Intravenous Lipid Emulsion Therapy

Alberto L. Fernandez Mojica, St. Georges, West Indies, Grenada

Intravenous lipid emulsion (ILE), also known as intravenous fat emulsion (IFE), has been used in human and veterinary medicine as a part of total parenteral nutrition (TPN) or partial parenteral nutrition (PPN) for the past several decades. It also has been used as a vehicle for drug delivery for emulsions, such as propofol. More recently, ILE has been recommended as a potential antidote for lipophilic drug toxicosis.

In the 1970s and 1980s, studies that evaluated the effects of ILE on the pharmacokinetics of chlorpromazine and cyclosporine in rabbits and phenytoin in rats demonstrated potential support for use of ILE in certain drug toxicities. Almost 2 decades later, Weinberg and colleagues reintroduced the potential beneficial effects of ILE in the treatment of the fat-soluble, local anesthetic bupivacaine toxicosis. Since then, several animal studies and human and animal case reports have reported successful use of ILE. Toxicoses that are reportedly responsive to ILE treatment include bupivacaine, lidocaine, clomipramine, verapamil, bupropion, mepivacaine, ropivacaine, haloperidol, quetiapine, doxepin, carvedilol, carbamazepine, flecainide, hydroxychloroquine, amlodipine, propranolol, calcium channel blockers (e.g., diltiazem), and macrocyclic lactones (e.g., moxidectin, ivermectin). However, success with ILE has been variable, ranging from no improvement to complete resolution of clinical signs. That said, ILE is considered a potential antidote in cases of lipid-soluble toxicities in which cardiopulmonary arrest (CPA) and standard resuscitation have failed to result in return of spontaneous circulation (ROSC). Currently, no prospective, randomized studies are available in human or veterinary medicine regarding the use of ILE because it is currently reserved for catastrophic toxicities and severe clinical signs.

In veterinary medicine, recent publications describe the use of ILE for macrocyclic lactones, lidocaine, pyrethrins, and calcium channel blocker toxicoses (Crandell et al, 2009; O’Brien et al, 2010; Clarke et al, 2011; Brückner et al, 2012; Maton et al, 2013). A state-of-the-art review was recently published introducing the first recommendations on the use of ILE in veterinary medicine (Fernandez et al, 2011). Pet Poison Helpline, an animal poison control center based in Minneapolis, has experienced anecdotal success with the use of ILE for certain additional medications with a narrow margin of safety (e.g., baclofen, cholecalciferol, β-blockers).

Mechanism of Action

The precise mechanism of action through which ILE increases the rate of recovery and augments conventional resuscitation efforts in various cases of lipophilic drug toxicosis is currently unknown. It is possible that the potential antidotal effects of ILE vary with the lipophilicity of the toxic agent or that more than one mechanism of action is operative. Current theories regarding ILE’s mechanism of action are:

• Providing myocytes with energy substrates, thereby augmenting cardiac performance.

• Restoring myocardial function by increasing intracellular calcium concentration.

• Acting as a lipid sink by sequestration of lipophilic compounds into the newly created intravascular lipid compartment (a lipid or pharmacologic sink). With this lipid sink hypothesis, compartmentalization of the drug into the lipid phase results in a decreased free drug concentration available to tissues.

• Increasing the overall fatty acid pool, which overcomes inhibition of mitochondrial fatty acid metabolism (e.g., bupivacaine toxicosis).

Currently, the most supported hypotheses are that ILE improves cardiac performance and provides a lipid sink effect in the vascular compartment.

Current Published Human Research Information and Data

The vast majority of ILE publications in human medicine stem from case reports. Initial human case reports related to the use of ILE as a treatment in local anesthesia-related CPA that was unresponsive to cardiopulmonary resuscitation (CPR). In 2006, the first case study was published involving a patient who developed seizures and cardiac arrest shortly after receiving a nerve block with a mixture of bupivacaine and mepivacaine (Rosenblatt et al, 2006). After 20 minutes of unsuccessful CPR and advanced cardiac life support (ACLS), 100 ml of a 20% ILE was administered (1.2 ml/kg IV bolus), followed by an additional constant rate infusion (CRI) (0.5 ml/kg/min, IV, over 2 hours). Sinus rhythm and ROSC occurred shortly after administration of the ILE bolus. The patient recovered uneventfully. Similar reports have since been published demonstrating an amelioration or reversal of the adverse effects of bupivacaine, mepivacaine, and ropivacaine with ILE. However, ILE has not proven to be consistently effective in all cases of lipophilic drug toxicosis, presumably related to the lipid solubility of the toxin in question.

Current Published Veterinary Information

Experimental studies: In contrast to the available human data, most of the animal publications are in the form of experimental studies. One of the first investigations performed in 1974 evaluated in vivo and ex vivo rabbit models of chlorpromazine toxicosis. In the in vivo arm of the study, all control rabbits dosed with 30 mg/kg IV chlorpromazine died, whereas all control rabbits in the ILE pretreatment group lived. The study also reported significantly decreased free chlorpromazine after the addition of ILE to rabbit blood. A similar study evaluating coadministration of 20% ILE on the pharmacokinetics of cyclosporine in rabbits reported decreased total body clearance and volume of distribution of cyclosporine with ILE administration.

In 1998, Weinberg and colleagues evaluated the effects of pretreatment with ILE in a rodent model of bupivacaine-induced asystole and reported a 48% increase in median lethal dose (LD₅₀) in the ILE-treated group. Several years later, this author evaluated the effect of saline fluid versus ILE in the treatment of bupivacaine-induced cardiotoxicity in 12 dogs in which all animals in the saline control group failed to develop ROSC and died, whereas all the ILE-treated patients survived. Additional details of these and related studies can be found in the review of Jamaty et al.