A20: Antidotes in Depth

The use of intravenous fat emulsion (IFE) as an antidote is most extensively studied for the treatment of local anesthetic systemic toxicity. However, new applications that are being investigated and reported include the treatment of overdose from lipophilic xenobiotics such as calcium channel blockers, cyclic antidepressants, and β-adrenergic antagonists, among others.

IFE has been used as a source of parenteral nutrition for over 40 years and is also used as a diluent for intravenous drug delivery of highly lipophilic xenobiotics such as amphotericin and propofol. Recently, liposomal suspensions containing local anesthetics such as bupivacaine have been formulated that slowly release xenobiotics to increase the duration of anesthetic effect.

Although rare, bupivacaine toxicity is usually refractory to standard cardiac resuscitative measures (Chap. 67). In the setting of cardiovascular collapse, fatalities are frequent. Previously, cardiopulmonary bypass was the only effective treatment for these patients, as most cases were unresponsive to less invasive therapy. IFE was first evaluated in several animal models and was successful for the treatment of bupivacaine toxicity. Because of the success in animal models and the ineffectiveness of other therapies, IFE was attempted in humans and multiple case reports document apparent benefit. Subsequently, IFE was recommended by several anesthesia specialty societies for the treatment of local anesthetic toxicity. The initial proposed mechanism of action of IFE is the binding of local anesthetic in the serum lipid phase and decreasing the amount of xenobiotic at the site of toxicity. Subsequently, IFE was evaluated in several animal models of toxicity from lipid soluble xenobiotics. Based on these studies, IFE was used in several case reports of poisoning.

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

Mechanism of Action

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.

Pharmacokinetics

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.

Pharmacodynamics

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.

IFE was first studied as an antidote to bupivacaine toxicity. In a rodent model, pretreatment with IFE (10%–30%) followed by a continuous infusion of bupivacaine (10 mg/kg/min) increased the dose of bupivacaine needed to induce asystole.⁹⁶ In the second part of this study, bupivacaine was infused into rodents until the development of cardiac arrest. Rodents were resuscitated with IFE (30% IFE, 7.5 mL/kg bolus, then 3 mL/kg/min for 2 minutes) or an equivalent volume of saline. Animals were more successfully resuscitated with IFE from larger doses of bupivacaine than when treated with saline. The LD₅₀ for saline resuscitation was 12.5 mg/kg, which increased to 18.5 mg/kg with IFE resuscitation. In a larger animal model, canines were administered bupivacaine until cardiac arrest and then resuscitated with IFE (20% IFE, 4 mL/kg bolus, then 0.5 mL/kg/min for 10 minutes) or saline. IFE resulted in a dramatic survival benefit—all animals survived following IFE versus none in the control arm.⁸⁹ In rodent models, IFE was superior to epinephrine, vasopressin, and the combination in bupivacaine toxicity.^14,93 These findings were not reproduced in several swine models in which epinephrine was superior to IFE and epinephrine alone or epinephrine plus IFE was superior to vasopressin alone or vasopressin plus IFE in bupivacaine toxicity.³² IFE was not effective in reversing local anesthetic toxicity and had minimal effect on bupivacaine and mepivacaine distribution.⁷¹ It is worth noting, however, that pH was not recorded in this study and the lipid solubility of bupivacaine is lower as pH decreases. This may explain the inability of IFE to change the distribution of the local anesthetics. Additionally, the swine model may not be appropriate to evaluate lipid resuscitation therapy. Swine develop complement activation-related pseudoallergy (CARPA), an acute hypersensitivity reaction to liposomes. CARPA is characterized by mottling, hypoxia, and cardiovascular instability, which might compromise IFE resuscitation. This may explain the incongruous effect of IFE in these swine models and hypotension when IFE is administered in some swine models.^30,90

