Advertisement

Lipid emulsion treatment as an antidote for chloroquine and hydroxychloroquine toxicity

  • Soo Hee Lee
    Affiliations
    Department of Anesthesiology and Pain Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, 15 Jinju-daero 816 beon-gil, Jinju-si, Gyeongsangnam-do, 52727, Republic of Korea
    Search for articles by this author
  • Ju-Tae Sohn
    Correspondence
    Corresponding author at: Department of Anesthesiology and Pain Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, 15 Jinju-daero 816 beon-gil, Jinju-si, Gyeongsangnam-do, 52727, Republic of Korea.
    Affiliations
    Department of Anesthesiology and Pain Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, 15 Jinju-daero 816 beon-gil, Jinju-si, Gyeongsangnam-do, 52727, Republic of Korea

    Institute of Health Sciences, Gyeongsang National University, Jinju-si 52727, Republic of Korea
    Search for articles by this author
Published:January 14, 2021DOI:https://doi.org/10.1016/j.ajem.2021.01.025
      Chloroquine and hydroxychloroquine, which have anti-malarial and anti-inflammatory effects, are used for treating malaria, rheumatoid arthritis, and systemic lupus erythematosus [
      • Lebin J.A.
      • LeSaint K.T.
      Brief review of chloroquine and hydroxychloroquine toxicity and management.
      ]. These drugs are quinine derivatives having similar cellular mechanisms behind their toxicities [
      • Lebin J.A.
      • LeSaint K.T.
      Brief review of chloroquine and hydroxychloroquine toxicity and management.
      ]. Because a toxic dose of chloroquine, which is a Vaughan–Williams Class IA antiarrhythmic, inhibits cardiac sodium, potassium, and calcium channels, it induces QT prolongation, QRS widening, and atrioventricular blockade, leading to hypotension and shock [
      • White N.J.
      Cardiotoxicity of antimalarial drugs.
      ]. In addition, acute toxicity of chloroquine and hydroxychloroquine results in other side effects including nausea, vomiting, sensorineural hearing loss, seizure, respiratory depression, aplastic anemia, agranulocytosis, hepatitis, visual disturbance, corneal opacity, tinnitus, and hypokalemia [
      • Lebin J.A.
      • LeSaint K.T.
      Brief review of chloroquine and hydroxychloroquine toxicity and management.
      ]. We have read the review article titled “Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians,” recently published in The American Journal of Emergency Medicine, with great interest [
      • Della Porta A.
      • Bornstein K.
      • Coye A.
      • Montrief T.
      • Long B.
      • Parris M.A.
      Acute chloroquine and hydroxychloroquine toxicity: a review for emergency clinicians.
      ]. Della Porta et al. described lipid emulsion treatment as a novel treatment modality for the toxicity induced by chloroquine and hydroxychloroquine [
      • Della Porta A.
      • Bornstein K.
      • Coye A.
      • Montrief T.
      • Long B.
      • Parris M.A.
      Acute chloroquine and hydroxychloroquine toxicity: a review for emergency clinicians.
      ]. Intralipid, an emulsion with 100% long-chain fatty acids, was initially introduced for parenteral nutrition in 1961. However, SMOFlipid, which comprises 30% soybean oil, 30% medium-chain triglyceride, 25% olive oil, and 15% fish oil, is widely used for parenteral nutrition because a high concentration of n-6 fatty acids such as linoleic acid contained in Intralipid increases inflammatory reactions and lipid peroxidation [
      • Raman M.
      • Almutairdi A.
      • Mulesa L.
      • Alberda C.
      • Beattie C.
      • Gramlich L.
      Parenteral nutrition and lipids.
      ]. Currently, Intralipid is mainly used for the treatment of cardiovascular collapse induced by the toxicity of local anesthetics, including bupivacaine [
      • Ok S.H.
      • Hong J.M.
      • Lee S.H.
      • Sohn J.T.
      Lipid emulsion for treating local anesthetic systemic toxicity.
      ]. Lipofundin MLC/LCT comprising 50% long-chain triglyceride and 50% medium-chain triglyceride, and SMOFlipid are sometimes used for treating local anesthetic-induced systemic toxicity [
      • Ok S.H.
      • Hong J.M.
      • Lee S.H.
      • Sohn J.T.
      Lipid emulsion for treating local anesthetic systemic toxicity.
      ]. Reportedly, lipid emulsion is effective in alleviating cardiovascular collapse induced by non-local anesthetic drugs with high lipid solubility (log [octanol/water partition coefficient] >2) [
      • Cao D.
      • Heard K.
      • Foran M.
