Lipid Rescue Resuscitation from Local Anaesthetic Cardiac Toxicity

Transcription

1 Toxicol Rev 2006; 25 (3): REVIEW ARTICLE /06/ /$39.95/ Adis Data Information BV. All rights reserved. Lipid Rescue Resuscitation from Local Anaesthetic Cardiac Toxicity Guy Weinberg University of Illinois College of Medicine, Chicago, Illinois, USA Contents Abstract Local Anaesthetic Toxicity Clinical Features Mechanisms of Toxicity Lipid Reversal Resuscitation Background Rat Studies Dog Studies Mechanisms of Lipid Rescue Alternative Novel Therapies Evidence of Clinical Efficacy for Lipid Rescue Resuscitation Future Issues Optimised Treatment Consensus Use in Other Poisonings Conclusions Abstract Systemic local anaesthetic toxicity is a rare but potentially fatal complication of regional anaesthesia. This toxicity is due to inhibition of ionotropic and metabotropic cell signal systems and possibly mitochondrial metabolism. It is associated with CNS excitation and, in the extreme, refractory cardiac dysfunction and circulatory collapse. Infusion of lipid emulsion has been shown in animal models to reliably reverse otherwise intractable cardiac toxicity and the mechanism of lipid rescue is probably a combination of reduced tissue binding by re-established equilibrium in a plasma lipid phase and a beneficial energetic-metabolic effect. Recent case reports have suggested the clinical efficacy of lipid infusion by the recovery of patients from intractable cardiac arrest. Future areas of investigation will focus on improved treatment regimes and better understanding of the mechanism of lipid rescue, which might allow superior alternative therapies, or treatment of other toxic events. An educational website has been established to help disseminate information about lipid emulsion therapy and to serve as a medium for physicians to share experiences or thoughts on the method and local anaesthetic toxicity. tumescent anaesthesia for liposuction carry the inherent risk of local anaesthetic systemic toxicity due either to direct intravascu- lar injection or absorption from a tissue depot. [1] Furthermore, the use of the potent lipophilic local anaesthetics, popular for their long duration of action, increases the chance of cardiac toxicity. Regional anaesthesia is employed in a high percentage of surgical procedures and its popularity continues to increase because of advantages in post-operative pain control and rapidity of discharge from the hospital. However, techniques that require a large dose of local anaesthetic, such as peripheral nerve block or

2 140 Weinberg Intravenous infusion of lipid emulsion has been reported in the heart is much more resistant to local anaesthetic toxicity than animal models to improve outcomes following overwhelming the brain and the dose required to produce cardiovascular collapse overdose with bupivacaine. This novel approach to treating poten- (CC) is greater for all local anaesthetics than the dose producing tially fatal cardiac toxicity is still in early development but holds CNS excitation symptoms. This can be expressed as a ratio (CC/ promise for clinical application. Two recent case reports of its CNS), which is significantly greater for the anaesthetics possessapparent successful use in humans reinforce the clinical efficacy ing lower lipophilicity and potency than for the lipophilic, potent of the method. This article will explain the background and agents. For instance, the CC/CNS ratio for lidocaine (lignocaine), rationale for lipid infusion as well as data supporting its efficacy. is ~7, while that of bupivacaine is ~3. [6] Therefore, bupivacaine Recommendations for the clinical use of this technique will be toxicity can occur with few premonitory symptoms of CNS excitaprovided. tion. Typically, severe bupivacaine cardiac toxicity presents as hypotension with bradycardia leading quickly to malignant ven- 1. Local Anaesthetic Toxicity tricular arrhythmias and CC that is highly resistant to standard resuscitation. [2,7] Most recommended drugs are supportive: Nearly 30 years ago, an editorial by Albright [2] reported several sympathomimetics for blood pressure and inotropic support, and cases of fatal cardiac toxicity associated with use of the longamiodarone for arrhythmias. [1] Use of β-adrenoceptor antagonists, acting lipophilic local anaesthetics bupivacaine and etidocaine. An calcium channel agonists and