(March 29, 2023)

Intravenous lipid emulsion (IVLE) is a nutritional supplement approved by the US-FDA for parenteral nutrition (22, 23), that have promising results for the treatment of lipophilic agents toxicity, mostly for local anesthetic systemic toxicity (LAST): 

• It has had favorable results in animal studies –mostly with bupivacaine– (2, 3, 4).

• Multiple case reports have shown promising results in treating LAST caused by lidocaine (7, 14, 16). There have been 147 case reports published until 2016 (11), many more have been published to this date, the majority with good outcomes. 

• In conjunction with advance cardiovascular and neurocritic support, toxicologists and AHA guidelines consider IVLE as a valid therapeutic option to treat LAST, particularly in severe cases (eg. cardiovascular collapse / arrest)(11, 17, 19). 

• Emergency physicians, toxicologists and anesthesiologists recommend that IVLE should be stocked in emergency departments in close proximity to resuscitation rooms and areas where local nerve blocks are performed (9, 10, 19).

Adult dose for Local Anesthetic Systemic Toxicity (LAST)(9, 11, 17, 18, 19)

Intralipid® 20%, 1,5 ml/kg IV bolus over 1 minute (approximately 100ml in adults), followed by an infusion of 0.25ml/kg/min IV over the next 30-60 minutes. 

Adult dose for Local Anesthetic Systemic Toxicity (LAST)(9, 11, 17, 18, 19)

• Intralipid® 20%, 1,5 ml/kg IV bolus over 1 minute (approximately 100ml in adults), followed by an infusion of 0.25ml/kg/min IV over the next 30-60 minutes. 

  • Bolus can be repeated one or two times in cases of persistent cardiovascular collapse

  • Maximal total dose of 10-12ml/kg

Adult dose for non-local anesthetics acute toxicity 

Usage of IVLE for other lipophilic agents overdose such as calcium channel blockers, tricyclic antidepressants, beta-adrenergic antagonists, etc, has not been yet validated as a  standard treatment measure. 

• If IVLE is considered as treatment please consult a toxicology specialist. 

US FDA-Labeled (22, 23)

• Provide a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods of time (usually for more than 5 days) and a source of essential fatty acids in order to prevent essential fatty acid deficiency (EFAD). 
  
  

Off-label (6, 10, 12, 19)

• Treatment for local anesthetic systemic toxicity (egs. bupivacaine, lidocaine overdoses).

• Treatment for non-local anesthetic toxicity (calcium channel blockers, cyclic antidepressant, b-adrenergic antagonists, organic phosphorus compounds, amiodarone, cocaine, etc).

Local Anesthetics Systemic Toxicity (LAST)

• Local anesthetics have a reversible blocking effect on voltage-gated sodium channels, and may cause LAST when toxic plasma levels are reached. Most often from accidental intravascular injection during other administration routes. 

• Incidence of LAST ranges from 0 to 2 per 1000 nerve blocks but appears to be decreasing as a result of increasing awareness of toxicity and improved techniques (20).

• Severity is usually dose-dependent, which can alert the provider to stop or reduce infusion rates velocity. It provokes neurologic and cardiovascular toxicity:
  
  

  • Neurologic toxicity:
    Initially presents with lightheadedness, dizziness, followed by visual and auditory disturbances such as difficulty focusing and tinnitus. 

    • Objective signs of neurotoxicity are usually excitatory and include shivering, muscular twitching, facial and distal extremities tremor. 

    • Ultimately and more severe toxicity is manifested by generalized seizures followed by generalized CNS depression state. Seizure activity ceases, and respiratory depression occurs (21).

  • Cardiovascular toxicity:
    Local anesthetics have direct actions on the heart and peripheral blood vessels, as well as indirect actions on the circulation by blockade of sympathetic or parasympathetic efferent activity. 

    • Negative inotropism and arrhythmias are caused by decreasing the conduction in Purkinje fibers and cardiomyocytes by prolonging recovery time (21). 

    • It can cause hypotension, bradycardia and finally cardiac arrest.

A precise dosing regimen is not yet well established (5, 6, 13, 17, 18, 19).

• 2012 - Guy L. Weinberg, an anesthesiologist authority and lifelong investigator about LAST and lipid emulsion, creator of Lipid Rescue™ website (5), proposes a dosing scheme based on limited data (9), a scheme that will continue to be used to this day, and which most case reports have follow through. 

• 2015 - Guidelines of the American Heart Association for Advance Cardiovascular Life Support on Special Circumstances recommends intralipid as an antidote for LAST (11). To be noticed, 2020 AHA guidelines did not formally review LAST, thereby did not update their 2015 recommendations on this issue (20). 

• 2016 - American College of Medical Toxicology Position Statement about Guidance for the Use of Intravenous Lipid Emulsion considers lipid emulsion as a reasonable therapeutic option for LAST (17, 18). 

