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LIPOSUCTION TEXTBOOK
The Tumescent Technique By Jeffrey A. Klein MD

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LIPOSUCTION TEXTBOOK

Chapter 22:
Bupivacaine, Prilocaine, and Ropivacaine

Lidocaine’s greater safety and prolonged duration of anesthesia make it the local anesthetic of choice for tumescent liposuction and dermatologic surgery. Because tumescent delivery of lidocaine can provide more than 10 hours of good surgical anesthesia, no justification exists for using longer-acting but more toxic local anesthetics such as bupivacaine.1

This chapter discusses the actions and effects of bupivacaine, prilocaine, and ropivacaine compared with lidocaine in local anesthetic solutions used for tumescent technique (Figure 22-1).

Bupivacaine

Some liposuction surgeons advocate general anesthesia with subcutaneous infiltration of dilute epinephrine and without local anesthesia during surgery, then the injection of bupivacaine for analgesia after surgery. This approach seems less than optimal for the following two reasons:

  1. No controlled comparisons have demonstrated improved analgesia with postliposuction infiltration of local anesthesia.
  2. Evidence indicates that preincisional infiltration of a surgical wound with a local anesthetic is a more effective method of providing postoperative analgesia than postincisional infiltration.2

Without the vasoconstrictive effects of epinephrine, the local anesthetic action of bupivacaine is longer than lidocaine. With epinephrine in the anesthetic solution, however, the effects of bupivacaine last only 27% longer than lidocaine.3 For tumescent liposuction, no clinically significant difference exists between local anesthesia that lasts 10 hours or one that lasts 12.7 hours. Lidocaine, however, is significantly less toxic than bupivacaine.

Myocardial Depression

Bupivacaine directly depresses the myocardium, lowering both inotropy (contractility) and chronotropy (heart rate). This in turn decreases cardiac output4 and coronary artery blood flow without producing vasoconstriction. Other factors that impair myocardial function and augment bupivacaine cardiotoxicity include hypoxia, hypercarbia, acidosis, β-adrenergic blockers, and digitalis.5 Bupivacaine is toxic to muscle after direct injection, causing myonecrosis and rhabdomyolysis.6

Mechanisms of Local Anesthesia. Local anesthetics reversibly bind sodium (Na) channels, impair the sodium-potassium (Na-K) pump, and thus block neural impulse conduction. Besides binding to Na channels, local anesthetics also interact with β2-adrenergic receptors. By inhibiting the binding of ligands to β2-adrenergic receptors, local anesthetics inhibit intracellular cyclic adenosine monophosphate (cAMP) production. The avidity of binding to β2-adrenergic receptors of different local anesthetics increases with length of the alkyl chain. The correlation between increased inhibition of β2-adrenergic receptors and alkyl chain length resembles the correlation between local anesthetic potency for nerve blocks and increased alkyl chain length.7

Thus a relationship exists among increasing molecular size, increasing receptor avidity, increasing anesthetic potency, and increasing cardiovascular toxicity. This relationship could explain the greater cardiovascular toxicity of bupivacaine in terms of its relatively potent inhibition of β2-adrenergic receptors and inhibition of cAMP production.

Blood Pressure. Arterial blood pressure may be a misleading indicator of cardiovascular status during bupivacaine overdose. With acute bupivacaine toxicity an increase in vascular resistance apparently maintains blood pressure but masks severe myocardial depression.8

Cardiotoxicity

Liposuction. Bupivacaine is unnecessarily dangerous and therefore contraindicated for tumescent liposuction. Bupivacaine cardiac toxicity is subtle and occurs without premonitory convulsions. Fatal cardiotoxic arrhythmias (dysrhythmias) precede convulsions; in cats, for example, cardiac dysrhythmias occur at only 60% of the convulsant bupivacaine dose.9 Lidocaine, however, usually gives warning signs of central nervous system (CNS) toxicity (e.g., seizures) before onset of dangerous cardiotoxic events.

