With the exception of lidocaine, amino-amide local anesthetics are enantiomeric compounds , which exist as two or more compounds with the same molecular formula but are nonsuperimposable mirror images of each other. In the case of amino-amide local anesthetics, the single asymmetric carbon adjacent to the amino group results in two isomeric forms that are mirror images of each other. Enantiomers are classified by two naming conventions. The R/S system classifies enantiomers by their molecular geometry according to the Cahn-Ingold-Prelog priority rules. Alternatively, enantiomers can be classified based on their optical rotation properties, the direction in which the enantiomers rotate plane-polarized light. Enantiomers that rotate plane-polarized light clockwise are denoted as (+) or dextrorotatory, while those that rotate plane-polarized light anticlockwise are denoted (−) or levorotatory. This distinction is important because individual isomers of the same drug may have different biologic effects. As a rule, the levorotatory isomer of a drug has greater vasoconstrictor activity and a longer duration of action, but less potential for systemic toxicity than the dextrorotatory form.

In the past, local anesthetics contained a racemic (50:50) mixture of both dextrorotatory and levorotatory forms of the drug. However, with improved techniques of selective extraction, two commercially available single-isomer formulations of local anesthetic, ropivacaine and levobupivacaine, are now available. Levobupivacaine is the levorotatory isomer of bupivacaine; it is currently not marketed in the United States. Ropivacaine is a homolog of bupivacaine that is formulated as a single levorotatory isomer rather than as a racemic mixture.

The reduction in systemic toxicity observed with administration of the levorotatory 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 is hydrolyzed rapidly by plasma pseudocholinesterase to chloroaminobenzoic acid and water. 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.

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). MEGX can be detected in maternal plasma within 10 to 20 minutes after neuraxial injection of lidocaine, whereas GX 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., less than 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. Given that pregnancy leads to a decreased concentration of AAG; the free plasma fraction of lidocaine tends to be higher in term pregnant women than in nonpregnant controls. This increase in the free fraction of lidocaine occurs early in gestation and is progressive.

At least two studies compared the pharmacokinetics of bupivacaine after epidural administration in pregnant and nonpregnant women. The absorption rate, area under the concentration-time curve, and 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 and 4.14 mg, respectively).

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 that of bupivacaine.

Peak plasma concentration (C _max ) of 0.5% ropivacaine and 0.5% bupivacaine after epidural administration for cesarean delivery are similar (1.3 and 1.1 µg/mL, respectively). The mean (± standard deviation [SD]) elimination half-life of ropivacaine is 5.2 ± 0.6 hours, which is shorter than that for bupivacaine (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.

The increasing demand for opioid-sparing analgesic techniques and rapid functional recovery have spurred development of extended-release local anesthetics aimed at providing sustained postoperative analgesia. Examples include Exparel (Pacira Pharmaceuticals, United States) and Zynrelef (HTX-011, Heron Therapeutics, United States).

Exparel consists of a preservative-free aqueous suspension of bupivacaine encapsulated within multivesicular liposomes (DepoFoam) at a nominal concentration of 13.3 mg/mL (liposomal bupivacaine). It is approved by the US Food and Drug Administration (FDA) for single-dose interscalene brachial plexus and sciatic nerve blocks, adductor canal blocks, and local infiltration. The maximum recommended dose of liposomal bupivacaine for local infiltration is 266 mg (20 mL). Plasma levels of liposomal bupivacaine follow a bimodal distribution. The first plasma peak occurs within an hour after drug infiltration followed by a second peak approximately 12 to 36 hours later, although the rate of systemic absorption depends on multiple factors, including drug dose and vascularity of the administration site. After bupivacaine is released from the liposomes and absorbed within the systemic circulation, its distribution and elimination are expected to mimic standard bupivacaine formulations. Mixture of liposomal bupivacaine with water, hypotonic agents, or other local anesthetics is not recommended as these can disrupt the liposomal particles, resulting in rapid bupivacaine release.

