Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning^*

Figures & data

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 therapy
	As part of treatment modalities
	If other therapies fail (in last resort)
ILE is indicated in non-life-threatening toxicity	As first-line therapy
	As part of treatment modalities
	If other therapies fail (in last resort)

Figure 1. Voting process.

Table 2. Strength of recommendation and level of evidence.

Strength of recommendation (consensus-based)

Level 1: Strong recommendation (The course of action is considered appropriate by the large majority of experts with no major dissension. The panel is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects.)

Level 2: Weak/conditional recommendation (The course of action is considered appropriate by the majority of experts but some degree of dissension exists among the panel. The desirable effects of adherence to the recommendation probably outweigh the undesirable effects.)

Neutral position: The course of action is neither preferred nor rejected by the majority of experts; either due to a balance in the desirable and undesirable effects of adherence to the recommendation or due to major uncertainties to its evaluation.

No recommendation: The group of experts reached no agreement

Level 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 substantially different.)

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

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

Toxins	Clinical situations (strength of recommendation & level of evidence)^a
Local anesthetics
Bupivacaine	In cardiac arrest: we recommend using ILE (1D) In life-threatening toxicity: we suggest using ILE as part of treatment modalities (2D) and we recommend using ILE if other therapies fail/in last resort (1D) In non-life-threatening toxicity: neutral recommendation
All 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 anesthetics
Antidysrhythmics Class 1	In cardiac arrest: neutral recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)
Amitriptyline	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 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 recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)
Beta receptor antagonists (Lipid-soluble)	In cardiac arrest: neutral recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)
Beta receptor antagonists (Non lipid-soluble)	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) 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 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)
Cocaine	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) 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 data
Ivermectin	In cardiac arrest: neutral recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)
Other insecticides	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)
Lamotrigine	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) 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 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)
Olanzapine	In cardiac arrest: neutral recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)
Other antipsychotics	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)
Selective serotonin reuptake inhibitors	In cardiac arrest: neutral recommendation In life-threatening toxicity: neutral recommendation In non-life-threatening toxicity: we suggest not using ILE as first-line therapy (2D)

^a Neutral position if not otherwise specified.

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

Appendix 3. Summary of the 72 patients included in the 2015 update on the efficacy of ILE in poisoning.

