Functional and Structural Components of a Peripheral Nerve

The functional nerve unit includes the nerve axon and its surrounding Schwann cell sheath. The Schwann cell (Fig. 29-1) may surround several unmyelinated axons or a single myelinated nerve fiber and form a myelin sheath. Junctions between sheaths along the axon called nodes of Ranvier contain sodium channels necessary for depolarization. As myelin sheath thickness increases from autonomic to sensory to motor fibers, the nodes of Ranvier are spaced farther apart. The most important structure affecting transmission of nerve impulses is the axon membrane (Fig. 29-2). The membrane consists of a double layer of phospholipids into which are embedded protein molecules that serve as channels containing pores for the movement of ions in and out of the cell. Most pores have a filter, or gate, that controls ion-specific movement and a sensory mechanism that opens or closes the gate. Bundles of nerve fibers (Fig. 29-3) are embedded in the endoneurium, which is made of collagen fibrils, and they are surrounded by a cellular layer, the perineurium. The perineurium functions as a diffusion barrier and maintains the composition of extracellular fluid around the nerve fibers. Surrounding the entire structure is the outer layer of a peripheral nerve, the epineurium, which is composed of areolar connective tissue.

The Nerve Impulse and Transmission

The inside of a nerve fiber, or axoplasm, is negative (−70 mV) at rest in comparison to the outside. This resting potential is the net result of the differences in ionic concentration on each side of the axonal membrane and the forces that tend to maintain that difference. Specifically, there is a surplus of sodium extracellularly and potassium intracellularly. The sodium channel is closed, thereby preventing these ions from moving along their concentration gradient (out → in). Although potassium can leave the cell to follow its concentration gradient (in → out), the need to maintain electrical neutrality inside the cell prevents it from completely doing so. Potassium is in equilibrium between the concentration gradient and the electrochemical gradient, thus creating the negative resting potential.

The sodium channel opens when a nerve is stimulated. Sodium ions enter slowly at first until a critical threshold is reached. They then enter the cell rapidly, along the electrochemical and concentration gradients, and cause depolarization. The influx of sodium is halted when the membrane potential reaches +20 mV, but potassium continues to move out of the cell and repolarizes it until the resting potential is reached. When the excitation process has been completed and the nerve cell is electrically quiet, the relative excess of sodium inside the cell and potassium outside the cell is readjusted by the adenosine triphosphate-dependent sodium-potassium pump.

Depolarization of a portion of the nerve causes a current to flow along the adjacent nerve fiber. This current makes the membrane potential less negative and actuates the sensor to open the next sodium channel. The action potential cycle is repeated, thereby propagating the impulse. Nerve conduction is essentially unidirectional because the sodium channel is not only closed but inactivated as well and delayed closure of specific potassium channels prevents the critical threshold from being reached in the segment just depolarized. An impulse spreads continuously down the axon in unmyelinated nerve fibers. In myelinated fibers, current flows from node to node and depolarizes intervening segments at once. This saltatory conduction causes a faster rate of impulse transmission in myelinated fibers.

The Active Form

Anesthetic solutions contain uncharged and charged forms. The concentration of the uncharged form increases in more alkaline milieus. Only this uncharged lipid-soluble form can cross tissue and membrane barriers. Once the uncharged drug is through a barrier, it reequilibrates into uncharged and charged forms in a proportion dependent on the prevailing pH. Because local anesthetics are more effective in alkaline solutions, it was originally thought that the uncharged form was responsible for conduction blockade. Alkaline solutions are currently believed to be more effective because of increased penetration through tissue barriers. The cationic charged form is responsible for the actual neuronal blockade.

The Physiologic and Cellular Basis for Neuronal Blockade

Prevention of sodium influx across the nerve membrane forms the physiologic basis for conduction blockade. Local anesthetics slow sodium influx, thereby decreasing the rate of rise and amplitude of depolarization. If sufficient anesthetic is present and the firing threshold is not reached, the action potential is not formed. With no action potential, no impulse is transmitted and conduction is blocked, which results in local anesthesia.