Despite the prolonged sustained release of bupivacaine, the clinical superiority of liposomal bupivacaine over standard bupivacaine for postcesarean delivery analgesia is unclear (see Chapter 27 ). A systematic review comparing liposomal bupivacaine with standard bupivacaine for a heterogeneous mix of surgeries, including abdominal and orthopedic surgery, with the local anesthetic administered by varying routes including local infiltration, reported that liposomal bupivacaine was associated with statistically significantly lower mean pain score difference (−0.37 on numerical rating scale 0 to 10; 95% confidence interval [CI], −0.56 to −0.19) and opioid consumption reported in intravenous morphine equivalents ratio of means (0.85; 95% CI, 0.82 to 0.89) at 24 hours. However, at 72 hours no significant reduction in mean pain score (−0.25; 95% CI, −0.71 to 0.20) was detected, although the ratio of morphine equivalents was significantly lower in patients who received liposomal bupivacaine (0.85; 95% CI, 0.77 to 0.95) than standard bupivacaine. The clinical relevance of these differences was questioned by the authors.

Randomized trials suggest that transversus abdominis plane (TAP) block with liposomal bupivacaine may improve postcesarean delivery analgesia. A multicenter randomized trial comparing TAP blocks with liposomal bupivacaine 266 mg plus bupivacaine 50 mg versus bupivacaine 50 mg alone after elective cesarean delivery under spinal anesthesia with intrathecal morphine 0.15 mg reported that the former regimen significantly reduced opioid consumption through 72 hours. A second randomized trial comparing TAP block with liposomal bupivacaine 266 mg, intrathecal morphine 0.05 mg plus TAP block with liposomal bupivacaine 266 mg, and intrathecal morphine 0.15 mg alone reported that TAP block with liposomal bupivacaine resulted in noninferior opioid consumption through 72 hours and a lower incidence of adverse events compared to TAP block plus intrathecal morphine or intrathecal morphine alone. Additional studies are warranted to determine the optimal dose of liposomal bupivacaine and whether there is a true benefit if the patient also receives intrathecal morphine.

Bupivacaine transfer into breast milk following TAP block with bupivacaine 52 mg plus liposomal bupivacaine 266 mg resulted in relative neonatal doses of less than 1% (<10% is considered to be acceptable by the FDA).

Zynrelef is a formulation of slow-release bupivacaine combined with meloxicam, a nonsteroidal antiinflammatory drug (NSAID), encapsulated within a biodegradable polymer (Biochronomer). Slow-release bupivacaine-meloxicam is FDA-approved in adults for soft tissue or periarticular administration after bunionectomy, open inguinal herniorrhaphy, and total knee arthroplasty. The pharmacokinetics, safety, and efficacy of slow-release bupivacaine-meloxicam for postcesarean delivery analgesia are still being investigated.

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 women with preeclampsia 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.

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).

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 a.m. and 7:00 p.m. than between 7:00 p.m. and 7:00 a.m. In contrast, another study found no diurnal variation with intrathecal bupivacaine administered for labor analgesia. The authors suggested the diurnal variation may also be explained by external influences such as shift changes for nurses and anesthesiologists.

Latency of local anesthetic 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.

The majority of LAST cases first present with CNS signs and symptoms. Generally, the severity of CNS effects is proportional to the blood concentration of local anesthetic. This relationship is well described for lidocaine ( Fig. 13.3 ) and is classically described as a two-stage process of CNS excitation followed by depression. Initially, the patient presents with prodromal symptoms such as numbness of the tongue, tinnitus, lightheadedness, or perioral numbness. At high plasma concentrations, seizures 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. However, it is important to note that LAST may not always present in this classical fashion when prodromal symptoms precede seizures, CNS depression, and cardiovascular toxicity. Instead, many cases of LAST first present with seizures or features of combined CNS and cardiovascular toxicity. Hence, providers should remain vigilant for atypical manifestations, and any abnormal neurologic or cardiovascular signs and symptoms following local anesthetic administration should raise suspicion of LAST.

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 . Lippincott; 1992:527.

The relative CNS toxicity of a local anesthetic correlates with its potency. For lidocaine and bupivacaine, the ratio of the mean cumulative doses that cause seizures in dogs and human volunteers is approximately 4:1, 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.