The cardiotoxicity of bupivacaine is often unresponsive to resuscitation efforts.10,11 In cats, successful resuscitation is less likely with bupivacaine than with lidocaine.12

Epinephrine. When cardiovascular collapse occurs with bupivacaine, an attempt to resuscitate the patient using epinephrine only worsens the situation. Bupivacaine-induced cardiac collapse therefore presents a therapeutic dilemma.

On the one hand, the American Heart Association recommends epinephrine as the drug of choice for patient resuscitation after sudden onset of ventricular fibrillation. On the other hand, adrenergic agents (e.g., epinephrine) increase the lethality of bupivacaine.13,14 The tachycardia associated with epinephrine escalates bupivacaine toxicity by increasing myocardial oxygen demand and augmenting the reentry phenomenon.15

Bupivacaine demonstrates a use-dependent toxicity in which tachycardia increases cardiac toxicity. This phenomenon occurs because charged cationic bupivacaine molecules more easily enter myocardial cells when the transmembrane Na channels are open, which occurs with each myocyte’s membrane depolarization-contraction cycle. With a pKa of 8.10, most bupivacaine molecules are charged cations at physiologic pH and are less likely to diffuse across the lipid cellular membrane. The respiratory acidosis associated with cardiac arrest only exacerbates this situation.

Lidocaine Comparisons. Long-acting amide local anesthetics such as bupivacaine have a much greater potential for serious cardiac toxicity than lidocaine.4,16,17 Atrioventricular (AV) heart block and ventricular dysrhythmias are more often associated with bupivacaine than with lidocaine.18-21

The dosage (mg/kg) of lidocaine that produces experimental cardiac toxicity (dysrhythmias) must be 16 times greater than the dosage (mg/kg) of bupivacaine that produces the same degree of cardiotoxicity. Thus bupivacaine is 16 times more cardiotoxic than lidocaine, and the ratio for cardiac dysrhythmia with toxicity between bupivacaine and lidocaine is 16:1.18 The bupivacaine/lidocaine ratio for anesthetic potency is 4:1.

When intravenous (IV) lidocaine (16 mg/kg) was compared with equipotent IV bupivacaine (4 mg/kg), lidocaine produced hemodynamic depression, whereas bupivacaine impaired both electrophysiologic and hemodynamic variables. In anesthetized dogs the lidocaine/bupivacaine ratio of dosages required to produce depressed myocardial contractility was 4.9:1.22

In another study, bupivacaine depressed cardiac conduction 70 times more than lidocaine, whereas local anesthetic potency of bupivacaine was only four times that of lidocaine.23

In a dog study, lidocaine induced only slight electrophysiologic effects, as manifested by bradycardia, whereas bupivacaine increased all electrophysiologic variables measured. Bupivacaine facilitated reentrant dysrhythmias and ventricular tachycardia by dramatically slowing ventricular conduction velocity.24

All local anesthetics can produce cardiac toxicity with hypotension, AV heart block, ventricular dysrhythmias, and cardiovascular collapse, as well as CNS toxicity. The dose that produces cardiovascular collapse, versus the dose causing CNS toxicity, is lower for bupivacaine and etidocaine than for lidocaine.25 Ventricular dysrhythmias are common with bupivacaine toxicity but rare with lidocaine.4,16,17

When given in doses that cause equivalent CNS toxicity in sheep, bupivacaine produces more serious cardiac toxicity than lidocaine.26

Bupivacaine cardiac toxicity is not simply a direct effect on the heart. Evidence indicates that cardiac depression is at least partially mediated by bupivacaine’s effect on the CNS.27,28

Anesthetic Mixtures

The toxicity of a combination of two amide-type local anesthetics is additive and not independent. In rats the lethal cardiorespiratory toxicity of lidocaine and bupivacaine is additively toxic by both intravenous infusion29 and subcutaneous infiltration.30 Similarly, the CNS toxicity of local anesthetics is additive.31 Bupivacaine and lidocaine lower the seizure threshold in an additive fashion. After administration of the maximum safe dose of one amide-type local anesthetic, it is not safe to administer more of another local anesthetic.

