Intravenous Lipid Emulsion As an Antidote in Clinical Toxicology: a Systematic Review K

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European Review for Medical and Pharmacological Sciences 2020; 24: 7138-7148 Intravenous lipid emulsion as an antidote in clinical toxicology: a systematic review K. TAMPAKIS1,2, N. VOGIATZAKIS3, C. KONTOGIANNIS2, M. SPARTALIS4, A. NTALIANIS2, E. SPARTALIS5, I. SIAFAKA6, N. IACOVIDOU7,8, A. CHALKIAS1,8, T. XANTHOS8,9

1National and Kapodistrian University of Athens, Medical School, Postgraduate Study Program (MSc) “Cardiopulmonary Resuscitation”, Athens, Greece 2Department of Clinical Therapeutics, Medical School, National and Kapodistrian University of Athens, “Alexandra” Hospital, Athens, Greece 31st Department of Cardiology, “Hippokration” Hospital, University of Athens Medical School, Athens, Greece 4Division of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece 5Laboratory of Experimental Surgery and Surgical Research, University of Athens, Medical School, Athens, Greece 6Department of Anesthesiology, National and Kapodistrian University of Athens, Medical School, Aretaieion Hospital, Athens, Greece 7Department of Neonatology, National and Kapodistrian University of Athens, Medical School, Aretaieion Hospital, Athens, Greece 8Hellenic Society of Cardiopulmonary Resuscitation, Athens, Greece 9European University Cyprus, School of Medicine, Nicosia, Cyprus

Abstract. – OBJECTIVE: Intravenous lipid mendations on administration are based on ani- emulsions (ILE) were developed many decades mal studies and published cases. Thus, the con- ago to supply nutritional requirements to pa- stantly increased knowledge about ILE therapy tients unable to obtain adequate enteral nutri- supports the need for a detailed appraisal. tion. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More Key Words: recently, the potential for ILE to act as an anti- Lipid emulsion, Lipid therapy, Drug toxicity, Resus- dote for inversion of drug toxicity has been rec- citation. ognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggest- ed mechanisms of action, safety profile, and recommendations on the administration of ILE Introduction in cases of drug intoxication are highlighted. MATERIALS AND METHODS: A complete lit- Intravenous lipid emulsions (ILE) were devel- erature survey was performed using the PubMed oped many decades ago as a source of essential database search to collect available information fatty acids to supply nutritional requirements in regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and case of not tolerated or insufficient enteral feed- presentation of adverse events. ing. Primarily being a dense source of cellular RESULTS: A total of 102 studies met the se- energy, fats also affect many cellular functions lection criteria for inclusion in the review. Mainly such as the formation of cell membranes, in- used for local anesthetics toxicity, ILE therapy volvement in signal cascades as second messen- has been expanded in clinical toxicology involv- gers, modulation of inflammation and platelet ing overdose treatment of drugs other than local function, as well as cholesterol and endogenous anesthetics. Partitioning in a lipid phase of fat 1 droplets is a mechanism named the lipid sink steroids biosynthesis . phenomenon that has primarily been described The utility of ILE was extended to therapeu- to explain this action of ILE and remains the tics, facilitating the delivery of drugs that are most widely accepted. At the same time, recent poorly soluble in water and are not well absorbed research has also revealed several molecular from the gastrointestinal tract, and nutraceu- mechanisms that may contribute to ILE efficacy. ticals, incorporating improved nutritional and CONCLUSIONS: ILE therapy comprises a recognized approach in clinical toxicology. Due to physical properties due to modifications of new 2,3 the lack of randomized clinical trials, recom- fatty acids .

7138 Corresponding Author: Michael Spartalis, MD; e-mail: [email protected] Intravenous lipid emulsion as an antidote in clinical toxicology