Other factors (e.g., the speed of injection) may affect CNS toxicity, and metabolic factors may also affect the seizure threshold. For example, in cats, an increase in PaCO 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 classically occurs in three phases. The first phase includes hypertension and tachycardia, followed by myocardial depression and hypotension. The terminal phase typically involves vasodilation, severe hypotension, and arrhythmias, including conduction blocks, tachyarrhythmias, and asystole.

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, with progressive depression of myocardial function and profound vasodilation occurring only at extremely high plasma concentrations. In contrast, the more potent amide local anesthetics (i.e., bupivacaine) have a narrower margin of safety, expressed as the ratio between the dose (or plasma concentration) required to produce cardiovascular collapse (CC) and the dose (or plasma concentration) required to produce seizures, termed the CC/CNS ratio.

In general, agents with higher CC/CNS ratio have a greater margin of safety as earlier presentation of CNS features may facilitate diagnosis and treatment of LAST before cardiovascular collapse occurs. For instance, the greater cardiotoxicity of bupivacaine compared to lidocaine is reflected in CC/CNS ratios of 2 versus 7, respectively.

A partial explanation for this discrepancy in cardiotoxicity may lie in 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.

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 is of concern only if larger doses of ropivacaine than bupivacaine are required to produce comparable regional block density. Indeed, several studies in laboring women suggest that epidural 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. Long-acting amide local anesthetics—even the newer drugs—are very potent and may cause cardiac arrest with an unintentional intravascular injection or relative overdose. Indeed, cardiac arrest has been reported with the use of ropivacaine, including one in a woman undergoing a cesarean delivery with epidural anesthesia. However, in contrast to bupivacaine, resuscitation from a cardiac arrest induced by ropivacaine may be successful more often than not.

Evidence suggests that levobupivacaine causes fewer arrhythmias than the racemic drug. Levobupivacaine caused less inhibition of inactivated sodium channels than either the dextrorotatory or racemic drug. In comparison with dextrorotatory 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 24 ). 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.

Patients with cardiac disease may be at increased risk of LAST. In particular, those with preexisting conduction disorders may be susceptible to cardiovascular toxicity, while patients with cardiac dysfunction may be predisposed to local anesthetic–induced myocardial depression and arrhythmias. Careful dosing and the use of less cardiotoxic agents may be considered.

In contrast, severe renal disease is typically associated with hyperdynamic circulation and reduced local anesthetic clearance, but increased AAG concentration. Hence, free plasma concentration of local anesthetics is largely unchanged and dose reduction is usually not required unless metabolic acidosis is present.

Hepatic disease may reduce the clearance of local anesthetics, but this effect is mitigated by a larger volume of distribution and maintenance of AAG concentration. Dose adjustment may be considered in patients receiving multiple local anesthetic boluses or continuous infusion, and in those with cardiac and renal comorbidities.

Available evidence suggest that the risk of LAST varies with the type of block, with infiltration techniques and epidural blocks most commonly implicated. This may be attributed to the dose of local anesthetic administered and site vascularity. For instance, fascial plane blocks such as the TAP block involve large volumes of local anesthetic administered into the intermuscular plane in contact with highly vascularized muscle tissue. It was reported that bilateral ultrasound-guided TAP blocks with bupivacaine following cesarean delivery may result in toxic plasma bupivacaine concentrations.

Continuous local anesthetic infusion via a nerve catheter has also been associated with increased risk of LAST. Following nonobstetric abdominal surgery, bilateral TAP blocks with ropivacaine 100 mg per side and 10 mL/h infusion of 0.2% ropivacaine resulted in some patients exceeding toxic total plasma concentration thresholds, although unbound ropivacaine concentrations were much lower, possibly due to perioperative increase in AAG levels.

Meticulous attention to good technique and adherence to guidelines for maximum recommended dose are critical. (The use of a test dose to identify misplaced epidural catheters is discussed in Chapter 12 .) Incremental injection of the therapeutic dose, use of the lowest effective dose, careful observation of the patient, and monitoring of vital signs may facilitate early detection and treatment of an impending reaction. In 2020, the American Society of Regional Anesthesia and Pain Medicine updated their checklist for managing LAST (see Chapter 24 ).

