Dr Sarah Walsh, Department of Dermatology, Normanby Building, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK E-mail: firstname.lastname@example.org
Local anaesthetic (LA) has long been an indispensable aid to dermatological practice. With the development and expansion of dermatological surgery as a subspecialty within dermatology, and the increasing complexity of procedures being undertaken by clinicians, it would seem reasonable to assume that the volume of LA being used in dermatology departments has increased. Although the volumes of LA used in individual patients are likely to be small, the potential for toxicity still exists. An inadvertent intravascular injection in a highly vascular area such as the head and neck may produce toxicity; a small, light patient or one with an irritable myocardium may have a lower threshold for developing LA toxicity. As with all drugs, dermatologists are responsible for the safe use of local anaesthetic in clinical practice, a responsibility that demands a knowledge of the mechanism of action, the available preparations and the recommended dose, an awareness of the early signs of toxicity, and a theoretical knowledge of how to manage toxicity.
The first description of use of local anaesthetic (LA) for therapeutic purpose is owed to the Spanish Jesuit missionary Bernabe Cobo (1582–1657) who mentioned in his manuscript on the New World that toothache could be alleviated by chewing coca leaves. It was much later that Albert Niemann, a German chemist, isolated the active component, which he named ‘cocaine’ in 1860. Experiments then began on the application of cocaine as the first LA. Those performed by the Viennese ophthalmologist Carl Koller (1857–1944) gained the most fame. A friend of Sigmund Freud (who was himself interested in the stimulant effects of cocaine), Koller conducted a series of experiments on the cornea in dogs and guinea pigs, culminating in the painless enucleation of a dog’s eye! Following the presentation and publication of reports on the use of cocaine in animals, the first successful operation on a patient with glaucoma was carried out in 1884. Enthusiasm for this exciting development was instantaneous. However, the alarming side-effects of cocaine gradually became apparent, with 200 cases of systemic toxicity and 13 deaths attributed to cocaine use recorded between 1884 and 1891. Cocaine addiction was also noted to be a problem, as several of those involved in its development, including Freud, fell victim to it.1 Attempts to find a less potentially toxic replacement for cocaine were met with disappointment until 1943, when Nils Lofgren and Bengt Lundquist developed lidocaine. Soon, other agents emerged, including bupivacaine in 1969 and even more recently, the development of ropivicaine in the 1980s.1
Types of local anaesthetic
Local anaesthetics consist of a lipophilic aromatic group joined to a hydrophilic amine group (Fig. 1). Local anaesthetics are divided into two groups (Table 1) according to the linkage between the lipophilic and hydrophilic group within each molecule, which can be either an ester or an amide. The esters, which include cocaine, procaine and amethocaine, are primarily metabolized by hydrolysis, producing the intermediary para-amino benzoic acid (PABA), which is highly allergenic. Thus, type I allergy is much more commonly seen with ester-type LAs. Crossreactivity is also seen between different ester-type LAs, and therefore all ester LA should be avoided in a patient known to be allergic to one of this group.
Table 1. Ester and amide local anaesthetic agents: duration of action and maximum doses.
Maximum dose, mg/kg
Equates to *0.3 mL/kg when using a 1% lidocaine solution without epinephrine; †0.7 mL/kg when using a 1% lidocaine solution with epinephrine.
The amide group includes most of the LAs commonly used in dermatological practice, including lidocaine, bupivacaine and ropivacaine. The amide LAs are metabolized hepatically via the p450 enzymatic pathway. Metabolism of the LA will therefore be slowed in patients taking drugs that inhibit this enzyme pathway. Allergic reactions to the amide LAs are much more uncommon, as members of this group are more stable.
