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 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. Drug classes that researchers have investigated include tricyclic antidepressants, calcium channel blockers, beta-blockers, antipsychotics, insecticides, and organophosphates.[7][8] 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.[[7][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 that were sensitive to the effects of local anesthetics, such as the heart and brain.[1][3]

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 in favor of the combined effects of multiple scavenging and non-scavenging mechanisms.[1][9]

A static lipid phase reservoir would become rapidly filled before removing enough drug from the plasma circulation to allow recovery from toxicity.[9] 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][9]

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.[1][9] Studies have also found a lipid-induced effect on vascular resistance separate from cardiac mechanisms.[9] Contractility and vascular tone improve only when the local anesthetic concentration in the heart falls below sodium channel blocking thresholds.[9] Overall, these cardiovascular benefits improve blood pressure and cardiac output, though the exact biochemical mechanisms are still unclear.[1][9]

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 doscussion due to the lack of experimental evidence at this time.

Administration

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.[1] 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.[1] The same bolus dose is repeatable along with doubling the infusion rate if cardiovascular instability continues.[1] The recommended dosing limit is approximately 12 mL/kg.[1] 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.[1] Also, the cardio depressant effects of propofol would worsen hemodynamic instability.[1]

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

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.[11][12] 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.

Adverse Effects

Within the recommended doses of 12 mL/kg, the complications are minor and few, so 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.[13] One report described filter obstruction from lipemic blood during continuous veno-venous hemofiltration.[14] 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.[15][16][15] However, the risk of allergy require measurement against the benefit of ILE administration. Caution should also be warranted on the administration to a patient with impaired lipid metabolism and lipid storage disorders.

Monitoring

Due to the potential for allergic reactions, monitoring for signs and symptoms, such as dyspnea, cyanosis, or fever, is essential.[15] 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.[15] Lipase levels, liver enzyme tests, and bilirubin levels are necessary if there is suspicion for acute pancreatitis or acute cholecystitis.[15]

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[17]. Both higher infusion rates and higher total dose administered increase the likelihood of these events[17].

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[18]. These symptoms improve as lipemia resolves.[18]

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.[19]

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 as such, 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 better explain its mechanism of action, other appropriate indications, optimal dosing, and associated complications.