Continuing Education Activity

Lipid emulsion therapy is a medication used in the management and treatment of Local anesthetic toxicity. This activity reviews the indications, action, and contraindications for lipid emulsion therapy as a valuable agent in the management of local anesthetic toxicity. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with Local anesthetic toxicity and related conditions.

Objectives:

• Review the indications of lipid emulsion therapy.
• Describe the proposed mechanism of action of lipid emulsion therapy.
• Summarize the potential complications and contraindications of lipid emulsion therapy.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when administering and monitoring lipid emulsion therapy to improve patient outcomes for patients receiving treatment for local anesthetic toxicity with lipid emulsion therapy.

Indications

Intravenous lipid emulsion (ILE) therapy (also known as lipid resuscitation therapy, LRT) is the current recommended treatment for local anesthetic systemic toxicity (LAST) by professional societies such as the American Society of Regional Anesthesia (ASRA).[1] ILE therapy is also recommended as an adjunct to advanced cardiac life support measures in suspected LAST-induced cardiac arrest, according to the 2015 American Heart Association guidelines for "Special Circumstances of Resuscitation."[2] Weinberg et al. first demonstrated in 1998 that ILE pretreatment increased the toxic dose of bupivacaine-induced asystole in rats.[3] Since then, researchers have published similar findings in larger mammal studies.[4][5] Eventually, a human clinical case was reported that supported the efficacy of ILE even after 20 minutes of LAST-induced arrest.[6]

ILE therapy also extrapolates to other lipophilic agents. It has been emerging in emergency rooms and critical care units as potential rescue therapy for many other acute toxicities and poisonings. Researchers have investigated drug classes, including tricyclic antidepressants, calcium channel blockers, beta-blockers, antipsychotics, insecticides, and organophosphates. Specific drugs also studied include bupropion, lamotrigine, cocaine, and diphenhydramine.[7] At this time, ILE use for non-local anesthetic toxicity and toxins mostly derives from animal models, low-quality human studies, and clinical case reports.[8] Therefore, higher quality human studies are needed to support non-LAST indications.

Mechanism of Action

The precise mechanism of action of ILE is unknown, though there have been several proposed theories. The early “lipid sink” theory by Weinberg et al. suggested that a lipid compartment gets created in the blood into which the lipophilic bupivacaine may dissolve, thereby removing bupivacaine from the aqueous plasma circulation.[3] By binding bupivacaine to this “lipid sink,” there would be a reduction in its free concentration available to organs sensitive to the effects of local anesthetics, such as the heart and brain.[1]

The “lipid sink” hypothesis had garnered widespread acceptance and was the basis for extrapolating ILE therapy with other lipophilic drug toxicities.[8] However, subsequent research has moved from the “lipid sink” theory to the combined effects of multiple scavenging and non-scavenging mechanisms.[9]

A static lipid phase reservoir would become rapidly filled before removing enough drug from the plasma circulation to recover toxicity. Instead, ongoing research better supports ILE as a dynamic “lipid shuttle” or “lipid subway.”[9] The lipid compartment 1) scavenges local anesthetic from high blood flow, sensitive organs (i.e., heart and brain), then 2) redistributes to muscles for storage and the liver for detoxification.[1]

Besides scavenging, animal and human models have indicated cardiotonic and postconditioning effects from lipid infusion. Lipid directly increases cardiac contractility, which improves cardiac output and increases preload through simple volume expansion. Studies have also found a lipid-induced effect on vascular resistance separate from cardiac mechanisms. Contractility and vascular tone improve only when the local anesthetic concentration in the heart falls below sodium channel blocking thresholds.[9] These cardiovascular benefits improve blood pressure and cardiac output, though the exact biochemical mechanisms are still unclear.[1]

LAST experiments suggest a similarity with cardiac ischemia-reperfusion injury at the cellular level, which seems to be mitigated by the cardioprotective effects of lipid through multiple biochemical pathways.[9] This postconditioning benefit needs further research to elucidate its contribution to ILE therapy better. Of note, other mechanisms of action for ILE therapy have been proposed but do not merit discussion due to the lack of experimental evidence at this time.

