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CARDIOVASCULAR ANESTHESIA

Insulin Reverses Bupivacaine-Induced Cardiac Depression in Dogs

Hyun S. Cho, MD^*, Jeong J. Lee, MD^*, Ik S. Chung, MD^*, Byung S. Shin, MD^*, Ji A. Kim, MD^*, and Kook H. Lee, MD

Department of Anesthesiology, *Samsung Medical Center, Sungkyunkwan University School of Medicine; and College of Medicine, Seoul National University, Seoul, 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 110-774. Address e-mail to leekh{at}plaza.snu.ac.kr

	Abstract

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We tested the hypothesis that an insulin infusion would effectively treat bupivacaine-induced cardiac depression in dogs. In 24 mongrel dogs anesthetized with pentobarbital (5 mgkg^-1h^-1, IV), 0.5% bupivacaine was administrated at a rate of 0.5 mgkg^-1min^-1 until the mixed venous oxygen saturation decreased to 60% or less. The bupivacaine infusion induced a decrease in mean arterial pressure, cardiac output, and heart rate. The dogs were randomly assigned to one of four groups after the end of bupivacaine infusion. The Control (C, n = 6) and Glucose (G, n = 6) groups received an IV infusion of normal saline (2 mL/kg) and glucose (2 mL/kg of 50% dextrose in water) for 15 min, respectively. The Insulin-Glucose (IG, n = 6) group received an IV bolus of regular insulin (1 U/kg), plus a glucose infusion (2 mL/kg of 50% dextrose in water) for 15 min. The Insulin-Glucose-Potassium (IGK, n = 6) group received the same dose of insulin and glucose as the IG group, plus potassium (1–3 mEqkg^-1h^-1). Mean arterial pressure, cardiac output, heart rate, and mixed venous oxygen saturation recovered toward baseline level more rapidly in the IG and IGK groups than in the C group (within 5 min versus more than 20 min). These results suggest that the infusion of insulin and glucose might reverse bupivacaine-induced cardiac depression in dogs.

Implications: We found that insulin and glucose rapidly reversed hemodynamic abnormality in dogs with bupivacaine-induced cardiac depression. This study implies a possible clinical application of insulin treatment for bupivacaine-induced cardiac depression.

	Introduction

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Accidental intravascular injection of bupivacaine during regional anesthesia has been implicated in the production of cardiovascular collapse that is resistant to conventional treatment (1). In in vitro studies, bupivacaine inhibits the transient outward K⁺ current (I_to) and repolarization of ventricular myocytes (2), as well as Ca⁺⁺ release from sarcoplasmic reticulum (3). Bupivacaine also blocks the sodium channels and inhibits the depolarization of myocardium (4), which is enhanced by hyperkalemia (5). Insulin, in contrast, enhances the transient outward K⁺ current and repolarization (6). Ca⁺⁺ transport activity of sarcoplasmic reticulum is increased by insulin (7). Insulin also induces hypokalemia (8), which enhances maximal rate of phase 0 depolarization (Vmax) (9).

We hypothesized that insulin might reverse bupivacaine-induced cardiotoxicity. The purpose of this study was to observe the effect of insulin and glucose on the recovery of bupivacaine-induced cardiac depression in dogs by assessing the hemodynamic and electrophysiologic variables after the insulin administration.

	Methods

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This study received approval from the animal care and use committee of the Seoul National University College of Medicine. Twenty-four mongrel dogs of either sex were randomly divided into four equal groups: Control (C, 17.0 ± 3.5 kg), Glucose (G, 16.0 ± 3.6 kg), Insulin-Glucose (IG, 16.7 ± 1.8 kg), and Insulin-Glucose-Potassium (IGK, 16.3 ± 4.0 kg) groups (n = 6 in each group).

