+++
Chemistry/Preparation
++
IFE is composed of two types of lipids: triglycerides and phospholipids. Triglycerides are hydrophobic molecules that are formed when three fatty acids are linked to one glycerol. The fatty acid chain lengths vary, producing different triglycerides. The primary triglycerides in IFE are linoleic, linolenic, oleic, palmitic, and stearic acids; their concentrations vary slightly in the different commercially available fat emulsions. These long-chain triglycerides (12 or more carbons) are extracted from safflower oil and/or soybean oil, depending on the brand of the emulsion.79 Newer fat emulsions contain long-chain triglycerides in addition to medium-chain triglycerides (6–12 carbons) derived from coconut, olive, and fish oils, but they are currently not available in the United States.54,84
++
Phospholipids contain two fatty acids bound to glycerol and a phosphoric acid moiety that is located at the third hydroxyl group (Fig. A20–1). Phospholipids are amphipathic; that is, the nonpolar fatty acids are hydrophobic while the polar phosphate head is hydrophilic. This imparts important pharmacological properties to this carrier molecule, allowing it to solubilize nonpolar xenobiotics in aqueous serum. IFE phospholipids are extracted from egg yolks.
++
++
The lipids in IFE are dispersed in the serum by forming an emulsion of small lipid droplets. To create the emulsion droplets, the phospholipids form a layer around a triglyceride core. The hydrophobic fatty acid component of the phospholipid molecule is directed toward the triglycerides while the hydrophilic glycerol component is directed outward away from the triglyceride core. The presence of small amounts of glycerol, which is hydrophilic, allows the lipid droplets to be suspended as an emulsion in water and serum.
++
IFE is a white, milky liquid. It is sterile and nonpyrogenic with a pH of about 8 (range, 6–9). IFEs are isoosmotic solutions (260–310 mOsm/L) and can be delivered through a peripheral or central vein.79
++
IFEs have different globule sizes depending on their uses.15 Microemulsions containing droplet sizes less than 0.1 µm are used for drug delivery. Mini-emulsions containing droplet sizes greater than 0.1 µm but less than 1.0 µm are used for parenteral nutrition. Droplet sizes in commercially available nutritional IFEs range from 0.4 to 0.5 µm. Phospholipid emulsifying xenobiotics such as egg phosphatide are added and prevent droplet coalescence. After intravenous administration, IFEs are found in the serum as lipid droplets that resemble chylomicrons and turn the serum turbid or milky. Macroemulsions containing droplet sizes greater than 1.0 µm are used for chemoembolization. These macroemulsions contain chemotherapeutics that are delivered intraarterially directly into the tumor blood supply. The lipid droplets occlude the artery and slowly release the chemotherapeutic.
+++
Related Lipid Formulations
++
Most case reports documenting successful treatment of local anesthetic toxicity with lipids have utilized Intralipid or standard long-chain triglyceride mixtures. IFE containing mixtures of long-chain and medium-chain triglycerides such as Medialipid (Braun, Germany) and Liposyn III (Hospira Inc., Lake Forest, IL) have been successfully used in clinical cases of poisoning, suggesting that all currently available parenteral lipid products will be effective.30,87 IFE containing medium-chain triglycerides are not routinely available in the United States.
++
Lipid emulsions containing both long-chain and medium-chain triglyceride mixtures may be more effective at partitioning xenobiotics. In human serum, a mixture of long-chain and medium-chain triglycerides increased the extraction of bupivacaine, ropivacaine, and mepivacaine compared to long-chain triglyceride mixtures.67 However, in a rodent model of bupivacaine toxicity, long-chain and medium-chain mixtures were equally effective in reversing bupivacaine toxicity, but the long-chain mixture resulted in fewer recurrences of asystole after resuscitation and lower myocardial bupivacaine concentrations.44
++
The mechanisms of action of IFE in toxicology are not clearly understood. The three proposed mechanisms of action of IFE are modulation of intracellular metabolism, a lipid sink or sponge mechanism, and activation of ion channels.
+++
Modulation of Intracellular Metabolism.
