Reports of serious local anesthetic toxicity are, thankfully, rare. Although valuable information comes from analyzing clinical accidents, acquisition of scientific data during these events is secondary to patient well-being; consequently, physiological/pharmacological data are acquired opportunistically rather than systematically. The need for systematic study of local anesthetic toxicity has required development of human and nonhuman models, whereby various characteristics of the clinical condition can be replicated and/or controlled.1–4 In human models, however, drug doses are normally small, with subjective end-points giving limited ability to describe and/or predict the more serious toxicity of clinical accidents.5–7 Various nonhuman models have therefore evolved with particular abilities to reflect human clinical responses.8–10
Each model requires implementation of mixed experimental factors. The vast literature on nonhuman in vivo models of local anesthetic toxicity shows the use of large and small animal species, chronic and acute preparation, conscious and anesthetized subjects, and various dosage regimens. It is therefore not surprising that reports of local anesthetic toxicity include assorted differences, depending upon the experimental factors. General anesthesia is often used in experimental studies, yet clinical local anesthetic toxicity mainly occurs in conscious patients undergoing regional anesthesia. General anesthesia can affect normal physiology as well as drug pharmacokinetics and drug action. Therefore, it is important to determine its effects in models of local anesthetic toxicity, so that they can be evaluated and considered during interpretation of results. This is particularly pertinent when results from acute and chronic animal experimental models are compared, and/or implications are extrapolated to human patient management without clear discrimination, and when combinations of local and general anesthesia may be used clinically. In this study, we compared the central nervous system (CNS) and cardiovascular system (CVS) responses to a range of common local anesthetics in conscious and anesthetized sheep, using a standardized anesthetic regimen.
The study was approved by the local animal care and ethics committee.
Animals and Their Preparation
Nonpregnant Merino first-cross ewes (≈45–50 kg, ≈2 yr) were chronically instrumented under general anesthesia using previously described techniques.11–15 This preparation has been used in many analogous studies to acquire longitudinal concurrent physiological/ pharmacological/pharmacokinetic data in conscious animals, unhampered by acute surgical preparation, with each animal able to act as its own control. A left thoracotomy via the 4/5 intercostal space provided access for hemiazygos vein ligation, coronary sinus cannulation, and placement of probes for continuous measurement of cardiac output (CO), left coronary artery blood flow (CABF), left ventricular pressure (LVP) and its first derivative (LV-dP/dt), and electrocardiogram (ECG). A second surgery at least 6 days later consisted of placement of an infusion cannula in the jugular vein, and cannulae in the left carotid artery for sampling blood and for continuous mean arterial blood pressure (MABP) measurement, electroencephalogram (EEG) electrodes, a probe on the dorsal sagittal sinus for measuring blood flow (SSBF) and a sampling cannula in it. At least 7 days were allowed for recovery before pharmacological studies were begun. Only one study, in either the conscious or anesthetized state, was performed on any day, and studies in individual sheep were at least 2 days apart to allow for drug washout.
Studies were performed for local anesthetic dose ranging and to ascertain likely differences using different volatile anesthetics. Some essential findings are presented in Figure 1 as they influenced the methods adopted for the systematic studies (described below). Bupivacaine 150 mg and ropivacaine 200 mg could be fatal; hence, smaller doses were chosen to avoid fatalities; doses of the other local anesthetics were scaled to these. We chose to induce anesthesia with halothane and isoflurane by mask to preclude effects of an IV induction drug. Both anesthetics modified the myocardial response to bupivacaine, ropivacaine, or lidocaine essentially equally, and their peak blood concentrations in animals anesthetized with either drug were nearly double those when conscious.
