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Hemodynamic Instability and Lipid Emulsion Resuscitation After Subcutaneous Injection of a Liposomal Bupivacaine Admixture: A Case Report

Tran, Bryant W. MD*; Liebman, Spencer T. MD*; Reichman, Trevor W. MD, PhD; Scott, Michael J. MBChB*

doi: 10.1213/XAA.0000000000000889
Case Reports
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This case report describes a patient whose blood pressure decreased from a systolic pressure of 130–140 to 70–80 mm Hg after receiving extended-release liposomal bupivacaine in combination with plain bupivacaine. An 83-year-old woman with hepatocellular carcinoma presented for right hepatectomy and cholecystectomy. No hemodynamic instability was noted during the procedure. When an admixture of liposomal bupivacaine and bupivacaine hydrochloride was infiltrated into the surgical incision site during skin closure, the patient then became profoundly hypotensive. Her blood pressure was supported with phenylephrine boluses and continuous phenylephrine infusion. Lipid emulsion therapy was given to treat suspected local anesthetic toxicity. In response, the patient’s blood pressure recovered and the vasopressor requirement was significantly reduced.

From the Departments of *Anesthesiology

Surgery, Virginia Commonwealth University, Richmond, Virginia.

Accepted for publication August 8, 2018.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Bryant W. Tran, MD, Department of Anesthesiology, Virginia Commonwealth University, 1200 E Broad St, Box 980695, Richmond, VA 23298. Address e-mail to bryant.tran@vcuhealth.org.

The use of liposomal bupivacaine in the perioperative setting is supported by studies that have shown prolonged analgesic effectiveness as compared to plain local anesthetics.1,2 Liposomal bupivacaine has been identified as having a safe cardiac profile.3 In this case report, we describe a patient who developed profound hypotension after receiving an admixture of liposomal bupivacaine and bupivacaine hydrochloride (HCl).

The patient provided written Health Insurance Portability and Accountability Act authorization for use of this information for medical research.

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CASE DESCRIPTION

An 83-year-old, 54-kg woman with hepatocellular carcinoma presented for right hepatectomy and cholecystectomy. Her medical history was significant for chronic kidney disease and tachycardia-bradycardia syndrome with a dual-chamber pacemaker. She was not pacer dependent and had a native sinus rhythm between 60 and 65 beats per minute. Her liver function tests were elevated on the day of the procedure, most likely secondary to compression of the hepatic parenchyma by the tumor. The patient had no known history of liver disease. The procedure required general endotracheal anesthesia and was performed through a large modified right subcostal incision with midline extension up to the xiphoid. No hemodynamic instability was noted during anesthesia induction or during critical portions of the procedure. The procedure was uneventful, and the estimated blood loss was 400 mL. The patient received a total of 3 L of crystalloid and 1 unit of packed red blood cells before closure of the surgical incision.

Figure.

Figure.

On closure of the abdominal incision, an admixture of 15 mL of liposomal bupivacaine and 15 mL of 0.25% bupivacaine HCl was infiltrated into the incision site by the surgeon. Shortly thereafter, the patient became profoundly hypotensive with a systolic blood pressure change from the 130 to 140 mm Hg range to the 70 to 80 mm Hg range as measured through continuous arterial line monitoring. The patient’s pacemaker had been placed in asynchronous mode (DOO) at 85 beats per minute with a magnet and therefore provided a fixed, paced rhythm during this period of hemodynamic instability. The patient’s native rhythm, whose baseline was between 60 and 65 beats per minute, did not reveal itself during this event. Hypotension was initially treated with phenylephrine boluses and a phenylephrine infusion at 0.7 µg·kg1·minute1 intravenously (IV). Fluid resuscitation during the event included 1 unit of packed red blood cells. Forty-two minutes elapsed before initiation of lipid emulsion therapy. A 1.5 mL·kg1 bolus of 20% lipid emulsion was given IV, followed by an infusion of 0.25 mL·kg1·minute1. After 27 minutes of lipid emulsion treatment, the patient’s systolic blood pressure recovered to 130 mm Hg with the phenylephrine infusion reduced to 0.2 µg·kg1·minute1. The lipid emulsion infusion was then suspended. The patient remained intubated, sedated, and hemodynamically stable on transfer from the operating room to the intensive care unit. A graphic representation of this event is described in the Figure.

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DISCUSSION

The purpose of this case report is to present a rare complication of a medication that is quickly growing in popularity, review the medication’s pharmacological profile, and review the typical manifestations and treatment of local anesthetic systemic toxicity. This patient represents the first reported case of hemodynamic instability after infiltration of an admixture containing liposomal bupivacaine. Surgical conditions likely placed the patient in a relative hypovolemic state, and when combined with chronic cardiac dysfunction, the patient could not tolerate the effects of a rapidly rising serum bupivacaine level.

Although hypotension is common for chronically ill patients undergoing liver resection, this patient was normotensive throughout the procedure and had little surgical stimulation before the described event. The temporal relationship between local anesthetic administration and subsequent severe hypotension places local anesthetic systemic toxicity or anaphylactoid reaction in the differential diagnosis. The absence of bronchospasm and tachycardia makes an anaphylactoid reaction less likely the cause of the hypotension.

