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Anesth Analg 2008; 106:1440-1449
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31816ba541
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ANESTHETIC PHARMACOLOGY

The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses

Susan E. Copeland, MVetClinStud, Leigh A. Ladd, PhD, Xiao-Qing Gu, BSc, and Laurence E. Mather, PhD

From the Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Australia.

Address correspondence to Emeritus Professor Laurence E. Mather, Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Sydney NSW 2065, Australia. Address e-mail to lmather{at}med.usyd.edu.au


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Local anesthetic toxicity is often studied experimentally in anesthetized subjects, but clinical toxicity usually occurs in conscious patients. In this study, we determined the influence of general anesthesia on the pharmacokinetics of six local anesthetics administered IV at approximately the highest recommended doses.

METHODS: Chronically instrumented ewes (approximately 45–50 kg, n = 18) were infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg), on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by equilibrium dialysis in vitro.

RESULTS: Blood local anesthetic concentrations were doubled with anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine > S-bupivacaine and R-prilocaine > S-prilocaine, but, mepivacaine clearance was not enantioselective. Halothane did not influence blood binding of the local anesthetics.

CONCLUSIONS: General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many pharmacological studies seek to relate blood concentrations to therapeutic and/or toxic effects of drugs, i.e., they try to establish a concentration–response relationship or a "therapeutic window." Such studies are often performed in human or laboratory animal subjects deemed a suitable surrogate for human patients. In research particularly related to anesthesia and pain management, the subjects of such studies may have been conscious, lightly or deeply anesthetized, initially conscious, and then in anesthetized states or vice versa. However, the inclusion of anesthesia in such subjects is seldom considered an experimental variable; mostly, it is described merely as part of the methodology.

Specifically, many studies in various species have determined blood concentrations and/or pharmacokinetics of local anesthetics as a function of the drug, dose, site of administration, and/or some anatomical, physiological, pharmacological, or pharmaceutical variable. Some have made attempts to describe a tolerated or a toxic blood level. Although it is intuitive that a higher blood drug concentration is more likely to be associated with toxicity than a lower one, the underlying conditions under which those concentrations are generated are important, but oftentimes neglected, variables. Three decades ago, it was noted that blood etidocaine concentration profiles after epidural administration in conscious volunteers and anesthetized surgical patients differed, suggesting an effect of anesthesia and/or surgery.1 Subsequent systematic studies have shown that general anesthesia can, indeed, alter the pharmacokinetics of disparate drugs through direct effects on drug elimination mechanisms and/or indirect effects on hemodynamics.2,3

General anesthesia is used in many laboratory models used to study local anesthetic toxicity,4 but no study has yet attempted to determine its role as an experimental variable or to interpret its contribution to the results. In a companion report, we demonstrated that the cardiovascular system (CVS) and central nervous system (CNS) toxicity of commonly used local anesthetics were strikingly different in conscious and anesthetized chronically prepared sheep.5 In this report, we present an analysis of the influence of general anesthesia on the whole body and regional pharmacokinetics of those local anesthetics.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was approved by the local Animal Care and Ethics Committee. The subjects were nonpregnant Merino first-cross ewes ({approx}45–50 kg, {approx}2 yr), chronically instrumented as described previously in detail5 and briefly here. Pilot studies for dose ranging and comparison of the effects of isoflurane and halothane anesthesia found that both volatile anesthetics similarly modified the CVS response to bupivacaine, ropivacaine, or lidocaine, and that blood concentrations of the local anesthetics were nearly doubled under anesthesia with each anesthetic. Halothane was chosen for the following systematic studies because of its lower cost, and for continuity with previous studies in this preparation.2,3

Surgical Preparation
A left thoracotomy (4/5 intercostal space) enabled placement of probes for hemodynamic and electrocardiogram measurements and a blood sampling cannula in the coronary sinus after ligation of the left hemiazygos vein, which drains noncoronary blood into the coronary sinus of sheep. In a second surgery at least 6 days later, we placed jugular venous and carotid arterial cannulae for drug infusion, sampling, and blood pressure measurement, a blood flow probe on the dorsal sagittal sinus, and a cannula therein for sampling dorsal sagittal sinus blood. The animal was allowed to recover in a metabolic crate for a minimum of 6 days before the first pharmacological study. Lines were flushed constantly (3 mL/h, 240–300 mm Hg) except during experiments.