Our specific aims were to determine the influences of general anesthesia on the CNS, hemodynamic, inotropic, and ECG responses to local anesthetics infused IV in toxic doses sufficient to produce convulsions in conscious animals. Three longer- and three shorter-acting local anesthetics were used in single, approximately equianesthetic, doses to determine whether the observed effects were drug-selective or common to the drug class. As there were major influences of general anesthesia on the local anesthetic blood concentrations, the systematic pharmacokinetic studies are presented in detail separately.16 The purpose was to compare the systemic effects of the local anesthetics on sheep when conscious and when anesthetized for a standardized (30 min) period. Death was not intended, but was possible from the use of doses sufficiently toxic to gain meaningful data. Resuscitation was not part of the study design. On the basis of clinical examination, demeanor, appetence, etc., we judged that surviving animals were not adversely affected by repeated studies, even if they had been instrumented for longer times. We tested this by longitudinal analysis of their prestudy baseline data. Any ewe that died was examined postmortem so that the probes could be checked, and to ensure that tissue damage had not occurred.
Before calibration of monitoring equipment, the animal was placed in a weight-bearing sling and allowed to settle before acquisition of 10 min of baseline data; the vehicle/drug was infused over 3 min, and data were collected for 60 min. Baseline data were similarly acquired in anesthetized subjects after CVS and blood gas stabilization. The procedures were repeated on separate days according to these principles: conscious vehicle-control (saline) studies were performed first, followed by anesthetized vehicle-control studies; studies with ropivacaine and levobupivacaine normally preceded those with bupivacaine because we surmised, incorrectly, that death was more likely from bupivacaine; studies with the shorter-acting local anesthetics were random; studies under anesthesia preceded conscious studies with individual drugs because conscious animals were more likely to die from adverse drug effects, requiring more animals to complete the studies than if the drug treatment order had been random.
Test Drugs and Doses
Infusions of 30 mL 0.9% saline were used as vehicle-controls. Doses (as base) of 100 mg bupivacaine, 125 mg levobupivacaine, 150 mg ropivacaine, 350 mg lidocaine, 350 mg mepivacaine, or 350 mg prilocaine (commercial preparations, HCl salts), diluted to 30 mL with 0.9% saline, were infused into a central venous catheter over 3 min, with the ewe conscious or anesthetized. These were similar to the officially recommended highest doses of these local anesthetics in a number of countries.17,18 The 3-min infusion was used to allow observation of the onset of effects, and is similar to the period used by many anesthesiologists for dose fractionation.
The pilot studies showed similar effects of halothane and isoflurane on dP/dt max and blood local anesthetic concentrations, consistent with evidence that the common volatile anesthetics have more pharmacological similarities than differences, and that the anesthetic state is the dominant effect.19–21 Halothane was chosen for the systematic studies for its low cost and continuity with our previous studies22; it is acknowledged that more modern general anesthetics are likely to be currently used clinically, but there is also much evidence that their effects, in the present context, are unlikely to differ greatly.20–23 After slinging the ewe, oxygen was given for 2 min; halothane/O2 anesthesia was induced by mask inhalation in gradual increments to the vaporizer maximum (5%). During induction of anesthesia, LVP and LV-dP/dt max MABP, CO, EEG, onset of relaxation, excursions of the reservoir bag, and palpebral reflex were monitored. When depth of anesthesia was sufficient, the trachea was intubated with a cuffed endotracheal tube, the vaporizer setting was decreased to 1.6%–1.8%, and the Fio2 was decreased to ≈35% with a fresh gas flow of 0.5 L/min O2 and 2 L/min air. Intermittent positive pressure ventilation was begun at 14 breaths/min and ventilation was adjusted so that Paco2 was within the range measured during the conscious control study (30–35 mm Hg). Thirty minutes after the start of the local anesthetic infusion, the halothane vaporizer was turned off, and ventilation was increased. Effects during recovery from anesthesia were observed for 30 min. The trachea was extubated when the sheep was breathing spontaneously and able to swallow.
