Hrev_master [Emergency Care Journal 2014; 10:1820] [page 41] Treatment with lipid therapy to resuscitate a patient suffering from toxicity due to local anesthetics Manuel Monti,1 Alessio Monti,2 Francesco Borgognoni,1 Giovanni Maria Vincentelli,3 Federico Paoletti1 1Emergency Department, Local Health Unit UMBRIA1, Assisi; 2Department of Engineering, Roma Tre University, Rome; 3Emergency Department, Fatebenefratelli Hospital, Rome, Italy Abstract Recently, although without a universal recognition, the use of lipid emulsions as a rescue therapy for the bupivacaine cardiac tox- icity has been proposed. In this article we report a successful resuscitation of a patient after the injection of bupivacaine in emer- gency room and a commented review of the related literature. The patient is a 73 years old man that, after a subcutaneous injection of bupivacaine (0.5%, i.e. 0.5 mL/h), developed circulatory arrest. After the failure of the initial treatment based on the advanced life support protocol, we have successfully performed a therapy with lipid emulsion. The bupivacaine intravascular injection, together with its inter- action with amitriptyline and carbamazepine, could lead to cardiac depression, severe arrhythmias, hypotension, and/or cardiac arrest. In the case of failure of traditional life support treatment, intravenous lipid emulsion proves to be the best therapy to treat bupiva- caine systemic toxicity. Introduction Local anesthetics (LAs) are frequently used in emergency therapy.1,2 They generally exhib- it a low incidence of adverse events, but they have a very high mortality rate.3,4 Local anes- thetics have common features: they are all composed of three chemical groups and pro- duce a reversible inhibition of the sensory con- duction of the nerve impulse at the regional level by selectively blocking sodium channels in the membrane (Figure 1). In particular, local anesthetics hinder the propagation of the action potential along the axon. This effect provokes the inhibition of the sodium chan- nels by acting on specific receptors. Under qui- escent condition, LA has a reduced functional- ity but, during depolarization, LA binds to the sodium receptor and it further decreases the sodium stream.5 This indicates that LA has dif- ferent binding affinities depending on the con- formation of the channel and, in particular, LAs are greater when the channel is depolar- ized. The first studies about the systemic toxi- city of local anesthetics were done by Murloy.3 More recently, Lee,6 performing a study named Closed Claims Database for the American Society of Anaesthesiology and using data from 1980 to 2000, pointed out that the toxici- ty of LA is the main cause of brain damage or death. Although it is difficult to calculate the precise impact of LA systemic toxicity, many studies on animals have established the direct effect of LAs on the systemic reaction.3,46,7 The organs mainly affected by LA toxicity are the central nervous and the cardiovascular system. Toxicity depends on many factors, among which the most important ones are the plasma concentration, the time required to reach the peak concentration, the drug type, the charac- teristics and the co-morbidities of the patient, apart from the way of administration.8 Between the main manifestations of neuro- toxicity, it is possible to include partial seizures and fasciculations and, with an increasing dose, a generalized tonic-clonic seizures until reaching a central nervous sys- tem (CNS) depression state.9,10 The cardiovas- cular system is less resistant to bupivacaine if compared to other anesthetics,11 and the toxic manifestations include deep sinus bradycar- dia, elongation of the PQ interval, QT and QRS complex to atrioventricular block and, finally, asystole and hypotension.12 Recent studies indicate that, beside the blockage of sodium the channel, LAs also act in the mechanisms of potassium and calcium channels and they are Manuel Montiresponsible of some alterations in the mitochondrial metabolism as well as in the ATP production.13 In 1998, in an experiment on animal in vivo, Weinberg was the first to demonstrate the effi- cacy of the intravenous lipid emulsion (ILE) in the treatment of cardiac arrest induced by a bolus of bupivacaine.1 Subsequent case reports14-21 have validated the clinical use of ILE in the treatment of severe systemic toxici- ty due to local anesthetics. The effectiveness mechanisms of the ILE treatment against the toxicity of local anes- thetics have not been yet clarified, but, proba- bly, one of the dominant effects of the emul- sion is the lipid intravascular expansion that is able to absorb the offending circulating lipophilic toxin and to reduce, in this way, their concentration in the sites of action (lipid sink theory).22-26 The hypothesized mechanism is schematized in Figure 2. At this regard, we observe that Mazoit et al.27 have studied the different formulations of fat emulsion used in the treatment of the local anesthetics toxicity and