Chirality

With the exception of lidocaine, amide local anesthetics are chiral compounds because they have a single asymmetric carbon adjacent to the amino group and thus exist in isomeric forms that are mirror images of each other. The direction in which the isomers rotate polarized light distinguishes them as either dextrorotary ( d ) or levorotary ( l ) isomers. This distinction is important, because individual isomers of the same drug may have different biologic effects. As a rule, the levorotary isomer of a drug has greater vasoconstrictor activity and a longer duration of action but less potential for systemic toxicity than the dextrorotary form.

In the past, single-isomer formulations were costly to produce; and for that reason, local anesthetics used clinically (e.g., bupivacaine ) have contained a racemic mixture of both the dextrorotary and levorotary forms of the drug. However, with improved techniques of selective extraction, two commercially available single-isomer formulations of local anesthetic are now available, ropivacaine and levobupivacaine. Levobupivacaine is the levorotary isomer of bupivacaine; it is currently not marketed in the United States. Ropivacaine is a homologue of mepivacaine and bupivacaine but is formulated as a single levorotary isomer rather than as a racemic mixture. A propyl group on the pipechol ring distinguishes ropivacaine from bupivacaine (which has a butyl group) and mepivacaine (which has a methyl group). Thus, it is not surprising that the physicochemical characteristics of ropivacaine are intermediate between those of mepivacaine and bupivacaine.

The reduction in systemic toxicity observed with administration of the levorotary isomers may be both drug and concentration dependent. For example, one study in isolated guinea pig hearts noted that bupivacaine isomers lengthened atrioventricular conduction time more than ropivacaine isomers did. In contrast to other measured variables, “atrioventricular conduction time showed evident stereoselectivity” for bupivacaine at the lowest concentration studied (0.5 µM) but only at much higher concentrations for ropivacaine (> 30 µM).

2-Chloroprocaine

2-Chloroprocaine is hydrolyzed rapidly by plasma pseudocholinesterase to chloroaminobenzoic acid and H ₂ O. Although pregnancy is associated with a 30% to 40% decrease in pseudocholinesterase activity, the half-life of 2-chloroprocaine in maternal plasma in vitro is 11 to 21 seconds. After epidural injection, the half-life of 2-chloroprocaine in the mother ranges from 1.5 to 6.4 minutes. The longer half-life after epidural administration results from continued absorption of the drug from the injection site. Administration of 2-chloroprocaine to patients with low pseudocholinesterase activity may result in prolonged local anesthetic effect and a greater potential for systemic toxicity.

Lidocaine

The volume of the central compartment and the volume of distribution of lidocaine are greater in pregnant than in nonpregnant ewes. Bloedow et al. observed that the total body clearance of lidocaine was similar in the two groups of animals but the elimination half-life of lidocaine, which depends on the balance between volume of distribution and clearance, was longer in pregnant ewes. In contrast, Santos et al. concluded that the elimination half-life of lidocaine was similar in the two groups of sheep because the total body clearance of the drug was greater in pregnant than in nonpregnant animals. This discrepancy could result from differences in the complexity of the surgical preparation and the allowed recovery period. In pregnant women, the elimination half-life of lidocaine after epidural injection is approximately 114 minutes.

Lidocaine is metabolized into two active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). Monoethylglycinexylidide can be detected in maternal plasma within 10 to 20 minutes after neuraxial injection of lidocaine, whereas glycinexylidide can be detected within 1 hour of epidural injection but rarely after subarachnoid injection. Urinary excretion of unchanged lidocaine is negligible in sheep (i.e., < 2% of the administered dose) and is not affected by pregnancy.

The physiologic changes that occur during pregnancy are progressive. However, little information is available about the pharmacokinetics of local anesthetics before term. In one study, total clearance of lidocaine was similar at 119 and 138 days’ gestation in gravid ewes (term is 148 days).

Lidocaine is predominantly bound to alpha ₁ -acid glycoprotein (AAG) in plasma. Pregnancy leads to a decreased concentration of AAG; thus, the free plasma fraction of lidocaine is higher in term pregnant women than in nonpregnant controls. The increase in the free fraction of lidocaine occurs early in gestation and is progressive.

