Tox Cards: Intralipid Rescue

Author: Jenna Otter, MD (Emergency Medicine resident at Temple University Hospital) // Edited by: Cynthia Santos, MD (Assistant Professor Emergency Medicine, Toxicology, Rutgers University Hospital), Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital), and Brit Long, MD (@long_brit)

Case:

A 17 year old girl presents to the emergency room after overdose with reported 60 bupropion at an unknown time period prior to being found. She was somnolent and seizing on EMS arrival, and they promptly intubated the patient and brought her to your emergency department. In the resuscitation bay she loses pulses, and CPR is initiated.

Background

  • Intralipid was researched by Dr. Weinberg, an anesthesiologist, who found its use by chance in local anesthetic toxicity experiments with rats in the 1990s.1
  • His research team found that lipids increase resistance to local anesthetic toxicity, which was the opposite of his initial hypothesis.
  • Subsequent series of experiments in rats and dogs found that those given lipid were more likely to be successfully resuscitated in local anesthetic toxicity.
  • In 2006, the first 2 case reports2,3 of patients with local anesthetic toxicity successfully treated with intralipid were published. These cases involved the inadvertent instillation of bupivacaine and ropivicaine, respectively, intravenously during orthopedic surgeries, resulting in asystolic cardiac arrest. In both cases, the patients achieved ROSC after intralipid was administered in the code.

Mechanism

Intralipid is purported to work via 2 mechanisms: as a “lipid sink” and by providing a source of cardiac fuel.4

  • It binds lipophilic drug and carries it to the liver and muscles (i.e. away from the brain) where it is taken up intracellularly.
  • The heart uses triglycerides as major fuel source and positive inotropic effects have been demonstrated in vivo.

Both mechanisms continue to be questioned and are the subject of ongoing research.

Does intralipid work for ORAL lipophilic medication overdose?

The kinetics of metabolism change with oral overdose compared with intravenous. There have been numerous case reports suggesting it is effective in oral overdose of some medications.

Case reports of the positive effect of intralipid administration have been shown in the following oral medication overdoses:

  • TCAs6,7
  • Cocaine8
  • Verapamil9
  • Olanzapine10
  • Quetiapine/Sertraline11
  • Diltiazem12
  • Bupropion5
  • Propranolol13
  • Caffeine14

How to administer it:

If 20% Intralipid:

  • 1.5 cc/kg initial bolus (typically will be about 100cc)
  • Followed by 0.25 cc/kg/min x 10 min after achieving ROSC
  • Repeat bolus 1 or 2 times if persistent cardiovascular collapse
  • Can double infusion rate to 0.5 cc/kg/min if persistently low BP
  • Not to exceed 10-12 cc/kg over the first 30 min (in 70kg person 700-840 cc total in 30 min)15

Adverse Effects

  • The adverse effects reported with high dose intralipid treatment include pancreatitis, direct hepatic toxicity, thrombophlebitis, and Lipid Overload Syndrome which is characterized by sudden onset of:
    • Headache, fever, jaundice, hepatosplenomegaly
    • Respiratory distress
    • Spontaneous hemorrhage
    • Anemia, leukopenia, thrombocytopenia, coagulopathy
  • These adverse effects are associated with high doses and fast rates of infusion of Intralipid infusion.16
  • Intralipid circulating in the blood can cause spuriously elevated hemoglobin and platelet count and may affect results of electrolyte lab tests.18, 19
  • Intralipid may clog machines that rely on small caliber tubing and membranes such as ECMO circuits and dialysis machines.

Pearls for using intralipid:

  • Less muscle mass = possibly less effective therapy because the medication bound to intralipid molecules gets sequestered in muscle4, 18
  • It has been observed that smaller-sized patients have higher risk of overdose from local anesthetic toxicity20
  • Fettiplace et al demonstrated a transient elevation in drug tissue concentration seen in skeletal muscle4, so less muscle = less storage space for the lipid-bound drug.
  • GOOD BASIC LIFE SUPPORT IS IMPERATIVE
    • Intralipid is just part of the treatment; high quality CPR is important to continue during resuscitation and will move the intralipid-bound drug into the muscles and liver.

 

This post is sponsored by www.ERdocFinder.com, a supporter of FOAM and medical education, who with their sponsorship are making FOAM material more accessible to emergency physicians around the world.

