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Anesthesiology:
Laboratory Investigations

Isoflurane Alters the Recirculatory Pharmacokinetics of Physiologic Markers

Avram, Michael J. Ph.D.*; Krejcie, Tom C. M.D.*; Niemann, Claus U. M.D.†; Enders-Klein, Cheri B.A.‡; Shanks, Colin A. M.D.§; Henthorn, Thomas K. M.D.∥

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Abstract

Background: Earlier studies have demonstrated that physiologic marker blood concentrations in the first minutes after administration, when intravenous anesthetics exert their maximum effect, are determined by both cardiac output and its distribution. Given the reported vasodilating properties of isoflurane, we studied the effects of isoflurane anesthesia on marker disposition as another paradigm of altered cardiac output and regional blood flow distribution.
Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1.7%, 2.6%, and 3.5% isoflurane (1.15, 1.7, and 2.3 minimum alveolar concentration, respectively) in a randomized order determined by a Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on very frequent early, and less frequent later, arterial blood samples. These models characterize the role of cardiac output and regional blood flow distribution on drug disposition.
Results: Isoflurane caused a significant and dose-dependent decrease in cardiac output. Antipyrine disposition was profoundly affected by isoflurane anesthesia, during which nondistributive blood flow was maintained despite decreases in cardiac output, and the balance between fast and slow tissue volumes and blood flows was altered.
Conclusions: The isoflurane-induced changes in marker disposition were different than those the authors reported previously for halothane anesthesia, volume loading, or hypovolemia. These data provide further evidence that not only cardiac output but also its peripheral distribution affect early drug concentration history after rapid intravenous administration.
EARLY drug distribution (i.e., front-end kinetics) determines the blood drug concentration versus time relationship during the time when rapidly administered intravenous anesthetics produce their maximum effect. 1 Early blood drug concentration history is affected by both cardiac output (CO) and drug recirculation.
Although the importance of CO in determining anesthetic induction dose may seem intuitive to anesthesiologists today, it was first formally recognized by Price 2 in 1960 and has only recently received renewed attention. The tissue distribution of alfentanil in humans was demonstrated to be largely dependent on CO. 3 The thiopental dose required to reach electroencephalogram burst suppression in humans was dependent on CO, 4 as were peak concentrations of rapidly infused hypnotics in computer simulations of drug administration 5 and studies in sheep. 6,7 CO has also been identified as a critical covariate in predicting fentanyl pharmacokinetic changes that occur with hemorrhagic shock. 8
The effect of recirculation on early drug concentrations is best understood by considering what we have called “nondistributive blood flow.”9,10 Nondistributive blood flow is that portion of CO that does not expose drug to tissue uptake (i.e., intercompartmental clearances to peripheral tissue compartments) or to elimination from the body (elimination clearance). Thus, nondistributive blood flow returns (shunts) drug to the central circulation after minimal tissue equilibration.
An index of drug exposure of the sites of drug action, such as the brain, is the area under the blood drug concentration versus time curve (AUC0-n min). 11 The time (n min) over which AUC0-n min should be calculated is that time during which blood concentrations are above an effective threshold for a given drug. For drugs used in anesthesia, this time is the first few minutes after rapid intravenous administration. The AUC0-n min in the first minutes after rapid intravenous drug administration can be broken down into two components. 12 The first component is the AUC calculated for the initial arterial drug concentrations resulting from the passage of drug from the site of injection through the heart and lungs of the central circulation and extrapolated to infinity from the slope of the downward limb before recirculation. This first-pass AUC (AUCfirst-pass) is determined by drug dose and CO, assuming no drug uptake by pulmonary tissue (i.e., AUCfirst-pass = dose/CO). The second component is determined by the amount of drug returning to the central circulation after loss from the blood due to uptake by peripheral tissues and elimination from the body. The resultant arterial concentrations are thus due to recirculation (AUCrecirc) and give rise to a recirculatory peak. 10 The sum of AUCfirst-pass and AUCrecirc thus results in the AUC0-n min, or active-site drug exposure over the time frame of interest. A recirculatory pharmacokinetic model is able to resolve these two components and thereby characterize the mechanism(s) responsible for interindividual differences in drug reactivity.
