Much uncertainty still exists surrounding intravenous lipid emulsion (ILE) therapy. The precise mechanism of action remains unknown, no definitive consensus exists regarding its clinical indications, and there are no high quality studies evaluating its potential benefits in humans. We seek to review the available literature discussing ILE and provide you with some recommendations on its clinical application.

 

Background

 

Intravenous lipids were originally created by Dr. Wretlind in 1962. The original intention of Intravenous Lipid Emulsion (ILE) was for total parenteral nutrition (TPN) (1)In 1997, Dr. Weinberg and colleagues noted a case of unexplained ventricular arrhythmia following a sub-toxic dose of bupivacaine in a healthy 16 year old woman. They later discovered that this patient had a carnitine deficiency, leading to their theory that carnitine deficiency was associated with increased susceptibility to bupivacaine toxicity (2,3).

Dr. Weinberg and colleagues tested their hypothesis in animal models in 1998. They injected intravenous lipids in animal models, as they believed this would mimic a carnitine deficient state. They discovered that rats pretreated with ILE required higher doses of bupivacaine to experience cardiac arrest. They also found that rats resuscitated with ILE following bupivacaine induced arrest had improved survival (2, 3, 4, 5). In 2003, they repeated these experiments in dogs, and again found that ILE improved survival following bupivacaine induced arrest (3, 5).

ILE was first used in human clinical therapy in 2006. A 58 year old male experienced local anesthetic systemic toxicity (LAST) following an uncomplicated interscalene nerve block. He exhibited refractory cardiac arrest, ongoing for 20 minutes, prompting a trial of ILE. This resulted in return of spontaneous circulation (ROSC) shortly thereafter (5).

In 2007, the first clinical use of ILE outside of LAST was documented. A 17 year old woman presented to the emergency department following an intentional overdose on her Lamotrigine and Bupropion. She experienced refractory cardiac arrest for over 50 minutes. ILE was trialed as a rescue therapy, resulting in ROSC shortly thereafter (6).

 

Mechanism of Action

 

The mechanism of action of Intravenous Lipid Emulsion (ILE) is not well understood. Many different theories have been proposed with the partitioning theory gaining widespread acceptance.

Originally, the lipid sink theory was favoured. This theory states that ILE creates an intravascular lipid layer, providing a binding surface for lipophilic toxins. It was postulated that this would subsequently remove the toxic drugs from the circulation (2, 3, 4, 7, 8, 9, 10, 11).

Critics have since stated that a static lipid reservoir would become saturated too quickly before removing sufficient toxin from circulation.

Research now supports the lipid shuttle theory, which builds on the lipid sink theory. This proposed modality states that, rather than a static lipid compartment, ILE acts as a scavenger of lipophilic toxins, removing the drug from sensitive organs and areas of high blood flow, such as the heart and brain, and redistributing them to other organs like the muscles for storage and the liver for detoxification (3, 4, 9).

There are proposed secondary modalities explaining the beneficial effects of ILE, including:

    • Increasing the intracellular myocardial fatty acid content, thereby replenishing tissue ATP stores (2, 3, 10, 12).
    • Acting as a direct inotrope by increasing intracellular calcium concentration in the myocardium (3, 4, 9).
    • Inhibiting endothelial nitric oxide synthase, thereby decreasing nitric oxide induced vasodilation (4).

 

Local Anesthetic Systemic Toxicity (13)

 

A 2016 systematic review performed by Hoegberg and colleagues studied every case of LAST treated with Intravenous Lipid Emulsion (ILE) published at that time. Their search yielded 76 publications on humans, consisting of 73 different case reports and one cases series, including 10 case reports not published elsewhere in the literature, totalling 83 unique cases. They found that 81 of the 83 cases treated with ILE survived.

Only 5% of cases did not identify a benefit following ILE use. 71% of cases stated a benefit was seen. The remaining cases either did not describe whether or not a benefit was observed following ILE, or stated that they could not attribute a benefit to a specific therapy as multiple interventions were being given simultaneously. 72% of cases used ILE in conjunction with other therapies.

Despite these promising findings, the authors noted a few significant limitations.The human cases were heterogenous, and the authors were not able to study the potential effects of these discrepancies on the intervention. The potential for publication bias was also discussed. The majority of studies included were case reports. With experimental therapeutic interventions, such as ILE, positive results are more likely to be published compared to negative results. This can result in false skewing of the data.

 

Overdose Ingestions (12)

 

A systematic review published in 2016 by Levine and colleagues assessed every case of drug toxicity, managed with Intravenous Lipid Emulsion (ILE) . This study identified 141 publications on humans, with 65 unique substances being treated with ILE. The majority of these cases experienced central nerve system or cardiovascular symptoms, with a portion of these patients in cardiac arrest.