Article	Study type	Age/sex	Drug, dose and route [Quantitative drug concentration] (coingestant)	Log D^c	Symptoms	ILE used	ILE bolus dose^a	ILE infusion dose (total dose)^a	Other treatments received	ILE effect	Outcome
Local anesthetics
Glavas et al. [44]	Case report	64 y/F	Levobupivacaine 10 mg Epidural/Intravenous (amoxicillin)	2.68	Hypotension Coma	20%	200 mL	NR (total: 200 mL)	IV fluids, Pressors, Anesthetics, Atropine	Yes	Survival
Goucher & Asher^b [45]	Case report	60 y/F	Lidocaine 18 mL 2% Intravenous	1.26	PVC Coma	NR	150 mL	NR (total: 150 mL)	Epinephrine	Yes; No hemodynamic compromise throughout	Survival
Kamel et al. [46]	Case report	51 y/F	Bupivacaine 80 mL 5% Nerve block	2.68	Dizziness Agitation Posturing Loss of left lower extremity sensation	20%	100 mL	400 mL in 20 min (total: 500 mL)	Epinephrine, Anesthetics	Unclear if drug effect had just worn off; Neurologic symptoms improved after administration	Survival
Musielak & McCall [47]	Case report	6 y/M	Bupivacaine 3 mg/kg Subcutaneous/ Intravenous	2.68	Hypotension Bradycardia, asystole Cardiac arrest Apnea Coma	NR	1.5 mg/kg^f	0.25 mg/kg/min for^f 6 h (total: 91.5 mg/kg)^f	Epinephrine, Pressors, (norepinephrine, epinephrine, vasopressin, phenylephrine)	Unclear	Survival
Procopio et al. [48]	Case report	43 y/M	Bupivacaine 10 mL Ropivacaine 30 mL Intrathecal	2.68 4.21	Hypotension Bradycardia Apnea Coma	20%	1.5 mL/kg	125 mL in 2 h (total: NR)	Pressors	Improved 30 min after ILE	Survival
Riff et al.^d [49]	Case series, No 1	Age NR/sex NR	Ropivacaine 220 mg Nerve block [4.20 mcg/mL]	4.21	Seizures Coma	NR	NR	NR	NR	Authors state “quick symptoms resolving”	NR
	Case series, No 3	Age NR/F, pregnant	Ropivacaine 150 mg Nerve block [4.80 mcg/mL]	4.21	Obtundation	NR	NR	NR	NR	Authors state “quick symptoms resolving”	NR
	Case series, No 4	Age NR/F, pregnant	Ropivacaine 100 mg Nerve block [0.66 mcg/mL]	4.21	Obtundation	NR	NR	NR	NR	Authors state “quick symptoms resolving”	NR
	Case series, No 7	Age NR/F, pregnant	Ropivacaine 40 mg [0.51 mcg/mL] Lidocaine 200 mg [1.01 mcg/mL] Nerve block	4.21 1.26	Seizure Mydriasis	NR	NR	NR	NR	Authors state “quick symptoms resolving”	NR
	Case series, No 8	Age NR/sex NR	Ropivacaine 40 mg [0.29 mcg/mL] Lidocaine 200 mg [0.58 mcg/mL] Nerve block	4.21 1.26	Hypotension Bradycardia Metallic taste	NR	NR	NR	NR	Authors state “quick symptoms resolving”	NR
Shih & Calello^b [50]	Case report	56 y/F, weight NR	Bupivacaine 30 mL 0.25% Nerve block	2.68	Hypotension Apnea Coma Lactate 4 mmol/L	20%	85 mL	NR (total: 85 mL)	IV fluids, Pressors, Anesthetics	Motor and sensory function improved over 4 h	Survival
Stella et al.^b [51]	Case report	<1 week/NR	Lidocaine 6 mg/kg, then 6 mg/kg/h for 18 h, then 4 mg/kg/h for 12 h Intravenous	1.26	Bradycardia, wide QRS	20%	2 mL/kg	NR	NR	Wide QRS and bradycardia resolved	Survival
Non-local anaesthetics
Agulnik [52]	Case report	15 y/F	Carbamazepine 56 g Oral ingestion [138 mcg/mL]	2.67	Status epilepticus Coma (induced with barbiturates, technically not from ingestion) Lactate reported as high	NR	NR	NR	Plasmapheresis, HDI, CVVHD	Unclear	Survival
Aksel et al. [53]	Case series, No 1	35 y/M	Synthetic cannabinoid receptor agonists, dose and route NR (heroin)	NA	wide QRS 150 ms, left bundle branch block, sinus tachycardia 100 beats/min Coma pH 6.9)	20%	1.5 mL/kg	0.25 mL/kg/h for 1 h (total: 1155 mL)	IV fluids	QRS narrowed within 5 min after ILE bolus improved in an unknown timeframe	Died
	Case series, No 2	19 y/M	Synthetic cannabinoid receptor agonists, dose NR Smoking	NA	Hypotension 70/30 mmHg Sinus bradycardia 42 beats/min	20%	1.5 mL/kg	0.25 mL/kg/h for 1 h (total: 990 mL)	IV fluids	Hemodynamics improved	Survived
	Case series, No 3	15 y/M	Synthetic cannabinoid receptor agonists, dose NR Smoking	NA	Hypotension 80/40 mmHg Sinus bradycardia 36 beats/min Coma	20%	1.25 mL/kg	0.50 mL/kg/h for 1 h (total: 2100 mL)	IV fluids	Hemodynamics and coma score improved	Survived
