Adverse Reactions To Local Anesthetics
Mark D. Tasch
John F. Butterworth IV
CASE SUMMARY
A 78-year-old, 55-kg woman requires an arteriovenous (AV) fistula in her right arm for hemodialysis. Her medical history includes end-stage renal disease, hypertension, and angina pectoris, and she takes furosemide, metoprolol, and isosorbide. Hemoglobin is 10.6 g per dL, packed cell volume 31%, Na+ 138 mEq per L, K+ 5.2 mEq per L, Cl− 97 mEq per L, HCO−3 19 mEq per L, blood urea nitrogen (BUN) 83 mg per dL, Cr 9.2 mg per dL. Chest radiograph reveals borderline cardiac enlargement and moderate pulmonary vascular congestion. The electrocardiogram shows evidence of left ventricular hypertrophy, along with nonspecific ST-T wave abnormalities, but is unchanged from a study performed 2 years earlier. Blood pressure is 176/105 mm Hg, heart rate is 76 bpm, and arterial oxygen saturation is 93% on room air.
After the intravenous administration of 2 mg of midazolam and 50 µg of fentanyl, an axillary block is performed using the transarterial approach. Mepivacaine 1.5% with epinephrine 1:200,000 is injected, with frequent negative aspiration for blood, to a total of 50 mL. Over a period of several minutes, after the local anesthetic injection, the patient becomes increasingly tremulous. The blood pressure is now 198/114 mm Hg, and the heart rate has increased to 106 bpm. Shortly thereafter, generalized tonic-clonic convulsions are noted, which cease after the intravenous administration of two doses of 50 mg of propofol. The patient remains unarousable and apneic for several minutes, requiring mask ventilation. Tracheal intubation proceeds uneventfully. The surgical procedure is performed under general anesthesia with nitrous oxide, oxygen, and desflurane. The patient awakens slowly after discontinuation of the inhaled anesthetics and is extubated in the postanesthesia care unit. Partial sensory and motor blockade of the right arm are noted.
What Are the Adverse Reactions to Local Anesthetics?
Local anesthetics can exert toxic side effects either locally or systemically. Local toxicity can include nerve or muscle injury, whereas systemic toxicity (from excessive blood concentrations of local anesthetics) affects the central nervous and cardiovascular systems, with potentially lethal consequences. Allergic reactions to local anesthetics are rare, but can occur. Each of these categories of adverse reactions will be discussed.
What Forms of Local Nerve and Muscle Injury Can Occur?
Application of any local anesthetic at a sufficiently high concentration can induce direct neurotoxicity.1 Nevertheless, for many years, local anesthetic-induced neurotoxicity was largely a laboratory curiosity. In 1980, clinical reports appeared in which prolonged paralysis followed the intended epidural administration of 2-chloroprocaine. In the early 1990s, concern arose regarding the neurotoxic potential of 5% lidocaine, especially when administered through the (then available) microcatheters for continuous spinal anesthesia. At about the same time, anesthesiologists became aware of the relatively common occurrence of transient radicular irritation—subsequently renamed transient neurologic symptoms—after uneventful lidocaine spinal anesthesia. This syndrome includes pain or dysesthesia in the lower back, buttocks, and legs following recovery from spinal anesthesia. These symptoms typically present from 1 to 4 weeks after spinal anesthesia and have been attributed to a lumbosacral radiculopathy. The relation between transient neurologic symptoms and more severe forms of radiculopathy (such as cauda equina syndrome with sacral paresthesias, lower extremity weakness, or fecal and urinary incontinence) remains unclear.2
Intramuscular deposition of all local anesthetics induces some degree of myonecrosis. Bupivacaine and chloroprocaine produce pathologic findings that are more severe than ropivacaine, procaine, or tetracaine. In recent years, such local anesthetic myotoxicity has been suggested as a possible etiology of diplopia following cataract surgery. Case reports and a retrospective review of cataract extractions have noted a small (<1%) but detectable increased incidence of diplopia (transient or
persistent) following retrobulbar or peribulbar block (when compared with topical or general anesthesia). To be fair, intramuscular hemorrhage or needle injury represent equally plausible alternative explanations for postoperative dysfunction of extraocular muscles.3,4
persistent) following retrobulbar or peribulbar block (when compared with topical or general anesthesia). To be fair, intramuscular hemorrhage or needle injury represent equally plausible alternative explanations for postoperative dysfunction of extraocular muscles.3,4
What Factors May Alter the Risk of Local Toxicity?
