Advances in Anesthesia, Vol. 28, No. 1, ** **
ISSN: 0737-6146
doi: 10.1016/j.aan.2010.07.007
Current Concepts in the Management of Systemic Local Anesthetic Toxicity
Local anesthetics are amphipathic compounds; they are both lipophilic and hydrophilic. The lipophilic component of the molecule allows local anesthetics to cross plasma and intracellular membranes, whereas the hydrophilic portion gives them the ability to interact with charged targets such as structural or catalytic proteins [1] and ion channels. When given at appropriate sites and doses, local anesthetics are safe. However, local anesthetic systemic toxicity (LAST) can occur from either accidental intravascular injection or when excessive amount of local anesthetic finds its way to the intravascular space. Patient factors can also reduce the threshold to LAST such that even normally safe serum concentrations of local anesthetic can lead to symptoms of clinical instability. Therefore, LAST is the end result of the interaction and contribution of patient-specific factors, the peak plasma concentration, and physicochemical properties of the specific local anesthetic [2]. Intrinsic anesthetic potency and the potential for causing acute cardiac and neurotoxicity parallel the lipid solubility of the drug.
The history of local anesthetics begins with the conquest of Peru by Pizarro in the early part of the 16th century and the introduction of the coca plant to Europe [2]. In 1850, Austrian von Scherzer first brought enough quantity of the coca plant to allow the isolation of cocaine by Niemann [3]. In the late 1880s Sigmund Freud suggested to his colleague Carl Koller the idea of using cocaine for its LA properties. In 1884 Koller performed the first eye surgery with the use of topical cocaine.
Shortly after the use of cocaine for topical anesthesia, physicians began to inject cocaine near peripheral nerves and into the spinal and epidural spaces [4]. In 1855 Alexander Wood first presented the idea of a nerve block by direct application of cocaine [2] and it was not long before the toxic effects of cocaine were identified. Cocaine not only led to addiction among medical staff but resulted in deaths among patients and medical staff alike. Before the introduction of cocaine as a local anesthetic, cocaine toxicity was reported in 1868 by Moreno y Maiz when he described cocaine-induced seizures in rats [4]. By 1887 J.B. Mattison had reported 30 cases of cocaine toxicity that involved a spectrum of symptoms from convulsions to death [3].
In 1919 Eggleston and Hatcher published a comprehensive summary of the prevention and treatment of LAST. They concluded that different local anesthetics were additive in their toxicity and that adding epinephrine to subcutaneous injection of local anesthetics apparently reduced the incidence of LAST [4]. In 1925 Tatum, Atkins and Collins identified that seizures from LAST could be controlled with barbiturate injection. By 1928 the medical community in the United States recognized a growing risk of mortality directly attributable to local anesthetics, which led to the formation of a specific ad hoc Council of the American Medical Association. The recommendations of the Council to treat toxicity from local anesthetics included cardiac massage and artificial respiration. The Council concluded that intracardiac adrenaline and digitalis were not useful to treat the toxicity [3].
As the frequency of central nervous system (CNS) and cardiovascular (CV) systemic toxicity from local anesthetics grew in number the medical community was prompted to search for new and less toxic local anesthetics [3]. Giesel isolated tropocaine in 1891 from a Javanese species of coca. Tropocaine proved to have similar degrees of toxicity to cocaine. However, structural modifications of tropocaine led to the preparation of newer local anesthetics such as eucaine, Holocaine, and orthoform [3]. In 1900 and 1905 Eihorn synthesized benzocaine and procaine, respectively. Procaine had relatively few side effects and quickly grew out of favor because of its low potency, slow onset, short duration of action, and limited ability to penetrate tissue [3]. Chloroprocaine was created by a chlorine substitution to the aromatic ring of procaine. Unfortunately, its use declined after 1980 because of reports of prolonged sensory and motor block following subarachnoid administration of an intended epidural dose. The last ester type local anesthetic to be developed was tetracaine in 1930. Tetracaine can be used to achieve 1.5 to 2.5 hours of spinal anesthesia as an isobaric, hypobaric, or hyperbaric solution [3]. It is also effective as a topical airway anesthetic. Lidocaine was created in 1944 and was first used clinically in 1948. It quickly became one of the most widely used local anesthetics because of its potency, rapid onset, and effectiveness for infiltration. The safety profile of lidocaine for neuraxial anesthesia was questioned in the late 1980s when numerous reports appeared of transient neurologic symptoms following uneventful spinal anesthesia and instances of cauda equina syndrome from high concentrations of lidocaine being administered through a continuous spinal catheter. All newer local anesthetics after the invention of lidocaine encompass the amide structure. Mepivacaine and prilocaine are both related to lidocaine and were introduced for clinical use in 1957 and 1960, respectively [3]. Prilocaine is limited for clinical use by its potential to cause methemoglobinemia.
