The Use of IV Lipid Emulsion for Lipophilic Drug Toxicities
IV lipid emulsion (ILE) therapy is emerging as a potential antidote for lipophilic drug toxicities in both human and veterinary medicine. ILE has already gained acceptance in human medicine as a treatment of local anesthetic systemic toxicity, but its mechanism of action, safety margins, and standardized dosing information remains undetermined at this time. Experimental and anecdotal use of ILE in the human and veterinary literature, theorized mechanisms of action, current dosing recommendations, potential adverse effects, and indications for use in human and veterinary emergency medicine are reviewed herein.
Introduction
Every year, animal poison control helplines receive thousands of calls regarding the consumption of household substances that can result in fatal toxicities. In 2009, the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center handled >45,000 calls related to pets ingesting human medications and >29,000 calls related to insecticide poisonings.1 Of the toxins ingested in that year, the most commonly reported toxins included painkillers, antipsychotics, and insecticides/herbicides.1 For the ingestion of toxic substances where no proven antidote exists, general recommendations for medical management center on decontamination and supportive care.1 Over the last decade there has been emerging experimental and anecdotal evidence published in both the human and (to a much lesser extent) veterinary literature supporting the use of IV lipid emulsion (ILE) to reverse hemodynamically and neurologically significant poisonings resulting from ingestion of lipophilic medications.2–24
ILE has proven to be an effective treatment of local anesthetic systemic toxicity in both humans and animals and shows promise as a novel antidote for a wide array of other lipophilic drug poisonings.25 Included in this review article is a comprehensive review of the use of ILE in the treatment of various lipophilic toxicities. A review of the experimental evidence in both the human and the veterinary literature, case reports of ILE use, theorized mechanisms of action, current dosing recommendations, and potential adverse effects of ILE are described. If ILE can be shown to be effective for treating lipid-soluble toxicities with minimal adverse effects, it could potentially be used as an antidote by emergency veterinarians for lipid-soluble toxicities that presently do not have effective antidotes. In turn, morbidity and mortality in poisoned small animals would decrease.
History
The use of ILE as an antidote was first introduced into human medicine as a rescue treatment of local anesthetic toxicities. Although rarely encountered in human medicine, systemic absorption of local anesthetics has the potential for causing cardiovascular collapse that is considered to be resistant to current resuscitative protocols.26 The potential benefit of ILE was first theorized in 1997 after the incidental discovery of carnitine’s relationship to local anesthetic cardiotoxicity.27 Dr. Guy Weinberg, a leading researcher in the field of ILE, was motivated by this discovery to perform a study in rats that documented a decrease in the cardiotoxic threshold of bupivacaine following ILE administration.2 That study, by Weinberg et al. (1998), laid the groundwork for continued research into the use of ILE as an antidote for local anesthetic toxicities. Eventually, the literary support for ILE’s potential effects against local anesthetic toxicities led to the first documented successful use of ILE in the clinical setting as a rescue treatment of bupivacaine-induced cardiovascular collapse in a human in 2006.3 A recent case report in the veterinary literature documents the successful use of ILE therapy in a cat suffering from a local anesthetic toxicity. That cat clinically recovered from the cardiovascular effects of lidocaine toxicity following the administration of a 1.5 mL/kg IV bolus of ILE over 30 min.24
Lipid Emulsions
ILEs, also referred to as IV fat emulsions, provide calories in IV parenteral nutrition formulations. They are also used as a vehicle for the delivery of lipid-soluble drugs such as propofol. ILEs are oil-in-water emulsions consisting of triglyceride-containing oils, a phospholipid emulsifier (10% or 20%), and glycerin.28 Commercially available ILEs in the US are made from soybean oil (Intralipida or Liposyn IIIb) or combined safflower/soybean oil (Liposyn IIc). The fat droplets in ILEs are similar to endogenous chylomicrons and are cleared by skeletal muscle, splanchnic viscera, myocardium, and subcutaneous tissues. Glycerol and free fatty acids are the breakdown products of the triglyceride, phospholipid, and choline components of ILE and are used by body tissues as energy sources.4,28
Theorized Mechanism of Action
Although there has been a push for researchers to identify potential mechanisms of action for ILE, the definitive mechanism of action has yet to be determined. Studies and anecdotal evidence support theories regarding lipid partitioning, mitochondrial recovery, and direct inotropy.29 Those three mechanisms are described below.
