Tom C. Krejcie

Cauda equina syndrome after continuous spinal anesthesia.

Four cases of cauda equina syndrome occurring after continuous spinal anesthesia are reported. In all four cases, there was evidence of a focal sensory block and, to achieve adequate analgesia, a dose of local anesthetic was given that was greater than that usually administered with a single-injection technique. We postulate that the combination of maldistribution and a relatively high dose of local anesthetic resulted in neurotoxic injury. Suggestions that may reduce the potential for neurotoxicity are discussed. Use of a lower concentration and a “ceiling” or maximum dose of local anesthetic to establish the block should be considered. If maldistribution of local anesthetic is suspected (as indicated by a focal sensory block), the use of maneuvers to increase the spread of local anesthetic is recommended. If such maneuvers prove unsuccessful, the technique should be abandoned.

Using Front-end Kinetics to Optimize Target-controlled Drug Infusions

Background The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target. Methods Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 &mgr;g/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated. Results Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters. Conclusions Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.

Determinants of thiopental induction dose requirements

Dose requirements for thiopental anesthetic induction have significant age- and gender-related variability. We studied the association of the patient characteristics age, gender, weight, lean body mass, and cardiac output with thiopental requirements. Doses of thiopental, infused at 150 mg/min, required to reach both a clinical end-point and an electroencephalographic (EEG) end-point were determined in 30 males and 30 females, aged 18--83 yr. Univariate least squares linear regression analysis revealed outliers in the relationships of age, weight, lean body mass, and cardiac output to thiopental dose at clinical and EEG endpoints. Differential weighting of data points minimized the effect of outliers in the construction of a robust multiple linear regression model of the relationship between several selected independent variables and the dependent variables thiopental dose at clinical and EEG endpoints. The multiple linear regression model for thiopental dose at the clinical end-point selecting the regressor variables age, weight, and gender (R2 = 0.76) was similar to that for age, lean body mass, and gender (R2 = 0.75). Thiopental dose at the EEG end-point was better described by models selecting the variables age, weight, and cardiac output (R2 = 0.88) or age, lean body mass, and cardiac output (R2 = 0.87). Although cardiac output varied with age, age always remained a selected variable. Because weight and lean body mass differed with gender, their selection as variables in the model eliminated gender as a selected variable or minimized its importance.

What determines anesthetic induction dose? It's the front-end kinetics, doctor!

ince IV anesthetics were first used to inducegeneral anesthesia, choosing the appropriatedose has been a combination of the art and sci-ence of the specialty. The dramatic evidence of thepotential consequences of this dosing challenge is per-haps best illustrated by the tragic outcomes of theadministration of a “standard dose” of thiopental tothe hypovolemic victims of the Japanese attack onPearl Harbor (1). Until recently, little has been accom-plished to improve the scientific basis of dosageselection.Fisher (2), in his editorial, “(Almost) everything youlearned about pharmacokinetics was (somewhat)wrong!” presented some of the problems associatedwith the application of conventional pharmacokineticcompartmental modeling to situations in which theplasma concentrations of the drug are changing rap-idly. In this editorial, we shall examine various ap-proaches to modeling

The relationship of age to the pharmacokinetics of early drug distribution: the concurrent disposition of thiopental and indocyanine green

The optimal dose of thiopental depends both on its initial distribution kinetics, which determine its concentrations at sites of action after iv administration, and on its pharmacodynamics. The disposition of concomitantly administered thiopental and indocyanine green (ICG), a marker of intravascular space, was determined in 21 patients, aged 20-80 yr, to determine the pharmacokinetic basis of increased reactivity of the elderly to thiopental. Data obtained from frequent early arterial blood samples and the simultaneous modelling of thiopental disposition with that of ICG allow a rigorous description of early drug distribution. Their disposition is described by a two-compartment ICG model and a four-compartment thiopental model that have a common central volume, V1, the central blood pool. ICG distributes, by intravascular mixing, from V1 to a peripheral blood volume that is a subset of a rapidly equilibrating (fast) peripheral thiopental compartment; elimination clearance of both drugs is modelled from these peripheral compartments. In contrast to the results of others, the results of this study demonstrate that V1 does not decrease with increasing age. The only pharmacokinetic variable that changed with age is the intercompartmental clearance (Cl21) from V1 to the rapidly equilibrating peripheral volume, V2, which decreased 35% between the ages of 20-80 yr. The authors suggest that V1 and the intercompartmental clearances may be used together to explain smaller dose requirements in individuals with increased reactivity to thiopental; such an analysis does not predict that dose adjustments should be made on the basis of age alone.