Anesthesia was induced with sodium pentobarbital 25 mg/kg IV, and maintained with a continuous infusion of 5 mgkg^-1h^-1. The trachea was intubated with an internal diameter 7-mm cuffed endotracheal tube. Vecuronium was injected IV as a bolus of 0.2 mg/kg, followed by an administration of 0.02 mg/kg at a 30-min interval. Mechanical ventilation was accomplished with a Servo 900C^TM ventilator (SIEMENS, Erlangen, Germany) to maintain normocarbia at a fraction of inspired oxygen of 1.0. Lactated Ringer’s solution was infused at a rate of 5 mLkg^-1h^-1 throughout the experiment. Rectal temperature was maintained at 37°–38°C by using a warming blanket and a radiant heater.

Cardiac rhythm and heart rate (HR) were monitored continuously by using the standard lead II of the electrocardiograph (ECG). Percutaneous polyvinyl catheters were inserted into the right and left femoral arteries to obtain blood samples and to monitor arterial blood pressure. A polyvinyl catheter was positioned in a cephalic vein for fluid and drug infusion. A pulmonary artery catheter (model 93A-132^TM, 5F; Baxter Healthcare, Irvine) was introduced via the right external jugular vein to continuously monitor the pulmonary arterial pressure (PAP) and central venous pressure (CVP) and to measure cardiac output (CO) by using the thermodilution method. A fiberoptic pulmonary artery catheter (model 93A-750H^TM, 7.5F; Baxter Healthcare) was inserted via the left external jugular vein for the continuous monitoring of the mixed venous oxygen saturation (SvO₂) (Explorer^TM; Baxter Healthcare). Lead II ECG and femoral arterial pressure were continuously monitored and recorded in 5-min intervals throughout the experiment with the HP Component Monitoring System^TM (Hewlett-Packard Model 54S, Andover, MA).

After a 30-min period of stabilization and after measurement of baseline variables, 0.5% bupivacaine was administrated at a rate of 0.5 mgkg^-1min^-1 via a venous catheter. At the same time, sodium bicarbonate was infused at a rate of 2–3 mmolkg^-1h^-1 via another venous catheter to maintain arterial pH at 7.35–7.45. Bupivacaine was infused continuously until SvO₂ decreased to approximately 60% or less, which in this study was defined as the point of cardiac depression. At this time, the dogs in the C and G groups received 2 mL/kg of normal saline and the same dose of 50% dextrose in water for 15 min, respectively. The IG animals received an IV bolus of regular insulin (1 U/kg) followed by a glucose infusion (2 mL/kg of 50% dextrose in water) for 15 min. The IGK dogs received insulin and glucose in the same manner as the IG group and additionally received the potassium at a rate of 1–3 mEqkg^-1h^-1 after the initiation of the insulin and glucose infusion to maintain normal serum potassium concentration. Mean arterial pressure (MAP), HR, CVP, PAP, pulmonary capillary wedge pressure (PCWP), CO, and SvO₂ were measured at baseline, at the end of the bupivacaine-infusion (BIE), at 5, 10, 15, 20, 25, and 30 min after treatment. Arterial blood samples were obtained for blood gas analysis each time with an assessment of serum Na⁺, K⁺, Ca⁺⁺, glucose, and plasma bupivacaine concentration. Pulmonary arterial blood was withdrawn to perform mixed venous blood gas analysis at the same time. Blood samples for bupivacaine concentration assay were centrifuged at 3000 rpm for 15 min to collect the plasma that was then stored at -20°C until required for analysis. Bupivacaine concentration was measured by using high-performance liquid chromatography (10).

We defined that the animals had successfully recovered from cardiac depression when hemodynamic variables reached the baseline values. At the end of each experiment, the animals were killed with KCL 40 mEq IV. Data were expressed as mean ± SD. One-way analysis of variance and the Tukey test were used to identify the differences among the four groups. Changes over time within each group were evaluated by using analysis of variance for repeated measures and Scheffé F tests. Probability values < 0.05 were accepted as significant. Statistical Analysis System^TM software (version 6.12; SAS Institute, Cary, NC) was used.