• 2019 - Goldfrank’s Toxicologic Emergencies, 11th edition (19): summarizing all the previous literature, Sophie Gosselin and Theodore C. Bania, toxicologists and authors of the Lipid Emulsion books chapter, suggest a dosing scheme, with which EMDrugs based their dosing recommendations.
  
  

• In conclusion, literature authors consider Weinberg original proposal as a reasonable recommendation to follow, which has been applied in the majority of case reports.

The mechanisms of action of IVLE in toxicology are not well understood. There are three proposed mechanisms (19):

• Modulation of intracellular metabolism:
  Theoretically, the addition of excess fatty acids overcomes blocked or inhibited enzymes by mass action, providing energy to an energy “starved” heart, reversing toxicity. 

• Lipid sink, sponge or conduit mechanism:
  It has been postulated that lipid emulsion “soaks up” lipid-soluble xenobiotics, removing it from the site of toxicity. 

• Activation of ion channels:
  Experimental models have hypothesized that IVLE activates both Ca2+ and Na+ channels, thus decreasing the blockage of local  anesthetics-induced Na+ channels . 

• Intralipid®, Fresenius Kabi (22). The most frequently used IVLE for acute toxicity.

• Smoflipid®, Baxter (23)

• Liposyn®, Hospira

• Medialipid®, Braun

In depth safety*concerns about Intralipid® and Smoflipid® are discussed in labeling information (22, 23). 

*Known safety data have been studied in IVLE as a nutritional supplement, not for acute toxicity management (6, 8). 

Black Box Warning** (22):

• “Deaths in preterm infants after infusion of intravenous fat emulsion have been reported”.

• “Autopsy findings included intravascular fat accumulation in the lungs. Treatment of premature and low birth weight infants with intravenous fat emulsion must be based upon careful benefit-risk assessment. Strict adherence to the recommended total daily dose is mandatory; hourly infusion rate should be as slow as possible in each case and should not in any case exceed 1 g fat/kg in four hours. Premature and small for gestational age infants have poor clearance of intravenous fat emulsion and increased free fatty acid plasma levels following fat emulsion infusion; therefore, serious consideration must be given to administration of less than the maximum recommended doses in these patients in order to decrease the likelihood of intravenous fat overload. The infant's ability to eliminate the infused fat from the circulation must be carefully monitored (such as serum triglycerides and/or plasma free fatty acid levels). The lipemia must clear between daily infusions”.

**Black box warning is not included in Smoflipid labeling (23).

Contraindications (22, 23)

• Disturbances of normal fat metabolism such as pathologic hyperlipemia, lipoid nephrosis or acute pancreatitis if accompanied by hyperlipidemia

• Triglyceridemia >1000 mg/dL.

• Known hypersensitivity to egg, soybean, peanut protein, or to any of the active ingredients or excipients of Intralipid 10%.

Comments

• Potential complications: fat embolism, pancreatitis, venous thromboembolism, fat overload syndrome, extracorporeal circulation machine circuit obstruction, acute kidney injury, ventilation perfusion mismatch, ARDS, allergic reactions (19). 

• Previous reports of pulmonary complications following lipid emulsion infusion have involved large volumes of high concentrations for parenteral nutrition, particularly in neonates. 

• Fortunately, no such events have been reported in lipid-based resuscitations and no serious clinical complications have been reported following use of lipid emulsion for treating drug-induced toxicity. It is important to implement clinical systems, protocols and guidelines focused on patient safety in preventing drug errors and iatrogenic harm. (9).

• Intralipid® 20% (22)
  Contains 100% long-chain triglycerides made from soybean oil. The long-chain fatty acids include 53% linoleic acid, 24% oleic acid, 11% palmitic acid, 8% alpha-linolenic acid and 4% stearic acid 

• Smoflipid® 20% (23)
  Each 100 mL of SMOFlipid contains approximately 6 g soybean oil, 6 g MCT, 5 g olive oil, 3 g fish oil, 1.2 g egg phospholipids, 2.5 g glycerin, 16.3 to 22.5 mg all-rac-alpha-tocopherol, 0.03 g sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9).

Pregnancy risk classification

• AU TGA pregnancy category: B3

• US FDA pregnancy category: C

Comments

• Pregnancy and lactation considerations are discussed in labeling information (22, 23). 

• It is not known whether IVLE can cause fetal harm when administered to pregnant women (19).

• Soybean lipid emulsions (Intralipid®) used for parenteral nutrition have been considered safe in pregnancy in comparison with other (1). 

• A case report of lipid emulsion use for LAST in a pregnant woman did not show term fetal or newborn adverse effects (15).

