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Anesth Analg 2000;91:362-368
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Concentrations of Lidocaine and Monoethylglycine Xylidide in Brain, Cerebrospinal Fluid, and Plasma During Lidocaine-Induced Epileptiform Electroencephalogram Activity in Rabbits: The Effects of Epinephrine and Hypocapnia

Yoshihiro Momota, DDS*, Alan A. Artru, MD{dagger}, Karen M. Powers, BS{dagger}, Douglas S. Mautz, PhD{dagger}, and Yutaka Ueda, MD, PhD*

Departments of Anesthesiology, *Osaka Dental University, Osaka, Japan; and {dagger}University of Washington School of Medicine, Seattle, Washington

Address correspondence and reprint requests to Alan A. Artru, MD, Department of Anesthesiology, Box 356540, University of Washington School of Medicine, Seattle, WA 98195-6540.


   Abstract
Top
 Abstract
Introduction
 Method
 Results
 Discussion
 References
 
When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO2. In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO2 on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg · kg-1 · min-1 with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 µg/mL with hypocapnia and 2 µg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 µg/mL without epinephrine and by 14 µg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain.

Implications: Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.


   Introduction
Top
 Abstract
 Introduction
Method
 Results
 Discussion
 References
 
Large blood concentrations of lidocaine may cause toxic effects, including lidocaine-induced seizures and death. Large blood concentrations may result from rapid absorption of lidocaine after its injection into tissues or from direct introduction into an artery or vein. The addition of epinephrine to lidocaine and reduction of the PaCO2 are recommended to minimize lidocaine toxicity after its injection into tissues (1–3). Epinephrine produces vasoconstriction, which decreases vascular absorption of lidocaine (1–3). Decreased PaCO2 reduces cerebral blood flow so that less lidocaine is delivered to the brain (2,3). Decreased PaCO2 also increases pH, which increases plasma protein-binding of lidocaine (decreasing the free portion of drug available for diffusion into the brain) and enhances the conversion of the cationic form of lidocaine to the base form (the cationic form being the one responsible for the effects of lidocaine on neural cell membranes) (2,3).

When lidocaine is introduced directly into an artery or vein, the effects of epinephrine on lidocaine toxicity are quite different from those when lidocaine is injected into tissue. When lidocaine was given intravascularly, the addition of epinephrine to lidocaine significantly decreased the dose of lidocaine producing convulsions or death (4,5,7–9).1,2 There are no comparable reports on the effects of decreased PaCO2 on the toxicity of lidocaine, with/without the addition of epinephrine, given directly into an artery or vein. Accordingly, the present study was designed to examine the effect of decreased PaCO2 on the dose of lidocaine producing seizures and on lidocaine concentrations in brain, plasma, and cerebrospinal fluid (CSF) when lidocaine was given IV either alone or with epinephrine.

In addition, there is little information on concentrations of monoethylglycine xylidide (MEGX), a metabolite of lidocaine, during seizures. Halkin et al. (10) reported a case in which MEGX may have contributed to central nervous system toxicity occurring during infusion of lidocaine. Walson (11) stated that MEGX and glycinexylide are formed on first pass clearance of lidocaine and may be as toxic or more toxic than lidocaine itself. Accordingly, we measured MEGX concentrations in brain, plasma, and CSF and examined the effects of epinephrine and decreased PaCO2 on MEGX concentrations.