How anesthetic agents prevent sodium influx is still not completely understood. It is believed that the cationic charged form blocks the action potential from inside the membrane; the agent enters the sodium channel from the axoplasmic side and binds to a receptor.4,5 This “specific receptor” theory is well accepted and is considered the predominant mechanism in preventing influx of sodium. However, this theory cannot account for the action of benzocaine and other neutral compounds or the uncharged base forms of the common local anesthetics.

In summary (Fig. 29-4), when a local anesthetic (other than benzocaine) surrounds the perineurium, it equilibrates into its uncharged and charged forms based on tissue pH and pK_a. In a more alkaline environment, a greater proportion of the uncharged form is present. The uncharged lipid-soluble form penetrates tissue, nerve sheath, and nerve membrane to gain access to the axoplasm and reequilibrates into both charged and uncharged forms. The charged form enters the sodium channel, decreases movement of sodium into the cell, and halts nerve transmission. The uncharged base is also involved in sodium channel blockade, but the exact nature of this mechanism is unknown.

Onset of Action

The pK_a of an anesthetic is the primary physiochemical factor that determines its onset of action. Increased tissue penetration and a shortened onset of action are found in drugs with a lower pK_a because more of the lipid-soluble uncharged form is present (Tables 29-2 and 29-3). Although in isolated nerve fibers the onset of action directly parallels pK_a, other physiochemical factors also influence drug activity. For example, prilocaine and lidocaine have the same pK_a, but lidocaine’s onset is faster because of its enhanced ability to penetrate through nonnerve tissue.

The site of administration also influences the onset of action. Onset times are prolonged as the amount of interspersed tissue or the size of the nerve sheath increases because of the greater distance that the agent must travel to reach its receptor. The pattern of onset for large nerves is determined by the structural arrangement of its fibers. Peripheral (mantle) fibers are blocked before core fibers. Because mantle fibers innervate more proximal regions, nerve blockade proceeds in a proximal to distal progression.

Adding sodium bicarbonate to raise the pH of the anesthetic solution (a technique that decreases pain on injection) yields a higher concentration of the uncharged lipid-soluble form and decreases onset time. Increasing the total dose by using a higher concentration of the same volume or a greater volume of the same concentration also shortens onset time. For most procedures performed in the ED, the time of onset of most agents is short enough that manipulation to achieve shorter times is unnecessary.

Potency

The lipid solubility of an anesthetic is a primary physicochemical factor determining potency. The drug’s partition coefficient, not the concentration of the lipid-soluble form determined by the pK_a or pH, confers its lipid solubility. Because the nerve membrane is lipid, lipophilic anesthetics pass more easily into the cell and few molecules are needed to block conduction (see Tables 29-2 and 29-3).

The degree of vasodilation produced by the anesthetic also affects potency because vasodilation promotes vascular absorption, thereby reducing the amount of locally available drug. Lidocaine is more lipid soluble than prilocaine or mepivacaine, but it produces more vasodilation. Although lidocaine is twice as potent as prilocaine or mepivacaine in vitro, it is equipotent in vivo. Though not a primary reason for its use, epinephrine, by producing vasoconstriction and making more molecules available to the nerve, increases the depth of anesthesia. Drugs more readily absorbed by fat have reduced potency. Increased concentration also increases potency. Choosing an anesthetic for its potency is not usually necessary for any given site because the commercially available concentration of an agent may be manipulated to make most drugs equianesthetic. For example, lidocaine, being one fourth as potent as bupivacaine, is usually used at four times the concentration (1% to 2% versus 0.25% to 0.5%, respectively). For different sites and techniques, different concentrations and volumes of a given agent are needed to produce adequate blockade.

Duration

The degree of protein binding of an anesthetic primarily determines its duration of action. Agents that bind more tightly to the protein receptor remain in the sodium channel longer (see Tables 29-2 and 29-3). Like potency, the duration of action is reduced by the vasodilation produced by local anesthetics. Prilocaine, which is less protein bound than lidocaine, has a longer duration of action because of its lesser degree of vasodilation. The duration of action also varies with the mode of administration. It is shorter when agents are applied topically.

