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Clinical Toxicology

ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20

Evidence-based recommendations on the use ofintravenous lipid emulsion therapy in poisoning

Sophie Gosselin, Lotte C. G. Hoegberg, Robert. S. Hoffman, Andis Graudins,Christine M. Stork, Simon H. L. Thomas, Samuel J. Stellpflug, Bryan D. Hayes,Michael Levine, Martin Morris, Andrea Nesbitt-Miller, Alexis F. Turgeon,Benoit Bailey, Diane P. Calello, Ryan Chuang, Theodore C. Bania, BrunoMégarbane, Ashish Bhalla & Valéry Lavergne

To cite this article: Sophie Gosselin, Lotte C. G. Hoegberg, Robert. S. Hoffman, Andis Graudins,Christine M. Stork, Simon H. L. Thomas, Samuel J. Stellpflug, Bryan D. Hayes, Michael Levine,Martin Morris, Andrea Nesbitt-Miller, Alexis F. Turgeon, Benoit Bailey, Diane P. Calello, RyanChuang, Theodore C. Bania, Bruno Mégarbane, Ashish Bhalla & Valéry Lavergne (2016) Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning, ClinicalToxicology, 54:10, 899-923, DOI: 10.1080/15563650.2016.1214275

To link to this article: http://dx.doi.org/10.1080/15563650.2016.1214275

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REVIEW

Evidence-based recommendations on the use of intravenous lipid emulsiontherapy in poisoning�Sophie Gosselina,b,c , Lotte C. G. Hoegbergd, Robert. S. Hoffmane , Andis Graudinsf, Christine M. Storkg,h,Simon H. L. Thomasi, Samuel J. Stellpflugj, Bryan D. Hayesk,l, Michael Levinem, Martin Morrisn ,Andrea Nesbitt-Millern , Alexis F. Turgeono, Benoit Baileyp,q , Diane P. Calellor, Ryan Chuangs,Theodore C. Baniat, Bruno M�egarbaneu, Ashish Bhallav and Val�ery Lavergnew

aDepartment of Emergency Medicine, McGill University Health Centre, Montr�eal, Qu�ebec, Canada; bCentre Antipoison du Qu�ebec,Montr�eal, Qu�ebec, Canada; cProvince of Alberta Drug Information Services, Calgary, Alberta, Canada; dDanish Poisons Information Centre,Anaesthesiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark; eDivision of Medical Toxicology, Ronald O. PerelmanDepartment of Emergency Medicine, New York University School of Medicine, New York, NY, USA; fMonash Clinical Toxicology Service,Program of Emergency Medicine, Monash Health and School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and HealthSciences, Monash University, Clayton, Victoria, Australia; gUpstate NY Poison Center, Syracuse, NY, USA; hDepartment of EmergencyMedicine, Upstate Medical University, Syracuse, New York, USA; iNational Poisons Information Service (Newcastle) and Medical ToxicologyCentre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK; jDepartment of Emergency Medicine, Regions Hospital, SaintPaul, MN, USA; kDepartment of Pharmacy, University of Maryland Medical Center, Baltimore, MD, USA; lDepartment of Emergency Medicine,University of Maryland School of Medicine, Baltimore, MD, USA; mDepartment of Emergency Medicine, Section of Medical Toxicology,University of Southern California, Los Angeles, CA, USA; nSchulich Library of Science and Engineering, McGill University, Montr�eal, Qu�ebec,Canada; oDivision of Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, and CHU de Qu�ebec, Universit�e LavalResearch Center, Population Health and Optimal Health Practices Unit, Universit�e Laval, Qu�ebec City, Qu�ebec, Canada; pDivision ofEmergency Medicine, Department of Pediatrics, CHU Sainte-Justine, Montr�eal, Qu�ebec, Canada; qCentre Antipoison du Qu�ebec, Quebec,Canada; rMedical Toxicology, Department of Emergency Medicine, Morristown Medical Center, Emergency Medical Associates, Morristown,NJ, USA; sDepartment of Emergency Medicine, Division of Clinical Pharmacology and Toxicology, University of Calgary, Poison and DrugInformation Service, Calgary, Alberta, Canada; tSt Luke's Roosevelt Hospital, New York, NY, USA; uDepartment of Medical and ToxicologicalIntensive Care, Lariboisi�ere Hospital, Paris-Diderot University, INSERM UMRS1144, Paris, France; vDepartment of Internal Medicine, PostGraduate Institute of Medical Education and Research, Chandigarh, India; wDepartment of Medical Biology, Sacr�e-Coeur Hospital, Universityof Montr�eal, Montr�eal, Qu�ebec, Canada

ABSTRACTBackground: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic(LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severemanifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-basedrecommendations for the use of ILE in poisoning.Methods: Following a systematic review of the literature, data were summarized in four publications: LA andnon-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categoriesand three clinical situations were selected for voting. Voting statements were proposed using a predeterminedformat. A two-round modified Delphi method was used to reach consensus on the voting statements.Disagreement was quantified using RAND/UCLA Appropriateness Method.Results: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while ourrecommendations are neutral regarding its use for all other toxins. For the management of life-threateningtoxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid solublebeta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine,malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupi-vacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recom-mend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, andbupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threateningtoxicity, recommendations are variable according to the balance of expected risks and benefits for eachtoxin.For LA-toxicity we suggest the use of IntralipidVR 20% as it is the formulation the most often reported. Thereis no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel isneutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendationswere based on very low quality of evidence.Conclusion: Clinical recommendations regarding the use of ILE in poisoning were only possible in a smallnumber of scenarios and were based mainly on very low quality of evidence, balance of expected risks andbenefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroupemphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required toadvance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILEtreatment.

ARTICLE HISTORYReceived 11 May 2016Revised 3 July 2016Accepted 13 July 2016Published online 8 Septem-ber 2016

KEYWORDSFat emulsion; lipidresuscitation; recommenda-tion; adverse effect; lipidinterference

CONTACT Dr. Sophie Gosselin sophie.gosselin@mcgill.ca 1001 Boulevard D�ecarie, Room CS1-6014, Montr�eal, Qu�ebec, H4A 3J1 Canada�On behalf of the Lipid Emulsion Therapy workgroup. The Lipid Emulsion Therapy workgroup also includes Ami Grunbaum MD, Brian Gilfix MD, Carol Rollins,PharmD, Jos�e A. Morais MD, and Sheldon Magder, MD� 2016 Informa UK Limited, trading as Taylor & Francis Group

CLINICAL TOXICOLOGY, 2016VOL. 54, NO. 10, 899–923http://dx.doi.org/10.1080/15563650.2016.1214275

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Introduction

The lipid emulsion workgroup was established as a collabora-tive effort among the American Academy of ClinicalToxicology, the European Association of Poison Centres andClinical Toxicologists, the American College of MedicalToxicology, the Asia Pacific Association of MedicalToxicology, the American Association of Poison ControlCenters, and the Canadian Association of Poison ControlCenters. This article presents the workgroup’s recommenda-tions regarding the use of intravenous lipid emulsion therapyin poisoning for a preselected set of toxins. These recom-mendations are based on the results of four systematicreviews,[1–4] derived from a comprehensive analysis of thepublished evidence and further followed by an expertconsensus.

Methods

The detailed methodology for the workgroup’s process waspreviously published.[5] Each association selected clinicalexperts to serve on this committee and additional selectionswere made for their specific expertise in related fields. Twomedical librarians assisted the workgroup in the design ofthe search strategies, article retrieval, and management ofcitations but did not vote on the recommendations. For thepublished systematic reviews, the following databases weresearched from inception to 15 December 2014: BIOSISPreviews (via Ovid), CINAHL (via EBSCO), the CochraneLibrary/DARE, Embase (via Ovid), Medline (Ovid), PubMed,Scopus, and Web of Science. The literature review wasupdated in December 2015 as described later. No languagerestrictions were applied. Articles in languages other thanEnglish were professionally translated. A methodologist withexpertise in systematic reviews and guideline developmentoversaw the process. The workgroup considered four system-atic reviews that summarized the evidence pertaining topotential benefits and harms of the use of lipid emulsion inpoisoning, which were published prior to finalizing the rec-ommendations, and an international survey evaluating ILEavailability and cost.[1–4,6]

The voting panel decided to evaluate only those toxins orcategories of toxins for which a minimum of three humancases were reported in the literature. The 22 toxins or cate-gories were selected as the following: amitriptyline, class 1antidysrhythmics, baclofen, bupivacaine, bupropion, lipid-soluble beta-receptor antagonists (defined as a positivelog D), non-lipid-soluble beta-receptor antagonists, cocaine,non-dihydropyridine calcium channel blockers (diltiazem andverapamil), dihydropyridine calcium channel blockers,diphenhydramine, ivermectin, lamotrigine, malathion, olanza-pine, selective serotonin receptor inhibitors, other cyclic anti-depressants, other antihistamines, other antipsychotics,other insecticides, other local anesthetics (LAs), and otherpesticides.

The workgroup determined clinical situations in whichlipid emulsion could be indicated. These were categorized as(1) cardiac arrest, (2) life-threatening toxicity, or (3) non-life-threatening toxicity (Table 1). Life-threatening toxicity was

defined as the presence of any of the following: dysrhyth-mias such as ventricular tachycardia with compromised organperfusion, ventricular fibrillation, status epilepticus, and/orhypotension with organ compromise. Shock or end-organcompromise was defined as the presence of cellular ischemiaas evidenced by increased lactate concentration, acute kid-ney injury as defined by the Kidney Disease ImprovingGlobal Outcomes (KDIGO) guideline,[7] increased troponin,altered mental status, or decreased capillary refill.Hypotension was defined as a low blood pressure as perage-related defined standards. Non-life-threatening toxicitywas defined as clinical situations without immediate threat tolife such as coma, altered mental status, simple seizure, hypo-tension without organ compromise, and dysrhythmias suchas sinus tachycardia or other stable dysrhythmias. Alteredmental status was defined as the impairment in one of thespheres of brain function: cognition, alertness or orientation,and coma a deep state of unconsciousness as per theAmerican Academy of Neurology.[8]

A generic format of voting statements was developed dur-ing several conference calls in order to refine the final word-ing and ensure generalizability to all toxins (Appendix 1).A two-round modified Delphi method was utilized to reach aconsensus on clinical recommendations. After consideringthe balance between desirable and undesirable outcomes,the quality of evidence for outcomes as well as costs andresource use, members of the voting panel cast their voteson a 9-point Likert scale for each proposed statement foreach toxin/category of toxins included. The RAND/UCLAAppropriateness Method was used to quantify disagreementbetween the votes cast by the panel. The median values, thelower/upper quartiles, and the disagreement indexes werecalculated for each of the two rounds of votes. Median val-ues ranging from 7 to 9 reflected that the workgroup was infavor of the proposed statement, 4 to 6 reflected a neutralposition, and 1 to 3 reflected that the workgroup was againstthe statement. The disagreement index describes the disper-sion of ratings and values less than or equal to 1 indicateagreement. A second round of voting determined the finalstrength of recommendations (Figure 1). A strong recommen-dation in favor (level 1) was defined as a median valuebetween 7 and 9 with a lower quartile between 7 and 9 anda disagreement index �1 (similarly, a strong recommenda-tion against was defined as a median value between 1 and 3with an upper quartile between 1 and 3 and a disagreementindex �1). A weak/conditional recommendation in favor(level 2) was defined as a median value between 7 and 9with a lower quartile between 4 and 6 and a disagreement

Table 1. Intravenous lipid emulsion (ILE) in poisoning: clinical situations.

Statements Clinical situations

ILE is indicated in cardiac arrest, after standard ACLS is started

ILE is indicated in life-threatening toxicity As first-line therapyAs part of treatment modalitiesIf other therapies fail (in last resort)

ILE is indicated in non-life-threateningtoxicity

As first-line therapyAs part of treatment modalitiesIf other therapies fail (in last resort)

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index �1 (similarly, a weak/conditional recommendationagainst was defined as a median value between 1 and 3 withan upper quartile between 4 and 6 and a disagreementindex �1). A neutral position was resulted when the medianvalue was between 4 and 6 with a disagreement index �1.To better understand the reason for a neutral vote, memberscould specify if their position was neutral due to majoruncertainties in the evidence or to a balance between thedesirable and undesirable effects of adherence to the pro-posed statement. When the disagreement index exceeded 1,no recommendation resulted as this illustrated an inability ofthe voting panel to reach consensus. All recommendationsare followed by the strength of recommendations (1 or 2)and the grading of the level of evidence (A to D) (Table 2),in accordance with the GRADE methodology (Grading ofRecommendations Assessment, Development andEvaluation).[9]

A first vote occurred in October 2014 and results werediscussed in a face-to-face meeting in the same month.A second vote in September 2015 determined the final rec-ommendations. Results were discussed in a second face-to-face meeting in October 2015. An update of the literaturefor publications through 31 December 2015 was performedin January 2016 using the same search strategy previouslymentioned and is presented in Appendices 2–4. The litera-ture update was summarized and presented to the membersof the voting panel. Members were given an opportunity toupdate their votes in March of 2016.

Clinical recommendations

In the discussions that follow if there is no specific mentionof a scenario, it is implied that the voting was neutral.

The complete voting results for each statement for eachtoxin/category of toxins are presented in Appendix 5. Anexecutive summary of the recommendations for all toxins/categories of toxins is presented in Table 3.

Recommendations for local anesthetics

Indications:

� In cardiac arrest due to toxicity of bupivacaine, we recom-mend using ILE after standard ACLS is started (1D), whileour recommendation is neutral regarding its use in car-diac arrest due to other local anesthetics.

Rationale: The voting panel noted that bupivacaine is theLA for which the most data exist with results supportingthe efficacy of ILE. However, controlled data from animalexperiments suffer from several methodological shortcom-ings. These include: reporting a statistical difference forshort experimental time frames not directly relevant toclinical situations, the failure to perform autopsies to searchfor potential adverse effects, and the lack of reporting ofacidosis and hypoxia in study animals, both of which arecommon in human poisonings and can affect outcome.Human case reports are too heterogeneous and patientsreceived concurrent multiple other medications making itimpossible to definitively attribute any positive outcome toILE alone.

However, while the level of evidence is very low, the risk/benefit ratio in cardiac arrest favors the use of ILE with bupi-vacaine and the voting panel had strong agreement for thisindication. There are no data to allow an informed decisionon which resuscitative medication to use first among sodium

Figure 1. Voting process.

