Lipid Emulsion Infusion

IT seems implausible that an injection of a simple, off-the-shelf, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose. But dozens of published case reports support this observation, first made more than a decade ago in a rodent model of bupivacaine toxicity. It is even more surprising that such a simple formulation can rapidly reverse severe clinical toxicity from a variety of vastly disparate medications with distinct pharmacodynamics and mechanisms of action. This review will focus on the clinical application of lipid emulsion therapy in resuscitation from drug-related toxicity and will provide an introduction to the development of the method, guidelines for its use, and insights into potential controversies and future applications.Weinberg et al. 1first showed in 1998 that an infusion of a soybean oil emulsion normally used as a total parenteral nutrition solution could prevent (by pretreatment) or improve resuscitation from cardiovascular collapse caused by severe bupivacaine overdose in the intact, anesthetized rat. Subsequent studies from the same laboratory confirmed these findings in isolated rat heart2and anesthetized dog.3Under the latter experimental model, return of spontaneous circulation after a bupivacaine challenge occurred in all animals receiving lipid, but in none of the saline controls.3This study was accompanied by an editorial asking whether lipid might be the long-sought “silver bullet” for local anesthetic systemic toxicity (LAST). Since then, the effectiveness of lipid emulsion infusion in reversing LAST has been confirmed in other laboratories and by systematic analysis4in the clinical setting, as well.The level of evidence from case reports is less rigorous than that provided by prospective, randomized, controlled clinical trials; however, such study designs are unethical and unsuited to clinical investigations of local anesthetic toxicity. Nonetheless, careful evaluation of even a single case can provide useful information about a particular toxic syndrome and its treatment. Taken together, dozens of such reports can provide valuable clinical insights, as a clear picture emerges of the typical course of a particular overdose and its response to lipid therapy.Rosenblatt et al. 5reported the first clinical application of lipid emulsion therapy in treating LAST. A middle-aged man developed cardiac arrest shortly after a peripheral nerve block combining mepivacaine and bupivacaine. The patient failed to respond to standard resuscitative efforts for approximately 20 min but achieved normal vital signs shortly after receiving a 100 ml bolus of lipid emulsion. He subsequently recovered completely with no neurologic deficit or cardiovascular sequelae.This case is now recognized as typical of many lipid resuscitation cases and exemplifies key features repeated in virtually every subsequent report of reversal by lipid infusion of LAST-related cardiac arrest: (1) the event was witnessed (meaning, little to no associated asphyxia or delay in treatment); (2) the patient failed to recover with epinephrine, vasopressin, and antiarrhythmic medications; and (3) spontaneous circulation was reestablished shortly after lipid infusion. An additional feature common to many of the early case reports of lipid therapy for severe LAST was the presence of underlying heart disease, suggesting that coronary ischemia, baseline conduction defects, or cardiomyopathy could lower the threshold for LAST, thereby defining one subgroup of vulnerable patients.McCutchen and Gerancher6reported that in a patient with seizures and ventricular tachycardia following a combined femoral catheter (ropivacaine) and sciatic (bupivacaine) block, the use of lipid emulsion early in the sequence of rapidly worsening toxicity appeared to attenuate or prevent progression of local anesthetic cardiac toxicity. This observation suggests that early lipid infusion might provide an advantage, presumably by interrupting the vicious cycle of low-output, tissue acidosis, and worsening toxicity, thereby preventing progression to a low-output state or frank cardiac arrest. Several other recent cases seem to support this notion. These reports contribute directly to the controversy surrounding optimal timing of the lipid emulsion infusion, which is addressed below.Lipid infusion can also reverse neurologic signs and symptoms of LAST, including seizures and altered mental status, suggesting that the benefit is not limited to the cardiovascular system.7,8This similarly contributes to the debate regarding the mechanisms underlying lipid resuscitation: the metabolic hypothesis would not hold in the case of neurotoxicity because the central nervous system does not normally depend on lipid substrates (see Mechanisms). Successful treatment of severe cardiac toxicity has been reported in children, including two neonates, one a 2-day-old9; the oldest patient reported in a successful lipid resuscitation was a 92-yr-old woman in asystole following an infraclavicular block with ropivavcaine. Though Intralipid (Fresenius Kabi, Uppsala, Sweden) has been the predominant lipid emulsion brand used in instances of lipid resuscitation reported in the medical literature, successful treatment of severe toxicity has also been reported with other formulations, including Liposyn III (Hospira, Lake Forest, IL) and Medialipid (B. Braun, Melsungen, Germany), a mixture of long- and medium-chain fatty acid triglycerides.More cases of lipid resuscitation from local anesthetic toxicity can be found in recent reviews of the topic.4,10Additional cases, along with descriptions of the use of lipid in treating many other types of drug toxicity, are posted at an educational Web site.