Lipid Partitioning
The prevailing theory of ILE’s mechanism of action is a phenomenon termed “lipid sink.”30 Administration of ILE results in the creation of an IV lipid phase within the plasma. This lipid phase sets up a gradient that pulls the offending lipid-soluble drug into the newly formed lipid partition in the blood, away from the heart and brain.29 As the ILE circulates throughout the body, it is cleared by skeletal muscle, splanchnic viscera, myocardium, and subcutaneous tissues, which help dilute and clear the offending toxin from the body.4
Animal experimental data and human case reports document lipid-soluble toxin clearance from the body/sequestration of the toxin in the plasma following ILE administration, thus supporting the theory of lipid partitioning. One porcine model demonstrates the sequestration of amiodarone in the plasma of pigs after ILE administration.5 A human case report documents increased plasma clearance of mepivacaine following ILE administration compared with controls.6 Movement of radiolabeled bupivacaine into the plasma lipid phase and enhanced clearance of bupivacaine from cardiac myocytes has been documented in murine models.2,7 Further, drug clearance from the myocardium is greater than expected from a hemodilutional effect of the ILE administered, thus supporting the “lipid sink” theory.8,30
A component of the “lipid sink” theory involves the degree of lipid solubility of the offending drug and how this chemical property may affect the clearance of the offending drug from the body. If the “lipid sink” theory is the correct mechanism of action, then it stands to theorize that the degree of lipid solubility of a substance, referred to as its lipid partition coefficient, may affect the clearance rate of the offending toxin following ILE administration.31 This relationship may have future implications regarding dosing recommendations of ILE as a reflection of the toxin’s lipid solubility. For lipid-soluble drug toxicities (both ingested and injected) that have no known antidote, ILE may serve as a means of eliminating the toxin from the body. The time frame (acute versus chronic) that ILE may prove beneficial in treatment may depend on the individual toxin’s half-life. If the toxin’s detrimental side effects are the result of a metabolite formed from the toxin, then ILE therapy may or may not be beneficial unless ILE is given in the acute setting to decrease metabolite formation.
Mitochondrial Recovery
Early studies investigating the effects of bupivacaine on the myocardium of dogs and rats led to the acceptance of ILE’s ability to reduce the cardiodepressant effect of bupivacaine on cardiac myocytes.7,9,10,32 Free fatty acids are the preferred energy source for myocardial mitochondria under aerobic conditions, but mitochondrial utilization of free fatty acids is blocked following IV bupivacaine administration. One theory suggests that ILE acts by overriding bupivacaine’s block on mitochondrial adenosine triphosphate production and by providing free fatty acids to the mitochondria.32 This theory is supported by documentation of ILE’s successful use in treating bupivacaine toxicity at a dose that theoretically should be too low to create an effective lipid partition, discounting the “lipid sink” theory.9
Direct Inotropy
An alternate theory for ILE’s successful reversal of local anesthetic drug toxicity may be related to its ability to increase intracellular Ca concentrations in cardiac myocytes. Studies of cardiac ischemia have shown that within the myocardium, free fatty acid levels rise in parallel with increasing ionized Ca levels. A study by Huang et al. (1992) proved that long-chain fatty acids are responsible for an increase in ionized Ca levels, most likely by activating the myocardial Ca channels, which results in a dose-dependent increase in the Ca current.33 Stehr et al. (2007) showed that in live rats, ILE administration did not produce an elevated heart rate, but did increase systolic blood pressure, which may support the theoretical role of ILE as an inotropic agent.9,34
Contradictory Evidence in the Literature
Careful consideration must be taken when reviewing the reported success of ILE's ability to reverse the clinical effects of lipid-soluble drug toxicities because not all experimental data support the use of ILE. After demonstrating successful use of ILE in murine and canine models, studies were carried over into porcine models to better mimic human cardiovascular anatomy.2,10,35,36 Two studies using the porcine model of cardiovascular collapse following bupivacaine injection did not share similar conclusions with preceding studies regarding ILE’s success in treating local anesthetic toxicity. Mayr et al. (2008) conducted an experiment to compare ILE therapy to the combination of vasopressin and epinephrine in a porcine model of bupivacaine-induced cardiovascular collapse.35 Hicks et al. (2009) conducted a similar study to evaluate the use of ILE as a rescue treatment of failed standard emergency resuscitative efforts in the porcine model.36 Both studies concluded that ILE administration did not provide any recovery benefits when used as either a primary therapy or as a rescue treatment.