Drugs and Doses
Doses (as base) of 100 mg bupivacaine, 125 mg levobupivacaine, 150 mg ropivacaine, 350 mg lidocaine, 350 mg mepivacaine, or 350 mg prilocaine (as HCl salts) were diluted to 30 mL with 0.9% saline, and infused into a central venous catheter over 3 min. These doses, which were similar to the maximum recommended doses in several countries,6 were intended to produce recognizable, but nonlethal, CNS and CVS toxicity in conscious sheep.

Study Procedures
Only one study of an animal was performed on any day, and studies in individuals were ≥2 days apart to allow drug washout. On the study day, the sheep was placed in a weight-bearing sling, and allowed to settle. Each study consisted of 10 min baseline CVS measurements, 60 min observation of CVS and CNS effects beginning with a 3 min infusion of drug/saline control, with appropriate blood sampling to 180 min. When the ewe was to be studied under anesthesia, halothane/O2 was administered by mask for induction of anesthesia, the trachea was intubated, and anesthesia was maintained with halothane (1.6%–1.8%, total fresh gas flow rate 2.5 L/min, and Fio2 0.33; intermittent positive pressure ventilation, 14 breaths per min). After stabilization of anesthesia, experiments were performed as when conscious, with termination of anesthesia after 30 min. The study order was: conscious control studies, anesthetized control studies; anesthesia studies preceded conscious studies; ropivacaine and levobupivacaine preceded bupivacaine; studies with the shorter-acting local anesthetics were random. Acquired CVS data consisted of electrocardiogram, mean arterial blood pressure, left ventricular pressure, cardiac output (CO), left coronary artery blood flow, and dorsal sagittal sinus blood flow from which stroke volume, heart rate, and LV-dP/dt were derived; arterial blood gases and acid–base status were also measured. Coronary artery blood flow and dorsal sagittal sinus blood flow data were used in the regional pharmacokinetics calculations below; these data are presented in detail elsewhere.5

Blood Sampling and Drug Assay Procedures
Blood samples from the aorta were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7.5, 10, 15, 20, 30, 33, 35, 45, 60, 90, 120, 150, and 180 min after starting the drug infusion; samples from the coronary and sagittal sinuses were collected at the same times up to 30 min. The blood was stored at –20°C pending high-performance liquid chromatography analysis of drug total concentration (Cyano column: 150 x 4.6 mm, 5 µm, Alltech-Waters Spherisorb; detection: 220 nm; mobile phase: 20%–30% acetonitrile in 5–10 mM, pH 4.0–6.0 phosphate buffer, diphenhydramine internal standard). Subsequently, chiral resolution of bupivacaine and mepivacaine was performed as previously described7 (Chiral-AGP column 100 x 4 mm; detection: 220 nm; mobile phase: 6% n-propanol in 50 mM phosphate buffer, pH 7.0); prilocaine, which could not be resolved on the Chiral-AGP column, was resolved on a Chiral-CBH column (100 x 4 mm; detection 220 nm; mobile phase: 5% n-propanol in 10 mM pH 6.8 phosphate buffer containing 50 µM EDTA, at 0.9 mL/min). If an animal died during a study, postmortem samples of right and left atria and ventricles, septum, cerebellum, cerebrum, and pons/medulla were collected for drug assay. After homogenization of tissue in phosphate buffer (2.5 vols, pH 4) containing the relevant internal standard, homogenate (0.4 mL) was alkalinized with NaOH (4M, 20 µL) to pH 12, then extracted with n-hexane (1.2 mL). The hexane was extracted with phosphate buffer (100 µL, pH 3), and aliquots (10 µL) of the aqueous extracts were analyzed by high-performance liquid chromatography as for blood.