++
In experimental models of poisoning from xenobiotics that alter intracellular energy metabolism, toxicity was successfully treated with IFE, suggesting that repairing or circumventing this dysfunction may be involved. Bupivacaine blocks carnitine-dependent mitochondrial lipid transport and inhibits adenosine triphosphatase (ATPase) synthetase in the electron transport chain.13,94 Verapamil inhibits intracellular processing of fatty acids,37,38 but it also inhibits insulin release and produces insulin resistance.38 The cyclic antidepressant amitriptyline depresses human myocardial contraction independent of an effect on conduction30 and inhibits medium- and short-chain fatty acid metabolism.87 Propranolol changes intracellular energy from primarily fatty acid to carbohydrate-dependent metabolism.49
++
Theoretically, adding excess fatty acids may overcome blocked or inhibited enzymes by mass action, providing energy to an energy “starved” heart, reversing toxicity. Some support for this mechanism comes from the IFE effect in reversing myocardial depression resulting from myocardial ischemia.80 In a canine model employing 10 minutes of regional myocardial ischemia, treatment with IFE following ischemia resulted in improved systolic wall thickening. In the same canine model, pretreatment with oxfenicine, which blocks carnitine palmitoyltransferase-1, blocked the beneficial effect of IFE.38 This finding suggests that the effects of IFE on myocardial contraction following ischemia are mediated by mitochondrial metabolism.
++
Unfortunately, there is limited experimental evidence to support a modulation of intracellular energy metabolism as the mechanism of action of the IFE. Some evidence comes from studies in bupivacaine toxicity. In an isolated rat heart model of bupivacaine-induced cardiotoxicity, doses of IFE in the perfusate that were too low to significantly decrease bupivacaine concentrations reversed bupivacaine-induced cardiac dysfunction.76 Similarly, in an in vivo model of bupivacaine-induced toxicity when rodents were pretreated with a single dose of a fatty-acid oxidation inhibitor (CVT-4325), IFE was unable to rescue these rodents, implying that IFE works by providing energy in the form of free fatty acids.59 Although these results imply that IFE works by a mechanism other than binding bupivacaine and suggest a metabolic effect, other studies support the theory that IFE works by a nonmetabolic mechanism. In one study, verapamil toxicity was induced when rodents were pretreated with the fatty acid oxidation inhibitor oxfenicine or control solution. Both groups were then resuscitated with IFE.3 There were no significant differences in survival time and mean arterial pressure between the oxfenicine-treated and control groups. Analogous to some models of bupivacaine toxicity, this study implies that in verapamil toxicity, IFE works by a mechanism other than mitochondrial energy supply.
+++
Lipid Sink or Sponge Mechanism.
++
In the lipid sink or sponge mechanism, IFE “soaks up” lipid-soluble xenobiotic and removes it from the site of toxicity. In a variation of this mechanism, IFE may pull the xenobiotic out of the aqueous plasma, which bathes the tissue, and into a nonaqueous part of the plasma that is not in contact with the site of toxicity. IFE may also alter the distribution of lipid-soluble xenobiotics and redistribute them away from the site of toxicity into an area with high lipid content (ie, create a “lipid conduit”). Some experimental support comes from studies of bupivacaine toxicity. In an isolated heart model, hearts perfused with bupivacaine until asystole were then treated with control or IFE. The IFE-treated hearts had a faster recovery from asystole, a lower concentration of bupivacaine in the tissue, and a higher concentrations of bupivacaine in the venous effluent.95 Stronger evidence for the lipid sink/sponge mechanism is seen in the effect of lipid emulsion on the pharmacokinetics and tissue distribution of bupivacaine in rats. Lipid emulsion decreased the distribution of bupivacaine into tissue, resulting in decreased concentrations in the brain and myocardium.71 Similarly, in a pharmacokinetic study of clomipramine toxicity, following IFE infusion, concentrations of clomipramine increased and volume of distribution decreased, in addition to an increase in blood pressure.28 In a pharmacokinetic study of amiodarone toxicity, IFE pretreatment resulted in higher concentrations of amiodarone and higher blood pressures compared to pretreatment with saline.58 In a well-perfused swine model, IFE decreased amitriptyline concentrations in the brain by 25% and decreased the heart-to-plasma ratio.30 In a successful resuscitation from bupropion overdose, bupropion concentrations increased dramatically after IFE administration.81 Concentrations also increased following successful treatment of verapamil.19 These findings in experimental models and case reports can be explained by the lipid sink/sponge model, where IFE pulls a xenobiotic away from the site of toxicity, although the increased concentrations could be explained by an increased perfusion of tissues and release of the drug.
