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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.

Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine describe intravascular mixing and tissue distribution after i.v. administration. These models characterized physiologic marker disposition in four awake, splenectomized dogs while they were normovolemic, volume loaded (15% of estimated blood volume added as a starch solution), and mildly and moderately hypovolemic (15 and 30% of estimated blood volume removed). ICG-determined blood volumes increased 20% during volume loading and decreased 9 and 22% during mild and moderate hypovolemia. Dye (ICG) dilution cardiac output (CO) increased 31% during volume loading and decreased 27 and 38% during mild and moderate hypovolemia. ICG-defined central and fast peripheral intravascular circuits accommodated blood volume alterations and the fast peripheral circuit accommodated blood flow changes. Inulin-defined extracellular fluid volume contracted 14 and 21% during hypovolemia. Early inulin disposition changes reflected those of ICG. The ICG and inulin elimination clearances were unaffected by altered blood volume. Neither antipyrine-defined total body water volume nor antipyrine elimination clearance changed with altered blood volume. The fraction of CO not involved in drug distribution had a significant effect on the area under the antipyrine concentration-versus-time relationships (AUC) in the first minutes after drug administration. Hypovolemia increased the fraction of CO represented by nondistributive blood flow and increased the antipyrine AUC up to 60% because nondistributive blood flow did not change, despite decreased CO. Volume loading resulted in a smaller (less than 20%) antipyrine AUC decrease despite increased fast tissue distributive flow because nondistributive flow also increased with increased CO.

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.

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 for 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 lidocaine's pulmonary disposition either before or after recirculation of drug was evident.

Pharmacokinetic models were developed to describe the disposition of markers of extracellular fluid (inulin) and total body water (antipyrine) from the moment of injection to incorporate the intravascular mixing component, determined by a marker of intravascular space (indocyanine green, ICG). The simultaneous dispositions of these markers were characterized in four halothane-anesthetized dogs. After injection of ICG, [14C]-inulin, and antipyrine into the right atrium, femoral arterial blood samples were collected every 3 sec for 1 min and less frequently to 20 min for ICG and to 360 min for inulin and antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and [14C]-inulin concentrations were measured by liquid scintillation counting. The marker concentration histories were characterized completely by fully identifiable recirculatory compartmental models. Because neither ICG nor inulin distribute beyond intravascular space before recirculation, their first-pass data were modelled simultaneously to improve confidence in central circulation model parameters. This central circulation model included an estimate of cardiac output that was retained in the recirculatory models of all markers. Three tissue compartments were identified for antipyrine, a lipid soluble marker that equilibrates with tissue (including the lung) and estimates total body water and tissue blood flow. The hydrophilic marker, inulin, diffuses into interstitial fluid so slowly that only two extravascular compartments were identified. These models may be used to determine how cardiac output and its distribution, pulmonary drug uptake, and nondistributive blood flow contribute to variability in patient response to drugs with a rapid onset of effect.

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.Dose-response and plasma concentration-effect study.11 clinically normal dogs.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.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.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.