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bicarbonate, epinephrine, or ILE. Some members pointed outthat if the total dose administered is within the known thera-peutic range and the route of exposure is clearly not intra-vascular, consideration of an allergic reaction to LA ratherthan LA systemic toxicity probably warrants the use of epi-nephrine first. Because of a lack of evidence for the use ofILE with other LAs, the voting panel was unable to provide afirm recommendation in the setting of cardiac arrest.However, several members noted that harm appears to below and there was a strong agreement for a neutral vote.Concerns about reports of an unclear interaction with con-current administration of epinephrine or other resuscitativemedications with ILE reported mainly in the local anestheticsliterature may explain the voting panel’s reticence to adviseon ILE administration during cardiac arrest associated withnon-bupivacaine LA toxicity.[10–13] Data were insufficient tomake an evidence-based recommendation for the use of ILEwith other LAs. In comparison with bupivacaine, both the lip-ophilicity and toxicity profiles of the other LAs vary consider-ably, thereby invalidating recommendations made byanalogy rather than data.

� In life-threatening toxicity due to bupivacaine, we suggestusing ILE as part of treatment modalities (2D) and we rec-ommend its use if other therapies fail/in last resort (1D).

Rationale: The voting panel had strong agreement in con-cluding that there are enough data to support the use of ILEas a part of treatment modalities for patients with life-threat-ening bupivacaine toxicity. Moreover, while the risk/benefitratio of this therapy is warranted if all other treatmentmodalities fail, the lack of data to guide the sequence ofadministration of resuscitative therapies made it impossibleto decide on whether ILE should be the first-line treatment.Some members of the voting panel were concerned thatwaiting for other therapies to fail may decrease the potentialefficacy of ILE and thus it should be given relatively early,

while there was consensus to use ILE if a patient was alreadyunresponsive to other treatments.

� In life-threatening toxicity due to other LAs, we suggestusing ILE if other therapies fail/in last resort (2D).

Rationale: There is a lack of convincing data for efficacy ofILE with other LAs. Despite this, there is a relatively favorablerisk/benefit ratio in cases of prolonged toxicity in patientswith a pulse but unresponsive to other treatments. As aresult, the voting panel agreed that ILE could be used ifother therapies fail or as a last resort. However, it was notedthat in only a minority of reported cases ILE was used as soletreatment.

� In non-life-threatening toxicity due to bupivacaine or otherLAs, our recommendation is neutral regarding the use of ILE.

Rationale: The voting panel agreed that, in this situation,there is equipoise between risk and benefits. There are notenough data reported to make an evidence-based decision.

Lipid regimen

1. ILE formulation:

� When ILE is indicated for bupivacaine and other LAstoxicity, we suggest using the brand IntralipidVR 20% (2D).

Rationale: Most of the data reported used this specific ILE for-mulation. The voting panel agreed that there were insuffi-cient data to discuss other formulations in human poisoningsuntil such time as comparative studies are reported.

2. ILE dosing:

� When ILE is indicated for bupivacaine and other LAs tox-icity, our recommendation is neutral regarding the choiceof ILE dosing.

Rationale: Although the voting panel agreement was for aneutral position, there was a slight preference for the mostcommonly reported dosing regimen: a bolus of 1.5mL/kgand an infusion of 0.25mL/kg/min of 20% ILE. Data are lack-ing with regards to ILE dose–response relationships for treat-ing any human toxicity. No studies evaluated the benefit ofan infusion after bolus vs. a bolus alone for toxins with arapid endogenous clearance compared with most other tox-ins. The literature reports a varied range of bolus doses, infu-sion rates, and durations that make analysis of the optimaldosing regimen impossible.

3. ILE cessation:

� When ILE is indicated for bupivacaine and other LAs tox-icity, our recommendation is neutral regarding which end-points to use to stop ILE administration (maximum doseor maximum duration).

Table 2. Strength of recommendation and level of evidence.

Strength of recommendation (consensus-based)Level 1: Strong recommendation (The course of action is considered appropri-

ate by the large majority of experts with no major dissension. The panel isconfident that the desirable effects of adherence to the recommendationoutweigh the undesirable effects.)

Level 2: Weak/conditional recommendation (The course of action is consideredappropriate by the majority of experts but some degree of dissension existsamong the panel. The desirable effects of adherence to the recommenda-tion probably outweigh the undesirable effects.)

Neutral position: The course of action is neither preferred nor rejected by themajority of experts; either due to a balance in the desirable and undesir-able effects of adherence to the recommendation or due to major uncer-tainties to its evaluation.

No recommendation: The group of experts reached no agreementLevel of evidence (GRADE system)Grade A: High level of evidence (The true effect lies close to our estimate of

the effect.)Grade B: Moderate level of evidence (The true effect is likely to be close to

our estimate of the effect, but there is a possibility that it is substantiallydifferent.)

Grade C: Low level of evidence (The true effect may be substantially differentfrom our estimate of the effect.)

Grade D: Very low level of evidence (Our estimate of the effect is just a guess,and it is very likely that the true effect is substantially different from ourestimate of the effect.)

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Table 3. Executive summary of indications regarding the use of ILE in poisoning.

Toxins Clinical situations (strength of recommendation & level of evidence)a

Local anestheticsBupivacaine In cardiac arrest: we recommend using ILE (1D)

In life-threatening toxicity: we suggest using ILE as part of treatment modalities (2D) and werecommend using ILE if other therapies fail/in last resort (1D)

In non-life-threatening toxicity: neutral recommendationAll other local anesthetics In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest using ILE if other therapies fail/in last resort (2D)In non-life-threatening: neutral recommendation

Non-local anestheticsAntidysrhythmics Class 1 In cardiac arrest: neutral recommendation

In life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Amitriptyline In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest using ILE if other therapies fail/in last resort (2D),

but we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we recommend not using ILE as first-line therapy (1D) and

we suggest not using ILE as part of treatment modalities (2D)Other tricyclic antidepressants In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE in any circumstances (2D)

Baclofen In cardiac arrest: neutral recommendationIn life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Beta receptor antagonists (Lipid-soluble) In cardiac arrest: neutral recommendationIn life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Beta receptor antagonists (Non lipid-soluble) In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D) nor as part

of treatment modalities (2D)Bupropion In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest using ILE if other therapies fail/in last resort (2D),but we suggest not using ILE as first-line therapy (2D)

In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)Calcium channel blockers: Diltiazem and verapamil In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Calcium channel blockers: Dihydropyridines In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE in any circumstances (2D)

Cocaine In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D) nor as part

of treatment modalities (2D)Diphenhydramine In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we recommend not using ILE as first-line therapy (1D) and

we suggest not using ILE otherwise (2D)Other antihistamines Insufficient dataIvermectin In cardiac arrest: neutral recommendation

In life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Other insecticides In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Lamotrigine In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D) nor as part

of treatment modalities (2D)Malathion In cardiac arrest: neutral recommendation

In life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Other pesticides In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Olanzapine In cardiac arrest: neutral recommendationIn life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Other antipsychotics In cardiac arrest: neutral recommendationIn life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

Selective serotonin reuptake inhibitors In cardiac arrest: neutral recommendationIn life-threatening toxicity: neutral recommendationIn non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

aNeutral position if not otherwise specified.

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Rationale: The voting panel attempted to define endpointsfor ILE treatment either with a maximum dose administered,a maximum duration of administration, or with resolution oftoxicity. Members expressed opinions that a maximum doseshould not be exceeded due to concerns about adverseeffects from lipid overload. There were no strong data toinform the threshold amount of ILE that results in lipid tox-icity. To avoid lipid overload, it was suggested from the vot-ing panel that ILE doses should be limited to a maximum of10% of total blood volume to limit possible complicationsarising from increased triglyceride concentrations in excess of15mmol/L (glycerol-blanked method) reported when ILE rep-resented more than 10% of test tube volumes.[14] This isalso to avoid fluid overload, which is an increasing concernin resuscitation as patients receiving ILE will likely havereceived other fluid solutions.[15] This is particularly of con-cern when administering ILE to obese patients, neonates, oryoung children. Assuming ILE remains mostly in the intravas-cular compartment, this rationale would indicate a total ILEdose of 560mL for a 70 kg adult patient with an estimatedblood volume of 5.6 L.

Also, given the pharmacokinetics of LAs and the lack ofhistorical data to indicate a recurrence of toxicity once clin-ical improvement occurs, resolution of toxicity may be con-sidered as an appropriate endpoint. The risk of prolonged ILEtherapy on immune function or other organ function is asyet undefined for infusions administered for less than 24 h.However, some members were of the opinion that waiting tosee a sustained improvement in the clinical status would beinadvisable, until such a time that studies report a benefit forcontinuation of therapy beyond the point of clinicalresolution.

There is no strong evidence guiding the maximum dur-ation of ILE therapy that could be safely administered if clin-ical improvement does not occur. However, the voting panelcommented that clinical protocols for the use of ILE shouldrecommend a specific duration and maximal volume of ther-apy to avoid administration of high doses of ILE over indefin-ite periods. This should take into consideration the adverseeffect profile and the maximum duration of ILE recom-mended during parenteral nutrition.[16] As most articlesreported use of ILE for 20–30min, it seems reasonable tolimit the duration of infusion to this time period until con-trolled experiments are published assessing specific treat-ment durations. Thus, the voting panel concluded that notenough evidence exists to inform on when to stop ILE.

Recommendations for non-local anesthetics

Amitriptyline and other tricyclic antidepressants

Indications:

� In cardiac arrest due to either amitriptyline or any othertricyclic antidepressants toxicity, our recommendation isneutral regarding the use of ILE.

� In life-threatening toxicity due to amitriptyline, we sug-gest using ILE if other therapies fail/in last resort (2D), butwe suggest not using ILE as first-line therapy (2D).

� In life-threatening toxicity due to other tricyclic antidepres-sants, we suggest not using ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to amitriptyline, werecommend not using ILE as first-line therapy (1D) andfurthermore we suggest not using ILE as part of treatmentmodalities (2D).

� In non-life-threatening toxicity due to other tricyclic anti-depressants, we suggest not using ILE in any circumstan-ces (2D).

Rationale: One human RCT (published only in abstract andnot specifying which TCAs were involved) failed to show abenefit of ILE on the duration of cardiotoxicity when patientswere randomized to standard treatment with bicarbonate orILE.[17] This explains why ILE therapy is discouraged either asfirst-line therapy either in life-threatening toxicity or withnon-life-threatening toxicity. However, the situation ofwhether ILE might be beneficial in cases refractory to stand-ard therapy, including epinephrine and bicarbonate therapy,was not explored. Many human case reports exist with inher-ent publication bias. However, the voting panel noted thatsome animal experiments, including one with an orogastric-poisoning model most similar to the clinical poisoningreported no benefit and possibly even harm.[18] Decades ofpublished evidence for the efficacy of bicarbonate therapyexist. Thus, the panel voted for the use of ILE only in life-threatening toxicity from amitriptyline after failure of stand-ard therapies, with moderate agreement.

Beta-receptor antagonists

Indications:

� In cardiac arrest due to toxicity of both lipid soluble andnon-lipid soluble beta-receptor antagonists, our recom-mendation is neutral regarding the use of ILE.

� In life-threatening toxicity due to lipid soluble beta-receptor antagonists, our recommendation is neutralregarding the use of ILE.

� In life-threatening toxicity due to non-lipid soluble beta-receptor antagonists, we suggest not using ILE as first-linetherapy (2D).

� In non-life-threatening toxicity due to lipid soluble beta-receptor antagonists, we suggest not using ILE as first-linetherapy (2D).

� In non-life-threatening toxicity due to non-lipid solublebeta-receptor antagonists, we suggest not using ILE asfirst-line therapy nor as part of treatment modalities (2D).

Rationale: The voting panel had consistent agreement in theirvotes. Reasons cited for the results are the balance existingbetween risks and expected benefit of using ILE, the evi-dence for the safety and efficacy of high dose insulin eugly-cemia therapy and the possible use of extracorporeal assistdevices reporting problems with concurrent ILE use.Moreover, the distinction between lipid-soluble and non-lipidsoluble drugs, which were initially divided into two distinctcategories to account for differences in log D did not

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influence the voting panel’s evaluation, except in cases oflife-threatening toxicity where benefits were not consideredto outweigh risk for non-lipid soluble beta receptor antagon-ist toxicity as a first-line therapy or in non-life-threateningtoxicity as part of treatment modalities.

Bupropion

Indications:

� In cardiac arrest due to bupropion toxicity, our recom-mendation is neutral regarding the use of ILE.

� In life-threatening toxicity due to bupropion, we suggestusing ILE if other therapies fail/in last resort (2D), but wesuggested not using ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to bupropion, we sug-gest not using ILE as first-line therapy (2D).

Rationale: Few case reports exist with survival outcome and itis unclear if the patients would have survived without ILE.However, the voting panel mentioned the likelihood of publi-cation bias. Also, most cases of bupropion toxicity do wellwith non-specific therapies aimed at maintaining vital func-tions. Several case reports demonstrate improvement withbicarbonate therapy. It is unclear whether higher doses ofbicarbonate, a medication with an established safety profile,would yield similar outcomes to ILE. More controlled data areneeded to inform on whether or not ILE interferes with theefficacy of standard therapies such as benzodiazepines orbarbiturates for seizures. The concurrent use of ILE and othertherapies has not been studied in any detail. However, in thesituation of prolonged and refractory status epilepticus, a trialof ILE seems reasonable. Hence, a 2D recommendation wasmade for cases with life-threatening toxicity if other therapiesfail. However, in pulseless cardiac arrest, the voting panel feltILE was not indicated given the reported interference it hason the effect of epinephrine or extracorporeal treatments.Hence, there was not a favorable enough risk/benefit ratio.Once ROSC (return of spontaneous circulation) is achieved,then ILE is suggested if life-threatening toxicity persists.

Calcium channel blockers

Indications:

� In cardiac arrest due to toxicity from calcium channelblockers (including diltiazem, verapamil and dihydropyri-dines), our recommendation is neutral regarding the useof ILE.

� In life-threatening toxicity due to diltiazem, verapamil, ordihydropyridine calcium channel blockers, we suggest notusing ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to diltiazem verapamil,or dihydropyridine calcium channel blockers, we suggestnot using ILE as first-line therapy (2D).