      • Koyfman A.
      Intravenous lipid emulsion in the emergency department: a systematic review of recent literature.
      ]. In addition, lipid emulsion has been reported to be effective in treating cardiovascular depression induced by the toxicity of chloroquine and hydroxychloroquine [
      • Bethlehem C.
      • Jongsma M.
      • Korporaal-Heijman J.
      • Yska J.P.
      Cardiac arrest following chloroquine overdose treated with bicarbonate and lipid emulsion.
      ,
      • Murphy L.R.
      • Maskell K.F.
      • Kmiecik K.J.
      • Shaffer B.M.
      Intravenous lipid emulsion use for severe hydroxychloroquine toxicity.
      ,
      • Haesendonck R.
      • de Winter S.
      • Verelst S.
      • Sabbe M.B.
      Intravenous lipid emulsion for intentional Chloroquine poisoning.
      ]. Recently, it was observed that chloroquine and hydroxychloroquine, which were used as alternative drugs for the treatment of coronavirus disease 2019, were able to inhibit the severe acute respiratory syndrome coronavirus 2 in laboratory experiments [
      • Liu J.
      • Cao R.
      • Xu M.
      • Wang X.
      • Zhang H.
      • Hu H.
      • et al.
      Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
      ]. However, clinical trials found that chloroquine and hydroxychloroquine induced cardiac toxicity due to the inhibition of cardiac sodium and potassium channels, leading to dangerous ventricular arrhythmia, conduction blockade, and myocardial depression [
      • Tleyjeh I.M.
      • Kashour Z.
      • AlDosary O.
      • Riaz M.
      • Tlayjeh H.
      • Garbati M.A.
      • et al.
      The cardiac toxicity of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-regression analysis.
      ]. The widely accepted underlying mechanism of lipid emulsion treatment as a nonspecific antidote is the lipid shuttle [
      • Ok S.H.
      • Hong J.M.
      • Lee S.H.
      • Sohn J.T.
      Lipid emulsion for treating local anesthetic systemic toxicity.
      ]. The lipid shuttle mechanism states that lipid emulsion absorbs highly lipid-soluble drugs (for example, bupivacaine; log [octanol/water partition coefficient]: 3.41), and lipid emulsions containing lipid-soluble drugs are subsequently transported to the liver and adipose tissue, leading to enhanced redistribution [
      • Ok S.H.
      • Hong J.M.
      • Lee S.H.
      • Sohn J.T.
      Lipid emulsion for treating local anesthetic systemic toxicity.
      , ]. In terms of responsiveness to lipid emulsion treatment as an antidote, the following pharmacologic characteristics of chloroquine and hydroxychloroquine may contribute to a positive response. First, the lipid solubility (log [octanol/water partition coefficient]) of chloroquine and hydroxychloroquine is 4.63 and 3.6, respectively, indicating that they are highly lipid soluble, similar to bupivacaine [ , ]. Second, similar to the inhibition of cardiac sodium and potassium channels induced by toxic doses of bupivacaine, the toxicity of chloroquine and hydroxychloroquine inhibits cardiac sodium and potassium channels, which leads to ventricular arrhythmia and cardiac depression [
      • White N.J.
      Cardiotoxicity of antimalarial drugs.
      ,
      • Christie L.E.
      • Picard J.
      • Weinberg G.L.
      Local anaesthetic systemic toxicity.
      ,
      • Yogasundaram H.
      • Putko B.N.
      • Tien J.
      • Paterson D.I.
      • Cujec B.
      • Ringrose J.
      • et al.
      Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment.
      ]. In addition, the lipid emulsion itself has a positive inotropic effect [
      • Fettiplace M.R.
      • Ripper R.
      • Lis K.
      • Lin B.
      • Lang J.
      • Zider B.
      • et al.
      Rapid cardiotonic effects of lipid emulsion infusion*.
      ]. Lipofundin MCT/LCT and Intralipid attenuated the cardiac sodium channel inhibition induced by bupivacaine [
      • Nadrowitz F.
      • Stoetzer C.
      • Foadi N.
      • Ahrens J.
      • Wegner F.
      • Lampert A.
      • et al.
      The distinct effects of lipid emulsions used for “lipid resuscitation” on gating and bupivacaine-induced inhibition of the cardiac sodium channel Nav1.5.
      ]. Linolenic acid (18:3n-3) and stearic acid, which are long-chain fatty acids in Intralipid, attenuated sodium channel blockade induced by bupivacaine in HEK-293 cells expressing cardiac sodium channels [
      • Mottram A.R.
      • Valdivia C.R.