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References:

  1. Weinberg et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine induced asystole in rats. Anesthesiology 1998;88:1071-5.
  2. Rosenblatt et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine related cardiac arrest. Anesth 2006;105:217-8.
  3. Litz et al. Successful resuscitation of a patient with ropivicaine-induced asystole arter axillary plexus block using lipid infusion. Anesth 2006;61:8oo-801.
  4. Fettiplace et al. Multimodal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion. J Control Release. 2015 Jan 28; 198: 62-70. doi:10.1016/j.jconrel.2014.11.018.
  5. Sirianni et al. Use of Lipid Emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Annals Em Med. 2008 April; vol 51.4:412-415.
  6. Blaber MS, et al. “Lipid Rescue” for Tricyclic Antidepressant Cardiotoxicity. Emerg Med. 2012 Jan 11. [Epub ahead of print]
  7. Argawala R, et al. Prolonged use of intravenous lipid emulsion in a severe tricyclic antidepressant overdose. J Med Toxicol. 2014 Jun:10(2):210-4.
  8. Jakkala-Saibaba R, et al. Treatment of cocaine overdose with lipid emulsion. Anesthesia. 2011 Dec;66(12):1168-70.
  9. Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation. 2009. May;80(5):591-3. Epub 2009 Mar 17.
  10. McAllister RK, Tutt CD, Colvin CS. Lipid 20% emulsion ameliorates the symptoms of olanzapine toxicity in a 4-year-old. Am J Emerg Med. 2011 Jun 2 [Epub ahead of print]
  11. Finn SD, et al. Early treatment of a quetiapine and sertraline overdosewith Intralipid Anesthesia. 2009 Feb;64(2):191-4.
  12. Montiel V, Gougnard T, Hantson P. Diltiazem poisoning treated with hyperinsulinemic euglycemia therapy and intravenous lipid emulsion. Eur J Emerg Med. 2011 Apr;18(2):121-3.
  13. Thompson AM, et al. Intravenous lipid emulsion and high-dose insulin as adjunctive therapy for propranolol toxicity in a pediatric patient. Am J Health Syst Pharm. 2016 Jun 15;73(12):880-5.
  14. Muraro L, et al. Intralipid in acute caffeine intoxication: a case report. J Anesth. 2016 Oct;30(5):895-9.
  15. Lipidrescue.org
  16. Hayes BD, et al. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila). 2016 Jun;54(5):365-404.
  17. Hiller DB, et al. Safety of high volume lipid emulsion infusion: a first approximation of LD50 in rats. Reg Anesth Pain Med. 2010 Mar-Apr;35(2):140-4.
  18. Matt Zuckerman. Episode 25 Lipid Rescue Part 2. ToxNow Podcast. Feb 27, 2015. http://toxnow.org/archives/359#.WUV5NmgrLic.
  19. Grunbaum AM, et al. Review of the effect of intravenous lipid emulsion on laboratory analyses. Clin Toxicol (Phila). 2016;54(2):92-102.
  20. Barrington MJ, Kluger R. Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade. Reg Anesth Pain Med. 2013;38:289-97.

 

2 thoughts on “Tox Cards: Intralipid Rescue”