We have developed such a recirculatory multicompartmental pharmacokinetic model of drug disposition based on very frequent early arterial blood samples. 10 This model describes the simultaneous disposition of physiologic markers, serving as pharmacokinetic surrogates for drugs, that mix within the intravascular space from which they distribute to interstitial fluid space and total body water by blood flow and free water diffusion. 13 The recirculatory model incorporates physiologic factors, such as CO and its distribution (i.e., regional blood flows), in a description of drug disposition. The model estimates blood flow to tissue compartments based on the calculated intercompartmental clearances of a flow-limited tissue distribution marker (i.e., intercompartmental clearance equals tissue blood flow in the absence of diffusion barriers). The model uses blood marker concentrations of the recirculatory peak to describe nondistributive blood flow that, because of arteriovenous anastomoses or significant diffusion barriers, returns blood to the central circulation after minimal marker loss due to tissue uptake or elimination.
Applying this model, we have described previously the distribution of physiologic markers in dogs under different levels of halothane anesthesia 14 and in volume-loaded as well as mildly and moderately hypovolemic dogs. 12 These studies have demonstrated that not only CO but also regional blood flow, including, specifically, that fraction of CO represented by nondistributive blood flow, affect early drug concentration history after rapid intravenous administration. These studies have also demonstrated that the relative impact of CO and regional blood flow vary, depending on the characteristics of the marker being studied and the physiologic circumstances of the subject.
Because of the reported vasodilating properties of isoflurane, 15 the purpose of the present study was to determine the effects of different levels of isoflurane anesthesia on physiologic marker distribution by mixing, flow, and diffusion in dogs as another paradigm of altered CO and regional blood flow.
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Materials and Methods

Experimental Protocol
Table 1
Table 1
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The design of this pharmacokinetic study entailed 16 individual experiments. Four purpose-bred male coonhounds, weighing 24–37 kg (28.4 ± 5.9 kg; see table 1), were studied on four occasions each in this Institutional Animal Care and Use Committee–approved study. Approximately 1 month before being studied, a Vascular-Access-Port (Access Technologies, Skokie, IL) was implanted with its catheter tip positioned near the aortic bifurcation via a femoral artery of each dog to facilitate frequent percutaneous arterial blood sampling. 16
All dogs were studied while awake (0% isoflurane, control) and while anesthetized with isoflurane at end-tidal concentrations of 1.7%, 2.6%, and 3.5%, which correspond to 1.15, 1.7, and 2.3 minimum alveolar concentration. 17,18 The order in which these studies were conducted in each dog was randomized using a Latin square experimental design. The details of the preparation and conduct of the individual studies have been described in detail previously. 14
In the isoflurane studies, anesthesia was induced with methohexital (10–15 mg/kg intravenously), the trachea was intubated, and the animal was placed in the left lateral decubitus position. Mechanical ventilation was instituted to control end-tidal carbon dioxide tension at 30 ± 5 mmHg. Anesthesia was maintained with 1.7%, 2.6%, or 3.5% isoflurane in oxygen, and end-tidal concentrations were monitored with a side-stream infrared analyzer.
A flow-directed thermal dilution pulmonary artery catheter was inserted through a right external jugular vein sheath introducer in both awake and anesthetized dogs. The pulmonary artery catheter was subsequently used to determine thermal dilution CO as well as to facilitate right atrial administration of the physiologic markers.
The study was not begun until the dog was hemodynamically stable (approximately 1 h) after the targeted end-tidal isoflurane concentration had been reached. This was defined as less than 10% variation of CO and pulmonary and systemic arterial blood pressures over a 30-min period when heart rate and blood pressures were measured continuously and CO was determined at least every 15 min.