The classes of overdose ingestion with the highest clinical relevancy and largest number of cases treated with ILE included:

Tricyclic Antidepressants

    • 22 total cases
    • Amitriptyline representing 11 cases
    • 18/19 improved
    • 22/22 survived

Bupropion

    • 7 total cases
    • 5/5 improved
    • 6/7 survived

Beta-Blockers

    • 21 total cases
    • 6 cases each of metoprolol and propranolol
    • 12/19 improved
    • 17/21 survived

Calcium Channel Blockers

    • 42 total cases
    • 16 cases of Verapamil toxicity, as well as 12 cases for Diltiazem and Amlodipine
    • 22/37 improved
    • 34/42 survived

Class 1 Antidysrhythmics

    • 9 total cases
    • Flecainide represented 5 cases
    • 7/7 improved
    • 8/9 survived

Anticonvulsants

    • 9 total cases
    • Lamotrigine represented 6 cases
    • 5/5 improved
    • 8/9 survived

Diphenhydramine

    • 5 total cases
    • 4/4 improved
    • 4/5 survived

Non-cyclic antidepressants

    • 8 total cases
    • Venlafaxine represented 4 cases
    • 7/8 improved
    • 7/8 survived

Antipsychotics

    • 10 total cases
    • Quetiapine represented 5 cases
    • 9/10 improved
    • 9/10 survived

Cocaine

    • 4 total cases
    • 3/4 improved
    • 3/4 survived

 

The majority of the documented patients and drug classes treated with ILE demonstrated improvement. An even larger majority of these cases subsequently survived. Despite these findings, the authors identified key limitations with the results. Similar to the previous systematic review, they noted that heterogeneity and publication bias were key limitations with the study.

 

Side Effects and Contraindications

 

Side Effects

 

Side effects of Intravenous Lipid Emulsion (ILE) differ based on the clinical context. When used as rescue therapy in the toxicity context, the side effects are uncommon and typically minor. When used as TPN, patients can experience the same side effects described in the rescue setting, as well as additional adverse outcomes. The side effects in TPN are typically proportional to the duration of therapy and the rate of the infusion (4).

Rescue Setting:

    • Disruption of lab analytes (2, 4, 10, 14, 15).
    • Pancreatitis (4, 8, 14, 15).
    • Acute respiratory distress syndrome (4, 14).
    • Acute renal failure (4, 14).
    • Priapism (14).
    • Deep vein thrombosis (14).
    • Dialysis catheter obstruction (14).

Note: there were two cases of asystolic arrest within 60 seconds of ILE implementation. Both cases exhibited refractory hemodynamic instability prior to intervention, with hypotension and bradycardia not responsive to vasopressors and standard of care therapy management. It was concluded that this relationship was temporal to ILE administration, rather than causative. (10, 14)

TPN setting:

    • Hypersensitivity reaction (14).
    • Hemolysis (14).
    • Fat emboli (4, 14).
    • ECMO catheter obstruction (4, 14).
    • Increased infection susceptibility (2, 4, 14).

 

Contraindications

 

Certain contraindications exist to ILE therapy. As it is typically composed of a soybean oil and egg yolk phospholipid, patients with severe allergies to these compounds should not receive ILE (4, 10). Patients with lipid storage and lipid metabolism disorders are also contraindicated to receive ILE (4). Finally, severe sepsis has been described as a contraindication to ILE therapy, given the associated infection risk (10).

 

Guideline Recommendations and Dosing

 

LAST Guidelines:

The Association of Anaesthetist of Great Britain and Ireland (AAGIB) (16)

    • Guidelines created in 2010.
    • Recommend treating arrest from LAST with ILE. 
    • Can consider treating hemodynamic instability from LAST with ILE. 

The American Society of Regional Anesthesia and Pain Medicine (ASRA) (9)

    • Guidelines created in 2017.
    • 1B recommendation to treat LAST with ILE. 
    • Recommend using ILE early in the resuscitation, after securing the airway. 

 

Resuscitation Guidelines:

American Heart Association (AHA) (17)

European Resuscitation Council (18)

Lipid Emulsion Workgroup (19)

    • Initiative created by the American Academy of Clinical Toxicology responsible for reviewing all available literature. surrounding ILE and providing clinical recommendations.
    • Collaboration among multiple international toxicology societies.
    • Guidelines published in 2016.
    • In situations of cardiac arrest, recommended to use ILE in bupivacaine toxicity.
    • In situations of life-threatening toxicity refractory to standard of care, recommended to use ILE in Amitriptyline, Bupropion, and local anesthetic toxicity. 