Bupivacaine

At least two studies compared the pharmacokinetics of bupivacaine after epidural administration in pregnant and nonpregnant women. The absorption rate, the area under the concentration-time curve, and the elimination half-life (12 to 13 hours) were similar in the two groups. The elimination half-life of bupivacaine after epidural administration is much longer than that after intravenous injection, largely because the drug is continuously absorbed over time from the epidural space.

In contrast to lidocaine, the volume of distribution of bupivacaine is lower in pregnant than in nonpregnant sheep after intravenous injection. The differences in gestational effects on the volume of distribution of the two local anesthetics may result from the greater binding of bupivacaine to plasma proteins during gestation (whereas the converse occurs with lidocaine). In one study, urinary excretion of unchanged bupivacaine was not affected by pregnancy and was less than 1% of the administered dose. Nonetheless, low concentrations of bupivacaine may be detected in the urine of pregnant women for as long as 3 days after delivery.

Bupivacaine undergoes dealkylation in the liver to 2,6-pipecolyxylidide (PPX). After epidural injection of bupivacaine for cesarean delivery, PPX was detected in maternal plasma within 5 minutes and remained detectable for as long as 24 hours. With the lower doses required for labor analgesia, PPX was found only if the block was maintained with multiple reinjections during a period that exceeded 4 hours. Pregnancy may affect metabolism of bupivacaine. For example, pregnant women have higher serum PPX concentrations, but the unconjugated 4-hydroxy metabolite is not produced in significant amounts. The reason for this finding is unclear but may be related to effects of hormonal changes on hepatic enzyme systems. Both progesterone and estradiol are competitive inhibitors of microsomal oxidases, whereas reductive enzymes are induced by progesterone. Bupivacaine is bound extensively to AAG and albumin. This protein binding is reduced during late pregnancy in humans.

Long-acting pipechol amide local anesthetics, such as bupivacaine, are beneficial for neuraxial labor analgesia because they produce a relative motor-sparing block compared with other local anesthetics. The effective dose in 50% of cases (ED ₅₀ ) for motor block after intrathecally administered bupivacaine was lower in pregnant than in nonpregnant women (3.96 mg and 4.14 mg, respectively).

Ropivacaine

Pregnant sheep have a smaller volume of distribution and a slower clearance of ropivacaine than nonpregnant animals. However, the relationship between volume of distribution and clearance is such that the elimination half-life is similar in pregnant and nonpregnant animals.

After intravenous injection in laboratory animals or nonpregnant volunteers, the elimination half-life of ropivacaine is shorter than that of bupivacaine. The shorter elimination half-life of ropivacaine has been attributed to a faster clearance and a shorter mean residence time than for bupivacaine.

Peak plasma concentration (C _max ) of 0.5% ropivacaine and 0.5% bupivacaine after epidural administration for cesarean delivery are similar (1.3 µg/mL and 1.1 µg/mL, respectively). The elimination half-life of ropivacaine is 5.2 ± 0.6 hours, which is shorter than that for bupivacaine, at 10.9 ± 1.1 hours. No difference in clearance between the two drugs has been noted.

Like bupivacaine, ropivacaine is metabolized by hepatic microsomal cytochrome P450. The major metabolite is PPX, and minor metabolites are 3′- and 4′-hydroxy-ropivacaine.

Ropivacaine is highly bound (approximately 92%) to plasma proteins but less so than bupivacaine (96%). Indeed, at plasma concentrations occurring during epidural anesthesia for cesarean delivery, the free fraction of ropivacaine is almost twice that of bupivacaine. In pregnant women undergoing epidural analgesia, the free fraction of ropivacaine decreases as the concentration of AAG increases, up to the point at which the receptors are saturated. However, there is little correlation between the free fraction and umbilical cord blood levels of ropivacaine at delivery.

Effect of Histamine (H ₂ )-Receptor Antagonists

Histamine (H ₂ )-receptor antagonists are administered to increase gastric pH and reduce the risk for aspiration pneumonitis. Drug disposition may be affected by binding to hepatic cytochrome P450, reducing hepatic blood flow and renal clearance, especially with cimetidine. However, short-term administration of H ₂ -receptor antagonists does not alter the pharmacokinetics of amide local anesthetics in pregnant women.