The duration of action may be prolonged by several methods. Increasing the dose, usually by increasing the concentration, prolongs the duration to limits imposed by toxic effects. Raising the pH of the anesthetic solution has also been shown to prolong duration.6,7 The most practical way to increase duration is to use solutions that contain epinephrine.⁸ Epinephrine causes vasoconstriction, decreases systemic absorption, and allows more drug to reach the nerve. The effect of epinephrine varies according to the agent. Anesthetics that intrinsically produce more vasodilation (e.g., procaine, lidocaine, mepivacaine) benefit more from epinephrine’s vasoconstrictive action. The long-acting, highly lipid-soluble agents (e.g., bupivacaine, etidocaine) are less affected because they are substantially taken up by extradural fat and released slowly. In fact, lidocaine with epinephrine may be effective for as long as bupivacaine without epinephrine. Generally, most ED procedures can be accomplished quickly before the anesthesia wears off regardless of which drug is selected. Choose agents with a long duration of action when the procedure is lengthy or if postoperative analgesia is desired.

Agents and Uses

Effective anesthesia of the intact mucous membranes (not intact skin) of the nose, mouth, throat, tracheobronchial tree, esophagus, and genitourinary tract may be provided by several anesthetics (Box 29-1). Tetracaine, lidocaine, and cocaine are the most effective commonly used agents (Table 29-4 and Box 29-1). Benzocaine (14% to 20%) is commonly used for intraoral or pharyngeal anesthesia (Fig. 29-5). The anesthesia produced is superficial and does not relieve pain that originates from submucosal structures. The onset of action may be slow, which limits its usefulness in urgent situations (such as passing a nasogastric tube). Agents applied topically can be absorbed systemically, and concentrated topical agents can cause toxicity.

Tetracaine solution is an effective and potent topical agent with a relatively long duration of action. It is used in concentrations from 0.25% to 1% with a recommended maximum adult dose of 50 mg. In overdose, it has the disadvantage of severe cardiovascular toxicity without any preceding central nervous system (CNS) stimulatory phase.

Lidocaine is also an effective topical agent that is marketed in a variety of forms (solutions, jellies, and ointments) and concentrations (2% to 10%). The 10% form is most effective, and minimal topical anesthesia is achieved with less potent concentrations. Lidocaine is commonly used as the 2% viscous solution prescribed for inflamed or irritated mucous membranes of the mouth and pharynx. Patient misuse of viscous lidocaine, by repeated self-administration, can lead to serious toxicity. Topical lidocaine provides an adequate duration for most procedures, with the maximum safe dose being 250 to 300 mg.

Cocaine is an effective, but potentially toxic topical agent that is applied to the mucous membranes of the upper respiratory tract. Although it is an ester, hepatic metabolism occurs, as does hydrolysis by plasma pseudocholinesterase. Absorption is enhanced in the presence of inflammation. Cocaine is the only anesthetic that produces vasoconstriction at clinically useful concentrations, hence its popularity for treating epistaxis. This major advantage is offset by its susceptibility to abuse and toxic potential. The toxic effects are due to direction stimulation of the CNS and blockade of norepinephrine reuptake in the peripheral nervous system. Cocaine should not be administered to patients who are sensitive to exogenous catecholamines or who are taking monoamine oxidase (MAO) inhibitor antidepressants. Clinical manifestations of toxicity include CNS excitement, seizures, and hyperthermia. Central and peripheral effects of hypertension, tachycardia, and ventricular arrhythmias may also be seen. Acute myocardial infarction has been reported after topical application.⁹ Cocaine is commonly used as a 4% solution with a maximum safe dose of 200 mg (2 to 3 mg/kg). A 10% solution is available, but this concentration adds little to the topical effect while enhancing the potential for toxicity. Coronary vasoconstriction may occur with doses as low as 2 mg/kg applied to the nasal mucosa. Although the clinical effect of this vasoconstriction is usually benign and without electrocardiographic changes, topical cocaine should be used cautiously in patients with known or suspected coronary artery disease. Dyclonine offers advantages over other topical anesthetic agents. It is a ketone derivative without an ester or amide linkage and may be used in patients who are allergic to the common anesthetics. Extensive experience with the topical preparation has shown it to be effective and safe.¹⁰ Dyclonine is marketed in 0.5% and 1% solutions, often in sore throat preparations, with a maximum adult recommended dose of 300 mg.