Pharmacologic, surgical, and technical variables have all been implicated in the etiology of local anesthetic neurotoxicity. The association of a spinal injection of 5% lidocaine with transient neurologic symptoms and cauda equina syndrome has been explored in both laboratory and clinical settings. Prospective and retrospective reports indicate that the incidence of transient neurologic symptoms or, more rarely, cauda equina syndrome following otherwise uncomplicated spinal anesthesia is increased by as much as 10-fold when lidocaine (2% to 5%) is the local anesthetic selected5,6,7 (see Table 60.1). In vitro studies have confirmed that lidocaine carries an increased risk of neurotoxicity.8 The cluster of cauda equina syndromes associated with the use of spinal microcatheters led to the abandonment of this promising anesthetic device. This association was attributed to the lesser degree to which lidocaine is diluted in the cerebrospinal fluid when administered through such catheters (as compared to lidocaine injections through relatively larger lumbar puncture needles), potentially exposing nerve roots to locally toxic drug concentrations. The likelihood of transient neurologic symptoms after spinal anesthesia with lidocaine appears to increase with surgical positions that tend to stretch the cauda equina, such as lithotomy procedures or knee arthroscopy.2,9
Which Agents May Be Substituted for Subarachnoid Lidocaine?
The controversy has taken its toll on the popularity of lidocaine for spinal anesthesia, and, therefore, the search for an alternative spinal anesthetic has ensued. Although subarachnoid bupivacaine is safe and effective, its duration of action (even with small doses) exceeds the ideal for outpatient surgeries. The same criticisms apply to tetracaine. Procaine, although of short duration, has been associated with an increased incidence of nausea and vomiting.10 Prilocaine also has been mentioned as an agent of limited duration and neurotoxicity, but is available in the United States only for topical use.6 Mepivacaine may prove to be a useful option. Initial studies reported a widely varying incidence of transient neurologic symptoms, perhaps depending upon the concentration of the anesthetic.
TABLE 60.1 Incidence of Transient Neurologic Symptoms following Spinal Anesthesia | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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In one series, none of 30 patients given 3 mL of subarachnoid 1.5% mepivacaine (45 mg) developed transient neurologic symptoms, whereas in another series, 30 of 100 patients who received 2 mL of hyperbaric 4% mepivacaine (80 mg) did develop symptoms.11,12 In the largest, most recent series, isobaric 1.5% mepivacaine was administered in doses of 30 to 70 mg for a variety of surgical procedures. The incidence of transient neurologic symptoms in this report was 6.4% (78 of 1,210 patients), significantly lower than that typically attributed to lidocaine. Interestingly, the incidence did not vary with surgical position. The authors concluded that “spinal anesthesia with mepivacaine is likely to be a safe and effective anesthetic for ambulatory patients”.13
When the initial reports implicating intrathecal 2-chloroprocaine in spinal neurotoxicity were published, the accompanying editorial erroneously attributed all cases cited to the “inadvertent” subarachnoid injection of an agent (2-chloroprocaine, per se) intended for the epidural space.14 Subsequently, several laboratories demonstrated that the local anesthetic did not act alone, implicating the bisulfite preservative and the acidic pH of the then available drug preparation. As is the case for local anesthetics, there are concentrations at which either bisulfite or hydronium ions can be demonstrably neurotoxic.