they have concluded that the formulations consisting of long-chain fatty acids are about 2.5 times more effective compared to that con- sisting of a mixture of fatty acids 50/50 long and media chain. Case Report The patient was a 73-year-old, 75 kg, 176 cm, male, that arrived at the emergency depart- ment for a major wound involving the skin and subcutaneous tissue (width 10 cm, length 5 cm) on the left leg. After his arrival in the emergency area, the patient shown the follow- ing clinical conditions: heart rate (HR) of 80/min, sinus rhythm, SpO2 100, noninvasive blood pressure (NIBP) 128/82 mmHg, periph- eral pulse was palpable, capillary refilling time was normal. Regarding his medical history, the patient did not report significant events except for a previous diagnosis of fatty liver, arterial hypertension treated with angiotensin-con- verting-enzyme inhibitors and a chronic neu- ropathic pain treated with amitriptyline and carbamazepine. We performed therapy with local anesthetic (bupivacaine 0.5%, i.e. 0.4 mL/kg) and we began the wound suturing. Emergency Care Journal 2014; volume 10:1820 Correspondence: Manuel Monti, Emergency Department, Local Health Unit UMBRIA1, Via V. Muller 1, Assisi (PG), Italy. Tel. +39.334.6617176 - Fax: +39.075.5412205. E-mail: montimanuel@tiscali.it Key words: local anesthetics, cardiac toxicity, resuscitation, lipid therapy. Contributions: MM is the main author and con- ceived the paper and drafted its first version; FP provided a critical revision of the paper in some important intellectual aspects; GMV contributed with literature review and pictures design; AM contributed in data analysis of the study and, in the final version of the paper, improved technical aspects and English-written; FB, as Emergency Department director, made the overall revision of the paper and guaranteed the integrity of the entire study. All the authors read and approved the manuscript. Conflict of interests: the authors declare no potential conflict of interests. Received for publication: 4 July 2013. Revision received: 16 December 2013. Accepted for publication: 20 December 2013. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright M. Monti et al., 2014 Licensee PAGEPress, Italy Emergency Care Journal 2014; 10:1820 doi:10.4081/ecj.2014.1820 Non -co mmerc ial us e o nly [page 42] [Emergency Care Journal 2014; 10:1820] Approximately 30 seconds after anaesthesia, the patient has abruptly lost consciousness and has developed a tonic-clonic seizure. An oxygen treatment was immediately started using a facemask attached to a self-inflating resuscitation bag. About 90 seconds later, the tonic-clonic seizure was interrupted and the patient remained unconscious. Immediately, we have applied to the patient the patches of a Zoll biphasic defibrillator that have shown an asystolic cardiac rhythm. Moreover, it was not possible to detect blood pressure. Advanced cardiac life support (ACLS®) was immediately started by perform- ing chest compressions. The patient was intu- bated and the tube position was confirmed by auscultation. During the first 20 minutes of the ACLS, a total of 3 mg epinephrine, given in three doses, was administrated to the patient without noticing an improvement of the clini- cal situation. Since there was no response with the nor- mal protocol of cardiac advanced support, we have used an initial intravenous bolus injec- tion of 20% lipid emulsion 1.5 mL/kg–1 over 1 min (Intralipid®; Fresenius Kabi, Bad Homburg, Germany) followed by administra- tion of 100 mL/h of lipid emulsion, while con- tinuing cardiopulmonary resuscitation. After 5 minutes of lipid administration, the electrocar- diogram tracing was reassessed and it showed a shockable rhythm (Figure 3), which was con- verted through the technique of biphasic defib- rillation (200 J). After 2 minutes of revalua- tion, we have noticed the presence of a sinus rhythm and of the carotid pulse. After the described emulsion lipid therapy, vital parame- ters were: HR 158/min, sinus rhythm NIBP 120/68 mmHg, SpO2 100 on O2, RR- 24/min. Blood tests are shown in Table 1. Thereafter, the patient remained hemodynamically stable. He has not required further inotropic/vasoac- tive medications during his persistence in the emergency department. An infusion of lipid emulsion was started and continued at 0.5 mL×kg−1×min−1 over the following 2 h and then discontinued. He was weaned from mechanical ventilation and extubated approxi- mately 2.5 h later. Then, the patient was transferred to the intensive care unit in stable conditions with a normal sinus rhythm (Figure 4) and, after one month, he was discharged with no neurologic abnormalities. Discussion Bupivacaine was first synthesized in 1963 and, since then, it have been used in many applications including local anaesthesia. In addition to its local anesthetic effect, it is a strong depressant of electric conduction which predisposes the heart to arrhythmias.28 The toxic dose of bupivacaine is generally 1.5 mL/kg. In