The Effect of Insulin on the Resuscitation of Bupivacaine-
Induced Severe Cardiovascular Toxicity in Dogs
Jin-Tae Kim, MD, Chul-Woo Jung, MD, and Kook-Hyun Lee,
Department of Anesthesiology and Pain Medicine, College of Medicine, Seoul National University, Korea
Resuscitation after bupivacaine-induced cardiovascular
collapse is difficult and often resistant to conventional
treatment. We tested the hypothesis that insulin treatment
would effectively reverse bupivacaine-induced cardio-
vascular collapse in pentobarbital-anesthetized dogs. Bu-
pivacaine was administered at 0.5 mg kg1 min1 until saturation, and end tidal CO2 recovered toward baseline
mean arterial blood pressure decreased to 40 mm Hg or
less. In the insulin-glucose-potassium (IGK) group (n 7),
an IV bolus of regular insulin (2 U/kg) was given,
followed by a glucose infusion (2 mL/kg of 50% dextrose
S
evere cardiovascular collapse can occur when
bupivacaine is accidentally injected into a blood
vessel or large doses of bupivacaine are admin-
istered. Bupivacaine-induced cardiovascular collapse
is resistant to conventional treatment (1), and resusci-
tation is difficult (2). The choice of resuscitation drug
for bupivacaine cardiovascular collapse remains con-
troversial (3).
Bupivacaine causes profound cardiac depression by
blocking transient outward K currents and repolar-
ization of ventricular myocytes (4) and by alteration of
Ca2 release from the cardiac sarcoplasmic reticulum
(5). Bupivacaine also depresses cardiac conduction by
blocking Na channels (6), which is enhanced by hy-
perkalemia (7). Insulin, in contrast, enhances the tran-
sient outward K current and repolarization (8). Ca2
transport activity of sarcoplasmic reticulum is in-
creased by insulin (9,10). In addition, insulin possibly
increases cytoplasmic glucose concentration and pyru-
vate availability to mitochondria, thereby improving
myocardial energetics and performance (11,12).
We have previously shown that insulin could re-
verse bupivacaine-induced cardiac depression in dogs
Supported, in part, by a grant of the Seoul National University
Hospital (212003 014 0).
Accepted for publication March 5, 2004.
Address correspondence and reprint requests to Kook Hyun Lee,
MD, Department of Anesthesiology, Seoul National University Hos-
pital, #28, Yongon-Dong, Chongno-Gu, Seoul, Korea 110-744. Ad-
dress e-mail to leekh@plaza.snu.ac.kr.
DOI: 10.1213/01.ANE.0000132691.84814.4E
728 Anesth Analg 2004;99:72833
MD
in water) for 30 min and a potassium infusion (1
2 mmol kg1 h1). In the control group (n 7), glucose
infusion was given as in the IGK group. In contrast to the
control group, all IGK dogs survived. Mean arterial blood
pressure, heart rate, cardiac output, mixed venous oxygen
levels in the IGK group. In conclusion, severe
bupivacaine-induced cardiovascular collapse in dogs was
effectively reversed with the insulin treatment.
(Anesth Analg 2004;99:728 33)
when mean arterial blood pressure (MAP) was
reduced to approximately 65 mm Hg (13). We hypoth-
esized that insulin also might be effective in revers-
ing severe bupivacaine-induced cardiovascular col-
lapse (MAP, 40 mm Hg). The purpose of study was
to investigate the effect of insulin on resuscitation
of bupivacaine-induced cardiovascular collapse in
pentobarbital-anesthetized dogs.
Methods
This study was approved by the Animal Care and Use
Committee of Seoul National University College of
Medicine. Fourteen mongrel dogs were randomly as-
signed to two equal groups: control (C) and insulin-
glucose-potassium (IGK) groups (n 7 in each
group). Dogs were fasted overnight but had access to
water. Anesthesia was induced with 10 mg/kg of IV
thiopental sodium and maintained with a continuous
infusion of sodium pentobarbital 5 mg kg1 h1.
After intubation of the trachea, vecuronium 0.2 mg/kg
was injected IV, followed by 0.02 mg/kg at 30-min
intervals to prevent spontaneous ventilation or move-
ment. The lungs of the dogs were ventilated with
100% O2 and adjusted to maintain normocarbia. Nor-
mal saline was infused at a rate of 5 mL kg1 h1
throughout the experiment. The urinary bladder was
catheterized. Core body temperature was maintained
at 37C38C with a heating pad and heated fluids.