Nonetheless, despite some contradictory findings (including one report that bisulfite could reduce the severity of neural pathology induced by the local anesthetic), a consensus is slowly emerging that 2-chloroprocaine in a preservative-free formulation can be safely administered for spinal anesthesia. This opinion is buttressed by an ever-growing series of published studies involving patients and volunteers.1,15 In 2005, Yoos and Kopacz reported their institution’s initial 10-month experience using preservative-free 2-chloroprocaine, usually 2% plain in doses of 1.5 to 2 mL (30 to 40 mg), for spinal anesthesia. Operating conditions were satisfactory in their 122 patients, with no cases of transient neurologic symptoms detected. The authors stated “the preservative-free formulation of 2-chloroprocaine appears to be a safe, reliable, and effective alternative for spinal anesthesia in the ambulatory surgical setting.”9 In 2006, these investigators at Virginia Mason Clinic have used 2-chloroprocaine for several hundred spinal anesthetics, with a favorable incidence of transient neurologic symptoms and no cases of persistent neuropathy or myelopathy.
What Factors May Alter the Risk of Systemic Toxicity?
▪ CLINICAL
The risk of serious central nervous system (CNS) or cardiovascular toxicity generally increases as the systemic concentration of unbound local anesthetics and the inherent toxicity of the agent administered increase. Physicians have attempted to maintain systemic drug levels at safe values by following guidelines for maximum safe local anesthetic dosing and by coadministering a vasoconstrictor (usually epinephrine) to reduce systemic uptake. In a recent review, Rosenberg et al. argued convincingly that “current recommendations regarding maximum doses of local anesthetics … are not evidence based…. In most cases, there is no scientific justification for presenting exact milligram doses or mg/kg doses as maximum dose recommendations.”16
It is well appreciated that the absorption of local anesthetics is site-specific, varying mostly with the vascularity of the local tissues. Therefore, when the same local anesthetic dose is administered at differing sites, the greatest concentrations will be notable after intratracheal injections, followed by intercostal and paracervical injections; progressively reduced local anesthetic concentrations will be measured after epidural, brachial plexus, or subarachnoid injections. Of course, this rank order assumes that an intravascular injection of a large mass of local anesthetics has not been given. Epinephrine, 5 µg per mL (1:200,000), substantially reduces the peak blood concentrations of local anesthetics following subcutaneous infiltration and superficial cervical plexus blocks and, to a lesser but still significant degree, following intercostal, epidural, and brachial plexus injection.16
In some situations (e.g., coronary artery disease), fear of adverse systemic responses to epinephrine itself has led physicians to avoid epinephrine in local anesthetic solutions. Interestingly, data collected from patients undergoing carotid thromboendarterectomy under cervical plexus block anesthesia demonstrated no differences in heart rate or incidence of arrhythmias or cardiac ischemia (assessed by Holter monitor) when epinephrinecontaining and “plain” local anesthetic solutions were compared.17
Lidocaine is, of course, commonly administered intravenously for its antiarrhythmic effects, and occasionally as a therapeutic agent for central pain syndromes. In intravenous regional anesthesia, the local anesthetic is intentionally deposited in a peripheral vein but (ideally) isolated from the central circulation, usually by means of a dual pneumatic tourniquet. Either intentionally, when the tourniquet pressure is released at the end of the operation, or accidentally, if the tourniquet fails or is prematurely deflated, the local anesthetic will gain access to the systemic circulation, heart, and brain. The consequent symptoms seem to depend inversely on the preceding duration of tourniquet inflation.