Administration

Dosage Formulations

There are many commercially available 20% intravenous lipid emulsion preparations. The most prevalent formulations have 100% long-chain fatty acids derived from soybean oil. Others in the market contain 50% medium-chain fatty acids from coconut oil and 50% long-chain fatty acids from soybean oil. Nevertheless, newer formulations such as that introduce other fatty acid sources from olive and fish oils.[10] 

• The formulations with 100% long-chain fatty acids contain linoleic acid (53%), oleic acid (24%), palmitic acid (11%), alpha-linolenic acid (8%), and stearic acid (4%).

• The formulations with 50% medium-chain triglycerides contain caprylic acid (28.5%), capric acid (20%), lauric acid (1%), and caproic acid (0.5%), and the long-chain fatty acids in the formulations contain linoleic acid (29.1%), oleic acid (11% ), palmitic acid (7.4%), alpha-linolenic acid (4.5%), and stearic acid (2%).[11]

• Other formulations with 50% MCT / 50% LTC contain 30% coconut oil, 30% soybean oil, 25% olive oil, and 15% fish oil.

• ILE is also available in 20% soybean oil and 80% olive oil combination.[12]

ILE formulated from 100% long-chain fatty acids and derived from soybean oil appears to be the predominant ILE in research studies and clinical use for LAST. It is the recommended lipid emulsion by ASRA for LAST treatment.[1] Animal studies suggest that the 100% long-chain fatty acid composition may be superior to 50% mixtures.[13] However, there is much need for additional research to determine whether other commercial lipid formulations are equivalent or superior to the known standard for ILE therapy.[14]

Dose

ASRA has published guidelines for LAST, including recommendations for ILE therapy.

• For patients over 70 kilograms, a rapid 100 mL bolus of 20% lipid emulsion followed by another 200 to 250 mL infusion over 15 to 20 minutes is the recommended course. 

• For patients below 70 kilograms, a rapid 1.5 mL/kg (of lean body weight) bolus of 20% lipid emulsion followed by a 0.25 mL/kg/minute infusion should start. 

• The same bolus dose is repeatable, along with doubling the infusion rate if cardiovascular instability continues. The recommended dosing limit is approximately 12 mL/kg.

• Propofol, which is reconstituted in 10% lipid emulsion, is not an acceptable ILE therapy alternative for LAST as a much larger volume of 10% lipid emulsion would be needed to match the effects of the more concentrated 20% emulsion. Also, the cardio depressant effects of propofol would worsen hemodynamic instability.[1]

Adverse Effects

The early and less frequent adverse effects of ILE include allergic reaction, dyspnea, hyperlipidemia, hypercoagulability, and irritation. The delayed and less frequent adverse effects of ILE include transient elevation of liver function test values, hepatomegaly, splenomegaly, and thrombocytopenia.[10]

As parenteral nutrition, adverse reactions of lipid emulsion treatment are infection, hyperlipidemia, acute pancreatitis, decreased immune response, interference with laboratory examinations using serum, and parenteral nutrition-associated hepatic diseases. In addition, hyperlipidemia and infection can be associated with impaired reticuloendothelial function, leading to impaired pulmonary gas exchange. However, the adverse effects induced by lipid emulsion infusion are mild and transient for a short-term infusion compared with the fatal complications, such as cardiovascular depression and cardiac arrest, induced by toxic doses of local anesthetic, which require immediate lipid emulsion treatment.[10]

The complications are minor and few within the recommended doses of 12 mL/kg, and early administration of ILE therapy for LAST is encouraged.[1] With its expanding clinical use outside of LAST as a general antidote for lipophilic drug overdoses, reports exist of adverse effects and complications from ILE therapy. There are published clinical cases of acute pancreatitis, laboratory interference from lipemia, and adult respiratory distress syndrome.[15] One report described filter obstruction from lipemic blood during continuous venovenous hemofiltration.[16] Additional dose-related effects appear under “Toxicity.” A risk-benefit evaluation is a recommendation before initiating ILE therapy.