Effects of Preeclampsia

Pathophysiologic changes associated with preeclampsia (e.g., reduced hepatic blood flow, abnormal liver function, decreased intravascular volume) may also affect maternal blood concentrations of local anesthetics (see Chapter 35 ). For example, Ramanathan et al. found that total body clearance of lidocaine after epidural injection was significantly lower in preeclamptic than in normotensive women; however, the elimination half-life of lidocaine was similar in the two groups. Nonetheless, decreased clearance may result in greater drug accumulation with repeated injections of lidocaine in women with preeclampsia. In contrast, long-acting amides have a relatively low hepatic extraction, and changes in liver blood flow with preeclampsia may have less effect on the metabolic clearance.

Effect of Gestational Diabetes Mellitus

Gestational diabetes mellitus may have profound transient effects on the microcirculation. The placental transfer of lidocaine was unchanged for women at term with diabetes who received epidural lidocaine 200 mg, but the transfer of its metabolite, MEGX, was increased. A weakness of the methodology was that umbilical artery/vein ratios were used to estimate placental transfer (see later in the chapter).

Effect of Diurnal Variation

Pain may exhibit temporal variation in intensity because of diurnal neuroendocrine or external factors. In one study, the duration of action of epidural bupivacaine was approximately 25% longer when it was administered between 7:00 am and 7:00 pm than between 7:00 pm and 7:00 am . In contrast, another study found no diurnal variation with intrathecal bupivacaine administered for labor analgesia. The authors of this study suggested the diurnal variation may also be explained by external influences such as shift changes for nurses and anesthesiologists.

Effect of Injectate Temperature

Latency of local anesthetic affect may be affected by temperature. For instance, onset of labor analgesia is faster when a solution of epidural bupivacaine 0.125% with fentanyl 2 µg/mL is injected at 37° C compared with 20° C.

Central Nervous System Toxicity

The severity of CNS effects is proportional to the blood concentration of local anesthetic. This relationship is well described for lidocaine ( Fig. 13.3 ). Initially, the patient may complain of numbness of the tongue, tinnitus, or lightheadedness. At high plasma concentrations, convulsions occur because of a selective blockade of central inhibitory neurons that leads to increased CNS excitation. At still higher concentrations, generalized CNS depression or coma may result from reversible blockade of both inhibitory and excitatory neuronal pathways. Finally, depression of the brainstem and cardiorespiratory centers may occur.

Signs and symptoms of systemic toxicity with increasing lidocaine concentrations. CVS, cardiovascular system.

(Modified from Carpenter RL, Mackey DC. Local anesthetics. In Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia . Philadelphia, PA: Lippincott; 1992:527.)

The relative toxicity of a local anesthetic correlates with its potency. For lidocaine, etidocaine, and bupivacaine, the ratio of the mean cumulative doses that cause convulsions in dogs and human volunteers is approximately 4 : 2 : 1, which is similar to their relative anesthetic potencies. Local anesthetics may be ranked in order of decreasing CNS toxicity as follows: bupivacaine, ropivacaine, levobupivacaine, lidocaine, and 2-chloroprocaine. Tetracaine, etidocaine, and mepivacaine are used rarely in obstetric anesthesia practice.

Other factors (e.g., the speed of injection) may affect CNS toxicity. In humans, the mean dose of etidocaine that elicited signs of CNS toxicity was lower during a 20-mg/min infusion than during a 10-mg/min infusion. Metabolic factors may also affect the seizure threshold. For example, in cats, an increase in Pa co ₂ or a decrease in pH results in a reduction in the seizure-dose threshold for local anesthetics. Respiratory acidosis may result in delivery of more drug to the brain; alternatively, respiratory acidosis may result in “ion trapping” of the local anesthetic and/or an increase in the unbound fraction of drug available for pharmacologic effect.