 

Dosing

 

    • For patients over 70kg: provide a 100mL bolus followed by a 250mL infusion over 15-20 minutes (9).
    • For patients under 70kg: provide a 1.5mL/kg bolus followed by a 0.25mL/kg/min infusion (9).
    • If the patient remains unstable, you can repeat the bolus or double the infusion (9).
    • Allow hemodynamics and clinical response guide therapy – recommended to continue the infusion for at least 10 minutes after clinical stability is achieved (9).
    • The maximum total dose of intravenous lipids has been defined as 10mL/kg (AHA) (17) to 12mL/kg (AAGBI) (16) – stop the infusion if this threshold is reached, regardless of patient response.
    • The dosing recommendations are similar when treating LAST and intentional overdose ingestions (2).

 

References

 

      1. Walter E, McKinlay J, Corbett J, Kirk-Bayley J. Review of management in cardiotoxic overdose and efficacy of delayed intralipid use. Journal of the Intensive Care Society. 2018 Feb;19(1):50-5.
      2. Ozcan MS, Weinberg G. Intravenous lipid emulsion for the treatment of drug toxicity. Journal of intensive care medicine. 2014 Mar;29(2):59-70.
      3. Ok SH, Hong JM, Lee SH, Sohn JT. Lipid emulsion for treating local anesthetic systemic toxicity. International journal of medical sciences. 2018;15(7):713.
      4. Sepulveda E, Pak A. Lipid Emulsion Therapy [Internet]. Ncbi.nlm.nih.gov. 2022 [cited 2 December 2021]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549897/
      5. 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. The Journal of the American Society of Anesthesiologists. 2006 Jul 1;105(1):217-8.
      6. Sirianni AJ, Osterhoudt KC, Calello DP, Muller AA, Waterhouse MR, Goodkin MB, Weinberg GL, Henretig FM. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Annals of emergency medicine. 2008 Apr 1;51(4):412-5.
      7. Muller SH, Diaz JH, Kaye AD. Intralipid emulsion rescue therapy: emerging therapeutic indications in medical practice. The Journal of the Louisiana State Medical Society. 2016 May 1;168(3):101-4.
      8. Arora NP, Berk WA, Aaron CK, Williams KA. Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose. The American journal of cardiology. 2013 Feb 1;111(3):445-7.
      9. 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. Regional Anesthesia & Pain Medicine. 2018 Feb 1;43(2):113-23.
      10. Cao D, Heard K, Foran M, Koyfman A. Intravenous lipid emulsion in the emergency department: a systematic review of recent literature. The Journal of emergency medicine. 2015 Mar 1;48(3):387-97.
      11. American College of Medical Toxicology jmt@ acmt. net. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. Journal of Medical Toxicology. 2011 Mar;7:81-2.
      12. Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R, Stellpflug SJ, Morris M, Miller-Nesbitt A, Gosselin S, Lipid Emulsion Workgroup*. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clinical Toxicology. 2016 Mar 15;54(3):194-221.
      13. Hoegberg LC, Bania TC, Lavergne V, Bailey B, Turgeon AF, Thomas SH, Morris M, Miller-Nesbitt A, Mégarbane B, Magder S, Gosselin S. Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity. Clinical toxicology. 2016 Mar 15;54(3):167-93.
      14. 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. Clinical toxicology. 2016 May 27;54(5):365-404.
      15. Levine M, Skolnik AB, Ruha AM, Bosak A, Menke N, Pizon AF. Complications following antidotal use of intravenous lipid emulsion therapy. Journal of Medical Toxicology. 2014 Mar;10(1):10-4.
      16. Cave G, Harrop-Griffiths W, Harvey M. AAGBI Safety Guideline: Management of Severe Local Anaesthetic Toxicity. London: The Association of Anaesthetists of Great Britain and Ireland; 2010 [cited 18 Jul 2017].
      17. 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 3;132(18_suppl_2):S501-18.
      18. Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J. European Resuscitation Council Guidelines 2021: cardiac arrest in special circumstances. Resuscitation. 2021 Apr 1;161:152-219.
      19. Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM, Thomas SH, Stellpflug SJ, Hayes BD, Levine M, Morris M, Nesbitt-Miller A. Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. Clinical Toxicology. 2016 Nov 25;54(10):899-923.

Authors

  • Dr. Kevin Durr is an FRCPC Emergency Medicine resident the University of Ottawa

  • Dr. Wilson (Sam) is a first-year Emergency Medicine FRCPC resident at The Ottawa Hospital. Aside from EMOttawa, Sam works as the CanadiEM CJEM Infographic editor, and is interested in PoCUS, medical teaching, knowledge dissemination, and all things chess.

  • Dr. Josée Malette is an Emergency Medicine Resident in the Department of Emergency Medicine, University of Ottawa. She is a Junior Editor with the Digital Scholarship and Knowledge Dissemination team for the EMOttawaBlog.