2004 by the International Anesthesia Research Society
0003-2999/04
ANESTH ANALG
2004;99:728 33
In addition to a 20-gauge polyvinyl catheter in the
right antecubital vein for the induction and mainte-
nance of anesthesia, a 20-gauge venous catheter was
placed into the left antecubital vein for continuous
infusion of bupivacaine. Both femoral arteries were
cannulated to obtain blood samples and to monitor
MAP. A fiberoptic pulmonary artery catheter (Opti-
cath, P 7110-EH, Abbott, Chicago, IL) was introduced
via the right external jugular vein to continuously
monitor the central venous pressure (CVP), pulmo-
nary artery occlusive pressure (PAOP), and mixed
venous oxygen saturation (Svo2; Oximetrix 3, Ab-
bott). Cardiac output (CO) was determined using the
thermodilution technique. Cardiac rhythm and heart
rate (HR) were monitored continuously using the
standard lead II of electrocardiogram (ECG) with a HP
Component Monitoring System (Hewlett-Packard
Model 54S, Andover, MA). The PR interval, QRS du-
ration, and the QTc interval were digitally measured
with resting ECG analysis system (MAC 8, Marque-
tte, Milwaukee, WI). End-tidal CO2 concentration
(ETco2; Cardiocap, Datex, Helsinki, Finland) was
monitored throughout the experiment.
After a 30-min stabilization period, 0.5% bupivacaine
was administered at a rate of 0.5 mg kg1 min1. At
the same time, sodium bicarbonate was infused at a rate
of 2 4 mmol kg1 h1 to maintain an arterial pH value
of 7.357.45. Bupivacaine was infused until MAP de-
creased to 40 mm Hg or less (end of bupivacaine infu-
sion: BIE), which was defined as the point of cardiovas-
cular collapse in this study. At this moment, the
infusions of sodium pentobarbital and bupivacaine were
stopped. Dogs in the IGK group were given an IV bolus
of regular insulin 2 U/kg followed by 2 mL/kg of 50%
dextrose in water for 30 min and additionally received
potassium at 12 mmol kg1 h1. Dogs in Group C the C group 10 min after BIE. SVR increased with the
received dextrose infusion as in the IGK group.
MAP, HR, CO, Svo2, CVP, PAOP, ETco2, and ECG
intervals were measured at baseline, at BIE, every 5 min
for 30 min after BIE, and then at 10-min intervals until
60 min. MAP and HR were continuously monitored and
recorded at 1-min intervals for 10 min after BIE. Systemic
vascular resistance (SVR) was calculated using a stan-
dard formula. Hemoglobin concentration was measured
using a blood sample taken at baseline. Arterial blood
samples were collected for immediate blood gas analysis
and measurement of serum Na, K, Ca2, glucose, and
plasma bupivacaine concentrations. Blood samples for
bupivacaine-concentration assay were centrifuged at
2500 rpm for 20 min, and the plasma was stored at
50C until analyzed. Bupivacaine concentration was
measured by high-performance liquid chromatography.
Dogs were considered to have been successfully
resuscitated if MAP was maintained more than 70 mm
Hg for more than 10 min and if ECG showed normal
sinus rhythm. When asystole was present after BIE,
ANESTHETIC PHARMACOLOGY KIM ET AL. 729
INSULIN FOR BUPIVACAINE CARDIOTOXICITY
the experiment was terminated. At the end of each
experiment, the dogs were killed with KCL 40 mEq IV.
Data were expressed as mean sd. Fishers exact
test was used for statistical analysis of the survival of
the dogs. The differences between two groups were
identified with two-way analysis of variance. Changes
over time within each group were evaluated by using
analysis of variance for repeated measure. A value of
P 0.05 was considered statistically significant.
Results
The two groups were comparable with respect to
weight (22.9 6.1 kg in the C group and 22.4 7.7 kg
in the IGK group), hemoglobin concentration, and
baseline hemodynamic variables. MAP decreased to
40 mm Hg or less in 49 11 min in Group C and in 49
13 min in Group IGK after the start of bupivacaine
infusion. In both groups, the infusion of bupivacaine
resulted in a significant decrease in MAP, HR, CO,
Svo2 and ETco2. All dogs receiving IGK survived,
whereas those in Group C developed irreversible car-
diac arrest within 9.9 2.8 min after BIE (P 0.05).