The differences in study conclusions between previous studies supporting ILE’s use and those two porcine studies may be attributable to differences in experimental design. In the study by Mayr et al. (2008), prolonged asphyxia may be a confounding factor in their reported unsuccessful use of ILE. Hypoxia has been shown to exacerbate bupivacaine-induced cardiotoxicity; therefore, ILE is not recommended as a rescue treatment in the face of prolonged hypoxia.37,38 Furthermore, fatty acid administration in ischemia may worsen myocardial oxidative damage.4
The high dose of epinephrine (100 ug/kg) was a potential confounding factor in the study by Hicks et al (2009).36 A follow-up study confirmed that the efficacy of ILE is impaired by high doses of epinephrine.39 This study concluded that even a single low dose of epinephrine (10 ug/kg) may be enough to impair ILE treatment. However, low doses of epinephrine (1–2.5 μg/kg) used in resuscitation may actually lead to improved recovery with the addition of ILE as a rescue treatment.39 The correlation between the effects of epinephrine and ILE, when used concurrently in either human or veterinary patients, is not clear at this time.
Dosing Recommendations
Dosing recommendations for ILE are presently lacking the support of clinical research; however, the American Society of Regional Anesthesia (ASRA) recommends an initial bolus of 1.5 mL/kg of 20% lipid emulsion followed by a constant rate infusion (CRI), ranging from 0.25 mL/kg/min to 0.5 mL/kg/min (not to exceed 10 mL/kg) over 30 min. The CRI should continue for an additional 10 min after return of hemodynamic stability, and repeated boluses can be given if initial therapy is not sufficient.40 However, dosing recommendations may need to be tailored for each lipophilic drug based on the offending compound’s degree of lipid solubility.11
A 20% lipid emulsion is preferred over the 10% lipid emulsion due to the higher proportion of free phospholipid available in the 10% formulation. Free phospholipids are thought to increase the potential for adverse effects due to their interference with lipoprotein lipase activity, which decreases ILE clearance.28 Large volumes of lipid emulsion are required for effective treatment. Propofol is therefore not recommended for use as an ILE formulation due to the high amounts of anesthetic that would be delivered with its lipid emulsion vehicle.41
Potential Risks
Despite the large volumes of lipid emulsion suggested by current dosing recommendations, ILE administration appears to have very few adverse effects.42 To the authors’ knowledge, only one study exists thus far investigating the safety of ILE using a murine model.11 Conclusions from that study estimated the lethal dose 50 (LD50) in rats for IV 20% soy-based oil emulsion was 67.7±10.7 mL/kg. That dose is higher than the proposed dose of ILE to reverse cardiovascular compromise from drug-induced cardiotoxicity in humans, suggesting a rather large margin of safety if used in accordance with the ASRA guidelines.29
Clinicians should be aware that administering lipid infusions can result in lipemia and biochemical abnormalities on routine blood tests. The previously referenced rat LD50 study identified elevations in amylase, aspartate aminotransferase (AST), phosphorus, and creatinine.11 The elevated amylase and AST can potentially be explained by the hypertriglyceridemia that results from high rates of ILE infusion. Despite the evidence of microvesicular steatosis in the LD50 rats, the AST abnormalities did not correlate with severity of liver disease.11
Reported adverse effects have not yet been documented for the use of ILE as an antidote for lipid-soluble drug toxicities in either humans or animals. The potential risks related to ILE use as an antidote may be extrapolated from documented risks of parenteral nutrition administration. However, when ILE is used in parenteral nutrition, the formulation is administered as a slow CRI over longer periods of time (days). The dosing of ILE, when used as an antidote, involves administering large volumes over a short duration (min to hr). Care must be taken to use aseptic technique when handling and administering any lipid emulsions as they can promote bacterial growth.