Pharmacokinetic Analysis
The primary objective was to determine whether general anesthesia affected the whole body and/or regional (heart and brain) pharmacokinetics of each local anesthetic. Secondary objectives were to determine whether anesthesia affected their blood binding, tissue concentrations, or the pharmacokinetics of the racemic local anesthetics enantioselectively. Data from sheep not surviving a particular drug/dose were excluded from the comparative pharmacokinetic analysis. Animals' arterial, coronary sinus, and sagittal sinus blood drug concentration–time data pairs, along with relevant experimental descriptors, were entered into spreadsheets (WinNonlin®, v.5.0.1, Pharsight Corp, Mountain View, CA) for pharmacokinetic analysis: this was performed in several stages.

(i) Noncompartmental analysis was performed on arterial blood total drug concentration–time data, weighted with the reciprocal of drug concentration. From this, the maximum blood drug concentrations (Cmax), Cmax per milligram dose (surrogate for initial dilution volume), time of Cmax (Tmax), mean total body clearance (CL), total apparent volume of distribution (Vss), slow half life (T[1/2]β), and mean residence time (MRT) were determined. (ii) The respective products of drug arteriovenous blood concentration differences and blood flows generated drug heart and brain net fluxes; these were integrated with respect to time to calculate the respective organ drug content, as previously described.8 (iii) Drug blood concentration–time and tissue concentration data for nonsurvivors were plotted for detection of trends. (iv) The effects of anesthesia were ascertained from the time course of the R-/S-enantiomer ratio of blood concentrations after chiral resolution of the racemic drugs.

Drug Binding in Blood
We speculated that halothane could affect drug tissue distribution by altering drug binding in blood.9–11 Blood binding, in an Acid Citrate Dextrose anticoagulated blood pool collected aseptically from a single drug-naive sheep, was measured over a relevant concentration range in the absence and presence of halothane in a 2-compartment equilibrium dialysis apparatus (2 mL polymethylmethacrylate cells, ViskingTM dialysis membrane) as previously described.12 Drug solutions (0.2, 0.5, 1, 5, 10, and 50 µg/mL) in isotonic phosphate buffer (0.067 M, pH 7.4) were dialyzed with shaking (0.1 Hz) overnight at 37°C, against pH-adjusted (pH 7.4) blood containing sodium fluoride (2 mg/mL) to prevent continuing metabolism.12 The experiments were repeated with halothane 50 µg/mL ({approx} end expired concentration 0.5%13) added to the blood compartment immediately before dialysis. Using paired data consisting of unbound drug concentration (buffer cell), and total concentration (blood cell), the bound concentration was calculated by difference; plots were made of %bound versus total concentration, as well as bound versus unbound concentrations (Freundlich adsorption isotherm).

Data Reduction and Statistical Analyses
Pharmacokinetic data were derived as geometric means and 95% confidence intervals.14 The null hypothesis was that anesthesia ("condition") had no effect on the pharmacokinetic variables of the local anesthetics ("drug") administered in a single, approximately equianesthetic dose that was CNS-toxic in all conscious animals. P < 0.05 was noted as weak evidence for rejection of the null hypothesis, and P < 0.01 was taken as strong evidence. Sample sizes for the different local anesthetics and conditions were not necessarily equal because more studies were done initially with the longer-acting local anesthetics, and because of unpredicted deaths of sheep and, mainly, random failure of monitoring probes and/or blood sampling catheters in various sheep. Data loss was considered inevitable in this complex chronic preparation and, when it occurred, replacement animals could not simply be introduced as required, because of practical reasons such as cost, time, and ethical board approvals. A linear mixed effects model procedure (Xtreg, Stata v.6, Statacorp, College Station, TX), in which subject was treated as the random effect, was used to analyze the pharmacokinetic data. This permitted values for the "condition-drug" interaction to be estimated from a model with unbalanced design due to different numbers of studies or otherwise arbitrarily missing data. Comparisons were also based upon grouping the local anesthetics as longer-acting drugs (bupivacaine, levobupivacaine, and ropivacaine) or shorter-acting drugs (lidocaine, mepivacaine, and prilocaine). Blood binding data were analyzed by two-way analysis of variance (drug and condition) with Tukey's HSD post-run comparison of means (Statistix for Windows v.8.1, Analytical Software, Tallahassee, FL).


