Steven Dewaele, and Alan C. Santos
Systemic toxicity of local anesthetics can occur after administration of an excessive dose, with rapid absorption, or because of an accidental intravenous injection. The management of local anesthetic toxicity can be challenging, and in the case of cardiac toxicity, prolonged resuscitation efforts may be necessary.1,2 Therefore, understanding the circumstances that can lead to systemic toxicity of local anesthetics and being prepared for treatment is essential to optimize the patient outcome.
Systemic toxicity is typically manifested as central nervous system (CNS) toxicity (tinnitus, disorientation, and ultimately, seizures) or cardiovascular toxicity (hypotension, dysrhythmias, and cardiac arrest).3The dose capable of causing CNS symptoms is typically lower than the dose and concentration result in cardiovascular toxicity. This is because the CNS is more susceptible to local anesthetic toxicity than the cardiovascular system. However, bupivacaine toxicity may not adhere to this sequence, and cardiac toxicity may precede the neurologic symptoms.4 Although less common, cardiovascular toxicity is more serious and more difficult to treat than CNS toxicity.
Other reported, but much less common, adverse effects of certain local anesthetics include allergic reactions,5 methemoglobinemia,6 and bronchospasm.7 Direct neural8 and local tissue toxicity9 have been reported also; however, discussion about these topics is beyond the scope of this chapter.
Signs and Symptoms of Systemic Local Anesthetic Toxicity
The earliest signs of systemic toxicity are usually caused by blockade of inhibitory pathways in the cerebral cortex.10 This allows for disinhibition of facilitator neurons resulting in excitatory cell preponderance and unopposed (generally enhanced) excitatory nerve activity. As a result, initial subjective symptoms of CNS toxicity include signs of excitation, such as lightheadedness and dizziness, difficulty focusing, tinnitus, confusion, and circumoral numbnesss.11,12 Likewise, the objective signs of local anesthetic toxicity are excitatory, for example, shivering, myoclonia, tremors, and sudden muscular contractions.13 As the local anesthetic level rises, tonic-clonic convulsions occur. Symptoms of CNS excitation typically are followed by signs of CNS depression: Seizure activity ceases rapidly and ultimately is succeeded by respiratory depression and respiratory arrest. In the concomitant presence of other CNS depressant drugs (e.g., premedication), CNS depression can develop without the preceding excitatory phase.
The CNS toxicity is directly correlated with local anesthetic potency.14–17 However, there is an inverse relationship between the toxicity of local anesthetics and the rate at which the agents are injected: Increasing speed of injection will decrease the blood-level threshold for symptoms to appear.
All local anesthetics can induce cardiac dysrhythmias,18,19 and all, except cocaine, are myocardium depressants.20–25 Local anesthetic–induced arrhythmias can manifest as conduction delays (from prolonged PR interval to complete heart block, sinus arrest, and asystole) to ventricular dysrhythmias (from simple ventricular ectopy to torsades de pointes and fibrillation). The negative inotropic action of local anesthetics is exerted in a dose-dependent fashion and consists of depressed myocardial contractility and a decrease in cardiac output. Dysrhythmias due to local anesthetic overdose may be recalcitrant to traditional therapies; the reduced myocardial contractility and low output state further complicate the treatment.
The sequence of cardiovascular events is ordinarily as follows: Low blood levels of local anesthetic usually generate a small increase in cardiac output, blood pressure, and heart rate, which is most likely due to a boost in sympathetic activity and direct vasoconstriction. As the blood level of local anesthetic rises, hypotension ensues as a result of peripheral vasodilation due to relaxation of the vascular smooth muscles. Further rise of local anesthetic blood levels leads to severe hypotension, resulting from the combination of reduced peripheral vascular resistance, reduced cardiac output, and/or malignant arrhythmias. Eventually, extreme hemodynamic instability may lead to cardiac arrest.
Acid–base status plays an important role in the setting of local anesthetic toxicity.26 Acidosis and hypercarbia amplify the CNS effects of local anesthetic overdose and exacerbate cardiotoxicity. Hypercarbia enhances cerebral blood flow; consequently, more local anesthetic is made accessible to the cerebral circulation. Diffusion of carbon dioxide across the nerve membrane can cause intracellular acidosis, and as such, it is promoting the conversion of the local anesthetic into the cationic, or active, form. Because it is impossible for the cationic form to travel across the nerve membrane, ionic trapping occurs, worsening the CNS toxicity of the local anesthetic. Hypercarbia and/or acidosis also reduce the binding of local anesthetics by plasma proteins,27 and as a result, the fraction of free drug readily available for diffusion expands.
Prevention of toxicity is key to safer practice, and it starts with making sure that the work environment is optimized for performing regional anesthesia.28 The logistics for treating an emergency, including equipment for airway management and treating cardiac arrest, must be readily available and functioning.