	Results

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SvO₂ decreased progressively to 60% or less in 29.0 ± 7.8 min in the C group, in 31.8 ± 8.7 min in the G group, in 33.6 ± 8.4 min in the IG group, and in 30.0 ± 9.0 min in the IGK group after the start of bupivacaine infusion. The doses of bupivacaine at which cardiac depression was established were 14.6 ± 7.1, 15.9 ± 4.4, 16.8 ± 7.5, and 15.4 ± 3.8 mg/kg in the C, G, IG, and IGK groups, respectively, and were not different among the groups. This corresponded to 11.5 ± 2.9, 12.3 ± 2.6, 12.2 ± 1.8, and 11.8 ± 1.9 µg/mL as the plasma bupivacaine concentration in the C, G, IG and IGK groups, respectively. The time course of plasma bupivacaine concentration was similar in all groups after the administration of bupivacaine (Table 1).

PAP did not change among the groups, ranging from 19.2 ± 2.2 to 21.0 ± 2.0 mm Hg. An increase in the PCWP occurred in all groups during the bupivacaine infusion. PCWP returned to baseline level within 10 min in IG and IGK groups; however, it remained significantly above the baseline level for 20 min in the C and G groups. After the treatment, CVP returned to the baseline level at 30 min in the C and G groups, and at 5 min in the IG and IGK groups. The bupivacaine infusion produced a statistically significant decrease of CO in all animals. There were no significant differences in CO between C and G groups throughout the experiment. CO of the IG and IGK groups reached the baseline values within 5 min, which was significantly greater for 10 and 5 min, respectively, than that of the C group. CO decreased again at 20 and 15 min and recovered at 25 and 30 min in the IG and IGK groups, respectively (Table 1). SvO₂ recovered to the baseline levels at 5 min in the IG and IGK groups and at 25 min in the C and G groups (Table 2).

There were no statistical differences in serum Na⁺ and Ca⁺⁺ concentration among the four groups (Table 3 ). In the IG group, mean serum potassium level decreased from 4.2 to 3.3 mEq/L at 5 min after the IV administration of insulin and glucose. The reduction in the serum potassium persisted for the duration of the experiment in the IG group. During this period, serum K⁺ concentration from the IG group was smaller than that of the C, G, and IGK groups. In the IGK group, the serum potassium concentration remained at the baseline value with the infusion of potassium at 0.9 ± 0.2 mEq/kg.

View larger version (12K): [in this window] [in a new window]   Figure 1. Electrocardiograph changes induced by bupivacaine. Lead II surface electrocardiogram recorded at 25 mm/s. In the baseline period, the values are: heart rate, 159 bpm; PR interval, 90 ms; QRS duration, 60 ms; and QTc interval, 348 ms. Bupivacaine at a concentration of 11.9 µg/mL at BIE (end of bupivacaine infusion) resulted in the following alterations: heart rate, 101 bpm; PR interval, 153 ms; QRS duration, 120 ms; and QTc interval, 390 ms. Bupivacaine depresses the infranodal conduction time and widens the QRS complex. The reduction in the maximal rate of depolarization, which results in the slowed conduction of the cardiac action potential, is manifested by prolongation of the PR and QRS intervals. High concentration of bupivacaine modifies the potassium permeability, as suggested by the prolongation of the corrected QT interval.

	Discussion

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Infusions of glucose, insulin, and potassium enhance left ventricular performance during burn injury (11) and after myocardial infarction (12). A close relationship between changes in serum osmolality and CO was observed during infusions of glucose, insulin, and potassium; glucose alone; or sorbitol in endotoxemic dogs (13). However, the present study shows that the time course of hemodynamic variables was similar in C and G groups regardless of the plasma glucose level. We speculate that the hyperosmolality effect reported in other experimental settings lacks importance for the initial enhancement in cardiac contractility in bupivacaine-induced cardiac depression.

The rapid production of acidosis and hypoxia after bupivacaine-induced toxicity has been documented in dogs (14). This may be caused by large lactic acid production during seizure, reduced CO, and ineffective removal of lactic acid from the circulation as a result of reduced hepatic blood flow (15). We infused sodium bicarbonate at a rate of 2–3 mmolkg^-1h^-1 to maintain arterial pH within normal range after the bupivacaine infusion was initiated.