   Method
Top
 Abstract
 Introduction
 Method
Results
 Discussion
 References
 
This study was approved by the Animal Care Committee of University of WA. The subjects were 24 New Zealand White rabbits, of both sexes, weighing 1.7–2.5 kg. Details of anesthesia and surgical preparation were published previously (12). Briefly, anesthesia was induced with halothane, an endotracheal tube was inserted via tracheostomy, the lungs were ventilated mechanically, two arteries and four veins were cannulated, rectal temperature was monitored, a catheter was inserted into the cisterna magna, the electroencephalogram (EEG) was monitored by using gold cup electrodes, and anesthesia was maintained with fentanyl/halothane/nitrous oxide/oxygen. The dosing of fentanyl was 16 µg/kg IV given over 10 min and then 0.18 µg · kg-1 · min-1 until the end of the study. The expired concentration of halothane was approximately 0.2% (12). The inspired concentrations of nitrous oxide and oxygen were approximately 67% and 33%. After completion of the surgical preparation and after stable measurements of cerebral and systemic variables were obtained (at least 30 min later), the 24 rabbits were divided into four groups randomly: lidocaine and hypocapnia (Group 1, n = 6), lidocaine + epinephrine and hypocapnia (Group 2, n = 6), lidocaine and normocapnia (Group 3, n = 6), and lidocaine + epinephrine and normocapnia (Group 4, n = 6). We examined all of the rabbits at two conditions: at baseline and during continuous seizures.

In all groups, the following values were determined during baseline: EEG activity, mean arterial blood pressure (MAP), heart rate, CSF pressure, PETCO2, rectal temperature, arterial blood gas tensions, pH, and concentrations of sodium, potassium, lactate, and glucose. After determining baseline values, in Groups 1 and 3, lidocaine at 4 mg · kg-1 · min-1 was infused IV, and in Groups 2 and 4, lidocaine at 4 mg · kg-1 · min-1 + epinephrine at 4 µg · kg-1 · min-1 was infused IV until the end of study. Preliminary studies with this model indicated that infusion of lidocaine at 4 mg · kg-1 · min-1 significantly decreased MAP, and infusion of lidocaine at 4 mg · kg-1 · min-1 + epinephrine at 4 µg · kg-1 · min-1 significantly increased MAP. We were concerned that failure to correct these changes in MAP would significantly decrease delivery of lidocaine to the brain in the case of hypotension and significantly increase delivery of lidocaine to the brain secondary to increased permeability of the blood-brain barrier (BBB) in the case of hypertension, as has been reported previously with lidocaine toxicity (8). Accordingly, we chose to prevent lidocaine-induced hypotension by infusing phenylephrine 7–20 µg · kg-1 · min-1 IV as needed and to prevent epinephrine-induced hypertension by infusing labetalol 3–17 µg · kg-1 · min-1 IV as needed. Phenylephrine infusion was not initiated prophylactically but was begun at the first sign of decrease of MAP after starting the infusion of lidocaine and was adjusted thereafter as necessary. Based on pilot studies, labetalol infusion was begun 2 min before starting the infusion of lidocaine + epinephrine and was adjusted thereafter as necessary.

At the onset of seizures, the following values were determined: EEG activity, the time of onset of seizures, the total lidocaine dose at the time of onset of seizures, MAP, heart rate, CSF pressure, PETCO2, rectal temperature, arterial blood gas tensions, pH, and concentrations of sodium, potassium, lactate, and glucose. In addition, after the onset of seizures arterial blood samples (5 mL) were obtained for measurement of plasma concentrations of lidocaine and MEGX in each group. After 10 min of continuous seizures, CSF samples (200 µL) were obtained for determination of CSF concentrations of lidocaine and MEGX. Plasma and CSF samples were stored at -20°C until analysis. After obtaining blood and CSF, the rabbits were immediately killed by IV infusion of saturated potassium chloride solution. At the same time, a catheter was inserted into the left carotid artery, and saline (5 mL) was injected to remove lidocaine remaining in the cerebral vessels. The pressure in the carotid catheter was monitored continuously, and the rate of flow of saline through the catheter was adjusted so that pressure in the catheter remained at the same value as baseline MAP. When the infusion of saline into the carotid artery was completed, a craniotomy was performed, and the brain was removed for measurement of total lidocaine and MEGX concentrations in brain tissue. Each brain was separated into right and left hemispheres. In one hemisphere, cortical tissue was separated from subcortical tissue, and only cortex lidocaine and MEGX concentrations were determined. In the other hemisphere, whole brain lidocaine and MEGX concentrations were measured.