†This Web site serves as a forum for discussing lipid therapy and related topics and contains useful links to relevant literature. Practitioners are invited to post cases here and at a sister site.‡Together, these two Web sites comprise an open-source registry for reporting the clinical experience with lipid-based resuscitation. Though presumably only a small fraction of all cases is reported, the hope is that over time, methods will be identified to increase the rate of case capture and reporting.Following the reports of laboratory success in resuscitation from bupivacaine toxicity, lipid emulsion infusion was studied in animal models of a variety of other overdoses, typically those expected to be seen in the emergency department. These include models showing a benefit of lipid in treating overdose of tricyclic antidepressants, β-blockers, and calcium channel blockers. However, the first use of lipid emulsion therapy in treating nonlocal anesthetic drug toxicity was described by Sirianni et al. ,11who reported on the remarkable rescue of an adolescent near-suicide who suffered a witnessed cardiac arrest hours after hospitalization for a massive overdose of bupropion and lamotrigine. After 90 min of ventricular tachycardia/fibrillation and narrow complex pulseless electrical activity, which were unresponsive to maximal medical therapy, including high-dose pressors and multiple countershocks, an anesthesiologist recommended using lipid. Within 1 min of a single bolus of lipid emulsion, the patient recovered normal vital signs and ultimately left the hospital with no major neurologic deficit.This publication, along with the above-mentioned animal studies, opened the door to more widespread use of lipid emulsion for emergency treatment of toxicities caused by a range of lipophilic drugs. Notably, published examples now include toxicities related to verapamil, diltiazem, amlodipine, quetiapine and sertraline, haldoperidol, lamotrigine, olanzapine, propranolol, atenolol, nevibolol, doxepin, dosulepin, imipramine, amitriptyline, glyosphate herbicide, flecainide, venlafaxine, moxidectin, and others. It is arguable whether lipid infusion was the proximate cause of toxic reversal in all these singlet case reports. However, on balance it appears lipid might be generally effective in cases where the agent(s) are lipophilic, despite possessing disparate pharmacologic profile infusions. This could apply to treating cases of multi-drug overdose, such as that reported by Harvey et al. 12Others have recently found that treatment of such mixed-drug overdose with lipid emulsion resulted in a reduced incidence of intubation and shorter duration of stay in the intensive care unit than matched controls not receiving lipid (personal communication, Dr. David Uncles, Consultant Anaesthetist, Department of Anaesthesia and Intensive Care, Worthing Hospital, Western Sussex Hospitals, West Sussex, England). Thus the salutary clinical effects of lipid infusion might extend to cost savings as well.Interestingly, the reversal of haldol-induced Torsades occurred in the same hospital where a year earlier the case report of rescue from bupropion overdose occurred. The treating physician was aware of the previous case and therefore ordered the infusion of lipid emulsion after 15 min of failed standard resuscitation. Similarly, Smith et al. 13reported an apparent save of a patient in cardiac arrest following a bupivacaine-based peripheral nerve block when physicians who had recently attended a simulator course that included a lipid scenario administered the emulsion. These cases emphasize the positive effect that education and awareness of the method can have on patient outcome.It is essential to consider the overall limitations inherent in the interpretation of and clinical extrapolation from such cases. Several types of reporting bias are at play. First is the bias to report positive outcomes and the correlative, presumed underreporting of failed lipid resuscitations. This could impart an overly optimistic account of the efficacy of this therapy. On the obverse, failures of lipid resuscitation should not be automatically ascribed to the use of emulsion since many other patient or treatment factors can contribute to a bad outcome. Severe comorbidities, overwhelming overdose, delayed intervention, inadequate support of the airway, poor-quality basic life support, and use of the wrong dose or formulation of lipid could each lead to a failed resuscitation. Another reporting failure occurs as use of lipid becomes more commonplace, and therefore fewer physicians are likely to report these cases and editors are less inclined to publish them. Unfortunately, potentially important information is lost in this manner. Such underreporting could “balance” the effect of positive reporting bias, but the relative importance of these opposing factors is unknown. Since prospective, randomized clinical studies are not feasible, a clinical registry of all resuscitations incorporating lipid could provide a more realistic assessment of therapeutic efficacy, and provide insight into the key factors that improve or reduce the odds of recovery. This underscores the need for establishing a robust method of tracking and evaluating use of lipid emulsion for this purpose.Previous reports of pulmonary complications following lipid emulsion infusion have involved large volumes of high concentrations for parenteral nutrition, particularly in