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 the drug, likely resulting from chelation of calcium by disodium EDTA and tetany of the affected muscles caused by local hypocalcemia. The current preparations of 2-chloroprocaine that are marketed for epidural and spinal administration do not contain EDTA or other preservatives. 2-Chloroprocaine intended for epidural administration is packaged in colored vials to reduce 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 1994, in response to concerns that intrathecal injection of hyperbaric 5% lidocaine might be associated with TNS, 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.

Of interest, 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.”

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 metaanalysis of randomized controlled trials comparing spinal lidocaine with other local anesthetics found that the relative risk (RR) for development of TNS was lower with bupivacaine, levobupivacaine, prilocaine, and procaine than lidocaine (RR ranging from 0.10 to 0.23), but similar to mepivacaine and 2-chloroprocaine. 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.

True Ig-E-mediated immediate hypersensitivity reactions to a local anesthetic are rare and account for less than 1% of adverse reactions to local anesthetics. Further, anaphylactic and anaphylactoid reactions may be the result of additives such as methylparaben and metabisulfite. In a study of 164 patients referred to an allergy clinic for suspected local anesthetic allergy, none was found to be allergic. Adverse reactions (e.g., CNS and cardiovascular symptoms) may mimic hypersensitivity but not actually be Ig-E-mediated reactions. The potential range of allergic manifestations is listed in Box 13.1 .

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 immediate hypersensitivity is suspected, patients should be referred to an allergist for further evaluation. Skin tested and graded challenge may be indicated. Delayed reading of skin testing and patch testing may be considered if a delayed hypersensitivity reaction is suspected. A second goal of allergy testing is to identify a safe alternative local anesthetic.

If the patient’s history suggests a low risk of local anesthetic allergy, a single-dose local anesthetic challenge can be considered, particularly with an alternative class of local anesthetic (amides and esters).

The association of paracervical block with fetal bradycardia has been attributed to the high concentration of local anesthetic deposited in the vicinity of the uterine arteries (see Chapter 23 ). Human uterine artery segments obtained at the time of cesarean hysterectomy constrict when exposed to high concentrations of lidocaine or bupivacaine.

These findings also have been confirmed in laboratory animals. Fishburne et al. observed a dose-related decrease in uterine blood flow during uterine arterial infusion of 2-chloroprocaine, lidocaine, or bupivacaine in gravid ewes. However, when plasma local anesthetic concentrations mimic those that occur in ordinary clinical practice, local anesthetics have no adverse effect on uterine blood flow.

Pregnancy itself may enhance uterine vascular reactivity to local anesthetic agents. Isolated human uterine artery segments obtained from term parturients constrict at a lower lidocaine concentration than uterine artery segments from nonpregnant patients. Uterine artery sensitivity to local anesthetics increases as early as the second trimester of pregnancy and may be related to an increase in estrogen. However, these studies were performed before the recognition of the importance of intact vascular endothelium in the in vitro assessment of vascular tone. The exact mechanism by which high concentrations of local anesthetics cause uterine artery vasoconstriction (while causing dilation in other vascular beds) is unclear. Clinical experience with the use of local anesthetics supports the view that clinical concentrations of these drugs do not adversely affect the uterine vasculature (see Chapter 3 ).

All local anesthetics can reduce uterine blood flow at plasma concentrations that greatly exceed those occurring during the routine practice of obstetric anesthesia. There has been an added concern that the levorotatory isomers of local anesthetics, which produce vasoconstriction at clinical doses, may reduce uteroplacental perfusion and adversely affect fetal well-being. It is reassuring to note that ropivacaine, even at plasma concentrations that are almost two times greater than would be expected to occur during clinical use, does not reduce uterine blood flow or affect fetal heart rate (FHR), blood pressure, or acid-base measurements in pregnant sheep. In humans, Doppler velocimetry studies have shown that ropivacaine has little effect on the uteroplacental or fetal circulation when it is administered to provide epidural anesthesia for cesarean delivery. Similarly, clinically relevant plasma concentrations of levobupivacaine had no adverse effect on uterine blood flow.