1. Amato P, Quercia RA. A historical perspective and review of the safety of lipid emulsion in pregnancy. Nutr Clin Pract. 1991;6(5):189-192. doi:10.1177/0115426591006005189
   Pubmed

2. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003;28(3):198-202. doi:10.1053/rapm.2003.50041
   Pubmed

3. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31(4):296-303. doi:10.1016/j.rapm.2005.02.011
   Pubmed

4. Felice K, Schumann H. Intravenous lipid emulsion for local anesthetic toxicity: a review of the literature. J Med Toxicol. 2008 Sep;4(3):184-91. doi: 10.1007/BF03161199. PMID: 18821493; PMCID: PMC3550038.
   Pubmed Central (Open Access)

5. Weinberg GL. LipidRescue™ Resuscitation website. February 11, 2010. Accessed February 15, 2023.
   LipidRescue™ website

6. Jamaty C, Bailey B, Larocque A, Notebaert E, Sanogo K, Chauny JM. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol (Phila). 2010;48(1):1-27. doi:10.3109/15563650903544124
   Pubmed

7. Dix SK, Rosner GF, Nayar M, et al. Intractable cardiac arrest due to lidocaine toxicity successfully resuscitated with lipid emulsion. Crit Care Med. 2011;39(4):872-874. doi:10.1097/CCM.0b013e318208eddf
   Pubmed

8. Waring WS. Intravenous lipid administration for drug-induced toxicity: a critical review of the existing data. Expert Rev Clin Pharmacol. 2012;5(4):437-444. doi:10.1586/ecp.12.27
   Pubmed

9. Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117(1):180-187. doi:10.1097/ALN.0b013e31825ad8de
   Anesthesiology (Open Access)

10. Cao D, Heard K, Foran M, Koyfman A. Intravenous lipid emulsion in the emergency department: a systematic review of recent literature. J Emerg Med. 2015;48(3):387-397. doi:10.1016/j.jemermed.2014.10.009
    Clinical Key (Open Access)

11. Lavonas EJ, Drennan IR, Gabrielli A, et al. Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [published correction appears in Circulation. 2016 Aug 30;134(9):e122]. Circulation. 2015;132(18 Suppl 2):S501-S518. doi:10.1161/CIR.0000000000000264
    Circulation (Open Access)

12. Levine M, Hoffman RS, Lavergne V, et al. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity [published correction appears in Clin Toxicol (Phila). 2016 Mar;54(3):297]. Clin Toxicol (Phila). 2016;54(3):194-221. doi:10.3109/15563650.2015.1126286
    Pubmed

13. Hoegberg LC, Bania TC, Lavergne V, et al. Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity. Clin Toxicol (Phila). 2016;54(3):167-193. doi:10.3109/15563650.2015.1121270
    Pubmed

14. Tierney KJ, Murano T, Natal B. Lidocaine-Induced Cardiac Arrest in the Emergency Department: Effectiveness of Lipid Therapy. J Emerg Med. 2016;50(1):47-50. doi:10.1016/j.jemermed.2015.07.035
    Pubmed

15. Dun-Chi Lin J, Sivanesan E, Horlocker TT, Missair A. Two for One: A Case Report of Intravenous Lipid Emulsion to Treat Local Anesthetic Systemic Toxicity in Term Pregnancy. A A Case Rep. 2017;8(9):235-237. doi:10.1213/XAA.0000000000000477
    Pubmed Central (Open Access)

16. Hasan B, Asif T, Hasan M. Lidocaine-Induced Systemic Toxicity: A Case Report and Review of Literature [published correction appears in Cureus. 2019 Aug 23;11(8):c24]. Cureus. 2017;9(5):e1275. Published 2017 May 25. doi:10.7759/cureus.1275
    Pubmed Central (Open Access)

17. American College of Medical Toxicology. ACMT Position Statement: Guidance for the Use of Intravenous Lipid Emulsion [published correction appears in J Med Toxicol. 2016 Dec;12 (4):416]. J Med Toxicol. 2017;13(1):124-125. doi:10.1007/s13181-016-0550-z
    Pubmed Central (Open Access)

18. American College of Medical Toxicology. Erratum to: ACMT Position Statement: Guidance for the Use of Intravenous Lipid Emulsion. J Med Toxicol. 2016 Dec;12(4):416. doi: 10.1007/s13181-016-0554-8. Epub 2016 May 25. Erratum for: J Med Toxicol. 2017 Mar;13(1):124-125. PMID: 27225187; PMCID: PMC5135669.
    Pubmed (Erratum - Open Access)

19. Nelson LS, Howland MA, Lewin NA. Goldfrank’s Toxicologic Emergencies. 11th edition. New York, NY: McGraw-Hill Education; 2019.
    McGraw-Hill

20. Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S366-S468. doi:10.1161/CIR.0000000000000916
    Circulation (Open Access)

21. Gropper MD. Miller’s Anesthesia. 9th edition. Philadelphia, PA: Elsevier; 2020.
    Elsevier

22. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Intralipid - i.v. fat emulsion. Updated in July 2022. Accessed February 11, 2023.
    DailyMed - Intralipid

23. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Smoflipid - smoflipid injection, emulsion. Updated in May 2022. Accessed February 15, 2023.
    DailyMed - Smoflipid