neonates. Fortunately, no such events have been reported in lipid-based resuscitations and no serious clinical complications have been reported following use of lipid emulsion for treating drug-induced toxicity. One notable case of massive lipid overdose reported by West et al. 14involved a 72-yr-old patient with severe amlodipine overdose; 2 l of 20% lipid emulsion were infused because of confusion about the treatment protocol. The patient suffered no direct cardiopulmonary complications from the massive overdose. However, the extreme lipemia interfered with various laboratory studies, and such instances serve to emphasize the importance of implementing clinical systems and guidelines focused on patient safety in preventing drug errors and iatrogenic harm. In this case, a protocol to prevent inadvertent continuous infusion beyond 30 min would have prevented the lipid and volume overload.Marwick et al. 15reported one patient who developed chemical hyperamylasemia without symptoms of pancreatitis following successful lipid rescue from cardiac arrest because of bupivacaine. Therefore, there is at least a theoretical concern for hyperlipidemia-induced pancreatitis and it is reasonable to assess patients for this after acute lipid infusion. Another instructive twist in this case is that cardiovascular instability recurred 45 min after stopping the lipid infusion and no additional lipid was available. Fortunately the patient responded to pressors and ultimately recovered. This occurrence suggests that patients need careful monitoring for several hours after lipid-based resuscitation and doctors should be prepared to reinstitute lipid therapy if needed. Furthermore, in this case and other reports, it has been noted that the extreme lipemia following lipid emulsion infusion can interfere with standard laboratory tests. Given the short (approximately 15 min) half-life of the resulting hypertriglyceridemia, it is expected that this effect should completely dissipate after a few hours.It is important to ask, “What is the acceptable upper limit of lipid infusion?” There is no clear-cut answer at this point. Hiller et al. 16used a Dixon up-down method to arrive at a first approximation for a LD50of 20% lipid infusion in anesthetized rats. Using death within 48 h as the endpoint, they found the maximum likelihood estimate as LD50= 67 ± 11 (SEM) ml/kg. The LD50is not the ideal metric for identifying the highest safe dose. However, given that the average dose used in the first dozen case reports of lipid resuscitation was 3.7 ml/kg, even scaling the dose to correct for size differences between rats and humans, there appears to be a reasonable margin of safety in limiting the total dose to approximately 10–12 ml/kg over 30 min.Understanding the mechanism(s) that underlie the effects of lipid emulsion infusion could lead to improved treatment of drug toxicity and possibly extend the use of lipid resuscitation to other clinical scenarios. The typical solutions used for parenteral nutrition are very complex mixtures of natural (e.g. , soy) and this might the of resulting and pharmacologic effects in and were to the benefit of lipid infusion bupivacaine toxicity. However, evidence has recently several other important potential sites of early of direct and an important for the in reversal of local anesthetic overdose. the infused lipid the in to drug from the thereby reversing the toxicity. evidence in support of this the that lipid can reverse neurologic and cardiac toxicity, the does not fatty as an to an Furthermore, as noted lipid infusion is reported to reverse toxicity caused by an of a common site of chemical or clinical effect (e.g. , calcium channel β-blockers, typical and tricyclic and other antidepressants, local and The only these is high lipid by a than et al. reported that after a bolus injection of bupivacaine into the isolated rat a subsequent lipid infusion in more of bupivacaine than in an effect by the direct evidence in support of the lipid model is provided by studies from et al. that lipid emulsion solutions very large of local this in et al. that with lipid Furthermore, the to of the drug that was into the lipid evidence in support of a lipid effect was provided by the observation that the resulting had a lower of than found in that of the given saline of lipid. Similarly, et al. at the of an experimental lipid treatment of rats from bupivacaine overdose. found the bupivacaine was in the than in the the animals the of bupivacaine concentrations in the lipid following was bupivacaine showed a positive with the and a with Therefore, lipid treatment resulted in lower bupivacaine lower and cardiac et al. the efficacy of by the of in by of lipid lipid emulsion reduced caused by the but not caused by less drugs. This the of a lipid in an drug-related et al. in of drug following of lipid emulsion to found that the of and volume of of were with the of in drug these factors the were to with the of in caused by lipid emulsion to solutions of 11 reported in cases of successful lipid resuscitation. Taken together, these studies provide support for the of in lipid resuscitation in treating bupivacaine toxicity and other lipophilic drug other studies not support a of to lipid resuscitation. et al. bupivacaine concentrations in the of given small of bupivacaine and with lipid or infusion. There was no in or bupivacaine a of a lipid However, lipid infusion the half-life of total bupivacaine by more than suggesting a positive effect on of bupivacaine to peripheral comprise the normal and it was that this could directly