More recently, however, the potential for ILE to was the first commercially available and remains act as an antidote for drug toxicity, such as local still the predominant fat source in parenteral nu- anesthetics, has been recognized. This review aims trition1,5. Mixed lipid emulsions containing soy- to summarize the literature on the use of ILE as bean oil, medium-chain triglycerides, olive oil, an antidote, as well as suggested mechanisms of and fish oil, as well as pure fish oil emulsion, con- action, safety profile, and recommendations on the stitute newly developed fat emulsions available administration of ILE in cases of drug intoxication. for parenteral use1,5. Egg yolk phospholipid is usually the emulsifying agent in a concentration of about 1%, while the emulsion comprises particles Material and Methods of a mean size less than 50 μm in diameter. The phospholipid emulsifier provides stability to the PubMed was searched from 1950 to December lipid compartment that is formed from these fat 2016 (MEDLINE search terms in ‘‘Appendix’’). Two droplets by providing both a mechanical and an independent reviewers screened all potentially rele- electrically charged barrier. The negative charged vant titles and abstracts for eligibility. The selection oil-water interface causes an electrostatic repul- was based on the criteria of suggestion of mechanisms sive force between oil droplets that are dispersed of ILE action as an antidote, publication of cases of in the internal phase of the emulsion and prevents ILE administration for drug toxicity with a relatively coalescence and an increase in droplet size2. clear outcome, defined as an immediate clinical im- Once a fat emulsion is administered intrave- provement after ILE infusion, and presentation of ad- nously, an expanded intravascular lipid phase is verse events assigned to ILE administration. Search formed. Partitioning of a lipophilic substance, results were limited to English-language publications, such as local anesthetics, into this lipid phase and further evaluation was performed by full-text. Fi- leads to the reduction of its plasma concentration. nally, hand searching of the reference lists and using The subsequent gradual difference in concentra- more targeted keywords (lipid emulsion AND ateno- tion of the lipophilic substance between target lol) led to additional selections (Figure 1). tissues and the aqueous plasma phase results in redistribution of the substance to the plasma and Physico-Chemical Characteristics of ILE then to the lipid plasma phase6. The so-called ILE is an oil-in-water emulsion. It consists of “lipid sink” phenomenon constitutes the predom- triglyceride-containing oils, a phospholipid emul- inant mechanism that supports the use of ILE as sifier, and glycerine4. A pure soybean oil emulsion an antidote for drug toxicity.

Figure 1. Flowchart of the study.

7139 K. Tampakis, N. Vogiatzakis, C. Kontogiannis, M. Spartalis, A. Ntalianis, et al

Local Anesthetics Toxicity Cardiovascular signs are associated with more Local anesthetics (LAs) are medications that severe toxicity and are presented in three phases. cause a reversible block of the transmission of a Early signs consist of tachycardia and hyperten- nerve impulse without any impact on the level of sion that are followed by a relatively rapid myo- consciousness. Cocaine was the first successfully cardial depression and hypotension. Standard used LA agent in ophthalmic and dental proce- resuscitation is usually unsuccessful, and a ter- dures during the 19th century7. Synthesis of the minal phase of cardiogenic shock, peripheral va- amino ester procaine contributed to the elimina- sodilation, and cardiovascular collapse is often tion of several adverse effects of natural esters, inevitable12. On the contrary, evidence-based on such as euphoria and addiction. However, amino animal research suggests that caution should be esters were gradually replaced by the newer ami- exercised in adding epinephrine to the treatment no amides that are less allergic and have an earli- protocol of LA toxicity, as induced hyperlactate- er onset of action7. Lignocaine is the most wide- mia and acidosis may impair resuscitation13. ly-used agent of this category, while articaine is Considering the lipophilic properties of LAs, considered to be the safest nowadays8. Despite ILE could be a potential antidote in the case of these improvements in the chemical structure of LA toxicity. Although evidence is relatively in- LAs, systemic cardiovascular, and neurological direct, partitioning of lipophilic substances into adverse effects remain a significant complication. the lipid plasma phase formed after ILE infusion The LAs are weak bases with poor water sol- is a widely accepted theory. Moreover, the direct ubility. They consist of an aromatic ring, a con- effect of fatty acids on sodium channels has been necting group (ester or amide for newer LAs), described among ILE properties14-17. Thus, inter- and an ionizable amino group. The unionized ference on sodium channels binding, the primary form is more lipid-soluble and facilitates the en- mechanism of LAs action, could also contribute trance of the LA molecule into neuronal cells via to the role of ILE as a potential antidote. Although the lipid bilayer, while intracellular ionization evidence of ILE benefit is limited, evidence from enables the LA agent to bind to sodium chan- animal studies and case reports has led to the nels and thus inactivate them reversibly. Binding incorporation of ILE into the management of also applies to the closed channels, which in this LA-induced toxicity in addition to standard life way remain inactivated and contribute to the in- support18 (Figure 2). terruption of nerve impulse propagation9. Other mechanisms of action of LAs that have been de- The Use of ILE as an Antidote in Humans scribed are incorporation in the cell membrane, Reports of the use of ILE as an antidote in blocking of potassium channels, and anti-in- humans are relatively limited. Rosenblatt et al19 flammatory effects mediated by G-protein cou- reported the first successful use of intravenous pled receptors7,10. lipids in a human case of bupivacaine systemic The action of LAs is not limited to the pe- toxicity in 2006. Subsequently, hundreds of cases ripheral neural system. In case of sufficient have been described, although about 45% of these concentration in other tissues, like the heart were considered unsuccessful20,21. Of note, the ex- and central nervous system, cell membrane de- isting reports do not concern LA toxicity only but polarization will also be affected. In this way, include more drugs, such as cardiovascular drugs, the systematic toxicity of LAs is explained. The antipsychotic agents, and herbicides. On the other central nervous system is considered more vul- hand, the lack of randomized clinical trials with nerable to toxicity, while higher concentrations sufficient power to detect meaningful differences of LAs are usually required to cause adverse is warranted in order to clarify the effectiveness effects from the cardiovascular system. The of ILE rescue therapy22. central nervous system toxicity is presented as a biphasic process. An early excitatory phase Mechanisms of ILE Action as an Antidote includes lightheadedness, dizziness, headache, Lipid sink phenomenon perioral paresthesia, visual disturbances, seda- The lipid sink phenomenon is the mechanism tion, slurred speech, metallic taste, hypersal- that has primarily been described to explain the ac- ivation, muscle twitching, and tremors. Pro- tion of ILE and remains the most widely accepted. gression of toxicity may lead to tonic-clonic The formation of an expanded intravascular lipid seizures. This may be followed by a depressive sink leads to the reduction of the unbound concen- phase of coma and respiratory depression11. tration of a toxin in plasma and distribution from or-