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Whole Body Response
Response data are presented in detail elsewhere.5 Briefly, repeated measures analysis of variance indicated that the baseline CVS values of the sheep did not systematically vary over time. All local anesthetics produced CNS excitotoxicity accompanied by acute CVS stimulation in all conscious sheep; no overt effects were observed in anesthetized sheep, but general anesthesia caused CVS depression, which was exacerbated by all local anesthetics. Fatalities occurred with bupivacaine (n = 3), levobupivacaine (n = 2), ropivacaine (n = 2), and prilocaine (n = 1), all in conscious sheep.

Whole Body Pharmacokinetics
Anesthesia approximately doubled the blood concentrations of all local anesthetics compared with the respective values while conscious (Figs. 1 and 2). Anesthesia affected the pharmacokinetic variables of all six drugs by decreasing their distribution and clearance, but with relatively minor differences between drugs (Tables 1 and 2). Within each condition, relatively few significant differences among drugs were found. Between longer-acting drugs, CL bupivacaine > levobupivacaine when anesthetized; between shorter-acting drugs, CL prilocaine > lidocaine > mepivacaine when conscious, and CL prilocaine > lidocaine = mepivacaine when anesthetized; Vss, T[1/2]β and MRT of the longer-acting drugs > shorter-acting when conscious (Table 2). The results of the random effects model for the pharmacokinetic variables (Table 1) were in close agreement with the raw arithmetic values that did not account for the unequal sample sizes (not shown for brevity).


Figure 120
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  		Figure 1. Mean (and 95% confidence intervals) of arterial blood concentrations of six local anesthetics infused over 3 min (shown by broken vertical line) in the nominated doses to adult female sheep when conscious or when anesthetized with halothane until 30 min after beginning of the infusion.

 

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  		Table 1. Pharmacokinetics (Noncompartment Analysis) of Local Anesthetics in Adult Female Sheep When Conscious and When Anesthetized With Halothane Before and During the First 30 Minutes After Injection

 

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  		Table 2. Effect of Anesthesia Determined by Random Mixed Effect Analysis Performed on Pharmacokinetic Data (Noncompartment Analysis) for All Local Anesthetics in Adult Female Sheep When Conscious and When Anesthetized With Halothane (Before and During the First 30 Minutes After Injection)

 


Figure 220
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  		Figure 2. Mean blood concentrations (normalized per mg dose to facilitate comparison) of six local anesthetics infused over 3 min (shown by broken vertical line) in the nominated doses to adult female sheep when conscious or when anesthetized with halothane until 30 min after beginning of the infusion. Error bars have been omitted for clarity.

 


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  		Table 1. Continued

 

Regional Pharmacokinetics
Maximal net influx occurred at maximal arterial drug concentrations, with smaller values for the longer-acting drugs (Fig. 3). When conscious, maximal heart efflux soon followed maximal influx; when anesthetized, efflux was smaller and more prolonged. Overall, the regional drug content was larger when anesthetized because of slower efflux from both regions; however, the values for the shorter-acting drugs in anesthetized sheep for brain are approximate, as data were obtained for only 1 or 2 sheep due to failure of sagittal sinus probes.


Figure 320
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  		Figure 3. Time course of mean net tissue flux (normalized to % dose per min) and tissue drug content (normalized to % dose) for heart and brain, as determined by mass balance principles from the respective products of the arterioregional venous blood concentration gradient and regional blood flow. Error bars have been omitted for clarity.

 

Pharmacokinetics in Nonsurvivors
Premortem arterial blood concentrations did not differ from those in survivors (Fig. 4). Death occurred close to the times of maximal drug content in heart and brain (Fig. 3). In two cases, levobupivacaine and ropivacaine concentrations in coronary sinus blood increased considerably immediately after death, almost certainly because of reflux of drug-enriched right atrial blood into the sinus as blood pressure equilibrated. Myocardial drug concentrations were generally largest in the left ventricle and least in the right atrium, but there was no consistent pattern for regional brain concentrations. All tissue drug concentrations were numerically larger than the nearest blood concentrations, reflecting drug tissue–blood distribution coefficients significantly larger than unity.


