Embed Size (px)
Citation preview
INTRAVENOUS LIPID EMULSION:
APPLICATIONS IN TOXICOLOGY
Nicole Spurlock DVM, DACVECC
Emergency and Critical Care Medicine
www.sashvets.com
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%
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
Anecdotal Evidence
• Baclofen• Loperamide• Bupropion• Sertraline• Carbamazepine• Carprofen• Chlorpromazine• Cyclosporine• Dexamethasone• Diazepam• Digoxin• Diltiazem
• Itraconazole• Ketoprofen• Loratadine• Mepivacaine• Metopolol• Naproxen• Nicotine• Vinblastine• Trazodone
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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)
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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”
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
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
www.sashvets.com
Thank you!
Questions?
www.sashvets.com
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.
www.sashvets.com.au twitter: @SASHvets
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
