Abstract

Cardiac toxicity of bupivacaine has long been documented and it could be potentiated in certain circumstances, such as preexisting cardiac conduction abnormality or uremic status. The concept that lipid emulsion acts as a rescue of bupivacaine’s toxicity has prevailed pending universal recognition. Herein, we report the successful use of lipid to resuscitate a female uremic patient who sustained junctional bradycardia while she was receiving ultrasound-guided infraclavicular brachial plexus block with the dose of local anesthetics far below the currently recommended maximum one. The possible mechanisms for the occurrence of cardiotoxicity in this case are discussed and the role of lipid emulsion as a treatment is reviewed.

Keywords

bradycardia; bupivacaine; drug toxicity; fat emulsions, intraveno; usuremia;

1. Introduction

Lipid emulsion has been shown to increase the successful rate of resuscitation in bupivacine’s cardiotoxicity both in animal models and in human case reports.1, 2, 3, 4, 5, 6, 7, 8 We report a successful use of lipid to resuscitate a uremic patient from junctional bradycardia, which was refractory to conventional chronotropic agents following infraclavicular brachial plexus block with bupivacaine and lidocaine.

2. Case report

The patient was a 69-year-old, 48.5 kg, 155 cm woman scheduled for carpel tunnel surgery. Her medical history was remarkable for Type 2 diabetes, hypertension, and end-stage renal disease under regular hemodialysis. Preoperatively, electrocardiography (ECG) showed normal sinus rhythm with first-degree atrioventricular (AV) block and her electrolyte status revealed nothing unusual (K: 4.5 mmole/L). An ultrasound-guided infraclavicular brachial plexus block was proposed for the procedure with which she complied.

On arrival in the preoperative holding area, standard monitors were applied. Her blood pressure was 152/58 mmHg, pulse oximetry was 96%, whereas breathing room air and heart rate was 62 beats/min. The patient was sedated with 1 mg midazolam and 50 μg fentanyl administered through a peripheral intravenous (IV) line. An ultrasound-guided infraclavicular brachial plexus block was preformed with an in-plane technique. A 45-mm, 18-gauge needle (Introcan Certo; B Braun, Melsungen, Germany) was directed to the posterior aspect of the radial artery under visualization. However, inadvertent arterial puncture occurred during needle advancement and a small hematoma was found immediately around the puncture site of the axillary artery. The needle was then withdrawn and was redirected to approach the posterior aspect of the radial artery. When the needle tip was thought to be in the target area, the local anesthetic solution was administered in divided bolouses of 3–4 mL over several minutes with repeated negative aspiration test. A total volume of 25 mL local anesthetic solution (15 mL 1.5% lidocaine, followed by 10 mL 0.375% bupivacaine) was administered to obtain a desired U-shaped spread under direct ultrasound visualization. After the procedure, the patient was continually monitored in the holding area, she did not complaint of any discomfort and her vital signs were stable. Five minutes later, she was transported to the operating room. During attachments of ECG, noninvasive blood pressure, and pulse oximeter devices to the monitor, the patient suddenly became obtunded and unable to be fully aroused. At this juncture, the ECG showed severe junctional bradycardia with a ventricular rate of 30 beats/min and blood pressure fell to 114/49 mmHg. Atropine 0.5 mg, followed by another 0.5 mg, and ephedrine 10 mg were administered through the peripheral IV line but in vain. An arterial catheterization was established. The initial direct arterial blood pressure was 110/52 mmHg and arterial blood gas analysis revealed metabolic acidosis (pH: 7.203, PaO₂: 76.2 mmHg, PaCO₂: 24.7 mmHg, HCO₃⁻: 9.5 mmol/L). Around 120 mL of 7% NaHCO₃ were given to correct the metabolic acidosis. Fifteen minutes later, junctional bradycardia still persisted and the patient remained obtunded. Another atropine dosage of 0.5 mg was administered but was still futile. Under the impression of refractory local anesthetic-induced cardiotoxicity, 50 mL of 20% Lipovenoes (Fresenius Kabi, Bad Homburg, Germany) was injected through peripheral IV line. Two minutes later, regular sinus beat with first-degree AV block with a rate around 40 beats/min emerged on the ECG and her arterial blood pressure increased from 108/46 mmHg to 150/54 mmHg. At this juncture, her consciousnesss returned to normal gradually. The surgery was called off and she was transferred to postanesthetic care unit for close observation. In the postanesthetic care unit, her consciousness was clear and no chronotropic agent or lipid emulsion was needed again because of stable hemodynamics. The infraclavicular block was tested and was thought to be adequate for the proposed surgery. Ninety minutes after anesthesia, the heart rate returned to the preanesthetic baseline level (>60 beats/min) and she was returned to ordinary ward. She was discharged with no sequelae the next day.