Figure 420
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  		Figure 4. Blood and postmortem tissue drug concentrations measured in individual subjects that did not survive the nominated dose of local anesthetic. Time of death is shown approximately by the indicated time of the tissue samples.

 

Pharmacokinetic Enantioselectivity
The pharmacokinetics of mepivacaine were not enantioselective; bupivacaine showed continuous decrease in the R-/S-ratio, consistent with a greater CL of R-bupivacaine; prilocaine had a biphasic profile, consistent with a greater CL of R-prilocaine and a greater Vss of S-prilocaine. Anesthesia did not produce a significant enantiomeric effect on the pharmacokinetics of bupivacaine or mepivacaine, but decreased the CL of R- and S-prilocaine disproportionately (Fig. 5).


Figure 520
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  		Figure 5. Effects of anesthesia on pharmacokinetic enantioselectivity of the racemic local anesthetics, bupivacaine, mepivacaine, and prilocaine, as shown by the time course of the R-/S-concentration ratios (log scale) in subjects when conscious and when anesthetized with halothane. Note time expansion for the period of anesthesia.

 

Drug Binding in Blood
Two-way analysis of variance indicated that blood binding differed according to drug (P < 0.01), but halothane did not significantly influence drug binding (P = 0.82). The mean values of %bound in the absence and presence of halothane, across all concentrations were, respectively, bupivacaine (69 and 73%) = levobupivacaine (72 and 69%) ≥ ropivacaine (57 and 58%) ≥ lidocaine (58% and 45%) > mepivacaine (39% and 35%) > prilocaine (15% and 31%). The Freundlich adsorption isotherms for each drug were linear both in the absence and presence of halothane with overlapping 95% confidence intervals (not shown for brevity); moreover, the blood binding isotherms of both enantiomers of the racemic drugs also overlapped, indicating no significant enantiomeric difference or effect of halothane on binding.


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we found that general anesthesia doubled the drug blood concentrations of all six local anesthetics, when compared with the conscious state, by increasing Cmax/unit dose (an indirect measure of distributional clearance), decreasing Vss (a direct measure of peripheral uptake), and decreasing CL (a direct measure of hepatic elimination). Anesthesia also decreased MRT and T[1/2] (by decreasing Vss more than CL), and Tmax was a little earlier in conscious animals (an indirect consequence of the CNS excitotoxicity). At the same time, the toxic response was altered: despite undergoing much greater CVS depression, all anesthetized animals survived doses that were lethal in some conscious sheep.5 Thus, drug blood concentration– response relationships were distorted by inclusion of general anesthesia in the model. Although prior studies, including some of our own with less well-developed methodology, have been performed to study various aspects of local anesthetic toxicity in concert with pharmacokinetics in chronically prepared sheep,15–25 the issue of general anesthesia as an experimental variable in the study design has not been previously addressed. It is not possible to deduce such information from post hoc analysis of various clinical studies because of the complicated nature of local anesthetic absorption.1

Our prior studies addressed the influence of general anesthesia on steady-state pharmacokinetic phenomena in which the ovine preparation was more oriented towards arteriovenous cannulation of drug eliminating organs than detailed CVS analysis. These found that general anesthesia with thiopental induction/halothane or enflurane or isoflurane maintenance, or total IV anesthesia with thiopental or propofol decreased the total body CL of various drugs through concomitant decreases in relevant regional blood flow and extraction/metabolism responsible for regional CL(s).2,3 The present study, designed to examine detailed CVS effects and pharmacokinetics of the local anesthetics concurrently, used halothane induction/maintenance, thereby precluding any effects of an IV induction drug. It demonstrated unequivocally that the toxicity and blood drug concentrations of all six local anesthetics were similarly altered by the incorporation of general anesthesia into the experimental design.