The evolution of modern regional anesthesia begins with the invention of bupivacaine in 1957. Shortly after its synthesis bupivacaine was initially discarded for clinical use because it was found to be 4 times more toxic than its homolog mepivacaine [3] and was not introduced into clinical practice until 1965. Bupivacaine belongs to the family of n-alkyl-substituted pipecholyl xylidines having a butyryl substitution and an asymmetric carbon atom that represents a chiral center [5]. Bupivacaine is a long-acting amide local anesthetic that can be used for neuraxial block, peripheral nerve block, and infiltration. It can be used for a differential blockade because lower concentrations mainly provide sensory blockade, whereas motor blockade is only seen at higher concentrations [3].
Hollmen reported the first clinical descriptions of bupivacaine toxicity in 1966. A total of 133 patients were studied for toxic reactions during epidural and caudal anesthesia for abdominal and urological surgery [3]. Five out of 6 patients had mild to severe CNS toxicity manifesting as tremor or convulsions. One case involved hypotension and bradycardia after a caudal block.
In 1969 Beck and Martin reviewed 19,907 cases of paracervical blockade with bupivacaine in women during labor [6]. They found 23 cases of infant death and evidence of newborn acidosis associated with paracervical blockade with bupivacaine. It was not until 1983 that bupivacaine was abandoned for use in paracervical blockade [3].
In the early 1970s there were several human volunteer studies of bupivacaine toxicity. Most of these involved continuous infusion of bupivacaine until symptoms appeared [3]. The sample sizes for these studies were extremely small, consisting of only 3 to 6 patients. The main observed symptoms were CNS in nature (lightheadedness, muscle twitching, dizziness, lip numbness, tinnitus, and slurred speech).
The first case of severe cardiovascular toxicity was reported in 1977 by Edde and Deutsch, 10 years after the introduction of bupivacaine to clinical use. They described ventricular fibrillation in a patient undergoing an interscalene block with 100 mg of bupivacaine [2]. Albright’s editorial in 1979 detailed bupivacaine-induced CV compromise such as ventricular arrhythmias, CV collapse and death. He implied a causal relationship between severe CV toxicity and the use of bupivacaine and etidocaine [7].
In the 1980s the pharmaceutical industry began to search for a less toxic, but potent and long-acting local anesthetic with reduced toxicity [3]. This led to the use of the potentially less toxic S-(−)-enantiomer of bupivacaine, levobupivacaine, and the new local anesthetic, ropivacaine. Ropivacaine was introduced into clinical practice in 1996 after evaluation in clinical trials starting in 1990. It is able to produce differential blockade and may have a better safety profile.
The latest focus on methods to reduce local anesthetic toxicity involves the delivery of local anesthetics mixed with substances capable of slowing release. Two approaches involve liposomes and microspheres. Boogaerts and colleagues [8] published the first study of epidural administration of liposomal bupivacaine in 1994.