Fetal well-being also depends on the adequacy of perfusion of the placenta. The regulatory mechanisms that control flow through the umbilical vessels are poorly understood. Lidocaine does not affect spiral strips obtained from human umbilical artery segments at concentrations up to 5 µg/mL, but it produces relaxation in concentrations from 30 to 900 µg/mL. Bupivacaine also does not constrict umbilical artery segments at clinically relevant concentrations of 0.3 and 1 µg/mL. At higher concentrations, the effect of bupivacaine appears to be biphasic. Constriction occurs at concentrations of 5 to 25 µg/mL, and relaxation occurs at concentrations > 125 µg/mL. Hypercarbia but not hypoxemia lessens the contractile response of umbilical vessels to bupivacaine in vitro .

Decreases in umbilical blood flow of as much as 43% accompany intravenous administration of lidocaine 4 mg/kg in pregnant sheep. However, plasma concentrations of the drug were higher than would be expected with clinical use, and all ewes exhibited signs of CNS toxicity, which may reduce umbilical blood flow itself.

Advances in noninvasive Doppler imaging have facilitated clinical assessment of umbilical cord blood flow velocity. The ratio of the systolic (S) peak to the diastolic (D) trough of the umbilical artery waveform is used as a measure of vascular resistance. The S/D ratio in the umbilical artery decreases during normal pregnancy, and high ratios usually are associated with fetal compromise (see Chapter 6 ). Local anesthetics administered for epidural anesthesia do not adversely affect the umbilical artery S/D ratio. In fact, labor epidural analgesia with 1.5% lidocaine or 2% 2-chloroprocaine resulted in a decrease in the S/D ratio. This favorable change may have resulted from pain relief. Other investigators have noted no appreciable change or a slight decrease in the S/D ratio after the epidural administration of amide local anesthetics for elective cesarean delivery.

Changes in uterine tone and contractility may affect uteroplacental perfusion. Local anesthetics exert direct effects on uterine smooth muscle. One study reported that exposure to high concentrations of local anesthetic in vitro led to contraction of human myometrial segments obtained at the time of cesarean delivery. These findings have been corroborated in laboratory animals. Further, Belitzky et al. observed that direct intramyometrial injection of 1% procaine resulted in uterine tachysystole and fetal compromise in pregnant women. In all of these reports, the myometrium was exposed to higher-than-normal concentrations of the drug. In other studies, intravenous infusion of lidocaine or bupivacaine that resulted in clinically relevant plasma concentrations did not affect uterine tone or uterine activity in pregnant ewes. In a study using electrohysterogram monitoring, levobupivacaine caused less uterine muscle relaxation after intramyometrial injection in rats than did bupivacaine.

Compounds with a molecular weight of less than 500 Da cross the placenta easily, whereas drugs such as digoxin, which have a molecular weight > 500 Da, have a slower rate of diffusion. Molecular weights of local anesthetics range from 234 to 288 Da (see Table 13.1 ). These small differences in molecular weight should not affect the rate of placental transfer because the diffusion constant ( K ) is inversely proportional to the square root of the molecular weight.

Local anesthetics are weak bases; they have a relatively low degree of ionization and considerable lipid solubility at physiologic pH. The basic un-ionized local anesthetic molecule is more lipid soluble than the ionized moiety and determines placental transfer in a protein-free perfusate.

The relationship between pH and pK _a may affect drug accumulation in the fetus. For the amide local anesthetics, pK _a values are close enough to physiologic pH that changes in fetal pH may alter the balance between ionized and un-ionized drug. In the acidotic fetus, a greater proportion of drug in the ionized form results in a larger total amount of local anesthetic in fetal plasma, because of “ion trapping” ( Fig. 13.4 ). Elimination of lidocaine from fetal blood is slower in the asphyxiated fetus than in the nonasphyxiated fetus. Accumulation of lidocaine may be greater in fetal tissues, where the pH is even lower than that in fetal blood.

“Ion Trapping” of a Local Anesthetic. The numbers in parentheses represent relative numbers of molecules.