Quantitatively, the pharmacokinetics in conscious sheep were consistent with previous findings for those drugs in this species, allowing for experimental differences.8,17,18,20,22,26 Across all drugs, the main effects of general anesthesia were to increase the Cmax (per unit dose), and decrease CL and Vss (respectively, to 224, 52, and 33% of the relevant values when conscious; Table 2). The effects on CL were thus consistent with previous studies involving general anesthesia; however, the effect on Vss is not as well documented. Isoflurane anesthesia has been shown to increase Cmax of IV lidocaine in cats, and sevoflurane anesthesia has been shown to decrease its Vss (and CL) in horses.27,28 By causing CNS and CVS toxicity, a drug can affect its own disposition, and thereby violate the condition of stationarity.29 CO, a major determinant of initial distribution of drugs into well-perfused tissue,30–35 was increased by CNS excitotoxicity in our sheep when conscious, but was decreased when anesthetized.5 Hence, it is not surprising that Cmax (per unit dose) was larger in anesthetized sheep, and this could be explained by conservation of mass alone. Overall, the consequences of decreased Vss are not necessarily deleterious and facilitate faster washout of drug from the body, as evinced by shorter MRT and T[1/2]β. It may result from decreased peripheral perfusion due to the combination of decreased myocardial contractility and increased peripheral vascular resistance occurring under general anesthesia.5 However, it is still not possible from the data or from literature to ascribe mechanisms to the pharmacokinetic changes with certainty. Also, distribution of local anesthetics into lung tissue is important in attenuating Cmax after IV administration25,36,37 but no studies have, as yet, reported the effects of general anesthesia per se on the pulmonary extraction or lung uptake of local anesthetics. The pulmonary extraction of another basic amine, propranolol, was found to be increased by halothane-based anesthesia.38 However, the extraction was inversely proportional to the decrease in CO with the different anesthetic regimens, so that their product was constant and thus could be explained by conservation of mass. Although there is good evidence that general anesthesia can decrease the pulmonary metabolism of many substances, many of which are endogenous hormones and autacoids,39 there is no evidence that local anesthetics are metabolized by lung.17,18

Higher level pharmacokinetic–pharmacodynamic modeling was not attempted in this study because of the levels of complexity involved in the CVS response. However, the implications of this study for local anesthetic toxicity at two levels appear to be clear.

At a macro level, the familiar associations between local anesthetic dose, circulating "blood" drug concentrations, and systemic toxic effects may pertain. These differ among drugs according to potency (e.g., bupivacaine is clearly more toxic than lidocaine at the same blood concentration), the sample analyzed (blood or plasma, total or free, etc.), and the sampling site (artery or (which?) vein, etc.).25,40 Such associations are based on the assumption that drug concentrations in blood are in pseudoequilibrium with those in tissue(s) causing effect. With the brief time scales of anesthesia, and in these experiments with brief infusions or accidental IV doses, equilibrium is not normally achieved even with such well-perfused tissues as heart and brain. A steady-state estimate of the time constant for equilibration in tissues can be obtained from the product of the mean volume/flow and mean tissue/blood distribution coefficient. For the whole myocardium, for example, for bupivacaine with constant CVS response, this would be {approx}200 mL/{approx}100 mL/min x {approx}5 = {approx}10 min, so that equilibration would occur essentially within 20 min. In fact, steady-state does not pertain, CVS response is not constant, and the effect sites in the myocardium cannot be simply represented by single values for either a tissue blood flow or drug distribution coefficient (Fig. 4). Equilibrium with less well-perfused nonvisceral tissues (e.g., those comprising the lower limb) can take such long periods (several hours) that the distribution of these drugs can imitate CL.41