	Case series, No 4	17 y/M	Synthetic cannabinoid receptor agonists, dose and route NR	NA	Accelerated junctional rhythm, bigeminy	20%	1.5 mL/kg	0.25 mL/kg/h for 1 h (total: 990 mL)	IV fluids	Hemodynamics improved	Survived
Barton et al. [54]	Case report	59 y/M	Metoprolol 7.5 g Oral ingestion [120 ng/mL] (methamphetamine, ketamine, caffeine)	−0.34	Hypotension 74/43 mmHg Bradycardia 50 beats/min, atrial fibrillation Cardiac arrest Apnea	20%	1.5 mL/kg (1st dose), 150 mL (2nd dose)	No (total: NR)	IV fluids, Pressors, HIET, atropine, glucagon	ILE was given at the same time as ACLS and HIET. ROSC and opened eyes	Survival
Baruah et al. [55]	Case series, No 1	40 y/F	Aluminum phosphide 3 g Oral ingestion	NA	Hypotension 80/60 mmHg Sinus tachycardia 100 beats/min Respiratory rate 30/min pH 7.33	20%	No	10 mL/h (total: NR)	Gastric lavage, Magnesium sulphate	Hemodynamics improved over time	Survival
	Case series, No 2	30 y/M	Aluminum phosphide 3 g Oral ingestion	NA	Hypotension 85/55 mmHg Sinus tachycardia 132 beats/min Respiratory rate 34/min pH 7.081	20%	No	10 mL/h (total: NR)	Gastric lavage, Magnesium sulphate	Hemodynamics improved over time	Survival
Bayram et al. [56]	Case report	21 y/F	Propafenone 1500 mg Oral ingestion (acetaminophen, acetyl salicylic acid	2.39	Hypotension Bradycardia, wide QRS >200 ms Cardiac arrest Single seizure Metabolic acidosis (details NR)	20%	1.5 mL/kg	0.25 mL/kg/h for 30 min (total: NR)	Sodium bicarbonate, IV fluids, Pressors	After cardiac arrest ILE narrowed QRS widening and improved hemodynamics	Survival
Besserer et al.^b [57]	Case report	36 y/M	Tilmicosin phosphate, dose NR Accidental self injection	1.52	Hypotension	20%	100 mL	500 ml in 30 min (total: 600 mL)	IV fluids, Pressors, HDI	Unclear	Survival
Brumfield et al. [58]	Case report	33 y/F	Flecainide, dose NR Oral ingestion	0.55	Cardiac arrest Altered mental status	20%	100 mL (1.5 mL/kg)	900 mL/h (12 mL/kg/h) (total: NR)	Sodium bicarbonate, IV fluids	ILE was given after ROSC and then the patient required another VT arrest and ECMO	Survival
Christianson et al.^b [59]	Case report	64 y/M	Diltiazem 19.4 g sustained release Oral ingestion	2.64	Hypotension Dysrhythmias Cardiac arrest Apnea Single seizure Coma	NR	NR	NR	IV fluids, Pressors, Anesthetics, HDI, calcium, glucagon, ECMO	NSR with hypotension, asystole at 12 h post-ingestion, then ROSC with hypotension, then ultimate recovery. Unknown ILE timing	Survival shock liver and still intubated on day 11
Czerwonka & Heim^b [60]	Case report	33 y/F	Atenolol, dose NR Oral ingestion (zolpidem, acetaminophen, ethanol)	−2.03	Hypotension Coma	NR	NR	NR	IV fluids, Pressors, Anesthetics HDI, blood products, activated charcoal, acetylcysteine, calcium	Unclear	Survival
Doepker et al.^e [61]	Case series, No 1	35 y/M	Metoprolol 1180 mg Amlodipine 150 mg Verapamil 10.26 g ER Oral ingestion (insulin)	−0.34 2.00 2.91	Non-measurable blood pressure Bradycardic arrest <20 beats/min Coma	20%	1.5 ml/kg (130 mL)	0.25 mL/kg/min for 1 h (total: NR)	IV fluids, Pressors, HDI, atropine, calcium, glucagon	Authors note a benefit of ILE therapy for the amlodipine overdose	Survival
	Case series, No 2	59 y/M	Metformin 30 g Amlodipine 300 mg Lisinopril 300 mg Simvastatin, dose NR Oral ingestion	−5.44 2.00 −1.80 4.60	Hypotension 78/36 mmHg Bradycardia 54 beats/min Lactate 6.6 mmol/L, anion gap 17	20%	1.5 mL/kg (105 mL)	0.25 mL/kg/min for 1 h (total: NR)	IV fluids, Activated charcoal, dextrose, calcium, glucagon, HDI	Authors note a benefit of ILE therapy for the amlodipine overdose	Survival
Gerard et al. [62]	Case report	58 y/F	Amlodipine 480 mg Valsartan 3680 mg Oral ingestion	2.00 −0.34	Hypotension 78/57 mmHg Tachycardia 103 beats/min, QT 555 ms Lactate 18 mmol/L pH 7.23	20%	No	8 mL/kg for 10 min (total: 80 mL/kg)	IV fluids, Pressors, Calcium, HIET, methylene blue, MARS	Improvement was not seen with ILE, responded to the use of MARS	Survival
