INTRAVENOUS LIPID EMULSION:

APPLICATIONS IN TOXICOLOGY

Nicole Spurlock DVM, DACVECC

Emergency and Critical Care Medicine

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Background

• IVLE historically utilized as a dense source of calories in parenteral nutrition admixtures

• Also effective as a drug delivery vehicle for drugs which are poorly water soluble (propofol)

• IV Lipid emulsions are composed of medium or long chain triglycerides (or a combination of both)

• Most formulations are composed of soybean oil in water stabilized by an egg phospholipid emulsifier

• Most common formulations used are in concentrations of 10-30%

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Human Data

• CPR – Initial reports related to the use of ILE as a treatment in cases of local

anesthesia related arrest– unresponsive to CPR

• Lipophilic drug overdose therapy– Antidepressants – Antipsychotics– Beta blockers

• Poison control centers in the United States currently recommend ILE administration as treatment for human patients intoxicated with lipophilic drugs

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Lipid emulsion is superior to vasopressin in a rodent

model of resuscitation from toxin-induced cardiac arrestDiGregorio et al. Crit Care Med 2009; 37 (3): 993-998

• Instrumented rats were given IV bupivacaine to induce asystole

• Rats were given 100% O2, given chest compressions, and randomized to receive 30% ILE alone or combined with epinephrine

• Lipid emulsion in this rat model provided superior hemodynamic and metabolic recovery from bupivacaine-induced cardiac arrest vs. vasopressors

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Veterinary Clinical Application

• IVLE therapy has received much recent attention as a potential antidote for a variety of lipophilic drug intoxications

– Unknown if effective with all lipophilic compounds

• Holds promise for shortening hospitalization times as well as decreasing expense, morbidity, and mortality

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Anecdotal Evidence

• Baclofen• Loperamide• Bupropion• Sertraline• Carbamazepine• Carprofen• Chlorpromazine• Cyclosporine• Dexamethasone• Diazepam• Digoxin• Diltiazem

• Itraconazole• Ketoprofen• Loratadine• Mepivacaine• Metopolol• Naproxen• Nicotine• Vinblastine• Trazodone

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Veterinary application: IVLE for

treatment of intoxication

• In vitro evidence:

– Local anesthetics

• Bupivicaine

– Calcium channel blockers

• Amlodipine

• Verapamil

– Avermectin pesticides

• Case Reports-

• Feline:

– Lidocaine

• Permethrin

• Ivermectin

• Canine:

– Ivermectin

– Moxidectin

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Moxidectin toxicosis in a puppy successfully treated

with intravenous lipids Crandell et al (JVECC ‘09)

• First clinical case report published in veterinary medicine

• 16 week old terrier exposed to moxidectin and subsequently treated with IVLE

– Initial presentation: vomiting, ataxia, seizures, & tremors progressing to coma

– Initial therapy: diazepam, glycopyrrolate, IVF

– Mechanical ventilation required for respiratory support

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Moxidectin toxicosis in a puppy successfully treated

with intravenous lipids Crandell et al (JVECC ‘09)

• IVLE therapy initiated 10 hours post exposure– Bolus of IVLE followed by CRI– Within 2 hours of initiation of IVLE therapy, puppy able to breathe

without MV– 11 hours after initiation of IVLE therapy, puppy was extubated

• Second dose of IVLE administered 25 hours post exposure– Patient ambulatory 30 min after administration of IVLE– Clinically normal within 4 hours; eating within 6 hours of IVLE therapy

• Discharged 2 days after admission

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Adjunctive therapy with IVLE and methocarbamol for

permethrin toxicity in 2 catsKuo et al (JVECC ’13)

2 cats presenting with severe (topical) permethrin toxicosis- Clinical signs: generalized tremors, hyperesthesia, hyperthermia, tachycardia- IVLE instituted in addition to external decontamination, methocarbamol, IVF,

diazepam

Cat 1: - Resolution of tremors 2 hours post initiation of IVLE therapy- Bright, alert, and responsive 12 hours after completion of IVLE therapy

Cat 2: - Tremors significantly improved after 30 min of IVLE- 5 hours post IVLE, tremors resolved- IVLE repeated due to recurrence of mild tremors- 17 hours after presentation, clinically normal and eating

Outcome- Reduction in recovery and hospitalization times (both patients)- Immediate reduction in severity of tremors prior to administration of other

medications (cat 1)

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Infusion of a lipid emulsion to treat lidocaine

intoxication in a catO’Brien et al (JAVMA ‘10)