Data Acquisition and Analysis
Data were acquired at 256 Hz (ECG, MABP, LVP, CO, CABF, SSBF, and EEG). Heart rate (HR) was derived from waveform peaks per 20 s intervals. Derived data were the maximum value of LV-dP/dt (LV-dP/dt max) as an index of myocardial contractility, stroke volume (SV) from CO/HR, estimated total peripheral resistance (TPR) from MABP/CO, ECG QRS complex width and QTc. Discrete data consisted of arterial blood gas, acid–base, and electrolyte status. Data were gathered by a physiological monitoring system (System 6®, Triton Technology Inc., San Diego, CA) and stored digitally for processing on a personal computer (MP100 analog-to-digital apparatus, Acknowledge® v.3.03 software; Biopac Systems Inc., Santa Barbara, CA). The data acquisition period was broken into baseline (prevehicle/drug) and effect (postvehicle/drug) data. Continuous data were broken into 20 s intervals, and the mean values from each were calculated and charted as continuous plots. For ECG analysis, the baseline data were broken into 1 min intervals, and the effect data were divided into 30 s intervals up to 5 min, 2.5 min intervals up to 10 min, 5 min intervals to 30 min, and 15 min intervals to 60 min. The ECG trace was examined for the occurrence, timing, and duration of arrhythmias. Outcome variables consisted of hemodynamic variables (MABP, CO, CABF, HR, LV dP/dt max, SSBF, TPR, and SV), QRS width, arrhythmia occurrence, incidence of deaths, occurrence of overt CNS stimulation, and acid–base changes.
Data Reduction and Statistical Analyses
Baseline data for each animal on each study day were tested for time-related tendencies using repeated measures analysis of variance with subject as the repeated measure and order of study as a within-subject variable. A finding of significance was investigated further by Dunnett's and Tukey's HSD procedures for comparison of mean values (Statistix for Windows® v.8.1, Analytical Software, Tallahassee, FL).
The null hypothesis was that there was no effect of anesthesia (“condition”) on CVS variables from local anesthetic doses (“drug”) that were toxic to the CNS in all conscious sheep. P < 0.05 was taken as weak evidence and P < 0.01 was taken as strong evidence for rejection of the null hypothesis. Sample sizes for the different variables were not necessarily equal because of the difficulty in generating complete sets of data for all variables in all sheep. Replacement animals could not be introduced as required in this complex chronic preparation for many reasons including cost, time, and ethical board approvals. Although some drug-induced deaths occurred, the main cause of missing data was unforeseen failure of data collection devices. 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 for data analysis. This permitted values for the “condition-drug” interaction to be estimated from a model with unbalanced design due to animals with missing data not depending on the previously administered treatments. To accommodate individual differences in baseline values and simplify presentation, drug effect data were converted to percentages of individual animals mean baseline values obtained immediately before drug administration. Drug effect data were analyzed for maximum effect (E max or E min, as appropriate), and the sums of effect differences to 10- and 30-min (respectively, SED10 and SED30, analogous to areas under the time-curves to quantitate time-related differences between treatments) were determined from the differences from individual baseline values.23 Results are reported as means and 95% confidence intervals. The proportions of cardiac arrhythmias and fatalities, when conscious and when anesthetized, were compared by two-tailed two sample proportion tests (corrected for continuity) and Fisher's exact tests (Statistix for Windows v.8.1).
Repeated measures analysis of variance indicated that the baseline CVS values of the sheep did not systematically vary over time; however, there were differences between the conscious and anesthetized states in the mean baseline values of HR, MABP, dP/dt max, CO, SV, and TPR, but not of CABF, SSBF, and QRS width.
Systemic Drug Effects
There was no effect of vehicle-control infusions in conscious or anesthetized sheep. The dominant effect of all local anesthetics was overt CNS excitotoxicity in all conscious sheep. There were eight fatalities, all in conscious animals and this was a significant finding (Table 1) (conscious versus anesthetized: proportion test Z corr = 2.54, P = 0.011; Fisher's exact test P = 0.0061). Postmortem findings in these subjects were unremarkable.
Sample physiographic traces showing baseline values, drug effects, and recovery in a conscious ewe are shown (Fig. 2). When conscious, initial myocardial depression (decreasing LV-dP/dt max) was quickly reversed with the onset of CNS excitotoxicity. The longer acting local anesthetics usually produced a transient, irregular bradycardia, premature contractions, then episodes of tachycardia, including polymorphic ventricular tachycardia (VT) which resolved, usually abruptly (Fig. 3A), or resulted in cardiovascular collapse and death (Fig. 3B). The one fatality from prilocaine infusion (Fig. 3C) differed in that the first abnormality was decreased contractility, which progressed to apparent electromechanical dissociation and protracted polymorphic VT.