Physiology of pain and of the nervous action potential
Understanding of the mechanism of action of LA requires knowledge of the physiology of nerve transmission. The sensation of pain is relayed to the central nervous system when primary afferent nociceptors are stimulated, and impulses are propagated along the afferent fibre to the dorsal horn of the spinal cord. These fibres may be myelinated or unmyelinated, and they may be further classified according to size (Table 2). Faster-conducting myelinated A delta fibres generally result in sharp, short-lasting pain, whereas activation of unmyelinated C fibres generally results in dull, poorly localized pain.
Table 2. Types of nerve fibre.
Conduction speed, m/s
In most neurones, the resting potential has a negative value of −70 mV. The resting potential is mostly determined by the concentrations of the ions in the fluids on both sides of the cell membrane and the ion-transport proteins that are in the cell membrane. The membrane contains the enzyme Na+/K+ ATPase, which actively maintains a 30-fold K+ gradient and a 10-fold Na+ gradient. Cell membranes are freely permeable to K+ but practically impermeable to Na+. When a neurone is stimulated, there is a rise in membrane potential until a threshold is reached, at about −50 mV. At this threshold, voltage-sensitive Na+ channels open within a millisecond, and allow Na+ ions to diffuse down their concentration gradient through the open pore, until the membrane potential reaches +30 mV. At this stage, the Na+ channels close, and the membrane potential returns to its resting level as Na flow ceases and there is outward current through voltage-gated K+ channels2 (Fig. 2).
Mechanism of action of local anaesthetics
Early hypotheses suggested that LAs nonspecifically interact with the lipid bilayer of cell membranes and cause disruption of the ion channels within the membrane. This theory has been superseded by the current idea that LA agents work by directly blocking membrane-associated ion channels.3
LAs are weak bases, and exist in equilibrium in an acid (ionized) or basic (nonionized) state. Changes in pH alter the proportion of drug that is in the ionized and nonionized state. Only the nonionized fraction can pass through the cell membrane, but it is the ionized drug that is active, so changes in surrounding pH can dramatically alter the effect of LA. Taking lidocaine as an example, at physiological pH about 25% of the drug is in a nonionized (lipophilic) state and will pass through the cell membrane. Once intracellular, where the pH is more acidic (−7.1), about 86% of lidocaine is ionized and so in the active form. This fraction of ionized drug binds to two binding sites in the pore of the Na channel; in effect, blocking the transmission of sodium ions. As more sodium channels are blocked, the upstroke of the action potential is attenuated, and eventually depolarization is insufficient for action potential propagation and neuronal transmission.4
Factors influencing activity of local anaesthetics
As previously mentioned, the degree of ionization of LA is critically important to its ability to inhibit nociception. This depends on the pH of the surrounding tissues into which it is injected. Infected tissue is acidic, and results in a high degree of ionization of the injected LA, thus reducing the unionized fraction of drug available to diffuse into the neurone.
Other factors to remember are that the duration of action of LA is determined by its degree of protein binding; LAs with higher protein binding have a longer duration of action. Bupivicaine is 96% protein-bound, whereas lignocaine, which is 64% protein-bound, has a shorter duration of action. In situations where protein binding is increased, such as in pregnancy, infancy, postoperatively and renal failure, the free fraction of drug is reduced.
Reduced hepatic metabolism or impaired hepatic blood flow can also decrease the metabolism of amide anaesthetics.
Generally, at the low concentrations used in dermatology, LAs causes vasodilatation, which facilitates tissue diffusion. As vasoconstriction may be desirable when carrying out dermatological procedures for purposes of haemostasis, LA solutions are typically available with a 1 : 200 000 epinephrine solution (5 μg/mL) added.4
Methods of achieving local anaesthesia used in dermatological practice
Preparations such as EMLA™ (eutectic mixture of local anaesthetic; AstraZeneca, London, UK) and Instillagel™ (Clinimed, High Wycombe, Buckinghamshire, UK) are occasionally used in dermatological practice, particularly before the administration of infiltrative anaesthesia in a young or needle-phobic patient. Preparations are typically produced as a gel or cream vehicle containing 2.5% lidocaine and 2.5% prilocaine (EMLA) or 2% lidocaine and 0.25% chlorhexidine (Instillagel). The anaesthetic effect lasts for approximately 90 min. Contact allergy to the active ingredients or to product excipients is a possible complication, as is the rapid systemic absorption of active drug when the product is applied to broken skin, leading to toxicity.