Prilocaine and lidocaine have long been considered the safest local anesthetics for intravenous regional anesthesia. In its original Nesacaine (Pennwalt Pharmaceutical Co, Philadelphia, PA) formulations, 2-chloroprocaine was generally considered unsuitable for intravenous regional anesthesia due to reports of associated thrombophlebitis. When the preservative-free reformulation of 2-chloroprocaine became available, initial European reports on its use for intravenous regional anesthesia found a variable incidence of minor vascular irritation but no thrombophlebitis. A 0.5% 2-chloroprocaine appears to be clinically similar to 0.5% lidocaine for this use and has achieved considerable popularity for intravenous regional anesthesia in some countries.18
Conditions in which cardiac output is substantially increased above normal, such as uremia and late-term pregnancy, will tend to increase the rate of systemic uptake of local anesthetics.19 The gravid uterus also increases the distention of epidural veins, reducing the volume of anesthetic solution required for spinal or epidural blocks, as well as potentially increasing the vascular surface available for drug absorption.20 In addition, pregnancy appears to sensitize both neural and cardiac tissue to some local anesthetics, presumably secondary to progesterone effects.21,22
Once a local anesthetic reaches the systemic circulation, various factors and mechanisms can modify the risk of a hazardous reaction. Ester-linked local anesthetics such as procaine and 2-chloroprocaine are rapidly metabolized by plasma esterases, reducing the likelihood of systemic toxicity. Amide-linked local anesthetics are largely bound to α1-acid glycoprotein and to albumin, reducing the concentration of free drug. Protein binding of bupivacaine has been shown to decrease both in pregnancy and with systemic acidosis, although the small magnitude of these effects minimize their clinical importance.23,24 Uremia appears to have opposing effects, increasing local anesthetic binding by α1-acid glycoprotein but impairing drug metabolism and excretion. Systemic clearance of amide-linked local anesthetics depends primarily upon hepatic metabolism, and is therefore delayed by severe hepatic dysfunction or reduced hepatic perfusion, the latter due to such factors as aging, certain drugs (histamine blockers and β-blockers), or congestive heart failure.16,18
▪ PHARMACOLOGIC
All local anesthetic molecules consist of an aromatic ring joined to a hydrocarbon chain by either an ester or an amide bond. Among local anesthetics, increasing molecular weight is associated with increasing lipid solubility. Increasing molecular weight and increasing lipid solubility are also associated with increasing duration of action. The more lipophilic agents permeate nerve membranes the more readily and more avidly they inhibit Na+ and other ion channels, thereby manifesting greater anesthetic potency and a greater potential to induce severe systemic toxicity.25 Bupivacaine has an asymmetric (chiral) carbon and therefore exists in the form of two stereoisomers.
As will be discussed later, the (R+) enantiomer is more potent at producing laboratory correlates of toxicity than the (S−) enantiomer; hence, levobupivacaine has been developed as the pure (S−) form of the drug in an attempt to reduce the likelihood and severity of systemic toxicity. Ropivacaine, also produced as a pure (S−) enantiomer, was derived from bupivacaine by substituting a propyl for a butyl moiety. Ropivacaine is slightly less lipophilic than bupivacaine, and perhaps less potent. Its advantage over racemic bupivacaine, and possibly over levobupivacaine, lies in a reduced risk for systemic toxicity.26
As will be discussed later, the (R+) enantiomer is more potent at producing laboratory correlates of toxicity than the (S−) enantiomer; hence, levobupivacaine has been developed as the pure (S−) form of the drug in an attempt to reduce the likelihood and severity of systemic toxicity. Ropivacaine, also produced as a pure (S−) enantiomer, was derived from bupivacaine by substituting a propyl for a butyl moiety. Ropivacaine is slightly less lipophilic than bupivacaine, and perhaps less potent. Its advantage over racemic bupivacaine, and possibly over levobupivacaine, lies in a reduced risk for systemic toxicity.26
When addressing the relative systemic safety profiles of local anesthetics, the issue of relative potency must also be addressed. This concept is not as straightforward as it could be, because there is no standard measurement of local anesthetic potency comparable to minimum alveolar concentration for general anesthetics. In the case of the bupivacaine isomers, the anesthetic potency of (S−) bupivacaine is considered to be comparable to that of (R−) bupivacaine and, therefore, of the racemic mixture.27 Therefore, any advantage of levobupivacaine over racemic bupivacaine in terms of reduced toxicity will not be counteracted by a greater dose requirement for neural blockade.