Details of the analytical technique used here to measure total lidocaine and MEGX concentrations (including reagents, instrumentation, sample preparation, quality control, calibration, limit of quantitation, reproducibility, and efficiency) were published previously (13). Briefly, plasma and CSF concentrations of lidocaine and MEGX were determined separately by gas chromatography with high performance liquid immunoassay chromatography. The brain samples were stored at -20°C until analysis. Brain tissue was homogenized and added to 100 µL of 0.25 M NaOH solution. Brain concentrations of lidocaine and MEGX were measured by using immunoassay gas chromatography.

Rabbits were allocated into the four experimental groups by using four-number random draw. Statistical comparisons of time to onset of seizures, total dose of lidocaine at time of seizures, and concentrations of lidocaine and MEGX in plasma, whole brain, cortical brain, and CSF were made by using two-way analysis of variance (ANOVA). Statistical comparisons of arterial blood gas tensions, plasma electrolyte, lactate and glucose concentrations, and EEG values were made by using three-way ANOVA. Statistical comparisons of MAP, heart rate, CSF pressure, PETCO2, and temperature were made by using three-way repeated measures ANOVA. Where appropriate, post hoc analysis was performed by using the Student-Newman-Keuls test. For all data analysis, P < 0.05 was considered significant. Values were tabulated as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Method
 Results
Discussion
 References
 
Baseline MAP, heart rate, and rectal temperature did not differ significantly among the four experimental groups (Table 1). Baseline CSF pressure and PETCO2 in the hypocapnia groups (Groups 1 and 2) were significantly decreased compared with values in the normocapnia groups (Groups 3 and 4). In all groups, the magnitude of change of MAP from prelidocaine values was not statistically significant during the time from the start of lidocaine infusion (with or without epinephrine) to the onset of seizures (Figure 1). During both baseline and seizures, arterial blood pH, PaCO2, PaO2, and bicarbonate concentrations in the hypocapnia groups were significantly different from values in the normocapnia groups (Table 2). With seizures, MAP, CSF pressure, PETCO2, and rectal temperature were not significantly altered, and heart rate, blood pH and bicarbonate, and plasma potassium decreased in all groups. In contrast, with seizures, plasma concentrations of lactate and glucose in Group 1 and lactate in Group 3 (the groups receiving lidocaine without epinephrine) decreased, but increased in the groups receiving lidocaine + epinephrine (Groups 2 and 4).


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  		Table 1. Systemic Values
 


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  		Figure 1. The stability of mean arterial blood pressure is shown for the four experimental groups for the time period from the beginning of lidocaine infusion (time = 0 min) until the onset of seizures. The vertical axis represents mean change of mean arterial blood pressure from pre-lidocaine values, expressed as mm Hg. The horizontal axis represents time, expressed as minutes. Each symbol indicates the mean of values for 6 animals (except where indicated by parentheses). Vertical bars above and below each symbol indicate SD. The number within the parentheses indicates the number of animals still receiving lidocaine (lidocaine being infused because seizures have not yet occurred).

 

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  		Table 2. Blood Gas Tensions and Plasma Electrolyte, Lactate and Glucose Concentrations
 
During seizures, the number of wave forms in each of the standard frequency bins and {delta} power decreased, and {theta}, {alpha}, ß, and total power and the edge frequency increased (Table 3). The onset time of seizures and the total dose of lidocaine at the time of seizures were decreased in Group 2 as compared with Group 1, and in Group 4 as compared with Group 3, i.e., for both of the epinephrine versus no epinephrine comparisons (Table 4). In contrast, the onset time of seizures and the total dose of lidocaine at the time of seizures were increased in Group 1 as compared with Group 3, and in Group 2 as compared with Group 4, i.e., for both of the hypocapnia versus normocapnia comparisons. Comparison of the combined effects of hypocapnia + epinephrine on onset time and lidocaine dose, i.e., Group 2 (lidocaine, epinephrine, hypocapnia) versus Group 3 (lidocaine, no epinephrine, normocapnia) revealed no significant difference between the two groups.