When ILE is used in parenteral nutrition, the risk for adverse effects appears to be affected by the rate of infusion, total daily dose, and duration of administration.28 Reported adverse effects associated with chronic parenteral nutrition supplementation in humans include effects on the immune system, pulmonary function, and hepatic function.28 Patients should be monitored closely during ILE infusion for nausea, vomiting, fever, and respiratory distress. In humans, a “fat overload” syndrome can occur that may result in fat emboli, jaundice, prolonged coagulation times, hepatomegaly, splenomegaly, thrombocytopenia, leukopenia, elevated liver function tests, pancreatitis, and seizures.28,42 This syndrome has not yet been described in animals. Hyperlipidemia may occur following the administration of large volumes of ILE and can be monitored on visual inspection of serial hematocrit tubes. Pigs have shown skin mottling and redness after ILE infusion.5 In adult human patients with acute respiratory distress syndrome or other severe inflammatory diseases, lipid emulsion administration has been associated with a transient decrease in the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen.43,44 However, no evidence of pulmonary emboli were found at necropsy in the LD50 study rats, suggesting that ILE may not typically cause pulmonary damage without pre-existing pulmonary compromise.11 Further studies evaluating short intervals of large volumes of lipid emulsion are necessary to identify potential adverse effects of ILE when used as an antidote.
Indications for Use in Human Medicine
Following the accumulation of successful case reports in the human literature, most human hospitals have accepted the use of 20% lipid emulsions for the treatment of local anesthetic toxicities.45 Current ASRA guidelines now recommend considering ILE as a first-line treatment in local anesthetic systemic toxicities in humans as opposed to as a rescue agent following the failure of conventional medical therapies.40 The classes of medications and drug compounds that may respond to ILE as an antidote are increasing as support is building for its use in treating overdoses of a variety of lipophilic medications and toxins.
Clinical experiments using animal models suggest that ILE may replace current treatment recommendations in both human and veterinary medicine for select drug overdoses. In human medicine, a standard treatment of clomipramine overdose involves the use of sodium bicarbonate in conjunction with circulatory and respiratory support measures.12 ILE outperformed the standard treatment of Na bicarbonate for the reversal of hypotension related to clomipramine overdose in a study using a rabbit model.12 Verapamil is the first medication for which an ILE dose recommendation was developed from clinical trials. An IV dose of 18.6 mL/kg of ILE reversed cardiovascular instability resulting from an overdose of verapamil in that murine model.13 Human and animal case reports have filtered into the literature over the past decade describing ILE’s success in treating various ingested lipophilic drug toxicities. Anecdotal evidence in the human literature now supports the use of ILE in treating psychotropics, β-blockers, and herbicides.14–19 Despite the anecdotal support for ILE use in treating various ingested lipophilic toxins, the published indication for ILE use in human medicine is still limited (at this time) to the treatment of local anesthetic systemic toxicities.40
Indications for ILE in Veterinary Medicine
Ingestion of either human or pet medications is among the most common type of poisoning in cats and dogs.46 Many medications do not have specific antidotes. Treatment options in those cases include immediate decontamination, symptomatic and supportive treatment with variable hospital stays, and the potential implementation of advanced life support measures. Documented use of ILE in veterinary medicine is limited at this time, perhaps due to underreporting, general lack of clinician familiarity with ILE use, and accessibility of lipid emulsions to veterinary hospitals. Despite the sparse anecdotal use of ILE in veterinary medicine, ILE may be effective in treating a multitude of ingested overdoses of both veterinary and human lipid-soluble medications in veterinary patients. Commonly ingested human and veterinary medications that have shown favorable response to ILE treatment include macrocyclic lactones, psychotropics, muscle relaxants, and blood pressure medications.46