Cardiovascular Toxicity

The cardiovascular system is typically much more resistant than the CNS to the toxic effects of local anesthetics. Severe, direct cardiovascular depression is rare, especially in association with the use of lidocaine. Prompt administration of oxygen and, if necessary, initiation of ventilatory and circulatory support usually prevent cardiac arrest after unintentional intravenous injection of lidocaine. Progressive depression of myocardial function and profound vasodilation occur only at extremely high plasma concentrations. In contrast, the more potent amide local anesthetics (i.e., bupivacaine) have a more narrow margin of safety, expressed as the ratio between the dose (or plasma concentration) required to produce cardiovascular collapse and the dose (or plasma concentration) required to produce convulsions. A partial explanation is the fact that supraconvulsant doses of bupivacaine (but not of lidocaine) precipitate lethal ventricular arrhythmias. These arrhythmias may be caused by exaggerated electrophysiologic effects (e.g., depression of ventricular conduction) out of proportion to bupivacaine’s anesthetic potency.

Two theories have been proposed to explain why malignant ventricular arrhythmias occur with bupivacaine but not with lidocaine. Both bupivacaine and lidocaine rapidly block cardiac sodium channels during systole, but bupivacaine dissociates from these channels during diastole at a much slower rate than lidocaine. Thus, at physiologic heart rates, the diastolic period is of sufficient duration for lidocaine to dissociate from sodium channels, whereas a bupivacaine block becomes intensified. This difference makes bupivacaine much more potent than lidocaine in depressing conduction and inducing reentrant-type ventricular arrhythmias. Alternatively, other investigators have suggested that high concentrations of local anesthetic in the brainstem may lead to systemic hypotension, bradycardia, and ventricular arrhythmias. These effects occur more commonly with bupivacaine because of its high lipid solubility, which facilitates transfer across the blood-brain barrier. An echocardiographic study in anesthetized dogs suggested that bolus injection of bupivacaine results in systolic dysfunction, especially involving the right ventricle, which precedes the occurrence of arrhythmias.

Metoclopramide is used in obstetric anesthesia as an anti-emetic and to enhance gastric emptying. In rat myocytes, metoclopramide inhibits cardiac sodium channels similar to local anesthetics. The potential interaction with bupivacaine is unknown and requires further study.

Systemic Toxicity of Ropivacaine and Levobupivacaine

In vitro , ropivacaine is intermediate between bupivacaine and lidocaine in its depressant effect on cardiac excitation and conduction as well as in its potential to induce reentrant-type ventricular arrhythmias. In dogs, the margin of safety between convulsive or lethal doses and plasma concentrations of drug is greater for ropivacaine than for bupivacaine but less than that for lidocaine. The arrhythmogenicity of ropivacaine in pigs also is intermediate between that of lidocaine and bupivacaine. In sheep, the ratio of fatal doses of bupivacaine, ropivacaine, and lidocaine is 1 : 2 : 9. Ropivacaine was found to cause fewer CNS symptoms and was 25% less toxic than bupivacaine (as defined by the doses and plasma concentrations that were tolerated) when administered to healthy male volunteers.

However, studies comparing the systemic toxicity of ropivacaine and bupivacaine have used equal doses of each, and, therefore, cannot resolve the controversy as to whether ropivacaine truly is less cardiotoxic or merely less potent than bupivacaine. This issue would be of concern only if larger doses of ropivacaine than bupivacaine were required to produce comparable regional blocks. Indeed, several studies in laboring women suggest that ropivacaine is 25% to 40% less potent than bupivacaine. Thus, the need for a larger dose of ropivacaine may negate the expected benefits of its wider margin of safety. Results from one laboratory study showed that ropivacaine produces less cardiotoxicity than bupivacaine, even when given at equipotent doses.

Long-acting amide local anesthetics—even the newer drugs—are very potent and may cause cardiac arrest with a misplaced injection or relative overdose. Indeed, several cardiac arrests have been reported with the use of ropivacaine, including one in a woman undergoing a cesarean delivery with epidural anesthesia. In contrast to bupivacaine, resuscitation from a cardiac arrest induced by ropivacaine may be successful more often than not.