7140 Intravenous lipid emulsion as an antidote in clinical toxicology

Figure 2. Nomogram for local anesthetic dose limits. (Figure is downloaded from Williams DJ, Walker JD. A nomogram for calculating the maximum dose of local anesthetic. Anesthesia 2014). gan tissues to the bloodstream. Fat droplets form a which is usually used to measure the solubility lipid compartment, separated from aqueous plasma, of a chemical substance25,26. Mazoit et al25 first- into which lipophilic substances are partitioned23. ly evaluated the binding capacity of lipid emul- Unfortunately, current evidence is scarce, and ran- sions for long-acting LAs of different solubility domized controlled trials to investigate the mecha- and found that LAs of high hydrophobicity, such nism of action are impossible to be performed. as racemic bupivacaine and levobupivacaine, Weinberg et al24 firstly proposed that parti- seem to be more rapidly cleared. Lipophilicity of tioning of bupivacaine into an expanded lipid LAs was also mentioned to affect ILE efficacy phase, created after intravenous lipid infusion, in an isolated rat heart model27. French et al26 de- was the predominant mechanism of inversion scribed the potential efficacy of ILE against tox- of bupivacaine toxicity in a rat model and sug- icity of drugs other than local anesthetics. Lipid gested the potential for a novel treatment of LA partition constant and volume of distribution of cardiotoxicity. Subsequent reports of successful a drug were shown to predict the utility of ILE in resuscitation with the use of ILE include main- reversing toxicity. ly local anesthetics, calcium channel blockers Cardiac myocytes preferentially use fatty acids (CCBs), beta-blockers, antidepressants, and as the primary source of energy28. Thus, beneficial antipsychotic agents, antihistamines and herbi- metabolic effects of lipid infusion could be a po- cides among others, referring to the treatment tential controversy for ILE mechanism of action. of toxicity of drugs that do not have a common However, the efficacy of ILE against not only car- mechanism and a site of action, chemical struc- diac toxicity but also against central nervous sys- ture, and clinical effects20. Only high lipid sol- tem toxicity cannot be explained adequately by a ubility appears to be common among the drugs metabolic hypothesis6,29,30. Neurons do not normal- mentioned above. Indeed, the binding capacity ly depend on lipids, and this fact is indirect evi- of ILE is in close relation to the octanol/water dence in support of “lipid sink” theory14. Neverthe- distribution coefficient (log P) of a drug, a ratio less, symptoms of central nervous system toxicity

