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.

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 micrograms/kg alfentanil and 0.5 mg/kg indocyanine green. Arterial blood samples were obtained at baseline, 1 minute, every 1/2 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.

Indocyanine green kinetics characterize blood volume and flow distribution and their alteration by propranolol.

BACKGROUND AND OBJECTIVES: Although indocyanine green can be used to estimate cardiac output and blood volume independently, a recirculatory multicompartmental indocyanine green model enables description of these and additional intravascular events. Our model was used to describe the effect of propranolol on blood volume and flow distribution in humans. METHODS: Indocyanine green disposition was determined twice in four healthy adult men, once during a propranolol infusion that decreased cardiac output. After injection of indocyanine green, arterial blood was collected frequently for 2 minutes and less frequently thereafter. Plasma indocyanine green concentrations were measured by HPLC. The recirculatory pharmacokinetic model incorporates data from both the initial transient oscillations and the later post-mixing portions of the blood indocyanine green concentration versus time curves to characterize not only blood volume and cardiac output but also their distribution among a central blood volume and fast and slow peripheral volumes in lumped parallel circuits. Flow through the central circulation (cardiac output) is described by two parallel Erlang distribution functions generated by two linear chains of compartments in parallel. RESULTS: Propranolol reduced cardiac output from 10.6 to 4.1 L/min. Most of the decrease in cardiac output was at the expense of blood flow to the fast peripheral circuit, which represented nonsplanchnic circulation. Propranolol also reduced the blood volume of the fast peripheral circuit by more than half. CONCLUSION: Our indocyanine green model is able to derive estimates of blood volume and cardiac output, as well as their systemic distribution during different physiologic conditions.

Pulmonary artery balloon counterpulsation for right ventricular failure: I. Experimental results.

The effects of pulmonary artery balloon counterpulsation (PABC) as a circulatory assist for the failing right ventricle were investigated. Sixteen anesthetized dogs underwent instrumentation to measure cardiac output and to record pressures in both ventricles, the pulmonary artery, and the aorta. Autonomic control of the heart was surgically and pharmacologically ablated. A specially designed counterpulsation balloon was inserted through the right ventricular (RV) outflow tract into the pulmonary artery. Pulmonary hypertension, induced acutely by the microembolization of the pulmonary circulation with glass beads combined with infusion of serotonin, served as a model for development of acute RV failure. Immediate effects of PABC were investigated in 10 dogs during normal function and failure of the right ventricle at different levels of preload. After further embolization which caused progressive cardiogenic shock, the effects of 10 minutes of PABC, and of its withdrawal, were examined. In all cases, PABC immediately decreased RV preload and afterload. In the failing right ventricle, counterpulsation also significantly increased cardiac output. Progressive cardiogenic shock was successfully reversed by PABC; after 10 minutes of counterpulsation, increases in cardiac output (+53%), arterial pressure (+55%), and RV minute work (+62%) were observed, paralleled by a fall in RV preload (-22%). After PABC was discontinued, the circulatory status again began to deteriorate. We conclude that PABC effectively improves function of the failing right ventricle caused by acute pulmonary hypertension.

Induction and maintenance of anesthesia in dogs by intravenous administration of methohexital.

OBJECTIVE: To devise and test an i.v. methohexital infusion regimen for induction and maintenance of surgical anesthesia in dogs from which they would rapidly recover. DESIGN: Dose-response and plasma concentration-effect study. ANIMALS: 11 clinically normal dogs. PROCEDURE: Bolus methohexital pharmacokinetic variables were determined in ketamine- and pentobarbital-anesthetized dogs. Plasma methohexital concentrations required to inhibit purposeful movement in response to painful stimuli were determined during a stepped methohexital infusion in the same dogs on a second occasion. These pharmacokinetic/pharmacodynamic data were next used to design a bolus and two-stage infusion regimen that would result in stable plasma methohexital concentrations with prolonged infusion. This regimen was tested in a second group of dogs. RESULTS: Mean steady-state volume of distribution of methohexital in the anesthetized dogs was 1.50 L/kg of body weight and mean elimination clearance was 10.2 ml/kg/min. Mean plasma concentrations required to prevent movement response to a noxious stimulus and at which the dogs could be extubated were 11.8 and 6.9 micrograms/ml, respectively. After a 6-hour infusion, recovery of airway reflexes sufficient to allow extubation required 67 minutes. CONCLUSIONS: An easily implemented i.v. methohexital infusion regimen for induction and maintenance anesthesia in dogs was developed. During a 6-hour infusion, hemodynamic variables did not change. Use of this regimen resulted in anesthesia of sufficient depth to prevent withdrawal in response to noxious stimuli and in reliable and acceptable emergence times for use in canine survival studies in a cost-effective manner.

Early drug distribution: a generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents.