local anaesthetics for rhythm disturunusual feature shared by these cases was the apparent lack of bances should be considered to be contraindicated. response to standard resuscitative measures in otherwise healthy [1] patients. Albright was prescient in pointing out that both bupivacaine and etidocaine are lipophilic, a physical characteristic that 1.2 Mechanisms of Toxicity has since been shown among local anaesthetics to correlate with particularly intransigent cardiac toxicity. [1] This observation led to Three decades of research focused on the molecular effects the implementation of practice standards that have reduced the underlying local anaesthetic cardiac toxicity have uncovered a incidence of cardiovascular catastrophes. These guidelines include wide range of mechanisms involving ionotropic, metabotropic and use of safe dose limits, an epinephrine-containing test dose to energy transduction systems. The standard model, established by detect intravascular injection by monitoring for tachycardia, and Clarkson and Hondeghem, [8] holds that the pronounced inhibition incremental administration of the drug with repeated aspiration to of cardiac voltage-gated sodium ion channels accounts for the detect intravascular injection. The observation of local anaesthetic differential toxicity of bupivacaine. They showed that bupivacaine cardiotoxicity also provided the impetus for considerable research avidly binds the sodium channel in the closed state, having a efforts directed both to understanding the mechanisms of this dissociation constant ten times longer than lidocaine and the fasttoxicity and evaluating possible methods for its treatment. in, slow-out model has dominated the landscape of research in the field for two decades. However, the cellular effects of bupivacaine 1.1 Clinical Features are pleiotropic. Sites of action include calcium excitation-contraction coupling, both calcium release and calcium sensitivity of the Despite awareness of the problem and utilisation of clinical contractile apparatus, [9,10] and lysophosphatidate, [11] β-adrenergic precautions, severe local anaesthetic toxicity continues to occur receptor [12] and potassium channel [13] signalling schemes. Bupivaboth in the setting of regional anaesthesia and in the use of local caine is also a classic uncoupler of oxidative phosphorylation anaesthetic-containing tumescence solution. The incidence of seand, more recently, has been shown to inhibit complex I of the [14] vere systemic toxicity is estimated by cohort studies to be as high as 1/1000 peripheral nerve blocks but may be considerably higher electron transport chain [15] and mitochondrial transport of fatty because of errors in ascertainment, diagnosis and under-report- acids, [16] the heart s preferred fuel during aerobic metabolism. ing. [3] The earliest clinical manifestations of local anaesthetic Such mitochondrial effects are not surprising given that the toxicity include lightheadedness, altered mental status, agitation, clinical effects of bupivacaine toxicity are seen predominantly in slurred speech and visual disturbance. [4] Early changes in vital heart and brain, organs with very high aerobic demands and low signs include tachycardia and hypertension. [5] The clinical presenlished tolerance for anaerobic metabolism. Furthermore, it is well estabtation of more severe toxicity is classically a combination of that hypoxia exacerbates bupivacaine toxicity, [17] sug- central nervous system (CNS) excitation, with cardiac arrhythcaine. gesting that respiration is a clinically important target of bupiva- mias, conduction blockade and contractile depression. However,

3 Lipid Emulsion for Systemic Local Anaesthetic Toxicity Lipid Reversal Resuscitation 2.1 Background 2.2 Rat Studies Blood pressure (mm Hg) B C Time (min) Fig. 2. Arterial pressure trace during a typical lipid rescue experiment in a dog model of bupivacaine toxicity. (B) indicates the start of a bupivacaine bolus infusion (10 mg/kg) and is taken as zero time. Circulatory collapse was reached at 4.5 minutes and internal cardiac massage (C) was instituted and continued until shortly after the lipid infusion (L) at 15 minutes. Blood pressure was sufficiently restored after 10 minutes of lipid therapy that isoflurane was restarted (I). Several years ago, it was reported that a patient with severe carnitine deficiency exhibited