Evidence suggests that levobupivacaine, which is not available for use in the United States, causes fewer arrhythmias than the racemic drug. Levobupivacaine caused less inhibition of inactivated sodium channels than either the dextrorotary or racemic drug. In comparison with dextrorotary and racemic bupivacaine, levobupivacaine resulted in less QRS widening and a lower frequency of malignant ventricular arrhythmias in isolated, perfused rabbit hearts. Similarly, levobupivacaine produced less second-degree heart block and atrioventricular conduction delay than the other two forms of the drug in isolated perfused guinea pig hearts.

In laboratory animals, the systemic toxicity of levobupivacaine is intermediate between that of bupivacaine and ropivacaine. Potency ratio data for epidural bupivacaine, ropivacaine, and levobupivacaine in laboring women are inconsistent, but studies suggest that levobupivacaine is equipotent or slightly less potent than bupivacaine (see Chapter 23 ). Altogether, published data and clinical experience suggest that the benefit of a lower risk for systemic toxicity with levobupivacaine is not obtained at the expense of efficacy. Like ropivacaine, levobupivacaine may cause cardiac arrest but is associated with a better response to resuscitation than racemic bupivacaine.

Effects of Pregnancy on Systemic Toxicity

Treatment of Systemic Toxicity

Meticulous attention to good technique and adherence to guidelines for maximum recommended dose are mandatory. (The use of a test dose to identify misplaced injections is discussed in Chapter 12 .) Incremental injection of the therapeutic dose, careful observation of the patient, and monitoring of vital signs usually provide early warning of an impending reaction. In mild cases, discontinuation of the administration of drug, administration of supplemental oxygen, and maintenance of normal ventilation often limit the severity of the reaction. In 2018, the American Society of Regional Anesthesia and Pain Medicine (ASRA) updated their checklist for managing LAST ( Box 13.1 ). In patients who show signs of CNS excitation, a small dose of an intravenous sedative-hypnotic drug with strong anticonvulsant properties such as a benzodiazepine (diazepam up to 5 mg or midazolam 1 to 2 mg) may prevent progression to convulsions. Prophylactic administration of a benzodiazepine or dexmedetomidine to laboratory animals reduced the incidence of both convulsions and possibly mortality after intoxication with amide local anesthetics. Propofol should be avoided in patients with cardiovascular instability because of its cardiovascular depressant properties.

If convulsions should occur, oxygenation and ventilation must be maintained to prevent hypoxemia, hypercarbia, and acidosis. Patency of the airway must be maintained. It may be necessary to suction the airway first in some patients. Management should consist of administration of 100% oxygen and tracheal intubation, if required. Convulsions may be terminated quickly with a small dose of an anticonvulsant; a benzodiazepine is preferred. Large doses of propofol should be avoided in the setting of hemodynamic instability. Maternal circulation should be supported by maintenance of left uterine displacement and administration of a vasopressor as needed. Because a high plasma concentration of local anesthetic may cause myocardial depression and vasodilation, a mixed alpha- and beta-adrenergic agonist (e.g., ephedrine or even epinephrine) may be preferable to a pure alpha-adrenergic agonist. Vasopressin, calcium entry-blocking agents, beta-adrenergic blocking agents, and local anesthetics should be avoided. Fortunately, convulsions induced by local anesthetics, with the exception of the long-acting amide local anesthetics, are usually self-limited because of rapid redistribution of the drug.

Persistent hypotension and bradycardia may require administration of epinephrine. However, individual epinephrine doses should not exceed 1 µg/kg. Although the mainstay of treatment, epinephrine itself may cause ventricular tachyarrythmias and binds the very same cardiac sodium channels that bupivacaine binds, in theory, potentially worsening cardiac toxicity. Bupivacaine-induced ventricular arrhythmias should not be treated with lidocaine, because local anesthetic toxicity is additive.

Cardiac arrest should be treated according to the American Heart Association’s Advanced Cardiac Life Support (ACLS) guidelines, modified for pregnancy (see Chapter 54 ). The uterus should be displaced leftward, generally best achieved with manual displacement, to prevent or relieve aortocaval compression, which renders cardiac massage ineffective. Prompt cesarean delivery of the infant may be necessary to relieve aortocaval compression (venous return) and restore maternal circulation. Prolonged resuscitation may be needed until myocardial washout of bupivacaine has occurred.