Indocyanine green (ICG; Cardio-Green; Hynson, Westcott, and Dunning, Baltimore, MD), 5 mg in 1 ml of ICG diluent, [14C]-inulin (DuPont NEN, Boston, MA), 30 μCi in 1.5 ml of ICG diluent, and antipyrine (Sigma, St. Louis, MO), 25 mg in 1 ml of ICG diluent, were placed sequentially in a 76-cm-long intravenous tubing (4.25 ml priming volume) and connected to the proximal injection port of the pulmonary artery catheter. At the onset of the study (time t = 0 min), the markers were flushed into the right atrium within 4 s using 10 ml of 5% dextrose in water, allowing the simultaneous determination of dye and thermal dilution COs. Arterial blood samples were collected via the Vascular-Access-Port every 0.03 min for the first 0.48 min and every 0.06 min for the next 0.54 min using a computer-controlled roller pump (Masterflex; Cole-Parmer, Chicago, IL). Subsequently, 35 3-ml arterial blood samples were drawn manually at 0.2-min intervals to 2 min, at 0.5-min intervals to 4 min, at 5 and 6 min, every 2 min to 20 min, at 25 and 30 min, every 10 min to 60 min, every 15 min to 120 min, and every 30 min to 360 min.
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Analytical Methods
Plasma ICG concentrations of all samples obtained up to 20 min were measured on the study day by the high-performance liquid chromatography technique of Grasela et al.19 as modified in our laboratory. 10 Plasma [14C]-inulin concentrations of all samples were determined by liquid scintillation counting, using an external standard method for quench correction. 20 Plasma antipyrine concentrations were measured in all samples using a modification of a high-performance liquid chromatography technique developed in our laboratory. 10,21
To interpret antipyrine intercompartmental clearances in relation to blood flow, the recirculatory models were constructed on the basis of whole blood marker concentrations. Plasma ICG and inulin concentrations were converted to blood concentrations by multiplying them by one minus the hematocrit, as neither ICG nor inulin partitions into erythrocytes. Plasma antipyrine concentrations were converted to blood concentrations using an in vivo technique that corrects for antipyrine partitioning into erythrocytes by calculating its apparent dose assuming an erythrocyte:plasma partition coefficient of one; the product of CO and AUCfirst-pass for the plasma antipyrine concentration versus time curve equals dose when its erythrocyte:plasma partitioning is one. 10,22
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Pharmacokinetic Model
Fig. 1
Fig. 1
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The pharmacokinetic modeling methodology (fig. 1) has been described in detail previously. 10,14 It is based on the approach described by Jacquez for obtaining information from outflow concentration histories, the so-called inverse problem. 23 Inulin and antipyrine distributions were analyzed as the convolution of their intravascular behavior, determined by the pharmacokinetics of concomitantly administered ICG, and tissue distribution kinetics. 10
Arterial ICG, inulin, and antipyrine concentration versus time data before evidence of recirculation (i.e., first-pass data) were weighted uniformly and fit to the sum of two Erlang distribution functions using TableCurve2D (ver 3.0; Jandel Scientific, San Rafael, CA) on a Pentium-based personal computer (Gateway 2000, North Sioux City, SD); two parallel, lumped pathways with different transit characteristics reflect the heterogeneity in the distribution of transit times in the pulmonary circulation. 22 Because neither ICG nor inulin distribute beyond the intravascular space before recirculation, they were modeled simultaneously to improve the confidence in the model parameters of the central (first-pass) circulation. Antipyrine has measurable pulmonary tissue distribution during this time and was modeled independently; the antipyrine pulmonary tissue volume (VT-P) is the difference between the antipyrine central volume (MTTantipyrine · CO) and the central intravascular volume codetermined by ICG and inulin (MTTICG,inulin · CO).