Whereas MAP in Group C decreased progressively
after BIE, MAP in Group IGK was significantly larger
than in Group C 2 min after BIE and increased to the
baseline level at 40 min after BIE (Fig. 1). At 3 min after
BIE, HR in the IGK group was faster than in the C
group. At 60 min after BIE, HR had returned to the
baseline value in Group IGK (Fig. 2). CO and Svo2 in
Group IGK were significantly higher than that of
Group C 5 min after BIE. CO of the IGK group re-
turned to the baseline values 60 min after BIE. CVP
and PAOP in both groups increased with the bupiva-
caine infusion. CVP in the IGK group was lower than
bupivacaine infusion in both study groups. SVR of the
C group decreased abruptly 5 min after BIE. Increased
SVR in the IGK group decreased to baseline at 50 min
after BIE. ETco2 decreased in all dogs during the
bupivacaine infusion. ETco2 between groups at base-
line and at BIE were similar. In contrast to Group C,
further increases in ETco2 occurred in Group IGK
after BIE. The amounts of bupivacaine to induce car-
diovascular collapse (MAP 40 mm Hg) and corre-
spondent plasma bupivacaine concentrations were
comparable in both groups (24.6 5.5 mg/kg and 20.1
4.8 g/mL in Group C; 24.5 6.6 mg and 19.8 8.6
g/mL in Group IGK). Five minutes after BIE, there
were significant decreases in the plasma bupivacaine
concentration in both groups. Plasma bupivacaine
concentration in Group C 10 min after BIE was larger
than in the IGK group (Table 1).
At baseline and at BIE, there were no statistical
differences between groups in arterial pH value, Pao2,
Paco2, and plasma glucose. In the IGK group, Paco2
730 ANESTHETIC PHARMACOLOGY KIM ET AL.
INSULIN FOR BUPIVACAINE CARDIOTOXICITY
Figure 1. Mean arterial blood pressure (MAP) for 60 min after the
end of bupivacaine infusion (BIE [MAP 40 mm Hg]; mean sd).
IGK regular insulin, glucose, and potassium injected (n 7); C
glucose injected (n 7); and B baseline. At 6 and 7 min after BIE
data from 6 control dogs; at 8 and 9 min after BIE data from 4
control dogs; and at 10 min after BIE data from 2 control dogs. *P
0.05 between the study groups; **P 0.01 between the study
groups; ***P 0.001 between the study groups.
Figure 2. Heart rate (HR) for 60 min after the end of bupivacaine
infusion (BIE [MAP 40 mm Hg]; mean sd). IGK regular
insulin, glucose, and potassium injected (n 7); C glucose in-
jected (n 7); and B baseline. At 6 and 7 min after BIE data
from 6 control dogs; at 8 and 9 min after BIE data from 4 control
dogs; and at 10 min after BIE data from 2 control dogs. *P 0.05
between the study groups; **P 0.01 between the study groups;
***P 0.001 between the study groups.
was higher and pH value was lower than the C group
5 min after BIE. At 10 min after BIE, plasma glucose of
the C group was higher than that of the IGK group. No
statistical differences in the serum Na, K, and Ca2
were found between the groups during the experi-
ment. At BIE, serum Ca2 decreased from the baseline
in both groups.
ANESTH ANALG
2004;99:728 33
All dogs had normal sinus rhythm before starting
the bupivacaine infusion. Bupivacaine infusion in-
creased the PR, QRS, and QTc interval on ECG. PR
interval and QRS complex were wider in Group C
than in Group IGK 5 min after BIE. Significant differ-
ences between groups were seen in the QTc interval
10 min after BIE. After BIE, dogs in Group C devel-
oped a slow idioventricular rhythm with wide QRS
complexes and electromechanical dissociation and
progressed to asystole. PR, QRS, and QTc intervals did
not return to baseline values in the IGK group during
the experiment (Table 2).
Discussion
IGK infusion has a beneficial effect on myocardial
performance during cardiac surgery (14) and after
myocardial infarction (15). Our study demonstrated
that insulin treatment is also effective in improving
survival from bupivacaine-induced cardiovascular
collapse in pentobarbital-anesthetized dogs. All con-
trol dogs died of cardiac depression and subsequent
cardiac arrest, whereas all dogs receiving IGK sur-
vived without another treatment. These beneficial ef-
fects are probably related to insulin-induced changes
in transient outward K current (8) and myocardial
Ca2 homeostasis (9,10) and improvements in myo-
cardial energetics (11,12).