CNS
Clinical central nervous system toxicity caused by bupivacaine consists of 2 phases. The first phase or the excitatory phase manifests as shivering, muscle twitching, and tremors progressing to tonic-clinic seizures [9]. The second or the inhibitory phase involves generalized depression leading to hypoventilation and respiratory arrest. The CNS symptoms usually occur before signs of cardiovascular toxicity. The specific mechanism underlying CNS toxicity involves neuronal desynchronization, possibly because of disturbances with the γ-aminobutyric acid neurotransmitter [10].
CVS
Bupivacaine blocks cardiac sodium channels in a time- and voltage-dependent manner. The sodium channel block is intensified as heart rate is increased or membrane potential is more depolarized [11]. Bupivacaine has a preference for inactivated sodium channels over those in the resting or open configuration. At low concentrations, bupivacaine blocks sodium channels in a slow-in slow-out manner and at high concentrations the channel is blocked in a fast-in slow-out manner. Non–protein-bound free bupivacaine concentrations of 0.5 to 5 μg/mL slow conduction of cardiac action potentials, which leads to a prolonged PR interval and a widened QRS complex. The persistence of sodium channel blockade into diastole further slows cardiac conduction and can predispose the heart to re-entrant arrhythmias and/or unifocal, multifocal beats or ventricular tachycardias.
Local anesthetics also inhibit cardiac contractility in a nonstereoselective manner, which might result from various effects on mitochondrial energy metabolism, intracellular calcium regulation [12,14] inhibition of cAMP [15] or interference with other metabotropic signaling pathways. Bupivacaine reduces both the mitochondrial transmembrane potential and lipid-based respiration in mitochondria [16]. The former reduces efficiency of oxidative phosphorylation; the latter impairs the transport of lipid fuel necessary for the 70% of myocardial energy that is normally derived from fatty acid oxidation in the mitochondrial matrix. The observation that bupivacaine inhibits carnitine-acylcarnitine translocase was an important step in the discovery of lipid emulsion (see later discussion). This specific inhibition of carnitine fatty acyl transfer into the mitochondrial matrix might explain the relatively low dose of bupivacaine that leads to cardiovascular collapse [16]. Bupivacaine also impairs cardiac relaxation (lusitropy), an effect that may be caused by impairment of calcium handling in the sarcoplasmic reticulum [17].
Evolution of lipid emulsion (bench to bedside) as treatment of local anesthetic toxicity
Several animal studies and case reports have demonstrated the effectiveness of intravenous lipid emulsion (ILE) infusion during resuscitation from symptomatic overdose of local anesthetic toxicity, and ILE has recently gained acceptance as a recommended treatment for LAST (Fig. 1). The investigation of ILE therapy for LAST resulted from unexpected clinical and laboratory observations. The first involved a patient with a history of isovaleric acidemia undergoing suction lipectomy. The surgeon used a tumescent solution containing 300 mL of 0.0075% bupivacaine and epinephrine 1:1,000,000 [18]. Minutes after the use of the tumescent solution the patient had ventricular dysrhythmias with hemodynamic instability. This patient was later discovered to have carnitine deficiency, and the investigators theorized that this could explain the patient’s increased susceptibility to the toxic effects of bupivacaine [18].
During normal aerobic conditions carnitine is necessary for transport of fatty acids into the mitochondrial matrix. These fatty acids are the predominant energy source for the heart. Weinberg and colleagues [16] went on to show that bupivacaine inhibits carnitine metabolism in cardiac mitochondria. They found evidence that bupivacaine inhibited mitochondrial state III respiration when acylcarnitines are the available substrates. Therefore, because of the heart’s respiratory dependence on fatty acids for energy and bupivacaine’s inhibition of the enzyme carnitine-acylcarnitine translocase, the investigators postulated that this contributed to the relatively low ratio of the toxic dose of bupivacaine needed for cardiovascular collapse in relation to that producing seizures.
Because cytoplasmic accumulation of fatty acyl molecules was known to be arrhythmogenic, the investigators postulated that pretreatment with an infusion of lipids might aggravate bupivacaine-induced arrhythmias; they observed exactly the opposite effect in rats pretreated with lipid. Lipid infusion increased the dose of bupivacaine required to induce asystole in rats [19]. There was a 48% increase in the LD50 for bupivacaine when the rats were resuscitated with lipid infusion. Paradoxically, isolated hearts using lipid substrates are more sensitive to bupivacaine toxicity than when burning only carbohydrates [20].