extreme sensitivity to bupivacaineinduced cardiac toxicity. [18] The patient was an adolescent with isovaleric academia who developed classic signs of bupivacaine toxicity despite having received only 22mg of bupivacaine, (roughly one-tenth of a toxic dose) via subcutaneous injection of a tumescent solution under general anaesthesia. This index case suggested that the carnitine cycle could be a site of bupivacaine action and eventually led to the finding that bupivacaine strongly inhibits carnitine acylcarnitine translocase (CACT), [19] a key enzyme of the mitochondrial fatty acid metabolism. Interestingly, patients having mutations in this enzyme experience bradyarrhythmias, conduction defects and contractile depression, abnormalities also seen in bupivacaine toxicity. [20] haemodynamics in all rats treated with lipid during chest compres- sions. These positive findings encouraged studies of lipid-infusion in bupivacaine toxicity in a larger animal. While studying the metabolic effects of bupivacaine, we made 2.3 Dog Studies the chance observation that pre-treating rats with a lipid soy bean A large dose of bupivacaine (10 mg/kg) was injected by intraoil emulsion resulted in marked resistance to the cardiac effects of venous bolus into dogs under general anaesthesia and then treated bupivacaine infusion. The next series of studies measured the with open-chest cardiac massage either alone or in combination influence of lipid delivered after a bupivacaine challenge in anaes- with an infusion of 20% lipid given as an intravenous bolus thetised rats. [21] Lipid-based resuscitation was found to improve followed by a continuous infusion. [22] All dogs developed severe recovery from a rapid intravenous bolus of bupivacaine across a hypotension and bradycardia and, in pilot studies, immediate range of doses otherwise sufficient to produce asystole in the infusion of lipid resulted in rapid recovery of normal ECG and control animals (figure 1). Supplementing chest compression with blood pressure, whereas all controls progressed to asystole and an intravenous injection of 20% lipid increased the dose of bupiva- died. In further experiments, lipid infusion was delayed for 10 caine that is lethal to 50% of rats tested (LD 50 ) from 12.5 to 18 mg/ minutes to mimic the clinical scenario where lipid would not be kg. Furthermore, 15 mg/kg bupivacaine resulted in unrecoverable immediately available for infusion. Nevertheless, all lipid-treated asystole in all controls but was uniformly resuscitated to normal animals recovered normal haemodynamics, whereas all control animals died despite continued cardiac massage and ventilation Saline treated Lipid treated with oxygen. The arterial pressure trace from a typical experiment 1.00 with lipid treatment is shown in figure These observations suggest that lipid infusion might be useful in treating local anaesthetic toxicity and a recent editorial [23] described lipid rescue as a possible silver bullet for bupivacaine 0.25 overdose. However, many important questions remain unanswered, including the mechanism of lipid s benefit, what consti tutes an optimal treatment regimen, the safety of lipid rescue and Bupivacaine bolus dose (mg/kg) its potential application in other forms of poisoning. Mortality fraction Fig. 1. Mortality after a bolus intravenous dose of bupivacaine, comparing resuscitation with either saline or lipid infusion. Each point represents the mortality fraction in a group of six animals after the corresponding bolus dose of bupivacaine (given over 10 seconds). LD 50 values are 12.5 mg/kg for saline resuscitation and 18.5 mg/kg for lipid resuscitation. LD 50 = the dose that is lethal to 50% of animals tested. 3. Mechanisms of Lipid Rescue The use of a lipid emulsion to treat toxicity due to a highly lipophilic drug suggests the possibility of a lipid sink mecha- L I