There is considerable variability in response to intravenously administered anesthetic drugs (e.g., hypnotics, benzodiazepines, and narcotics) that have a rapid onset of effect (such as hypnosis, anxiolysis, and analgesia) and a low margin of safety (because of cardiovascular or respiratory depression, etc.). Although the onset of effect for these drugs occurs seconds to minutes after injection, traditional pharmacokinetic models are based on blood samples that are first obtained after drug effects have peaked. As a result, many studies have failed to provide a pharmacokinetic rationale for dosage adjustments of these drugs.

Using a microcomputer to convert percent response values to probits.

Certain relationships between dose/concentration and percent response/binding in various biochemical systems are sigmoidal rather than linear. This sigmoid relationship is considered linear only over the 20-80 percent range. Appropriate analysis of such data over nearly the entire response/binding range requires the conversion of the percent response data to probits or probability units, producing a linear relationship. While tables of probits are available, the author has incorporated the probability function for probit conversion into a commercially available spreadsheet program. Also included is the Rohlf and Sokal approximation for the area under the normal distribution curve (conversion of probits to cumulative percent). These functions allow use of a spreadsheet to automate the creation of dose-response curves, or standard curves as part of chemical assays (i.e., radioimmunoassay).

Alfentanil clearance is independent of the polymorphic debrisoquin hydroxylase.

Because alfentanil has been shown to inhibit debrisoquin hydroxylase in vitro, and there is considerable variability in the reported elimination clearance of alfentanil, the possible influence of the debrisoquin metabolic phenotype on the elimination clearance of alfentanil was studied. The disposition of alfentanil was determined after rapid intravenous administration to four extensive debrisoquin metabolizers and three poor debrisoquin metabolizers. Debrisoquin hydroxylation phenotype was determined using the urinary dextromethorphan/dextrorphan metabolic ratio test. The disposition of alfentanil was characterized by a three-compartment open mammillary model. There was no relationship between the dextromethorphan/dextrorphan metabolic ratio and the elimination clearance of alfentanil despite a nearly seven hundred-fold range of the metabolic ratio in the seven volunteers. This indicates that the variability in the elimination clearance of alfentanil is not due to the polymorphism of debrisoquin hydroxylase. Nor is this variability due to variable hepatic blood flow because in this study alfentanil clearance was not related to indocyanine green clearance.

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.

Drug-induced hemodynamic perturbations alter the disposition of markers of blood volume, extracellular fluid, and total body water.

Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine facilitate description of intravascular mixing and tissue distribution following intravenous administration. These models characterized physiologic marker disposition in four awake dogs under control conditions and during phenylephrine, isoproterenol, and nitroprusside infusions. Systemic vascular resistance was more than doubled by phenylephrine and was decreased more than 50% by both isoproterenol and nitroprusside. Dye (ICG) dilution cardiac output (CO) was decreased nearly one-third by phenylephrine, was more than doubled by isoproterenol, and was largely unaffected by nitroprusside. Although phenylephrine reduced CO, the fraction of CO represented by nondistributive blood flow nearly doubled at the expense of blood flow to rapidly equilibrating tissues. The area under the blood antipyrine concentration versus time relationship for 3 min after administration (AUC(0-3 min)) during the phenylephrine infusion was nearly 75% larger than control due to both increased first-pass AUC and an increased fraction of CO represented by nondistributive blood flow. The large increase in CO produced by isoproterenol increased blood flow to rapidly equilibrating tissues and relatively decreased blood flow to slowly equilibrating tissues, because some appeared to equilibrate rapidly. Antipyrine AUC(0-3 min) during the isoproterenol infusion decreased more than 30%, due to decreased first-pass AUC. Nitroprusside changed antipyrine intercompartmental clearances in proportion to CO and, hence, had little effect on antipyrine AUC(0-3 min). These data provide further evidence that changes in antipyrine (a lipophilic drug surrogate) blood flow-dependent distribution after rapid i.v. administration are not proportional to changes in CO but depend on both CO and its distribution.

Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells.

BACKGROUND: Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs. METHODS: Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake. RESULTS: Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMVE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamil, but not by UIC2, in a concentration-dependent manner. CONCLUSIONS: The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.

Awake fibreoptic intubation in the patient at high risk of aspiration.

This report describes our experiences with 129 awake oral and nasal fibreoptic intubations in 123 patients considered to be at high risk of aspiration of gastric contents. I.v. sedation was used on all but six occasions. Local anaesthesia was applied to the larynx and trachea through the working channel of the fibrescope on 85 occasions, and by transtracheal injection on 29. Rigid laryngoscopy was necessary after fibreoptic laryngoscopy failed in one patient (with a bleeding peptic ulcer) who vomited a large amount of fresh and clotted blood. No other patient regurgitated during the procedure, and no patient developed evidence of aspiration.

Calculation of an effect compartment rate constant using recovery indices obtained with an isolated arm technique.