This is the commonest method of achieving local anaesthesia in dermatological practice, and relies on the slow introduction of the LA agent into the skin. As most dermatologists use a 1% solution of lidocaine, the maximum safe dose in a 70-kg man will be 49 mL if 1 : 200 000 epinephrine is included in the solution, and 21 mL if used without epinephrine. To minimize pain, infiltration should be performed slowly with the narrowest gauge needle possible (28 or 30G), with the LA at room temperature. Injecting into the subcutis will result in less discomfort and tissue distortion than if intradermal infiltration is used, but anaesthesia will be slower in onset than with the latter method. Duration of action is usually 2–3 h. Inadvertent intravascular injection can occur with this method, leading to toxicity from either the LA itself or from any added epinephrine. Mechanical damage to nerves at or near the injection site is another possible complication, as are bleeding and infection. True allergy to LA agents is rare, and many people who report such allergy are in fact sensitive to methylparabens or to sodium metabisulfite, commonly used as a preservative agent in multiuse vials of LA solutions. Preservative-free LA agents are available in 5 or 10 mL single-use ampoules.
Digital ring blocks
This method of anaesthesia involves bathing in LA of the four digital nerves of the finger or toe to be operated on, achieving circumferential anaesthesia along the length of the digit. Although slower in onset than simple infiltrative anaesthesia at another site, the digital ring block is a highly effective technique for nail surgery and other procedures on the fingers and toes. Duration of action is 2–3 h. It has long been taught that a plain LA solution should be used for digital blocks (i.e. one without the addition of epinephrine) as the digit is supplied by end arteries that, if constricted by epinephrine, could lead to digital ischaemia. However, a recent review of the evidence for avoidance of epinephrine in digital anaesthesia suggests that the risk of ischaemia is overstated.5
Nerve blocks allow a large area to be anaesthetized with a relatively small amount of LA, and avoid the discomfort of infiltrative anaesthesia at sensitive sites such as the tip of the nose and the vermilion lip. Nerve blocks commonly used in dermatological surgery include supraorbital and supratrochlear blocks for procedures on the forehead, and mental nerve blocks for surgery on the lower lip or the chin. Infraorbital nerve blocks (IOBs) are useful for surgery on the cheek, lower eyelid, upper lip and nasal side wall. For procedures involving the nasal ala, the IOB alone will produce adequate anaesthesia in about two-thirds of patients; the addition of an anterior ethmoidal nerve block to the IOB produces anaesthesia in the remainder.6 An IOB may therefore be usefully combined with an anterior ethmoidal nerve block for procedures involving the nasal side wall, the nasal ala and the nasal tip. Median nerve blocks and posterior tibial nerve blocks have been described for the purpose of achieving anaesthesia of the palms and soles, respectively, before injection of botulinum toxin for treatment of hyperhidrosis. Nerve blocks carry the same risks of bleeding and infection as infiltrative anaesthesia, but a higher risk of nerve damage.
This is a technique in which a volume of LA (with or without epinephrine) is diluted with normal saline to achieve a larger volume of a more dilute anaesthetic solution (usually 0.05–0.1% lidocaine). Its commonest application is for dermatological procedures requiring a large area to be anaesthetized, which might ordinarily require a volume of LA at which toxicity might be a concern. A longer period of latency before onset of anaesthesia is typical, but large areas can be successfully numbed using a lower volume of the LA agent. The risk of inadvertent toxicity is lessened because the absorption kinetics of lidocaine change when high-volume, low-concentration solutions are used. Decreased concentrations of lidocaine result in slower plasma absorption with decreased peak plasma levels. Other complications of tumescent anaesthesia are similar to those seen with infiltrative anaesthesia.