7141 K. Tampakis, N. Vogiatzakis, C. Kontogiannis, M. Spartalis, A. Ntalianis, et al may be short-lived and self-limiting, and recovery assessing the relationship between improved mi- may not be related to lipid treatment. tochondrial function after ILE administration and the reverse of cardiotoxicity is controversial38,39. Alternative mechanisms of action Finally, the involvement of opioid receptors and The metabolic effects of lipid infusion on modulation of protein kinase B pathway have re- cardiac contractility do not appear to be insig- cently been described40,41. nificant, as the partitioning of a drug into a lipid Although the molecular mechanisms of action compartment could not explain the in vivo ob- of ILE may not be fully understood, existing data served rapid onset of cardiac toxicity inversion. demonstrate a multifactorial effect. Emulsions Long-chain fatty acids have been shown to in- used for parenteral nutrition are complexed mix- crease intracellular calcium by directly activating tures of natural products, and this may explain

ICa, possibly by acting at some lipid sites near the the wide range of action. Further studies may channels or on the channel protein itself15. An in- enhance the comprehension of mechanisms of crease in voltage-dependent calcium currents in action of ILE and extend its use to more clinical cardiac myocytes is associated with positive ino- cases of drug toxicity. Suggested mechanisms of tropic and chronotropic effects. Huang et al15 de- ILE action are summarized in Table I. scribed this action in 1992 in order to demonstrate that the accumulation of many fatty acids during ILE for the Toxicity of Other Drugs myocardial ischemia enhances cytotoxic calcium Calcium channel blockers overload and triggers calcium-dependent arrhyth- Calcium channel blockers are commonly pre- mogenic activity. scribed in a variety of cardiovascular diseases. Mottram et al16 demonstrated that fatty acids However, their widespread use coincides with an have a direct effect on the human cardiac sodium increased incidence of unintentional and deliber- channel, modulating bupivacaine-induced ton- ate poisonings. In the 31st Annual Report of the ic- and use-dependent sodium channel blockade. American Association of Poison Control Centers, Xiao et al17 had already supported the concept of cardiovascular drugs were mentioned as the sev- competitive inhibition for closely approximated enth most frequent substance category involved binding sites and the displacement of the offend- in human exposures42. They have also been char- ing drug in 2001. This may be one of the several acterized as the category with the fourth-fastest mechanisms by which ILE manifests its benefi- rate of increase in exposures with more severe cial effect in bupivacaine-induced cardiotoxicity outcomes42. Miscellaneous cardiovascular drugs and has also been confirmed from more recent are the second most frequent generic category studies31,32. Also, Sterh et al33 suggested a signif- associated with exposure-related fatalities, while icant direct positive inotropic effect of lipids in a CCBs are considered responsible for at least 11730 rat model of l-bupivacaine toxicity. The use of iso- pharmaceutical exposures and 73 deaths in 2013 lated rat hearts exposed to lipid microemulsions in the United States42. was in order to avoid the additional effect of the Despite those mentioned above, the treatment lipid sink mechanism. Recently, Xanthos et al34 of CCB intoxication is supported by low-quality demonstrated that ILE infusion could prevent hy- evidence18. Management is typically supportive potension in a swine model of amiodarone over- due to the shortage of available antidote. Alterna- dose. Similar findings had also been observed by tive approaches have led to animal studies for the Niiya et al35 using a mixed lipid emulsion of ol- investigation of lipid emulsion efficacy in CCB ive and soybean oil. Attenuation of the hypoten- poisoning43,44. Tebbutt et al43 reported in 2006 sive effects of amiodarone and increased cardiac that ILE treatment prolongs survival and doubles output may confirm the mechanisms mentioned above of ILE impact on cardiac contractility. Table I. Suggested mechanisms of ILE action. Furthermore, inhibition of mitochondrial permeability transition pore opening has also been Lipid sink phenomenon described as a potential mechanism of the suc- Direct activating to calcium channels cessful rescue of bupivacaine-induced cardiotox- Displacement of the offending drug of sodium channels icity by ILE36. This action is mediated through Inhibition of mitochondrial permeability transition fatty acid oxidation and has also been reported in pore opening a rat model of ILE cardioprotection against isch- Involvement of opioid receptors emia/reperfusion injury37. Nevertheless, the data Modulation of protein kinase B pathway