A mixture of different local anesthetics is occasionally indicated for peripheral nerve blocks to achieve rapid onset of action, as provided by lidocaine, and prolonged duration of action, as provided by bupivacaine.32,33 With tumescent liposuction the local anesthetic effect of lidocaine is sufficiently long, and the addition of bupivacaine is never indicated.

Milligram for milligram, IV bupivacaine is four times more toxic than IV lidocaine, whereas subcutaneous bupivacaine is only twice as toxic as subcutaneous lidocaine.34,35 This does not mean, however, that a subcutaneous mixture of bupivacaine and lidocaine is safe for cosmetic surgery.36

Because the toxic effects of local anesthetics are additive, lidocaine should not be used to treat a bupivacaine-induced cardiac dysrhythmia.

Solubility. Amide local anesthetics are sold commercially in acidic solutions. Lidocaine and bupivacaine are weak bases and therefore more soluble at an acidic pH.

A local anesthetic solution of lidocaine is less painful on cutaneous or subcutaneous infiltration when it has been neutralized to pH near 7.0 by the addition of sodium bicarbonate to the solution. For example, pain is significantly less on infiltration of dilute lidocaine with epinephrine if 10 mEq of bicarbonate is added to each liter of tumescent anesthetic solution. Alkalinization of a local anesthetic solution speeds the onset of anesthesia and enhances the effectiveness of a nerve block.

One of the reasons that bupivacaine without epinephrine has a longer duration of action than lidocaine is that bupivacaine has a greater lipid solubility and is less aqueous than lidocaine. As a result of its decreased solubility in water, bupivacaine depends more on an acid pH for water solubility, and bupivacaine will precipitate more readily than lidocaine when the pH of the solution is increased.

The addition of bicarbonate to an aqueous solution of bupivacaine is dangerous because it can readily cause bupivacaine to precipitate. The intradermal or subcutaneous injection of precipitated bupivacaine can cause tissue necrosis.

Prilocaine

Some European surgeons have considered using prilocaine instead of lidocaine in a tumescent local anesthetic solution. The only published information on tumescent prilocaine (35 mg/kg) involved a study in which the plasma concentration of prilocaine was measured in only four liposuction patients; the average peak plasma concentration was 0.91 μg/ml (range 0.44 to 1.27 μg/ml).37 Without clearly specifying the plasma concentration threshold for prilocaine toxicity and without controls using lidocaine, the authors concluded that prilocaine is safer than lidocaine.

Lidocaine and Toxicity

Prilocaine is similar to lidocaine in that both are amide-type local anesthetics, and they have approximately equal potency,7 onset of anesthetic action,40 and duration of action. They also have equal neurologic and cardiovascular toxicity.38,39

Prilocaine is cleared more quickly than lidocaine, however, because of its fast rate of tissue redistribution and its rapid hepatic metabolism.40 Prilocaine metabolism by hepatic and renal amidases yields o-toluidine and N-propylalanine. Prilocaine is not metabolized by plasma esterases. Although the more rapid clearance of prilocaine may suggest that it might be safer than lidocaine, the metabolites of prilocaine are much more toxic than those of lidocaine. One of the prilocaine metabolites, o-toluidine, has been shown to be carcinogenic in mice and rats and also causes methemoglobinemia. When a metabolite of a drug is toxic, the rapid production of that metabolite may not be desirable.

Safety Factors. To compare the safety of two local anesthetics in the setting of tumescent lidocaine, one needs the following information on each drug:

  1. Plasma concentration thresholds for toxicity. Although this information is available for lidocaine, I know of no published data on the toxicity threshold for plasma prilocaine.
  2. Peak plasma concentrations of each drug after tumescent infiltration without and with subsequent liposuction.
  3. Plasma concentration versus time profile of all potentially toxic metabolites of each drug after tumescent infiltration. The toxicity of the prilocaine metabolite o-toluidine may be a function of total hours of exposure as well as its peak plasma concentration.
  4. Drug metabolism and potential drug interactions. Prilocaine might prove to be exceedingly toxic in certain clinical situations that increase the toxic effects of o-toluidine. Thus prilocaine may be safe in healthy patients but more dangerous in patients with renal impairment.