Rationale: Due to the inconsistent outcomes reported, rang-ing from sudden death to immediate response, in both

animal experiments and human case reports, no clear rec-ommendation can be made. Some members felt cardiacarrest presents a situation where little harm seems to existfor a “trial” of ILE. However, as noted above, other membersexpressed their concerns that ILE can enhance intestinalabsorption of toxins as is demonstrated in oral drug poison-ing models.[19] In addition, problems associated with theconcurrent use of ILE with extracorporeal assist devices andthe potential for interference with resuscitative medicationswith evidence of benefit, such as vasopressors and insulin–glucose, were also highlighted. A single study that mim-icked an oral overdose of verapamil demonstrated worseoutcomes when ILE was given. Animal studies showed noclinical benefit or benefit at dose requirements exceeding adose of 12mL/kg of 20% ILE.[19,20] No studies comparingthe current standard of care with vasopressors or insulin–glucose therapy are available in a model consistent withhuman clinical poisoning. Considering the lack of informa-tion on dose, potential adverse effects and especially inter-ference with extracorporeal assist devices or interferencewith medications known to be effective, the voting paneldetermined that the benefits were probably equal to therisks and thus, a neutral position resulted in the presenceof cardiac arrest.

Unless organ perfusion is compromised, the voting panelfelt that there was not enough information to make a deci-sion and at the very least a balance exists between risks andpotential benefits of ILE. Thus, there is a question as towhether ILE should be a part of the treatment modalities orused after standard therapy fails (last resort) in life-threaten-ing toxicity for all calcium channel blockers.

Furthermore, the reason for not suggesting lipid emulsionif other therapies fail, in cases of non-life-threatening toxicitydue to diltiazem and verapamil, and not suggesting ILE in allother circumstances of non-life-threatening toxicity due dihy-dropyridines, is based on a risk/benefit analysis. Certain signsand symptoms of CCB toxicity, such as ileus or bradycardiaand hypotension, may not respond or entirely correct withvarious therapies but only resolve with time and metabolismof the toxicant.

Cocaine

Indications:

� In cardiac arrest due to cocaine toxicity, our recommenda-tion is neutral regarding the use of ILE.

� In life-threatening toxicity due to cocaine, we suggest notusing ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to cocaine, we suggestnot using ILE as first-line therapy (2D) or as part of treat-ment modalities (2D).

Rationale: Too few case reports exist, all with varied outco-mesto make a favorable recommendation. Several experi-mental studies with cocaine and ILE using pre-treatmentanimal models [21,22] were excluded a priori due to the lackof generalizability to the clinical setting of human cocainepoisoning. The voting panel was in agreement on a neutral

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recommendation concerning the use of ILE in cardiac arrestand commented there was a paucity of data on the efficacyof ILE to reverse signs and symptoms of cocaine toxicity. Thebody of evidence and published experience with other treat-ments such as sodium bicarbonate, and benzodiazepines ismuch greater than that for ILE therapy. More controlled dataare needed to assess whether or not ILE interferes with theefficacy of the standard therapies.

Diphenhydramine

Indications:

� In cardiac arrest due to diphenhydramine toxicity, our rec-ommendation is neutral regarding the use of ILE.

� In life-threatening toxicity due to diphenhydramine, wesuggest not using ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to diphenhydramine,we recommend not using ILE as first-line therapy (1D) andwe suggest not using ILE otherwise (2D).

Rationale: Due to the efficacy of bicarbonate therapy and thelack of superiority of ILE over bicarbonate reported in one ani-mal experiment, the voting panel concluded there was noscenario where ILE would be clearly indicated at this time.There are no data to inform on the best timing of ILE adminis-tration. Diphenhydramine possesses sodium channel blockingproperties and a trial of ILE has clinical equipoise when con-sidering the possible risks of an acute administration of ILE incases otherwise unresponsive to repeated administration ofsodium bicarbonate (e.g. more than 200 mEq [23]). However,the role of ILE in non-life-threatening toxicity, such as anti-cholinergic delirium, was not reported in the literature at all.

A comment was made regarding the use of ILE with “otherantihistamines”. It was noted that if the lipid sink or conduittheories proves to be valid, there might be a theoretical bene-fit for ILE in severe toxicity from sedating antihistamines. Inparticular, those agents with a log D value of 2 or 3 whenother therapies have failed. However, more than 70% of thepanel voted that there were insufficient data to consider rec-ommendations in the category “other antihistamines”. Thismade it impossible to make a statement about any particularantihistamine, as described in the methodology.

Lamotrigine

Indications:

� In cardiac arrest due to lamotrigine toxicity, our recom-mendation is neutral regarding the use of ILE.

� In life-threatening toxicity due to lamotrigine, we suggestnot using ILE as first-line therapy (2D).

� In non-life-threatening toxicity due to lamotrigine, wesuggest not using ILE as first-line therapy (2D) nor as partof treatment modalities (2D).

Rationale: The voting panel determined that too few casereports exist with survival outcome reported. It is also unclear

if these patients would have survived without ILE.Additionally, the voting panel mentioned publication biasand the fact that most cases of lamotrigine toxicity do wellwith supportive care. More controlled data are needed toinform clinicians on whether or not ILE interferes with theefficacy of the standard therapies such as benzodiazepinesand sodium bicarbonate to reverse the proconvulsant andsodium channel blocking properties of lamotrigine. Severelamotrigine poisoning can also result in metabolic acidosisand acute kidney injury, which may require dialysis. The con-current use of ILE and other therapies has not been studiedin enough detail to provide comment. Of note, as describedin our adverse effect review article,[5] the use of ILE with anyextracorporeal circuit such as occlusion of the circulation.

Other toxins

This section includes the other toxins and categories oftoxins for which the voting results were similar. Therefore,rather than lengthy individual statements, the results are dis-cussed in aggregate. Once again the readers are referred tothe Appendices and tables for a complete record of thevoting.

� In cardiac arrest due to toxicity of Class 1Vaughan–Williams antidysrhythmics, baclofen, ivermectinand other insecticides, malathion and other pesticides,olanzapine and other antipsychotics, and selective sero-tonin reuptake inhibitors, our recommendation is neutralregarding the use of ILE.

� In life-threatening toxicity due to other insecticides, mala-thion and other pesticides, olanzapine, and other antipsy-chotics, we suggest not using ILE as first-line therapy (2D).

� In life-threatening toxicity due to Class 1Vaughan–Williams antidysrhythmics, baclofen, ivermectin,and selective serotonin reuptake inhibitors, our recom-mendation is neutral regarding the use of ILE.

� In non-life-threatening toxicity due to Class 1Vaughan–Williams antidysrhythmics, baclofen, ivermectin,and other insecticides, malathion and other pesticides,olanzapine and other antipsychotics, and selective sero-tonin reuptake inhibitors, we suggest not using ILE asfirst-line therapy (2D).

Rationale: Even though some of these toxins are lipid-soluble(defined by their log D) due to the paucity of data, the panelprimarily considered possible benefit, possible risks, and theavailability of other alternative treatments in their votes.

Animal data provide conflicting results for the pesticideand insecticide groups. Thus, adverse effects and potentialinterferences were a major consideration influencing the vot-ing. Moreover, these toxins represent a heterogeneous groupof chemicals that are not amenable to a common statementon treatment with ILE. Antipsychotics rarely cause significantcardiovascular mortality and status epilepticus is uncommon.Class 1 antidysrhythmics produce their toxic effect by block-ing sodium channels and no studies have compared bicar-bonate to ILE for these drugs. The controversy surrounding

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efficacy, the adverse effect profile, and the potential interfer-ences with essential laboratory testing question the inclusionof ILE in the care of these poisonings. Clinically relevant stud-ies with clear meaningful endpoints and drug concentrationmeasurements to assess the toxic burden are required beforestronger recommendations can be made for these toxins.Thus, the panel vote resulted in a neutral recommendation,leaving the decision to the clinician to weigh the pros andcons of ILE in these situations.

Lipid regimen

The panel chose to vote on a preferred lipid regimen foreach category of toxins. However, the results were not sig-nificantly different from one toxin to another. In all cases, thevote was neutral with the median ranging from 4 to 6 andthe disagreement index always below 1, reflecting the con-sensus among panel members.

1. ILE formulation:

� When ILE is indicated in non-LAs toxicity, our recommen-dation is neutral regarding the formulation of ILE.

Rationale: Not enough data exist comparing various formula-tions of ILE. Most articles do not report the brand of ILE usedand simply list a concentration of 20%. There is no evidenceto support a recommendation for the best formulation of ILEfor non-LAs, even though the most common formulationused was IntralipidVR 20%. While there is experimental evi-dence suggesting that one lipid formulation might be prefer-able to another, it is unclear if the relationship is true for alltoxins or is applicable to human poisonings.[24]

2. ILE dosing:

� When ILE is indicated in non-LAs toxicity, our recommen-dation is neutral regarding the dosing of ILE.

Rationale: In the only ILE dose-finding study, the greatestbenefit to survival in a rodent model of IV verapamil toxicityoccurred with an ILE dose of 18.6mL/kg.[20] However, thegreatest benefit to HR, MAP occurred at 24.8mL/kg ILE. It isunknown how these doses would translate to human poison-ings. Additional concern was expressed over the IV model ofpoisoning and the risk for lipid-induced increase in gastro-intestinal absorption, as noted above. Nevertheless, the find-ing that increased survival occurred in the group treatedwith a lower dose of ILE suggests that a higher dose,although associated with greater hemodynamic improve-ment, may not be necessary in all cases.

Members expressed opinions that until the adverse effectprofile for acute ILE administration is properly defined, thelowest possible dose should be used. ILE dosing should beguided by clinically significant physiological endpoints, ratherthan arbitrary hemodynamic parameters. Importantly, analyt-ical interferences are likely to be shorter in duration or lesssignificant if a lower blood concentration of ILE is

achieved.[1] The maximum safe dose of ILE is unknown.Moreover, the reported ILE regimens may vary significantlyfrom the commonly recommended regimen of 1.5mL/kgbolus of ILE 20% followed by 0.25–0.5mL/kg/min.[25,26] Fora 70 kg person, this dose translates to more than 1 L of lipidemulsion in the first hour at the lowest rate and more than2 L if the highest infusion rate (0.5mL/kg/min) is adminis-tered. Parenteral nutrition guidelines limit the daily amountof ILE to between 500 and 1200mL per 24-h period or 10mLper kg of a 20% formulation.[27] Several reports cite a singlerodent study assessing the apparent safety and LD50 of ILE innine rats.[28] The LD50 is an imperfect measure of safety.Also, this study only included one ILE dose within the rangecurrently used in the clinical setting. No studies haveassessed varying doses and infusion rates or their combina-tions in humans.

The panel agreed that a maximum dose (per kg bodyweight) should be specified and the rate of infusion keptlow. Termination of the infusion should be considered whenthere is sustained clinical improvement or the maximumdose has been reached. This is speculative and dose-findingstudies are much needed. A recent publication called intoquestion cases where exceedingly large volumes of ILE wereused and created a pharmacokinetic–pharmacodynamicmodel to predict an infusion rate that would only produce“modestly lipemic plasma”. Although, based on their model,these authors recommend a regimen of 1.5mL/kg followedby 0.25mL/kg/min for 3min and then an infusion of0.025mL/kg/min for up 6.5 h,[29] this regimen should be vali-dated for safety and efficacy before it can be routinelyrecommended.

3. ILE cessation:

� When ILE is indicated in non-LAs toxicity, our recommen-dation is neutral regarding which endpoints to use tostop ILE administration (maximum dose or maximumduration).

Rationale: The group reached consensus that there is insuffi-cient information to determine when ILE should be stopped.The literature is heterogeneous in the endpoints to therapyfrom resolution of symptoms to an arbitrary decrease ofserum TCA concentration resulting in duration of therapy ofup to several days.[30] No clinical studies exploring differentendpoints to therapy have been published to date. The work-group suggests that clinical resolution is a desirable endpointif toxicity is unlikely to recur, but if this endpoint takes time,consideration should be made not to exceed the rate ofendogenous triglyceride metabolism as discussed above. Thegroup noted that in many of the reports ILE was startedalong with other therapies and continued for hours or dayseven though the effect of ILE was unclear. The workgroupcould not find evidence to suggest a specific endpoint.However, adverse effects seem to be associated with highervolume and faster infusion rates of ILE.[3] Analytical interfer-ences and inability to measure several biochemical parame-ters and the unknown effect of ILE on other medicationsmay justify lower doses and a shorter duration of infusion.[1]

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Limitations

Despite the fact that our combined search strategies wereexhaustive and not limited by language, it is possible thatsome publications were missed; especially abstracts not yetpublished as full articles. The literature infrequently reportsthe concentration of the toxin, precise timing of interven-tions with regards to clinical improvement or importantinformation on the formulation, or total amount of ILEgiven. Also, in most case reports, multiple therapies wereadministered simultaneously, making the specific efficacy oflipid emulsion difficult to ascertain. Case reports are knownto be subject to publication bias. We also noticed themajority of publications failed to mention the presence orabsence of adverse effects and when events occurred therewas a tendency to attribute them to the toxin rather thanthe therapy. Our clinical appraisal for the non-LA toxins waslimited because most of the controlled studies occurred inanimals and the majority were not performed with modelsbearing any resemblance to clinical poisonings, which usu-ally involve ingestion of the toxin. The greatest limitation ofthese recommendations may be their reliance on publisheddata which is often of poor quality, may have significantpublication delay of up to several years, and cannot capturethe vast numbers of positive and negative outcomes of ILEthat remain unreported. Additionally, it should be notedthat the Delphi method is itself imperfect, with the greatestcriticism being its tendency to force “middle-of-the-road”consensus.[31] We feel we have addressed this concern inthree ways: limiting the number of rounds of voting to two,in order not to artificially force consensus by repeatedregression to the mean, using a disagreement index todemonstrate the true strength of the recommendations,and the inclusion of minority opinions in the commentsand rationale when they were provided by the workgroupmembers. Also, patients’ views and preferences were notdirectly sought in the development of the clinical recom-mendations due to the highly heterogeneous target popula-tion under study. Finally, as the study and clinical use ofILE continues to evolve, we recognize additional informationmay emerge to alter this analysis.