7142 Intravenous lipid emulsion as an antidote in clinical toxicology median lethal dose in a rat model of verapamil affect triglyceride levels, a finding that is con- toxicity, while a less marked decrease in heart sistent with the lipid sink phenomenon as the rate was mentioned. Subsequently, Bania et al44 predominant mechanism of toxicity reversion. demonstrated that ILE treatment had more pos- However, the authors did not observe a similar itive hemodynamic effects in comparison with fluctuation for lamotrigine, a drug of low lipo- the standard resuscitation strategy. These animal philicity that is rarely reported for severe car- studies were followed by case reports of success- diotoxicity, at any rate. ful administration of ILE to patients with CCB Cases of ILE efficacy as an antidote for poi- intoxication. The first human case was published soning from psychotropic drugs have also been by Young et al45 in 2009. Despite the high number described, with amitriptyline, citalopram, and que- of reports, however, ILE is not still proposed by tiapine being the most commonly reported19. Pre- the current guidelines for the treatment of CCB vious animal studies have demonstrated the bene- poisoning. Interestingly, a recent consensus doc- ficial effect of ILE compared to normal saline and ument suggests ILE as rescue treatment for the sodium bicarbonate in clomipramine intoxication therapy of patients in refractory shock or peri-ar- even though it might not be attributed through se- rest period despite increasing doses of inotropes questration to circulating lipid droplets54-57. In con- and vasopressors46. trast, the hemodynamic effects of ILE in a rat model of amitriptyline toxicity were not significant58. Beta-blockers Published reports of ILE therapy are constant- Animal studies in rodents with propranolol ly extending and have already included cases of toxicity have demonstrated reduced QRS pro- several lipophilic drugs, such as antiarrhythmic longation, amelioration of bradycardia and hy- agents59-63, the first-generation antihistamine di- potension, and prolonged survival after ILE ad- phenhydramine64, anti-malarial medications chlo- ministration47-49. However, lipid infusion failed roquine and hydroxychloroquine65,66 and a recent to improve hemodynamic instability in a simi- case of caffeine intoxication67. lar study of atenolol toxicity in a rabbit model50. Interestingly, some reports are describing an These controversial findings placed doubt on the improvement after water-soluble drug intoxica- efficacy of ILE against beta-blocker intoxication. tion. These reports should be evaluated thought- Nevertheless, atenolol is a beta-blocker more hy- fully, as polysubstance intentional ingestion is drophilic than propranolol, and thus, pharmaco- usual, especially in cases of psychotropic drug kinetics may have contributed to the results of poisoning42. Of note, drugs of unknown solubility the studies mentioned above. Although case re- are also included in the reported cases, such as ports in humans did not pertain to beta-blockers the herbicides aconite and glyphosate-surfactant, of high hydrophilicity, ILE has been incorporat- while animal studies on amphiphilic cocaine re- ed into current guidelines as a treatment adjunct vealed controversial results68-71. for beta-blocker toxicity18. Some reports include the moderately lipophilic metoprolol, co-admin- Safety of ILE Administration istration of hyperinsulinemia/euglycemia therapy Severe pulmonary adverse events have been might be crucial yet51,52. Further study appears to reported after the use of ILE for parenteral nutri- be necessary for elucidating the effect of ILE on tion, especially in newborns, with the coalescence beta-blocker toxicity. of oil droplets, leading to the increase of their size, and subsequent fat embolization appearing to be Other drugs the main causal factor72. Exposure to divalent and A significant number of reports describe the trivalent cations or an acid pH are considered po- use of ILE in human cases of toxicity of drugs tential factors of emulsion instability, while ex- other than local anesthetics. The first report posure to a high temperature does not seem so was published by Sirianni et al53 in 2008 and crucial2,73. Nevertheless, complete degradation described a deliberate poisoning of bupropion requires prolonged exposure to these extreme and lamotrigine that led to seizure activity and conditions. Headaches, jaundice, hepatospleno- cardiovascular collapse. Standard efforts of megaly, and spontaneous hemorrhage may also cardiopulmonary resuscitation were unsuccess- be presented, in addition to respiratory distress, ful, while sustained circulation was restored constituting the so-called fat overload syndrome, rapidly after the administration of ILE. Serum a well-known complication of ILE administration bupropion levels before and after lipid infusion in parenteral nutrition5.

