Lipid Emulsion Therapy for Local Anesthetic Systemic Toxicity

Written by: Dana Loke, MD (NUEM ‘20) Edited by: Jim Kenny, MD (NUEM ‘18) Expert Commentary by: Patrick Lank, MD, MS

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Local anesthetic systemic toxicity (LAST) is a feared complication of local anesthetic use. Current estimates of LAST toxicity in adults range from 7.5 to 20 per 10,000 peripheral nerve blocks and 4 per 10,000 epidurals.[1] Although rare, this complication can be fatal. Unfortunately, many physicians are unaware of the toxic dose of local anesthetics and are unable to recognize the signs and symptoms of this toxicity.[2] For this reason and the fact that local anesthetic toxicity is rare, by the time this syndrome is identified, patients are often in cardiac arrest or peri-arrest. Thankfully, lipid emulsion such as Intralipid is a safe and effective therapy used to treat LAST.

 How does lipid emulsion therapy work?

Lipid emulsion therapy is an intravenous therapy that binds lipophilic toxins and therefore reverses their toxicity. There are several brand name lipid emulsion therapies, however Intralipid, a soy-based lipid emulsion that contains long-chain triglycerides, is the most commonly used (Figure 1).[3] The ability of lipid emulsion therapy to counteract the toxic effects of local anesthetics was discovered in 1998 by Weinberg et al when it was incidentally found that lab rats pre-treated with an infusion of lipids could withstand larger doses of bupivacaine before arresting.[4] The rats were also more easily resuscitated if given lipid emulsion therapy.[1]  These findings were subsequently confirmed in other laboratories and clinical systemic analyses.[5] Once studied more directly, it was found that intralipid acts as a “sink” by creating a lipid compartment within the plasma that attracts lipophilic compounds, such as local anesthetics, into the lipid sink, which is separate from the aqueous phase of the plasma.[1]

Figure 1: Composition of Various Brands of Lipid Emulsions[1]

How does LAST manifest?

Toxicity is a rare but potentially lethal side effect of local anesthetic. However, since patients often present without any knowledge that they were administered toxic doses of local anesthetic, it is important that the EM physician be cognizant of the signs of this toxicity. Symptoms typically start after a toxic dose of local anesthetic is administered or if local anesthetic is inadvertently administered directly into a vessel instead of subcutaneously (Figure 2). Onset of LAST is typically 30 seconds to 60 minutes after administration of the anesthetic but more often than not occurs within 1-5 minutes.[6]

Figure 2: Maximum Doses and Durations of Various Local Anesthetics[9]

Symptoms of LAST can vary, however there are 5 general ways in which LAST presents.[6] One or all of these manifestations may be present.

• CNS (excitement) – an early manifestation of LAST that often begins with confusion or slurred speech but may include subjective symptoms like metallic taste in the mouth, tinnitus, oral numbness, dizziness, lightheadedness, or visual or auditory disturbances. If not treated promptly, these symptoms often progress to seizures, syncope, coma, respiratory depression, or cardiovascular collapse.

• Cardiovascular – often preceded by CNS symptoms but not always. May include hypertension, tachycardia or bradycardia, arrhythmias, and asystole. Depressed contractility of the heart then leads to progressive hypotension and ultimately cardiac arrest.

• Hematologic – methemoglobinemia, cyanosis

• Allergic – urticaria, rash, and rarely anaphylaxis

• Local tissue response – numbness, paresthesia

The EM physician should maintain a high level of suspicion should a patient present after a same day surgery or procedure with any constellation of these symptoms.

How is lipid emulsion therapy administered?

Once LAST is recognized, the EM physician should immediately consider giving lipid emulsion therapy. An initial dose of 20% lipid emulsion at 1.5 ml/kg or a 100 ml bolus can be administered over a few minutes. This can be repeated after 5 minutes for 2 or more times for persistent hemodynamic instability. The bolus(es) should immediately be followed by a continuous infusion at 0.25-0.5 ml/kg/min.[3] The infusion should run for a minimum of 10 minutes after return of hemodynamic stability, however there are documented reports of recurrent systemic toxicity even after this. For this reason, patients should be admitted for at least 12 hours for observation and additional doses of intralipid as needed for rebound symptoms or hemodynamic compromise.[3] Consultation with your facility’s poison center is also crucial to further guide management.

Efficacy

In terms of efficacy, case reports and systemic analyses have found that lipid emulsion therapy:

• Can reverse both neurologic and cardiac toxicity [5]

• Leads to significantly higher rates of ROSC compared to saline controls in animal models [5]

• Is more effective for witnessed events (for example, brief down time for patients that arrest)5

• Is often effective in patients in which epinephrine, vasopressin, and antiarrhythmic medications did not work

Both hypoxia and acidosis worsen the toxicity of local anesthetics and may inhibit lipid emulsion therapy, so it is imperative that oxygenation and acid-base status are optimized when lipid emulsion therapy is needed.[3, 5]

 Contraindications, Complications, and Special Populations

There are no absolute contraindications to intravenous lipid emulsion therapy and no clinically significant complications documented in the literature. The benefits of lipid emulsion therapy will often outweigh any potential risks in patients with LAST, especially if hemodynamically unstable or coding.

Potential complications of lipid emulsion therapy are mainly related to hypersensitivity. Patients allergic to soybean protein or eggs theoretically may develop allergic or anaphylactic reactions. These reactions should be treated like all other allergic or anaphylactic reactions: with anti-histamines, steroids, and epinephrine as needed. Additionally, there are reported cases of hyperamylasemia however no documented progression to clinical pancreatitis.[3] There are also case reports of extreme lipemia, however even a patient that was inadvertently given 2 L of 20% lipid emulsion did not develop any cardiopulmonary complications.[5] The lipemia however did interfere with standard laboratory tests.[5]

Intralipid is safe in pregnancy and has documented use for treating LAST in term pregnancy.[7] Furthermore, it has documented uncomplicated use in pediatric and neonatal patients.[3, 8]

 Key Points

• Systemic toxicity is a rare but potentially fatal complication of local anesthetic use.