Based on the experimental evidence in bupivacaine toxicity, IFE was successfully used in several reported human cases of cardiovascular collapse from local anesthetic overdose. The first human case occurred following the inadvertent intravenous administration of bupivacaine and mepivacaine during an interscalene block.⁶³ The patient developed cardiac arrest and was treated with cardiopulmonary resuscitation (CPR) and advanced cardiac life support (ACLS) for 20 minutes, but only had return of spontaneous circulation following administration of the first dose of IFE (100 mL of 20% IFE followed by 0.5 mL/kg/min for 2 hours). The second successfully treated case occurred when a patient developed asystole after inadvertent intravenous administration of ropivacaine during an axillary plexus block.⁴⁵ The patient received CPR and ACLS and had return of spontaneous circulation 10 minutes after IFE administration (100 mL of 20% or 2 mL/kg followed by an infusion at 10 mL/min for an additional dose of 100 mL). A comparable example was a 60 year-old man with diabetes, coronary artery disease, and end-stage kidney failure who became unresponsive and developed ventricular fibrillation and torsade de pointes after administration of mepivacaine and bupivacaine for a supraclavicular brachial plexus block. He received CPR and ACLS for 10 minutes and then was treated with IFE (250 mL of 20% over 30 minutes). His pulse and blood pressure returned 11 minutes later.⁸⁶

In addition to its use during resuscitation, IFE has been used to treat milder symptoms of local anesthetic toxicity such as CNS symptoms and dysrhythmias without loss of pulse. A patient developed agitation, dizziness, unresponsiveness, and atrial premature contractions and bigeminy after administration of mepivacaine and prilocaine for a brachial plexus block. IFE treatment alone (1 mL/kg of 20%, repeated at 3 minutes for a total of 100 mL, followed by a continuous infusion of 0.25 mL/kg/minutes or 14 mL/min) rapidly resolved his dysrhythmia and restored consciousness.⁴⁷ A 75 year-old woman developed a seizure, wide complex dysrhythmia, and hypotension following levobupivacaine administration for a lumbar plexus block. She was treated with propofol, metaraminol, and IFE (20%, 100 mL over 5 minutes). During IFE infusion, the QRS narrowed and blood pressure and electrocardiogram normalized within 10 minutes.²⁰ A 13 year-old patient developed ventricular tachycardia at 150 beats/min after receiving lidocaine with epinephrine and ropivacaine for a lumbar plexus block. Treatment with IFE alone (150 mL or 3 mL/kg of 20% IFE over 3 minutes) restored a normal QRS complex within 2 minutes. Subsequent reviews of published human case reports document 19 case reports using IFE for resuscitation for local anesthetic toxicity, and the majority report improvement.^{11,35,62,64,85}

IFE was first studied as an antidote to bupivacaine toxicity and then evaluated for calcium channel blocker, cyclic antidepressant, β-adrenergic antagonist, organic phosphorus compounds, amiodarone, cocaine, and thiopental toxicity. In a controlled rodent study, a continuous infusion of verapamil followed by treatment with 12.4 mL/kg bolus of 20% IFE resulted in an increase in heart rate and survival compared with control.⁷⁸ In a larger animal model of verapamil toxicity in which animals also received calcium and atropine, 7 mL/kg of 20% IFE over 30 minutes resulted in improved blood pressure and survival.⁴

In an experimental model of clomipramine toxicity,²⁸ rabbits were given clomipramine until mean arterial pressure decreased to 50% of baseline. They were then treated with sodium bicarbonate (3 mL/kg of 8.4%), IFE (12 mL/kg of 20%), or sodium chloride (12 mL/kg of 0.9%). IFE resulted in an increase in mean arterial pressure greater than sodium chloride and sodium bicarbonate. In a second part of this study, clomipramine was administered until cardiovascular collapse, which was followed by resuscitation with sodium bicarbonate (2 mL/kg of 8.4%) or IFE (8 mL/kg of 20%) delivered over 2 minutes. With four animals in each study arm, IFE markedly improved survival compared to sodium bicarbonate (100% versus 0%).

In a rodent model using a constant infusion of propranolol, IFE decreased QRS prolongation, but the study was underpowered to detect an effect on heart rate or survival.¹¹ In another rodent and rabbit model of propranolol toxicity, IFE resulted in an increase in blood pressure.⁶ In contrast, in a metoprolol model, IFE was not effective in reversing hypotension and bradycardia, which was attributed to the lower lipid solubility of metoprolol compared to propranolol.⁷

In an oral organic phosphorus compound toxicity model, IFE administered 20 minutes after parathion exposure prolonged the time to apnea compared to saline and administering IFE 5 minutes after exposure.¹⁶