• 5 yo MN DSH presenting 30 min after receiving 20 ml/kg SQ lidocaine (!)– Presented obtunded, hypotensive, and in respiratory distress – Arrhythmia ausculted

• 30 min after presentation, IVLE CRI initiated– 15 minutes post initiation, patient was rousable & improving– Upon conclusion of infusion, cat aware and grooming– Clinically normal 12 hours later & discharged

• Methemoglobin concentration normal

• No adverse effects of IVLE observed

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Use of intravenous lipid emulsion to treat

ivermectin toxicosis in a Border Collie Clarke et al (JAVMA ‘11)

• 2yo FS Border Collie

• Ingestion of 6 mg/kg ivermectin paste 8 hours prior to presentation

• Presenting symptoms: lethargy, ataxia, blindness

• IVLE therapy instituted: bolus followed by CRI – Protocol repeated 12 hours after initial treatment

• Outcome:– Significant neurologic improvement noted 6 hrs after initial infusion

– Dog bright and alert after completion of second infusion

– Discharged 48 hours after presentation

– Full return of vision reported 2 days after discharge

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ABCB1-1Δ gene mutation?

• Intravenous fat emulsion as treatment for ivermectin toxicosis in three dogs homozygous for the ABCB1-1Δ gene mutation: Wright et al (JVECC ’11)

• 3 dogs homozygous for the ABCB1-1Δ gene mutation were treated with IVLE after ivermectin tocixosis

• All dogs exhibited tremors, ptyalism, and CNS depression progressing to stupor or coma

• 20% formulation of IVLE was administered as a bolus followed by a CRI to all dogs– Doses standard as compared to other case reports

• No change was observed in the neurologic status of any patient– Lipemia was visible upon blood sampling

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Lack of IVLE efficacy with ABCB1-1Δ

• Dogs with ABCB1-1Δ genotype have decreased ability to excrete ivermectin from the brain– Genotype produces nonfunctional p-glycoprotein

• P-glycoprotein normally functions to excrete substances out of the brain and into capillary lumen

• Does accumulation in brain parenchyma require higher IVLE dosing to eliminate toxin from CNS?

• Does mutation create decreased ability to excrete ivermectin from systemic circulation?– P-glycoprotein also important for biliary clearance mechanisms

• More studies required to identify source of therapeutic failure & implications

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Mechanism of Action

Two proposed theories:

• Augmentation of cardiac function

– Supplemental lipid (FFA) augments cardiac performance and increases mitochondrial ATP production

– Increases in intracellular calcium concentration restores myocardial function

• Creation of lipid partition within intravascular space and preferential sequestration of lipophilic drugs into the newly formed “lipid sink”

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IVLE: Adverse Effects

• Most AE associated with IVLE are associated with long term administration or with plasma clearance impairment

• Toxicity has not been documented for one-time infusions– No adverse clinical reactions have been reported from the use of IVLE for

various toxicosis

• Most common AE in humans – Hypersensitivity to egg stabilizer

• “colloid reaction”

– Thrombophlebitis at IVC site

– Contamination

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Fat Overload Syndrome (FOS)

• Delayed or sub-acute reaction

• Usually results after administration of excessive volumes or high administration rates– Overwhelms endogenous lipid clearance mechanisms

• FOS effects (humans)– Hyperlipidemia– Hepatomegaly– Icterus– Splenomegaly– Thormbocytopenia, – Coagulopathy– Hemolysis– Seizures

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Heparin and Hyperlipidemia

• Heparin significantly increases rate of lipid metabolism

– Stimulates release of hepatic lipase from the endothelium

• Heparin infusion may prevent secondary complications of ILE via enhancement of lipid metabolic rate

– Thought to minimize hyperlipidemia and secondary risks of FOS

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Heparin & ILE Therapy

• Routine use of heparin with ILE therapy not currently recommended– Administration of heparin reduces the lipid compartment in the

blood & decreases efficacy of “lipid sink”– Use only in patients at high risk for FOS or secondary effects from

severe hyperlipidemia

• Nasstrom et al (2011): – LPL released as a result of heparin administration has a short half-life

and storage depletion occurs soon after administration– Use heparin CRI for continuous effects of LPL concentrations

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Safety Considerations

• Adverse effects associated with ILE therapy are rare in veterinary patients – Safety of ILE is determined by globule size distribution

• Emulsions become potentially unsafe when lipid droplets coalesce & form large globules that separate from the aqueous phase