Discussion

Despite some early enthusiasm for the use of ILE in the treat-ment of acute poisoning, the voting panel found an absenceof evidence to recommend its use in most poisonings andclinical scenarios where its use is previously reported. Thusthe preponderance of neutral votes likely represents theworkgroups’ caution to make recommendations for oragainst a therapy where so little moderate- or high-qualityhuman data exist. Furthermore, it is worth reiterating thatthe neutral recommendations result from a balance betweenpro and con assessments (rather than a lack of data whichwould result in no recommendation at all) but rather; basedon disagreement index, represent a strong consensus aroundneutrality.

Moreover, many specific aspects of ILE therapy have notbeen validated in the clinical setting. These include the

optimal dose of ILE for clinical efficacy, the threshold dosefor adverse effects, and the minimum or maximum durationof therapy. It is acknowledged that clinicians may have per-sonal preferences for indication, dose, and duration of ILEtreatment. Given that there is a lack of evidence to supportany particular approach, the workgroup felt that it reason-able to comment that the most common formulationreported was IntralipidVR 20%, and that the most commonregimen was a bolus of 1.5mL/kg of ILE 20% followed byan infusion of 0.25mL/kg/min, in order to provide someguidance in situations were favorable recommendations orsuggestions were made. Additionally, the workgroup recog-nized the lack of data on which to guide the duration oftherapy, and, therefore, some members proposed a max-imum dose of 10% of blood volume based on safety con-cerns but this position was not officially voted upon. This issomewhat in keeping with parenteral nutrition recommen-dations to limit the maximum dosage of ILE between 10and 12.5mL/kg/d of 20% ILE [32] as well reported increasedtriglyceride concentrations in excess of 15mmol/L (glycerol-blanked method) when ILE represented more than 10% oftest tubes volumes,[14] which for a 70 kg individual with ablood volume of 80mL/kg would yield 8.0mL/kg.Indications in which it is easier to measure the risk andbenefit of ILE therapy, such as cardiac arrest or systemictoxicity with no other treatment alternatives, may warrant a“trial” of ILE therapy. Conversely, ILE should not be consid-ered in clinical scenarios where the risk of death or organdamage is small, or when there are other accepted treat-ments, which have not been used first. Concern wasexpressed as to the lack of data regarding the impact ofILE on the effectiveness of other resuscitative medicationsor antidotes, or the ability of ILE to interfere with the bio-chemical and drug assay testing. In addition, outcome datafrom animal models may not be directly translatable toclinical practice. Notably, the majority of animal studies ofILE efficacy administered toxins intravenously, whereas themajority of clinical poisonings (except for local anesthetics)are the result of oral exposure.

Future research questions

The voting panel is hopeful that randomized controlled tri-als will be undertaken to enable a more informed evalu-ation of the role of ILE in select poisonings. Efforts inanimals should be directed at designing controlled studiesevaluating the timing of administration, using orogastricadministration of the toxin. In particular, studyingthe dose–response relationship for the loading–dose andthe infusion is important, while clearly reporting on thepresence or absence of adverse effects. Ideally, these stud-ies would also focus on determining the optimal endpointfor ILE therapy. In vitro studies may be sufficient toevaluate the potential interferences of ILE on assays ofcommon co-ingestants or binding affinity with other medi-cations. Moreover, the efficacy of commercially availablelipid emulsions should be compared in order to determine

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the relative effectiveness of the commercially availableproducts.

Conclusion

ILE is a recent therapy for which there is an incompleteunderstanding of its efficacy, mechanisms of action, safety,and associated analytical interferences. Clinical recommenda-tions regarding the use of ILE in poisoning were only pos-sible in a small number of scenarios based on a very lowquality of evidence, balance of risks and benefits, andresource use. The workgroup emphasizes that human dose-finding and randomized controlled studies are required toadvance knowledge of limitations, indications, adverseeffects, effectiveness, and best regimen for ILE treatment.

External review

The American Academy of Clinical Toxicology, the AmericanCollege of Medical Toxicology, the American Association ofPoison Control Centers, the Asia Pacific Association ofMedical Toxicology, the European Association of PoisonCentres and Clinical Toxicologists, and the CanadianAssociation of Poison Control Centers endorsed these recom-mendations prior to publication.

Applicability

The recommendations will be circulated to the membershipof each association, published in a participating association’ssponsored-journal and presented at internationalconferences.

Planned update

These recommendations are to be updated in 5 years unlessnew data warrants an earlier review.

Acknowledgements

The workgroup gratefully acknowledge the work of the AACT staff forthe arrangement of meetings and conference calls and MarielleCarpenter for copy editing.

Disclosure statement

All members completed a conflict of interest form for the AACT andreceived no honoraria. Webcast conference and rooms for meeting wereprovided by the AACT. No member with a financial or academic conflictof interest preventing an objective assessment of the literature partici-pated in the reviews or the elaboration of the recommendations (i.e. nocommittee member’s livelihood or academic career is depending on agrant studying lipid emulsion in poisoning).

Funding

Dr. Turgeon is a recipient of a New Investigator Award from theCanadian Institutes of Health Research (CIHR). Dr. Lavergne is a recipientof a salary support award from the Fonds de la Recherche du Qu�ebec –Sant�e (FRQS).

ORCiD

Sophie Gosselin http://orcid.org/0000-0002-0694-5588Robert. S. Hoffman http://orcid.org/0000-0002-0091-9573Martin Morris http://orcid.org/0000-0002-5659-2995Andrea Nesbitt-Miller http://orcid.org/0000-0002-0054-7132Benoit Bailey http://orcid.org/0000-0003-2520-1258

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[30] Agarwala R, Ahmed SZ, Wiegand TJ. Prolonged use of intravenouslipid emulsion in a severe tricyclic antidepressant overdose.J Med Toxicol: Off J Am Coll Med Toxicol. 2014;10:210–214.

[31] Yousuf MI. Using experts’ opinions through Delphi technique.Pract Assess Res Eval. 2007;12:1–8.

[32] Mirtallo JM, Dasta JF, Kleinschmidt KC, et al. State of the art review:intravenous fat emulsions: current applications, safety profile, andclinical implications. Ann Pharmacother. 2010;44:688–700.

[33] Udelsmann A, Melo S. Hemodynamic changes with two lipidemulsions for treatment of bupivacaine toxicity in swines. ActaCirurgica Brasileira/Sociedade Brasileira Para DesenvolvimentoPesquisa Em Cirurgia. 2015;30:87–93.

[34] Zaballos M, Sevilla R, Gonzalez J, et al. Analysis of the temporalregression of the QRS widening induced by bupivacaine afterIntralipid administration. Study in an experimental porcine model.Revista Espanola Anestesiol Y Reanimacion. 2016;63:13–21.

[35] Bourque S, Panahi S, Mittal R, et al. Intralipid reverses propofolmediated hypotension in rats. FASEB J Conference: Exp Biol.2015;29. 1 (Meeting Abstracts).

[36] Ceccherini G, Perondi F, Lippi I, et al. Intravenous lipid emulsionand dexmedetomidine for treatment of feline permethrin intoxi-cation: a report from 4 cases. Open Vet J. 2015;5:113–121.

[37] Herring JM, McMichael MA, Corsi R, et al. Intravenous lipid emul-sion therapy in three cases of canine naproxen overdose. J VetEmerg Crit Care (San Antonio). 2015;25:672–678.

[38] Jourdan G, Boyer G, Raymond-Letron I, et al. Intravenous lipidemulsion therapy in 20 cats accidentally overdosed with ivermec-tin. J Vet Emerg Crit Care (San Antonio). 2015;25:667–671.

[39] Peacock RE, Hosgood G, Swindells KL, et al. A randomized, con-trolled clinical trial of intravenous lipid emulsion as an adjunctivetreatment for permethrin toxicosis in cats. J Vet Emerg Crit Care(San Antonio). 2015;25:597–605.

[40] Saqib M, Abbas G, Mughal MN. Successful management of iver-mectin-induced blindness in an African lion (Panthera leo) byintravenous administration of a lipid emulsion. BMC Vet Res.2015;11:287.

[41] Seitz MA, Burkitt-Creedon JM. Persistent gross lipemia and sus-pected corneal lipidosis following intravenous lipid therapy in acat with permethrin toxicosis. J Vet Emerg Crit Care (SanAntonio). 2016.

[42] Varney SM, Bebarta VS, Boudreau SM, et al. Intravenous lipidemulsion therapy for severe diphenhydramine toxicity: a random-ized, controlled pilot study in a swine model. Ann Emerg Med.2016;67:196–205 e3.

[43] Williams K, Wells RJ, McLean MK. Suspected synthetic cannabin-oid toxicosis in a dog. J Vet Emerg Crit Care (San Antonio).2015;25:739–744.

[44] Glavas J, Flam D, Istvanic T, et al. Abstracts and Highlight Papersof the 34th Annual European Society of Regional Anaesthesia &Pain Therapy (ESRA) Congress 2015. Reg Anesth Pain Med.2015;40:e1–e72. [WorldCat]

[45] Goucher HC, Asher Y. The best-laid plans: a case report of an epi-dural anesthetic gone awry in a medically challenging patient.Anesth Analg. 2015;1:S471.

[46] Kamel I, Trehan G, Barnette R. Intralipid therapy for inadvertentperipheral nervous system blockade resulting from local anes-thetic overdose. Case Rep Anesthesiol. 2015;2015:486543.

[47] Musielak M, McCall J. Lipid rescue in a pediatric burn patient.J Burn Care Res: Off Publ Am Burn Assoc. 2015.

[48] Procopio G, Gupta A, Hernandez M, et al. Lipid emulsion for inad-vertent intrathecal administration of local anesthetics in the ED.Crit Care Med. 2015;1:309.

[49] Riff C, Guilhaumou R, Dupouey J, et al. Amino-amides anestheticssystemic toxicity: about nine cases. Fundam Clin Pharmacol.2015;29:48.

[50] Shih RD, Calello D. Complete spinal paralysis following a brachialplexus block treated with lipid infusion. Clin Toxicol.2015;53:310–311.

[51] Stella FA, Panzavolta FG, Sesana F, et al. Intravenous lipid emul-sion for treatment of local anesthetic systemic toxicity. ClinToxicol. 2015;53:313.

[52] Agulnik A, Kelly D, Bruccoleri R, et al. Severe carbamazepine over-dose treated with lipid emulsion therapy, hemodialysis, andplasmapheresis. Crit Care Med. 2015;43:154.

[53] Aksel G, Guneysel O, Tasyurek T, et al. Intravenous lipid emulsiontherapy for acute synthetic cannabinoid intoxication: clinicalexperience in four cases. Case Rep Emerg Med. 2015;2015:180921.

[54] Barton CA, Johnson NB, Mah ND, et al. Successful treatment of amassive metoprolol overdose using intravenous lipid emulsionand hyperinsulinemia/euglycemia therapy. Pharmacotherapy.2015;35:e56–e60.

[55] Baruah U, Sahni A, Sachdeva HC. Successful management of alu-minium phosphide poisoning using intravenous lipid emulsion:report of two cases. Indian J. 2015;19:735–738.

[56] Bayram B, Kose I, Avci S, et al. Successful treatment of propafe-none intoxication with intravenous lipid emulsion.Pharmacotherapy. 2015;35:e149–e152.

[57] Besserer F, Chuang R, Mink M, et al. Tilmicosin toxicity success-fully treated with calcium, insulin, and lipid emulsion. ClinToxicol. 2015;53:711–712.

[58] Brumfield E, Bernard KR, Kabrhel C. Life-threatening flecainideoverdose treated with intralipid and extracorporeal membraneoxygenation. Am J Emerg Med. 2015;33:1840 e3–5.

[59] Christianson D, Vazquez-Grande G, Strumpher J, et al. Veno-arter-ial extracorporeal membrane oxygenation to treat cardiovascularcollapse following a massive diltiazem overdose. AmericanJournal of Respiratory and Critical Care Medicine Conference:American Thoracic Society International Conference, ATS; 2015.P. 191 (no pagination).

[60] Czerwonka E, Heim M. Lipid rescue therapy and hyperinsuline-mia/euglycemia for atenolol and zolpidem overdose. Crit CareMed. 2015;43:316.

[61] Doepker B, Healy W, Cortez E, et al. High-dose insulin and intra-venous lipid emulsion therapy for cardiogenic shock induced byintentional calcium-channel blocker and Beta-blocker overdose:a case series. J Emerg Med. 2014;46:486–490.

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[63] Hatten BW. QRS widening associated with quetiapine toxicity.Clin Toxicol. 2015;53:698–699.

[64] Johnson-Arbor K, Salinger L, Luczycki S. Prolonged laboratoryinterference after administration of intravenous lipid emulsiontherapy. J Med Toxicol: Off J Am Coll Med Toxicol. 2015;11:223–226.

[65] Jovic-Stosic J, Putic V, Zivanovic D, et al. Failure of intravenouslipid emulsion in treatment of cardiotoxicity caused by mixedoverdose including dihydropyridine calcium channel blockers.Vojnosanit Pregl. 2016;73:88–91.

[66] Khan A, Raman J, Lateef O. ECMO for shock due to drug over-dose: timely transfer to ECMO capable center can save lives.Chest. 2015;148:197A.

[67] Laes JR, Williams DM, Cole JB. Improvement in hemodynamicsafter methylene blue administration in drug-induced vasodilatoryshock: a case report. J Med Toxicol: Off J Am Coll Med Toxicol.2015;11:460–463.

[68] Li K, Gugelmann H, Tabas JA. Young woman with seizures. AnnEmerg Med. 2015;66:363–367.

[69] Lookabill SK, Carpenter C, Ford MD. Accidental pediatric flecainideoverdose treated with intravenous lipid emulsion and sodiumbicarbonate. Clin Toxicol. 2015;53:701–702.

[70] Markota A, Hajdinjak E, Rupnik B, et al. Treatment of near-fatalbeta blocker and calcium channel blocker intoxication withhyperinsulinemic euglycemia, intravenous lipid emulsions andhigh doses of norepinephrine. Signa Vitae. 2015;10:144–150.

[71] Matsumoto H, Ohnishi M, Takegawa R, et al. Effect of lipid emul-sion during resuscitation of a patient with cardiac arrest afteroverdose of chlorpromazine and mirtazapine. Am J Emerg Med.2015;33:1541 e1–2.

[72] McBeth PB, Missirlis PI, Brar H, et al. Novel therapies for myocar-dial irritability following extreme hydroxychloroquine toxicity.Case Rep Emerg Med. 2015;2015:692948.