cardiac Therefore, an early was that a large lipid could the of fatty acid caused by bupivacaine. in support of this was first published by et al. showed that in isolated rat concentrations of lipid to reduce bupivacaine in the were to reverse in cardiac et al. a metabolic effect by showing that of fatty acid lipid reversal of cardiac toxicity. The lipid infusion was associated with additional effects that the a key in from the reversal of bupivacaine toxicity, have that lipid infusion can a direct effect in rats and isolated rat the of this is it occurs very rapidly and might contribute to lipid et al. in a tissue system that fatty reduced bupivacaine of channel that of cardiac could contribute to reversal of bupivacaine toxicity. a et al. that lipid infusion cardiac found that infusion of lipid in as in the with metabolic reduced the likelihood of and It is very that such of contributes to the benefit of lipid-based a more complex clinical than was can now consider the of lipid infusion into and will all the underlying of lipid emulsion infusion and relative to reversing drug is evidence that and local anesthetic toxicity and potentially lipid resuscitation. Therefore, the local anesthetic toxicity by first optimal if circulation and basic life the relevant should lipid be in the of , cardiac life This is a complex and are for the because the are not completely lipid with standard resuscitation methods for local anesthetic toxicity found that lipid was to a of the two in treating bupivacaine overdose in the rat. studies used a of cardiac as the key of recovery. including and central were also after lipid than in of the However, by et al. et al. using models of bupivacaine overdose, has these et al. showed that the of high-dose and was to lipid in treating bupivacaine overdose. et al. found no benefit in treating with lipid with saline Several factors are likely to account for these model reported by et al. a challenge of several of following the bupivacaine Furthermore, they used as the key metric of a for which pressors will a positive it has been that reduce the efficacy of lipid infusion. et al. high of and for resuscitation treatment with lipid or Notably, Hiller et al. in a rat model of bupivacaine overdose that a single dose of at or the efficacy of lipid resuscitation from bupivacaine overdose. animals recovered and high early in the resuscitation. However, animals receiving the of developed pulmonary and and metabolic after 15 despite the robust and heart rate The mechanisms underlying this delayed are not but might the findings of et al. the very large of would be expected to benefit from lipid infusion. it should be noted that et al. have reported that of the after lipid infusion. This is very with the of seen when It is not clear whether these are however, the observation does into the of a model for lipid optimal formulation of lipid emulsion has recently been by et al. and mixtures of long- and medium-chain have been reported to reverse local anesthetic toxicity. However, et al. showed in an using that an mixture and mepivacaine to a than the emulsion. The on the of this in study that for the standard be into However, et al. in an rat model that and were effective in reversal of severe bupivacaine overdose, but that of rats given subsequently developed cardiac only 2 of animals in the were and cardiac and bupivacaine concentrations were lower in the the emulsion will of these and other for the use of lipid emulsion in resuscitation are the of from the Web the of of and has also included lipid emulsion infusion in its for resuscitation in for local anesthetic overdose. The on in that every of in have for a range of including of LAST. These are differences these there is a generally establishing as the first in to optimal and with a lipid emulsion infusion to reverse signs and symptoms of toxicity. life support including be used when in to tissue and circulation of resuscitation including lipid infusion is it a large intravenous bolus of 20% lipid emulsion (approximately ml/kg of that is by a continuous infusion (approximately for min following of vital The bolus injection is key to clinical because a large of lipid is to the A single bolus has been used in case however, this should be repeated or the infusion for failure of return of spontaneous circulation or Given that the lipid infusion to the coronary basic life support is a of lipid resuscitation in the of a low-output this min of at least in an of the after each and (e.g. , for a or for a It is important to that cardiovascular collapse from LAST is from other more common of cardiac such as In toxic peripheral with can cardiac and resuscitation. Therefore, is not useful in this setting, and should be used in small (e.g. , less than 1 other that reduce (e.g. , β-blockers, calcium channel or should be when there is evidence of cardiovascular Given the in of the of lipid these guidelines will likely be to on the experimental and clinical et al. showed that in of LAST was improved with use of a This important is in the of and for is important that the use and methods of lipid emulsion therapy be by laboratory evidence and clinical One important in this will be the of a registry to and of a of lipid resuscitation cases. A first at this is found at the Web These will regarding the factors in treatment that improve or patient also from in lipid formulation or in the of (e.g. , by it to clinical it is that potential in other clinical will be such as pulmonary the to and in all to the guidelines for treating LAST. can improve patient safety and save