      • Makielski J.C.
      Fatty acids antagonize bupivacaine-induced I(Na) blockade.
      ]. Third, lipid emulsions attenuate bupivacaine-induced cardiotoxicity by inhibiting oxidative stress caused by bupivacaine [
      • Yang L.
      • Bai Z.
      • Lv D.
      • Liu H.
      • Li X.
      • Chen X.
      Rescue effect of lipid emulsion on bupivacaine-induced cardiac toxicity in cardiomyocytes.
      ]. Furthermore, lipid emulsion attenuates doxorubicin-induced cardiotoxicity by inhibitingrun reactive oxygen species [
      • Subbarao R.B.
      • Ok S.H.
      • Lee S.H.
      • Kang D.
      • Kim E.J.
      • Kim J.Y.
      • et al.
      Lipid emulsion inhibits the late apoptosis/cardiotoxicity induced by doxorubicin in rat cardiomyoblasts.
      ]. Similar to bupivacaine, the toxicity of chloroquine was found to increase reactive oxygen species in a rat model of pressure overload hypertrophy and the glial cells of the inner ear, leading to oxidative stress [
      • Chaanine A.H.
      • Gordon R.E.
      • Nonnenmacher M.
      • Kohlbrenner E.
      • Benard L.
      • Hajjar R.J.
      High-dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy.
      ,
      • Oliveira K.R.H.M.
      • Dos Anjos L.M.
      • Araújo A.P.S.
      • Luz W.L.
      • Kauffmann N.
      • Braga D.V.
      da Conceição Fonseca Passos A, de Moraes SAS, de Jesus Oliveira Batista E, Herculano AM. Ascorbic acid prevents chloroquine-induced toxicity in inner glial cells.
      ]. Fourth, it was reported that the magnitude of drug concentration reduction induced by lipid emulsion was mainly dependent on the lipid solubility constant and partial volume of distribution [
      • French D.
      • Smollin C.
      • Ruan W.
      • Wong A.
      • Drasner K.
      • Wu A.H.
      Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies.
      ]. Chloroquine and hydroxychloroquine have a large volume of distribution of more than 100 L/kg [
      • White N.J.
      • Watson J.A.
      • Hoglund R.M.
      • Chan X.H.S.
      • Cheah P.Y.
      • Tarning J.
      COVID-19 prevention and treatment: a critical analysis of chloroquine and hydroxychloroquine clinical pharmacology.
      ]. Thus, this high volume of distribution may contribute to a greater reduction in the plasma concentration of chloroquine and hydroxychloroquine by lipid emulsion. These pharmacologic characteristics may contribute to alleviating cardiovascular depression induced by toxic doses of chloroquine and hydroxychloroquine. However, further research is needed to examine the effect of lipid emulsion on the toxicity induced by chloroquine and hydroxychloroquine. Thus, lipid emulsion may be considered for treating cardiovascular depression caused by toxic doses of chloroquine and hydroxychloroquine, which is not responsive to supportive treatment including vasopressor, diazepam, fluid, sodium bicarbonate, and mechanical ventilation.
      To read this article in full you will need to make a payment
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Emergency Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lebin J.A.
        • LeSaint K.T.
        Brief review of chloroquine and hydroxychloroquine toxicity and management.
        West J Emerg Med. 2020; 21: 760-763https://doi.org/10.5811/westjem.2020.5.47810
        • White N.J.
        Cardiotoxicity of antimalarial drugs.
        Lancet Infect Dis. 2007; 7: 549-558
        • Della Porta A.
        • Bornstein K.
        • Coye A.
        • Montrief T.
        • Long B.
        • Parris M.A.
        Acute chloroquine and hydroxychloroquine toxicity: a review for emergency clinicians.
        Am J Emerg Med. 2020; 38: 2209-2217
        • Raman M.
        • Almutairdi A.
        • Mulesa L.
        • Alberda C.
        • Beattie C.
        • Gramlich L.
        Parenteral nutrition and lipids.
        Nutrients. 2017; 9: 388https://doi.org/10.3390/nu9040388
        • Ok S.H.
        • Hong J.M.
        • Lee S.H.
        • Sohn J.T.
        Lipid emulsion for treating local anesthetic systemic toxicity.
        Int J Med Sci. 2018; 15: 713-722
        • 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: 387-397
        • Bethlehem C.
        • Jongsma M.
        • Korporaal-Heijman J.
        • Yska J.P.
        Cardiac arrest following chloroquine overdose treated with bicarbonate and lipid emulsion.
        Neth J Med. 2019; 77: 186-188
        • Murphy L.R.