3. Discussion

Since Weinberg et al1, 2 had demonstrated that IV lipids would enhance resuscitation of animals exposed to toxic bupivacaine dose, there were increasing reports demonstrating that IV lipid infusion was effective in reversal of local anesthetic-induced cardiotoxicity and cardiac arrest.3, 4, 5, 6, 7, 8 It is recommended that 20% lipid emulsion should be available in perioperative areas and operating rooms where local anesthetics are used.9, 10 IV lipid emulsion is readily available in the operation theater of our institution. In this case, we started lipid use because of severe refractory junctional bradycardia because of cardiac toxicity of local anesthesia and the patient soon regained sinus rhythm, heartbeat and hemodynamic stability, and normal consciousness.

Cardiac toxicity of bupivacaine has long been documented. High plasma levels of bupivacaine have been reported to produce a variety of ECG irregularities and chaotic cardiac rhythms.11, 12, 13, 14, 15 Lancombe et al¹² infused isolated rabbit heart with bupivacaine in different concentrations and found a statistically significant increase in PR and AV interval duration in higher concentration groups. They concluded that conduction of the electrical impulse, rather than automaticity, was markedly impaired by bupivacaine. Although Scott et al¹³ recorded ECG continuously during infusing bupivacaine intravenously in human volunteers and Borgeat et al¹⁵ recorded ECG changes after performing interscalene brachial plexus anesthesia with bupivacaine, they both demonstrated that the early signs of bupivacaine’s cardiotoxicity might be expressed as a delay in AV conduction time. Borgeat et al¹⁵ even suggested that prolongation of the AV conduction might be the first sign of cardiotoxicity associated with relatively low plasma local anesthetic concentration. This conduction-depressive effect of bupivacaine might change the ECG, from sinus rhythm with first-degree AV block to junctional bradycardia in our patient because minor dose of bupivacaine was used, in sharp contrast to their cases in whom total cardiac arrest occurred.

Other local anesthetics, such as lidocaine used in our case, also possess cardiotocixity, which correlates positively with their lipid solubility and nerve blocking potency. Compared with lidocaine, bupivacaine has an exceptionally potent depressant effect on electrical conduction in the heart and appears to be more cardiodepressant at equivalent anesthetic concentrations.¹⁴ Bupivacaine was found to be between 11-fold and 36-fold more potent than lidocaine in depressing conduction in isolated rabbit heart.¹¹ In isolated rat hearts, the concentration of bupivacaine that produced 50% depression of conduction and heart rate was between 6-fold and 17-fold higher than lidocaine.¹⁴ Considering that lidocaine’s dose used in our case was relatively lower in cardiodepressant effect (lidocaine 225 mg vs. bupivacaine 37.5 mg), it could be more rational to attribute the conductive depression in this patient to bupivacaine rather than to lidocaine, even with or without lidocaine’s synergistic or additive effect.

The total amount of local anesthetics we used in this case (lidocaine 225 mg and bupivacaine 37.5 mg) was far below the maximum doses of the local anesthetics currently recommended.¹⁶ Nonetheless, cardiotoxicity still occurred. Taking the unusual features of this case into account, we presume three possible explanations for this discrepancy. First, there was inadvertent arterial puncture in this case, which might have played an important role in augmenting the systemic absorption of local anesthetics. Several case reports had revealed inadvertent intravascular injection of local anesthetics during ultrasound-guided nerve blocks even after repeated negative aspirations.17, 18, 19 In these cases, intravascular injection was implied either by failure to observe local anesthetic spread after injection or by a grayish blush immediately noted on the ultrasound screen within the artery. However, neither had been noted in our case. Furthermore, the supposed cardiotoxicity occurred 5 minutes after injection, a time lying between the onset time for toxicity in intravascular injection (within seconds) and that of systemic absorption (20–30 minutes later).²⁰ We highly deem that the preceding arterial puncture in this case accelerated the systemic absorption rather than inadvertent intravascular injection. Second, uremic status had been demonstrated to increase blood flow (hyperdynamic circulation) with rapidly flushing the deposits of local anesthetics.21, 22 Pere et al²³ reported larger total plasma concentration of ropivacaine and its main metabolites in uremic patients than in nonuremic patients after axillary brachial plexus block, which could be resultant from enhanced absorption into circulation and reduction of urinary excretion. Third, before surgery, our patient was found to have first-degree AV block, and there are two reports in which impairment of electrical conduction might have predisposed a patient to the development of local anesthetic-induced cardiac toxicity at a lower milligram/kilogram level than expected. In one case report, cardiovascular collapse was induced by a bupivacaine dose of less than 1.1 mg/kg in a patient receiving a lumbar sympathetic ganglion radio frequency ablation, and Levsky and Miller²⁴ noted that the patient was found to have a first-degree AV block in preoperative ECG. In the other case report, Rosenblatt et al³ described a 58-year-old, 72 kg man with a right bundle branch block who saw cardiac arrest after receiving an injection of 20 mL of 0.5% bupivacaine and 20 mL of 1.5% mepivacaine for interscalene brachial plexus block. Considered together, preceding arterial puncture, uremic status, and preexisting conduction abnormality might play their own role in augmenting the patient’s vulnerability to bupivacaine’s cardiotoxicity with lower dosage anesthetics.