In subsequent pharmacokinetic analysis, these descriptions of the central circulation were incorporated as parallel linear chains, or delay elements, into independent recirculatory models for the individual markers using SAAM II (SAAM Institute, Seattle, WA) implemented on a Pentium-based personal computer. 22,24 The concentration–time data were weighted, assuming a proportional variance model, in proportion to the inverse of the square of the observed value. Possible systematic deviations of the observed data from the calculated values were sought 25 using the one-tailed one-sample runs test, 26 with P < 0.05, corrected for multiple applications of the runs test, as the criterion for rejection of the null hypothesis. Possible model misspecification was sought by visual inspection of the measured and predicted marker concentrations versus time relationships.
In general, peripheral drug distribution can be lumped into identifiable volumes and clearances: a fast nondistributive peripheral pathway (VND-F and ClND-F); a slow nondistributive peripheral pathway (VND-S and ClND-S); rapidly (fast) equilibrating tissues (VT-F and ClT-F); and slowly equilibrating tissues (VT-S and ClT-S). The fast and slow nondistributive peripheral pathways (delay elements) represent intravascular circuits in the ICG and inulin models; the only identifiable nondistributive peripheral pathway in the antipyrine model, determined by the recirculation peak, represents blood flow that quickly returns the lipophilic marker to the central circulation after minimal apparent tissue distribution (i.e., a pharmacokinetic shunt). 10,14 In the inulin and antipyrine models, the parallel rapidly and slowly equilibrating tissues are the fast and slow compartments of traditional three-compartment pharmacokinetic models, respectively; therefore, the central circulation and nondistributive peripheral pathway(s) are detailed representations of the ideal central volume of the three-compartment model. 21 Because of the direct correspondence between the recirculatory model and three-compartment models, ClE was modeled from the arterial (sampling) compartment to enable comparison of these results with previous ones.
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AUC
The AUC was determined for both the first-pass fit (AUCfirst-pass, calculated for the sum of two parallel Erlang functions) and for the full recirculatory model. 12 The AUCs for the full model were calculated for the interval 0–3 min (AUC0-3 min) because most intravenous drugs used in the practice of anesthesia (e.g., hypnotics and muscle relaxants) have demonstrable onset within this time. AUC0-3 min is the sum of AUCfirst-pass, which is determined by CO (i.e., AUCfirst-pass = dose/CO), and the AUC resulting from marker recirculation (AUCrecirc). To resolve the factors influencing AUC0-3 min, both AUCfirst-pass and AUCrecirc were determined.
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Statistical Analysis
The effects of treatment as well as the order of treatment on observed pharmacokinetic parameters were assessed using a general linear model analysis of variance for a Latin square experimental design (NCSS 6.0.2 Statistical System for Windows; Number Cruncher Statistical Systems, Kaysville, UT). Post hoc analysis was conducted using Scheffé multiple comparison test. The relationship of the pharmacokinetic parameters to CO and end-tidal isoflurane concentration was sought using standard least squares linear regression and the Spearman rank order correlation, respectively, (SigmaStat; SPSS, Chicago, IL) using the Bonferroni correction of the criterion for rejection of the null hypothesis. The criterion for rejection of the null hypothesis was P < 0.05.
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Results

Table 2
Table 2
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There were large and isoflurane dose-related decreases in blood pressure and CO, whereas heart rate increased slightly and systemic vascular resistance decreased slightly, but not significantly, during isoflurane anesthesia (table 1). The thermal dilution COs (averaged over t = 0 to t = 60 min;table 1) and dye (ICG) dilution COs (determined once at t = 0;table 2) were similar, indicating our sampling schedule and identification of first-pass data were appropriate. The hematocrit also decreased slightly but significantly with increasing isoflurane concentrations (table 1).