In a rodent model of thiopental anesthesia, IFE administered postanesthesia resulted in an increase in respiratory rate compared to saline.⁶⁶ Similarly, in a model of thiopental anesthesia, pretreatment with IFE decreased anesthesia time as measured by a return in righting reflex in rodents.¹⁰ However, in one animal model of thiopental anesthesia, IFE increased the CNS effects.³⁶

In a rodent model of cocaine toxicity, IFE was administered as pretreatment for cocaine toxicity. Pretreatment with IFE blunted the hypotensive effect of cocaine and increased survival.⁸

Based on the experimental evidence, IFE use was expanded to non–local anesthetic toxicity. IFE was successfully used to resuscitate a 17-year-old patient with prolonged cardiovascular collapse after bupropion and lamotrigine overdose. In this case, the patient had experienced seizures and underwent ACLS and CPR for 70 minutes, with return of spontaneous circulation after IFE administration (a bolus of 100 mL of 20%).⁷²

In the largest case series to date of IFE in non–local anesthetic toxicity, using the Toxicology Investigators’ Consortium (ToxIC) database, investigators report nine cases with drug-induced cardiovascular collapse treated with IFE in addition to standard resuscitative measures. Five of the nine patients treated with IFE survived, although several adverse effects were probably or possible as a result of the IFE such as acute respiratory distress syndrome (ARDS), acute kidney injury, and deep vein thrombosis.²¹ Subsequent reviews and published human case reports document more than 55 case reports of IFE for resuscitation in non–local anesthetic toxicity. Improvement is reported for amlodipine, diltiazem, verapamil, atenolol, nebivolol, propranolol, carvedilol, flecainide, haloperidol, amitriptyline, dosulepin, doxepin, imipramine, quetiapine, venlafaxine, carbamazepine, lamotrigine, phenobarbital, diphenhydramine, bupropion, hydroxychloroquine, cocaine, and bromadiolone.^1,2,12,64,85 Despite these successful reports, data are limited by reporting biases, therapeutic effects resulting from additional coadministered therapies, and coingestant xenobiotic toxicity. Current case report data only suggest a possible benefit of IFE tricyclic ­antidepressant bupropion, lipophilic β-adrenergic antagonist, and calcium channel blocker toxicity.¹²

The adverse effects attributed to IFE administration are infrequent and limited primarily to pulmonary toxicity and pancreatitis.^12,91 The doses and short durations of administration used in most patients result in full recovery without any significant adverse effects.^12,35,64,85 Based on case reports, a dose of 1.5 mL/kg bolus of 20% IFE followed by 0.25 mL/kg/min or 15 mL/kg/h to infuse for 30 to 60 minutes appears to be safe in xenobiotic-induced cardiac arrest and severe toxicity.

Because of the limited number of case reports, toxicity from IFE remains a concern. Pulmonary toxicity is reported when IFE is used as a source of parenteral nutrition. In patients with ARDS, 500 mL of 20% IFE administered over 8 hours resulted in increased pulmonary artery pressures, pulmonary shunting, pulmonary vascular resistance, and decreased partial pressures of oxygen in the alveoli/fraction of inspired oxygen (Pao₂/Fio₂).⁸³ Similar results were found in patients with ARDS administered 500 mL of 10% IFE over 4 hours, resulting in an increase in pulmonary shunting and a decrease in the fraction of Pao₂/Fio₂.³⁴ The pulmonary effect of IFE in ARDS may be related to infusion rate. In patients with ARDS, 500 mL of 20% IFE infused over 5 hours resulted in an increase in pulmonary pressures, while a slower infusion over 10 hours left pulmonary pressures unchanged.⁵⁰ There are conflicting results of the effects of IFE in patients without ARDS. In septic and nonseptic patients without ARDS, 500 mL of 20% IFE administered over 10 hours resulted in an increase in pulmonary artery pressures and pulmonary shunting.⁸² In patients with chronic obstructive pulmonary disease and pneumonia, 500 mL of 10% IFE administered over 4 hours had no pulmonary effects, and in a group of healthy postoperative patients this dose actually decreased pulmonary shunting and increased Pao₂/Fio₂ ratio.³⁴

In these studies, when pulmonary effects occurred, they were mild and resolved after the IFE infusion was stopped or within 3 to 4 hours. Larger doses may result in clinically significant toxicity and more prolonged effects. However, studies using fat emulsions with medium-chain triglycerides have shown less pulmonary toxicity.^18,73