The relationship between alfentanil distribution kinetics and cardiac output

The relationship between cardiac output and the tissue distribution of alfentanil was investigated in seven healthy volunteers. Subjects were given 10 µg/kg alfentanil and 0.5 mg/kg indocyanine green. Arterial blood samples were obtained at baseline, 1 minute, every ½ minute until 5 minutes, and then every minute until 15 minutes after the drug injection was begun. Subsequent samples were collected to 6 hours. Cardiac output was measured continuously by use of thoracic bioimpedance. Alfentanil pharmacokinetics were modeled with both a standard three‐compartment model and a four‐compartmental model based in part on the two‐compartmental pharmacokinetics of indocyanine green. The sum of intercompartmental clearances for both the three‐ and four‐compartment models were significantly correlated with the measured cardiac outputs, r = 0.93 and r = 0.88, respectively. These findings indicate that the intercompartmental clearance (i.e., tissue distribution) of alfentanil is largely determined by cardiac output (i.e., tissue blood flow).

Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis

From a sample of 149 unrelated Spaniards, individuals were phenotyped for their ability to hydroxylate debrisoquin and O‐demethylate dextromethorphan. The distribution of urinary metabolic ratios for each test was analyzed by univariate gaussian mixture distributions analysis to determine the number of populations, the mean and standard deviation of the metabolic ratios for each population, and the proportion belonging to each population. For the 124 subjects phenotyped with both the debrisoquin and dextromethorphan tests a bivariate analysis was performed. The results demonstrate that both tests similarly separated this sample into two populations, with 10% belonging to poor metabolizer phenotypes. In addition, the correlation between the metabolic ratios from each test is significant, indicating that they are measuring the same biologic trait and the certainty of correctly identifying the debrisoquin oxidation phenotype of an individual is improved by using the results of both tests.

Use of parallel erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog.

A Recirculatory Model of the Pulmonary Uptake and Pharmacokinetics of Lidocaine Based on Analysis of Arterial and Mixed Venous Data from Dogs

Pulmonary uptake of basic amine xenobiotics such as lidocaine may influence the onset of drug effect and ameliorate toxicity. To date, pharmacokinetic analysis of pulmonary drug uptake has been only semiquantitative and ill-suited for relating pharmacodynamics to pharmacokinetics or jar estimating the time course of the fraction of drug dose residing in the lung during a single pass. We have developed recirculatory models in an experiment in which lidocaine was injected into the right atrium simultaneously with markers of intravascular space (indocyanine green) and total body water (antipyrine): this was followed by rapid arterial and mixed venous blood sampling. Such models are interpretable physiologically and are capable of characterizing the kinetics of the pulmonary uptake of lidocaine in addition to peripheral tissue distribution and elimination. The apparent pulmonary tissue volume of lidocaine (39 ml/kg) was nearly ninefold greater than that of antipyrine (4.5 ml/kg). The recirculatory model characterized both arterial and mixed venous data, but the latter data were not essential for estimating lidocaines pulmonary disposition either before or after recirculation of drug was evident.

Intravascular mixing and drug distribution: The concurrent disposition of thiopental and indocyanine green

The dispositions of concomitantly administered indocyanine green (ICG) and thiopental were determined in 12 patients undergoing general anesthesia and surgery. These were best characterized by a two‐compartment ICG model and a four‐compartment thiopental model, chiefly because of data obtained from frequent early arterial blood samples. The models had a common central volume (V1), and the peripheral ICG compartment was the subset of a peripheral thiopental compartment. The two‐compartment ICG model described its mixing within the intravascular space. The traditional Vc of three‐compartment models of thiopental disposition is described by the present four‐compartment model as an initial distribution volume, V1, codetermined by ICG as central blood volume, and a rapidly equilibrating peripheral volume, V4. The combined simultaneous ICG‐thiopental model more clearly reflects physiology than do the results of earlier curve‐fitting techniques and may be useful in studying the pharmacokinetic basis of altered reactivity to thiopental.