Investigators have reached contradictory conclusions regarding the comparative anesthetic potency of ropivacaine. Polley et al. assessing the median effective local anesthetic concentration for obstetric epidural analgesia, found ropivacaine to be only 60% as potent as bupivacaine.28 Capogna et al., reported very similar findings.29 On the other hand, Casati et al. “conclude[d] that the volume of 0.5% ropivacaine required to produce effective block of the femoral nerve in 50% of patients is similar to that required when using 0.5% bupivacaine.”30 Any quantitative differences between the cardiotoxic potencies of ropivacaine and bupivacaine could, therefore, be attenuated by differences in anesthetic dose requirements. Some investigators have compared ropivacaine with bupivacaine or levobupivacaine at identical doses or concentrations, whereas some have administered what they consider to be equipotent doses or concentrations, assuming the potency ratios determined by Polly et al. or Capogna et al.
What Is the Significance of “Allergic Reactions” to Local Anesthetics?
Although allergic reactions are discussed in detail elsewhere in this text, we note that such reactions to local anesthetics are far more often discussed than documented. It is traditionally taught that ester local anesthetics are more prone to induce anaphylactic reactions than are amide local anesthetics, presumably because of their chemical similarity to para-aminobenzoic acid. Skin tests with local anesthetics at 1:100 dilution were applied by deShazo and Nelson to 90 patients referred for evaluation of suspected allergic reactions. None of these tests was positive.31 Gall et al. evaluated 177 patients with a history of 197 suspected reactions. No positive responses to either intracutaneous tests with local anesthetics at 1:10 dilution, sodium metabisulfite, or parahydroxybenzoic acid ester were noted, leading the authors to conclude that “true allergic reactions caused by local anesthetics are extremely rare,” and that suspected episodes are probably attributable to “accidental intravascular injections [of local anesthetic or vasoconstrictor], psychomotor reactions, and … hidden allergens, such as latex.”32
What Are the Systemic Manifestations of Central Nervous System Toxicity?
In the CNS, elevated concentrations of local anesthetics initially produce excitation by suppressing inhibitory mechanisms and pathways. The symptoms associated with elevated local anesthetic concentrations can progress from shivering, tremors, tinnitus, agitation, and muscle twitching to tonic-clonic seizures. With further increases in local anesthetic concentrations, generalized depression of the CNS (most likely from blockade of both inhibitory and excitatory pathways) and profound respiratory depression may ensue.
Cardiovascular toxicity can take the form of arrhythmias or myocardial depression, and differing local anesthetics may produce toxicity in varied ways. Resuscitation is notoriously difficult after bupivacaine-induced cardiac arrest. Although lidocaine is, of course, a commonly used antiarrhythmic, the more potent local anesthetics (such as bupivacaine) can induce life-threatening arrhythmias. Local anesthetics inhibit a variety of ion channels and, thereby disrupt impulse conduction in both neural and cardiac pathways. Local anesthetics with prolonged duration of action also tend to have increased lipid solubility, increased anesthetic potency, and an increased tendency to produce profound cardiovascular toxicity33 Electrical disturbances resulting from toxic systemic levels of local anesthetics include sinoatrial and atrioventricular nodal depression, widening of the PR interval and QRS complex, bradyarrhythmias with or without AV block, and reentrant arrhythmias including ventricular tachycardia or fibrillation.27,34 All local anesthetics can severely depress myocardial contractility, resulting in hypotension and electromechanical dissociation.
What Mechanisms Underlie Systemic Central Nervous System Toxicity?