The rate of administration of an intravenous anesthetic induction agent is an important variable determining the total dose required to reach a given endpoint, such as loss of consciousness (LOC). The influence of infusion rate on the dose-response relationship has not been described rigorously. In this study we characterized the effect of different thiopental infusion rates on the times and doses required to reach a clinical (induction) endpoint.Fifty-six healthy, non-premedicated men, aged 19-59 yr, were randomly assigned to receive one of seven different thiopental infusion rates (40, 60, 75, 150, 300, 600, and 1,200 mg/min). The infusion was continued until the patient dropped a held object, indicating LOC. The infusion rates were selected using a simulation which predicted the relationship between the rate of administration and cumulative dose administered at the time of LOC. Average population pharmacokinetic parameters from a three-compartment thiopental model were combined with an effect-site rate constant for thiopental equilibration of 0.58 min-1 and a median effect-site concentration of 13.8 mg/l from previously published pharmacokinetic and pharmacodynamic models for thiopental. This derived model was used to predict the total amount of thiopental required, at each infusion rate, to produce LOC.The observed median effective doses for infusion rates of 40-150 mg/min were similar and ranged from 296 to 318 mg. Dose requirements increased significantly with increasing infusion rates greater than 150 mg/min; median effective doses for infusion rates of 300, 600, and 1,200 mg/min were significantly different from each other (436, 555, and 711 mg, respectively). The original simulation underestimated the observed thiopental doses at all but the lowest infusion rate. A new simulation was performed using a recently developed combined pharmacokinetic-pharmacodynamic model. This model incorporated a four-compartment thiopental pharmacokinetic model with quantal dose-response data to derive an effect-site rate constant for thiopental equilibration of 0.29 min-1 and a median effect-site concentration for LOC of 11.3 mg/l. The median thiopental doses predicted by this new simulation under the extreme conditions of a 30-fold range of infusion rates were within 13% of the observed doses.In this study we quantified the relationship between the rate of thiopental administration and the resultant cumulative thiopental dose necessary to produce LOC. This study validated a novel pharmacokinetic-pharmacodynamic model based on a four-compartment pharmacokinetic model and infusion quantal dose-response data. Finally, we demonstrated that thiopental dose-response relationships are dependent on drug administration rate, and found that the ability to predict this dependence accurately is influenced by the pharmacokinetics, pharmacodynamics, and median effect-site concentration used to simulate the dose-response relationships.

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.

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 kinetics of inulin and gallamine were studied after simultaneous i.v. injection in anesthetized dogs. The distribution of both compounds in extracellular fluid space was characterized by a three-compartment model in which the mean central compartment blood volume of 1.37 liters was identical with the expected value. The two peripheral compartments of the model appear to represent rapid and slow equilibrating interstitial fluid compartments. A mammillary model structure was selected in which intercompartmental clearance corresponds to transcapillary exchange. Previous studies indicate that inulin and smaller hydrophyllic molecules diffuse across capillary walls at rates proportional to their respective free water diffusion coefficients. For the ratio of the transcapillary permeability coefficients of inulin and gallamine to equal their free water diffusion coefficient ratio of 5.34 +/- 0.02 (+/- S.D)., it appears that the sum of blood flow to the fast and slow interstitial fluid compartments is less than cardiac output. When this assumption is made, blood flow to fast equilibrating interstitial fluid is estimated to be 39% of cardiac output, in agreement with previous measurements of splanchnic blood flow. This supports the hypothesis that the fast equilibrating interstitial fluid space is supplied by porous splanchnic capillaries that lack a continuous investment of basement membrane.

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.

Polyethylene glycol (PEG) is a polymeric compound used as a vehicle for depot steroid preparations such as methylprednisolone acetate and triamcinolone diacetate injected into the epidural or intrathecal space to relieve low back pain. There have been reports of neurodysfunction associated with these injections, and it has been postulated that the PEG vehicle is the offending agent. Studies supporting such a possibility have, however, relied upon concentrations of PEG higher than those used clinically (3%) or have used PEG in combination with other drugs. Using an in vitro rabbit sheathed-nerve preparation, we investigated the effects of a 1-hr exposure to different concentrations (3-40%) of PEG in Liley solution on the transmission of impulses of the A, B, and C nerve fibers. The 3% and 10% PEG had no effect on mean amplitudes of the compound action potentials (CAPs) nor did they significantly decrease conduction velocity. Twenty percent PEG slightly depressed and 30% markedly decreased CAPs. Both 20% and 30% PEG significantly slowed the conduction velocities of A, B, and C nerve fibers. Forty percent PEG abolished CAPs. With washout CAPs recovered to at least 80% of their baseline levels, and conduction velocities returned toward baseline levels. The pH of the Liley solution decreased with an increasing concentration of PEG, from 7.4 in the control Liley solution to 6.45 in the solution of 40% PEG.(ABSTRACT TRUNCATED AT 250 WORDS)