• IV lipid formulations are categorized in 3 main groups based on mean droplet size (MDS)– Macro: MDS > 1.0 um– Mini: MDS < 1.0 um– Micro: MDS<0.1 um

• Droplets >1um are phagocytized by the RES– Increases risk of microembolization secondary inflammatory response

• To optimize safety of final emulsion:– Mean droplet size (MDS) <500 nm– Volume-weighted percentage of fat < 0.05% of total dispersed phase– Free FA concentration < 0.07 mEq/g

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Available Formulations

• Commercial 20% lipid preparations are appropriate for ILE therapy

• Van de Velde et al (2010)

– Comparison of hemodynamic effects of ILE preparations in conscious, instrumented canines

• Intralipid 20% infusion:

– Slight increase in HR, transient decrease in arterial pH

• Medialipide 20% & Omega-3 PUFA emulsion infusion:

– Reduction in myocardial contractile performance

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IV Lipid Handling

• Physical and chemical stresses can decrease the shelf life and safety of ILE

• pH must be maintained between 6.0-9.0- Hydrolysis of triglycerides into FFA decreases emulsion pH from an initial

9.0 to 6.0 by expiration date

• Aseptic technique is imperative to decrease risk of bacterial contamination and destabilization

• Unused portion of ILE can be refrigerated; discard after 24 hours

• Specific indications for storage vary depending on manufacturer

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Administration Guidelines

• Required equipment

– 20% Intralipid

– In-line filters

• Tonicity of IVLE: 600-900 mOsm/L

– Commercially available ILE preparations are isotonic, may be administered via a peripheral catheter

• Aseptic technique required as IVLE is susceptible to bacterial overgrowth

• Must be administered in dedicated line

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Dosing Protocol

• 1.5 ml/kg Intralipid (20%) over 5-15 minutes, followed by 0.25 ml/kg/min for 30-60 min– Simplified: 1.5 ml/kg over 10 min followed by 15 ml/kg over 1 hour

• Dose can be repeated in 4-6 hours if clinical signs of toxicity return

• Many studies suggest checking for gross lipemia via micro-HCT tubes prior to administration of additional doses

• Maximum daily dosing has not been determined in veterinary patients

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Summary

• Administration of ILE for treatment of LA or other lipophilic drug toxicity in veterinary medicine is in its infancy

• Judicious use of ILE should be considered based on the lipophilic nature of the drug– The more lipophilic a drug, the more suitable ILE therapy is for

treatment of toxicity

• The use of ILE appears to be a safe therapy for lipophilic intoxications

• Adverse effects associated with ILE in veterinary medicine are rare and anecdotal

• Standard resuscitation protocols should be employed prior before administration of ILE

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Thank you!

Questions?

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References• Clarke et al. Use of intravenous lipid emulsion to treat ivermectin toxicosis in a Border Collie. JAVMA 2011; 239(10): 1328-1332.

• Crandell D.E and Weinberg G.L. Moxidectin toxicosis in a puppy successfully treated with intravenous lipids. JVECC 2009; 19(2): 181-186.

• Epstein et al. Ivermectin-induced blindness treated with intravenous lipid therapy in a dog. JVECC 2013; 23(1): 58-62.

• Fernandez AL, Lee JA, Tahilly L, et al. The use of intravenous lipid emulsion as an antidote in veterinary toxicology. JVECC 2011; 21(4):309-320.

• Jamaty et at. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Tox 2010; 48, 1-27.

• Kuo et at. Adjunctive therapy with intravenous lipid emulsion and methocarbamol for permethrin toxicity in 2 cats. JVECC 2013;23(4): 436-441

• O’Brien et al. Infusion of a lipid emulsion to treat lidocaine intoxication in a cat. JAVMA 2010; 237(12);1455-1457

• Pritchard J. Treating ivermectin toxicity in cats. VetRec 2010; 166:766.

• Weinberg et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced systole in rats. Anesthesiology 1998;88(4):1071-1075.

• Wright et al. Intravenous fat emulsion as treatment for ivermectin toxicosis in three dogs homozygous for the ABCB1-1 gene mutation. JVECC 2011; 21(6):666-672.

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Phone - (02) 9889 0289 Fax - (02) 9889 0431

Level 1, 1 Richardson Place, North Ryde 2113, Sydney, NSW

www.sashvets.com.au twitter: @SASHvets

Phone - (02) 9889 0289 Fax - (02) 9889 0431

Level 1, 1 Richardson Place, North Ryde 2113, Sydney, NSW