Bupivacaine cardiovascular toxicity variously man-
ifests as asystole, ventricular tachycardia, and hypo-
tension. Unanesthetized animals are apparently more
likely to develop ventricular arrhythmias in response
to bupivacaine infusion than are pentobarbital-
anesthetized animals (16).
Bupivacaine cardiotoxicity is aggravated by hy-
poxia and acidosis (17). Therefore, we maintained the
arterial pH value within normal range with infusion of
sodium bicarbonate, and the dogs were ventilated
with 100% O2. The cardiotoxic effect of bupivacaine is
also enhanced by hyperkalemia (7). In our study, we
maintained serum potassium levels within the normal
range. Plasma bupivacaine concentrations were signif-
icantly smaller in the IGK group after BIE. This was
probably the result of the recovery of circulation in the
IGK group.
We performed this study in anesthetized and ven-
tilated dogs that continuously received bicarbonate
and 100% O2. Cardiovascular collapse was induced by
continuous infusion of bupivacaine. This situation
might not be comparable to the clinical situation of
bupivacaine-induced cardiovascular collapse. Consid-
ering pH value was still far less than baseline value
and CO remained depressed despite markedly in-
creased right- and left-sided filling pressures, dogs in
the IGK group recovered partially from the cardiovas-
cular collapse, even 60 minutes after BIE.
 2004;99:728 33
ANESTH ANALG

Table 1. Changes in Cardiopulmonary Hemodynamic Variables and Plasma-Bupivacaine Concentration

0 min
(baseline) BIE 5 min 10 mina 15 min 20 min 25 min 30 min 40 min 50 min 60 min
CO (L/min)
IGK 4.2 1.0 0.6 0.1 1.0 0.3* 1.2 0.4* 1.5 0.3 1.5 0.3 1.8 0.5 2.0 0.6 2.4 0.7 2.8 0.8 3.3 0.7
C 4.5 0.7 0.6 0.1 0.4 0.1 0.2 0.1
Svo2 (%)
IGK 96 3 44 6 53 8* 61 8* 66 8 70 10 74 8 78 6 82 3 89 4 92 3
C 93 3 44 1 35 7 23 4
CVP (mm Hg)
IGK 42 10 2 9 2 8 2* 8 3 8 2 8 2 8 2 8 2 7 2 7 2
C 43 10 2 11 2 11 2
PAOP (mm Hg)
IGK 82 16 2 16 2 16 1 15 2 15 3 14 3 14 3 14 4 13 3 14 4
C 84 14 3 14 3 15 3
SVR (dyn s cm5)b
IGK 2204 560 4249 828 4064 1106* 5622 1950 4804 2148 4874 1674 4318 1620 4003 1602 3540 1521 3302 1407 2649 679
C 1975 530 4052 824 1488 849
ETco2 (mm Hg)
IGK 41 2 26 2 34 4* 37 2* 39 3 40 5 42 4 42 5 46 5 49 6 48 6
C 40 9 29 5 21 8 10 2
Bupivacaine (g/mL)
IGK 0 19.8 8.6 9.9 4.9 7.0 3.4* 6.6 3.2 6.5 3.4 5.8 4.0 5.5 3.3 4.6 3.7 3.6 1.8 4.2 3.0
C 0 20.1 4.8 13.8 4.3 12.0 4.1

Values are mean sd.

IGK regular insulin, glucose, and potassium injected (n 7); C glucose injected (n 7); BIE end of bupivacaine infusion; CO cardiac output; Svo2 mixed venous oxygen saturation; CVP central
venous pressure; PAOP pulmonary artery occlusive pressure; SVR systemic vascular resistance; ETco2 end tidal CO2.
a
At 10 min from 2 control animals.
b
SVR at 10 min was not calculated.
* P 0.05 between the study groups; P 0.05 versus baseline.
ANESTHETIC PHARMACOLOGY
INSULIN FOR BUPIVACAINE CARDIOTOXICITY
731 KIM ET AL.
 732

Table 2. Changes in Arterial Blood Gas Values, Plasma Electrolytes, Glucose Level, and Electrocardiograph (ECG) Intervals
0 min
(baseline) BIE 5 min 10 mina 15 min 20 min 25 min 30 min 40 min 50 min 60 min
pH value
IGK 7.39 0.05 7.43 0.05 7.35 0.04* 7.33 0.04* 7.32 0.04 7.31 0.03 7.29 0.03 7.29 0.03 7.28 0.03 7.27 0.02 7.27 0.02
C 7.38 0.06 7.41 0.05 7.48 0.05 7.56 0.06
Pao2 (mm Hg)
IGK 528 57 575 61 569 66 559 65 548 49 555 59 569 44 563 51 540 32 568 40 575 36
C 520 65 508 31 490 64 454 59
Paco2 (mm Hg)
IGK 39 6 33 5 40 5* 41 6* 43 4 43 7 45 5 45 6 48 6 50 4 49 5
ANESTHETIC PHARMACOLOGY KIM ET AL.