Hatten [63]	Case report	32 y/F	Quetiapine, dose NR Oral ingestion [5929 ng/mL] (heroin; positive, unknown matricx for morphine, oxycodone)	1.82	Hypotension Tachycardia, wide QRS >160 ms (previous 92 ms) Cardiac arrest Apnea Coma Lactate 25 mmol/L pH 7.27	NR	NR	NR	Sodium bicarbonate, IV fluids, Pressors, Anesthetics, Naloxone	Hemodynamics did not change in relation to ILE, QRS narrowed with bicarbonate	Died; No complications reported to ILE
Johnson-Arbor et al.^e [64]	Case report	43 y/F	Propranolol 12 g [3.5 mg/L after 23 h] Tramadol 1.5 g Zolpidem 200 mg Alprazolam 15 mg Acetaminophen, dose NR Oral ingestions	0.99 0.40 2.35 2.50 0.40	Hypotension 64/47 mmHg Cardiogenic shock, ejection fraction 20% Apnea Coma	20%	1.5 mL/kg x3	0.25 mL/kg/min (total: NR)	IV fluids, Pressors, Anesthetics, Insulin, Glucagon	No	Died, Laboratory evaluation impossible due to lipemia
Jovic-Stosic et al. [65]	Case series, No 1	24 y/F	Amlodipine 150 mg [0.05 mg/L] Metformin 10 g [6.32 mg/L] Gliclizide 2.4 g [3.95 mg/L] Oral ingestion	2.00 −5.44 0.16	Hypotension Dysrhythmias Cardiac arrest Lactate 4.9 mmol/L, pH 7.27	20%	100 mL	900 mL (total: 1000 mL)	IV fluids, Pressors, Anesthetics, Glucagon	Transient blood pressure improvement then none further	Died
	Case series, No 2	41 y/M	Nifedipine, dose NR [0.62 mg/L] Metoprolol, dose NR [0.57 mg/L] Diazepam, dose NR [1.04 mg/L] Oral ingestion	3.45 −0.34 3.86	Hypotension Dysrhythmias, type 2, then type 3 AV block Cardiac arrest Apnea Coma	20%	500 mL	NR (total: 500 mL)	IV fluids, Pressors, Calcium, Glucagon	No improvement in hemodynamics	Died
Khan et al. [66]	Case report	31 y/F	Amlodipine, dose NR Losartan, dose NR Oral ingestion	2.00 1.61	Hypotension Apnea Coma	NR	NR	NR	IV fluids, Pressors, ECMO	No improvement with pharmacologic therapy	Survival
Laes et al.^e [67]	Case report	61 y/M	Atenolol 500 mg Amlodipine 200 mg Losartan 375 mg Oral ingestion	−2.03 2.00 1.61	Hypotension, MAP 55 mmHg, ejection fraction 60-65% Lactate 4.5 mmol/L	20%	1.5 mL/kg	NR	IV fluids, Pressors, HIET/CVVHD, methylene blue 2 mL/kg in 30 min	Minimal change in blood pressure or heart rate	Survival
Li et al. [68]	Case report	25 y/F	Diphenhydramine oral mixture, dose NR Oral ingestion	1.92	Hypotension Wide QRS 120 ms Status epilepticus	20%	Yes, dose NR	NR	Sodium bicarbonate, IV fluids, Pressors	ILE given after other treatments failed and better <1 h with improved hemodynamics and narrowed QRS	Survival
Lookabill et al.^b [69]	Case report	17 mth/F	Flecainide 100 mg Route NR	0.55	Hypotension 64/41 mmHg Wide QRS 162 ms Coma	20%	11 mL (1 mL/kg)	165 mL/h 0.25 mL/kg/min (total: NR)	Sodium bicarbonate	Unclear; Symptoms improved after concurrent bolus of bicarbonate	Survival
Markota et al. [70]	Case report	66 y/M	Bisoprolol 450 mg Amlodipine 300 mg Doxazosin 200 mg Nifedipine 600 mg Torsemide 150 mg Acetyl salicylic acid 4000 mg Ibuprofen 5000 mg Oral ingestion	0.11 2.00 0.54 3.45 1.44 −1.69 0.45	Hypotension Coma Lactate 8.5 mmol/L pH 7.12	20%	100 mL	150 mL in 60 min (total: 250 mL)	IV fluids, Pressors, Calcium, Glucagon, HDI	Unclear Possible improvement coinciding with ILE	Survival
Matsumoto et al. [71]	Case report	24 y/F	Chlorpromazine 3 g Mirtazapine 990 mg Oral ingestion	3.42 2.40	Hypotension 80/50 mmHg Asystole Cardiac arrest Apnea Coma Lactate 138 mg/dL pH 7.13	20%	100 mL x2	No (total: 200 mL)	Pressors, ECMO	No response to 1st dose. ECMO initiated after ROSC 2 min after 2nd dose ILE	Survival
McBeth et al. [72]	Case report	23 y/F	Hydroxychloroquine 40 g Oral ingestion [6425 mmol/L at 12 h]	1.96	Hypotension 92/60 mmHg and declining Ventricular fibrillation, PMVT, QRS 140 ms, QT 576 ms Apnea Coma pH 7.33	20%	1.5 mL/kg	Dose NR, duration 30 min (total: 500 mL)	Sodium bicarbonate, IV fluids, Pressors, HD, calcium channel blocker	Authors report “improvement after ILE and HD”	Survival