From the American College of Obstetricians and Gynecologists. Obstet Gynecol . 1976;48:29.

Perhaps most confusing and least understood are the effects of protein binding on placental transfer. Amide local anesthetics are bound to AAG and to a lesser extent to albumin. The extent of protein binding varies among the local anesthetic agents (see Table 13.1 ). For a given local anesthetic, the proportion of free drug increases as blood concentration increases because of the saturation of binding sites. Binding of local anesthetics in the fetal plasma is approximately half that in the mother.

The fetal-to-maternal (F/M) blood concentration ratios of amide local anesthetic agents are listed in Table 13.1 . The lower F/M blood concentration ratios of highly protein-bound drugs (e.g., bupivacaine) have been attributed to their more restricted placental transfer compared with less protein-bound drugs (e.g., lidocaine). Indeed, the rate of bupivacaine transfer across rabbit placenta perfused in situ is lower than that of lidocaine transfer. Some investigators have suggested that protein binding in the maternal plasma should not affect the diffusion of drugs across the placenta because the dissociation from plasma proteins is essentially instantaneous. In subsequent studies, the relatively low umbilical vein-to-maternal vein blood concentration ratio for bupivacaine has been attributed to differences in protein binding between maternal plasma and fetal plasma ( Fig. 13.5 ). Let us assume that the total concentration of lidocaine or bupivacaine in the maternal plasma is 2 mg/L. Lidocaine and bupivacaine are approximately 50% and 90% bound to maternal plasma proteins, respectively. Thus, the free concentrations of drug available for placental transfer are 1.0 and 0.2 mg/L, respectively. At equilibrium, the concentration of free drug is equal on the two sides of the placenta. In the fetus, however, lidocaine and bupivacaine are approximately 25% and 50% bound to fetal plasma proteins, respectively. Thus, the total lidocaine concentration in fetal plasma is 1.33 mg/L, resulting in an F/M ratio of 0.67; for bupivacaine, the corresponding values are 0.4 mg/L and 0.2, respectively.

Demonstration of how distribution of local anesthetics across the placenta may be predicted from differences in drug protein binding in maternal and fetal plasma. Left , lidocaine (L); f, b, t , free, bound, and total drug concentrations, respectively. Right , bupivacaine (B) . Lidocaine umbilical cord-to-maternal plasma ratio (F/M) = 0.67; bupivacaine F/M = 0.20.

From Mather LE, Tucker GT. Properties, absorption, and disposition of local anesthetic agents. In: Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain . 4th ed. Lippincott Williams & Wilkins; 2009:85.

In fact, accumulation of bupivacaine occurs in human fetuses whose mothers received the drug for epidural anesthesia. After delivery, measurable plasma and urine concentrations persisted for as long as 3 days. In vitro studies using a perfused human placental model have found that the placental transfer of ropivacaine is similar to that of bupivacaine. Tissue concentrations of ropivacaine in fetal heart, brain, liver, lung, kidneys, and adrenal glands were similar to those of bupivacaine. Datta et al. noted that the free fraction of ropivacaine at delivery was approximately twice that of bupivacaine in neonates whose mothers received the drug for epidural anesthesia during labor or cesarean delivery.

The maternal blood concentration of local anesthetic is determined by (1) the dose, (2) the site of administration, (3) metabolism and excretion, and (4) the effects of adjuvants such as epinephrine. For a given local anesthetic, the maternal blood concentration determines fetal drug exposure and is the only variable of the Fick equation that may be influenced by the clinician.

Local anesthetics, once transferred across the placenta, are distributed in the fetus. Factors that influence fetal tissue uptake of the drug include (1) fetal plasma protein binding, (2) lipid solubility, (3) the degree of ionization of the drug, and (4) hemodynamic changes that affect the distribution of fetal cardiac output. Fetal plasma protein-binding capacity of local anesthetics is approximately 50% that of maternal plasma; thus, there is greater availability of free drug in the fetus than in the mother. Studies have examined the distribution of lidocaine in fetal tissues after an intravenous injection of the drug to animals. The higher concentration of lidocaine in the liver, myocardium, and brain (compared with other fetal tissues) reflects rapid distribution of the drug to highly perfused tissues. Only the fetal liver had lidocaine concentrations that exceeded those in the mother. This finding is not surprising, given the high lipid content of the fetal liver and the fact that it receives most of the blood returning from the placenta by means of the umbilical vein. Fetal asphyxia results in adaptations that increase blood flow to vital organs (e.g., brain, heart, adrenal glands). The concentration of lidocaine in these organs is higher in asphyxiated fetuses than in healthy fetuses.

