1 What role do local anesthetics play in the practice of anesthesiology?

As local anesthetics reversibly block nerve conduction, they are used to provide regional anesthesia for surgery and postoperative analgesia for painful surgical procedures. Local anesthetics given intravenously attenuate the pressor response to tracheal intubation, decrease coughing during intubation and extubation, and are antiarrhythmic.

2 How are local anesthetics classified?

Aminoesters: Esters are local anesthetics the intermediate chain of which forms an ester link between the aromatic and amine groups. Commonly used ester local anesthetics include procaine, chloroprocaine, cocaine, and tetracaine (Figure 14-1).

Aminoamides: Amides are local anesthetics with an amide link between the aromatic and amine groups. Commonly used amide anesthetics include lidocaine, prilocaine, mepivacaine, bupivacaine, levobupivacaine, ropivacaine, and etidocaine.

Figure 14-1 Structure of esters and amides.

3 How are local anesthetics metabolized?

Esters undergo hydrolysis by pseudocholinesterases found principally in plasma. Amides undergo enzymatic biotransformation primarily in the liver. The lungs may also extract lidocaine, bupivacaine, and prilocaine from circulation. Chloroprocaine is least likely to produce sustained elevation in blood levels because of very rapid hydrolysis in the blood. Risk of toxicity to esters is increased in patients with atypical pseudocholinesterase and severe liver disease and in neonates. Liver disease or decreases in liver blood flow as may occur in patients with congestive heart failure or during general anesthesia can decrease the metabolism of aminoamides.

4 How are impulses conducted in nerve cells?

Transmission of impulses depends on the electrical gradient across the nerve membrane, which in turn depends on the movement of sodium (Na·) and potassium (K·) ions. Application of a stimulus of sufficient intensity leads to a change in membrane potential (from −90 mV to −60 mV), subsequent depolarization of the nerve, and propagation of the impulse. Depolarization is caused by inflow of Na ions from the extracellular to the intracellular space. Repolarization is caused by outflow of K· ions from the intracellular to the extracellular space. The Na-K· pump restores equilibrium in the nerve membrane after completion of the action potential.

5 What is the mechanism of action of local anesthetics?

The cascade of events (Figure 14-2) follows:

Diffusion of the unionized (base) form across the nerve sheath and membrane

Reequilibration between the base and cationic forms in the axoplasm

Binding of the cation to a receptor site inside of the Na channel, resulting in its blockade and consequent inhibition of Na conductance

Figure 14-2 Mechanism of action of local anesthetics.

6 Your patient states that he was told he is allergic to Novocain, which he received for a tooth extraction. Should you avoid using local anesthetics in this patient?

Probably not. Allergy to local anesthetics is rare despite frequent use of local anesthetics. Less than 1% of adverse reaction to local anesthetics is true allergy. Most reactions labelled as allergy are probably one of the following: vasovagal response, systemic toxicity, or systemic effects of epinephrine. True allergy would be suggested by history of rash, bronchospasm, laryngeal edema, hypotension, elevation of serum tryptase, and positive intradermal testing.

Esters produce metabolites related to p-aminobenzoic acid and are more likely to produce allergic reactions than are amide local anesthetics. Allergic reactions following use of local anesthetics may also be caused by methylparaben or other preservatives in commercial preparations of local anesthetics. There is no cross-sensitivity between classes of local anesthetics. Therefore patients known to be allergic to ester local anesthetics could receive amide local anesthetics. Caution is still warranted in case the patient is allergic to the preservative that may be common to both classes of drugs.

7 What determines local anesthetic potency?

The higher the solubility, the greater the potency (Table 14-1). This relationship is more clearly seen in isolated nerve than in clinical situations when factors such as vasodilation and tissue redistribution response to various local anesthetics influence the duration of local anesthetic effect. For example, high lipid solubility of etidocaine results in profound nerve blockade in isolated nerve. Yet, in clinical epidural use etidocaine is considerably sequestered in epidural fat, leaving a reduced amount of etidocaine available for neural blockade.

8 What factors influence the duration of action of local anesthetics?

The greater the protein binding, the longer the duration of action. The duration of action is also influenced by peripheral vascular effects of the local anesthetics. For example, lidocaine, prilocaine, and mepivacaine provide anesthesia of similar duration in an isolated nerve. However, lidocaine is a more potent vasodilator, increasing absorption and metabolism of the drug, thus resulting in a shorter clinical blockade than that produced by prilocaine or mepivacaine.