Montague [73]	Case report	7 mth/F	Propranolol 108 mg Oral ingestion	0.99	Hypotension Bradycardia Coma	20%	No	1.5 mL/kg in 2 h (total: 1.5 mL/kg)	IV fluids, HIET	Hemodynamics did not improve with ILE	Survival
Muktar [74]	Case report	13 y/F	Flecainide 900 mg Oral ingestion (bisoprolol, acetyl salicylic acid)	0.55	Hypotension 70/39 mmHg VT, ventricular fibrillation, TdP, Brugada pattern Cardiac arrest Venous pH 7.55	20%	70 mL	225 mL in 20 min (total: 295 mL)	Sodium bicarbonate, IV fluids, Pressors, Glucagon	ILE given after ROSC for cardiac arrest not before	Survival
Ovakim et al.^b [75]	Case report	21 y/F	Yew 250 mL cut leaves Oral ingestion	NA	Hypotension Wide QRS, irregular heart rhythm Coma	NR	NR	NR	Sodium bicarbonate, IV fluids	No description of any changes after ILE	Survival
Ozcete et al. [76]	Case report	35 y/F	Propafenone 150 mg Oral ingestion	2.39	Hypotension Dysrhythmias, QRS 160 ms Cardiac arrest Single seizure Status epilepticus Coma	NR	100 mL	0.25 mL/kg/h for 1 h (total: NR)	Sodium bicarbonate, IV fluids, Pressors, Atropine	Unclear	Survival
Radley [77]	Case report	NR/NR	Amitriptyline 4.8 g Oral ingestion (ethanol, venlafaxine, zopiclone)	3.96	Hypotension QTc prolongation 3 isolated seizures x3 pH 7.45-7.6	NR	NR	NR (total: 500 mL)	Sodium bicarbonate, IV fluids, Pressors, Midazolam	Improvement in MAP and decreased use of Pressors required late, but no toxin confirmation	Survival; ARDS on day 3
Reynolds & Judge [78]	Case report	24 y/F	Flecainide, dose NR Oral ingestion [11,085 ng/mL at 4 h]	0.55	Hypotension Bradycardia, wide QRS Cardiac arrest (PEA) Apnea Single seizure Status epilepticus Coma Lactate 4 mmol/L Arterial pH 7.08	20%	200 mL	No (total: 200 mL)	Sodium bicarbonate, IV fluids, Pressors	No effect of ILE	Survival
Sampson^e [79]	Case report	24 y/F	Verapamil 7.2 g ER and 80 mg immediate-release Oral ingestion	2.91	Hypotension 65/30 mmHg Tachycardia 80 beats/min	20%	60 mL IO and then 60 mL IV	No (total: 120 mL)	IV fluids, Pressors, Glucagon, HIET	No effect of ILE	Died (The patient reported pain during IO bolus infusion)
Schult et al. [80]	Case report	12 y/F	Amlodipine 240 mg [87 ng/mL] Benazepril 480 mg Oral ingestion	2.00 −0.71	Hypotension Coma	20%	100 mL	NR	NR	NR	NR
Sebe et al. [81]	Case series, No 1	27 y/F	Diltiazem 2400 mg (40 mg/kg) Oral ingestion	2.64	Hypotension 2nd degree heart block	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Calcium, HIET, Temporary pacemaker	Normotensive after ILE	Survived
	Case series, No 2	21 y/F	Amlodipine 140 mg (1.86 mg/kg) Oral ingestion	2.00	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Calcium, HIET	Normotensive after ILE	Survived
	Case series, No 3	51 y/M	Metoprolol 1800 mg (30 mg/kg) Oral ingestion	−0.34	Cardiac arrest	20%	1.5 mL/kg x3	No (total: 4.5 mL/kg)	IV fluids, Glucagon, Mechanical ventilation	No improvement in hemodynamics	Died (ARDS)
	Case series, No 4	44 y/F	Valsartan 1600 mg (17.7 mg/kg) Amlodipine 100 mg (1.11 mg/kg) Oral ingestion	−0.34 2.00	Hypotension	20%	1.5 mL/kg x3	No (total: 4.5 mL/kg)	IV fluids, Calcium, HIET	No improvement in hemodynamics	Survived
	Case series, No 5	22 y/F	Amlodipine 90 mg (1.63 mg/kg) Oral ingestion	2.00	Hypotension	20%	1.5 mL/kg x3	No (total: 4.5 mL/kg)	IV fluids, Calcium, HIET	No improvement in hemodynamics	Survived
	Case series, No 6	32 y/F	Amlodipine 150 mg (1.76 mg/kg) Oral ingestion Acetaminophen (paracetamol)	2.00	3rd degree heart block	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Calcium, Acetylcysteine, Temporary pacemaker	Normotensive after ILE	Survived
	Case series, No 7	31 y/F	Amlodipine 110 mg (1.46 mg/kg) Oral ingestion	2.00	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids Calcium, HIET	Normotensive after ILE	Survived
	Case series, No 8	23 y/F	Carvedilol 750 mg (12.5 mg/kg) Oral ingestion	3.16	Hypotension Bradycardia	20%	1.5 mL/kg x2	No (total: 3.0 mL/kg)	IV fluids, Glucagon Temporary pacemaker	Normotensive after ILE	Survived