4 142 Weinberg 1.1 Control 1.0 Lipid Time (sec) Fig. 3. Cardiac bupivacaine content. The trends for myocardial bupivacaine content are shown during the 2 minutes following a 30-second infusion of bupivacaine 500 μmol/l for control and lipid-treated hearts. Values are normalised to zero-time, and error bars indicate standard deviation (n = 5 for both groups). Regression curves were fitted by single exponential decay functions with time constants 83 seconds, R2 = and 37 seconds, R2 = for control and lipid groups, respectively. Zero-time (%) sink or at least suggest that lipid infusion accelerates the loss of bupivacaine from myocardial tissue and that this loss is contemporaneous with more rapid return of cardiac function. Despite the simplicity and appeal of this mechanism, lipid rescue in vivo seems to occur more rapidly than could be explained by the bulk extraction of a highly protein-bound, lipophilic drug across several tissue diffusion barriers into equilibrium with a plasma phase containing oil droplets. Therefore, the speed of action of lipid rescue seems to suggest that additional or alternative mechanisms might also be at play. One possible alternative mechanism is reversal of the aforementioned inhibition of mitochondrial fatty acid transport. Under normal aerobic conditions, fatty acids are the preferred fuel of the heart for oxidative phosphorylation and are responsible for 80 90% of cardiac adenosine triphosphate (ATP) synthesis. [25] If fatty acid transport is suddenly interrupted, the rapid loss of ATP production could contribute to cardiac toxicity. Eledjam et al. [26] showed that depression of contractility in cardiac strips treated with bupivacaine is reversed by incubation with ATP. It is possible that lipid infusion increases intracellular fatty acid content sufficiently to reverse or over- whelm bupivacaine-induced inhibition of CACT. Lipid infusion has been shown in animal models of myocardial ischaemia to improve energy charge and functional recovery suggesting a salu- tary effect of lipid treatment on myocardial metabolism. [27,28] Notably, Stehr et al. [29] have recently found in isolated rat heart that lipid emulsion reverses bupivacaine-induced contractile de- pression at concentrations that are too low to provide a lipid sink effect and thus propose a metabolic explanation for this beneficial effect. nism, where the offending agent is removed from affected tissues by partitioning into a plasma lipid phase created by the infusion. This effect is supported by the observation that radiolabelled bupivacaine added in vitro to plasma drawn from a rat treated with lipid moves preferentially to the lipid phase (partition coefficient ~11). [21] We subsequently compared recovery profiles in rat isolated hearts infused for 30 seconds with bupivacaine 0.5 mmol/l then treated with or without 1% soy oil emulsion added to the perfusion buffer. [24] All hearts quickly developed asystole after the start of bupivacaine, but isolated hearts perfused with lipid exhibited a more rapid return to baseline rate-pressure product (RPP) values: mean time to 90% baseline RPP ± standard error of the mean (SEM) was 124 ± 12 and 219 ± 25.6 for lipid (n = 12) and 4. Alternative Novel Therapies control (n = 8) hearts, respectively (p < 0.01). We then measured bupivacaine content in isolated rat hearts using radiolabelled Cho et al. [30] and Kim et al. [31] have shown that infusion of bupivacaine in the same experimental protocol. Myocardial con- glucose, insulin and potassium reverses cardiovascular depression tent was determined by taking serial mini-biopsies of cardiac in a dog model of bupivacaine toxicity. They postulated a mechatissue in controls and lipid-treated hearts immediately after stop- nism targeting potassium channel activity or intracellular calcium ping the bupivacaine (figure 3). Lipid-treated hearts showed a dynamics. However, the benefit of insulin could also result from more rapid decline in myocardial bupivacaine content than con- improved myocardial energetics since increased glycolysis and trols: mean time constants (95% confidence intervals) were 37 (32, glucose oxidation would provide additional ATP or substrate for 43) seconds and 83 (66, 110) seconds for lipid-treated and control oxidative phosphorylation. [32] Such metabolic modulation has hearts, respectively (n = 5 for both groups, p < 0.002). Bupivacaine been considered for decades as possible treatment of myocardial content was also measured in larger (~200mg) tissue samples at ischaemia, another scenario where myocardial depression results the end of the experiment to avoid sampling errors due to the small from ATP depletion. The experimental models in both studies size of the mini-biopsies and was significantly different in the two used doses of bupivacaine that reduced blood pressure without groups: 22.1 ± 2.2 nmol/g and 75.7 ± 5.8 nmol/g (mean ± SEM) inducing asystole. Furthermore, while insulin, glucose and potasfor lipid-treated and control hearts, respectively (n = 3 for both sium are readily available, some clinicians would consider the use groups, p < 0.01). These findings support the concept of a lipid of two units of insulin/kg with a large bolus of glucose in the