[73] Montague AJ, Topeff JM, Katzung KG, et al. High dose insulin totreat propranolol toxicity in a 7-month-old infant. Clin Toxicol.2015;53:740.

[74] Mukhtar O, Archer JR, Dargan PI, et al. Lesson of the month 1:acute flecainide overdose and the potential utility of lipidemulsion therapy. Clin Med (London, England). 2015;15:301–303.

[75] Ovakim DH, Gill GK, Kaila KS, et al. Near cardiovascular collapsefollowing intentional European Yew (Taxus baccata) ingestion.Clin Toxicol. 2015;53:747–748.

[76] Ozcete E, Uz I, Kiyan S. Cardiac arrest due to a lethal dose ofpropafenone and first case to survive following treatment withintravenous fat emulsion. Nobel Med. 2015;11:89–92.

[77] Radley D, Droog S, Barragry J, et al. Survival following massiveamitriptyline overdose: the use of intravenous lipid emulsion ther-apy and the occurrence of acute respiratory distress. J IntensiveCare Soc. 2015;16:181–182.

[78] Reynolds JC, Judge BS. Successful treatment of flecainide-inducedcardiac arrest with extracorporeal membrane oxygenation in theED. Am J Emerg Med. 2015;33:1542 e1–1542.

[79] Sampson CS, Bedy SM. Lipid emulsion therapy given intraos-seously in massive verapamil overdose. Am J Emerg Med.2015;33:1844 e1.

[80] Schult R, Gorodetsky RM, Wiegand TJ. Intravenous lipid emulsionfor amlodipine/benazepril toxicity: a case report. Clin Toxicol.2015;53:251–252.

[81] Sebe A, Disel NR, Acikalin Akpinar A, et al. Role of intravenouslipid emulsions in the management of calcium channel blockerand beta-blocker overdose: 3 years experience of a universityhospital. Postgrad Med. 2015;127:119–124.

[82] Su J. Early venoarterial extracorporeal membrane oxygenation forrefractory shock secondary to amlodipine overdose. J Am CollCardiol. 2015;65:A627.

[83] Szadkowski M, Caravati EM, Gamboa D, et al. Treatment of flecai-nide toxicity in a 12-monthold child using intravenous lipid emul-sion. Clin Toxicol. 2015;53:724.

[84] Tse CW, Chan YC, Lau FL. Intravenous lipid emulsion as antidote:experience in Hong Kong. Hong Kong J Emerg Med. 2015;22:100–107.

[85] Tse J, Ferguson K, Whitlow KS, et al. The use of intravenous lipidemulsion therapy in acute methamphetamine toxicity. Am JEmerg Med. 2016;34:1732.e3–4.

[86] Vodnala D, Rosman H, Shakir A. A wide complex rhythm, does ittell the whole story? J Am Coll Cardiol. 2015;65:A750.

[87] Watt P, Malik D, Dyson L. Gift of the glob – is it foolproof?Anaesthesia. 2009;64:1031–1033.

[88] Yesilbas O, Kihtir HS, Altiti M, et al. Acute severe organophos-phate poisoning in a child who was successfully treated withtherapeutic plasma exchange, high-volume hemodiafiltration, andlipid infusion. J Clin Apher. 2015. Epub 2015 Aug 14.

Appendix 1: Voting statements

General statement

Lipid emulsion is indicated in the treatment of XYZ toxicity.

Specific indications

Lipid emulsion is indicated in the treatment of XYZ toxicity:

a. In the presence of cardiac arrest, after Standard ACLS (CPR, airways)has been started

b. In the presence of LIFE-THREATENING toxicity� Lipid emulsion should be administered as first line therapy� Lipid emulsion be administered as part of treatment modalities� Lipid emulsion should be administered if other therapies fail

(last resort)c. In the presence of NON LIFE-THREATENING toxicity

� Lipid emulsion should be administered as first line therapy� Lipid emulsion be administered as part of treatment modalities� Lipid emulsion should be administered if other therapies fail

(last resort)

Types of ILE

The type of ILE to be used is…

� IntralipidVR 10%� IntralipidVR 20%� IntralipidVR 30%� ClinOleicVR 20%� LipofundinVR 20%� Other

If using a bolus of ILE the dose of the bolus indicated is…

� 0.25mL/kg� 0.50mL/kg� 0.75mL/kg� 1.0mL/kg� 1.25mL/kg� 1.5mL/kg� 1.75mL/kg� 2.0mL/kg� Other

CLINICAL TOXICOLOGY 911

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If using an infusion of ILE the dose of the infusion indicated is…

� 0.25mL/kg/min� 0.5mL/kg/min� 0.75mL/kg/min� 1.0mL/kg/min� Other

Cessation of ILE

The decision to terminate the ILE treatment is indicated based on:

� Total (maximum) duration of the infusion regardless of dose or clin-ical improvement status

� Total (maximum) dose administered regardless of duration of infusionor clinical improvement status

� Clinical improvement regardless of dose or duration administered� Other

In considering the total duration of the infusion as a criterion, lipid emul-sion cessation is indicated, regardless of other factors such as clinicalimprovement or dose after…

� 10–20min� 21–30min� 31–40min� 41–50min� 51–60min� Other

In considering the maximum dose of lipid emulsion administered as acriterion, lipid emulsion cessation is indicated, regardless of clinicalimprovement or duration after…

� 8mL/kg or less� 8.1–10.0mL/kg� 10.1–12.0mL/kg� 12.1–14.0mL/kg� 14.1–16.0mL/kg� 16.1–18.0mL/kg� 18.1–20.0mL/kg� Other

In considering the clinical improvement as a criterion, lipid emulsion ces-sation is indicated, regardless of dose or duration after…

� As soon as symptoms resolution occurred� After resolution of symptoms for 15–30min� After resolution of symptoms for 31–45min� After resolution of symptoms for 46–60min� Other

Appendix 2

Literature update

Search results for the year 2015 update: 1026 citations were reviewed toidentify studies reporting the use of ILE in poisoning (Figure 2). Of those,942 were excluded after reviewing abstracts since the ILE administrationwas not related to poisoning. Of the 84 remaining articles, 28 were fur-ther excluded after reviewing complete manuscripts: one was excludedbecause ILE was not used for the treatment of poisoning, two were pre-treatment studies, one was an animal experiment that was not generaliz-able to humans, 18 were review articles without original data, two onlyreported survey information, and four did not present sufficient data forevaluation. A total of 56 studies were included in the update, from

which eleven were animal reports, two regarding LA and nine non-LApoisonings.[33–43]. Forty-five human reports, eight regarding LA and 37non-LA were included.[44–88] A summary of the new included articles ispresented in Appendices 3 and 4.

Local anaesthetics

No new clinical trials were found in humans. Seven case reports and onecase series reported a total of twelve cases.[44–51] The LAs reportedwere lidocaine (n¼ 2), levobupivacaine (n¼ 1), bupivacaine (n¼ 3), ropi-vacaine (n¼ 3), combination of bupivacaine and ropivacaine (n¼ 1), andropivacaine and lidocaine (n¼ 2). Patients experienced LA toxicity fromdifferent routes of exposure: nerve block (n¼ 7), intravenous (n¼ 4), epi-dural (n¼ 1), subcutaneous (n¼ 1), and intrathecal (n¼ 1) use. Tworeports included two routes of LA exposure, intravenous plus epiduraland intravenous plus subcutaneous. The toxic effects from LAs includeda variety of cardiovascular and central nervous system symptoms includ-ing hypotension, cardiac arrest, agitation and coma. The concentrationof ILE used was reported as 20% (n¼ 5) or not reported (n¼ 7). Dosingregimens and other treatments received were often not reported. Ineight cases, authors noted that the symptoms resolved following ILEdosing. Details are provided in Appendix 3.

Two controlled animal experiments in swine assessed the response ofbupivacaine toxicity to ILE. In one trial, 12 swine were administered4–6mg/kg of bupivacaine until the QRS complex duration was 150% ofbaseline value. Six swine were then given ILE 1.5mL/kg followed by0.25mL/kg/min and six were given the same volume of 0.9% saline ascontrols. All animals survived. QRS duration decreased from 184± 62%ms to 132± 65% ms in the ILE-treated group, while there was no changein QRS duration (230± 56% ms) in the control animals (p¼ 0.03).[34] Theother trial included 30 swine, 10 serving as control, 10 receiving ILE aslong-chain triglycerides (LCT) and 10 receiving ILE as 50% LCT and 50%medium-chain triglycerides (MCT). All animals were administered 5mg/kg of bupivacaine followed by the study drug while monitoring hemo-dynamic parameters. A dose of 4mL/kg of either ILE preparation orsaline was administered to each group one minute after bupivacainedosing. Both ILE groups had a similar improvement in the majority ofthe hemodynamic parameters compared to control.[33] Details arereported in Appendix 4.

There were no new LA case reports described in animals.

Non-local anesthetics

No new clinical trials in humans were identified. Thirty-seven casereports or case series with miscellaneous toxins were found.[52–88] Thesummary of human case reports is presented in Appendix 3.

Three animal experiments studied ILE for non-LA toxicity.[35,39,42] Inone trial, 20 cats with 14 additional controls were exposed dermally topermethrin. ILE was administered to the treatment group at 15mL/kg asa continuous intravenous infusion over 60minutes. A grading system forneurologic effects detected a decrease in the duration and severity ofpoisoning in the treatment group reported as a decrease in the durationand severity of poisoning in the treatment group.[39] Another random-ized experiment in swine sought to determine a difference in meanarterial blood pressure (MAP), QRS duration and survival after diphen-hydramine poisoning. Twenty-four animals were equally divided into twogroups. One group received ILE (7mL/kg) and the other sodium bicar-bonate. Diphenhydramine was administered intravenously until MAP fellby 50%. No differences were found between groups in the measuredparameters.[42] In the third study, rats received intravenous propofol10mg/kg to achieve a 55%±2% drop in MAP. The rats were not rando-mised but the study included a control group receiving saline. Theauthors reported that propofol-mediated hypotension was completelyreversed by ILE, and the effects on the anaesthetic potency of the drugwere minimal.[35] Of note, propofol was not chosen as a toxin to beevaluated for clinical recommendations by the workgroup because ofthe lack of human data. A summary of the animal case reports is avail-able in Appendix 4.

912 S. GOSSELIN ET AL.

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Search dates: December 16, 2014-December 30, 2015

Records iden�fied through database searching

(n = 3205)

Addi�onal records iden�fied through other sources

(n = 10)

Records a�er duplicates removed (n = 1026)

Ar�cles excluded (n = 28) REASONS ILE not used in poisoning (n = 1) Pre-treatment models (n = 2) Review/opinion ar�cle (no new data) (n = 18) Animal trials could not be extrapolated to humans (n = 1) Survey only (n = 2) Not enough data (n = 4)

Ar�cles included in qualita�ve synthesis for local and non-local anesthe�cs

(n = 56)

11 animal studies 45 human studies

5 RCSs

Full text assessed for eligibility (n = 84)

0 RCTs

6 case reports or case series

45 case reports or series

Records screened (n = 1026)

Records excluded (n = 942)

Figure 2. Selection of articles flow diagram for 2015 update. RCS: randomized controlled studies; RCT: randomized controlled trials; ILE: intravenous lipid emulsion.

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App

endix3.

Summaryof

the72

patientsinclud

edin

the2015

update

ontheefficacyof

ILEin

poison

ing.

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(total

dose)a

Other

treatm

ents

received

ILEeffect

Outcome

Locala

nesthetics

Glavaset

al.[44]

Case

repo

rt64

y/F

Levobu

pivacaine10

mg

Epidural/In

travenou

s(amoxicillin)

2.68

Hypotension

Coma

20%

200mL

NR

(total:2

00mL)

IVfluids,

Pressors,

Anesthetics,

Atropine

Yes

Survival

Gou

cher

&Asherb

[45]

Case

repo

rt60

y/F

Lido

caine18

mL2%

Intravenou

s1.26

PVC

Coma

NR

150mL

NR

(total:1

50mL)

Epinephrine

Yes;

Nohemod

ynam

iccom-

prom

isethroug

hout

Survival

Kamel

etal.[46]

Case

repo

rt51

y/F

Bupivacaine80

mL5%

Nerve

block

2.68

Dizziness

Agitatio

nPosturing

Loss

ofleftlower

extrem

-ity

sensation

20%

100mL

400mLin

20min

(total:5

00mL)

Epinephrine,

Anesthetics

Unclear

ifdrug

effect

hadjust

wornoff;

Neurologicsymptom

simproved

after

administration

Survival

Musielak&McCall[47]

Case

repo

rt6y/M

Bupivacaine3mg/kg

Subcutaneous/

Intravenou

s

2.68

Hypotension

Bradycardia,asystole

Cardiacarrest

Apnea

Coma

NR

1.5mg/kg

f0.25

mg/kg/m

inforf6h

(total:9

1.5mg/kg)f

Epinephrine,

Pressors,(no

repineph

-rin

e,epinephrine,vaso-

pressin,

phenylephrine)

Unclear

Survival

Procop

ioet

al.[48]

Case

repo

rt43

y/M

Bupivacaine10

mL

Ropivacaine30

mL

Intrathecal

2.68

4.21

Hypotension

Bradycardia

Apnea

Coma

20%

1.5mL/kg

125mLin

2h

(total:N

R)Pressors

Improved

30min

after

ILE

Survival

Riffet

al.d[49]

Case

series,No1

AgeNR/sexNR

Ropivacaine220mg

Nerve

block

[4.20mcg/m

L]

4.21

Seizures

Coma

NR

NR

NR

NR

Authorsstate“quick

symptom

sresolving”

NR

Case

series,No3

AgeNR/F,pregnant

Ropivacaine150mg

Nerve

block

[4.80mcg/m

L]

4.21

Obtun

datio

nNR

NR

NR

NR

Authorsstate“quick

symptom

sresolving”

NR

Case

series,No4

AgeNR/F,pregnant

Ropivacaine100mg

Nerve

block

[0.66mcg/m

L]

4.21

Obtun

datio

nNR

NR

NR

NR

Authorsstate“quick

symptom

sresolving”

NR

Case

series,No7

AgeNR/F,pregnant

Ropivacaine40

mg

[0.51mcg/m

L]Lido

caine200mg

[1.01mcg/m

L]Nerve

block

4.21

1.26

Seizure

Mydriasis

NR

NR

NR

NR

Authorsstate“quick

symptom

sresolving”