The maximal effects generally occurred at or near the time of completion of local anesthetic infusion but, in conscious sheep, were influenced by the time at which CNS excitotoxicity began. The preexisting myocardial depression from halothane anesthesia was markedly exacerbated by infusion of all local anesthetics, with further decreases in dP/dt max, MABP, CO, and SV (Fig. 4) that were usually maximal at ≈5 min and resolved by ≈30 min (Fig. 5). QTc was decreased by 15%–20% in anesthetized ewes only. The effects of anesthesia began to regress soon after the halothane was turned off (30 min), and cardiovascular variables had returned to baseline by ≈60 min. CVS stimulation sometimes occurred during recovery from anesthesia before tracheal extubation. Malignant dysrhythmias were not seen in anesthetized animals, and all anesthetized animals survived.
SED10 and SED30 were correlated, and only SED10 is shown for brevity. The effects shown in Figures 5 and 6, except for E max for QRS width, differed between conscious and anesthetized conditions (all P < 0.001); in anesthetized sheep, increases in QRS width lasted longer, resulting in greater values of SED10 and SED30 (P < 0.001). There were no important differences between drugs but, overall, the changes were greater in magnitude and/or duration for the longer-acting local anesthetics than for the shorter-acting (and least for prilocaine), and were more prolonged in anesthetized sheep.
With local anesthetic infusion in conscious animals, there was a transient respiratory alkalosis followed by metabolic acidosis. In anesthetized ventilated ewes, arterial pH increased, presumably from decreased CO with unchanged ventilation (Fig. 7).
Serious arrhythmias did not occur during anesthesia. In conscious animals, sinus rhythm was more likely to prevail with the shorter-acting local anesthetics, although significant arrhythmias (mainly VT) without hemodynamic impairment occurred within several minutes of commencement of infusion in 1 of 8 animals with lidocaine and 1 of 7 with mepivacaine. In addition, in 1 of 9 with prilocaine, there was a fatality consequent to electromechanical dissociation, followed by polymorphic VT. In conscious sheep, serious but nonfatal arrhythmias (mainly VT and torsades de pointes-like polymorphic VT, accompanied by decreased CO) occurred within several minutes of commencement of infusion in 7 of 10 sheep with bupivacaine, 4 of 11 with levobupivacaine, 5 of 12 with ropivacaine, and were observed in each fatal case. Episodes of VT, although not necessarily continuous, lasted from <1 to 15 min, and duration of polymorphic VT with decreased CO, ranged from <1 to 11 s in the survivors. The frequency of arrhythmias differed between conscious and anesthetized subjects (Z corr = 5.85, P < 0.0001; Fisher's exact test P < 0.0001), and between longer- and shorter-acting local anesthetics in conscious subjects (Z corr = 4.35, P < 0.0001; Fisher's exact test P < 0.0001) but not between the various longer- or shorter-acting local anesthetics.
Serious local anesthetic toxicity is not amenable to systematic study in humans; thus, nonhuman laboratory models are necessary to allow systematic study of its characteristics and to evaluate possible treatments. Most animal models involve acute preparation and/or subsequent observation of local anesthetic systemic effects in anesthetized animals. In our intact chronic ovine preparation, general anesthesia was found to alter CNS and CVS effects, and drug blood concentrations of six local anesthetics in different, but clinically equivalent, doses chosen to be recognizably toxic but not lethal.17,18 The systemic effects of these drugs were qualitatively similar, suggesting that the effects were common to the drug class but differed quantitatively, mainly due to more protracted effects of the longer-acting drugs and a briefer effect of prilocaine (Fig. 6).