Macrocyclic Lactones
The macrocyclic lactones are lipophilic medications commonly used as oral and topical heartworm preventatives. A case report published in 2009 described the successful use of ILE in the treatment of a puppy with moxidectin toxicity.23 Moxidectin is the most lipophilic of the currently available macrocyclic lactone preparations and has a longer half-life in the body than ivermectin. In that case report, the puppy received a 2 mL/kg IV bolus of a 20% lipid emulsion followed by a CRI of 4 mL/kg/hr for 4 hr. A second CRI was administered 25.5 hr postexposure at a rate of 0.5 mL/kg/min for 30 min. Although some improvement in neurologic status and ability to swallow was noted after the first round of lipid therapy, a more drastic improvement was noticed after the second bolus. A similar case report documented the effective resolution of coma and respiratory depression following ILE administration in a puppy suspected to have ingested avermectin.25 The puppy’s clinical signs resolved within 1 hr following a 1.5 mL/kg IV bolus of ILE followed by a CRI of 0.25 mL/kg/min for 30 min.25 Given the lipophilic nature of the macrocyclic lactones, ILE therapy should be effective in treating overdoses of these compounds. Another insecticide group of importance to veterinary medicine that may respond favorably to ILE therapy is the lipid-soluble pyrethrin compounds, which are commonly used for agricultural and domestic purposes.
Psychotropic Drugs
The drug classes within this category include the selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), and cyclic antidepressants. Serotonin is also known as 5-hydroxytryptamine.47 Medications in this group aim at increasing the amount of serotonin available in the central nervous system to treat conditions such as obsessive compulsive and anxiety disorders in both humans and animals.47 Small overdoses of SSRIs (e.g., fluoxetine, sertraline, paroxetine) in animals may cause sedation and lethargy, but large overdoses can cause hyperactivity, hypersalivation, diarrhea, mydriasis, ataxia, tremors, an altered mental state, and seizures.46,47 Those clinical signs are part of the “serotonin toxicity,” otherwise known as “serotonin syndrome”.47 A single agent or multiple agents can work synergistically to result in the stimulation of both central and peripheral serotonin receptors.47 Clinical signs observed in patients with SSNRI overdoses, such as venlafaxine, are similar to those seen with overdoses of SSRIs with the added clinical signs of hyperthermia, hypertension, and tachycardia from the increased sympathomimetic component of this toxicity.46 The cyclic antidepressants (e.g., clomipramine, amitriptyline, bupropion) cause cardiotoxic effects, resulting in bradycardia, hypotension, and arrhythmias, which can result in cardiovascular collapse.46
Typical treatment of SSRI overdoses includes supportive and symptomatic care with benzodiazepines used to treat seizures if serotonin syndrome is not present. If serotonin syndrome is suspected, benzodiazepines are avoided so as not to exacerbate neurologic signs, and barbiturates are an effective option for seizure control.46 Cyproheptadine and chlorpromazine are serotonin receptor antagonists and may be used in the treatment of serotonin syndrome.47 In both the human literature and in unpublished veterinary case reports, ingested buproprion overdoses were treated successfully with ILE therapy in humans and in animals.16,48 Clinical trials involving clomipramine overdoses in rabbits demonstrated that ILE therapy is more successful than current conventional therapies at resolving the clinical signs related to this lipophilic medication.12 Due to the lipophilic nature of SSRIs, SSNRIs, and cyclic antidepressants, ILE is an effective treatment for overdoses of medications within these groups.