The assertion that prilocaine is safer than lidocaine simply because prilocaine is metabolized faster than lidocaine is overly simplistic. Rapid clearance might be a positive safety feature when prilocaine is given at relatively low total doses over a short period. When a huge dose of prilocaine is absorbed over an extended time, however, its rapid clearance may produce prolonged exposure to a toxic metabolite. Although prilocaine has a faster total body clearance rate (ClT) than lidocaine (2.03 versus 0.85 L/kg/hr), it also has a larger volume of distribution at steady state (Vdss) (2.73 versus 1.30 L/kg). Thus a greater volume of prilocaine must be cleared compared with lidocaine. The volume of distribution at steady state Vdss is related to ClT by the following equation:

ClT = k(Vdss)

where k is ln 2/t1/2, and t1/2 is plasma half-life. Lidocaine and prilocaine have the same serum half-life of 1.6 hours.41

Animal Data. Because a drug’s median lethal dose (LD50) varies between species, comparison of the LD50 of prilocaine and lidocaine cannot be directly applied to human clinical situations. Furthermore, because of variation among different statistical estimates of LD50, the results of any one study cannot be regarded as conclusive.

For example, one estimate of the LD50 of subcutaneous prilocaine in female mice is 550 mg/kg (range 359 to 905 mg/kg).42 Another estimate is 820 mg/kg, which is 50% greater than 550 mg/kg.43 Clearly, with such wide variation, physicians must be cautious when using such data to guide clinical decision making about a particular drug’s safety.

Large Doses. With no pharmacologic studies of large subcutaneous doses of prilocaine, virtually nothing is known about the clinical toxicity of tumescent prilocaine. I believe, however, that prilocaine and its metabolites are more dangerous than lidocaine and its metabolites.

In the United States, prilocaine does not have Food and Drug Administration (FDA) approval to be marketed as an injectable local anesthetic for dermatologic surgical procedures. It is only available as an injectable dental anesthetic in 1.8-ml “dental cartridges” containing 4% prilocaine and as a component of topical EMLA cream.

The pharmacologic literature does not fully describe the risks of using large doses of subcutaneous prilocaine. Thus any preference for using prilocaine with the tumescent technique is based on conjecture rather than a detailed knowledge of the full range of prilocaine toxicity.

When evaluating the manufacturer’s assertion that prilocaine is safer than lidocaine, the physician must be aware of potential financial conflicts of interest. In contrast to lidocaine, no generic equivalents are available for prilocaine. Thus, despite the absence of comparative safety data, a manufacturer might have a financial incentive to promote a drug such as prilocaine over lidocaine.

Methemoglobinemia

Methemoglobinemia is a condition similar to carbon monoxide poisoning in which hemoglobin is not capable of binding oxygen. Specifically, the ability of blood to transport oxygen is impaired when oxyhemoglobin (the ferrous form) is oxidized to methemoglobin (the ferric form) by a large dose of prilocaine.44

The prilocaine metabolite o-toluidine causes oxidation of hemoglobin and can produce methemoglobinemia after systemic doses in excess of 600 mg, or dosages of 7 mg/kg.45 Patients may show signs of dyspnea and cyanosis and may complain of headache. Pulse oximetry readings are inaccurate and overestimate the true arterial oxygen saturation. The diagnosis of methemoglobinemia is confirmed by laboratory analysis, with 5 ml of blood collected in a tube containing ethylenediaminetetraacetic acid (EDTA).

Patients who are especially susceptible to developing methemoglobinemia include very young children, patients with glucose-6-phosphatase deficiency, and those taking drugs associated with drug-induced methemoglobinemia, such as acetaminophen, antimalarials, sulfonamides, dapsone, nitrites, nitrofurantoin, phenobarbital, phenytoin, and quinine.