The next set of experiments involved a dog model, a species closer in size to humans. Cardiovascular collapse occurred in all dogs after 10 mg/kg of bupivacaine injected intravascularly [21]. Cardiac massage alone failed to resuscitate any of the dogs. An infusion of lipid emulsion plus internal cardiac massage led to full recovery whether the treatment was initiated immediately or 10 minutes after complete cardiovascular collapse. All 6 of the dogs in the experimental group recovered normal hemodynamic parameters but none of dogs in the control group survived.
Clinical use of ILE
In 2006 Rosenblatt and colleagues [22] published the first case report of successful lipid-based resuscitation of a patient with cardiac arrest secondary to LAST. The patient was given 40 mL of a 1:1 mixture of 0.5% bupivacaine plus 1.5% mepivacaine for an interscalene brachial plexus block followed quickly by loss of consciousness and seizures. Within minutes of the seizure the patient’s electrocardiograph (ECG) showed asystole. After 20 minutes of advanced cardiac life support, 100 mL of 20% lipid emulsion was administered via peripheral intravenous access and the patient rapidly recovered normal vital signs and normal sinus rhythm. Within 2.5 hours the patient was awake, alert and responsive, and extubated without any neurologic sequelae.
Mechanisms of ILE
Lipid Sink Mechanism
Lipid emulsion is a 20% formulation of fat emulsion and consists of 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, water, and sodium hydroxide. Egg yolk phospholipid exists in a 1% concentration with oil particles of about 0.5 μm in diameter and acts as the emulsifying agent. The emulsified fat droplets, when infused into an aqueous medium, such as blood, form a lipid compartment into which lipophilic substances, such as local anesthetics, are theoretically partitioned. As local anesthetics are drawn into the lipid sink a corresponding concentration gradient develops between tissue and blood causing the local anesthetics to move away from the heart or brain (areas of high concentration) to the lipid sink. In an experimental rat model, Weinberg and colleagues [19] demonstrated that radiolabeled bupivacaine added in vitro to lipid-treated rat plasma preferentially moves to the lipid phase. This concentration gradient reduces the total local anesthetic drug concentration in contact with tissue. The bupivacaine lipid/aqueous partition coefficient of 11.9 found in this model suggests that the lipid phase retains highly lipophilic drugs, such as bupivacaine. The solubility of long-acting local anesthetics in lipid emulsion and the high binding capacity of these emulsions likely explain the clinical efficacy when lipid emulsion is rapidly infused as in the treatment of LAST.
Alternative Mechanisms
ILE might also affect ATP synthesis in the myocyte by increasing intracellular fatty acid content and thereby overcoming the reduced ATP production secondary to local anesthetic block of fatty acid oxidation. Eledjam and colleagues [23] demonstrated that ATP repletion reverses bupivacaine toxicity in isolated myocardial strips. Van de Velde and colleagues [24] demonstrated in a dog model that infusion of 20% lipid emulsion improves contractility because of improved fatty acid oxidation. Furthermore, fatty acids have also been shown to increase calcium levels in cardiac myocytes. Lipid emulsion infusion may therefore directly increase intramyocyte calcium levels and lead to a direct positive inotropic effect [25]. Lipid emulsion was initially observed as acting faster in in vivo settings than was anticipated based on a simple lipid sink mechanism [26]. This suggested to the experimentalists that additional, potentially direct cardiotonic effects might be in play. Subsequently, Stehr and colleagues [27] demonstrated in isolated rat heart models that lipid emulsion reverses bupivacaine-induced contractile depression at concentrations that are too low to provide a lipid sink phenomenon, suggesting an alternative, possibly metabolic explanation for the beneficial effect. Although the precise contribution of these mechanisms of benefit in ILE treatment of LAST remains unclear, it is likely that the key component is the local anesthetic binding property of the emulsion [28].