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Global Model Parameters
Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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Fig. 4
Fig. 4
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Table 3
Table 3
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Table 4
Table 4
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The blood ICG, inulin, and antipyrine concentration versus time relationships were well characterized by the models from the moment of injection (time t = 0;figs. 2–4). The one-sample runs test did not identify systematic deviations of the observed data from the calculated values. As described below, our recirculatory model of physiologic marker disposition was able to describe the effect of isoflurane anesthesia on CO and its distribution (the ICG model;table 2) and the effect of reduced and redistributed CO on inulin (table 3) and antipyrine (table 4) disposition. The total volumes of distribution (VSS) of ICG, inulin, and antipyrine were unaffected by isoflurane anesthesia (tables 1–4), but their ClEs were significantly decreased by isoflurane, as reflected in the decreased slopes of their terminal marker concentration versus time relationships (tables 1–4 and insets of figs. 2–4).
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ICG
Isoflurane anesthesia had no effect on the volumes of the central and peripheral circulations described by ICG disposition; nearly 30% of the blood volume was in the central circuit (VC), less than 10% was in the fast nondistributive circuit (VND-F), and approximately 60% was in the slow nondistributive circuit (VND-S) (fig. 1 and table 2). Isoflurane produced a progressive and dose-related decrease in flow through the central circuit (dye-dilution CO), from a 36% reduction at 1.7% isoflurane to a 68% reduction at 3.5% isoflurane. Both the fast nondistributive intercompartmental clearance (ClND-F) and the slow nondistributive intercompartmental clearance (ClND-S) of ICG were significantly correlated with end-tidal isoflurane concentration and were significantly different from the baseline value at all end-tidal isoflurane concentrations. Flows through each circuit decreased directly in proportion to the decrease in CO (ClND-F = 0.45 CO − 0.30, R2 = 0.86; ClND-S = 0.54 CO + 0.10, R2 = 0.90), hence the fractions of the CO not represented by ClE (i.e., 87–95% of CO) flowing through ClND-F and through ClND-S were approximately 40% and 60%, respectively, under all experimental conditions.
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Inulin
The volumes of the recirculatory inulin pharmacokinetic model were also largely unaffected by isoflurane anesthesia; approximately 20% of the volume of inulin was in the central and peripheral nondistributive circuits (VC, VND-F, and VND-S), whereas nearly 30% of the volume was the rapidly equilibrating (fast) tissue (VT-F), and the balance was the slowly equilibrating tissue (VT-S) (table 3). All inulin clearances, except that to the fast nondistributive circuit (ClND-F), were correlated with end-tidal isoflurane concentrations; ClND-F decreased significantly at 1.7% isoflurane and remained essentially unchanged at higher isoflurane concentrations. Both ClND-F and ClND-S were correlated with CO (ClND-F = 0.59 CO − 0.86, R2 = 0.75; ClND-S = 0.25 CO + 0.67, R2 = 0.53). Approximately 75% of CO was nondistributive in the inulin models in the dogs under all experimental conditions because the transcapillary distribution of inulin is limited by free water diffusion, not blood flow. Neither the fast nor the slow distributive (intercompartmental, tissue) clearance (ClT-F and ClT-S) of inulin was correlated with CO, but both decreased significantly at 2.6% and 3.5% isoflurane. Inulin ClE (glomerular filtration rate) was significantly less than the baseline value only at 3.5% isoflurane.
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Antipyrine
Although the total volume of distribution did not change, the antipyrine peripheral distribution volumes were affected by isoflurane anesthesia (table 4). As the rapidly equilibrating (fast) tissue volume (VT-F) decreased in an isoflurane dose-dependent and CO-related manner (VT-F = 1.37 CO + 0.05, R2 = 0.91), the slowly equilibrating tissue volume (VT-S) increased in such a way that together they always accounted for 95% of the antipyrine distribution volume. The central (VC), pulmonary tissue (VT-P), and the peripheral nondistributive volumes (VND) were unaffected by isoflurane anesthesia.