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  		Table 3. Electroencephalogram Values
 

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  		Table 4. Time of Onset of Seizures, Total Dose of Lidocaine at Time of Seizures, and Concentrations of Lidocaine and MEGX in Plasma, Whole Brain, Cortical Brain, and CSF
 
Concentrations of lidocaine in plasma, whole brain, cortical brain, and CSF did not differ significantly among groups. Within each group, concentrations of lidocaine were whole brain = cortical brain > plasma > CSF. The concentration of MEGX in plasma was increased in Group 2 as compared with Group 1, and in Group 4 as compared with Group 3, i.e., for both of the epinephrine versus no epinephrine comparisons. The concentration of MEGX in whole brain was increased in Group 1 as compared with Group 3, and in Group 2 as compared with Group 4, i.e., for both of the hypocapnia versus normocapnia comparisons. Concentrations of MEGX in cortical brain and CSF did not differ significantly among groups. Within each group, the concentrations of MEGX were cortical brain > whole brain > plasma > CSF.


   Discussion
Top
 Abstract
 Introduction
 Method
 Results
 Discussion
References
 
One principal finding was that hypocapnia increased the time to seizures and therefore the total dose of lidocaine at the time of seizures. This PaCO2-related effect occurred regardless of whether epinephrine was added to lidocaine. Hypocapnia did not alter the concentration of lidocaine in plasma at the time of onset of seizures, nor did it alter the concentration of lidocaine in whole brain, cortical brain, or CSF. These findings suggest that the increased pH of blood accompanying the decrease of PaCO2 may either increase the passage of lidocaine into peripheral tissues or increase the metabolism/clearance of lidocaine from the blood. Consequently, the plasma lidocaine concentrations in the hypocapnia groups were similar to those in the normocapnia groups, even though a larger dose of lidocaine had been administered by the onset of seizures in the hypocapnia groups.

The intravascular dose of lidocaine required to produce seizures has been reported to be inversely related to PaCO2 (14–16). This relationship, well documented at PaCO2 values between 40 and 95 mm Hg, has been stated to be true also during hypocapnia (17). However, data on the relationship between PaCO2 and the lidocaine dose-causing seizures are less clear during hypocapnia than during hypercapnia. In cats given lidocaine IV at 5 mg · kg-1 · min-1, the lidocaine dose-causing seizures was 22.0 mg/kg at PaCO2 = 40 mm Hg and pH = 7.4, 25.8 mg/kg at PaCO2 = 30 mm Hg and pH = 7.5, and 26.6 mg/kg at PaCO2 = 30 mm Hg and pH = 7.4 (16). In the same study when lidocaine was given at 3 mg · kg-1 · min-1, the lidocaine dose-causing seizures was 15.8 mg/kg at PaCO2 = 40 mm Hg and pH = 7.4, 18.7 mg/kg at PaCO2 = 30 mm Hg and pH = 7.5, and 22.0 mg/kg at PaCO2 = 30 mm Hg and pH = 7.4. In this study, the variability of mean doses was not given, and rather than comparing data at hypocapnia to those at normocapnia, a linear correlation was done on all data over a PaCO2 range of 30–90 mm Hg. In another study in cats, giving 12.5–15.0 mg/kg lidocaine IV over five seconds caused seizures in two of two infusions at PaCO2 = 40–45 mm Hg, one of two infusions at PaCO2 = 35 mm Hg, and zero of two infusions at PaCO2 = 30 mm Hg (14). In contrast, in the same study, giving 10 mg/kg lidocaine caused seizures in one of three infusions at PaCO2 = 40–45 mm Hg, zero of four infusions at PaCO2 = 35 mm Hg, one of four infusions at PaCO2 = 30 mm Hg, and zero of one infusions at PaCO2 = 20 mm Hg. Again, rather than comparing data at hypocapnia to those at normocapnia, a correlation was done on all data over a PaCO2 range of 20–95 mm Hg.