IFE may cause pulmonary toxicity by at least two mechanisms. IFE may occlude the pulmonary vasculature with microfat emboli. Macrophages containing lipid droplets can be demonstrated in the bronchioalveolar lavage fluid of ARDS patients treated with IFE.⁴² Experimental evidence also suggests that a substantial amount of the high concentrations of linoleic acid in IFE is converted to arachidonic acid and then into vasoactive prostaglandins. Indomethacin, an inhibitor of prostaglandin synthesis, prevented any pulmonary vascular effect caused by IFE in a sheep model.⁵³

Adverse effects resulting from IFE use in resuscitation from xenobiotic toxicity are uncommon. Investigators using the ToxIC database report that three of the five patients successfully resuscitated with IFE developed ARDS that was probably attributed to IFE.³⁵ It is difficult to attribute the etiology solely to IFE as these patients were predisposed to ARDS due to xenobiotic toxicity, hypotension, and potential aspiration.

Elevated triglycerides and pancreatitis is reported when IFE is used for parenteral nutrition. The precise mechanism of IFE-induced pancreatitis is unknown but may be the result of the large concentration of triglycerides forming large lipid droplets that obstruct the small vessels of the pancreas, leading to ischemia. Lipase then degrades the triglycerides, releasing cytotoxic free fatty acids.

Hyperamylasemia and pancreatitis were reported in two cases of IFE use in treatment of xenobiotic toxicity. Following successful resuscitation with IFE from bupivacaine-induced cardiac arrest, an elevated amylase concentration without associated elevated lipase or associated symptoms was reported.⁸¹ Elevated lipase concentrations were reported after administering IFE to a 13 year-old girl who developed delayed seizures and cardiac arrest following an amitriptyline ingestion. Lipase concentrations peaked at 1849 U/L 5 days after IFE and was associated with elevated triglycerides and abdominal pain.⁴²

Large doses and/or rapid infusions of IFE have the potential to induce a fat overload syndrome. Fat overload syndrome is characterized by hyperlipemia, fever, fat infiltration, hepatomegaly, jaundice, splenomegaly, anemia, leukopenia, thrombocytopenia, coagulation disturbances, seizures, and coma. Multiple end-organ dysfunction is attributed to inadequate clearance of lipids and sludging in the lungs, brain, kidney, retina, and liver.^{15,17,25,31,39,42,68,70,77} Because of the rapid redistribution of most local anesthetics, prolonged IFE infusion should not be required (Chap. 67). However, many other lipid-soluble xenobiotics have a long duration of toxicity, and prolonged and repeated IFE infusions may be recommended, predisposing to fat overload syndrome.

Particularly when administered early in the clinical course of an overdose, IFE has the potential to increase gastrointestinal absorption or facilitate distribution of lipid-soluble xenobiotics, resulting in increased toxicity. Although this currently remains a theoretical concern, some animal models suggest certain xenobiotics could partition into IFE and contribute to additional toxicity. In an orogastric model of amitriptyline overdose, IFE increased amitriptyline concentrations and resultant toxicity.⁶¹ In a model of thiopental anesthesia, IFE increased sedation, possibly by increasing concentrations of thiopental in the serum, permitting extended time for distribution into the CNS.³⁶ IFE also has the potential to interact with other essential antidotes. If an antidote is lipid soluble, it may be incorporated by the IFE and result in decreased effectiveness. Both thiopental and lidocaine are highly lipid soluble, and IFE may decrease their effectiveness. In a rodent model, pretreatment with IFE delayed the peak effect and prolonged the duration of effect of epinephrine on mean arterial pressure.⁹ Clinical data are absent. IFE has been used with several medications during resuscitation from bupivacaine toxicity, including epinephrine, atropine, amiodarone, vasopressin, sodium bicarbonate, magnesium sulfate, calcium chloride, naloxone, and metaraminol.^12,36,64,85

The addition of IFE to high-dose insulin-euglycemia (HIE) was evaluated in a model of severe verapamil toxicity, and there was no improvement in hemodynamics, metabolic parameters, or survival.⁵ Therefore, while other resuscitative xenobiotics should be used as indicated, there is no evidence yet to support or refute the simultaneous use of IFE and HIE therapy.

