol with EDTA (the commercially available formulation of propofol in the United States after July 1996) in each study session. All volunteers received a manually delivered bolus over a median time of 18 s (range, 13-24 s; individual times were not correlated with age). Volunteers aged 65 yr and younger received a bolus dose of 2 mg/kg. Volunteers older than 65 yr received a smaller bolus of 1 mg/kg because of safety concerns. One hour after the bolus dose, a 60-min infusion of propofol was administered. The infusion rate was assigned randomly to 25, 50, 100, or 200 $\mu\text{g} \cdot \text{kg}^{-1} \cdot \text{min} ^ {-1}$, with two volunteers in each age group assigned to each infusion rate. Arterial blood samples were taken at 0, 1, 2, 4, 8, 16, 30, 60, 62, 64, 68, 76, 90, 120, 122, 124, 128, 136, 150, 180, 240, 300, and 600 min during each study session.

To measure the electroencephalograhic (EEG) response, gold cup electrodes were placed over Cz, FP3, FP4, P3, and P4 according to the international 10/20 system. After we gently rubbed the scalp with an abrasive gel (Omniprep; D.O. Weaver Co., Aurora, CO), the electrodes were fixed to the skin with a sticky electrode cream (Grass EC2; AstroMed, West Warwick, RI). The electrodes were manipulated until the impedance was less than 1,500 $\Omega$. The volunteers were asked to lie quietly with closed eyes for 5 min of baseline recording. The EEG was digitized at 128-Hz, 12-bit resolution and stored on a computer hard disk for subsequent processing.

Commentary and Notes

The dosing and blood sample collection protocols were already discussed in the 1998 companion paper and analysis. This paper adds an additional protocol for measuring brain activity via an EEG response.

Using electrodes attached to the head, they were able to record brain wave activity. These are time-series signals which one can perform an FFT on to get the frequency components, which fall into one of the following categories:

  • Gamma and high gamma waves (30 - 100) Hz | heightened awareness
  • Beta waves (12 - 30 Hz) | problem-solving
  • Alpha waves (8 - 12 Hz) | relaxed
  • Theta waves (4 - 8 Hz) | meditation & creativity
  • Delta waves (1 - 4 Hz) | deep sleep

Sleep Duration Analysis

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Electroencephalographic Pharmacodynamic Analysis

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The Electroencephalographic Pharmacodynamic Model

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Estimation of the Effect-site Concentration

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Loss of Consciousness Pharmacodynamic Analysis

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Model Validation

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Results

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Clinical Protocol

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Sleep Duration Analysis

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Electroencephalographic Pharmacodynamic Analysis

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Loss-of-consciousness Pharmacodynamic Analysis

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Model Validation

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Discussion

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Sleep Duration Analysis

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Electroencephalographic Pharmacodynamics Analysis

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Loss-of-consciousness Pharmacodynamic Analysis

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Model Validation

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Conclusions

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References

  1. Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs EJ. The influence of age on propofol pharmacodynamics. Anesthesiology. 1999 Jun;90(6):1502-16. doi: 10.1097/00000542-199906000-00003. PMID: 10360845.
  2. Schnider et al. 1998 - Propofol Pharmacokinetics (companion PK paper)
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