• Lipid emulsion therapy such as Intralipid mitigates the toxic effects of local anesthetics and can reverse both neurologic and cardiac toxicity.

• LAST may manifest initially with CNS symptoms but can progress to seizure, respiratory depression, coma, and cardiovascular collapse.

• An initial bolus of 1.5 ml/kg or 100 ml 20% lipid emulsion followed by an infusion starting at 0.25 ml/kg/min is crucial to reverse toxicity and prevent recurrence.

• Hypoxia and acidosis both worsen LAST and may inhibit lipid emulsion therapy.

• Patients should be admitted in order to monitor for recurrent toxicity.

• There are no contraindications to and minimal side effects of lipid emulsion therapy.

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Expert Commentary

Thank you both for the above thorough review of local anesthetic systemic toxicity (LAST) from the emergency physician perspective! I only want to add a few points to consider when learning more about LAST.

Without going into too much detail, there has been a lot of research done to figure out exactly how lipids aide in the treatment of patients with severe LAST. The lipid sink model is wonderfully understandable and explains many of the clinical and laboratory we see (e.g., a greater decrease in free serum concentration of more lipophilic local anesthetics).  However, there are some other models and theories to be aware of. One I am fascinated by is the “lipid shuttle.” Fundamentally, this describes the phenomenon that lipid therapy will decrease the concentration of local anesthetic at sites of toxicity (i.e., heart and CNS) and increase its concentration in the liver. So instead of lipids acting only as a “sink” to remove a toxin from free availability, it is helping mobilize the toxin to an area where it can go through the process of elimination from the body. Additionally, there are wonderful biochemical explanations (e.g., fatty acid supply, inhibition of nitric oxide release, reversal of mitochondrial dysfunction) to the positive cardiovascular effects seen after lipid treatment in LAST. All of these explanations, it seems, combine to contribute to the hemodynamic response seen in LAST.

Second, I would like to point your readers towards a resource that may help them work through the mechanics of administering lipid rescue therapy in LAST – lipidrescue.org. On that website, one can find links to various protocols, compilations of prior research done on the topic, and much more background on the science of the treatment than I provided above.

Third, in the emergency department, I think you are correct in saying that the most likely source of LAST we would see would come from outpatient surgery centers. A few other clinical scenarios to be aware of would include the following: ingestion of local anesthetics – mostly benzonatate (Tessalon); non-surgical outpatient aesthetic offices that may use topical anesthetics; inappropriate and excessive home use of local anesthetics for pain relief.

Finally, a very brief comment on the use of lipid rescue therapy in non-LAST toxic exposures although that was not the subject of your post. While lipid rescue therapy for LAST has a remarkable record of being effective, that is not yet the case with its use in other toxic exposures. A list of the side effects of lipid rescue therapy includes but is not limited to ARDS, pancreatitis, infection, and significant laboratory interference. While in the setting of severe LAST, the risk: benefit often favors administering lipid rescue, this may not be the case in the setting of non-LAST exposures.  For those non-LAST cases (as well as with LAST cases) in which you are wondering if lipid rescue would be appropriate, I would strongly recommend you call your regional poison center to discuss further focused therapy. 

Patrick Lank, MD, MS

Assistant Professor of Emergency Medicine

Medical Toxicologist

Department of Emergency Medicine

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How To Cite This Post:

[Peer-Reviewed, Web Publication] Loke D, Kenny J. (2020, July 20). Lipid Emulsion Therapy for Local Anesthetic Systemic Toxicity. Expert Commentary by Lank P. Retrieved from http://www.nuemblog.com/blog/lipid-emulsion-therapy

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References

1.     Manavi, M. (201). Lipid infusion as a treatment for local anesthetic toxicity: a literature review. AANA Journal, 78(1), 69-78.

2.     Cooper, B.R., Moll, T., & Griffiths, J.R. (2010) Local anaesthetic toxicity: are we prepared for the consequences in the Emergency Department. J Emerg Med, 27(8), 599.

3.     Mercado, P. & Weinberg, G.L. (2011). Local anesthetic systemic toxicity: prevention and treatment. Anesthesiology Clin, 29(2), 233-242.

4.     Weinberg, G.L., VadeBancouer, T., Ramarju, G.A., Garcia-Amaro, M.F., & Cwik, M.J. (1998). Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology, 88(4), 1071-5.

5.     Weinberg, G.L. (2012). Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology, 117(1), 180-7.

6.     Wadlund, D. (2017). Local anesthetic systemic toxicity. ARON Journal, 106(5), 367-77.

7.     Dun-Chi Lin, J., Sivanesan, E., Horlocker, T.T., & Missair, A. (2017). Two for one: a case report of intravenous lipid emulsion to treat local anesthetic systemic toxicity in term pregnancy. A&A Case Reports, 8(9), 235-7.

8.     Shah, S., Gopalakrishnan, S., Apuya, J., Shah, S., & Martin, T. (2009). Use of intralipid in an infant with impending cardiovascular collapse due to local anesthetic toxicity. J Anesth, 23(3), 439-441.

9. “Missouri Society of Health-System Pharmacists - Overview of Management of Local Anesthetic Systemic Toxicity (LAST) Based on Updated 2017/18 ASRA Practice Guidelines.”