Benzocaine is an ester that is marketed in its neutral form in 14% to 20% preparations (Cetacaine, Americaine, Hurricaine) (see Fig. 29-5). Its low water solubility prevents significant penetration of the mucous membranes, thus reducing systemic toxicity if applied to intact mucosa. However, it is not a potent anesthetic and has a brief duration of action. It is more allergenic than other topical agents. Benzocaine is usually dispensed in an admixture with other therapeutic ingredients and is clinically effective only at relatively high (>14%) concentrations. Benzocaine is available as a nonprescription gel and liquid (6.3% to 20% Anbesol, for example) and is used for a variety of maladies, including ear pain, mouth pain, and teething. It is commonly used by dentists to produce mucosal anesthesia before intraoral nerve blocks (see Chapter 30). Adriani and Zepernick¹⁰ recommended this agent for lubricating catheters, airways, endotracheal tubes, and laryngoscopes and reported only one adverse reaction (methemoglobinemia) in their experience with approximately 150,000 patients. Methemoglobinemia occurs rarely after mucosal absorption of benzocaine used repeatedly for teething infants and after standard doses of benzocaine sprays used in endoscopic procedures.¹¹

An excellent topical preparation is a combination of lidocaine, prilocaine, and tetracaine, especially useful for dental mucosa anesthesia (see Fig. 30-3). Topical gel mixtures of 2.5% lidocaine and 2.5% prilocaine (eutectic mixture of local anesthetics [EMLA]) are commonly used on intact skin but have also been used on mucous membranes. EMLA is more effective than 20% benzocaine when applied to the oral mucosa before needle injection for dental anesthesia. One study demonstrated that pain was reduced more quickly with EMLA than with benzocaine when applied to the buccal mucosa.¹²

As with infiltrated anesthesia, toxic reactions to topically applied anesthetics correlate with the peak blood levels achieved and not necessarily with the dose administered. Systemic absorption of a topical agent is more rapid, with a higher level being achieved than with the same dose given by infiltration (Fig. 29-6). The total dose of a topical anesthetic should be considerably less than that used for infiltration at a given site. Fractionating the total dose into three portions administered over a period of several minutes effectively reduces peak blood levels. Inadvertent suppression of the gag reflex, combined with difficulty swallowing, may lead to aspiration, an important potential adverse reaction to topical anesthesia of the nose, mouth, and pharynx. Infections from drug solutions in multidose vials for topical anesthesia of the larynx and trachea have not been substantiated.

Technique and Precautions

A commonly used “magic mouthwash” for the topical treatment of painful gingivostomatitis in children is often prescribed by emergency clinicians and pediatricians. There has been little scientific study of the preparation and it is not available commercially, but it has been used safely for decades. It consists of equal parts viscous lidocaine (2%), Maalox as a binder, and diphenhydramine elixir. Corticosteroids or nystatin is often added when the mixture is used to treat chemotherapy-induced mucositis.¹³ However, a recent review found no evidence that magic mouthwash is effective in treating this condition.¹⁴ The creamy mixture is swished around the mouth and expectorated or painted on specific lesions with a cotton swab. Packing an area with a cotton ball soaked with this mixture is one option. Repeated doses or swallowing of the elixir can produce systemic toxicity, so careful instruction should be given to limit use of the solution to every few hours. This combination would be theoretically less toxic than simply using topical lidocaine.