A judicious selection of the type, dose, and concentration of the local anesthetic, and the regional anesthesia technique, is important. As a rule, the optimal dose and concentration is the lowest one that achieves the aimed for effect. The effects of pretreatment with a benzodiazepine is often debated but almost routinely used in our practice. Benzodiazepines lower the probability of seizures29–32 but can mask early signs of toxicity.33 A sedated patient is theoretically less able to keep the physician updated on the subjective symptoms of light toxicity, and severe toxicity can establish itself without a recognizable toxic prodrome. This concern remains only theoretical; many symptoms of limited, mild CNS toxicity can be prevented by routine premedication with benzodiazepines in addition to making the PNB procedure more pleasant to patients.
Therefore, the presence of premedication or general anesthesia is not perceived to increase the risk of local anesthetic toxicity. Considerable research has been invested into the subject of the ideal test for detecting intravenous injection and to what constitutes the ideal test dose. Epinephrine (5–15 μg) is still widely in use as a marker of intravascular injection. End points with an acceptable sensitivity are defined by an increase in heart rate >10 bpm, increase in systolic blood pressure by >15 mm Hg,34 or a 25% decrease in lead II T-wave amplitude.35 However, elderly patients are less responsive to beta stimulation36 as are those on beta-blocking agents. Low cardiac output can prolong drug circulation and delay the clinical effect of the beta mimetic, and therefore, the sensitivity of the test. Accordingly, the interpretation of the test result is not always as straightforward as one would wish. The significant proportion of false negative test results warrants a reevaluation of the routine use of this test as a sole determinant to detect inadvertent intravenous injection.
Regardless of whether epinephrine is used as a marker of an intravascular injection, it is of utmost importance to use slow, incremental injections of local anesthetic, with frequent aspirations (every 3–5 mL) between injections while monitoring the patient for signs of toxicity.37 A slow rate of injection of divided doses at distinct intervals can decrease the possibility of summating intravascular injections. With a rapid injection the seizures may occur at higher blood level because there is no time for distribution of the drug as compared to a slow infusion where the seizure occurs at a lower drug level because of the distribution. It is prudent to decrease the local anesthetic dosage in elderly or debilitated patients and in any patient with diminished cardiac output. However, there are no firm recommendations on the degree of dose reduction.
Early recognition of the toxicity and early discontinuation of the administration is of crucial importance.38 The administration of local anesthetics should be stopped immediately. The airway should be maintained at all times, and supplemental oxygen is provided while ensuring that the monitoring equipment is functional and properly applied. Neurologic parameters and cardiovascular status should be assessed until the patient is completely asymptomatic and stable.39
Administration of a benzodiazepine to offset or ameliorate excitatory neurological symptoms or a potential tonic-clonic seizure is indicated.40 Early treatment of convulsions is particularly meaningful because convulsions can result in metabolic acidosis, thus aggravating the toxicity. Seizures should be controlled at all times. Based on the recent data in animal studies,41–43 as well as mounting case reports,44–53starting an infusion of lipid emulsion (intralipid), especially in those cases where symptoms of cardiac toxicity are present, should be contemplated early.54 Importantly, there is a mounting consensus that infusion of intralipids may be initiated early, to also prevent, rather then treat cardiac arrest. If available, arrangements for transfer to an operating room where cardiopulmonary bypass can be instituted should also be contemplated in situations where the response to early treatment is not favorable.55–58
Malignant arrhythmias and asystole are managed using standard cardiopulmonary resuscitation protocols,59,60 acknowledging that a prolonged effort may be needed to increase the chance of resuscitation. The rationale of this approach is to maintain the circulation until the local anesthetic is redistributed or metabolized below the level associated with cardiovascular toxicity, at which time spontaneous circulation should resume. Because the contractile depression is a core factor underlying severe cardiotoxicity, it would be intuitive to believe that the use of sympathomimetics should be helpful. Nonetheless, epinephrine can induce dysrhythmia or it can exacerbate the ongoing arrhythmia associated with local anesthetic overdose.61,62 Consequently, in the setting of local anesthetic toxicity, vasopressin may be more appropriate to maintain the blood pressure, support coronary perfusion, and facilitate local anesthetic metabolism.63 The appropriateness of phosphodiesterase inhibitors administration is not corroborated by published research results. Although these inhibitors can promote hemodynamics, there is no evidence of a better outcome. As potent vasodilators, phosphodiesterase inhibitors do no support blood pressure,64 and they have been associated with ventricular arrhythmias.65
The current advanced cardiac life support algorithm emphasizes amiodarone as the mainstay drug for treatment of arrhythmias.66,67 Also, for ventricular arrhythmias prompted by local anesthetic overdose, current data favor amiodarone. Published studies of using lidocaine to treat arrhythmias reveal conflicting results, but it is logical to think that treating local anesthetic–induced arrhythmias with just another local anesthetic antiarrhythmic is likely to add to the cardiotoxicity. The use of bretylium is no longer endorsed. Occurrence of Torsades des Pointes with bupivacaine toxicity may require overdrive pacing if that rhythm predominates.