Toxicity of local anaesthetics
Reported rates of systemic toxicity from LA use have decreased over the past several decades.1,6 Peripheral nerve blocks carry the highest rates of systemic toxicity, estimated to occur in 0.075–0.025% of procedures.7,8 Systemic reactions from LA use are generally due to inadvertent intravascular administration of the agents, as opposed to a gross excess of LA use.9 This is an important point to note in the dermatological setting, where procedures may not demand high volumes of LA, but may be needed at highly vascular sites.
Symptoms and signs
Local anaesthetics penetrate the blood–brain barrier rapidly, and early signs of toxicity are typically central nervous system (CNS) effects, which are firstly stimulant and then depressive in nature. They classically present in the following order: numbness and paraesthesia of the tongue/lips/mouth; metallic taste; light-headedness; tinnitus; slurred speech; muscle twitching; grand mal convulsions; and finally, respiratory arrest. If the patient then becomes apnoeic and respiratory acidosis ensues, this will increase the proportion of ionized drug, which will effectively be trapped within cells and slow clearance.4
The CNS effects described above are followed by cardiovascular effects if plasma levels continue to rise. Local anaesthetics block sodium, potassium and possibly even calcium channels in the myocardium, reducing the duration of the cardiac action potential, which results in bradycardia and hypotension.8 Obviously, epinephrine-containing solutions will cause tachycardia and hypertension. Some of the arrhythmias that may be seen include: prolonged PR interval, supraventricular tachycardia, T-wave changes, widening of the QRS, and pulseless ventricular arrhythmias. The onset of symptoms is usually rapid, occurring in < 5 min. More immediate onset suggests intravenous injection. Toxicity may present > 15 min after injection. Although CNS symptoms usually precede signs of CVS toxicity, it is important to note that patients may not volunteer that they are experiencing the classic CNS prodromal symptoms that are described above, so they should be specifically asked about these. In addition, an atypical presentation can occur with simultaneous presentation of CNS and cardiac toxicity.9,10
Guidelines for prevention
1 Carry out a careful patient preoperative assessment, including:
• Weight: for calculating maximum allowable dosage.
• Current medicines: their potential effect on the p450 enzyme pathway.
• Assessment of the anatomy of the site undergoing surgery, with particular regard to vascularity and nerve anatomy.
• Patient risk factors: pre-existing cardiac, respiratory or hepatic disease, extremes of age.
2 Have a low threshold for considering the diagnosis of LA toxicity by questioning patients about prodromal symptoms.
3 Use the lowest effective dose of LA for the procedure, combined with epinephrine if appropriate.
4 Use incremental injections (i.e. 5 mL) with regular test aspiration in highly vascular areas.
5 Monitor patients for at least 30 min after injection, as signs and symptoms may be delayed.
As many dermatology departments are not located on an acute hospital site, early recognition of the signs and symptoms of incipient LA toxicity is vital. If such features are recognized, the patient should be moved to an area where they can be appropriately monitored, and with access to anaesthetic and acute medical expertise. As with any emergency, a structured ABC (airway, breathing, circulation) approach is advocated. Airway management is of the utmost importance to prevent hypoxia and acidosis, both of which exacerbate LA toxicity and may make the patient refractory to treatment. Intravenous access and circulatory support should also be initiated, as maintaining cardiac output and tissue oxygenation will prevent and treat acidosis.11
Over the past decade the most significant advance in treatment of LA toxicity is the use of lipid emulsion (Intralipid™; Fresenius Kabi, Runcorn, Cheshire, UK). It was initially used in rodent and canine models of bupivicaine overdose. Following publication of several case reports, it is gaining widespread clinical acceptance, and is now included in guidelines for the management of LA toxicity produced by the Association of Anaesthetists of Great Britain and Ireland (AAGBI)12 and the American Society of Regional Anaesthesia (ASRA).13 The underlying mechanism of action is not fully understood, but it may act as a ‘lipid sink’ that draws the lipophilic LA from cardiac tissue, thus improving cardiac conduction and contractility.14,15 In some case reports,16,17 it has been used successfully after > 20 min of standard CPR with no subsequent evidence of myocardial damage. Lipid emulsion is recommended for use in cases where there is rapid progression of the toxidrome or where signs of cardiac toxicity are evolving.