NR

Case

series,No8

AgeNR/sexNR

Ropivacaine40

mg

[0.29mcg/m

L]Lido

caine200mg

[0.58mcg/m

L]Nerve

block

4.21

1.26

Hypotension

Bradycardia

Metallic

taste

NR

NR

NR

NR

Authorsstate“quick

symptom

sresolving”

NR

Shih

&Calello

b[50]

Case

repo

rt56

y/F,

weigh

tNR

Bupivacaine30

mL

0.25%

Nerve

block

2.68

Hypotension

Apnea

Coma

Lactate4mmol/L

20%

85mL

NR

(total:8

5mL)

IVfluids,

Pressors,

Anesthetics

Motor

andsensoryfunc-

tionimproved

over

4h

Survival

Stella

etal.b[51]

Case

repo

rt<1week/NR

Lido

caine6mg/kg,then

6mg/kg/h

for18

h,then

4mg/kg/h

for12

hIntravenou

s

1.26

Bradycardia,wideQRS

20%

2mL/kg

NR

NR

WideQRS

andbradycar-

diaresolved

Survival

Non-locala

naesthetics

Agulnik[52]

Case

repo

rt15

y/F

Carbam

azepine56

gOraling

estio

n[138

mcg/m

L]

2.67

Status

epilepticus

Coma(in

ducedwith

barbitu

rates,technically

notfrom

ingestion)

Lactaterepo

rted

ashigh

NR

NR

NR

Plasmapheresis,HDI,

CVVH

DUnclear

Survival

(continued)

914 S. GOSSELIN ET AL.

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App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(totaldo

se)a

Other

treatm

ents

received

ILEeffect

Outcome

Aksele

tal.[53]

Case

series,No1

35y/M

Synthetic

cann

abinoid

receptor

agon

ists,

dose

androuteNR

(heroin)

NA

wideQRS

150ms,left

bund

lebranch

block,

sinu

stachycardia100

beats/min

Coma

pH6.9)

20%

1.5mL/kg

0.25

mL/kg/h

for1h

(total:1

155mL)

IVfluids

QRS

narrow

edwith

in5min

afterILEbo

lus

improved

inan

unknow

ntim

eframe

Died

Case

series,No2

19y/M

Synthetic

cann

abinoid

receptor

agon

ists,d

oseNR

Smoking

NA

Hypotension

70/30mmHg

Sinu

sbradycardia42

beats/min

20%

1.5mL/kg

0.25

mL/kg/h

for1h

(total:9

90mL)

IVfluids

Hem

odynam

ics

improved

Survived

Case

series,No3

15y/M

Synthetic

cann

abinoid

receptor

agon

ists,d

oseNR

Smoking

NA

Hypotension

80/40mmHg

Sinu

sbradycardia36

beats/min

Coma

20%

1.25

mL/kg

0.50

mL/kg/h

for1h

(total:2

100mL)

IVfluids

Hem

odynam

icsand

comascoreimproved

Survived

Case

series,No4

17y/M

Synthetic

cann

abinoid

receptor

agon

ists,

dose

androuteNR

NA

Acceleratedjunctio

nal

rhythm

,bigem

iny

20%

1.5mL/kg

0.25

mL/kg/h

for1h

(total:9

90mL)

IVfluids

Hem

odynam

ics

improved

Survived

Barton

etal.[54]

Case

repo

rt59

y/M

Metop

rolol7

.5g

Oraling

estio

n[120

ng/m

L](m

ethamph

etam

ine,

ketamine,caffe

ine)

�0.34

Hypotension

74/43mmHg

Bradycardia50

beats/min,

atrialfibrillatio

nCardiacarrest

Apnea

20%

1.5mL/kg

(1st

dose),

150mL(2nd

dose)

No

(total:N

R)IV

fluids,

Pressors,

HIET,atropine,g

lucago

n

ILEwas

givenat

the

sametim

eas

ACLS

and

HIET.RO

SCandop

ened

eyes

Survival

Baruah

etal.[55]

Case

series,No1

40y/F

Alum

inum

phosph

ide3g

Oraling

estio

nNA

Hypotension

80/60mmHg

Sinu

stachycardia100

beats/min

Respiratory

rate

30/m

inpH

7.33

20%

No

10mL/h

(total:N

R)Gastriclavage,

Magnesium

sulphate

Hem

odynam

icsimproved

over

time

Survival

Case

series,No2

30y/M

Alum

inum

phosph

ide3g

Oraling

estio

nNA

Hypotension

85/55mmHg

Sinu

stachycardia132

beats/min

Respiratory

rate

34/m

inpH

7.081

20%

No

10mL/h

(total:N

R)Gastriclavage,

Magnesium

sulphate

Hem

odynam

icsimproved

over

time

Survival

Bayram

etal.[56]

Case

repo

rt21

y/F

Prop

afenon

e1500

mg

Oraling

estio

n(acetaminop

hen,

acetyl

salicylicacid

2.39

Hypotension

Bradycardia,wideQRS

>200ms

Cardiacarrest

Sing

leseizure

Metabolicacidosis(details

NR)

20%

1.5mL/kg

0.25

mL/kg/h

for30

min

(total:N

R)Sodium

bicarbon

ate,

IVfluids,

Pressors

Aftercardiacarrest

ILE

narrow

edQRS

widening

andimproved

hemod

ynam

ics

Survival

Besserer

etal.b[57]

Case

repo

rt36

y/M

Tilmicosin

phosph

ate,

dose

NR

Accidental

selfinjection

1.52

Hypotension

20%

100mL

500mlin30

min

(total:6

00mL)

IVfluids,

Pressors,

HDI

Unclear

Survival

Brum

field

etal.[58]

Case

repo

rt33

y/F

Flecainide,d

oseNR

Oraling

estio

n0.55

Cardiacarrest

Alteredmental

status

20%

100mL

(1.5mL/kg)

900mL/h

(12mL/kg/h)

(total:N

R)

Sodium

bicarbon

ate,

IVfluids

ILEwas

givenafterRO

SCandthen

thepatient

requ

iredanotherVT

arrest

andECMO

Survival

Christianson

etal.b[59]

Case

repo

rt64

y/M

Diltiazem

19.4gsus-

tained

release

Oraling

estio

n

2.64

Hypotension

Dysrhythm

ias

Cardiacarrest

Apnea

Sing

leseizure

Coma

NR

NR

NR

IVfluids,

Pressors,

Anesthetics,

HDI,calcium,g

lucago

n,ECMO

NSR

with

hypo

tension,

asystole

at12

hpo

st-

ingestion,

then

ROSC

with

hypo

tension,

then

ultim

aterecovery.

Unkno

wnILEtim

ing

Survival

shockliver

andstill

intubatedon

day11

(continued)

CLINICAL TOXICOLOGY 915

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(total

dose)a

Other

treatm

ents

received

ILEeffect

Outcome

Czerwon

ka&Heim

b[60]

Case

repo

rt33

y/F

Atenolol,d

oseNR

Oraling

estio

n(zolpidem,acetamino-

phen,ethanol)

�2.03

Hypotension

Coma

NR

NR

NR

IVfluids,

Pressors,

Anesthetics

HDI,bloodprod

ucts,

activated

charcoal,ace-

tylcysteine,calcium

Unclear

Survival

Doepker

etal.e[61]

Case

series,No1

35y/M

Metop

rolol1

180mg

Amlodipine

150mg

Verapamil10.26gER

Oraling

estio

n(in

sulin)

�0.34

2.00

2.91

Non

-measurableblood

pressure

Bradycardicarrest

<20

beats/min

Coma

20%

1.5ml/kg

(130

mL)

0.25

mL/kg/m

infor1h

(total:N

R)IV

fluids,

Pressors,

HDI,atropine,calcium

,glucagon

Authorsno

teabenefit

ofILEtherapyforthe

amlodipine

overdo

se

Survival

Case

series,No2

59y/M

Metform

in30

gAm

lodipine

300mg

Lisino

pril300mg

Simvastatin,d

oseNR

Oraling

estio

n

�5.44

2.00

�1.80

4.60

Hypotension

78/36mmHg

Bradycardia54

beats/min

Lactate6.6mmol/L,

aniongap17

20%

1.5mL/kg

(105

mL)

0.25

mL/kg/m

infor1h

(total:N

R)IV

fluids,

Activated

charcoal,d

ex-

trose,calcium,g

lucago

n,HDI

Authorsno

teabenefit

ofILEtherapyforthe

amlodipine

overdo

se

Survival

Gerardet

al.[62]

Case

repo

rt58

y/F

Amlodipine

480mg

Valsartan3680

mg

Oraling

estio

n

2.00

�0.34

Hypotension

78/57mmHg

Tachycardia103beats/min,

QT555ms

Lactate18

mmol/L

pH7.23

20%

No

8mL/kg

for10

min

(total:8

0mL/kg)

IVfluids,

Pressors,

Calcium,H

IET,methylene

blue,M

ARS

Improvem

entwas

not

seen

with

ILE,respon

ded

totheuseof

MAR

S

Survival

Hatten[63]

Case

repo

rt32

y/F

Quetiapine,d

oseNR

Oraling

estio

n[5929ng

/mL]

(heroin;

positive,

unknow

nmatricxfor

morph

ine,oxycod

one)

1.82

Hypotension

Tachycardia,wideQRS

>160ms(previou

s92

ms)

Cardiacarrest

Apnea

Coma

Lactate25

mmol/L

pH7.27

NR

NR

NR

Sodium

bicarbon

ate,

IVfluids,

Pressors,

Anesthetics,

Naloxon

e

Hem

odynam

icsdidno

tchange

inrelatio

nto

ILE,

QRS

narrow

edwith

bicarbon

ate

Died;

Nocomplications

repo

rted

toILE

John

son-Arbo

ret

al.e

[64]

Case

repo

rt43

y/F

Prop

rano

lol1

2g

[3.5mg/Lafter23

h]Tram

adol

1.5g

Zolpidem

200mg

Alprazolam

15mg

Acetam

inop

hen,

dose

NR

Oraling

estio

ns

0.99

0.40

2.35

2.50

0.40

Hypotension

64/47mmHg

Cardiogenic

shock,ejectio

nfractio

n20%

Apnea

Coma

20%

1.5mL/kg

x30.25

mL/kg/m

in(total:N

R)IV

fluids,

Pressors,

Anesthetics,

Insulin,G

lucago

n

No

Died,

Labo

ratory

evalu-

ationimpo

ssible

dueto

lipem

ia

Jovic-Stosicet

al.[65]

Case

series,No1

24y/F

Amlodipine

150mg

[0.05mg/L]

Metform

in10

g[6.32mg/L]

Gliclizide2.4g

[3.95mg/L]

Oraling

estio

n

2.00

�5.44

0.16

Hypotension

Dysrhythm

ias

Cardiacarrest

Lactate

4.9mmol/L,p

H7.27

20%

100mL

900mL

(total:1

000mL)

IVfluids,

Pressors,

Anesthetics,Glucago

n

Transientbloodpressure

improvem

entthen

none

further

Died

Case

series,No2

41y/M

Nifedipine,d

oseNR

[0.62mg/L]

Metop

rolol,do

seNR

[0.57mg/L]

Diazepam,d

oseNR

[1.04mg/L]

Oraling

estio

n

3.45

�0.34

3.86

Hypotension

Dysrhythm

ias,type

2,then

type

3AV

block

Cardiacarrest

Apnea

Coma

20%

500mL

NR

(total:5

00mL)

IVfluids,

Pressors,

Calcium,G

lucago

n

Noimprovem

entin

hemod

ynam

ics

Died

(continued)

916 S. GOSSELIN ET AL.

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(total

dose)a

Other

treatm

ents

received

ILEeffect

Outcome

Khan

etal.[66]

Case

repo

rt31

y/F

Amlodipine,d

oseNR

Losartan,d

oseNR

Oraling

estio

n

2.00

1.61

Hypotension

Apnea

Coma

NR

NR

NR

IVfluids,

Pressors,

ECMO

Noimprovem

entwith

pharmacolog

ictherapy

Survival

Laes

etal.e[67]

Case

repo

rt61

y/M

Atenolol

500mg

Amlodipine

200mg

Losartan

375mg

Oraling

estio

n

�2.03

2.00

1.61

Hypotension

,MAP

55mmHg,

ejectio

nfrac-

tion60-65%

Lactate4.5mmol/L

20%

1.5mL/kg

NR

IVfluids,

Pressors,

HIET/CV

VHD,m

ethylene

blue

2mL/kg

in30

min

Minimal

change

inblood

pressure

orheartrate

Survival

Liet

al.[68]

Case

repo

rt25

y/F

Diphenh

ydramineoral

mixture,d

oseNR

Oraling

estio

n

1.92

Hypotension

WideQRS

120ms

Status

epilepticus

20%

Yes,do

seNR

NR

Sodium

bicarbon

ate,

IVfluids,

Pressors

ILEgivenafterother

treatm

ents

failedand

better

<1hwith

improved

hemod

ynam

ics

andnarrow

edQRS

Survival

Lookabill

etal.b[69]

Case

repo

rt17

mth/F

Flecainide

100mg

RouteNR

0.55

Hypotension

64/41mmHg

WideQRS

162ms

Coma

20%

11mL

(1mL/kg)

165mL/h

0.25

mL/kg/m

in(total:

NR)

Sodium

bicarbon

ate

Unclear;Sym

ptom

simproved

afterconcur-

rent

bolusof

bicarbon

ate

Survival

Markota

etal.[70]

Case

repo

rt66

y/M

Bisoprolol

450mg

Amlodipine

300mg

Doxazosin

200mg

Nifedipine

600mg

Torsem

ide150mg

Acetylsalicylicacid

4000

mg

Ibup

rofen5000

mg

Oraling

estio

n

0.11

2.00

0.54

3.45

1.44

�1.69

0.45

Hypotension

Coma

Lactate8.5mmol/L

pH7.12

20%

100mL

150mLin

60min

(total:2

50mL)

IVfluids,

Pressors,

Calcium,G

lucago

n,HDI

Unclear

Possible

improvem

entcoinciding

with

ILE

Survival

Matsumotoet

al.[71]

Case

repo

rt24

y/F

Chlorpromazine3g

Mirtazapine990mg

Oraling

estio

n

3.42

2.40

Hypotension

80/50mmHg

Asystole

Cardiacarrest

Apnea

Coma

Lactate138mg/dL

pH7.13

20%

100mLx2

No

(total:2

00mL)

Pressors,

ECMO

Norespon

seto

1stdo

se.