In the present study, concentrations of lidocaine in whole brain and in cortical brain were increased compared with plasma lidocaine concentrations, consistent with the retention of lidocaine in the brain after passage of lidocaine from blood to the brain. The similarity between lidocaine concentrations in whole brain and cortical brain suggests that the capacity for lidocaine to reside in subcortical brain is not significantly different from that of cortical brain. Smaller concentrations of lidocaine in CSF than in brain or plasma presumably reflect passage of lidocaine into CSF along a concentration gradient with inadequate time for and/or no capacity for CSF to retain lidocaine against a concentration gradient.

A second principal finding was that the addition of epinephrine to lidocaine affected concentrations of MEGX in plasma, and PaCO2 affected concentrations of MEGX in whole brain (gray and white matters combined) but not in cortical tissue (gray matter only). Addition of epinephrine to lidocaine increased the concentration of MEGX in plasma as compared to the groups receiving lidocaine without epinephrine. Possible explanations include epinephrine-induced a) decrease of peripheral blood volume of distribution, b) facilitated passage of MEGX from sites of lidocaine metabolism into blood, and c) increased capacity for residence of MEGX in blood. Hypocapnia increased whole brain (but not cortical tissue) MEGX concentration as compared to that during normocapnia, while during both hypocapnia and normocapnia cortical MEGX concentration was greater than that in whole brain. The decreased concentration of MEGX in whole brain as compared to cortical brain presumably reflects a) greater metabolism of lidocaine in cortical brain, b) increased capacity for residence of MEGX in cortical brain, and/or c) increased passage of MEGX out of subcortical brain. That the concentration of MEGX in whole brain was increased during hypocapnia as compared to normocapnia suggests that the above-mentioned proposed explanations for decreased concentration of MEGX in subcortial brain may be pH dependent. As with concentrations of lidocaine in CSF, smaller concentrations of MEGX in CSF than in brain or plasma presumably reflect passage of MEGX into CSF along a concentration gradient with inadequate time for and/or no capacity for CSF to retain MEGX against a concentration gradient.

Our finding that addition of epinephrine to lidocaine decreased the onset time to seizures and the total dose of lidocaine at the time of seizures as compared to lidocaine without epinephrine agrees with the results of previous studies (4,5,7–9).1,2 In those studies addition of epinephrine to lidocaine decreased the dose of lidocaine causing seizures, convulsions or death, increased or did not change MAP and PaCO2, and decreased or did not change the concentration of lidocaine in plasma or brain. Further, in those studies addition of epinephrine to lidocaine increased regional cerebral blood flow, and did not alter CSF pressure, cerebral perfusion pressure, brain tissue PO2, or BBB permeability to Evans Blue dye. Proposed explanations for the effect of epinephrine on lidocaine toxicity included 1) decreased distribution of lidocaine from blood to nonneural tissue, 2) ischemia, hypoxia, or increased lidocaine concentration in a focal brain area responsible for initiating convulsion, and 3) epinephrine-induced neuroexcitation.