Contraindications

Lipid emulsion formulations in the United States are derived from egg phospholipids and thus contraindicated in patients with documented severe egg allergy.[17] However, the risk of allergy requires measurement against the benefit of ILE administration. Caution should also be warranted to administer to a patient with impaired lipid metabolism and lipid storage disorders.[18]

Monitoring

Due to the potential for allergic reactions, monitoring for signs and symptoms, such as dyspnea, cyanosis, or fever, is essential. As lipemia may occur with ILE, patients require assessment for hypertriglyceridemia and symptoms of pancreatitis. Regular triglyceride levels require monitoring, especially when doses are adjusted. Lipase levels, liver enzyme tests, and bilirubin levels are necessary if there is a suspicion of acute pancreatitis or acute cholecystitis.[17]

Toxicity

Higher ILE doses have correlated with hypertriglyceridemia, acute pancreatitis, lipid embolus, extracorporeal circulation machine circuit obstruction, acute kidney injury, cardiac arrest, acute lung injury, and increased susceptibility to infections. Both higher infusion rates and higher total dose administered to increase the likelihood of these events.[19]

Fat overload syndrome is another well-known complication of ILE; initial reports of this condition appeared in the setting of parenteral nutrition. Characteristic symptoms include sudden elevation of triglyceride levels, fever, liver dysfunction, splenomegaly, pancreatitis, coagulopathy, and hemolysis. These symptoms improve as lipemia resolves.[20]

In a severe case of ILE toxicity, clinicians observed somnolence and metabolic acidosis with elevated lactic acid levels after administration of 66 mL/kg, which is well above the recommended threshold.[21]

Enhancing Healthcare Team Outcomes

Since its initial proposal for bupivacaine toxicity, ILE therapy has become recognized as the standard treatment for LAST and is recommended for local anesthetic-mediated cardiac arrest. Furthermore, ILE therapy has been used for experimental rescue treatment of other lipophilic drug overdoses, toxicities, and toxin antidotes, though with variable success. As such, ILE therapy is relevant to physicians, advanced care providers, nursing teams, pharmacists, and ancillary staff across the interprofessional healthcare team, especially in anesthesiology, emergency medicine, and critical care.

The decision to use ILE requires strong clinical judgment on the part of the ordering clinician. Nursing staff will typically administer the therapy and must be familiar with administration protocol and potential adverse effects. The pharmacist must have involvement from the standpoint of dosing, medication reconciliation, and working with the nursing staff regarding administration and adverse events. These are but a few examples of the need for interprofessional teamwork when using ILE therapy in patients experiencing anesthetic toxicity. [Level 5] Despite the increasing awareness of ILE therapy, more clinical studies and research are needed to explain better its mechanism of action, other appropriate indications, optimal dosing, and associated complications.

Review Questions

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References

1.

Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, Mörwald EE, Rubin DS, Weinberg G. The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017. Reg Anesth Pain Med. 2018 Feb;43(2):113-123. [PubMed: 29356773]

2.

Lavonas EJ, Drennan IR, Gabrielli A, Heffner AC, Hoyte CO, Orkin AM, Sawyer KN, Donnino MW. Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 03;132(18 Suppl 2):S501-18. [PubMed: 26472998]

3.

Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. 1998 Apr;88(4):1071-5. [PubMed: 9579517]

4.

Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003 May-Jun;28(3):198-202. [PubMed: 12772136]

5.

Cave G, Harvey MG, Winterbottom T. Evaluation of the Association of Anaesthetists of Great Britain and Ireland lipid infusion protocol in bupivacaine induced cardiac arrest in rabbits. Anaesthesia. 2009 Jul;64(7):732-7. [PubMed: 19624627]

6.

Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006 Jul;105(1):217-8. [PubMed: 16810015]

7.

Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM, Thomas SH, Stellpflug SJ, Hayes BD, Levine M, Morris M, Nesbitt-Miller A, Turgeon AF, Bailey B, Calello DP, Chuang R, Bania TC, Mégarbane B, Bhalla A, Lavergne V. Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. Clin Toxicol (Phila). 2016 Dec;54(10):899-923. [PubMed: 27608281]

8.

Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med. 2009 Sep;16(9):815-24. [PubMed: 19845549]

9.

Fettiplace MR, Weinberg G. The Mechanisms Underlying Lipid Resuscitation Therapy. Reg Anesth Pain Med. 2018 Feb;43(2):138-149. [PubMed: 29356774]

10.

Ok SH, Hong JM, Lee SH, Sohn JT. Lipid Emulsion for Treating Local Anesthetic Systemic Toxicity. Int J Med Sci. 2018;15(7):713-722. [PMC free article: PMC6001420] [PubMed: 29910676]

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Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr. 2007 May;85(5):1171-84. [PubMed: 17490951]

12.

Raman M, Almutairdi A, Mulesa L, Alberda C, Beattie C, Gramlich L. Parenteral Nutrition and Lipids. Nutrients. 2017 Apr 14;9(4) [PMC free article: PMC5409727] [PubMed: 28420095]

13.

Tang W, Wang Q, Shi K, Dong J, Lin S, Zhao S, Wu C, Xia Y, Papadimos TJ, Xu X. The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long-Chain Triglyceride Versus Long- and Medium-Chain Triglyceride. Anesth Analg. 2016 Nov;123(5):1116-1122. [PubMed: 27224931]

14.

Yilmaz M, Celebi H, Akcali D, Gurel N. Pre-treatment of bupivacaine-induced cardiovascular depression using different lipid formulations of propofol. Acta Anaesthesiol Scand. 2014 Mar;58(3):298-302. [PubMed: 24438483]

15.

Levine M, Skolnik AB, Ruha AM, Bosak A, Menke N, Pizon AF. Complications following antidotal use of intravenous lipid emulsion therapy. J Med Toxicol. 2014 Mar;10(1):10-4. [PMC free article: PMC3951645] [PubMed: 24338451]

16.

Rodríguez B, Wilhelm A, Kokko KE. Lipid emulsion use precluding renal replacement therapy. J Emerg Med. 2014 Dec;47(6):635-7. [PubMed: 25271183]

17.

Spray JW. Review of Intravenous Lipid Emulsion Therapy. J Infus Nurs. 2016 Nov/Dec;39(6):377-380. [PMC free article: PMC5102272] [PubMed: 27828934]

18.

Lunn M, Fausnight T. Hypersensitivity to total parenteral nutrition fat-emulsion component in an egg-allergic child. Pediatrics. 2011 Oct;128(4):e1025-8. [PubMed: 21911353]

19.

Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D, Morris M, Nesbitt-Miller A, Morais JA, Lavergne V., Lipid Emulsion Workgroup. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila). 2016 Jun;54(5):365-404. [PubMed: 27035513]

20.

Haber LM, Hawkins EP, Seilheimer DK, Saleem A. Fat overload syndrome. An autopsy study with evaluation of the coagulopathy. Am J Clin Pathol. 1988 Aug;90(2):223-7. [PubMed: 3394663]

21.

Corwin DJ, Topjian A, Banwell BL, Osterhoudt K. Adverse events associated with a large dose of intravenous lipid emulsion for suspected local anesthetic toxicity. Clin Toxicol (Phila). 2017 Jul;55(6):603-607. [PubMed: 28489457]

22.

Aditya A, Amar P, Chander A, Goel N, Jain K, Samra T. Ropivacaine induced systemic toxicity in a patient with phacomatosis pigmentokeratotica. Indian J Pharmacol. 2021 Mar-Apr;53(2):153-156. [PMC free article: PMC8265418] [PubMed: 34100399]

Disclosure: Ernesto Sepulveda declares no relevant financial relationships with ineligible companies.

Disclosure: Aimee Pak declares no relevant financial relationships with ineligible companies.