Systemic bupivacaine in this patient could have reached toxic levels either by inadvertent intravascular injection or by rapid absorption from subcutaneous tissue. The patient was hemodynamically unstable for approximately 30 minutes before phenylephrine treatment became effective. Pharmacokinetic studies show that peak plasma concentrations of local anesthetic are highly dependent on the route of administration. As reported by Pacira Pharmaceuticals, Inc (Parsippany, NJ), peak concentrations for EXPAREL can occur at >24 hours with nerve block injection but can occur in <12 minutes when injected IV.4,5 Pharmacokinetic profiles for admixtures of liposomal bupivacaine and bupivacaine HCl have not been performed in humans, but, in an animal model, subcutaneous administration of this admixture produces a peak plasma concentration at 12 minutes.6 Because of the slow release of bioavailable local anesthetic, liposomes appear to prevent sudden and rapid changes in local anesthetic levels when liposomal bupivacaine is used alone. However, when mixed with other local anesthetics, the liposomes may not be able to sufficiently buffer the peak plasma concentration.7

The typical sequelae of cardiovascular toxicity from local anesthetic are tachycardia and hypertension followed by myocardial depression and hypotension. Peripheral vasodilation and cardiac arrhythmias can occur, and in severe cases, the terminal phase is cardiac arrest.8 The patient in this report exhibited hypotension likely as a result of myocardial depression and peripheral vasodilation but did not exhibit cardiac arrhythmias or pulseless electrical activity.

Local anesthetics, especially bupivacaine, have an affinity for sodium channels in cardiac myocytes. Binding of local anesthetic to these sodium channels prevents normal electrical conduction. Lipid emulsion treatment decreases the amount of binding to the sodium channels by a number of different proposed mechanisms, including the provision of a “lipid sink” for the local anesthetic to travel through the bloodstream without binding to organ tissue. Cardiac inotropy is also seen with lipid emulsion treatment, which may result in an increase in blood pressure regardless of the etiology of hypotension.9

In this case study, blood pressure was brought to a normal range with a modest dose of vasopressor treatment after approximately 30 minutes. This return toward hemodynamic stability suggests that serum bupivacaine had reached toxic levels but had cleared to subclinical effect when lipid emulsion treatment was initiated. In cases of severe local anesthetic systemic toxicity, guidelines from the American Society of Regional Anesthesia prioritize the following treatments: cardiopulmonary resuscitation, airway management, seizure suppression, and prompt use of lipid emulsion. The recommended dose of 20% lipid emulsion is a 1.5 mL·kg1 bolus over 2–3 minutes, followed by an infusion at 0.25 mL·kg1·minute1.10

The Food and Drug Administration has approved EXPAREL for surgical site administration and, more recently, for use in interscalene brachial plexus nerve blocks to produce postsurgical analgesia. The instruction label for EXPAREL states that liposomal bupivacaine and bupivacaine HCl may be administered in the same syringe as long as the ratio of the milligram dose of bupivacaine HCl to liposomal bupivacaine does not exceed 1:2. Mixing with lidocaine rather than bupivacaine is cautioned against by the manufacturer due to creation of an unstable mixture. Further instructions clarify that one 20-mL vial of liposomal bupivacaine contains 266 mg of free base bupivacaine, which is molar equivalent to 300 mg of bupivacaine HCl. Finally, the instructions conclude that this administration should be used with caution, and appropriate neurological and cardiac monitoring should be used. EXPAREL dosing recommendations by Pacira Pharmaceuticals, Inc, are summarized in the Table. The patient in this case study received an admixture dose that was within recommended range.

Table.

Table.

In conclusion, doses of liposomal and plain bupivacaine that are considered within the safe, recommended range may not be risk free.11 Our case suggests that additional research may be warranted.

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DISCLOSURES

Name: Bryant W. Tran, MD.

Contribution: This author helped write and edit the manuscript.

Name: Spencer T. Liebman, MD.

Contribution: This author helped care for the patient and edit the manuscript.

Name: Trevor W. Reichman, MD, PhD.

Contribution: This author helped care for the patient and edit the manuscript.

Name: Michael J. Scott, MBChB.

Contribution: This author helped care for the patient and edit the manuscript.

This manuscript was handled by: Raymond C. Roy, MD.

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REFERENCES

1. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54:1552–1559.
2. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28:776–788.
3. Bergese SD, Onel E, Morren M, Morganroth J. Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile. Reg Anesth Pain Med. 2012;37:145–151.
4. Pacira Pharmaceuticals, Inc. EXPAREL briefing document: February 2018.Silver Spring, MD, FDA Advisory Committee Meeting.
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7. Kharitonov V. A review of the compatibility of liposome bupivacaine with other drug products and commonly used implant materials. Postgrad Med. 2014;126:29–138.
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9. Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117:180–187.
10. Neal JM, Mulroy MF, Weinberg GL; American Society of Regional Anesthesia and Pain Medicine. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg Anesth Pain Med. 2012;37:16–18.
11. Aggarwal N. Local anesthetics systemic toxicity association with EXPAREL (bupivacaine liposome) - a pharmacovigilance evaluation. Expert Opin Drug Saf. 2017:1–7.
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