Any drug that reaches the fetus undergoes metabolism and excretion. The term newborn has the hepatic enzymes necessary to metabolize local anesthetics. Nonetheless, the elimination half-life of these drugs is longer in the neonate than in the adult. The use of mepivacaine in obstetric epidural analgesia fell into disfavor after a report indicating that the elimination half-life of the drug in the neonate was approximately 9 hours, or three times as long as the neonatal half-life for lidocaine. It is ironic that the neonatal elimination half-life for bupivacaine may be as long as 14 hours.

Morishima et al. compared the pharmacokinetics of lidocaine among adult ewes and fetal and neonatal lambs. The metabolic (hepatic) clearance in the lambs was similar to that in adults, but renal clearance was greater in neonates. Nonetheless, the elimination half-life was prolonged in the lambs. This latter finding has been attributed to a greater volume of distribution in the neonatal lamb. Thus, at any given time, a smaller fraction of lidocaine accumulated in the body is available for clearance by hepatic metabolism. The greater renal clearance noted in neonates is a result of decreased protein binding, which increases the proportion of drug available for excretion.

The elimination half-life of local anesthetics in the fetus is similar to that in the adult because, unlike the newborn, the fetus can excrete drug across the placenta back to the mother. With bupivacaine, this transfer may occur even though the total plasma drug concentration in the mother may exceed that in the fetus.

In general, the neonate is more sensitive than the adult to the depressant effects of drugs. However, the seizure threshold for local anesthetics in the neonate appears to be similar to that in the adult. Morishima et al. compared the relative CNS toxicity and cardiovascular toxicity of lidocaine in adult ewes and fetal and neonatal lambs. Greater doses (when calculated on a milligram-per-kilogram basis) were required to elicit toxic manifestations in the fetus and neonatal lamb than in the adult. However, the plasma concentrations of the drug associated with toxic manifestations were similar in the three groups of animals. The greater dose tolerated by fetuses than by neonates and adults was attributed to placental clearance of drug back to the mother and better maintenance of blood gas tensions during seizures. In the neonate, a large volume of distribution is most likely responsible for the high doses of local anesthetic required for fetal toxicity.

Studies of bupivacaine cardiotoxicity are inconsistent. In vitro , the sinoatrial node of neonatal guinea pigs was found to be more sensitive than that of adults to the cardiodepressant effect of bupivacaine. In contrast, 2-day-old piglets demonstrated greater resistance than older animals to the arrhythmogenic and CNS effects of bupivacaine.

Changes in FHR after administration of local anesthetics are most often related to indirect effects such as maternal hypotension and uterine tachysystole (see Chapter 24 ). Local anesthetics probably have little direct effect on FHR, except perhaps after paracervical block. Rather, labor itself may be the single most important factor that alters FHR patterns. Transient changes in FHR variability and an increase in the incidence of periodic decelerations have been observed during neuraxial analgesia in laboring women. In contrast, in the absence of labor, FHR patterns are not affected even by the larger doses of local anesthetics required during epidural anesthesia for cesarean delivery. The FHR changes noted in laboring women were transient and did not affect the condition of the newborns. Further, Becker et al. found no significant difference in the number or type of fetal electrocardiographic ST-segment changes (ST-waveform analysis events) in women with a high-risk singleton gestation who received epidural analgesia for labor compared with a control group of women who did not receive epidural analgesia.

Many neurobehavioral tests have been developed to detect subtle changes in organized behavior in the newborn. However, these tests are not reliable because they are subjective and lack specificity. Other perinatal factors appear to have a more important effect on neonatal test performance than the choice of local anesthetic.