At a micro level, deterministic relationships between circulating drug concentration and CVS effect are questionable anyway, because effects are derived from specific susceptible tissues (muscle, nerve, etc.), with differing sensitivities, rather than blood. Response will be partially related to regional blood flow and tissue permeability, and the toxic effects associated with nonlinear (chaotic) state changes (i.e., once the changes are initiated, local neurohumoral factors affect their propagation or extinction), as well as regional pharmacodynamic interactions (i.e., CNS effects influencing CVS effects).25,42 Specifically, local anesthetic-induced myocardial depression is well-correlated variously with coronary sinus blood and mean myocardial tissue drug concentrations, but only to the point where the drug produces a CNS-toxic state change; afterwards, neurogenic myocardial stimulation occurs, and the myocardial response is no longer related to the blood or myocardial drug concentrations.8,19–21 An anesthetized subject cannot respond with the same CNS effects as a conscious subject. Thus, general anesthesia attenuates the CVS influence of neural mediators arising from sympathetic stimulation induced by CNS excitotoxicity with both deleterious and beneficial effects: direct myocardial depression is exacerbated, but malignant cardiac arrhythmias are prevented. And it is clear from this that the rate of drug administration is also a determinant of both response and pharmacokinetics through the drug blood and tissue concentrations produced. Others, for example, observed that conscious dogs responding with CNS excitotoxicity had a lower CL of several local anesthetics compared with those not responding that way from the same dose with a more prolonged infusion.43

The time course of drug influx/efflux into heart and brain was consistent with previous studies in conscious subjects,8,20,21 and was similar among drugs, being independent of binding in blood, which has negligible influence in controlling access of these drugs into these organs.44,45 Binding was essentially linear and not altered by halothane. Anesthesia caused greater uptake, however, apparently from slower efflux. Nevertheless, because drug concentrations in various regions of heart and brain tissue differ quite markedly, the deterministic notion of a "toxic" or "lethal" blood or tissue concentration of local anesthetic appears invalid even with standardized conditions. Others have noted that blood concentrations of local anesthetic in dogs that survived a particular dose were not significantly different from premortem blood concentrations in those that died.46

In this intact ovine model, general anesthesia affected survival, CNS and CVS responses, and pharmacokinetics from potentially toxic doses of local anesthetics. Specifically, this study shows the hazards of nominating a "toxic" drug concentration and extrapolating data from models of local anesthetic toxicity to clinical practice, and of associating pharmacologic effects with drug blood concentrations, in general, without considering experimental factors that could influence the outcome.


   ACKNOWLEDGMENTS
 
This paper is dedicated to the memory of Ray Kearns (1939–2008), without whose wonderful ability the work may not have been done. The authors are also pleased to acknowledge the skilled technical assistance of Wayne Roach, Chi Ming Lee, Cath Mundy, Rob Preston, and Steve Edwards.


   Footnotes
 
Accepted for publication January 23, 2008.

Supported by the Australian and New Zealand College of Anaesthetists, Melbourne, Australia, a grant-in-aid from Abbott Laboratories Pty Ltd., Sydney, Australia, and donations of local anesthetic products from AstraZeneca, Sydney, Australia. Professor Mather has received departmental and personal grants and financial support from the manufacturers of various drugs mentioned in this paper, and is listed as an "inventor" on some patents involving levobupivacaine.

Presented, in part, as a poster (abstract P70022) at the 15th World Congress of Pharmacology, Beijing, July 2–7, 2006.

Reprints will not be available from the author.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Tucker GT, Mather LE. Pharmacology of local anaesthetic agents. Pharmacokinetics of local anaesthetic agents. Br J Anaesth 1975;47(suppl):213–24[Web of Science][Medline]
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  3. Runciman WB, Myburgh J, Upton RN, Mather LE. Effects of anaesthesia on drug disposition. In: Feldman SA, Scurr CF, Paton W, eds. Mechanisms of action of drugs in anaesthetic practice. 2nd ed. London: Edward Arnold, 1993:83–128
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  7. Gu XQ, Fryirs B, Mather LE. High-performance liquid chromatographic separation and nanogram quantitation of bupivacaine enantiomers in blood. J Chromatogr B 1998;719:135–40
  8. Mather LE, Huang YF, Pryor ME, Veering BT. Systemic and regional pharmacokinetics of bupivacaine and levobupivacaine in sheep. Anesth Analg 1998;86:805–11[Abstract]
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S. E. Copeland, L. A. Ladd, X.-Q. Gu, and L. E. Mather
The Effects of General Anesthesia on the Central Nervous and Cardiovascular System Toxicity of Local Anesthetics
Anesth. Analg., May 1, 2008; 106(5): 1429 - 1439.
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