9 What determines local anesthetic onset time?

Degree of ionization: the closer the pKa of the local anesthetic is to tissue pH, the more rapid the onset time. pKa is defined as the pH at which the ionized and unionized forms exist in equal concentrations. Because all local anesthetics are weak bases, those with pKa that lies near physiologic pH (7.4) will have more molecules in the unionized, lipid-soluble form. At physiologic pH less than 50% of the drug exists in unionized form. As mentioned, the unionized form must cross the axonal membrane to initiate neural blockade. The latency of a local anesthetic can also be shortened by using a higher concentration and carbonated local anesthetic solutions to adjust the local pH.

10 How does the onset of anesthesia proceed in a peripheral nerve block?

Conduction blockade proceeds from the outermost (mantle) to the innermost (core) nerve bundles. Generally speaking, mantle fibers innervate proximal structures, and core fibers innervate distal structures. This accounts for early block of more proximal areas, and muscle weakness may appear before the sensory block if motor fibers are more peripheral.

11 What are the maximum safe doses of various local anesthetics?

See Table 14-2.

12 Which regional anesthetic blocks are associated with the greatest degree of systemic vascular absorption of local anesthetic?

Intercostal nerve block > caudal > epidural > brachial plexus > sciatic-femoral > subcutaneous. Because the intercostal nerves are surrounded by a rich vascular supply, local anesthetics injected into this area are more rapidly absorbed, thus increasing the likelihood of achieving toxic levels.

13 Why are epinephrine and phenylephrine often added to local anesthetics? What cautions are advisable regarding the use of these drugs?

These drugs cause local tissue vasoconstriction, limiting uptake of the local anesthetic into the vasculature and thus prolonging its effects and reducing its toxic potential (see Question 14). Epinephrine, usually in 1:200,000 concentration, is also a useful marker of inadvertent intravascular injection. Epinephrine is contraindicated for digital blocks or other areas with poor collateral circulation. Systemic absorption of epinephrine may also cause hypertension and cardiac dysrhythmias, and caution is advised in patients with ischemic heart disease, hypertension, preeclampsia, and other conditions in which such responses may be undesirable.

14 How does a patient become toxic from local anesthetics? What are the clinical manifestations of local anesthetic toxicity?

Systemic toxicity is caused by elevated plasma local anesthetic levels, most often a result of inadvertent intravascular injection and less frequently a result of systemic absorption of local anesthetic from the injection site. Toxicity involves the cardiovascular and central nervous systems (CNS). Because the CNS is generally more sensitive to the toxic effects of local anesthetics, it is usually affected first. The manifestations are presented below in chronologic order:

CNS toxicity

Light-headedness, tinnitus, perioral numbness, confusion

Muscle twitching, auditory and visual hallucinations

Tonic-clonic seizure, unconsciousness, respiratory arrest

Cardiotoxicity

Less common, but can be fatal

Hypertension, tachycardia

Decreased contractility and cardiac output, hypotension

Sinus bradycardia, ventricular dysrhythmias, circulatory arrest

15 Is the risk of cardiotoxicity the same with various local anesthetics?

There have been multiple case reports of cardiac arrest and electrical standstill after bupivacaine administration, many associated with difficult resuscitation. The cardiotoxicity of more potent drugs such as bupivacaine and etidocaine differs from that of lidocaine in the following manner:

The ratio of the dosage required for irreversible cardiovascular collapse and the dosage that produces CNS toxicity is much lower for bupivacaine and etidocaine than for lidocaine.

Pregnancy, acidosis, and hypoxia increase the risk of cardiotoxicity with bupivacaine.

Cardiac resuscitation is more difficult following bupivacaine-induced cardiovascular collapse. It may be related to the lipid solubility of bupivacaine, which results in slow dissociation of this drug from cardiac sodium channels (fast-in, slow-out). By contrast, recovery from less lipid-soluble lidocaine is rapid (fast-in, fast-out).

In an effort to minimize the risk of cardiac toxicity in the event of an accidental intravascular injection, the use of bupivacaine in concentrations greater than 0.5% should be avoided, especially in obstetric epidural anesthesia. For postoperative analgesia bupivacaine concentrations of 0.25% generally provide excellent effect.

16 How will you prevent and treat systemic toxicity?

Most reactions can be prevented by careful selection of dose and concentration, use of test dose with epinephrine, incremental injection with frequent aspiration, monitoring patient for signs of intravascular injection, and judicious use of benzodiazepine to raise the seizure threshold.

Seizures can quickly lead to hypoxia and acidosis, and acidosis worsens the toxic effects. A patent airway and adequate ventilation with 100% oxygen should be ensured.

If seizures develop, small doses of intravenous diazepam (0.1 mg/kg) or thiopental (1 to 2 mg/kg) may terminate the seizure. Short-acting muscle relaxants may be indicated for ongoing muscle activity or to facilitate intubation if necessary.