Muscle Relaxants
Baclofen and cyclobenzaprine are two muscle relaxants implicated in ingested overdoses in animals.48 ILE has successfully treated both of those toxicities in animals, although published case reports are not presently available.48 Baclofen is a γ-aminobutyric acid GABAB receptor antagonist that is used in human medicine to decrease muscle spasms related to spinal cord injuries and neurologic diseases including multiple sclerosis.46 The toxic dose of this lipophilic medication in animals is relatively small and clinical effects are seen within minutes after ingestion, including ataxia and vocalization. This can progress to respiratory depression, coma, or seizures depending on the ingested dose.49 Treatment of this particular drug overdose centers on supportive and symptomatic care because no antidote currently exists. Bradycardia can be treated with atropine, hypotension can be supported with IV fluids and vasopressors, and respiratory depression may require mechanical ventilation.49 Veterinarians reported improvement in clinical signs shortly after administration of ILE in patients suffering from baclofen overdoses.50 Due to the lipophilic nature of baclofen, both the Pet Poison Helpline and the American Society for the Prevention of Cruelty to Animals Animal Poison Control consider ILE therapy a standard of care in treating baclofen overdoses as well as other lipid-soluble toxicities.48
Blood Pressure Medications
These medications are used in human and veterinary medicine to lower blood pressure in medical conditions such as kidney disease and heart disease. This drug category includes Ca channel blockers (e.g., amlodipine, diltiazem, verapamil), β-adrenergic blockers (e.g., atenolol, propranolol, sotalol), and angiotensin-converting enzyme inhibitors (e.g., enalapril, benazepril). Overdoses of either the Ca channel blockers or β-adrenergic blockers involve aggressive monitoring and treatment. Experimental data in rabbits supports the use of ILE in verapamil toxicities, and ILE is implicated in the successful treatment of propranolol and nebivolol overdoses in humans.17,18 The medications listed in the Ca channel blocker and angiotensin-converting enzyme inhibitor groups are lipid soluble compounds that would theoretically respond favorably to ILE treatment. However, the β-adrenergic blockers have significantly varying degrees of lipid solubility and may not all be effectively cleared by ILE therapy.
Conclusion
Animal studies and case reports from both human and veterinary studies guide the current use of ILE for the treatment of local anesthetic toxicities and ingested lipophilic toxicities. ILE has already gained widespread acceptance in the human medical community as a rescue treatment of local anesthetic systemic toxicities. Human case reports suggest the use of ILE as a primary treatment after the onset of clinical signs related to local anesthetic systemic toxicities to either prevent or reverse cardiovascular collapse.6,14,20,21 Dosing guidelines for ILE therapy are limited to anecdotal reports at this time, and information on adverse effects for ILE used in this manner is lacking. Through case reports, research, and case series, the knowledge of possible adverse effects will grow, aiding the development of clinical guidelines for use. Clinicians in both human and veterinary medicine are encouraged to share their success or failure with ILE therapy on the noncommercial website http://www.lipidrescue.org, which was designed by Dr. Weinberg to provide information and encourage discussion on lipid administration.51 Continued research into the mechanism of action for ILE may open new doors for ILE use in treating various lipophilic toxicities.
Implementing ILE therapy in veterinary emergency medicine may provide a cost-effective antidote for various lipophilic toxicities.14,46 Although not yet widely accepted as a first-line treatment of lipophilic toxicities, the authors of this report recommend that the use of ILE be considered in appropriate cases of lipid-soluble toxins that have no effective antidote. Special attention should be given to patient selection, client understanding and willingness to try an understudied treatment, and correct identification of the ingested or injected toxin as being lipid-soluble. With the development of dosing recommendations and margins of safety, ILE may gain acceptance as a primary treatment of severe lipophilic toxicities that have otherwise been associated with high morbidity and mortality in both animals and humans.
Contributor Notes