Calcium channel blockers and phenytoin are contraindicated because their coadministration with local anesthetics may increase the risk of mortality.68,69 Recovery from local anesthetic–induced cardiac arrest can take enduring resuscitation efforts for more than an hour. Propofol is not an adequate alternative for treatment with intralipid, although judicious administration to control seizures when used in small divided doses is appropriate.70,71Administration of the lipid emulsion has become an important addition to the treatment of severe local anesthetic toxicity.72 Because it is still an innovative therapy, future laboratory and clinical experiences are needed for a better understanding of the mechanisms and further refinement of the treatment protocols.73
The amino-esters, such as chloroprocaine, are all derivatives of the allergen paraaminobenzoic acid (PABA). Accordingly, the local anesthetics belonging to the ester group may cause positive skin reactions, ranging from toxic eruptions in situ to generalized rash or urticaria.74 Previous study results indicate an incidence of 30%, but no subject developed anaphylaxis. However, true allergic reactions to the local anesthetics of the amino-amide group are extremely rare. By and large, preparations of amide anesthetics do not cause allergic reactions, unless they contain the preservative methylparaben, which is in its chemical structure virtually the same as PABA.75 For patients who reported an allergy to amino-amides, one can safely use a preservative-free amide anesthetic unless a well-documented allergology reports point to an unambiguous allergy. Anaphylaxis due to local anesthetics remains a rare event, even within the ester group. It should be considered if the patient starts wheezing or develops respiratory distress instantly following injection. However, many symptoms can be explained by a variety of other causes including anxiety, hyperventilation, toxic effects of the drug, vasovagal reactions, reactions to epinephrine, or contamination with latex.
Management of local anesthetic triggered allergic reactions does not differ from the treatment algorithms for other more common allergic reactions. Intravenous lidocaine can result in paradoxical airway narrowing and bronchospasm in patients with asthma. The mechanism of this reaction is not well understood. Apparently, it is not explained by an exacerbation of the asthmatic condition itself or by some anaphylactoid cascade activated by lidocaine or its preservatives.
A unique side effect of some local anesthetics is methemoglobinemia.76,77 It has been associated with the topical, epidural, and intravenous administration of prilocaine. Hepatic metabolism of prilocaine produces orthotoluidine, which converts hemoglobin into methemoglobin. The doses needed to effectuate diminished oxygen saturation levels that are clinically significant, however, are typically above what is used in the clinical practice of regional anesthesia. Regardless, because of this theoretical possibility, in some countries, the use of prilocaine in regional anesthesia is banned. The condition of methemoglobinemia caused by prilocaine is spontaneously self-limiting and reversible. Reversal can be accelerated with the administration of methylene blue intravenously (1 mg/kg).
• Always maintain a high degree of suspicion.
• Monitor electrocardiogram, blood pressure, and arterial oxygen saturation.
• When feasible, communicate with the patient.
• Be conservative with local anesthetic (LA) dose in patients with advanced age, poor cardiac function, conduction abnormalities, or abnormally low plasma protein concentration.
• Gently aspirate every 3–5 mL.
• Inject slowly (<20 mL/min), and avoid forceful high-pressure injections.
• Use a pharmacologic marker (e.g., epinephrine 5 μg/mL of LA) with high-volume blocks.
• Monitor the patient after high-dose blocks for 30 minutes.
• Be prepared: A plan for managing systemic local anesthetic toxicity should be established in facilities where local anesthetics are used.
• Current recommendations are to have 20% lipid emulsion stocked close to sites where local anesthetics are used.
• Consider infusing lipid emulsion early to help prevent cardiac toxicity.
Detection of Systemic LA Toxicity
• Maintain a high degree of suspicion.
• The single most important step in treating local anesthetic toxicity is to consider its diagnosis.
• CNS symptoms are often subtle or absent.
• Cardiovascular signs (e.g., hypertension, hypotension, tachycardia, or bradycardia) may be the first signs of local anesthetic toxicity.
• CNS excitation (agitation, confusion, twitching, seizure), depression (drowsiness, obtundation, coma, or apnea), or nonspecific neurologic symptoms (metallic taste, circumoral paresthesias, diplopia, tinnitus, dizziness) are typical of LA toxicity.
• Ventricular ectopy, multiform ventricular tachycardia, and ventricular fibrillation are hallmarks of cardiac toxicity of LA.
• Progressive hypotension and bradycardia, leading to asystole, are the hallmark of severe cardiovascular toxicity.
Treatment of Systemic LA Toxicity
• Get help and call for 20% lipid emulsion.
• Perform airway management. Hyperventilate with 100% oxygen.
• Abolish the seizures.
• Perform cardiopulmonary resuscitation
• Epinephrine–controversial; may have to use higher doses then recommended in ACLS.
• Consider using vasopressin to support circulation
• Alert the nearest facility having cardiopulmonary bypass capability.
• Perform lipid emulsion treatment (for a 70-kg adult patient):
Bolus 1.5 mL/kg intravenously over 1 minute (about 100 mL)
Continuous infusion 0.25 mL/kg per minute (about 500 mL over 30 minutes)
Repeat bolus every 5 minutes for persistent cardiovascular collapse.
Double the infusion rate if blood pressure returns but remains low.
Continue infusion for a minimum of 30 minutes.
DIAGNOSIS AND TREATMENT OF LOCAL ANESTHETIC TOXICITY
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