LA is in such common use in dermatological practice that it behoves the practitioner to have a firm grounding in the pharmacology of these drugs. Although the risk of toxicity is small, the potential for harm is great. With many dermatologists working in a predominantly nonacute setting, more specialist assistance may not be immediately available from anaesthesiologists or acute physicians, hence, the need for recognition of the early signs of toxicity and the prompt institution of early management is essential.
• Dermatologists are responsible for the safe use of LA in clinical practice, a responsibility that demands a knowledge of the mechanism of action, the available preparations and the recommended dose, an awareness of the early signs of toxicity, and a theoretical knowledge of how to manage toxicity.
• The commonest cause of LA toxicity is not excessive dose but inadvertent intravascular injection of the anaesthetic solution; it follows that even in dermatological procedures where the volume of LA being used is low, the risk of toxicity is still present.
• Amide LA agents such as lidocaine and bupivicaine are less allergenic than ester LA agents such as procaine and amethicaine, because PABA, which is highly allergenic, is produced as a byproduct of ester LA metabolism.
• Many cases of reported allergy to LA can be accounted for by sensitivity to a preservative used in the solution, such as sodium metabisulfite, rather than an allergy to the anaesthetic agent itself.
• Early recognition of the signs and symptoms of LA toxicity, such as numbness and paraesthesia of the tongue/lips/mouth, metallic taste, light-headedness, tinnitus, slurred speech and muscle twitching, is imperative after administration of LA.
• The AAGBI has recommended the use of intravenous lipid emulsion in the management of LA toxicity in certain circumstances: in the case of a rapidly progressing toxidrome, seizures or cardiac arrhythmia.
The purpose of this activity is to review recent developments in local anaesthesia, and to demonstrate up-to-date knowledge in the safe use of local anaesthetic in dermatological clinical practice.
Which one of the following is true of infiltrative anaesthesia?
a) Intradermal injection causes less discomfort for the patient than subcuticular injection
b) Injection of local anaesthetic into the subcutis results in faster onset of numbness than intradermal injection
c) A large-diameter needle is preferable for drug delivery as the LA can be injected faster
d) Neuropraxia is an inevitable consequence of infiltrative local anaesthesia
e) Inadvertent intravascular injection of small amounts of local anaesthetic may produce symptoms of toxicity
What is the maximum dose of 1% lidocaine with epinephrine 1 : 200 000 that can be used when anaesthetizing the cheek of a 50-kg woman before removal of a large basal cell carcinoma?
a) 10 mL
b) 20 mL
c) 25 mL
d) 35 mL
e) 50 mL
What is the new agent recommended by the Association of Anaesthetists of Great Britain and Ireland for use in the management of local anaesthetic toxicity?
a) Diazepam intramuscularly
b) tenolol intravenously
c) Amide-binding complex intravenously
d) Lipid emulsion intravenously
e) Atropine intravenously
Which one of the following nerve blocks is useful when performing surgery of the nasal tip?
a) Supratrochlear nerve block
b) Anterior ethmoidal nerve block
c) Occipital nerve block
d) Mental nerve block
e) Supraorbital nerve block
Regarding the physiology of pain, which of the following statements is correct?
a) C fibres transmit sharp pain
b) Aδ fibres transmit dull, poorly localized pain
c) A needle introduced into the skin will stimulate nociceptors, resulting in action potentials that are conducted to the dorsal horn of the spinal cord
d) During the nerve action potential, Na+ channels in the nerve cell membrane close