Lipid emulsion therapy has been incorporated into guidelines for the treatment of LAST and should be readily available. The mechanism of lipid emulsion therapy includes a direct scavenging effect that removes the local anesthetic from tissue and a direct cardiac effect that serves to improve cardiac output once the drug is removed from cardiac tissue; the mechanisms of these effects are incompletely understood. Lipid emulsion is now an accepted therapy, and the updated 2018 American Society of Regional Anesthesia and Pain Medicine (ASRA) checklist for the treatment of LAST states that lipid emulsion therapy should be considered at the first sign of a serious LAST event (see Box 13.1 ). Propofol should not be used to treat LAST; its lipid content is inadequate, and the cardiodepressant effects of the drug are detrimental during resuscitation from LAST. In a suspected case of bupivacaine intoxication in a parturient, manifested by facial and limb twitching and unconsciousness, prophylactic administration of 100 mL of lipid emulsion prevented progression to full cardiovascular collapse. A protocol for treatment of LAST in pregnancy, including the administration of lipid emulsion, is presented in Box 13.1 .

After maternal recovery, fetal condition should be assessed promptly. In theory, a delay in delivery may allow back-diffusion of local anesthetic from the fetus to the mother, which may be of benefit to the neonate by decreasing neonatal plasma bupivacaine levels. Laboratory studies have demonstrated this phenomenon after the administration of bupivacaine but not lidocaine.

Tissue Toxicity

Neurologic complications of neuraxial anesthesia are rare and result mostly from direct neural trauma, infection, injection of toxic doses of local anesthetic, or the injection of the wrong drug.

Several cases of prolonged or permanent sensory and motor deficits after subarachnoid injection of a large dose of 2-chloroprocaine intended for epidural block have been described. Studies comparing the neurotoxicity of 2-chloroprocaine with that of other local anesthetics have yielded conflicting results, most likely related to the use of different methodologies and different species. It has been suggested that neurotoxicity was caused by sodium metabisulfite, an antioxidant present in the commercial formulation used in the reported cases and a low pH (2.7 to 4.0) of the formulation. In CSF rendered more acidic by 2-chloroprocaine, metabisulfite generates sulfur dioxide, which is lipid soluble and can diffuse into the nerve cells. Intracellular hydration of sulfur dioxide generates sulfurous acid, which may cause profound intracellular acidosis and irreversible damage. In contrast, others have suggested that 2-chloroprocaine itself, and not metabisulfite, was the cause of neurologic deficits.

Subsequently, the manufacturer released another preparation of 2-chloroprocaine, which was free of bisulfite but contained ethylenediaminetetraacetic acid (EDTA). This was followed by several reports of severe, incapacitating paralumbar pain and spasm associated with epidural injection of large volumes of drug, likely resulting from chelation of calcium by disodium EDTA and tetany of the affected muscles caused by local hypocalcemia. The current preparation of 2-chloroprocaine that is marketed for epidural administration does not contain EDTA or other preservatives. It is packaged in colored vials to reduce the oxidation.

Lidocaine has been used for spinal anesthesia for more than 50 years, in thousands upon thousands of patients, with apparent safety. However, cauda equina syndrome, sacral nerve root deficits, or transient neurologic toxicity can occur after subarachnoid injection of lidocaine. Neurotoxicity of local anesthetics is concentration dependent and is not unique to lidocaine. Some investigators have speculated that slow injection of local anesthetic through a spinal microcatheter results in maldistribution and pooling of high concentrations of hyperbaric lidocaine in the cauda equina area, resulting in increased risk for neurotoxicity and cauda equina syndrome.

Milder manifestations of neurotoxicity also may occur. As early as 1954, mild, transient neurologic symptoms were reported after spinal anesthesia with lidocaine. Transient neurologic symptoms (TNS) (dysesthesia or low back pain radiating to the buttocks, thighs, and calves) have been observed in surgical patients even after conventional (i.e., single-shot) spinal anesthesia with hyperbaric 5% lidocaine (see Chapter 31 ). In response to concerns that intrathecal injection of hyperbaric 5% lidocaine might be associated with TNS, in 1994 the FDA Advisory Committee on Anesthetic Drugs recommended that the injected drug concentration be reduced by dilution with an equal volume of either preservative-free saline or CSF. However, Pollock et al. reported that there was no difference in the incidence of TNS when spinal lidocaine 50 mg was diluted to 2%, 1%, or 0.5% solutions before administration and that the overall incidence of TNS did not differ from that of historic controls given 5% lidocaine.