5 Lipid Emulsion for Systemic Local Anaesthetic Toxicity Evidence of Clinical Efficacy for Lipid Rescue Resuscitation Given the highly reproducible benefit in reversing animal mod- els of bupivacaine-induced toxicity, some have suggested that lipid emulsion should be stocked at sites where regional anaesthesia is performed. [34] This recommendation has raised concern among some that the clinical use of lipid emulsion is premature and would detract from the importance of taking needed precautions to prevent local anaesthetic overdose. The missing piece in making such a general recommendation has been evidence of the safety and efficacy of lipid rescue in a clinical setting. Clinical efficacy was recently suggested by a case report from Mt Sinai in New York of a middle-aged man who experienced CC shortly after a brachial plexus block with bupivacaine and mepivacaine. [35] After 20 minutes of standard Advanced Cardiac Life Support (ACLS), including several countershocks and multiple doses of epinephrine, atropine, amiodarone and vasopressin, the patient remained in asystolic with intermittent ventricular tachycardia and fibrillation. However, shortly after the infusion of 100mL of 20% Intralipid, a single heart beat was noted, followed almost immediately by return of normal sinus rhythm and blood pressure. A continuous infusion of lipid at 0.5 ml/kg/min was maintained for 2 hours. The patient was extubated after 3 hours and recovered without neurological deficit. A second case was reported shortly thereafter from Germany. [36] In this report, the patient developed refractory asystole 15 minutes after a brachial plexus block with ropivacaine, another lipophilic local anaesthetic. Shortly after 100mL of 20% Intralipid was injected, spontaneous circulation was restored and the patient recovered fully with no deficits. The rapid recovery of both patients in apparently refractory CC was nearly identical to the effect of lipid emulsion in animal models of otherwise fatal context of circulatory collapse and reduced cerebral perfusion as lacking sufficient experimental support. Another novel strategy is the use of scavenging nanopar- ticles. [33] These tiny droplets of oil (ethylbutyrate emulsified with Pluronic detergent) are approximately times smaller than the particles in Intralipid and therefore provide greater interfacial surface area for adsorbing bupivacaine. These compounds have been shown to reduce aqueous bupivacaine concentrations and to improve the QRS interval prolongation caused by bupivacaine in both an isolated heart model and, when co-infused with bupivacaine, in intact rats. [26] However, there is no report as yet of nanoparticles reversing bupivacaine toxicity when used as a component of resuscitation in an intact animal. Such micro-emulsions are not yet available for clinical use. bupivacaine overdose. These cases provide evidence of clinical efficacy. I propose that lipid should be stocked and kept with a recommended dosing regimen (table I) in operating rooms and locations where regional anaesthesia is performed. Many of our experiments in rat and dog models seem to show that haemodynamic improvements after the initial bolus often regress if a continuous infusion does not follow. Therefore, I recommend the lipid bolus be followed by a continuous infusion; however, rigorous studies are still needed to test this observation. Propofol is formulated with 10% lipid and has been reported to improve bupivacaine toxicity. [37] This has prompted some clini- cians to consider, or perhaps confuse, using propofol as a lipid source during resuscitation from bupivacaine toxicity. However, propofol should not be used when there is any sign of cardiac compromise. Standard formulations of propofol do not contain enough lipid to have any benefit when it is used in anti-convulsant doses. In contrast, large enough doses for lipid rescue would massively overdose the patient with propofol. Additionally, propofol typically lowers blood pressure; thus its use in cardiac arrest is not rational. Furthermore, propofol is a known mitochondrial poison and should not be used in a patient with an overdose of a local anaesthetic, which strongly inhibits oxidative phosphoryl- ation. 