Systemic Anesthesia. The risk of prilocaine-associated methemoglobinemia may be increased by concomitant administration of systemic anesthesia.46 No prospective studies have investigated the possible drug interaction between systemic anesthesia and prilocaine. Using tumescent prilocaine with systemic anesthesia, however, may increase the plasma concentration of o-toluidine, thus inducing methemoglobinemia. In two patients, when local anesthesia with prilocaine was supplemented by systemic anesthesia (thiopental, alfentanil, and atracurium), methemoglobin levels increased by 70% and 25% compared with levels before the systemic anesthesia.46

Pregnancy. A liposuction patient may not know that she is pregnant, as occurred with one of my patients. One week after tumescent liposuction with lidocaine, she realized that she was approximately 4 weeks’ pregnant. The fetus was healthy at birth and was not affected by exposure to lidocaine.

Prilocaine may cause fetal methemoglobinemia and should not be used in a woman who might be pregnant. Whereas toxicity studies in fetal lambs have shown lidocaine to be safe during pregnancy, the same cannot be said for prilocaine or many of the drugs used for general anesthesia.

The effects of fetal methemoglobinemia are not well described. Also, the rate of o-toluidine clearance in the fetus and the affinity of fetal hemoglobin for o-toluidine are not known. Fetal glucose-6-phosphatase deficiency predisposes the fetus to prilocaine toxicity because of methemoglobinemia.

Methemoglobinemia has been reported in a genetically normal newborn after delivery under pudendal anesthesia with prilocaine.47,48 Maternal/fetal total concentration ratio for lidocaine is 0.5 and for prilocaine is 1.0.49 Since the amide-type local anesthetics are weak bases, fetal acidosis will increase the maternal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects.

Treatment. When a patient who has been given prilocaine becomes dyspneic, first-line treatment of methemoglobinemia is oxygen. Definitive treatment requires a slow IV infusion of methylene blue (1% solution) at 1 to 4 mg/kg over 5 minutes. Extravasation of methylene blue into the subcutaneous tissue can cause tissue necrosis.

Postoperative dyspnea cannot simply be treated with methylene blue. The surgeon must also consider pulmonary edema or pulmonary embolus in the differential diagnosis of acute dyspnea in the immediate postoperative period. Any unnecessary drug that can cause dyspnea in surgical patients should be avoided.

The treatment of choice for pulmonary edema is furosemide (Lasix), a sulfonamide derivative, but sulfonamide-related drugs are contraindicated with methemoglobinemia. Thus, if a patient develops pulmonary edema after liposuction with prilocaine, the use of furosemide may precipitate methemoglobinemia, decrease oxygenation, and worsen cardiopulmonary function.

Tumescent Doses. The tumescent delivery of large doses of prilocaine might increase the risk of methemoglobinemia. Methemoglobinemia caused by prilocaine is a function of total dose, not rate of systemic absorption. The tumescent delivery of lidocaine or prilocaine slows the rate of systemic absorption and reduces the risk of cardiovascular toxicity associated with amide-type local anesthetics. To the extent that tumescent liposuction might use a total dose of prilocaine that is greater than 600 mg, the tumescent technique might be associated with an increased risk of methemoglobinemia.

Prilocaine Versus Lidocaine

Based on the extensive clinical experience and pharmacologic data available on lidocaine and the relative paucity of information about the pharmacokinetics of prilocaine and o-toluidine, I believe that lidocaine is safer than prilocaine for tumescent liposuction.

Ropivacaine

Ropivacaine is a new, long-acting, amide-type local anesthetic and the first local anesthetic on the market as a single isomer.50 Ropivacaine is the S(-) propyl homolog of bupivacaine and mepivacaine. Human and animal studies show that ropivacaine resembles bupivacaine, with a similar pharmacodynamic and pharmacokinetic profile. Ropivacaine has a pKa of 8.07 and a protein binding of approximately 94%. Lipid solubility of ropivacaine, however, is lower than that of bupivacaine.