ECMOinitiated

after

ROSC

2min

after2nd

dose

ILE

Survival

McBethet

al.[72]

Case

repo

rt23

y/F

Hydroxychloroqu

ine40

gOraling

estio

n[6425mmol/L

at12

h]

1.96

Hypotension

92/60mmHg

anddeclining

Ventricular

fibrillatio

n,PM

VT,Q

RS140ms,QT

576ms

Apnea

Coma

pH7.33

20%

1.5mL/kg

DoseNR,

duratio

n30

min

(total:5

00mL)

Sodium

bicarbon

ate,

IVfluids,

Pressors,

HD,calcium

channel

blocker

Authorsrepo

rt“im

provem

entafterILE

andHD”

Survival

Mon

tagu

e[73]

Case

repo

rt7mth/F

Prop

rano

lol1

08mg

Oraling

estio

n0.99

Hypotension

Bradycardia

Coma

20%

No

1.5mL/kg

in2h

(total:1

.5mL/kg)

IVfluids,

HIET

Hem

odynam

icsdidno

timprovewith

ILE

Survival

Muktar[74]

Case

repo

rt13

y/F

Flecainide

900mg

Oraling

estio

n(bisop

rolol,acetylsali-

cylic

acid)

0.55

Hypotension

70/39mmHg

VT,ventricular

fibrillatio

n,TdP,

Brug

adapattern

Cardiacarrest

Veno

uspH

7.55

20%

70mL

225mLin

20min

(total:2

95mL)

Sodium

bicarbon

ate,

IVfluids,

Pressors,

Glucago

n

ILEgivenafterRO

SCfor

cardiacarrest

notbefore

Survival

Ovakim

etal.b[75]

Case

repo

rt21

y/F

Yew

250mLcutleaves

Oraling

estio

nNA

Hypotension

WideQRS,irregular

heart

rhythm

Coma

NR

NR

NR

Sodium

bicarbon

ate,

IVfluids

Nodescrip

tionof

any

changesafterILE

Survival

(continued)

CLINICAL TOXICOLOGY 917

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(totaldo

se)a

Other

treatm

ents

received

ILEeffect

Outcome

Ozceteet

al.[76]

Case

repo

rt35

y/F

Prop

afenon

e150mg

Oraling

estio

n2.39

Hypotension

Dysrhythm

ias,QRS

160ms

Cardiacarrest

Sing

leseizure

Status

epilepticus

Coma

NR

100mL

0.25

mL/kg/h

for1h

(total:N

R)Sodium

bicarbon

ate,

IVfluids,

Pressors,

Atropine

Unclear

Survival

Radley

[77]

Case

repo

rtNR/NR

Amitriptyline4.8g

Oraling

estio

n(ethanol,venlafaxine,

zopiclon

e)

3.96

Hypotension

QTc

prolon

gatio

n3isolated

seizures

x3pH

7.45-7.6

NR

NR

NR

(total:5

00mL)

Sodium

bicarbon

ate,

IVfluids,

Pressors,

Midazolam

Improvem

entin

MAP

anddecreaseduseof

Pressorsrequ

iredlate,

butno

toxin

confirm

ation

Survival;

ARDSon

day3

Reynolds

&Judg

e[78]

Case

repo

rt24

y/F

Flecainide,d

oseNR

Oraling

estio

n[11,085ng

/mLat

4h]

0.55

Hypotension

Bradycardia,wideQRS

Cardiacarrest

(PEA

)Ap

nea

Sing

leseizure

Status

epilepticus

Coma

Lactate4mmol/L

Arterialp

H7.08

20%

200mL

No

(total:2

00mL)

Sodium

bicarbon

ate,

IVfluids,

Pressors

Noeffect

ofILE

Survival

Sampson

e[79]

Case

repo

rt24

y/F

Verapamil7.2gER

and

80mgimmediate-release

Oraling

estio

n

2.91

Hypotension

65/30mmHg

Tachycardia80

beats/min

20%

60mLIO

andthen

60mLIV

No

(total:1

20mL)

IVfluids,

Pressors,

Glucago

n,HIET

Noeffect

ofILE

Died

(The

patient

repo

rted

pain

dur-

ingIO

bolus

infusion

)Schu

ltet

al.[80]

Case

repo

rt12

y/F

Amlodipine

240mg

[87ng

/mL]

Benazepril480mg

Oraling

estio

n

2.00

�0.71

Hypotension

Coma

20%

100mL

NR

NR

NR

NR

Sebe

etal.[81]

Case

series,No1

27y/F

Diltiazem

2400

mg

(40mg/kg)

Oraling

estio

n

2.64

Hypotension

2nddegree

heartblock

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Calcium,H

IET,

Tempo

rary

pacemaker

Normotensive

afterILE

Survived

Case

series,No2

21y/F

Amlodipine

140mg

(1.86mg/kg)

Oraling

estio

n

2.00

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Calcium,H

IET

Normotensive

afterILE

Survived

Case

series,No3

51y/M

Metop

rolol1

800mg

(30mg/kg)

Oraling

estio

n

�0.34

Cardiacarrest

20%

1.5mL/kg

x3No

(total:4

.5mL/kg)

IVfluids,

Glucago

n,Mechanicalventilation

Noimprovem

entin

hemod

ynam

ics

Died

(ARD

S)

Case

series,No4

44y/F

Valsartan1600

mg

(17.7mg/kg)

Amlodipine

100mg

(1.11mg/kg)

Oraling

estio

n

�0.34

2.00

Hypotension

20%

1.5mL/kg

x3No

(total:4

.5mL/kg)

IVfluids,

Calcium,H

IET

Noimprovem

entin

hemod

ynam

ics

Survived

Case

series,No5

22y/F

Amlodipine

90mg

(1.63mg/kg)

Oraling

estio

n

2.00

Hypotension

20%

1.5mL/kg

x3No

(total:4

.5mL/kg)

IVfluids,

Calcium,H

IET

Noimprovem

entin

hemod

ynam

ics

Survived

Case

series,No6

32y/F

Amlodipine

150mg

(1.76mg/kg)

Oraling

estio

nAcetam

inop

hen

(paracetam

ol)

2.00

3rddegree

heartblock

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Calcium,A

cetylcysteine,

Tempo

rary

pacemaker

Normotensive

afterILE

Survived

Case

series,No7

31y/F

Amlodipine

110mg

(1.46mg/kg)

Oraling

estio

n

2.00

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids

Calcium,H

IET

Normotensive

afterILE

Survived

Case

series,No8

23y/F

Carvedilol7

50mg

(12.5mg/kg)

Oraling

estio

n

3.16

Hypotension

Bradycardia

20%

1.5mL/kg

x2No

(total:3

.0mL/kg)

IVfluids,

Glucago

nTempo

rary

pacemaker

Normotensive

afterILE

Survived

(continued)

918 S. GOSSELIN ET AL.

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(totaldo

se)a

Other

treatm

ents

received

ILEeffect

Outcome

Case

series,No9

18y/F

Verapamil2880

mg

(41.1mg/kg)

Oraling

estio

n

2.91

Cardiacarrest

20%

1.5mL/kg

x2No

(total:3

.0mL/kg)

IVfluids,

Calcium,H

IET

Mechanicalventilation

Normotensive

afterILE

Hypoxic,ischemic

enceph

alop

athy

Case

series,No10

21y/F

Prop

rano

lol9

60mg

(11.3mg/kg)

Oraling

estio

n

0.99

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Glucago

nNormotensive

afterILE

Survived

Case

series,No11

31y/M

Amlodipine

210mg

(2.33mg/kg)

Oraling

estio

n

2.00

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Calcium,H

IET

Normotensive

afterILE

Hypoxicischem

icenceph

alop

athy

Case

series,No12

26y/F

Carvedilol6

25mg

(9.6mg/kg)

Oraling

estio

n

3.16

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Glucago

nNormotensive

afterILE

Survived

Case

series,No13

44y/F

Verapamil1320

mg

(16.5mg/kg)

Oraling

estio

n

2.91

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Calcium,H

IET

Normotensive

afterILE

Survived

Case

series,No14

24y/M

Prop

rano

lol,do

seNR

Oraling

estio

n0.99

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids,

Glucago

nNormotensive

afterILE

Survived

Case

series,No15

33y/M

Prop

rano

lol8

00mg

(0.94mg/kg)

Oraling

estio

n

0.99

Hypotension

20%

1.5mL/kg

No

(total:1

.5mL/kg)

IVfluids

Glucago

nNormotensive

afterILE

Survived

Sub[82]

Case

repo

rt17

y/M

Amlodipine

1.25

gOraling

estio

n(m

anycoingestants

(unspecified))

2.00

Hypotension

50/30mmHg

Bradycardia40

beats/min,

3rddegree

block

NR

NR

NR

IVfluids,

Pressors,

Calcium,Insulin,

Glucago

n,ECMO

Improvem

entwas

not

seen

with

ILE,patient

improved

with

ECMO

Survival

Szadkowskie

tal.[83]

Case

repo

rt12

mth/M

Flecainide,d

oseNR

RouteNR

[2.57mcg/m

L]

0.55

Hypotension

Dysrhythm

ias

Apnea

Coma

20%

1.5mL/kg

0.25

mL/kg/h

for2h.

Then

stop

pedfor30

min

andthen

restarted

Sodium

bicarbon

ate,

IVfluids,

Pressors

VTrecurred

30min

after

1stinfusion

ended,

resolved

afterrestartin

gILEinfusion

andsodium

bicarbon

ate.

Survival

Tseet

al.[84]

Note:Poison

center

stud

yof

avariety

oftox-

ins,2ndhand

inform

ation

Case

series,No1

45y/M

Prop

rano

lol,do

seNR

Dothiepin,d

oseNR

Oraling

estio

n

0.99

2.92

Cardiacarrest

20%

100mL

NR

Sodium

bicarbon

ate

Positiveeffect

ofILEon

ROSC

Survival

Case

series,No2

46y/F

Amitriptyline,do

seNR

Oraling

estio

n3.96

QRS

changes(detailsNR)

Cardiacarrest

20%

100mL

0.25

mL/kg/m

infor30

min

(total:N

R)

Sodium

bicarbon

ate,

Pressors

Authorsrepo

rt“Effe

cton

hemod

ynam

ics”

Survival

Case

series,No3

45y/F

Amitriptyline,do

seNR

Oraling

estio

n3.96

WideQRS

NR

No

0.25

mL/kg/m

infor2h

Sodium

bicarbon

ate

NR

Survival

Tseet

al.[85]

Case

repo

rt55

y/M

Methamph

etam

ine“egg

size”do

seOraling

estio

n

�0.57

Tachycardia

Adrenergicsymptom

s20%

1.5mL/kg

NR

(total:1

.5mL/kg)

NR

Resolutio

nof

hyperadre-

nergicexcess

in20

min

Survival

Vodn

ala[86]

Case

repo

rt50

y/M

Flecainide,d

oseNR

Oraling

estio

n[5.89mcg/m

L](cardizem,arip

iprazole)

0.55

Hypotension

WideQRS,Q

T700ms

Cardiacarrest

Sing

leseizure

Coma

NR

NR

NR

Sodium

bicarbon

ate,

IVfluids

ILEdidno

tappear

toaffect

theou

tcom

eDied

Wattet

al.[87]

Case

Series,No1

Youn

g/F

Quetiapine

4.3g

Oraling

estio

n(diazepam

300mg,

acet-

aminop

hen(paraceta-

mol)/dihydrocod

eine,fer-

rous

fumarate)

1.82

Coma

20%

NR

NR

(reports‘Stand

ardlipid

rescue

protocol’)

NR

No

Survival

Case

series,No2

Middle-aged/F

Quetiapine

4.6g

Oraling

estio

nAcetam

inop

hen

(paracetam

ol)

1.82

Hypotension

Sinu

stachycardia120

beats/min,Q

Tc550ms

Coma

20%

NR

NR

(reports‘Stand

ardlipid

rescue

protocol’)

IVfluids,

Acetylcysteine

No

Survival

(continued)

CLINICAL TOXICOLOGY 919

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix3.

Continued

Article

Stud

ytype

Age/sex

Drug,

dose

androute

[Quantitativedrug

con-

centratio

n](coing

estant)

LogDc

Symptom

sILEused

ILEbo

lusdo

sea

ILEinfusion

dose

(totaldo

se)a

Other

treatm

ents

received

ILEeffect

Outcome

Yesilbas

etal.[88]

Case

repo

rt8y/M

Organop

hosphate

(from

eatin

gleeks)

Oraling

estio

n

NA

Bradycardia

Coma

20%

NR

8g/kg/day

for2days

(total:1

6g/kg)

Atropine,P

ralidoxime,

CVVH

DNoimmediate

improve-

mentandothertreat-

ments

given.

Improved

over

4days

Survival

ACLS:Ad

vanced

cardiaclifesupp

ort;AR

DS:

Acuterespiratory

distress

synd

rome;

BP:BLoodPressure;CV

VHD:Co

ntinuo

usVeno

veno

usHem

odialysis;

ECMO:Extracorpo

real

mem

braneoxygenation;

ER:Extend

edrelease;

HDI:Highdo

seinsulin;HD:

Hem

odialysis;HIET:

High-do

seinsulin

euglycem

iatherapy;

ILE:

Intravenou

slipid

emulsion

;MAR

S:Molecular

AdsorbentRecirculationSystem

;MAP

:Meanarterialpressure;NA:

notapplicable;NR:

Not

repo

rted;NSR:Normal

sinu

srhythm

;PEA:

Pulseless

electrical

activity;P

MVT:P

olym

orph

icventricular

tachycardia;PV

C:Prem

atureventricular

contractions;R

OSC:R

eturnof

spon

taneou

scirculation;

RSI:Rapidsequ

ence

indu

ction;

TdP:

Torsadede

pointes;VA

:Veno-arterial;VES:

Ventricular

extrasystoles;VT:

Ventricular

tachycardia.

a The

totald

osein

g/kg

was

infrequentlyavailable,andcouldon

lybe

calculated

ifbo

dyweigh

twas

repo

rted.

bAvailableas

abstract

onlyat

thetim

eof

writing.

c Adapted

from

www.chemspider.com

.The

logDrefersto

thelogarithm

ofoctano

l/water

partition

coefficient.

dIndividu

alpatient

details

areno

trepo

rted

forthecase

series.

e Fulltextarticle

includ

edas

itisavailableat

thetim

eof

writing,

andinclud

esmoreinform

ationcomparedto

abstract

referenceinclud

edin

thesystem

aticreview

(5).

f These

dosesarelikelyin

mL/kg

butaretranscrib

edas

repo

rted

intheoriginalarticle.

