Anesth Analg 2004;99:728-733
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132691.84814.4E
ANESTHETIC PHARMACOLOGY
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, MD
Department of Anesthesiology and Pain Medicine, College of Medicine, Seoul National University, Korea
Address correspondence and reprint requests to Kook Hyun Lee, MD, Department of Anesthesiology, Seoul National University Hospital, #28, Yongon-Dong, Chongno-Gu, Seoul, Korea 110-744. Address e-mail to leekh{at}plaza.snu.ac.kr
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Abstract
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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 cardiovascular collapse in pentobarbital-anesthetized dogs. Bupivacaine was administered at 0.5 mg · kg–1 · min–1 until 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 in water) for 30 min and a potassium infusion (1–2 mmol · kg–1 · h–1). 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 saturation, and end tidal CO2 recovered toward baseline levels in the IGK group. In conclusion, severe bupivacaine-induced cardiovascular collapse in dogs was effectively reversed with the insulin treatment.
IMPLICATIONS: Bupivacaine-induced cardiac toxicity is extremely difficult to treat. We found that profound cardiovascular depression by bupivacaine in dogs was effectively reversed with insulin-glucose-potassium infusion.
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Introduction
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Severe cardiovascular collapse can occur when bupivacaine is accidentally injected into a blood vessel or large doses of bupivacaine are administered. Bupivacaine-induced cardiovascular collapse is resistant to conventional treatment (1), and resuscitation is difficult (2). The choice of resuscitation drug for bupivacaine cardiovascular collapse remains controversial (3).
Bupivacaine causes profound cardiac depression by blocking transient outward K+ currents and repolarization 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 hyperkalemia (7). Insulin, in contrast, enhances the transient outward K+ current and repolarization (8). Ca2+ transport activity of sarcoplasmic reticulum is increased by insulin (9,10). In addition, insulin possibly increases cytoplasmic glucose concentration and pyruvate availability to mitochondria, thereby improving myocardial energetics and performance (11,12).
We have previously shown that insulin could reverse bupivacaine-induced cardiac depression in dogs when mean arterial blood pressure (MAP) was reduced to approximately 65 mm Hg (13). We hypothesized that insulin also might be effective in reversing severe bupivacaine-induced cardiovascular collapse (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.
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Methods
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This study was approved by the Animal Care and Use Committee of Seoul National University College of Medicine. Fourteen mongrel dogs were randomly assigned 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 · kg–1 · h–1. 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 movement. The lungs of the dogs were ventilated with 100% O2 and adjusted to maintain normocarbia. Normal saline was infused at a rate of 5 mL · kg–1 · h–1 throughout the experiment. The urinary bladder was catheterized. Core body temperature was maintained at 37°C–38°C with a heating pad and heated fluids.
In addition to a 20-gauge polyvinyl catheter in the right antecubital vein for the induction and maintenance 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 (Opticath®, P 7110-EH, Abbott, Chicago, IL) was introduced via the right external jugular vein to continuously monitor the central venous pressure (CVP), pulmonary artery occlusive pressure (PAOP), and mixed venous oxygen saturation (SvO2; Oximetrix® 3, Abbott). 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 SystemTM (Hewlett-Packard Model 54S, Andover, MA). The PR interval, QRS duration, and the QTc interval were digitally measured with resting ECG analysis system (MAC 8®, Marquette, 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 · kg–1 · min–1. At the same time, sodium bicarbonate was infused at a rate of 2–4 mmol · kg–1 · h–1 to maintain an arterial pH value of 7.35–7.45. Bupivacaine was infused until MAP decreased to 40 mm Hg or less (end of bupivacaine infusion: BIE), which was defined as the point of cardiovascular 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 1–2 mmol · kg–1 · h–1. Dogs in Group C 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 standard 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 –50°C 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, 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. Fisher’s 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.
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Results
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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 cardiac 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 returned to the baseline values 60 min after BIE. CVP and PAOP in both groups increased with the bupivacaine infusion. CVP in the IGK group was lower than the C group 10 min after BIE. SVR increased with the 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 baseline 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 cardiovascular collapse (MAP = 40 mm Hg) and correspondent plasma bupivacaine concentrations were comparable in both groups (24.6 ± 5.5 mg/kg and 20.1 ± 4.8 µg/mL in Group C; 24.5 ± 6.6 mg and 19.8 ± 8.6 µg/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).
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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.
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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 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.
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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 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 experiment. At BIE, serum Ca2+ decreased from the baseline in both groups.
All dogs had normal sinus rhythm before starting the bupivacaine infusion. Bupivacaine infusion increased 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 differences between groups were seen in the QTc interval 10 min after BIE. After BIE, dogs in Group C developed 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).
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Table 2. Changes in Arterial Blood Gas Values, Plasma Electrolytes, Glucose Level, and Electrocardiograph (ECG) Intervals
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Discussion
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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 control dogs died of cardiac depression and subsequent cardiac arrest, whereas all dogs receiving IGK survived without another treatment. These beneficial effects are probably related to insulin-induced changes in transient outward K+ current (8) and myocardial Ca2+ homeostasis (9,10) and improvements in myocardial energetics (11,12).
Bupivacaine cardiovascular toxicity variously manifests as asystole, ventricular tachycardia, and hypotension. 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 hypoxia 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 significantly 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 ventilated 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. Considering pH value was still far less than baseline value and CO remained depressed despite markedly increased right- and left-sided filling pressures, dogs in the IGK group recovered partially from the cardiovascular collapse, even 60 minutes after BIE.
In our previous study (13), insulin 1 U/kg facilitated 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 resuscitation of bupivacaine-induced cardiovascular collapse (18–20).
We intended to investigate if insulin treatment might even resuscitate dogs with cardiovascular collapse. 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 amrinone at such a degree of cardiac depression (18–20). However, insulin 2 U/kg resuscitated dogs with cardiovascular 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. Decreased pH value represented the increase in elimination of accumulated CO2 from peripheral tissue to central circulation. In our observations, once they have recovered from bupivacaine-induced cardiac depression and maintained MAP and HR associated with adequate tissue perfusion, dogs might not hemodynamically deteriorate, even without aggressive treatments, 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 potassium current, the activation of Ca2+-stimulated ATPase associated with Ca2+ transport activity, and the improvement of energetic metabolism. This suggests insulin could be an effective alternative to conventional therapy in the management of bupivacaine-induced cardiovascular collapse. The clinical impact of the use of insulin in bupivacaine cardiac toxicity deserves further research.
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Acknowledgments
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Supported, in part, by a grant of the Seoul National University Hospital (21–2003–014–0).
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References
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Accepted for publication March 5, 2004.
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Abstract
Introduction