Hyperlipidemia after using IFE may interfere with laboratory studies and make them uninterpretable.⁴² This interference may last for several hours and may depend on the type of laboratory system used. IFE may alter analytical test results and result in erroneous measurement, no significant effect, or the inability to perform a laboratory test. In vitro testing of IFE demonstrated that colorimetric methods were more prone to the effects of IFE than potentiometric methods. In the setting of IFE, glucose measurement by colorimetric method did not accurately report hypoglycemia. For example, a glucose concentration of 2.7 mmol/L (48.6 mg/dL) may be falsely reported as 12.4 mmol/L (223.2 mg/dL). Centrifugation at 140,000 g for 10 minutes minimized most interference. Troponin-I, sodium, potassium, chloride, calcium, bicarbonate, or urea assays had the least interference. Albumin and magnesium assays demonstrated significant interference. Amylase, lipase, phosphate, creatinine, total protein, alanine aminotransferase, creatine kinase, and bilirubin became unmeasurable.²² The effect of IFE on toxicology testing is unknown. Ideally, analytic testing should be performed prior to the IFE administration.

Based on a risk benefit analysis, relative contraindication to IFE is egg or soybean allergy, disorders of fat metabolism, and liver disease. Consideration should also be made in patients with myocardial ischemia and infarction. In animal models, IFE increased dysrhythmias and impaired cardiac pump performance when administered during ischemia^40,74 but was of benefit when administered after the resolution of ischemia. In an ischemic myocardial cell, fatty acid metabolism is thought to result in lipid peroxidation and free radical production, which increases dysrhythmias and impairs myocardial performance.⁷¹

Pregnancy and Lactation

IFE is a pregnancy category C pharmaceutical. It is not known whether IFE can cause fetal harm when administered to gravid patients. Potentially, large doses can result in elevated triglyceride concentrations, and lipid globules may potentially occlude placental vasculature. Risk of potential toxicity should be weighed against potential benefit to the pregnant woman and fetus. There is no reported risk of IFE on the nursing infant.

Although the optimal dosing regimen for human poisonings remains undefined, several animal models of high-dose IFE have been performed. In both rodent and canine models of verapamil toxicity, 12.4 and 7 mL/kg boluses of 20% IFE were given,^5,78 and in a rabbit model of clomipramine, 12 mL/kg of 20% IFE was used.⁷⁹ These animal models used large doses of xenobiotic and were designed to produce a rapid onset of toxicity; it is difficult to extrapolate to typical human cases. In a rodent model, the LD₅₀ of IFE is 67 mL/kg, which is much higher than the current recommended clinical doses. Additionally, only microscopic abnormalities were observed in the lung and liver at doses of 60 and 80 mL/kg, which improved over 24 hours. Higher doses of IFE also are more effective than lower doses. In a model of verapamil toxicity, higher doses up to a maximum of 18.6 mL/kg of 20% IFE were more effective in improving blood pressure, acidemia, and survival than lower doses. Higher doses improved hemodynamic parameters transiently, but may have also resulted in overall decreased survival times.⁶⁰

The dose of IFE administered depends on the implicated xenobiotic and the patient’s clinical condition. Dosing is best defined for local anesthetic toxicity, specifically bupivacaine, with generalization of this dosing regimen to poisoning by other local anesthetics and other xenobiotics. The American Society of Regional Anesthesia and Pain Management, the Association of Anesthetists of Great Britain and Ireland, and the American Heart Association^23,57 have similar guidelines and recommendation on the use of IFE in local anesthetic toxicity. Lipid treatment is recommended for clinically severe cardiovascular toxicity or rapid progression of toxicity.

The recommended dose of 20% IFE is 1.5 mL/kg bolus followed by 0.25 mL/kg/min or 15 mL/kg/h to run for 30 to 60 minutes.^23,57 The bolus may be repeated several times for persistent dysrhythmias, and the infusion rate can be increased if blood pressure decreases. For local anesthetic poisoning, earlier recommendations limited use of IFE only to situations following the failure of standard resuscitative measures. As a result of the experimental evidence and many successful case reports, some authors recommend adding IFE at the first signs of local anesthetic toxicity or, in the setting of cardiovascular collapse, to use IFE concomitantly with CPR and ACLS and to avoid high doses of epinephrine.⁹² We recommend that rapid progression of local anesthetic toxicity affecting the CNS (agitation, confusion, seizures) or cardiovascular system (hypertension, tachycardia, ventricular dysrhythmias, hypotension, conduction blocks) should be treated with IFE. In the setting of cardiovascular collapse, IFE can be used with CPR and standard ACLS. IFE should be stored for easy and rapid access in operating rooms or in areas where local anesthetics are frequently used.⁶⁵ Generalization of this practice to other xenobiotics is not currently studied or recommended.