Despite the profound effect of isoflurane on CO, antipyrine nondistributive clearance (ClND) did not change, as a result of which the fraction of CO represented by ClND increased from approximately 10% of CO in awake animals to nearly 30% of the reduced CO in 3.5% isoflurane anesthetized animals (table 4). Antipyrine tissue distribution clearances (ClT-F and ClT-S) and ClE decreased in an isoflurane dose-dependent manner. As a result of the CO-related decrease in ClT-F (ClT-F = 0.85 CO − 0.78, R2 = 0.96), the fraction of CO represented by ClT-F decreased from 71% in awake animals to 46% in 3.5% isoflurane-anesthetized animals. ClT-S was approximately 20% of CO, and ClE was nearly 3% of CO in all experimental conditions. Thus, the fraction of CO represented by ClN-D increased with isoflurane anesthesia at the expense of ClT-F.
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AUC
Table 5
Table 5
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Indocyanine green AUC0-3 min was significantly increased only at 3.5% isoflurane (fig. 2 and table 5) due to an increase in AUCfirst-pass (i.e., the CO-determined value) since there were no isoflurane-induced changes in ICG AUCrecirc. Inulin and antipyrine AUC0-3 mins increased in an isoflurane dose-dependent manner to more than 1.6 and 2.5 times awake values, respectively, at 3.5% isoflurane (figs. 3 and 4, table 5). The inulin and antipyrine AUC0-3 mins also increased with decreasing CO (AUC0-3 min, inulin × 103 = −7.45 CO + 95.07, R2 = 0.55; AUC0-3 min, antipyrine = −3.81 CO + 30.55, R2 = 0.82). Antipyrine AUCrecirc more than doubled in an isoflurane dose-dependent and CO-related manner (AUCrecirc, antipyrine = −1.62 CO + 14.37, R2 = 0.60), but the inulin AUCrecirc did not. Thus, during isoflurane anesthesia, antipyrine AUC0-3 min increased because of not only the increase in AUCfirst-pass secondary to the decreased CO, but also the increased fraction of CO represented by nondistributive blood flow.
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Discussion

Our recirculatory pharmacokinetic model 10 accurately describes changes in physiologic marker disposition due to altered CO and regional blood flow distribution caused by potent volatile anesthetics. In a previous publication, we reported the effects of halothane 14 and now describe the effect of isoflurane, which has been reported to cause more peripheral vasodilation. 15 In these studies, isoflurane and halothane were used as means to create changes in CO and regional blood flow distribution to allow us to study the effects of these physiologic changes on marker disposition rather than to study the affects of the anesthetics per se. In both of these studies, in addition to the inhalation anesthetic in oxygen, each dog initially received methohexital and was mechanically ventilated, each of which may contribute to results different from those achieved with an inhalation anesthetic alone. Nonetheless, although the three different levels of inhaled anesthetics in both of these repeated measures studies were each given with the same anesthetic adjuncts, most of the significant changes observed were correlated with end-tidal anesthetic concentration. Thus, in the present study we determined the impact of isoflurane-induced alterations in CO and its distribution on the disposition of physiologic markers acting as surrogates for various intravenous drugs used in the practice of anesthesia.
The observed isoflurane-induced decrease in mean arterial pressure, CO, and systemic vascular resistance (table 1) are consistent with the cardiovascular effects of isoflurane observed by other investigators, 27–29 as is the decrease in hematocrit. 27
In the recirculatory pharmacokinetic models, CO can flow through either distributive (i.e., tissue) or nondistributive circuits. ICG ClND-F, which represents nonsplanchnic (e.g., muscle) blood flow, 10 and ICG ClND-S, which represents the splanchnic blood flow, 10 were consistently approximately 40% and 60% of CO under all experimental conditions. Inulin nondistributive blood flow was always 75% of CO and was nearly evenly divided between ClND-F and ClND-S in awake animals, but during isoflurane anesthesia inulin ClND-F and ClND-S represented approximately 40% and 60% of nondistributive blood flow, respectively. Nondistributive antipyrine clearance (ClND) was represented by a single peripheral pathway, 10 the absolute value of which was not affected by isoflurane anesthesia despite the decreasing CO with increasing isoflurane concentration. As a result, the fraction of CO that antipyrine ClND represented increased from 10% in the awake animals to 30% in dogs anesthetized with 3.5% isoflurane.