Emergency clinicians often prescribe 2% viscous lidocaine (20 mg/mL) for patients with pharyngitis, stomatitis, dental pain, or other inflammatory or irritative lesions in the oropharynx. Although this intervention is widely used and generally safe, the common misconception that topical anesthesia is totally innocuous may result in poor patient instructions and serious consequences. Topical lidocaine is helpful for painful mouth lesions but is of little practical value for acute pharyngitis, for which systemic analgesics are usually a better option. Seizures and death from topical lidocaine have been reported when excessive repeated doses have been administered.15,16 Toxic blood levels may occur because the anesthetic effect of viscous lidocaine lasts for only 30 to 60 minutes and patients with recurrent pain may either ignore or be ignorant of the safe dosing interval of 3 hours and medicate themselves more frequently. Patients tend to increase each dose to obtain greater relief, and inflammation may increase systemic absorption. In addition, painful oral lesions may last for several days.

Children are at higher risk for the rare toxicity of oral lidocaine. When compared with adults, children may exhibit increased lidocaine absorption, decreased clearance, and a longer half-life.¹⁷ Continued medication use allows lidocaine and its major metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX) to accumulate. Both MEGX and GX are produced from the hepatic metabolism of lidocaine and are excreted in urine. They possess anesthetic and antiarrhythmic activity and have the potential for CNS toxicity. Although these metabolites are less potent than lidocaine, their elimination half-lives are considerably longer. Several investigators regard MEGX and GX to be the cause of CNS toxicity with prolonged topical use of lidocaine.¹⁶ The length of time that viscous lidocaine is retained in the mouth and whether the excess is expectorated or swallowed also affect the blood level produced. Expectorating the medication after swishing it in the mouth produces much lower blood levels than when it is swallowed. It seems logical that the most hazardous mode of administration would be to retain the solution in the mouth “until absorbed.”

Clearly explain the proper way to use viscous lidocaine and inform patients not to dose themselves ad libitum. Note that a 2% solution contains 20 mg/mL, or 100 mg per standard teaspoon (5 mL). The recommended maximum adult dose is 300 mg (15 mL of a 2% solution) no more frequently than every 3 hours. When possible, instruct the patient to decrease the dose by using direct cotton swab application. When gargled or swished in the mouth, limit application time to 1 to 2 minutes, and instruct the patient to expectorate excess solution. Limit use to 2 or 3 days, especially if swallowing the solution is necessary to obtain relief. Prescribe lower doses for patients at risk for decreased clearance (see “Systemic Toxic Reactions” later in this chapter). Doses for children are prescribed at 3 mg/kg. Because infants cannot expectorate well, do not use viscous lidocaine for minor oral irritation and teething. Recommend that no food be eaten for 1 hour after application because anesthesia of the oropharynx can interfere with swallowing and cause aspiration. Special note should be made of the over-the-counter availability of benzocaine, commonly used for toothaches and teething. A gel or liquid (Anbesol) is available in 6.3% to 20% formulations. When used repeatedly in the oral cavity on irritated tissue, systemic toxicity, including methemoglobinemia, may occur.

Lidocaine 4% solution can be atomized with a standard nebulizer device commonly used for delivering asthma medications and inhaled by the patient before insertion of a nasogastric tube. This method effectively anesthetizes the nasopharyngeal and oropharyngeal tissues, thereby easing the pain with tube insertion.18,19

Agents and Uses

The stratum corneum provides a cutaneous barrier that prevents the commonly marketed aqueous solutions (acid salts) from producing anesthesia, but saturated solutions of the bases of local anesthetics are effective on intact skin. When applied topically to abraded skin, most anesthetic agents result in peak blood levels similar to those resulting from infiltration in 6 to 10 minutes.

Technique

Complications

General adverse reactions to anesthetic agents are discussed in the “Complications” section later in this chapter.