The bupivacaine infusion decreases CO, MAP, and HR in dogs (16). The major decrease of Vmax of the action potential by bupivacaine might be a result of the preferential binding in the inactivated state of the sodium channels in ventricular muscles (4). Bupivacaine depresses myocardial contractility by altering the Ca⁺⁺ release from cardiac sarcoplasmic reticulum (3,17). Changes in HR are caused by the inhibition of sodium channels and I_to by bupivacaine (18,19). Bupivacaine blocks the I_to of ventricular myocytes and prolongs the action potential duration by delaying repolarization (2). Delayed repolarization prolongs the QTc (2,17) and forms a U wave or "slow wave" after the T wave (20). In our study, QTc was significantly prolonged, and a U wave was found at the BIE in each one of the dogs in the C and IGK groups. The U wave disappeared at 10 and 5 minutes in the C and IGK groups, respectively. The QRS complex was widened with bupivacaine infusion. Such modification can be interpreted as the inhibition of the fast inward current INa (17). Working on papillary muscles, Clarkson and Hondeghem (4) have demonstrated that a perfusion of bupivacaine results in a reduction of the action potential upstroke velocity, which also leads to the conclusion that this drug blocks the sodium channels. We found PR interval prolongation in all animals as in other studies (17,21), which have revealed that bupivacaine depresses the atrioventricular nodal function by affecting the calcium channels.

However, insulin promotes I_to (6,22), and we hypothesized that it might antagonize the I_to-blocking effect of bupivacaine. In our study, it could be interpreted that the rapid recovery of HR and QTc in the IG and IGK groups was caused by the I_to-stimulating effect of insulin. I_to is believed to be a major contributor in the repolarization of atrial and ventricular myocytes, including those present in the human myocardium (23–25).

Insulin has an inotropic effect mediated by the release of adrenal catecholamine induced by hypoglycemia (26) or a small increase of norepinephrine by a direct action of insulin on the central nervous system (27). We found the mean blood glucose level was higher than 94 mg/dl (Table 2), which suggests that sympathetic stimulation by hypoglycemia might be excluded. In pilot experiments using six normal dogs, no significant changes in hemodynamic and catecholamine values were observed after the same infusion of glucose alone or insulin and glucose, as in this study. However, a role for sympathetic nervous system activation cannot be excluded because serum catecholamines were not measured during the present investigation. Gupta et al. (7) conclude that insulin activated Ca⁺⁺-adenosine triphosphatase of the sarcoplasmic reticulum, and the inotropic effect of insulin was related to Ca⁺⁺ homeostasis in the sarcoplasmic reticulum of myocytes. This, in part, may explain the rapid recovery of hemodynamic variables from bupivacaine-induced cardiac depression after the insulin infusion.

Regular insulin stimulates potassium uptake in the liver and skeletal muscles by enhancing the activity of the Na-K pump and effectively decreases the serum potassium concentration within 10 minutes and for at least 60 minutes (8). There is some evidence that the inward sodium current can be activated by hypokalemia. Hypokalemia in the extracellular spaces can result in an increase in the resting membrane potential and in action potential height associated with an increase in Vmax (9). We expected that the insulin would alleviate the bupivacaine-induced sodium inward current and Vmax inhibition and rapidly recover hemodynamic variables and QRS duration. The recovery of the QRS duration was slow, but it was more rapid in IG group than in the IGK group (20 vs 30 minutes). In addition, hemodynamic variables were not different between the IG and IGK groups throughout the experiment. HR in the IG and IGK groups decreased again below the baseline level after the initial recovery. A possible reason for this may be the decline of insulin concentration because the serum half-life of porcine insulin was reported 5.1 ± 0.9 minutes after the bolus injection (28). CO also decreased again below the baseline level after the initial recovery, and the duration of diminution in CO was shorter in the IG group than in the IGK (5 vs 15 minutes). However, we believe that hypokalemia, induced by the insulin infusion, did not play a major role in the recovery from bupivacaine-induced cardiac depression.

We found that both IG and IGK have a prompt effect on the recovery of cardiac depression by the bupivacaine infusion. This suggests that insulin-glucose has a role in the treatment of bupivacaine-induced cardiac depression.

	Footnotes

 
June 6, 2000.

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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