Potential Complications of ILE
Adverse effects of ILE have been reported largely in the setting of its use as a nutritional supplement, particularly in the neonatal intensive care unit. Some reported complications include pulmonary dysfunction, allergic reactions, increased liver function tests, hypercoagulability, thrombocytopenia, and hyperthermia [29]. The only published complication of ILE during resuscitation was reported by Marwick and colleagues [30] who described a single increased amylase level in a patient who had received 500 mL of lipid emulsion. Despite the increased amylase level, no clinical development of pancreatitis occurred, and no change in treatment was necessary. Therefore, the reported and potential complications of ILE probably do not outweigh its potential benefit, particularly in its use during the rescue of a patient with cardiovascular instability secondary to LAST.
ILE in ACLS
ILE is a novel method for treating LAST that shows promise as an effective antidote for lipophilic drug poisoning, including local anesthetics (Fig. 2). Cardiovascular collapse is the most life-endangering complication of local anesthetic absorption or intravascular injection during regional anesthesia. Reports in the past several years have focused on the merits of ILE in the setting of standard resuscitation protocols.
Weinberg [31] published the first recommendation for the use of ILE in a letter to the editor in 2004 then a revised version in 2006 on an educational Web site (www.lipidrescue.org). These recommendations served as the basis for all subsequent recommendations for ILE. For instance, the Association of Anaesthetists of Great Britain and Ireland (AAGBI) published a set of guidelines for the management of LAST in 2007 that outline specific dosing information and recommend that lipid emulsion should be available in locations where potentially toxic doses of local anesthetics are administered [32]. The AAGBI’s guidelines added credence to the use of ILE in the setting of LAST. One year later, in 2008, the American Society of Critical Care Anesthesiologists and the American Society of Anesthesiologists Committee on Critical Care Medicine as well as the Resuscitation Council (UK) incorporated the use of lipid emulsion in their published protocols for the treatment of LAST [33,34]. More recently, the American Society of Regional Anesthesia and Pain Medicine published practice guidelines for management of LAST that included specific recommendations for its prevention, diagnosis, and treatment [35]. The treatment guidelines included the use of ILE as an adjunct to airway management and good CPR, stating, “….lipid emulsion therapy can be instrumental in facilitating resuscitation, most probably by acting as a lipid sink that draws down the content of lipid-soluble local anesthetics from within cardiac tissue, thereby improving cardiac conduction, contractility, and coronary perfusion.”
Lipid emulsion’s success depends on prompt and effective airway management to prevent hypoxia and acidosis, which are known to potentiate LAST [36]. However, the question remains whether ILE should replace or supplement standard pharmacologic therapy. Recent reports highlight the detrimental effect that standard pharmacologic therapies might have in the setting of lipid emulsion administration. In a rat model, Hiller and colleagues [37] found that epinephrine doses equal to or greater than 10 μg/kg increased lactate concentration, worsened acidosis, and resulted in worse recovery at 15 minutes compared with lipid-treated animals. Prior studies by Weinberg and colleagues [38] in rat models of bupivacaine-induced asystole, showed that lipid is superior to epinephrine, vasopressin [39] or the combination of both vasopressors for measured hemodynamic variables at 10 minutes. Therefore, epinephrine might aggravate local anesthetic toxicity by severe systemic vasoconstriction and increased lactate production. These observations resulted in the 2010 American Society of Regional Anesthesia (ASRA) practice advisory recommending use of low-dose epinephrine, and avoiding vasopressin completely in the context of LAST.
Lipid emulsion might also be effective in preventing progression of clinically significant LAST. Clinicians are now perhaps more likely to administer lipid emulsion earlier in the progression of adverse reactions from local anesthetic toxicity, with the hope of preventing severe, refractory cardiovascular collapse following progression of LAST. For instance, Foxall and colleagues [40] reported using lipid emulsion to treat CNS toxicity and ventricular ectopy to prevent progression to cardiac arrest in a 75-year-old woman who experienced seizures following a posterior lumbar plexus block with levobupivacaine; this was the first reported use of lipid emulsion in a periarrest situation. Additional reports demonstrate the ability of lipid emulsion to effectively treat CNS symptoms and prevent further progression of LAST [41,43].