In conscious sheep, initial CVS depression was followed by CVS stimulation and QRS widening, with similar maximal effects for all local anesthetics, apparently reflecting the causative CNS excitotoxicity. The ameliorating effect of anesthesia on CNS toxicity was consistent with research reports and clinical practice.24–29 In the anesthetized state, profound CVS depression and prolonged increases in TPR occurred; notwithstanding, all animals survived, despite doubled local anesthetic blood concentrations (Fig. 1). However, other experimental models have shown that although general anesthesia suppresses convulsions and arrhythmias, it does not necessarily promote survival, apparently depending upon the drug and the model.24,25 This demonstration of biphasic CVS effects is partly a consequence of the dosage regimen chosen, compared to other models in which continuous or repeated drug administration are used to achieve a particular end-point, e.g., onset of convulsions, QRS widening, arrhythmogenesis, or CVS collapse, thereby producing other patterns according to experimental factors including state of consciousness and resuscitation.30–34 We believe that our dosing regimen reasonably represents the situation when conscious patients undergoing major neural blockade accidentally receive local anesthetic IV.
The first sign of serious local anesthetic-induced toxicity in conscious subjects is often generalized CNS excitotoxicity, with or without CVS signs, but prodromal signs may be apparent5–7,35 depending mainly on diligent observation and the rate of local anesthetic administration/absorption. Our results show that CVS depression normally precedes CNS excitotoxicity in conscious animals but might not be detected by usual clinical monitoring; a rapidly acting anesthetic for treatment of CNS toxicity would exacerbate the CVS depression. The CNS response to local anesthetics has been implicated in their CVS toxicity,13–15,36,37 but its role remains unclear, partly due to the variations in experimental factors in the various models used for its description. Halothane causes profound myocardial depression, and may predispose the heart to arrhythmias19–21,38; however, isoflurane and sevoflurane can suppress multiform QRS waves resulting from bupivacaine.24 Thus, it could reasonably be argued that the combination of toxic concentrations of local anesthetic and anesthesia with a volatile anesthetic other than halothane might cause less CVS depression. The last stage of CVS toxicity, especially from bupivacaine, is typically the sudden development of malignant ventricular arrhythmias (VT preceding fibrillation) resulting in cardiovascular collapse as previously described13,39–41; nevertheless, this did not occur in anesthetized subjects. In this study, the blood gas changes in conscious sheep were consistent with a clear airway and good oxygenation; CABF was also maintained, and thus it is unlikely that cardiac ischemia or hypoxemia contributed significantly to the cardiac dysrhythmias caused by the longer-acting drugs in conscious sheep, and dysrhythmias were not found in anesthetized sheep.
In summary, we found that local anesthetic toxicity in halothane-anesthetized sheep was very different from that in conscious sheep (Table 2). In the latter, CNS excitotoxicity stimulated the CVS with malignant, sometimes fatal, cardiac arrhythmias. In the former, marked cardiovascular depression predominated and, despite the blood drug concentrations being approximately doubled in sheep under general anesthesia,16 all sheep survived. This study therefore provides evidence that general anesthesia protects against a dangerous toxic effect of local anesthetics, arrhythmias, and possibly against death. As this study did not address mechanisms, it is not possible to tell from the available evidence whether these observations can be extended to larger doses of local anesthetic or to other forms of general anesthesia.
Because general anesthesia affects the CNS, CVS, and drug disposition, its influence needed to be studied as an isolated variable in a validated model of local anesthetic toxicity. Toxicity in anesthetized sheep was very different from that in conscious sheep, indicating the importance of general anesthesia as an experimental factor. This raises important implications for research into local anesthetic toxicity (other drugs also?), and possibly for future prevention, treatment and improved understanding of the mechanisms involved. Research conclusions obtained from an anesthetized preparation should be applied to clinical situations only if the patients are anesthetized; and results from a conscious preparation should be applied to conscious patients, since the presence or absence of anesthesia makes such a large difference.
This paper is dedicated to the memory of Ray Kearns (1939–2008), without whose wonderful skills the work may not have been done. The authors are also pleased to acknowledge the skilled technical assistance of also Wayne Roach, Chi Ming Lee, Cath Mundy, Rob Preston, and Steve Edwards.
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© 2008 International Anesthesia Research Society
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