7143 K. Tampakis, N. Vogiatzakis, C. Kontogiannis, M. Spartalis, A. Ntalianis, et al

In contrast, the administration of ILE for serum can be used in order to decrease the pos- inversion of drug toxicity has not been associ- sible influence of ILE on treatment decisions and ated with such complications74. Also, in an ex- patient care13,83. traordinary case of amlodipine poisoning, car- Hypersensitivity and allergic adverse effects diopulmonary implications were not presented are also potential complications of ILE adminis- despite the fallacious apprehension of thera- tration, although only one case of bronchospasm peutical protocol that resulted in an excessive has been reported among patients that received administration of 2 liters of ILE75. On the other ILE for drug intoxication84. hand, two cases of immediate asystole follow- Interaction of ILE with other drugs is not well ing ILE infusion have been reported76. Despite demystified. No adverse events were observed in the temporal association, a clear causative ex- the case of co-administration with atropine, bi- planation was not defined yet. carbonate, or calcium44,54. On the contrary, results ILE-related adverse events have been evaluat- from a rat model of bupivacaine overdose sug- ed in recent studies in order to define the maxi- gest that caution should be exercised in adding mum safe dose. In a rodent study, Hiller et al77 used epinephrine to a lipid emulsion treatment proto- the “Dixon-up-down” method and determined the col, as induced hyperlactatemia and acidosis was median lethal dose (LD50) of ILE 20% at 67 ± 11 the suggested mechanism that epinephrine over 85 ml/kg. Although LD50 is not the final parameter a threshold dose impaired lipid resuscitation . for the evaluation of drug safety, in this study, it Based on these findings, ASRA emphasized that was significantly larger than the dose that is usu- the pharmacological treatment of local anesthetic ally administered. In the same study, histological systemic toxicity is different from other cardiac analysis of major organs tissue did not reveal any arrest scenarios and recommended to avoid doses pathological findings at myocardium, central ner- of epinephrine above 1 mcg/kg78. Of note, a re- vous system, pancreas, and kidneys. Although cent experimental study suggests that co-admin- the transient effects of ILE were revealed at pul- istration of levosimendan may be beneficial86. The monary and liver tissues, these findings were adverse effects of ILE administration reported in observed only after large doses of ILE (> 60 ml/ human cases of clinical toxicology are summa- kg). On the contrary, ASRA recommends ILE at rized in Table II84. a dose of 10-12 ml/kg in 30 minutes78. Hyperlipidemia in the form of hypertriglyceridemia or chylomicronemia is one of the well-accept- Table II. Adverse effects of ILE administration reported in ed underlying causes of acute pancreatitis. Chylomi- human cases of clinical toxicology. crons are triglyceride-rich lipoprotein particles that Cardiovascular effects are present in the circulation when triglycerides are Brady/asystolic arrest above the level of 900 mg/dl and are large enough Hematologic effects to occlude the pancreatic capillaries, resulting in DIC inflammation. The release of pancreatic lipase and Renal failure enhanced lipolysis mediates inflammation, edema, Metabolic acidosis and necrosis79. Despite the fact that lipid emulsions Pulmonary adverse effects are designed to be similar to endogenous chylomi- Acute lung injury ARDS crons, there is only one case of acute pancreatitis VQ mismatch that is associated with ILE administration, while re- Hypersensitivity and allergic adverse effects ports of chemical hyperamylasemia without symp- Bronchospasm 74,80,81 toms are more frequent . Furthermore, lipemia Vascular occlusion and line complications interferes with blood samples analysis, especially DVT when spectrophotometric techniques are performed Superficial thrombosis for laboratory examination. Phlebitis CVVHF circuit clot As a consequence, hematology and biochem- ECMO line interference istry values are commonly affected after lipid Immune modulation infusion, even at not extremely high triglyceride Sepsis levels. Hemoglobin and platelet levels may be el- Lipemia, hypertriglyceridemia related evated, while liver and coagulation tests may be Hyperamylasemia affected74,82. Blood collection prior to ILE admin- Pancreatitis istration and brief high-speed centrifugation of Laboratory interference