920 S. GOSSELIN ET AL.

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix4.

Summaryof

the11

animalstud

iesinclud

edin

the2015

update.

Article

(Species)

Mod

elPoison

,doseand

route

LogD

Symptom

sILEused

ILEbo

lusa

ILE

infusion

Stud

yarms

Timingof

rescue,

timefrom

LAterm

ination

Other

treatm

ents

received

bParameter

measured

Outcome

Supp

orteffect

ofILE

Locala

nesthetics

RCS

Udelsman

[33]

(Pigs)

Rand

omized

trial

Bupivacaine

5mg/kg

Intravenou

s

2.68

Fallin

arterialB

P,andventricular

sys-

tolic

workindex

NR

4mL/kg

No

LCT

vs LCT/MCT

vs Saline

Stud

ytreatm

ents

1min

afterLA

NR

ArterialB

P,CI

and

ventricular

systolic

workindex

Survival

NR

Yes;Bo

thlipid

emulsion

swereeffi-

cientandsimilar

optio

nsto

reverse

hypo

tension

Zaballos[34]

(Pigs)

Rand

omized

trial

Bupivacaine

4–6mg/kg

Intravenou

s

2.68

150%

increase

inQRS

20%

1.5mL/kg

0.25

mL/kg/m

inTimeNR

ILE

vs Saline(detailsNR)

NR

NR

QRS

Survival:

ILE6/6

Saline6/6

Yes;Bu

tcontrol

grou

pQRS

was

wider

Non-locala

nesthetics

RCS

Bourqu

e[35]

(Rats)

Controlledtrial

Prop

ofol

10mg/kg

Intravenou

s3.88

Hypotension

NR

4mL/kg

No

ILE

vs Saline

NR

NR

MAP

,cortical

activ-

ityassessmentsby

EEG

Survival

rate

NR

ILEsuperio

rto

salinein

therever-

salo

fdecreased

MAP

with

minimal

effect

ontheanes-

theticprofile

ofprop

ofol

Yes

Peacock[39]

(Cats)

Rand

omized

trial

Perm

ethrin,d

ose

NR

Topical

6.47

Somehadsing

leseizures

20%

No

15mL/kg

in60

min

ILE

vs Saline

Variable

Supp

ortive,details

NR

Metho

carbam

olfor

seizure-likeactivity,

diazepam

Authorsgraded

the

cats’n

eurologicsta-

tusesandfoun

da

decrease

inthe

timeandseverityof

poison

ingin

the

treatm

entgrou

p

Survival:

ILENR/20

SalineNR/14

Yes;ILE-treatedcats

improved

earlier

comparedto

con-

trol

cats

Varney

[42]

(Pigs)

Rand

omized

trial

Diphenh

ydramine

1mg/kg/m

inIntravenou

s

1.92

Diphenh

ydramine

dosing

continued

until

MAP

was

60%

ofbaseline

20%

7mL/kg

0.25

mL/kg/m

inILE

vs Bicarbon

ate

Other

treatm

entand

stud

ytreatm

ent

immediatelyafter

diph

enhydram

ine

Bicarbon

ate:2

mEq/kgplus

anequalvolum

eof

norm

alsalinesolu-

tion

systolicBP,M

AP,

cardiacou

tput,Q

RSandtim

eto

death

Survival:

ILE1/12

Bicarbon

ate2/12

No;

nodiffe

rencein

outcom

emeasures

betweengrou

ps

Case

Repo

rts/

Series

Ceccherin

i[36]

(Cats)

Case

series

(N¼4)

Perm

ethrin,d

ose

androuteNR

6.47

Musclefascicula-

tions

andseizures

NR

Variabledo

ses

Variabledo

ses

NA

NR

Dexmedetom

idine,

dose

NR

NR

Survival:

4/4

Yes;seizure-like

activity

respon

ded

Herrin

g[37]

(Dog

s)Case

series

(N¼3)

Naproxen2.2–2.5g

Oraling

estio

n0.45

NR

20%

2mL/kg

0.25

mL/kg/m

infor

30min

NA

NR

NR

NR

Survival:

3/3

Theanimalswere

empiricallytreated

dueto

thehigh

dose

anditis

impo

ssible

toinfer

anyclinical

benefit

over

supp

ortive

care

alon

eJourdan[38]

(Cats)

Case

series

(N¼20)

Ivermectin

4mg/kg

Subcutaneous

5.76–6.21

NR

20%

1.5mL/kg

(N¼16)

andotherILE

bolusesgivenun

tilclinical

resolutio

ncom-plete

0.25

mL/kg/m

infor

30min

(following

thebo

lusin

N¼4

animals)

NA

Early

initiation

NR

NR

Survival:

20/20

Theanimalswere

empiricallytreated

dueto

thehigh

dose

anditis

impo

ssible

toinfer

anyclinical

benefit

over

supp

ortive

care

alon

e (continued)

CLINICAL TOXICOLOGY 921

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

App

endix4.

Continued

Article

(Species)

Mod

elPoison

,doseand

route

LogD

Symptom

sILEused

ILEbo

lusa

ILE

infusion

Stud

yarms

Timingof

rescue,

timefrom

LAterm

ination

Other

treatm

ents

received

bParameter

measured

Outcome

Supp

orteffect

ofILE

Saqib[40]

(Lion)

Case

repo

rtIvermectin

3mg/kg

Oraling

estio

n5.76–6.21

Hypotension

Bradycardia50-60

beats/min

Ataxia,app

arent

hallucinatio

ns,sin-

gleseizure

Coma

Blindn

ess

Bradypnea10–15

breath/m

inDecreasingbo

dytemperature

20%

1stdo

se:1

.5mL/kh

1stdo

se:0

.25mL/

kg/m

infor30

min

2nddo

se:0

.5mL/

kg/m

infor30

min

NA

1stILEdo

seafter

app.

72h

2ndILEdo

seafter

92h

IVfluids

Activated

charcoal

andlatergastric

lavage

Glucose,d

iazepam,

atropine,n

eostig-

mine,ceftriaxone

Mechanical

ventilatio

n

NR

Survival

Yes

Seitz

[41]

(Cat)

Case

repo

rtPerm

ethrin,d

ose

NR

Topical

6.47

Sing

leseizure

20%

1.5mL/kh

0.25

mL/kg/m

infor2h

(total:3

1.5mL/kg)

NA

NR

IVfluids

Metho

carbam

ol,

diazepam

NR

Survival;seizure

ter-

minationpriorto

ILE

persistent

grosslip-

emiaandsuspected

corneallipidosis

Yes

Williams[43]

(Dog

)Case

repo

rtSynthetic

cann

abin-

oidreceptor

agon

ist

NR

Bradycardia60

beats/min

Coma

Perio

dicapnea

Hypotherm

ia32.5

� C

20%

1.5mL/kh

0.5mL/kg/h

for6h

(total:2

mL/kg)

NA

NR

IVfluids

Supp

ortivecare

Mechanical

ventilatio

n

Vitalp

aram

eters

Drugs

measured:

9-TH

C,AM

-2201,

JWH-122

Survival;m

entalsta-

tusimproved

fol-

lowingILE

Unclear

a The

bolusdo

sein

g/kg

andinfusion

dose

ing/kg/h

couldon

lybe

calculated

iflipid

concentrationwas

repo

rted.

bDrugs

used

forgeneralanesthesiaor

euthanasia

areno

tinclud

ed.

BP:B

lood

pressure;C

I:Cardiacindex;EEG:electroenceph

alog

raph

y;ILE:Intravenou

slipid

emulsion

;IV:

Intravenou

s;LA:Localanesthetic;LCT:Lon

gchaintriglycerid

e;MAP

:Meanarterialp

ressure;MCT:M

edium

chaintriglycerid

e;NA:

Not

applicable;N

R:Not

repo

rted;R

CS:R

ando

mized

controlled

stud

ies.

922 S. GOSSELIN ET AL.

Dow

nloa

ded

by [

Uni

vers

ity o

f Sy

dney

Lib

rary

] at

17:

45 1

6 A

ugus

t 201

7

Appendix 5. Vote results

Life-threatening toxicity Non-life-threatening toxicity

Toxins Cardiac arrestAs first linetherapy

As part of treatmentmodalities

If other therapies fail (inlast resort)

As first linetherapy

As part of treatmentmodalities

If other therapies fail (inlast resort)

Local anestheticsBupivacaine Recommended

(M:7, LQ:7, DI:0.2)Neutral(M:6, DI:0.5)

Suggested(M:7, LQ:6, DI:0.2)

Recommended(M:8, LQ:7, DI:0.2)

Neutral(M:5, DI:0.5)

Neutral(M:5, DI:0.5)

Neutral(M:6, DI:0.5)

All other local anesthetics Neutral(M:6, DI:0.3)

Neutral(M:5, DI:0.4)

Neutral(M:6, DI:0.5)

Suggested(M:7, LQ:6, DI:0.4)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:1.0)

Neutral(M:6, DI:0.3)

Non-local anaestheticsAntidysrhythmics Class 1 Neutral

(M:5, DI:0.3)Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0)

Neutral(M:6.5, DI:0.5)

Not suggested(M:3, UQ:5, DI:0.7)

Neutral(M:5, DI:0.6)

Neutral(M:5, DI:0.4)

Amitriptyline Neutral(M:6, DI:0.5)

Not suggested(M:2.5, UQ:4.5, DI:0.3)

Neutral(M:5, DI:0.5)

Suggested(M:7, UQ;5, DI:0.4)

Not recommended(M:1, UQ:2, DI:0.1)

Not suggested(M:3, UQ:4, DI:0.5)

Neutral(M:5, DI:0.8)

Other tricyclicantidepressants

Neutral(M:5.5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.9)

Neutral(M:6, DI:0.6)

Not suggested(M:1, UQ:4, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Not suggested(M:3, UQ:5, DI:0.8)

Baclofen Neutral(M:5, DI:0.1)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:0)

Neutral(M:5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.7)

Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0.7)

Beta receptor antagonists(lipid-soluble)

Neutral(M:6, DI:0.3)

Neutral(M:4, DI:0.4)

Neutral(M:5, DI:0.3)

Neutral(M:6, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0.6)

Beta receptor antagonists(Non lipid-soluble)

Neutral(M:5, DI:0.5)

Not suggested(M:2, UQ:4, DI:0.5)

Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0.3)

Not suggested(M:1, UQ:3.5, DI:0.2)

Not suggested(M:1, UQ:5, DI:0.8)

Neutral(M:5, DI:0.8)

Bupropion Neutral(M:6, DI:0.5)

Not suggested(M:2, UQ:5, DI:0.4)

Neutral(M:5, DI:0.4)

Suggested(M:7, LQ:5, DI:0.7)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:4, DI:0.8)

Neutral(M:5, DI:0.8)

Calcium channel blockersDiltiazem and verapamil

Neutral(M:6, DI:0.5)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.1)

Neutral(M:6, DI:0.1)

Not suggested(M:1, UQ:4, DI:0.5)

Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0.7)

Calcium channel blockersDihydropyridines

Neutral(M:5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.5)

Neutral(M:5, DI:0.2)

Neutral(M:6, DI:0.5)

Not suggested(M:1, UQ:4.5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Not suggested(M:2, UQ:5, DI:0.8)

Cocaine Neutral(M:5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.5)

Neutral(M:5, DI:0.7)

Neutral(M:6, DI:0.4)

Not suggested(M:1, UQ: 3.75, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.8)

Diphenhydramine Neutral(M:5, DI:0.3)

Not suggested(M:1, UQ:4, DI:0.2)

Neutral(M:5, DI:0.4)

Neutral(M:6, DI:0.6)

Not recommended(M:1, UQ:2, DI:0.1)

Not suggested(M:1, UQ:4, DI:0.2)

Not suggested(M:2, UQ:5, DI:0.8)

Other antihistamines N/A N/A N/A N/A N/A N/A N/AIvermectin Neutral

(M:5, DI:0)Neutral(M:4.5, DI:0.7)

Neutral(M:5, DI:0)

Neutral(M:5, DI:0.4)

Not suggested(M:2, UQ;5, DI:0.8)

Neutral(M:5, DI:0.8)

Neutral(M:5, DI:0.7)

Other insecticides Neutral(M:5, DI:0)

Not suggested(M:3, UQ:5, DI:0.8)

Neutral(M:5, DI:0.3)

Neutral(M:5, DI:0.4)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:4, DI:0.7)

Neutral(M:5, DI:0.4)

Lamotrigine Neutral(M:6, DI:0.4)

Not suggested(M:3, UQ: 5, DI:0.8)

Neutral(M:5, DI:0.4)

Neutral(M:6.5, DI:0.4)

Not suggested(M:1.5, UQ: 5, DI:0.5)

Not suggested(M:3, UQ:5, DI:0.8)

Neutral(M:5, DI:0.8)

Malathion Neutral(M:5, DI:0)

Not suggested(M:3, UQ:5, DI:0.7)

Neutral(M:5, DI:0.1)

Neutral(M:5, DI:0.2)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:4, DI:0.6)

Neutral(M:5, DI:0.3)

Other pesticides Neutral(M:5 DI:0.1)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0)

Neutral(M:5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.5)

Neutral(M:5, DI:0.8)

Neutral(M:5, DI:0.5)

Olanzapine Neutral(M:5, DI:0.3)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:0.1)

Neutral(M:5, DI:0.4)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:0.7)

Other antipsychotics Neutral(M:5, DI:0.3)

Not suggested(M:3, UQ:5, DI:0.7)

Neutral(M:5, DI:0)

Neutral(M:5, DI:0.4)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:0.6)

Selective SerotoninReuptake Inhibitors

Neutral(M:5, DI:0.1)

Neutral(M:4, DI:0.8)

Neutral(M:5, DI:0.1)

Neutral(M:5, DI:0.3)

Not suggested(M:2, UQ:5, DI:0.8)

Neutral(M:5, DI:0.7)

Neutral(M:5, DI:0.6)

M: Median; LQ: Lower quartile; UQ: Upper quartile; DI: Disagreement index; N/A: not applicable.

CLINICAL TOXICOLOGY 923

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