Our results indicate that epinephrine-induced increase of either MAP or PaCO2 cannot be the sole mechanism by which epinephrine can decrease the convulsant-inducing dose of lidocaine because in our study epinephrine-induced hypertension and hypercapnia were eliminated. Also, the addition of epinephrine to lidocaine did not alter the concentration of lidocaine in plasma at the time of onset of seizures. Several previous studies reported similar findings (6,8,9). In contrast, Yokoyama et al. (7) reported that epinephrine decreased the concentration of lidocaine in plasma. Yokoyama et al. (7) postulated that epinephrine decreased the convulsant-inducing dose of lidocaine because epinephrine increased MAP thereby increasing the permeability of the BBB and increasing the passage of lidocaine from blood into brain tissue. Our results indicate that an epinephrine-induced increase in the concentration of lidocaine in brain cannot be the sole mechanism by which epinephrine can decrease the convulsant-inducing dose of lidocaine, because we measured whole brain, cortical brain, and CSF concentrations of lidocaine and found no significant difference among the experimental groups. Consistent with our findings, Yokoyama et al. (8) in a follow-up to their earlier study reported that when the epinephrine-induced increase of MAP was blocked by sodium nitroprusside, lidocaine concentrations in plasma and brain were not altered by the presence or absence of epinephrine, yet the convulsant dose of lidocaine was smaller when lidocaine was given with epinephrine than without epinephrine. Our findings suggest that epinephrine may either decrease the systemic volume of distribution of lidocaine or decrease the metabolism/clearance of lidocaine from blood, so that a smaller administered dose of lidocaine with epinephrine results in a plasma concentration similar to that occurring when a larger dose of lidocaine without epinephrine is infused. Therefore, lidocaine concentrations in the central nervous system reached a critical concentration to evoke seizures with a shorter time of lidocaine infusion in the epinephrine groups as compared to the nonepinephrine groups.

Phenylephrine and labetalol were used to control blood pressure because they are reported to exert minimal direct effects on cerebral vessels and therefore would not cause cerebral vasoconstriction (which would decrease the delivery of lidocaine to the brain) or cerebral vasodilatation (which would increase the delivery of lidocaine to the brain) (18–22). Additional evidence supporting the use of phenylephrine in the specific circumstance of lidocaine toxicity was presented by Yokoyama et al. (8). In that study it was reported that, when MAP was maintained at baseline values, the convulsant dose of lidocaine + phenylephrine was similar to that of lidocaine alone (as compared to being decreased with lidocaine + epinephrine). It was concluded that phenylephrine does not increase the concentration of lidocaine in brain areas responsible for initiating convulsion, nor does phenylephrine cross the BBB to exert a direct excitatory effect. For the present study, alternative methods to prevent hypotension and hypertension, such as external compression/decompression of the body, or infusion/withdrawal of IV fluids, were not selected on the basis that such treatments would alter the volume of distribution of lidocaine in blood.

In summary, our results indicate that hypocapnia increases the toxic dose of intravascular lidocaine. This effect of hypocapnia is similar to that previously reported when lidocaine is injected into tissue. In our study hypocapnia did not alter plasma or central nervous system concentrations of lidocaine, suggesting that hypocapnia either increased the passage of lidocaine into peripheral tissues and/or increased the metabolism/clearance of lidocaine from blood. In contrast, the effect of epinephrine on intravascular lidocaine is opposite to that on lidocaine injected into tissue. In our study addition of epinephrine to lidocaine decreased the toxic dose of intravascular lidocaine, whereas it is recommended for co-administration with lidocaine in order to increase the toxic dose of lidocaine injected into tissue. Addition of epinephrine to lidocaine increased the concentration of MEGX in plasma. The concentration of MEGX in whole brain (but not cortical tissue) was greater during hypocapnia than during normocapnia.


   Acknowledgments
 
Supported by research funds from the Departments of Anesthesiology at Osaka Dental University, Osaka, Japan and the University of Washington School of Medicine, Seattle, Washington.


   Footnotes
 
1Hardin RL, Yagiela JA, Bilger PAL, Hunt LM. Influence of epinephrine on intravascular lidocaine toxicity [abstract]. J Dent Res 1981;60(A):463. Back

2Thompson L, Yagiela JA. Epinephrine potentiation of lidocaine toxicity during slow intravenous infusion [abstract]. J Dent Res 1986;65:248. Back


   References
Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 References
 

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Accepted for publication May 1, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press