C 36 4 33 6 28 3 22 3
INSULIN FOR BUPIVACAINE CARDIOTOXICITY

Plasma
Na (mmol/L)
IGK 148 2 149 4 150 3 151 5 151 3 152 3 151 3 152 4 151 3 153 5 153 5
C 149 3 150 2 151 2 150 2
K (mmol/L)
IGK 4.4 0.4 4.2 0.4 4.2 0.5 4.2 0.7 4.1 0.8 4.0 0.8 4.1 0.8 4.1 0.8 4.0 0.6 4.1 0.6 4.0 0.6
C 4.1 0.4 4.0 0.7 4.0 0.7 4.1 0.8
Calcium (mmol/L)
IGK 2.5 0.0 2.2 0.1 2.2 0.2 2.2 0.1 2.2 0.1 2.2 0.1 2.2 0.1 2.1 0.1 2.2 0.1 2.2 0.1
C 2.5 0.1 2.2 0.1 2.1 0.1 2.0 0.1
Glucose (mg/dL)
IGK 105 11 96 16 95 30 100 22* 99 14 96 30 99 16 111 19 103 18 101 7 102 33
C 92 9 88 15 128 36 208 46
ECG
PR (ms)
IGK 116 11 187 40 175 44* 169 48* 185 29 166 41 177 27 176 23 166 26 148 34 150 12
C 101 17 182 17 204 27 290 85
QRS (ms)
IGK 41 6 128 34 116 32* 110 48* 100 52 83 22 75 15 69 14 67 16 63 16 61 13
C 41 8 138 36 153 35 203 40
QTc (ms)
IGK 362 20 411 57 401 47 375 54* 377 34 398 50 395 40 391 33 399 32 393 53 390 22
C 359 32 407 68 420 37 425 71
Values are mean sd.
IGK regular insulin, glucose, and potassium injected (n 7); C glucose injected (n 7); BIE end of bupivacaine infusion.
a
At 10 min from 2 control animals.
* P 0.05 between the study groups; P 0.05 versus baseline.
2004;99:728 33
ANESTH ANALG
ANESTH ANALG
2004;99:728 33
In our previous study (13), insulin 1 U/kg facili-
tated recovery from bupivacaine-induced mild cardiac
depression (Svo2 was 60%; MAP was 65 mm Hg)
within 5 minutes, and all dogs without treatment also
recovered spontaneously within 25 minutes. For this
study, we postulated that there might be a critical
point of resuscitation at a MAP less than 65 mm Hg,
where spontaneous recovery is unattainable after the
bupivacaine infusion. We adopted the end-point of
MAP 40 mm Hg based on other studies on the resus-
citation of bupivacaine-induced cardiovascular col-
lapse (18 20).
We intended to investigate if insulin treatment
might even resuscitate dogs with cardiovascular col-
lapse. Clinically, the same medication or treatment
does not frequently help, and drugs of choice need to
be determined for cardiac collapse. In this study, CO
decreased by approximately 85% at MAP 40 mm Hg.
Recovery might be difficult with epinephrine or am-
rinone at such a degree of cardiac depression (18 20).
However, insulin 2 U/kg resuscitated dogs with car-
diovascular collapse, and none of them given only
glucose infusion survived with a MAP of 40 mm Hg.
Because the cardiac depression was so severe, dogs
recovered partially, even 60 minutes after insulin
treatment. IGK dogs were in the course of recovering,
even 60 minutes after the start of resuscitation. De-
creased pH value represented the increase in elimina-
tion of accumulated CO2 from peripheral tissue to
central circulation. In our observations, once they have
recovered from bupivacaine-induced cardiac depres-
sion and maintained MAP and HR associated with
adequate tissue perfusion, dogs might not hemody-
namically deteriorate, even without aggressive treat-
ments, along with the decrease of plasma bupivacaine
concentration.