6. Future Issues 6.1 Optimised Treatment The protocol offered in table I is a suggestion based on laboratory observations in rat and dog models of bupivacaine toxicity. Table I. Preliminary recommendations for lipid rescue in severe local anaesthetic toxicity Lipid infusion is reserved for use in cardiac arrest due to local anaesthetic toxicity that resists standard resuscitative measures. If asystole, malignant arrhythmias or severe hypotension persist, continue standard Advanced Cardiac Life Support (including ventilation with 100% oxygen and chest compressions), then: infuse 20% Intralipid intravenously as: bolus injection 1.5 ml/kg; followed by continuous infusion 0.25 ml/kg/min, for 30 min repeat bolus 1 2 times if no improvement increase rate of infusion to 0.5 ml/kg/min for declining blood pressure Once a sinus rhythm returns, ventricular ectopy or other arrhythmias may persist but additional bolus doses are probably not required. The infusion should continue for a full hour and may need to be restarted if blood pressure declines after it is stopped Propofol is contraindicated in local anaesthetic toxicity with cardiovascular compromise

6 144 Weinberg While the precise mechanism(s) of lipid rescue resuscitation have yet to be unequivocally established, the action of a lipid sink does appear to contribute. It is reasonable to entertain the possibili- ty that lipid rescue might therefore apply to treatment of acute overdose with other lipophilic or amphiphilic poisons. This might include cocaine, tricyclic antidepressants, calcium channel antago- nists, organic solvents, petrochemicals or other organic com- pounds. Reports by Cave et al. [40] have suggested a modest potential benefit of lipid emulsion therapy in rat models of propranolol toxicity. Minton et al. [41] showed in a small clinical study that infusion of lipid did not alter plasma concentration of amitriptyline. A strategy to screen for the potential efficacy of lipid therapy for severe toxicity could include determining the lipid partition coefficient for various offending agents, or the shift in their LD 50 after pre-treating animals with a lipid emulsion. Subse- quent experiments to assess efficacy of resuscitation in controls and lipid-treated animals would validate the benefit of using lipid to treat such poisoning events. Substantial additional work is required to establish optimised protocols to maximise rates of clinical salvage and minimise risk to patients. Rigorous experimental design should control for a variety of possible confounding variables to define the best lipid composition, the optimal concentration, total dose, and what combination of bolus or continuous infusion is best. The question of whether lipid is more effective when used alone or in combination with other components of ACLS (e.g. epinephrine or vasopressin) must also be studied. The clinician also needs to know whether the administration of lipid should depend on total local anaesthetic dose or the cardiac pathophysiology and whether the type of local anaesthetic matters. It would be very useful to compare the effica- cy of lipid, glucose/insulin and nanoparticles in a well defined animal model of local anaesthetic toxicity. These strategies should also be compared with standard resuscitation techniques and efficacies measured when used alone, in combination and in concert with standard drugs. The therapeutic index for high-dose lipid therapy should also be established. There is a long history of safe use of lipid emulsion as parenteral nutrition and as delivery vehicle (e.g. propofol). However, the regimens reported for lipid rescue in the laboratory to date involve very large doses of lipid infused rapidly in animals whose subsequent neurological status was not evaluated. The safety of such large lipid burdens is not known and case reports of complications following lipid infusion in infants [38] suggest there is a limit to safe lipid therapy. 