Interestingly, the exposure of frog sciatic nerve to lidocaine results in a progressive, irreversible loss of impulse activity beginning at a concentration of 1%. The investigators of this study noted that “the range of lidocaine that produces such changes in mammalian nerve awaits determination.” Meanwhile, it seems prudent to take the following precautions :

• 1.
  

  Dilute the commercial 5% lidocaine for intrathecal injection as recommended by the FDA.

  
  
• 2.
  

  Administer the lowest possible dose.

  
  
• 3.
  

  Avoid the use of hyperbaric lidocaine in clinical conditions (e.g., obesity) or situations (e.g., the lithotomy position) that may be associated with a higher incidence of TNS.

Generally, if pencil-point, side-hole spinal needles are used, it is recommended that the injection port should be directed cephalad. However, an epidemiologic survey did not implicate dose and needle-bevel direction as factors that affect the risk for TNS. A meta-analysis of randomized controlled trials comparing spinal lidocaine with other local anesthetics (bupivacaine, prilocaine, procaine, and mepivacaine) found that the relative risk (RR) for development of TNS was higher with lidocaine than with the other local anesthetic agents (RR, 4.35; 95% confidence interval [CI], 1.98 to 9.54). It has not been conclusively proven that TNS are manifestations of neurotoxicity.

Pregnancy may be associated with a reduced risk for TNS. Studies suggest that the incidence of TNS after spinal anesthesia with lidocaine or bupivacaine is equally low (< 3%) in women having cesarean delivery and those undergoing postpartum tubal ligation.

Allergic Reactions

True allergy to a local anesthetic is rare. Further, anaphylactic and anaphylactoid reactions may be the result of additives such as methylparaben and metabisulfite. Experts judged that only 15% of patients referred to an allergy clinic for suspected local anesthetic allergy actually had a clinical reaction (urticaria, bronchospasm, facial edema, and/or cardiovascular instability) consistent with a real allergic response. Adverse reactions (e.g., CNS and cardiovascular symptoms) may mimic hypersensitivity but not actually be a result of hypersensitivity. The potential range of allergic manifestations are listed in Box 13.2 .

Obstetricians should refer women with alleged allergy to an anesthesiologist for appropriate evaluation well before the expected date of delivery. In many cases, a carefully obtained history excludes true hypersensitivity. If IgE-mediated hypersensitivity is suspected, patients should be referred to an allergist for further evaluation. Skin prick or intradermal testing using appropriate positive (diluted histamine) and negative (normal saline) controls is recommended. Intradermal testing is more sensitive but is associated with a false-positive rate of 8% to 15%. If the skin testing is negative, subcutaneous provocative dose testing is a useful method to confirm that the drug is safe to use clinically. Alternatively, if skin testing is positive, the testing sequence (skin testing followed by provocative subcutaneous testing) should be repeated with an alternative agent.

The subcutaneous provocative test can be performed by any physician qualified to manage hypersensitivity reactions. Appropriate emergency equipment and drugs (e.g., epinephrine, H ₁ – and H ₂ -receptor antagonists) should be immediately available. Establishing intravenous access before testing is prudent. The back and the ventral aspects of the forearm are the preferred sites for testing. Areas with abnormal skin coloration or dermographia should be avoided. A history of recent treatment with antihistamines, salicylates, or corticosteroids may alter the test results.

The following protocol has been proposed by Chandler et al. ( Table 13.2 ). After a negative needle-prick test, increasing volumes of undiluted local anesthetic (typically 1% concentration) are injected subcutaneously at 15-minute intervals. In patients with an especially strong history of a prior severe reaction, the series may be preceded by injection of diluted solutions (e.g., a 1 : 100 solution, followed by a 1 : 10 solution). A fresh syringe should be used for each subsequent injection. A negative control and a positive control injection may also be used. A local anesthetic that is not in the same class as the drug in question should be tested; if an ester is suspected as the offending agent, testing should be performed with an amide agent, and vice versa. If possible, the drug tested should be suitable for local infiltration and for epidural and subarachnoid block.