Bupivacaine and Toxicity

Extensive animal toxicologic studies have shown a lower propensity for cardiotoxicity with ropivacaine than with bupivacaine. In comparative human studies, ropivacaine and bupivacaine appear to be associated with a similar incidence of comparable adverse effects, except that the incidence of cardiovascular and CNS toxicities is lower with ropivacaine. The adverse effects associated with epidural administration of ropivacaine include hypotension, nausea, bradycardia, transient paresthesia, back pain, urinary retention, and fever.51

At equal mg/kg dosages, ropivacaine appears to be safer than bupivacaine. At equipotent doses, however, the two drugs appear to have similar degrees of toxicity. At equal mg/kg dosages, ropivacaine has been shown to be less potent and less toxic. For example, ropivacaine was significantly less potent than bupivacaine for epidural analgesia in the first stage of labor.52

Pregnancy. Subcutaneous bupivacaine and ropivacaine were given to pregnant rats, with the mg/kg dosages in the same range as proposed for humans: bupivacaine, 5.5 to 24 mg/kg; ropivacaine, 5.3 to 26 mg/kg.53 Deaths from clonic convulsions were occasionally seen in rats receiving 14 mg/kg or more of bupivacaine. The results suggest an increased safety margin before onset of toxic side effects after treatment with ropivacaine compared with bupivacaine.

Studies of pregnant women in labor have shown that ropivacaine and bupivacaine appear to be equally effective in producing epidural sensory block, but motor block seems to be less pronounced with ropivacaine. Equal doses (20 to 30 ml) of ropivacaine 0.5% and bupivacaine 0.5% in epidural anesthesia for cesarean section were equally effective.54 No adverse side effects and no differences in efficacy were reported with ropivacaine 0.25% or bupivacaine 0.25% when administered epidurally for relief of labor pain.55

Central Nervous System. Acute tolerance of IV infusion (10 mg/min to a maximum dose of 150 to 250 mg) of ropivacaine and bupivacaine was studied in a crossover, randomized, double-blind study in 12 volunteers previously acquainted with the CNS effects of lidocaine. At equal doses the maximum tolerated dose for CNS symptoms was higher with ropivacaine in nine subjects and higher with bupivacaine in three subjects.56

Ropivacaine has caused convulsions in humans. After epidural injection, ropivacaine has been reported to cause neurologic toxicity (convulsions), with minimal signs of cardiovascular toxicity.57,58

Equipotent Dosages. Ropivacaine is half as potent as bupivacaine. In equipotent doses ropivacaine has a higher incidence of side effects than bupivacaine. Low-dose hyperbaric spinal ropivacaine does not appear to offer an advantage over bupivacaine for use in outpatient anesthesia.59

Ropivacaine 0.5% produces sensory and motor blockade that is similar to that resulting from equal concentrations of bupivacaine after epidural administration in sheep. Peak serum concentrations occurred within 8 minutes after administration, without signs of systemic toxicity. The terminal elimination half-life in serum for ropivacaine was 3½ to 4 hours and for bupivacaine 6 hours.60

Vasoconstriction

Ropivacaine has been found to be somewhat vasoconstrictive, unlike other local anesthetics in its class, such as bupivacaine. A statistically significant difference, however, does not necessarily imply a clinically significant difference in vasoconstrictive effects. At least one study has shown that the ropivacaine vasoconstriction is insufficient for reduction mammoplasty, a procedure in which considerable blood loss may occur.61

Before breast reduction, each breast of five female patients was infiltrated with 60 ml of 0.9% saline containing either ropivacaine (75 mg) without epinephrine or bupivacaine (75 mg) with epinephrine (0.3 mg) by random allocation. Ropivacaine was associated with much greater intraoperative blood loss than bupivacaine with epinephrine. Vasoconstrictive properties of ropivacaine are not sufficiently great to merit its use as a sole agent for infiltration before reduction mammoplasty.61

Ropivacaine Versus Lidocaine and Bupivacaine

When given in equal dosages, lidocaine and ropivacaine are both less potent and less toxic than bupivacaine in animals and humans. Again, ropivacaine is less potent and less toxic than bupivacaine at equal mg/kg dosages, but there is no apparent difference in toxicity at equipotent dosages. Insufficient data are available to allow a reasonable comparison between ropivacaine and lidocaine in terms of safety and efficacy. Lidocaine is less toxic than bupivacaine or ropivacaine, however, and thus remains the drug of choice for tumescent anesthesia.62

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Figure 22-1 Bupivacaine, prilocaine, and ropivacaine compared with two other amide-linked local anesthetics, lidocaine and mepivacaine.

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