++
Additional indirect evidence supports the lipid sink/sponge and a nonmetabolic mechanism. While the myocardium can utilize fatty acids for metabolism, the central nervous system (CNS) does not use fatty acids to a substantial degree, implying that the reversal in sedation results from xenobiotic removal from the CNS as opposed to an altered metabolism. This reversal of CNS effects was demonstrated in two animal models of thiopental sedation,10,66 whereas in another animal model of thiopental anesthesia, IFE increased the CNS effects. These findings may support the lipid sink/sponge mechanism, as in this model it was proposed that the IFE kept serum thiopental concentration high, permitting additional thiopental diffusion into the CNS.36 Reversal of CNS effects is also described in several clinical cases where the neurologic effects of bupivacaine were reversed with IFE,48 and arousal was reported in olanzapine toxicity.56 Additionally, a nonmetabolic effect of IFE in reversing toxicity is described in an in vitro model of methemoglobin formation. IFE added to whole blood blocked methemoglobin formation subsequent to exposure to the lipid-soluble glycerol trinitrate in a dose-dependent manner. IFE did not block methemoglobin production from non–lipid-soluble compounds such as 2-amino-5-hydroxytoluene or sodium nitrite, which supports a nonmetabolic effect of IFE and implies reversal of effect is related to lipid solubility.69
++
The degree of lipid solubility of a xenobiotic can be measured using the partition coefficients log P or log D. Both measure the xenobiotic partition between a lipophilic organic phase (usually octanol) and a polar aqueous phase (usually water) and are the logarithm of the ratio of concentration of the xenobiotic between the two phases. Log P measures the partition of the nonionized form of the xenobiotic between the two phases, while log D measures the partition of both the un-ionized and the ionized form of the xenobiotic and varies based on pH. Log D can be reported across a range of pH values, and the log D at pH of 7 is considered an evaluation of lipid solubility in normal plasma. When determining if a xenobiotic is lipid soluble, the log P is most commonly reported. The log D at pH of 7 may represent a more accurate estimation of lipid solubility in a normal physiologic state, while the log D at a lower pH might more accurately represent lipid solubility during xenobiotic toxicity with hemodynamic compromise. Variations in lipid solubility may be clinically important and may alter the amount of xenobiotic partitioning into the serum lipid. In an in vitro model, the distribution of bupivacaine and ropivacaine in fat emulsion decreased at lower pH.51
+++
Activation of Ion Channels.
++
The mechanism of action of IFE may be the activation of, both Ca2+ and Na+ channels. Linolenic acid and stearic acid decreased bupivacaine-induced Na+ blockade in a human cardiac Na+ channel model.55 Fatty acids directly activate myocardial Ca2+ channels and induce a dose-dependent increase in the Ca2+ current. Oleic, linoleic, and linolenic acids act directly on the Ca2+ channel to increase Ca2+ current.32
+++
Mechanism of Action: Conclusion.
++
Despite the lack of definitive studies on mechanisms of action, the lipid sink/sponge model is the most likely, since beneficial effects from IFE are most frequently noted for lipid-soluble xenobiotics independent of their mechanisms of toxicity. Multiple consequential mechanisms of action may exist, and depending on the xenobiotic, the mechanism(s) of action may vary and be multifactorial.
++
Lipid droplets that are less than 1 µm are primarily removed from circulation as they pass through the capillaries of adipose and hepatic tissue. The capillary endothelium in these tissues contains lipoprotein lipase, which hydrolyzes triglycerides, releasing fatty acids and glycerol that then diffuses into the cells. Fatty acids enter the cardiac myocyte either by passive diffusion or protein-mediated transport.75
++
The half-life of IFE is 30 to 60 minutes and can vary substantially depending on the patient’s clinical status, IFE dose, and droplet size.17 More than 2.5 g of lipid/kg/d (12.5 mL/kg of 20% IFE or 875 mL in a 70 kg person) overwhelms lipoprotein lipase activity, resulting in decreased clearance. Larger droplet sizes have slower clearances and are removed by reticuloendothelial phagocytosis. These larger droplets are more likely to induce an inflammatory response, obstruct the microvasculature, and produce capillary fat emboli.
++
Once inside the cells, fatty acids are used as energy or resynthesized into triglycerides and stored. For use as energy, triglycerides are transported into the mitochondria by carnitine palmitoyltransferase, where they undergo β oxidation sequentially releasing acetylcoenzyme A (acetyl-CoA) as the fatty acid chain is reduced in length. These acetyl-CoA molecules enter the Krebs cycle, where they ultimately generate adenosine triphosphate (ATP) (Figs. 13–3 and 13–8). Although glucose, lactate, and fatty acid metabolism may ultimately lead to the production of acetyl-CoA, fatty acid metabolism produces the largest amount of energy. For example, one mole of glucose produces 38 ATP, while one mole of stearic acid produces 146 ATPs97; the metabolism of longer fatty acid chains may produce more ATP.