The test is considered positive if there is a change in the patient’s clinical status or if a skin wheal more than 10 mm in diameter, with or without a flare, arises within 10 minutes of injection and persists for at least 30 minutes. If provocative dose testing is completed without a reaction, the local anesthetic used and the final dose given should be recorded; the patient (and the referring physician) should be informed that her risk for an adverse reaction to subsequent administration of that drug and dose is no greater than that for the general population.

Management of an allergic reaction.

Pharmacologic therapy of a severe allergic reaction involves (1) inhibition of mediator synthesis and release, (2) reversal of the effects of these mediators on target organs, and (3) prevention of the recruitment of other inflammatory processes. In general, catecholamines, especially epinephrine, but also phosphodiesterase inhibitors, antihistamines, and corticosteroids, have been used for this purpose ( Box 13.3 ). Higher doses of catecholamines may be required in a patient who has a sympathetic blockade. In addition, pregnancy itself decreases responsiveness to catecholamines. Once the patient is stable, a serum tryptase level should be obtained; an elevated level is suggestive of anaphylaxis.

Box 13.3

Management of Anaphylaxis

Immediate Management

• •
  

  If cardiac arrest, follow ACLS guidelines.

  
  
• •
  

  Discontinue or remove all triggers (e.g., chlorhexidine, synthetic colloids, latex).

  
  
  
  
  • •
    

    Stop procedure; use minimal volatile anesthetic agents.

  
  
  
  
• •
  

  Call for help.

  
  
• •
  

  Maintain airway: Fi o ₂ 1.0, consider need for tracheal intubation.

  
  
• •
  

  Rapid large-volume fluid administration

  
  
  
  
  • •
    

    Crystalloid bolus: 2 L, repeat as needed

    
    
  • •
    

    Large-bore IV access

    
    
  • •
    

    Elevate legs

  
  
  
  
• •
  

  IV epinephrine bolus, repeat every 1–2 min as needed

  
  
  
  
  • •
    

    Mild hypotension: 5–10 µg

    
    
  • •
    

    Moderate hypotension: 20 µg

    
    
  • •
    

    Life-threatening hypotension: 100–200 µg

    
    
  • •
    

    Epinephrine infusion: 3–40 µg/min (0.05–0.5 µg/kg/min)

  
  

Refractory Management

• •
  

  Consider requesting more help.

  
  
• •
  

  Consider cesarean delivery if still pregnant (initiate within 4 min of cardiovascular collapse).

  
  
• •
  

  Make sure triggers have been removed.

  
  
• •
  

  Monitoring: consider arterial line, transthoracic or transesophageal echocardiography.

  
  
• •
  

  Resistant hypotension

  
  
  
  
  • •
    

    Norepinephrine infusion: 3–40 µg/min (0.05–0.5 µg/kg/min)

    
    
  • •
    

    Vasopressin bolus 1–2 U, then infusion 2 U/h

    
    
  • •
    

    Glucagon: 1–2 mg IV every 5 min until a response

  
  
  
  
• •
  

  Resistant bronchospasm

  
  
  
  
  • •
    

    Continue epinephrine infusion.

    
    
  • •
    

    Salbutamol metered dose inhaler 12 puffs (1200 µg)

    
    
  • •
    

    Magnesium 2 g over 20 min

    
    
  • •
    

    Consider volatile anesthetic agent or ketamine.

  
  
  
  
• •
  

  Consider other diagnoses.

Post-Crisis Management

• •
  

  Consider steroids: dexamethasone 0.1–0.4 mg/kg or hydrocortisone 2–4 mg/kg.

  
  
• •
  

  Consider oral antihistamines.

  
  
• •
  

  Consider canceling surgical procedure, ICU monitoring.

  
  
• •
  

  Investigations: draw blood for tryptase level.

  
  
• •
  

  Documentation in medical record, letter for patient, referral for allergy assessment

ACLS, Advanced cardiac life support; IV, intravenous.

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