Front-End Kinetics Determines the Induction Dose,

Michael J. Avram, Ph.D.

Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL USA

Since IV agents were first used to induce general anesthesia, choosing the appropriate dose has been part of the art and science of the specialty. The dramatic evidence of the potential consequences of this dosing challenge is illustrated by the tragic consequences of the administration of a “standard dose” of thiopental to hypovolemic casualties at Pearl Harbor ⁽¹⁾. Until recently, little has been accomplished to improve the scientific basis of dosage selection.

Studies of the distribution and elimination of IV anesthetics have often used multicompartmental pharmacokinetic models. (Figure 1) ⁽²⁾. However, traditional kinetic parameters are of little use in understanding the kinetic basis of interindividual variability in response to induction doses or rapidly administered loading doses of these agents. Variability in response to IV anesthetics is not due to differences in total volume of distribution, elimination clearance, or elimination half-life, since these minimally affect the plasma drug concentration versus time relationship while these drugs exert their maximal effect and while their effect is being terminated. In addition, a multicompartmental kinetic model often fails to provide a useful estimate of V_C because it is based on infrequently collected blood samples beginning after peak drug concentrations have begun to wane. Finally, the traditional model fails to account for the processes responsible for drug distribution and variability in the dose-response relationship: intravascular mixing; flow (both cardiac output and its peripheral distribution); and diffusion of drug into active and indifferent tissues ⁽³⁾.

Physiologically based pharmacokinetic models describe measured blood and tissue drug concentration histories by apportioning cardiac output, hence drug distribution, among tissues or tissue groups with similar perfusion and drug solubility characteristics⁽²⁾. Physiologic models have provided valuable insights into drug disposition. Price used his model to simulate the fraction of injected dose in the brain of patients in whom cardiac output and blood flow to indifferent tissues, such as muscle and portal tissues, are decreased or increased ⁽⁴⁾. These simulations explained reduced dose requirements of patients in hemorrhagic shock because in this condition the fraction of the dose received by the brain is very high and its rate of removal is very slow owing to decreased blood flow to other tissues. Price also predicted that patients with increased blood flow to indifferent tissues (e.g., apprehensive patients) would require larger doses of thiopental because a smaller fraction of the dose would appear in the brain.

Wada et al. developed a physiologic model of thiopental disposition in humans on the basis of a scale up of a model developed in rats ⁽⁵⁾. They used their model to simulate arterial plasma thiopental concentrations during and after a one minute infusion to “patients” of different age, gender, and body habitus and to “patients” who differed only in their cardiac output. They predicted slightly higher peak concentrations in women and the elderly and a nearly 50% higher peak concentration in patients with a 50% decrease in cardiac output. Patients who have a 50% increase in cardiac output were predicted to have about 25% lower peak concentrations.

Despite the clear evidence of the importance of cardiac output in early drug distribution, a study of patient variability in thiopental dose requirements needed to reach EEG burst suppression found that the variability could not be explained by cardiac output alone. ⁽⁶⁾

A recirculatory multicompartmental model of the disposition of physiologic markers based on frequent early arterial blood sampling (Figure 2) describes drug disposition from the moment of injection. ⁽⁷⁾ The recirculatory model retains the best aspects of traditional and physiologically-based models in addition to having unique advantages. The traditional and recirculatory models describe data collected from individuals under various conditions while the physiologic model requires tissue drug concentrations and organ blood flow measurements, which are often unavailable. The physiologic and recirculatory models incorporate physiologic factors, such as cardiac output and its distribution, in describing drug disposition. The recirculatory model estimates tissue compartment blood flows based on the intercompartmental clearance of a flow-limited tissue distribution marker. However, because of arteriovenous anastamoses or diffusion barriers, a portion of cardiac output returns blood to the central circulation after minimal drug loss due to tissue distribution. The recirculatory model uses drug concentrations of the recirculation peak to describe this nondistributive blood flow, or clearance, which can be thought of as a pharmacokinetic shunt.

Early drug distribution kinetics (front-end kinetics) of IV anesthetics, the importance of which has been appreciated recently, ^(VIII) have implications for the practicing anesthesiologist. Because both cardiac output and nondistributive blood flow are influenced by patient physiology and determine the drug concentration versus time relationship in the critical first minutes after drug administration, front-end kinetics determine the rate and extent of both drug distribution to the brain and its dilution by distribution to indifferent tissues, hence dose requirements.

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