	Case series, No 9	18 y/F	Verapamil 2880 mg (41.1 mg/kg) Oral ingestion	2.91	Cardiac arrest	20%	1.5 mL/kg x2	No (total: 3.0 mL/kg)	IV fluids, Calcium, HIET Mechanical ventilation	Normotensive after ILE	Hypoxic, ischemic encephalopathy
	Case series, No 10	21 y/F	Propranolol 960 mg (11.3 mg/kg) Oral ingestion	0.99	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Glucagon	Normotensive after ILE	Survived
	Case series, No 11	31 y/M	Amlodipine 210 mg (2.33 mg/kg) Oral ingestion	2.00	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Calcium, HIET	Normotensive after ILE	Hypoxic ischemic encephalopathy
	Case series, No 12	26 y/F	Carvedilol 625 mg (9.6 mg/kg) Oral ingestion	3.16	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Glucagon	Normotensive after ILE	Survived
	Case series, No 13	44 y/F	Verapamil 1320 mg (16.5 mg/kg) Oral ingestion	2.91	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Calcium, HIET	Normotensive after ILE	Survived
	Case series, No 14	24 y/M	Propranolol, dose NR Oral ingestion	0.99	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids, Glucagon	Normotensive after ILE	Survived
	Case series, No 15	33 y/M	Propranolol 800 mg (0.94 mg/kg) Oral ingestion	0.99	Hypotension	20%	1.5 mL/kg	No (total: 1.5 mL/kg)	IV fluids Glucagon	Normotensive after ILE	Survived
Su^b [82]	Case report	17 y/M	Amlodipine 1.25 g Oral ingestion (many coingestants (unspecified))	2.00	Hypotension 50/30 mmHg Bradycardia 40 beats/min, 3rd degree block	NR	NR	NR	IV fluids, Pressors, Calcium, Insulin, Glucagon, ECMO	Improvement was not seen with ILE, patient improved with ECMO	Survival
Szadkowski et al. [83]	Case report	12 mth/M	Flecainide, dose NR Route NR [2.57 mcg/mL]	0.55	Hypotension Dysrhythmias Apnea Coma	20%	1.5 mL/kg	0.25 mL/kg/h for 2 h. Then stopped for 30 min and then restarted	Sodium bicarbonate, IV fluids, Pressors	VT recurred 30 min after 1st infusion ended, resolved after restarting ILE infusion and sodium bicarbonate.	Survival
Tse et al. [84] Note: Poison center study of a variety of toxins, 2nd hand information	Case series, No 1	45 y/M	Propranolol, dose NR Dothiepin, dose NR Oral ingestion	0.99 2.92	Cardiac arrest	20%	100 mL	NR	Sodium bicarbonate	Positive effect of ILE on ROSC	Survival
	Case series, No 2	46 y/F	Amitriptyline, dose NR Oral ingestion	3.96	QRS changes (details NR) Cardiac arrest	20%	100 mL	0.25 mL/kg/min for 30 min (total: NR)	Sodium bicarbonate, Pressors	Authors report “Effect on hemodynamics”	Survival
	Case series, No 3	45 y/F	Amitriptyline, dose NR Oral ingestion	3.96	Wide QRS	NR	No	0.25 mL/kg/min for 2 h	Sodium bicarbonate	NR	Survival
Tse et al. [85]	Case report	55 y/M	Methamphetamine “egg size” dose Oral ingestion	−0.57	Tachycardia Adrenergic symptoms	20%	1.5 mL/kg	NR (total: 1.5 mL/kg)	NR	Resolution of hyperadrenergic excess in 20 min	Survival
Vodnala [86]	Case report	50 y/M	Flecainide, dose NR Oral ingestion [5.89 mcg/mL] (cardizem, aripiprazole)	0.55	Hypotension Wide QRS, QT 700 ms Cardiac arrest Single seizure Coma	NR	NR	NR	Sodium bicarbonate, IV fluids	ILE did not appear to affect the outcome	Died
Watt et al. [87]	Case Series, No 1	Young/F	Quetiapine 4.3 g Oral ingestion (diazepam 300 mg, acetaminophen (paracetamol)/dihydrocodeine, ferrous fumarate)	1.82	Coma	20%	NR	NR (reports ‘Standard lipid rescue protocol’)	NR	No	Survival
	Case series, No 2	Middle-aged/F	Quetiapine 4.6 g Oral ingestion Acetaminophen (paracetamol)	1.82	Hypotension Sinus tachycardia 120 beats/min, QTc 550 ms Coma	20%	NR	NR (reports ‘Standard lipid rescue protocol’)	IV fluids, Acetylcysteine	No	Survival
Yesilbas et al. [88]	Case report	8 y/M	Organophosphate (from eating leeks) Oral ingestion	NA	Bradycardia Coma	20%	NR	8 g/kg/day for 2 days (total: 16 g/kg)	Atropine, Pralidoxime, CVVHD	No immediate improvement and other treatments given. Improved over 4 days	Survival