We have examined the implications of the theoretical single pharmacokinetic compartment associated with blocker-induced paralysis, in relation to the isolated arm technique. It is assumed that the blocker concentration-effect relationship can be characterized by a sigmoid curve, which incorporates an exponent, s. After tourniquet release, the concentration gradient between the effect compartment and plasma should be large, and elimination related to the rate constant, keo. The major measurement of spontaneous recovery with the isolated arm is the time interval between 75% and 25% twitch depression, T25-T75. The general equation relating these three variables is developed: keo = 2.2/(s x (T25-T75)). Insertion of published values for T25-T75 with isolated arm studies into this equation gave estimates for an intrinsic keo for atracurium, vecuronium, rocuronium and pancuronium.

A recirculatory pharmacokinetic model describing the circulatory mixing, tissue distribution and elimination of antipyrine in dogs.

A model of antipyrine disposition from the moment of its injection was developed incorporating the intravascular mixing component as determined by indocyanine green (ICG) kinetics. The simultaneous dispositions of antipyrine and ICG were characterized in five dogs anesthetized with halothane. After injecting antipyrine and ICG into the right atrium, femoral arterial blood samples were collected every 3 sec for the 1st min and less frequently to 20 min for ICG and to 360 min for antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and modeled with SAAM 30.1. A fully identifiable recirculatory compartmental model, incorporating the ICG recirculatory model with blood flows and time delays, was used to describe antipyrine disposition. Four distinct antipyrine pharmacokinetic tissue compartments and the distribution clearances assigned to them could be estimated: a pulmonary tissue (0.13 +/- 0.05 I, and 2.51 +/- 0.39 liters/min), a very fast equilibrating tissue (0.12 +/- 0.08 I, and 1.33 +/- 0.22 liters/min), a fast equilibrating tissue (3.21 +/- 0.45 I, and 0.74 +/- 0.09 liters/min) and a slow equilibrating tissue (15.94 +/- 1.8 I, and 0.44 +/- 0.13 liters/min). Although this recirculatory model retains the predominant attributes of traditional pharmacokinetic models, it also can describe completely drug concentrations during the mixing transient when many drugs reach peak effect as well as ascertain the role of cardiac output and its distribution in drug disposition.

Uptake of fentanyl in pulmonary endothelium.

Fentanyl is a basic amine shown to have extensive first-pass pulmonary uptake. To evaluate the role of the pulmonary endothelium in this uptake process, the simultaneous pharmacokinetics of [3H]fentanyl and two marker drugs, blue dextran, and [14C]antipyrine, were evaluated in a flow-through system of pulmonary endothelial cells. Fentanyl equilibrium kinetics were determined in a static culture system. The flow-through system consisted of monolayers of bovine pulmonary artery endothelial cells cultured on solid microcarrier beads placed in a chromatography column and perfused at 1.0 ml/min (37 degreesC). Fentanyl and the markers were injected into the perfusate at the top of the column and samples were collected from the eluate at 9-s intervals for 10 min. The pharmacokinetic analyses were based on determinations of mean transit time and flow. Fentanyl was partitioned into the pulmonary endothelial cells 60 times more than the tissue water space marker antipyrine. In the static system, monolayers of bovine pulmonary artery endothelial cells were cultured in 3.8-cm2 wells to which were added 0 to 946 micromol (0-500 microgram/ml) of unlabeled fentanyl citrate and 0.14 micromol of [3H]fentanyl. After a 10-min incubation, solubilized cells were assayed for [3H]fentanyl. Pulmonary endothelial cells contained a higher relative fentanyl concentration at lower fentanyl supernatant concentrations than would be expected if uptake occurred by diffusion alone. These observations can be explained with a model of fentanyl uptake that includes both passive diffusion and saturable active uptake. This suggests that the extensive first-pass pulmonary uptake of fentanyl observed in vivo is due largely to vascular endothelial drug uptake by both a passive and a saturable active uptake process.

Reduction in slow intercompartmental clearance of urea during dialysis.

The kinetics of urea and inulin were analyzed in five anesthetized dogs during sequential 2-hour periods before, during, and after hemodialysis. The distribution of both compounds after simultaneous intravenous injection was characterized by three-compartment models, and the total volumes of urea (0.66 +/- 0.05 L/kg) and inulin (0.19 +/- 0.01 L/kg) distribution were similar to expected values for total body water and extravascular space, respectively. Intercompartmental clearances calculated before dialysis were used to estimate blood flows to the fast and slow equilibrating compartments. In agreement with previous results, the sum of these flows was similar to cardiac output, averaging 101% of cardiac output measured before dialysis (range 72% to 135%). Dialysis was accompanied by reductions in the slow intercompartmental clearances of urea (81%) and inulin (47%), which reflected a 90% attenuation in blood flow supplying the slow equilibrating compartments. This was estimated to result in a 10% average reduction in the efficiency with which urea was removed by dialysis (range 2.0% to 16.4%). Mean arterial pressure fell by less than 5% during dialysis, but total peripheral resistance increased by 47% and cardiac output fell by 35%. In the postdialysis period, total peripheral resistance and cardiac output returned toward predialysis values, but blood flow to the slow equilibrating peripheral compartment was still reduced by 80%. These changes parallel activation of the renin-angiotensin system, but further studies are required to establish causality.