The rapidly equilibrating (fast) inulin and antipyrine tissue volumes (VT-F) represent splanchnic tissues, and the slowly equilibrating tissue volumes (VT-S) represent nonsplanchnic tissues. 30 Although the total antipyrine peripheral tissue volume (VT-F + VT-S) was not affected by isoflurane anesthesia, the fraction of tissue volume represented by VT-F decreased from nearly 40% in the awake animals to approximately 20% in isoflurane-anesthetized animals. Total clearance to these tissue volumes (ClT-F + ClT-S) decreased compared with the awake total up to 75% in absolute terms and from 87% of CO in awake animals to 67% of CO in 3.5% isoflurane–anesthetized animals. The fraction of distributive blood flow represented by ClT-F decreased from 83% in awake animals to 68% in 3.5% isoflurane–anesthetized animals because the fraction of CO represented by ClT-F decreased during anesthesia, whereas that represented by ClT-S remained constant. In contrast to antipyrine, the inulin tissue volumes were little affected by isoflurane, and total distributive blood flow for inulin remained a relatively constant 20% of CO, with ClT-F representing approximately 80% of that total under all experimental conditions.
Given that some pharmacokinetic heterogeneity exists within single tissue types, 31 the shift in both antipyrine tissue volume and distributive blood flow from the rapidly equilibrating tissues to the slowly equilibrating tissues could be explained by a change in the balance of tissue blood supply that is not apparent in the ICG or inulin models. For example, radioactive microsphere studies revealed an isoflurane dose-dependent decrease in preportal blood flow due to both a decrease in CO and vasodilation, yet total hepatic blood flow was only slightly changed by isoflurane because hepatic arterial blood flow nearly doubled. 27,28,32,33 Similar but more subtle changes might occur in muscle beds due to a change in the balance of their dual circulations. 34
The marker elimination clearances (ClE) were all decreased by isoflurane anesthesia (tables 1–4). ICG ClE was only modestly affected by isoflurane (tables 1 and 2), but antipyrine ClE was dramatically affected by isoflurane, presumably as a result of inhibition of the hepatic mixed function oxidase system responsible for its metabolism. 35,36 Inulin ClE was similarly decreased by isoflurane due to decreased glomerular filtration rate. 37 The AUC0-∞ of a complete drug concentration history can increase significantly as a result of a decrease in the ClE of the drug (AUC0-∞ = dose/ClE). This ClE-dependent increase in AUC is readily apparent in the curves in the insets of figures 2–4. However, changes in ClE of these low ClE markers cannot explain the increase in the marker AUCs in the first minutes after marker administration, long before ClE becomes the major determinant of the drug concentration versus time relationships (figs. 2–4).
The progressive decreases in CO with increasing isoflurane concentrations are associated with the expected increases in AUCfirst-pass (AUCfirst-pass = dose/CO) for each marker (figs. 2–4). In isoflurane-anesthetized animals, ICG and inulin AUC0-3 mins were greater than those in awake animals (tables 2–4), but these differences were due to the large differences in AUCfirst-passs (table 5). In contrast, the increase in antipyrine AUC0-3 min during isoflurane anesthesia was due to both a decreased CO (AUCfirst-pass) and an increased amount of marker returning to the central circulation (AUCrecirc;table 5). Increased return of antipyrine to the central circulation during isoflurane anesthesia was therefore due to maintenance of the apparent flow of blood not involved in marker distribution to the tissues (i.e., ClND), despite an isoflurane-induced decrease in CO, at the expense of decreased ClT-F (table 4). Thus, isoflurane-induced changes in CO and its distribution alters the balance of antipyrine nondistributive and distributive blood flows to various tissues that are not proportional to changes in CO. Similar changes in inulin AUC are not observed because, despite an isoflurane-induced alteration in the balance of inulin ClND-F and ClND-S, the proportion of CO represented by all nondistributive flow in the inulin model was unaffected by isoflurane anesthesia.