The uremic status may exhibit certain long-term physiological changes, such as hyperkalemia, lower plasma protein level, and metabolic acidosis, all of which have some influence on the cardiac toxicity of local anesthetics. Hyperkalemia was proved to potentiate the negative effect of lidocaine and bupivacaine on heart rate and conductivity,²⁵ but the preoperative laboratory data of this patient revealed balanced electrolyte status. Local anesthetics are generally highly bound to protein, particularly to alpha-1 glycoprotein, which, however, is known to be significantly elevated in uremic patients.26, 27 Therefore, the free fractions of local anesthetics are theoretically decreased in such patients and this can not explain the toxicity induced by lower dose local anesthetics in our patient. The arterial blood gas showed metabolic acidosis in this patient. Some studies proved that the combination of hypoxia and acidosis would enhance cardiac depressive effect of local anesthetics, but the influence of acidosis alone remained controversial.²⁸ Beside, this patient’s arterial blood sampled during resuscitation could not reflect the real acid-base status at the time we preformed nerve block.

Current protocols recommend the use of lipid emulsion for cardiac arrest in conjunction with standard resuscitation maneuvers.9, 10 However, as lipid therapy has become more acceptable, clinicians would become accustomed to administer lipid emulsion earlier in the spectrum of adverse local anesthetic reactions, preferring immediate act before refractory cardiac arrest occurs.5, 6, 7, 8 Cordell et al⁵ presented a case of early lipid infusion after only one single ineffective dose of epinephrine to reverse pulseless ventricular tachycardia to sinus rhythm and stable hemodynamic status after accidental bupivacaine intravascular injection in axillary block. McCutchen and Gerancher⁶ also reported a case in whom intralipid was administered within 3 minutes after the onset of ventricular tachycardia induced by bupivacaine. Although in this case they did not know whether the resolution of the arrhythmia was because of administration of amiodarone, intralipid, or the combination of the two plus the counter shock, they speculated that without the intervention with intralipid, the patient might have progressed to a pulseless arrhythmia. In our case, a bolus dose of IV lipid seemed to successfully reverse the junctional bradycardia induced by bupivacaine, which was refractory to repeated doses of atropine and ephedrine. Although the systemic absorption of local anesthetics would not peak until 20–30 minutes after injection, we cannot exclude the possibility of progression of the arrhythmia to cardiovascular collapse in our case if Lipovenoes was not available. The current regimen recommended is IV lipid emulsion given as a bolus at 1.5 mL/kg over 1 minute, which may be repeated one or two times every 3–5 minutes, followed by a continuous infusion of 0.25 mL/kg/min for 30–60 minutes until hemodynamic stability is restored.¹⁰ We administered a bolus dose of 50 mL of 20% Lipovenoes for this 48.5 kg female without continuous infusion because sinus rhythm regained immediately after the bolus dose and the patient’s hemodynamics remained stable without any signs of recurrence of cardiotoxicity, and this unique event might partly be because of the minor doses of local anesthetics we had given.

In summary, we report an instance of lipid emulsion as partaker of the successful treatment of bupivacaine’s cardiotoxicity after an inadvertent arterial puncture for infraclavicular brachial plexus block in a uremic patient with preexisting conduction abnormality.