Areas of future research and application for other drug toxicities
Several animal models as well as case reports have sparked intense interest in lipid emulsion’s potential lifesaving effects on resuscitation from poisonings of tricyclic antidepressants, beta blockers, and other lipophilic medications. Many of these medications share physicochemical properties with local anesthetics; it is believed that lipid emulsion exerts the same lipid sink effect with these lipophilic drugs, thereby decreasing the amount of active drug in the target tissue [44].
Animal Studies
Yoav and colleagues [45] used a rat model to show decreased mortality when clomipramine was given in a lipid infusion compared with a saline control. Following this observation, Bania and Chu [46] demonstrated the protective effects of pretreatment with lipid emulsion before toxic doses of amitriptyline were administered. Harvey and Cave [47] used a rabbit model to show a quicker recovery from clomipramine-induced hypotension with lipid emulsion rescue compared with controls treated with saline or sodium bicarbonate. Both rat [48] and canine [49] models of verapamil toxicity also supported the use of lipid emulsion in stabilizing and even resuscitating animals exposed to toxic doses of verapamil. Many other similar animal studies also point to lipid emulsion as having protective or even lifesaving effects when used in the setting of lipophilic drug toxicities.
Case Reports
The first report of lipid emulsion’s successful use in a human as an antidote for a lipophilic, nonlocal anesthetic toxicity was described by Sirianni and colleagues [50]. This case involved a 17-year-old girl who had ingested enormous amounts of bupropion and lamotrigine, both known to potentially cause sodium channel blockade when taken in large quantities. Ten hours after the overdose, the patient experienced complete cardiovascular collapse with ensuing ventricular fibrillation and pulseless electrical activity. After more than 70 minutes of standard resuscitation, a single bolus of lipid emulsion was given as a last attempt to restore stable cardiac output. Approximately 1 minute later a normal pulse was observed and within 15 minutes, she returned to sinus rhythm and vasopressor therapy was decreased. This patient was subsequently discharged with minimal neurologic deficits. Another case report involves a 61-year-old man who presented to the emergency department with a Glascow Coma Scale (GCS) of 3 after overdosing on quetiapine and sertraline [51]. The patient was given a bolus of 20% lipid emulsion 4 hours after the overdose. Within seconds the patient’s level of consciousness increased to a GCS of 9, and airway reflexes were restored within 15 minutes. The patient no longer needed intubation and was subsequently discharged to a psychiatric unit less than a day later, with GCS of 15.
Summary
Recommendations about the use of lipid emulsion are complex and still evolving but several governing bodies have compiled guidelines on their Web sites to help standardize the treatment of LAST with lipid emulsion. ASRA has published a practice advisory on the treatment of local anesthetic systemic toxicity (Fig. 1) [35]. Two educational Web sites, www.lipidrescue.org and www.lipidregistry.org, provide additional information on ILE and a forum for posting and discussing cases of toxicity in which ILE was used.
References
[2] H.S. Feldman. Anesthetic toxicity. New York: Raven Press Ltd; 1994. p. 107–27
[4] D.L. Brown. Complications of regional anesthesia. New York: Springer; 2007. p. 61–70
[32] Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe localanaesthetic toxicity. Available at: http://aagbi.org/publications/guidelines/docs/la_toxicity_2010.pdf. Accessed August 21, 2010.
[33] Resuscitation Council of the United Kingdom. Cardiac arrest or cardiovascular collapse caused by local anaesthetic. Available at: http://www.resus.org.uk/pages/caLocalA.htm Accessed August 21, 2010
[34] Available at: http://www.asahq.org/clinical/Anesthesiology-CentricACLS.pdf Accessed August 21, 2010