It has become axiomatic that the preterm infant is more vulnerable than the term infant to the effects of analgesic and anesthetic drugs. Causes of enhanced drug sensitivity in the preterm newborn that have been postulated are as follows: (1) less protein is available for drug binding, (2) higher levels of bilirubin are present and may compete with the drug for protein binding, (3) greater access of the drug to the CNS occurs because of a poorly developed blood-brain barrier, (4) the preterm infant has greater total body water and less fat content, and (5) the preterm infant has a diminished ability to metabolize and excrete drugs. Unfortunately, few systematic studies have determined the maternal and fetal pharmacokinetics and pharmacodynamics of drugs throughout gestation; nevertheless, these deficiencies of the preterm infant may not be as serious as we have been led to believe. Although the plasma albumin and AAG concentrations are lower in the preterm fetus, these factors primarily affect drugs that are highly bound to these proteins. Most local anesthetics, however, exhibit only low to moderate degrees of binding in fetal plasma.

The placenta efficiently eliminates fetal bilirubin. Thus, the hyperbilirubinemia of prematurity normally occurs in the postpartum period. Bupivacaine has been implicated as a possible cause of neonatal jaundice. High affinity of the drug for fetal erythrocyte membranes may lead to a decrease in filterability and deformability, which may render red blood cells more prone to hemolysis. However, increased bilirubin production has not been demonstrated in newborns whose mothers received bupivacaine for epidural anesthesia during labor and cesarean delivery.

Greater total body water in the preterm fetus results in a larger volume of distribution for drugs. Thus, to achieve equal blood concentrations, the immature fetus must receive a greater amount of drug transplacentally than the mature fetus.

The diminished ability to metabolize or excrete drugs associated with prematurity is certainly not a universal phenomenon. One study of the pharmacokinetics of lidocaine in preterm newborns noted that plasma clearance was similar to that in adults.

During anesthesia for preterm labor, concerns about drug effects on the newborn are far less important than the prevention of asphyxia and trauma to the fetus. Indeed, healthy preterm fetal lambs tolerated clinically relevant plasma concentrations of lidocaine (e.g., approximately 1.5 µg/mL) as well as mature lambs.

Circulatory adaptations important for fetal survival during asphyxia result in increased blood flow and oxygen delivery to vital organs (e.g., heart, brain, adrenal glands). Little information exists about the effects of local anesthetics on these fetal responses. Adaptation to asphyxia was unaffected in mature fetal lambs exposed to lidocaine. In contrast, lidocaine adversely affected asphyxiated preterm fetal lambs, which experienced a further deterioration of acid-base status and a reduction in cardiac output and blood flow to the brain and heart ( Fig. 13.6 ). Similarly, in asphyxiated preterm fetal lambs, exposure to bupivacaine reduced blood flow to vital organs; however, FHR, blood pressure, and acid-base measurements did not change.

Blood flow to the brain and heart in the preterm fetal lamb before and during asphyxia and during exposure to lidocaine while asphyxiated (mean ± SEM). *Significantly different from control. †Significantly different from asphyxia.

Modified from Morishima HO, Pedersen H, Santos AC, et al. Adverse effects of maternally administered lidocaine on the asphyxiated preterm fetal lamb. Anesthesiology . 1989;71:110–115.

After performing an in vitro study using perfused human placentas, Johnson et al. suggested that bupivacaine might be preferable to lidocaine in the presence of fetal acidosis because the greater maternal protein binding of bupivacaine may limit its placental transfer. However, this methodology does not consider the potential for greater fetal tissue uptake of bupivacaine (than of lidocaine) because it is more lipid soluble and more protein bound than lidocaine.

In 1997, Santos et al. reported that the effects of bupivacaine appeared less severe than those of lidocaine in asphyxiated preterm fetal lambs. However, the lidocaine data were generated in a separate experiment reported in 1989. There are inherent limitations in a historical comparison of two studies performed 8 years apart. Further, it is unclear whether these findings are applicable to humans because both lidocaine and bupivacaine have enjoyed a long history of safe use in obstetric anesthesia practice; prospective clinical studies are required before one drug can be recommended over the other in the setting of fetal asphyxia.