our case, it is a very unusual that a low dosage of bupivacaine 0.5% (0.5 mL/kg) has given such dramatic effects. In our opin- ion, there are several causes that could explain these tragic consequences. In particular, the local anesthetics toxicity probably has depend- ed on the unintentional fast intravenous injec- tion (considering the emergency department where we have operated) that, as already described in other studies,28 and is responsible of toxicity effects on the cardiac function (hypotension, aritmia, etc.29) and on the CNS.9-30 Moreover, we noted that the rapid appearance of cardiovascular depressant effect of the LA agent affects, as a probably contributory cause, the association among bupivacaine, carba- mazepine and amitriptyline. Case Report Figure 1. Model of the fourth homologous domain (D4) of the human skeletal muscle sodium channel (hNaV1.4) with the S4 segment depicted as a rotating cylinder. Figure 2. The theoretical mechanisms of lipid rescue. Figure 3. Ventricular fibrillation. Figure 4. Sinus rhythm after defibrillation. Non -co mmerc ial us e o nly [Emergency Care Journal 2014; 10:1820] [page 43] In fact, the unusual combination of the amitriptyline and carbamazepine,31,32 used for chronic neuropathic pain, can exacerbate bupivacaine toxicity. As it is well known, amitriptyline is a pharmacologically weak base capable of accepting protons to become cation- ic, thus generating an acidic environment. This effect may induce a reduction of the bupi- vacaine lipophilicity with a consequent increase in the active bupivacaine concentra- tion. This phenomenon has been first observed by Strichartz, who demonstrated an increase of the aqueous:octanol partitioning of bupiva- caine in case of pH reduction,33 and confirmed by Mazoit et al.34 Moreover, carbamazepine is able to reduce the propagation of abnormal impulses in the brain, by blocking sodium channels, and to interfere with the action potential of the Purkinje fibers and of the bundle of His, lead- ing, finally, to atrioventricular blocks and arrhythmias.35 In our case, characterized by an high-level of active bupivacaine concentration, the carbamazepine could have facilitated the appearance of tonic-clonic seizure and ventric- ular fibrillation. Finally, our patient had an undiagnosed severe hypoalbuminemia (2.5 g/dL) that could have definitely increased the toxic effect of the anesthetic.32 Conclusions The experience provided by this case report suggests to make immediately available in all areas of our emergency department a proper number of 100 mL of 20% lipid emulsion. Since 2006, the Association of Anaesthesiology of Britain recommends that intralipid 1000 mL of 20% should be immediately available in all areas where potentially cardiotoxic doses could be administered through local anesthet- ics. Intravenous lipid emulsion is also recom- mended in the guidelines of Australian and New Zealand College of Anaesthetists for car- diac arrest due to lipophilic molecules respon- sible for blocking and calcium channel beta, when conventional therapies fail resuscita- tion.36,37 The expected benefits of ILE are difficult to quantify, but on the basis of limited animal and human data, it can be classified as life-preserv- ing. However, human cases of LA poisoning are infrequent and a systemic evaluation is not yet possible. We agree with Picard38 when he states that fat emulsion is a crucial antidote to the toxicity of local anesthetics. References 1. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion rescues dogs from bupivacaine-induced cardiac toxicity. Region Anesth Pain M 2003;28:198-202. 2. Ludot H, Tharin JY, Belouadah M. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhyth- mia following posterior lumbar plexus block in a child. Anesth Analg 2008; 106:1572-4. 3. Mulroy M. Systemic toxicity and cardiotox- icity from local anesthetics incidence and preventive measure. Region Anesth Pain M 2002;27:556-61. 4. Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 1994;265:1724- 8. 5. Horn R. Coupled movements in voltage- gated ion channels. J Gen Physiol 2002; 120:449-53. 6. 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Myocardial uptake of bupivacaine: pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rab- bit heart. Anesth Analg 1993;77:477-82. 12. Blair MR. Cardiovascular pharmacology of local anesthetics. Br J Anaesth 1975;47: 247-52. 13. Scholz A. Mechanisms of (local) anaes- thetics on voltage‐gated sodium and other ion channels. Brit J Anaesth 2002;89:52- 61. 14. Foxall G, McCahon R, Lamb J, et al. Levobupivacaine-induced seizures and cardiovascular collapse treated with intralipid. Anaesthesia 2007;62:516-8. 15. Litz RJ, Popp SN, Koch T. Successful resus- citation of a patient with ropivacaine- induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006;61:800-1. 16. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg 2008;106:1575-7. 17. Ludot H, Tharin JY, Belouadah M, et al. 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