6.2 Consensus Corcoran et al. [39] recently surveyed >60 academic anaesthesi- ology departments in the US regarding their plans for treating severe local anaesthetic toxicity. They found that only a small percentage of departments would consider using lipid in the resus- citation. Furthermore, there was no uniformity or agreement among the various departments methods for prevention or treatment of such toxicity. The authors concluded that the extreme process variation among anaesthesiologists contributed to inadequate preparation and possibly increased morbidity and mortality from severe local anaesthetic toxicity. They further commented on the need to reach a consensus for treating this potentially catastrophic event. A parallel can be drawn with malignant hyperthermia for which both an effective therapy and a well defined approach for treatment exists. Life-threatening local an- aesthetic toxicity is far more common, also has an apparently effective treatment, but no general agreement on implementing this therapy. 6.3 Use in Other Poisonings 7. Conclusions Infusing a lipid emulsion during resuscitation from local anaes- thetic toxicity reliably rescues animals from overwhelming, other- wise fatal bupivacaine overdose. Recent case reports of clinical efficacy of lipid rescue resuscitation support the value of this technique in treating patients with severe local anaesthetic toxicity. The general use of this method in the framework of a standardised approach to treating local anaesthetic systemic toxicity is likely to improve survival from this potentially catastrophic complication of regional anaesthesia. Further work is required to optimise the treatment regimens with respect to efficacy and safety and to determine whether it is useful in treating other forms of poisoning. Educating clinicians is the first step to achieving this goal. It is possible that lipid rescue resuscitation will also benefit patients in other toxic scenarios. To that end, a group of interested physicians has collaborated to establish a website [42] to dissemi- nate information about the method and serve as a means for clinicians to share experiences and thoughts about local anaesthet- ic toxicity in general. Acknowledgements The preparation of this review was funded in part by grant NIH R21DA The author has applied for a patent describing certain aspects of this method. A patent has not been granted and no patent licensing arrangements have been made. The author does not have equity interests or stocks in any commercial institution related to this method and does not intend to prohibit or restrict the practice of this method on any patient requiring treatment.

7 Lipid Emulsion for Systemic Local Anaesthetic Toxicity Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of References bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. 1. Weinberg GL. Current concepts in resuscitation of patients with local anesthetic Reg Anesth Pain Med 2006; 31: cardiac toxicity. Reg Anesth Pain Med 2002; 27: Collins-Nakai RL, Noseworthy D, Lopaschuk GD. Epinephrine increases ATP 2. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or production in hearts by preferentially increasing glucose metabolism. Am J bupivacaine. Anesthesiology 1979; 51: Physiol 1994; 267: H Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: incidence 26. Eledjam JJ, de La Coussaye JE, Brugada J, et al. In vitro study on mechanisms of and preventive measures. Reg Anesth Pain Med 2002; 27: bupivacaine-induced depression of myocardial contractility. Anesth Analg 4. Scott DB. Evaluation of clinical tolerance of local anaesthetic agents. Br J Anaesth 1989; 69: ; 47 Suppl.: Van de Velde M, Wouters PF, Rolf N, et al. Long-chain triglycerides improve 5. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that recovery from myocardial stunning in conscious dogs. Cardiovasc Res 1996; of bupivacaine. Anesth Analg 1989; 69: : Morishima HO, Pedersen H, Finster M, et al. Bupivacaine toxicity in pregnant and 28. Van de Velde M, DeWolff M, Leather HA, et al. Effects of lipids on the functional nonpregnant ewes. Anesthesiology 1985; 63: and metabolic recovery from global myocardial stunning in isolated rabbit 7. Groban L, Deal DD, Vernon JC, et al. Cardiac resuscitation after incremental hearts. Cardiovasc Res 2000; 48: overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in 29. Stehr SN, Ziegler J, Pexa A, et al. Lipid effects on myocardial function in L- anesthetized dogs. Anesth Analg 2001; 92: bupivacaine induced toxicity in the isolated rat heart [abstract]. Reg Anesth 8. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac Pain Med 2005; 30: 5 conduction: fast block of sodium channels during the action potential with slow 30. Cho HS, Lee JJ, Chung IS, et al. Insulin reverses bupivacaine-induced cardiac recovery from block during diastole. Anesthesiology 1985; 62: depression in dogs. Anesth Analg 2000; 91: Mio Y, Fukuda N, Kusakari Y, et al. Comparative effects of bupivacaine and 31. Kim JT, Jung CW, Lee KH. The effect of insulin on the resuscitation of bupivaropivacaine on intracellular calcium transients and tension in ferret ventricular caine-induced severe cardiovascular toxicity in dogs. Anesth Analg 2004; 99: muscle. Anesthesiology 2004; 101: Lynch C. Depression of myocardial contractility in vitro by bupivacaine, etido- 32. Weinberg G, VadeBoncouer T. Improved energetics may explain the favorable caine, and lidocaine. Anesth Analg 1986; 65: effect of insulin infusion on bupivacaine cardiotoxicity. Anesth Analg 2001; 92: 11. Nietgen GW, Chan CK, Durieux ME. Inhibition of lysophosphatidate signaling by lidocaine and bupivacaine. Anesthesiology 1997; 86: Renehan EM, Enneking FK, Varshney M, et al. Scavenging nanoparticles: an 12. Butterworth JF, Brownlow RC, Leith JP, et al. Bupivacaine inhibits cyclic-3,5 - emerging treatment for local anesthetic toxicity. Reg Anesth Pain Med 2005; adenosine monophosphate production: a possible contributing factor to cardio- 30: vascular toxicity. Anesthesiology 1993; 79: Picard J, Meek T. A response to lipid emulsion to treat bupivacaine toxicity. 13. Courtney KR, Kendig JJ. Bupivacaine is an effective potassium channel blocker in Anaesthesia 2005; 60: 1158 heart. Biochim Biophys Acta 1988; 939: Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid emulsion 14. Dabadie P, Bendriss P, Erny P, et al. Uncoupling effects of local anesthetics on rat to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. liver mitochondria. FEBS Lett 1987; 226: Anesthesiology 2006; 105: Sztark F, Malgat M, Dabadie P, et al. Comparison of the effects of bupivacaine and 36. Litz RJ, Popp M, Stehr SN, et al. Successful resuscitation of a patient with ropivacaine on heart cell mitochondrial bioenergetics. Anesthesiology 1998; ropivacaine-induced asystole after axillary plexus block using lipid infusion. 88: Anaesthesia 2006; 61: Weinberg GL, Palmer JW, VadeBoncouer TR, et al. Bupivacaine inhibits acyl- 37. Ohmura S, Ohta T, Yamamoto K, et al. A comparison of the effects of propofol and carnitine exchange in cardiac mitochondria. Anesthesiology 2000; 92: sevoflurane on the systemic toxicity of intravenous bupivacaine in rats. Anesth 17. Rosen MA, Thigpen JW, Shnider SM, et al. Bupivacaine-induced cardiotoxicity in Analg 1999; 88: hypoxic and acidotic sheep. Anesth Analg 1985; 64: Barson AJ, Chistwick ML, Doig CM. Fat embolism in infancy after intravenous fat 18. Weinberg GL, Laurito CE, Geldner P, et al. Malignant ventricular dysrhythmias in infusions. Arch Dis Child 1978; 53: a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesth 1997; 9: Corcoran W, Beck JM, Gerancher J, et al. Local anesthetic-induced cardiac toxicity: a survey of contemporary practice strategies among academic anesthe- 19. Indiveri C, Tonazzi A, Prezioso G, et al. Kinetic characterization of the reconstitut- siology departments [abstract]. Anesth Analg 2006; 102: S-316 ed carnitine carrier from rat liver mitochondria. Biochim Biophys Acta 1991; 1065: Cave G, Harvey M, Castle C. The role of fat emulsion therapy in a rodent model of propranolol toxicity: a preliminary study. Med Toxicol 2006; 2: Rubio-Gozalbo ME, Vos P, Forget PP, et al. Carnitine-acylcarnitine translocase deficiency: case report and review of the literature. Acta Paediatr 2003; 92: 41. Minton N, Goode A, Henry J. The effect of a lipid suspension on amitryptiline disposition. Arch Toxicol 1987; 60: Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or resuscitation 42. LipidRescue : resuscitation for local anesthetic toxicity [online]. Available from with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in URL: [Accessed 2006 Oct 5] rats. Anesthesiology 1998; 88: Weinberg G, Ripper R, Feinstein DL, et al. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: Correspondence and offprints: Prof. Guy Weinberg, Department of Anesthe siology, M/C515, University of Illinois Hospital, 1740 W. Taylor, Chicago, 23. Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver IL 60612, USA. bullet been identified? Reg Anesth Pain Med 2003; 28: guyw@uic.edu