ACLS: Advanced cardiac life support; ARDS: Acute respiratory distress syndrome; BP: BLood Pressure; CVVHD: Continuous Venovenous Hemodialysis; ECMO: Extracorporeal membrane oxygenation; ER: Extended release; HDI: High dose insulin; HD: Hemodialysis; HIET: High-dose insulin euglycemia therapy; ILE: Intravenous lipid emulsion; MARS: Molecular Adsorbent Recirculation System; MAP: Mean arterial pressure; NA: not applicable; NR: Not reported; NSR: Normal sinus rhythm; PEA: Pulseless electrical activity; PMVT: Polymorphic ventricular tachycardia; PVC: Premature ventricular contractions; ROSC: Return of spontaneous circulation; RSI: Rapid sequence induction; TdP: Torsade de pointes; VA: Veno-arterial; VES: Ventricular extrasystoles; VT: Ventricular tachycardia.

^a The total dose in g/kg was infrequently available, and could only be calculated if body weight was reported.

^b Available as abstract only at the time of writing.

^c Adapted from www.chemspider.com. The log D refers to the logarithm of octanol/water partition coefficient.

^d Individual patient details are not reported for the case series.

^e Full text article included as it is available at the time of writing, and includes more information compared to abstract reference included in the systematic review (5).

^f These doses are likely in mL/kg but are transcribed as reported in the original article.

Appendix 4. Summary of the 11 animal studies included in the 2015 update.