Tetracaine base is quite safe, with a low blood concentration after proper use. In one study, cutaneous erythema developed at the site of application in approximately 25% of patients.²⁴ This vasodilatory effect may actually be an advantage when starting IV lines or performing venipuncture. EMLA is also quite safe. Although it has a high rate of local skin reactions, they are mild and transient, with disappearance 1 to 2 hours after removal of the cream. Despite the reported successful use of EMLA cream on skin ulcers, Hansson and associates²⁵ and Powell and coworkers³⁸ described an increase in bacterial growth, infection, and inflammation when used in experimental wounds. Methemoglobinemia resulting from the metabolites of prilocaine may occur with EMLA.²³ The risk for clinically significant methemoglobinemia seems remote when EMLA is used properly. It is contraindicated in any infant younger than 3 months and in infants between 3 and 12 months of age who are currently taking methemoglobinemia-inducing drugs (nitrites, sulfonamides, antimalarials, phenobarbital, and acetaminophen). The risk for adverse effects is increased in patients with anemia, respiratory or cardiovascular disease, and deficiencies in glucose-6-phosphate dehydrogenase or methemoglobin reductase. Prolonged inhalation of ethyl chloride spray may produce general anesthesia, coma, or cardiorespiratory arrest. Ethyl chloride is also flammable, thus precluding its use with electrocautery.

Topically applied anesthetics are often covered with an occlusive dressing to contain the medication. Covering the medication with an occlusive dressing may dramatically increase drug absorption and the amount of metabolites. Oni and associates demonstrated that 4% lidocaine cream applied to volunteers with an occlusive dressing resulted in three times the level of serum lidocaine and double the level of MEGX when the same dose was applied to volunteers without occlusion.³⁹ Use caution when occluding topical anesthetics over intact skin because markedly elevated serum level of drug may be reached.

Background

In 1980, Pryor and colleagues⁴⁰ reported their experience with a topical anesthetic solution (tetracaine-adrenaline-cocaine [TAC]) for wound repair. The original formula, used in most subsequent studies, consists of a solution of 0.5% tetracaine, 1 : 2,000 epinephrine (adrenaline), and 11.8% cocaine. Traditionally, anesthesia is produced by firmly applying a solution-saturated gauze pad or cotton ball directly to the laceration for 10 minutes. The resulting loss of cutaneous sensation is centered about the area of application. Gel formulations of topical wound anesthesia (TWA) with alternative mixtures of agents promise to improve the ease and safety of topical anesthetic solutions for wound repair in the ED. Advantages of TWA include painless application, no distortion of wound margins, good hemostasis, and good patient and parental acceptance in the pediatric age group.

Indications and Contraindications

Use of TWA is generally restricted to young children with wounds less than 5 cm in length in whom the delay in application of an anesthetic is acceptable and proper application can be ensured (Fig. 29-7). TWA containing vasoconstricting agents is not generally used in structures without a collateral blood supply (e.g., digits, tip of the nose, pinna of the ear, penis), although there is no evidence that this is unsafe. When some wound preparation is desired before anesthesia, remove large debris and clotted blood to allow the appropriate application of TWA and then finish wound preparation once the wound is properly anesthetized.

TWA appears to be less effective on the trunk and extremities than on the face and scalp and less effective than lidocaine infiltration in these areas. The 10- to 20-minute onset time may be unacceptable in a busy ED.⁴¹ Two other often mentioned drawbacks may be more theoretical than real. Vasoconstrictor-induced higher infection rates (see “Complications” later in this chapter) have not been clearly demonstrated. The argument that the necessary 10-minute application period is time-consuming and takes valuable nursing time is partially offset by using the child’s caretaker or adhesive paper tape alone to hold the solution in place. It is not necessary for anyone to “hold” the medicine in place when gel is used.

Some EDs still stock topical anesthetic gels that contain cocaine. Cocaine use is complex because of cost and federal regulations requiring storage in a locked cabinet and maintenance of separate written records of its use. In view of the evidence that mixtures without cocaine are efficacious, avoid the potential complications related to cocaine, and do not have the potential for abuse that cocaine does, the practicality of cocaine-containing TWA has been questioned.⁴²