7144 Intravenous lipid emulsion as an antidote in clinical toxicology

Administration of ILE According Conclusions to Current Guidelines The 2015 European Resuscitation Council ILE therapy comprises a recognized approach in (ERC) Guidelines on Resuscitation recommend clinical toxicology. Lack of randomized clinical tri- an initial bolus of 1.5 ml/kg intravenously over als appears to be inevitable, and recommendations 1 minute, followed by a continuous infusion of on ILE administration is mainly based on animal 15 ml/kg/h. In case of persistent cardiovascu- studies and case reports. Nevertheless, ILE therapy lar collapse, bolus should be repeated two more has been expanded in the intoxication of drugs other times at 5-min intervals. The infusion should than local anesthetics. Not only the lipid sink phe- be continued, at least since hemodynamic re- nomenon but also molecular mechanisms have been covery has been obtained or until the maximal suggested in order to explain this wide range of ILE dose of 12 ml/kg. Standard resuscitation should efficacy. Having a favorable safety profile, ILE em- be performed according to ALS guidelines18. piric administration in situations of failed standard These guidelines include the particular circum- resuscitation may be sensible. stance of cardiovascular collapse and cardiac arrest attributable to LAs toxicity, while ILE is also mentioned in beta-blocker intoxication18. Conflict of Interests The American Heart Association extends the The Authors declare that they have no conflict of interests. recommendation to neurotoxicity of LAs and suggests that it may be reasonable to admin- ister ILE to patients with other forms of drug References toxicity who are failing standard resuscitative measures. Despite the weak and conflicting ev- 1) Fell GL, Nandivada P, Gura KM, Puder M. Intrave- idence, the prognosis of patients who are fail- nous lipid emulsions in parenteral nutrition. Adv ing standard resuscitative measures is poor, and Nutr 2015; 6: 600-610. 2) Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. empiric administration of ILE in this situation State of the art review: intravenous fat emulsions: 87 may be sensible . current applications, safety profile, and clinical im- The optimal ILE dose is not well determined, plications. Ann Pharmacother 2010; 44: 688-700. and it is relatively empiric; it comprises a gener- 3) Pouton CW. Lipid formulations for oral adminis- al statement based on recommendations for the tration of drugs: non-emulsifying, self-emulsifying and “self-microemulsifying” drug delivery sys- toxicity of local anesthetics. ASRA has published tems. Eur J Pharm Sci 2000; 11: S93-98. a more detailed practice advisory on LAs toxici- 4) Teitelbaum D, Guenter P, Howell WH, Kochevar ME, ty in 2010, in which the need for decreasing the Roth J, Seidner DL. Definition of terms, style, and epinephrine dose to less than 1 mcg/kg is high- conventions used in A.S.P.E.N. guidelines and lighted78 (Table III). Regarding the intraosseous standards. Nutr Clin Pract 2005; 20: 281-285. 5) Gura KM, Puder M. Rapid infusion of fish oil-based administration of ILE, the only available data are emulsion in infants does not appear to be associ- 88 derived from animal experiments . ated with fat overload syndrome. Nutr Clin Pract 2010; 25: 399-402. 6) Taftachi F, Sanaei-Zadeh H, Sepehrian B, Zamani N. Lipid emulsion improves Glasgow coma scale Table III. Lipid emulsion 20% therapy for local anesthetic and decreases blood glucose level in the setting toxicity according to ASRA (values in parenthesis are for 70 of acute non-local anesthetic drug poisoning-a kg patient). randomized controlled trial. Eur Rev Med Phar- macol Sci 2012; 16: 38-42. Bolus 1.5 ml/kg (lean body mass) intravenously over 7) Ciechanowicz S, Patil V. Lipid emulsion for local an- 1 minute (~100 ml) esthetic systemic toxicity. Anesthesiol Res Pract Continuous infusion 0.25 ml/kg/min 2012; 2012: 131784. (~18 ml/min; adjust by roller clamp) 8) Nizharadze N, Mamaladze M, Chipashvili N, Vad- Repeat bolus once or twice for persistent achkoria D. Articaine–the best choice of local cardiovascular collapse anesthetic in contemporary dentistry. Georgian Double the infusion rate to 0.5 ml/kg/min if blood Med News 2011; 190: 15-23. Nau C, Wang GK. pressure remains low 9) Interactions of local anesthetics with voltage-gated Na+ channels. J Membr Biol Continue infusion for at least 10 minutes after 2004; 201: 1-8. attaining circulatory stability 10) Hollmann, MW, Strumper D, Herroeder S, Durieux Recommended upper limit: approximately 10 ml/kg ME. Receptors, g proteins, and their interactions. lipid emulsion over the first 30 minutes Anesthesiology 2005; 103: 1066-1078.

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