Experimental evidence indicates that IFE may be potentially beneficial in verapamil,^4,60,79 clomipramine,^28,29 propranolol,^6,26 amiodaroine,¹⁷ and cocaine⁸ toxicity, and this may be extrapolated to other lipid-soluble calcium channel blockers, cyclic antidepressants, or lipophilic β-adrenergic antagonists. These xenobiotics will usually demonstrate continued absorption, long duration of toxicity, severe hypotension, and either dysrhythmias or bradycardia over several hours or days. The precise indications and dose of IFE for these situations has not been studied, and it is not known if boluses or infusion are more effective. The reasonable safe total dose is also unknown but would depend upon the degree of toxicity and response to previous doses of IFE. Based on the current data available from animal models and clinical case reports, the American College of Medical Toxicology published interim guidance on the use of IFE in lipophilic xenobiotic toxicity.¹ Published guidance states that IFE is a reasonable consideration in serious hemodynamic, or other, instability from a xenobiotic with a high degree of lipid solubility, even if the patient is not in cardiac arrest. However, IFE can be considered for patients with hemodynamic instability refractory to standard resuscitation measures. No standards for use were set, and the dosing recommended was similar to the dose recommended for local anesthetic toxicity. We recommend that IFE be used in the setting of severe toxicity (prolonged cardiovascular instability such as hypotension, severe bradycardia or dysrhythmias or seizures) resulting from a lipid soluble xenobiotic despite maximal treatment with standard resuscitation measures. When used, we recommend a bolus dose of 1.5 mL/kg of 20% IFE, which should be followed by an infusion for 30 to 60 minutes of 0.25 mL/kg/min or 15 mL/kg/h. Repeat boluses of IFE can be administered for persistent severe symptoms.

Propofol is formulated as a 10% lipid emulsion, but it is not recommended for use in lipid rescue because of the adverse effect of the propofol from the dose needed to achieve lipid rescue.⁸⁸ A 1.5 mL/kg bolus of 20% IFE equates to 3 mL/kg of the 10% lipid emulsion in the propofol solution. A normal dose of propofol (1%) for general anesthesia is 2.5 mg/kg or 0.25 mL/kg.⁶⁸ If propofol is used as a lipid rescue agent, it would deliver a bolus of 12 times the recommended dose of propofol. This would exacerbate any drug-induced hypotension and bradycardia.

IFE is available in 5%, 10%, 20%, and 30% solutions. The 20% solution is recommended and used most often. The 30% solution is a pharmacy bulk admixture and is used to prepare dilute concentrations. The 30% solution should be diluted before administration and has not been used clinically for xenobiotic toxicity.

There are some current shortages reported for IFE. There are no recommended alternative agents, but if available, dose adjustment can be made to the lower and higher concentrations, and medium chain preparations can be used as a substitute.

• IFE is recommended for the treatment of local anesthetic systemic toxicity, particularly in the case of rapidly progressive toxicity or cardiac arrest.

• In local anesthetic systemic toxicity, IFE can be used with standard resuscitation medications and should be stored where local anesthetics are administered.

• IFE use for other xenobiotics is unclear at this time, although animal data and some human case reports support its use for several lipid-soluble xenobiotics such as verapamil, clomipramine, and some lipophilic β-adrenergic antagonists.

• IFE use for other xenobiotics should be considered when severe toxicity resulting from a lipid-soluble xenobiotic persists despite maximal treatment with standard resuscitation measures.

• For both local anesthetic and non–local anesthetic toxicity, a bolus dose of 1.5 mL/kg of 20% IFE should be followed by an infusion for 30 to 60 minutes of 0.25 mL/kg/min or 15 mL/kg/h. Repeat boluses of IFE can be administered for persistent severe signs and symptoms.

References