        • Maskell K.F.
        • Kmiecik K.J.
        • Shaffer B.M.
        Intravenous lipid emulsion use for severe hydroxychloroquine toxicity.
        Am J Ther. 2018; 25: e273-e275
        • Haesendonck R.
        • de Winter S.
        • Verelst S.
        • Sabbe M.B.
        Intravenous lipid emulsion for intentional Chloroquine poisoning.
        Clin Toxicol (Phila). 2012; 50: 223
        • Liu J.
        • Cao R.
        • Xu M.
        • Wang X.
        • Zhang H.
        • Hu H.
        • et al.
        Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
        Cell Discov. 2020; 6: 16https://doi.org/10.1038/s41421-020-0156-0
        • Tleyjeh I.M.
        • Kashour Z.
        • AlDosary O.
        • Riaz M.
        • Tlayjeh H.
        • Garbati M.A.
        • et al.
        The cardiac toxicity of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-regression analysis.
        Mayo Clin Proc Innov Qual Outcomes. 2020; https://doi.org/10.1016/j.mayocpiqo.2020.10.005
      1. (Accessed, 21 December 2020)
      2. (Accessed, 21 December 2020)
      3. (Accessed, 21 December 2020)
        • Christie L.E.
        • Picard J.
        • Weinberg G.L.
        Local anaesthetic systemic toxicity.
        BJA Education. 2015; 15: 136-142
        • Yogasundaram H.
        • Putko B.N.
        • Tien J.
        • Paterson D.I.
        • Cujec B.
        • Ringrose J.
        • et al.
        Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment.
        Can J Cardiol. 2014; 30: 1706-1715
        • Fettiplace M.R.
        • Ripper R.
        • Lis K.
        • Lin B.
        • Lang J.
        • Zider B.
        • et al.
        Rapid cardiotonic effects of lipid emulsion infusion*.
        Crit Care Med. 2013; 41: e156-e162
        • Nadrowitz F.
        • Stoetzer C.
        • Foadi N.
        • Ahrens J.
        • Wegner F.
        • Lampert A.
        • et al.
        The distinct effects of lipid emulsions used for “lipid resuscitation” on gating and bupivacaine-induced inhibition of the cardiac sodium channel Nav1.5.
        Anesth Analg. 2013; 117: 1101-1108
        • Mottram A.R.
        • Valdivia C.R.
        • Makielski J.C.
        Fatty acids antagonize bupivacaine-induced I(Na) blockade.
        Clin Toxicol (Phila). 2011; 49: 729-733https://doi.org/10.3109/15563650.2011.613399
        • Yang L.
        • Bai Z.
        • Lv D.
        • Liu H.
        • Li X.
        • Chen X.
        Rescue effect of lipid emulsion on bupivacaine-induced cardiac toxicity in cardiomyocytes.
        Mol Med Rep. 2015; 12: 3739-3747
        • Subbarao R.B.
        • Ok S.H.
        • Lee S.H.
        • Kang D.
        • Kim E.J.
        • Kim J.Y.
        • et al.
        Lipid emulsion inhibits the late apoptosis/cardiotoxicity induced by doxorubicin in rat cardiomyoblasts.
        Cells. 2018; 7 (pii: E144)https://doi.org/10.3390/cells7100144
        • Chaanine A.H.
        • Gordon R.E.
        • Nonnenmacher M.
        • Kohlbrenner E.
        • Benard L.
        • Hajjar R.J.
        High-dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy.
        Physiol Rep. 2015; 3 (pii: e12413)https://doi.org/10.14814/phy2.12413
        • Oliveira K.R.H.M.
        • Dos Anjos L.M.
        • Araújo A.P.S.
        • Luz W.L.
        • Kauffmann N.
        • Braga D.V.
        da Conceição Fonseca Passos A, de Moraes SAS, de Jesus Oliveira Batista E, Herculano AM. Ascorbic acid prevents chloroquine-induced toxicity in inner glial cells.
        Toxicol In Vitro. 2019; 56: 150-155
        • French D.
        • Smollin C.
        • Ruan W.
        • Wong A.
        • Drasner K.
        • Wu A.H.
        Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies.
        Clin Toxicol (Phila). 2011; 49: 801-809
        • White N.J.
        • Watson J.A.
        • Hoglund R.M.
        • Chan X.H.S.
        • Cheah P.Y.
        • Tarning J.
        COVID-19 prevention and treatment: a critical analysis of chloroquine and hydroxychloroquine clinical pharmacology.
        PLoS Med. 2020; 17e1003252https://doi.org/10.1371/journal.pmed.1003252