Article (Species)	Model	Poison, dose and route	Log D	Symptoms	ILE used	ILE bolus^a	ILE infusion	Study arms	Timing of rescue, time from LA termination	Other treatments received^b	Parameter measured	Outcome	Support effect of ILE
Local anesthetics
RCS
Udelsman [33] (Pigs)	Randomized trial	Bupivacaine 5 mg/kg Intravenous	2.68	Fall in arterial BP, and ventricular systolic work index	NR	4 mL/kg	No	LCT vs LCT/MCT vs Saline	Study treatments 1 min after LA	NR	Arterial BP, CI and ventricular systolic work index	Survival NR	Yes; Both lipid emulsions were efficient and similar options to reverse hypotension
Zaballos [34] (Pigs)	Randomized trial	Bupivacaine 4–6 mg/kg Intravenous	2.68	150% increase in QRS	20%	1.5 mL/kg	0.25 mL/kg/min Time NR	ILE vs Saline (details NR)	NR	NR	QRS	Survival: ILE 6/6 Saline 6/6	Yes; But control group QRS was wider
Non-local anesthetics
RCS
Bourque [35] (Rats)	Controlled trial	Propofol 10 mg/kg Intravenous	3.88	Hypotension	NR	4 mL/kg	No	ILE vs Saline	NR	NR	MAP, cortical activity assessments by EEG	Survival rate NR ILE superior to saline in the reversal of decreased MAP with minimal effect on the anesthetic profile of propofol	Yes
Peacock [39] (Cats)	Randomized trial	Permethrin, dose NR Topical	6.47	Some had single seizures	20%	No	15 mL/kg in 60 min	ILE vs Saline	Variable	Supportive, details NR Methocarbamol for seizure-like activity, diazepam	Authors graded the cats’ neurologic statuses and found a decrease in the time and severity of poisoning in the treatment group	Survival: ILE NR/20 Saline NR/14	Yes; ILE-treated cats improved earlier compared to control cats
Varney [42] (Pigs)	Randomized trial	Diphenhydramine 1 mg/kg/min Intravenous	1.92	Diphenhydramine dosing continued until MAP was 60% of baseline	20%	7 mL/kg	0.25 mL/kg/min	ILE vs Bicarbonate	Other treatment and study treatment immediately after diphenhydramine	Bicarbonate: 2 mEq/kg plus an equal volume of normal saline solution	systolic BP, MAP, cardiac output, QRS and time to death	Survival: ILE 1/12 Bicarbonate 2/12	No; no difference in outcome measures between groups
Case Reports/ Series
Ceccherini [36] (Cats)	Case series (N = 4)	Permethrin, dose and route NR	6.47	Muscle fasciculations and seizures	NR	Variable doses	Variable doses	NA	NR	Dexmedetomidine, dose NR	NR	Survival: 4/4	Yes; seizure-like activity responded
Herring [37] (Dogs)	Case series (N = 3)	Naproxen 2.2–2.5 g Oral ingestion	0.45	NR	20%	2 mL/kg	0.25 mL/kg/min for 30 min	NA	NR	NR	NR	Survival: 3/3	The animals were empirically treated due to the high dose and it is impossible to infer any clinical benefit over supportive care alone
Jourdan [38] (Cats)	Case series (N = 20)	Ivermectin 4 mg/kg Subcutaneous	5.76–6.21	NR	20%	1.5 mL/kg (N = 16) and other ILE boluses given until clinical resolution com-plete	0.25 mL/kg/min for 30 min (following the bolus in N = 4 animals)	NA	Early initiation	NR	NR	Survival: 20/20	The animals were empirically treated due to the high dose and it is impossible to infer any clinical benefit over supportive care alone
Saqib [40] (Lion)	Case report	Ivermectin 3 mg/kg Oral ingestion	5.76–6.21	Hypotension Bradycardia 50-60 beats/min Ataxia, apparent hallucinations, single seizure Coma Blindness Bradypnea 10–15 breath/min Decreasing body temperature	20%	1st dose: 1.5 mL/kh	1st dose: 0.25 mL/kg/min for 30 min 2nd dose: 0.5 mL/kg/min for 30 min	NA	1st ILE dose after app. 72 h 2nd ILE dose after 92 h	IV fluids Activated charcoal and later gastric lavage Glucose, diazepam, atropine, neostigmine, ceftriaxone Mechanical ventilation	NR	Survival	Yes
Seitz [41] (Cat)	Case report	Permethrin, dose NR Topical	6.47	Single seizure	20%	1.5 mL/kh	0.25 mL/kg/min for 2 h (total: 31.5 mL/kg)	NA	NR	IV fluids Methocarbamol, diazepam	NR	Survival; seizure termination prior to ILE persistent gross lipemia and suspected corneal lipidosis	Yes
Williams [43] (Dog)	Case report	Synthetic cannabinoid receptor agonist	NR	Bradycardia 60 beats/min Coma Periodic apnea Hypothermia 32.5 °C	20%	1.5 mL/kh	0.5 mL/kg/h for 6 h (total: 2 mL/kg)	NA	NR	IV fluids Supportive care Mechanical ventilation	Vital parameters Drugs measured: 9-THC, AM-2201, JWH-122	Survival; mental status improved following ILE	Unclear

^a The bolus dose in g/kg and infusion dose in g/kg/h could only be calculated if lipid concentration was reported.

^b Drugs used for general anesthesia or euthanasia are not included.

BP: Blood pressure; CI: Cardiac index; EEG: electroencephalography; ILE: Intravenous lipid emulsion; IV: Intravenous; LA: Local anesthetic; LCT: Long chain triglyceride; MAP: Mean arterial pressure; MCT: Medium chain triglyceride; NA: Not applicable; NR: Not reported; RCS: Randomized controlled studies.

Appendix 5. Vote results

		Life-threatening toxicity			Non-life-threatening toxicity
Toxins	Cardiac arrest	As first line therapy	As part of treatment modalities	If other therapies fail (in last resort)	As first line therapy	As part of treatment modalities	If other therapies fail (in last resort)
Local anesthetics
Bupivacaine	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 anaesthetics
Antidysrhythmics 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 tricyclic antidepressants	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 blockers Diltiazem 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 blockers Dihydropyridines	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/A
Ivermectin	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 Serotonin Reuptake 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.

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