  1. Lipid has been used in nutrition for years (Levine 2012), with the first investigative steps into its use as an antidote made by Minton et al 1987, suggesting that it did not seem to have an effect on amitriptyline disposition. In 1998 it was shown that soybean oil reversed bupivicaine toxicity in rats (Weinberg 1998) and then 10 years later the first use in non-local anaesthetic toxicity was seen (Serianni 2008). The mechanism of action is thought to be due to, among other things, a lipid sink and also myocardial substrate (Levine 2012). In the literature Serianni et al 2008 seems to be the genesis of a rapidly growing body of evidence supporting the use of intravenous lipid emulsion (ILE) despite the evidence being labelled as low or very low in a recent systematic review (Levine 2016).
    By 2009 there were 4 animal studies, 2 of which showed improved survival, 1 human study and only 4 case reports (Cave 2009) with no consensus on timing of administration or dose. In fact the infusion rates suggested for non-local anaesthetic toxicity (NLT) were those used for local anaesthetic toxicity (Cave 2009). 2 years later this had swelled to 42 case reports, 19 for local anaesthetic toxicity and 23 for NLT (Cave 2011). All of these reports showed significant heterogeneity in their approach to dose, infusion and timing of administration making it difficult to find anything meaningful in the outcomes of the patients. 5 years after this and more evidence has come to the fore. 142 human studies consisting of 3 Randomised Controlled Trials (RCTs), 137 case reports and 63 unique substances (Levine 2016). Some showed benefit, some no change and some, more worryingly, showed harm.
    The main side effects of ILE are allergy, emboli, lowered immunity, pancreatitis, hypertriglyceridaemia and thrombophlebitis (Levine 2012), with case reports of pancreatitis in children (Levine 2012). The adverse effects seem to be proportional to the rate of infusion and the total dose (Hayes 2016). In spite of this and with further evidence showing that the dose, duration of infusion and safety of ILE are still unclear (Agarwala 2014) some researchers and clinicians are making early forays into unknown territory. There have been isolated paediatric case reports showing the benefit of ILE with Tricyclic overdose (Hendron 2011) and one case report administering ILE early in the clinical course, with positive outcomes (Harvey 2012).
    Despite the recommendations of Toxbase there remains no RCTs on timing of administration/dose, antidotal experience is lacking and there is an increasing body of evidence demonstrating significant side effects (Levine 2012). I would support the recommendation if ILE were reserved for life threatening, refractory cases and even then, as a consideration rather than a necessity. I would think of it as, ‘Lipid rescue’ (Blaber 2017).

  2. Ref list

    1. Weinburg, GL. 2012. Lipid Emulsion Infusion. Anesthesiology. 117:180-7. http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931121/ on 03/19/2017
    2. Sirianni, AJ. Osterhoudt, KC. et al. 2008. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdoes of bupropion and lamotrigine. Ann Emerg Med. 51:412-5.
    3. Levine, M. Brooks, DE. et al. 2012. Delayed-Onset Seizure and Cardiac Arrest After Amitriptyline Overdose, Treated With Intravenous Lipid Emulsion Therapy. Pediatrics. 130(2):432-8
    4. Cave, G. Harvey, M. 2009. Intravenous Lipid Emulsion as Antidote Beyond Local Anaesthetic Toxicity: A Systematic Review. Acad Emerg Med. 16:815-24. doi: 10.1111/j.1553-2712.2009.00499.x
    5. Harvey, M. Cave, G. 2012. Case Report: successful lipid resuscitation in multi-drug overdose with predominant tricyclic antidepressant toxidrome. International Journal of Emergency Medicine. 5:8. doi:10.1186/1865-1380-5-8
    6. Agarwala, R. Ahmed, S. et al. 2014. Prolonged Use of Intravneous Lipid Emulsion in a Severe Tricyclic Antidepressant Overdose. J Med Toxicol. 10:210-4. DOI 10.1007/s13181-013-0353-4
    7. Blaber, MS. Khan, JN. et al. 2017. “Lipid Rescue” for Tricyclic Antidepressant Cardiotoxicity. Journal of Emergency Medicine. 52(1):103. doi: 10.1016/j.jemermed.2011.09.010
    8. Hendron, D. Menagh, G. et al. 2011. Tricyclic Antidepressant Overdose in a Toddler Treated with Intravenous Lipid Emulsion. Pediatrics. 128(6)
    9. Minton, NA. Goode, AG. et al. 1987. The effect of a lipid suspension on amitriptyline disposition. Arch Toxicol. 60:467-9. doi: 10.1007/BF00302392
    10. Hayes, BD. Gosselin, S. et al. 2016. Systematic review of clinical adverse events reported after the acute intravenous lipid emulsion administration. Journal of Clinical Toxicology. 54(5):365-404. DOI: 10.3109/15563650.2016.1151528
    11. Levine, M. Hoffman, RS. et al. 2016. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila). 54(3):194-221. DOI: 10.3109/15563650.2015.1126286
    12. Cave, G. Harvey, M. et al. 2011. Intravenous Lipid emulsion as antidote: a summary of published human experience. Emerg Med Australas. 23(2):123-41. DOI: 10.1111/j.1742-6723.2011.01398.x

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