Simple criteria were used to evaluate the statistical analyses in 243 articles from two American anesthesia journals published in the latter six months of 1981 and 1983. Eighty-two percent of the articles reported the use of control measures and 37% reported randomization of treatment, where they were possible. Data were classified as nominal, ordinal, or interval; as independent or related samples; as two-sample or more-than-two-sample cases. The descriptive, inferential, and correlative tests used were evaluated for appropriate application and primary errors were identified. Nine percent of the 722 descriptive statistics had major errors, most of which were a description of ordinal data as though they were interval. The incidence of erroneous applications of 394 inferential statistical tests was 78%. Nearly three-quarters of the 308 primary inferential statistical errors involved either use of a test for independent samples on related data (and vice versa) or multiple applications of an uncorrected test to the same data. Only 4% of the 113 statistics of association were considered erroneous, most because the method was not identified. No differences were detected in the incidence of errors in either experimental design or statistical analysis across time or across the two anesthesia journals. Fifteen percent of the 243 articles in both journals at both times were without major errors in statistical analysis. Recognition of potential sources of error should make it easier for investigators to use experimental designs and statistical analyses appropriate to their needs.

The kinetics of urea and inulin were studied after simultaneous i.v. injection in six anesthetized dogs. The distribution of both compounds was characterized by a three-compartment model. The initial volume of urea distribution averaged 2.21 +/- 0.39 liters (+/- S.D.) and was similar to the expected volume of intravascular space. Although the 0.66 +/- 0.05 liters/kg of total volume of urea distribution corresponds to total body water, transcapillary exchange between intravascular space and rapid and slow equilibrating interstitial fluid spaces is the rate-limiting step in urea distribution and accounts for the three-compartmental structure of the system used to model the distribution kinetics of both urea and inulin. The free-water diffusion coefficient ratio of urea and inulin and the intercompartment clearances calculated after the simultaneous injection of these compounds were used to estimate blood flows to the fast and slow equilibrating interstitial fluid compartments. The sum of these flows averaged 97% of measured cardiac output (range, 83-113%) and was not significantly different from cardiac output. These studies suggest that the rate of urea removal during dialysis may be affected by hemodynamic factors, as we have shown previously for drugs.

An etomidate infusion regimen for hypnosis as part of balanced, totally intravenous anesthesia was designed to maintain plasma etomidate concentrations above the awakening concentration of 300 ng/ml while avoiding dose-related side effects. The etomidate infusion regimen of 0.1 mg/kg/min for 3 min, 0.02 mg/kg/min for 27 min, and 0.01 mg/kg/min for the remainder of the anesthesia was used together with intravenous bolus doses of fentanyl, droperidol, and pancuronium. This was evaluated in 11 patients and the kinetics of etomidate were reexamined. The anesthetic technique seemed clinically satisfactory for the infusion periods of 30-109 min. The average time and plasma concentration at the end of the infusion was 59.5 min and 583 ng/ml, at awakening was 9.3 min and 307 ng/ml, and at alertness was 19.5 min and 227 ng/ml. The main difference between the kinetics observed in the present study and those of previous studies is in the elimination clearance. The average plasma elimination clearance of the present study was 1210 ml/min and the whole-blood clearance was estimated to be 1357 ml/min, giving an apparent hepatic extraction ratio of approximately 0.90. The negative correlation of patient mass and elimination clearance normalized for body mass suggests that the terminal infusion should not be adjusted to body mass.

A technique combining an intravenous bolus and intravenous infusion regimen of gallamine based on its pharmacokinetics was developed to produce continuous relaxation during surgery. The combination of a bolus dose of gallamine, 2.5 mg/kg, and infusion, 0.8 mg/kg/hr, was tested in 11 patients. In 10 patients, surgery continued long enough to allow demonstration of an apparent plateau in the serum gallamine concentrations. At the cessation of the infusion, the mean gallamine concentration of 11.8 microgram/ml was associated with an average paralysis intensity of 92%. Pharmacokinetic analysis of the gallamine serum concentration-time data was fitted to a three-compartment model. In this study of 50- to 76-year-old patients, the most striking difference from other studies was that the elimination halflife averaged 247 minutes in this study whereas 128 to 141 minutes has been reported previously.