Although the isoflurane-induced increase in the fraction of CO represented by ClND in the antipyrine model can be due to the opening of arteriovenous anastomoses or an increase in significant diffusion barriers, it is most likely due to opening of arteriovenous anastomoses. Increased arteriovenous shunting is consistent with observed shunt rates of 9-μm radiolabeled microspheres through arteriovenous anastomoses in control and isoflurane-anesthetized dogs. 38 Their control shunt rate of 8.9% is consistent with the 9.6% of CO that antipyrine ClND represented in our awake dogs, whereas the shunt rates of 19.9% and 17.4% in dogs anesthetized with 1% and 2% isoflurane, respectively, are consistent with the 21.6% of CO that antipyrine ClND represented in our dogs when they were anesthetized with 1.7% isoflurane. Isoflurane dose-related increases in the shunting of microspheres have been observed in other studies. 28
The effects of isoflurane on marker distribution is quite different from that observed in dogs under different levels of halothane anesthesia 14 and in mildly and moderately hypovolemic dogs. 12 Antipyrine AUC was increased in the first minutes after marker administration in all three paradigms of decreased CO and its altered distribution. In contrast to isoflurane, which reduced CO but maintained antipyrine ClND and therefore increased it as a percentage of CO, halothane actually increased antipyrine ClND both absolutely and as a percentage of CO. Total antipyrine distribution clearance (i.e., ClT-F + ClT-S) during all levels of isoflurane anesthesia was always at least twice ClND, whereas at the highest halothane concentrations (i.e., at 2.0% halothane, equivalent minimum alveolar concentration to 3.5% isoflurane), ClND equaled total distribution clearance. Moderate hypovolemia produced a decrease in CO similar to that of 1.7% isoflurane and, like isoflurane, had no effect on the absolute value of antipyrine ClND, but the antipyrine AUC did not increase as much during moderate hypovolemia as it did during isoflurane anesthesia because ClT-F was a higher fraction of CO during hypovolemia and VT-F was unaffected by hypovolemia.
The increased arterial antipyrine concentrations (fig. 4) and the consequent increase in AUC0-3 min up to 2.5 times awake values during isoflurane anesthesia (table 5) is the result of both a decreased CO (AUCfirst-pass) and increased fraction of CO represented by nondistributive blood flow (AUCrecirc;table 4). The increased antipyrine AUC in the first minutes after rapid intravenous administration simulates the expected increased drug exposure of the sites of action of lipophilic drugs with a rapid onset of effect, for which antipyrine is a pharmacokinetic surrogate. 10,21,39 This increased drug exposure would be expected to result in a more profound and prolonged effect. 11 Because the majority of CO in the recirculatory inulin model is nondistributive and the balance between distributive and nondistributive clearance is unaffected by isoflurane anesthesia (table 3), the increase in early arterial inulin concentrations (fig. 3) and the consequent increase in AUC0-3 min (table 5) during isoflurane anesthesia is less pronounced than that of antipyrine. Therefore, the onset and duration of effect of the hydrophilic drugs for which inulin is a surrogate (e.g., the relatively slow onset neuromuscular blockers) 10 will be less affected than that of more rapid-onset lipophilic drugs.
These data provide further evidence, along with those from similar studies in dogs under different levels of halothane anesthesia 14 and in volume-loaded as well as mildly and moderately hypovolemic dogs, 12 that not only CO but also its peripheral distribution affect early physiologic marker concentration history after rapid intravenous administration. 1 These studies have also demonstrated that changes in antipyrine distribution are not proportional to changes in CO. Furthermore, the relative impact of CO and regional blood flow changes on early marker disposition vary, depending on the characteristics of the marker being studied and the physiologic circumstances of the subject. Alteration in CO and its distribution are likely to provide the pharmacokinetic bases of interindividual differences in response to drugs with a rapid onset of effect, such as thiopental. 1,4
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References

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Keywords:
Blood flow; cardiac output; physiologic models.

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