In summary, IGK treatment effectively resuscitated
bupivacaine-induced cardiovascular collapse in dogs,
possibly through the enhancement of outward potas-
sium current, the activation of Ca2-stimulated AT-
Pase associated with Ca2 transport activity, and the
improvement of energetic metabolism. This suggests
insulin could be an effective alternative to conven-
tional therapy in the management of bupivacaine-
induced cardiovascular collapse. The clinical impact
of the use of insulin in bupivacaine cardiac toxicity
deserves further research.
References
1. Feldman HS, Arthur GR, Pitkanen M, et al. Treatment of acute
systemic toxicity after the rapid intravenous injection of ropi-
vacaine and bupivacaine in the conscious dog. Anesth Analg
1991;73:373 84.
ANESTHETIC PHARMACOLOGY KIM ET AL. 733
INSULIN FOR BUPIVACAINE CARDIOTOXICITY
2. Albright GA. Cardiac arrest following regional anesthesia with
etidocaine or bupivacaine. Anesthesiology 1979;51:2857.
3. de La Coussaye JE, Bassoul BP, Gagnol JP, et al. Experimental
treatment of bupivacaine cardiotoxicity: what is the best choice?
Reg Anesth 1991;16:120 2.
4. Castle NA. Bupivacaine inhibits the transient outward K cur-
rent but not the inward rectifier in rat ventricular myocytes.
J Pharmacol Exp Ther 1990;255:1038 46.
5. Lynch C. Depression of myocardial contractility in vitro by
bupivacaine, etidocaine, and lidocaine. Anesth Analg 1986;65:
5519.
6. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine
depression of cardiac conduction: fast block of sodium channels
during the action potential with slow recovery from block dur-
ing diastole. Anesthesiology 1985;62:396 405.
7. Timour Q, Freysz M, Mazze R, et al. Enhancement by hypona-
tremia and hypokalemia of ventricular conduction and rhythm
disorders caused by bupivacaine. Anesthesiology 1990;72:
1051 62.
8. Zieler K, Wu FS. An early outward transient K current that
depends on a preceding Na current and is enhanced by insu-
lin. Eur J Physiol 1992;422:26772.
9. Gupta MP, Innes IR, Dhalla NS. Characterization of insulin
receptors in cardiac sarcolemmal and sarcoplasmic reticular
membranes. J Cardiovasc Pharmacol 1987;10:259 67.
10. Gupta MP, Lee SL, Dhalla NS. Activation of heart sarcoplasmic
reticulum Ca2-stimulated adenosine triphosphatase by insulin.
Pharmacol Exp Ther 1989;249:62330.
11. Weinberg G, VadeBoncouer T. Improved energetics may ex-
plain the favorable effect of insulin infusion on bupivacaine
cardiotoxicity [letter]. Anesth Analg 2001;92:1075 6.
12. Tune JD, Mallet RT, Downey HF. Insulin improves cardiac
contractile function and oxygen utilization efficiency during
moderate ischemia without compromising myocardial energet-
ics. J Mol Cell Cardiol 1998;30:202535.
13. Cho HS, Lee JJ, Chung IS, et al. Insulin reverses bupivacaine-
induced depression in dogs. Anesth Analg 2000;91:1096 102.
14. Haider W, Benzer H, Schutz W, Wolner E. Improvement of
cardiac preservation by preoperative high insulin supply. J Tho-
rac Cardiovasc Surg 1984;88:294 300.
15. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy
for treatment of acute myocardial infarction: an overview of
randomized placebo-controlled trials. Circulation 1997;96:
1152 6.
16. Liu P, Feldman HS, Covino BM, et al. Acute cardiovascular
toxicity of intravenous amide local anesthetics in anesthetized
ventilated dogs. Anesth Analg 1982;61:31722.
17. Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth
1986;58:71731.
18. Groban L, Deal DD, Vernon JC, et al. Cardiac resuscitation after
incremental overdosage with lidocaine, bupivacaine, levobupi-
vacaine, and ropivacaine in anesthetized dogs. Anesth Analg
2001;92:37 43.
19. Saitoh K, Hirabayashi Y, Shimizu R, Fukuda H. Amrinone is
superior to epinephrine in reversing bupivacaine-induced car-
diovascular depression in sevoflurane-anesthetized dogs. Anes-
thesiology 1995;83:12733.
20. Lindgren L, Randell T, Suzuki N, et al. The effect of amrinone on
recovery from severe bupivacaine intoxication in pigs. Anesthe-
siology 1992;77:309 15.