Inhibitory pathways in the CNS are primarily activated by receptors for gamma-aminobutyric acid (GABA). GABAA receptors are effector sites for barbiturates, benzodiazepines, propofol, ethanol, and other CNS depressants,
and stimulate intracellular chloride currents. Lidocaine, tetracaine, procaine, and bupivacaine have been shown to interfere with this GABA-induced chloride flux. The resulting suppression of inhibitory influences increases the excitability of the CNS. Despite the widespread acceptance of the GABA “paradigm” for local anesthetic-induced seizures by reviewers of this topic, this could represent a misunderstanding. The generation of convulsions by local anesthetics also may involve activation of excitatory pathways through receptors for N-methyl-D-aspartate.35 Finally, alterations in other inhibitory pathways and transmitters (e.g., galanin) have been linked to the medical condition of epilepsy, but have not yet been considered part of the underlying mechanisms for local anesthetic-induced seizures.36
and stimulate intracellular chloride currents. Lidocaine, tetracaine, procaine, and bupivacaine have been shown to interfere with this GABA-induced chloride flux. The resulting suppression of inhibitory influences increases the excitability of the CNS. Despite the widespread acceptance of the GABA “paradigm” for local anesthetic-induced seizures by reviewers of this topic, this could represent a misunderstanding. The generation of convulsions by local anesthetics also may involve activation of excitatory pathways through receptors for N-methyl-D-aspartate.35 Finally, alterations in other inhibitory pathways and transmitters (e.g., galanin) have been linked to the medical condition of epilepsy, but have not yet been considered part of the underlying mechanisms for local anesthetic-induced seizures.36
▪ DIFFERENCES IN CENTRAL NERVOUS SYSTEM TOXICITY
In a well prepared surgical environment, local anesthetic-induced convulsions, although far from desirable, can be managed easily and safely by an attentive anesthesiologist. Cardiac toxicity, therefore, has received far more investigative attention than has CNS toxicity. Nonetheless, studies have compared the epileptogenic potency of the longer-acting local anesthetics. In rats that were either awake or anesthetized with intraperitoneal thiopental, Dony et al. found that a significantly greater dose of ropivacaine than bupivacaine was required to initiate convulsions. In accord with other laboratory and clinical reports, some animals receiving bupivacaine suffered cardiovascular collapse without first convulsing.37 Similarly, Ohmura et al. found that ropivacaine and levobupivacaine were less potent than racemic bupivacaine at inducing seizure activity in anesthetized rats.38 The longer-acting local anesthetics have been found to have up to four times the potency of lidocaine for producing seizures, in accord with their greater local anesthetic potency, with the pure (S−) enantiomers having a somewhat greater margin of safety than racemic bupivacaine.34
What Mechanisms Underlie Systemic Cardiovascular Toxicity?
▪ ARRHYTHMOGENESIS
Local anesthetics inhibit voltage-gated Na+ channels in excitable cells, thereby reducing impulse conduction. This conduction blockade, heterogeneous within the heart, enhances the likelihood of reentrant arrhythmias. Bupivacaine has a greater affinity for Na+ channels that are in the open or inactivated states than in the closed (resting) state. Na+ channels inactivate when depolarized during an action potential, which, in myocardial cells, is of relatively long duration. Increased concentrations of local anesthetics will also inhibit K+ channels. Inhibition of K+ channels prolongs cardiac action potentials, thereby enhancing the binding of bupivacaine to Na+ channels. K+ channel blockade also increases the heterogeneity of cardiac depolarization and repolarization, exacerbating the risk of ventricular arrhythmias.39,40
Data from some animal models suggest that CNS toxicity may also contribute, directly or indirectly, to the production of arrhythmias by local anesthetics. If not promptly treated, seizures and respiratory depression create a milieu of acidosis, hypoxia, and hyperkalemia in which the cardiac toxicity of local anesthetics is intensified. In animals, direct application of local anesthetics to selected regions of the brain can induce bradycardia, hypotension, and ventricular arrhythmias. Therefore, CNS toxicity of local anesthetics may play an etiologic role in catastrophic cardiovascular events.34,41
▪ MYOCARDIAL DEPRESSION
Besides producing life-threatening arrhythmias, toxic systemic levels of local anesthetics can depress myocardial contractility and stroke volume, elevating left ventricular end-diastolic pressure and inducing severe hypotension. Local anesthetics bind to voltage-gated Ca2+ channels. The potency of local anesthetics in inhibiting these channels generally correlates with their lipid solubility and with their potency in producing both local anesthesia and myocardial depression. Local anesthetics also disturb the intracellular flux of Ca2+ ions in myocardial cells, in part by inhibiting Ca2+ release from the sarcoplasmic reticulum.42,43
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