Cardiovascular collapse with refractory ventricular fibrillation following local anesthetics, particularly bupivacaine, can be extremely difficult to resuscitate. Treatment includes sustained cardiopulmonary resuscitation, repeated cardioversion, high doses of epinephrine, and use of bretylium to treat ventricular dysrhythmias. Intravenous intralipid has been used successfully in cases in which conventional resuscitation measures were unsuccessful. Suggested dose is initial bolus of 1.5 ml/kg of 20% intralipid solution, which can be repeated every 3 to 5 minutes up to a total maximum dose of 8 ml/kg.

17 What is the risk of neurotoxicity with local anesthetics?

The overall risk of permanent neurologic injury from regional anesthesia is extremely small. However, in recent years the following two complications have been described after spinal and epidural anesthesia:

Transient neurologic symptoms manifest in the form of moderate-to-severe pain in the lower back, buttocks, and posterior thighs. These symptoms appear within 24 hours of spinal anesthesia and generally resolve within 7 days. The delayed onset may reflect an inflammatory etiology for these symptoms. They are seen most commonly with lidocaine spinal anesthesia and are rare with bupivacaine. Patients having surgery in the lithotomy position appear to be at increased risk of neurologic symptoms following either spinal or epidural anesthesia.

Cauda equina syndrome: A few cases of diffuse injury to the lumbosacral plexus were initially reported in patients receiving continuous spinal anesthesia with 5% lidocaine dosed via microcatheters. The mechanism of neural injury is thought to be that nonhomogeneous distribution of spinally injected local anesthetic may expose sacral nerve roots to a high concentration of local anesthetic with consequent toxicity. Rare cases in the absence of microcatheters have also been described. Avoid injecting large amounts of local anesthetic in the subarachnoid space, especially if less than an anticipated response is obtained with the initial dose.

18 Which local anesthetic is associated with the risk of methemoglobinemia?

Prilocaine and benzocaine are the two local anesthetics responsible for most cases of local anesthetic–related methemoglobinemia, although in rare instances other agents have been implicated. Prilocaine is metabolized in the liver to O-toluidine, which is capable of oxidizing hemoglobin to methemoglobin. Prilocaine in a dose greater than 600 mg can produce clinical methemoglobinemia, making the patient appear cyanotic. Benzocaine, used as a spray for topical anesthesia of mouth and throat, can result in methemoglobinemia if excessive amounts are used in the form of multiple sprays or spraying the area for a longer duration than recommended. Methemoglobin is reduced through methemoglobin reductase, and this process is accelerated by intravenous methylene blue (1 to 2 mg/kg).

19 Describe the role of lipid infusion in the treatment of local anesthetic toxicity

Systemic local anesthetic toxicity is rare but can be fatal because of relative resistance of local anesthetic–induced cardiac arrest to standard resuscitative measures. Cardiotoxicity from bupivacaine has almost always been fatal, often requiring placement of the patient on cardiopulmonary bypass while the drug slowly clears from the cardiac muscle tissue. Animal studies demonstrated that lipid infusion increases resistance to local anesthetic toxicity and improves success of resuscitation from local anesthetic overdose. In the past few years there have been several case reports of successful use of lipid emulsion in treatment of local anesthetic toxicity in humans. The mechanism of beneficial effect is thought to be a reduction in tissue binding of local anesthetic and a beneficial energetic-metabolic effect. The protocol for intralipid administration is as follows:

Initially administer intralipid 20% at a dose of 1.5 ml/kg over 1 minute.

Follow immediately with an infusion at a rate of 0.25 ml/kg/minute.

Continue chest compressions (lipid must circulate).

Repeat bolus every 3 to 5 minutes up to 3 ml/kg total dosage until circulation is restored.

Continue infusion until hemodynamic stability is restored.

Increase the rate to 0.5 ml/kg/min if blood pressure declines.

A maximum total dose of 8 ml/kg is recommended.

20 What are some of the newer local anesthetics and what are their potential applications?

Ropivacaine is a new amide local anesthetic that is structurally and behaviorally similar to bupivacaine. Like bupivacaine, it is highly protein bound and has a long duration of action. When compared to bupivacaine, it is less cardiotoxic and produces less motor block, thus allowing analgesia with less motor compromise (differential blockade). However, some of these benefits may be related to somewhat lower potency of ropivacaine and may not exist when equipotent doses are compared. Levobupivacaine is an S(−) isomer of the racemic bupivacaine and has a safer cardiac and CNS toxicity profile compared to bupivacaine. Local anesthetic effects are similar to those of bupivacaine. Because of their superior toxicity profile, both ropivacaine and levobupivacaine are suitable for situations requiring relatively large doses of local anesthetics.