Flexible bronchoscopy is usually performed using topical lidocaine to anesthetize the upper airway and tracheobronchial tree. Those rare occasions, however, when patients present with a history of lidocaine allergy may prompt a decision-making dilemma for the bronchoscopist. The purpose of this article, therefore, is to (1) describe the diverse properties of local and topical anesthetics of the amide and ester groups, (2) identify indications for various forms of lidocaine preparations available for use in flexible bronchoscopy, (3) review existing literature for documented cases of true allergic reactions to lidocaine, and (4) to discuss a practical decision-making approach that assures patient safety in the context of suspected or known lidocaine allergy.
TOPICAL AND LOCAL ANESTHETICS
Topical and local anesthetics are classified into 2 groups, the amides and the esters. These anesthetics are comprised of an ionizable hydrophilic group, a lipophilic aromatic group, and a joining intermediate group. It is this intermediate group that separates local anesthetics into group 1 (esters) or group 2 (amides) agents. Examples of esters are tetracaine, benzocaine, and procaine. Examples of amides are lidocaine, prilocaine, mepivacaine, and bupivacaine (notice that each of the amides are spelled using the letter “i” twice). When applied topically or locally, these anesthetic agents inhibit the transfer of sensory signals from the periphery to the central nervous system by inhibiting sodium channels in the nerve membrane. Unmyelinated nerve fibers carrying autonomic, pain, and temperature impulses are most sensitive to the actions of local and topical anesthetics. The widespread use of these agents is primarily owing to their ability to provide satisfactory desensitization to a limited area without inducing unconsciousness.
When selecting a topical anesthetic, attention should be paid to 3 criteria. The first is that the agent should provide adequate anesthesia, the second is that its administration should be safe for the patient, and the third is that the mode of administration should be simple for the patient and the physician.1 The most commonly used topical anesthetics are lidocaine, cocaine, and tetracaine.2,3
LIDOCAINE'S PROPERTIES, ADVERSE EFFECTS, INDICATIONS, AND TECHNIQUES OF ADMINISTRATION
Lidocaine is the most commonly used topical anesthetic agent in flexible bronchoscopy, although bronchoscopists have also used cocaine to vasoconstrict the nasal passages and bupivicaine to anesthetize the upper airway. It comes in various preparations including creams, gels, infusion, injection solutions, jelly, liquid, lotion, and spray. Lidocaine can be found in 1%, 2%, and 4% solutions. Lidocaine dosage can be easily calculated from knowing the percentage of lidocaine used, which is on the label of most bottles. For example, a 1% bottle of lidocaine contains 1 g/100 mL or 1000 mg/100 mL. This can be further reduced to a dosage of 10 mg/mL. Therefore, a 30 mL bottle of 1% lidocaine contains 300 mg of lidocaine.
The majority of lidocaine-related adverse effects involve the central nervous system,4,5 the cardiovascular system, and the gastrointestinal tract. With the exception of the gastrointestinal system, these side effects are primarily dose related. Neurologic side effects include seizures, tremors, dysarthria, ataxia, hallucinations, nystagmus, and memory impairment. Cardiac side effects are sinus slowing, asystole, hypotension, and shock. Gastrointestinal side effects include nausea, vomiting, and anorexia. The maximum duration of lidocaine's anesthetic effect, regardless of the mode of administration, is between 20 and 30 minutes. In regards to specific organ systems, no dosage modification is needed in case of renal impairment, although the elimination of glycinexylidide (a metabolite of lidocaine) is dependent on renal function. This metabolite can accumulate in patients with renal insufficiency and result in central nervous system toxicity.6 The presence of liver disease, on the other hand, requires lower infusion rates because of decreased hepatic clearance, but does not require a change in loading dose.7 Intratracheal lidocaine doses of 2.4 to 7.7 mg/kg have resulted in peak serum levels in the toxic range in some patients. In 1 study, therapeutic serum levels were attained in approximately 5 minutes using these doses and therapeutic levels were maintained for 30 to 60 minutes.8 Furthermore, blood levels are dependent on the location of application within the airways with lower concentrations achieved in the upper airways and higher in the lower airways. This is believed to occur because of the smaller surface area and reduced vascularization of the upper airways compared with the lower.9
Regardless of the route of administration, monitoring should include electrocardiogram, lidocaine plasma concentration (usually obtained only as part of specific research protocols), and mental status examination to identify seizure activity because serum concentrations >5 mcg/mL can result in seizure activity and central nervous system depression. If there is evidence of central nervous system involvement or changes in cardiac rhythm, the infusion rate should be immediately decreased or the drug should be immediately discontinued.
Four different techniques can be used to instill the topical anesthetic for flexible bronchoscopy. These are dropper instillation, transtracheal injection, local nerve block, atomized or nebulized solution, and “spray as you go” with the latter being the most common approach in our center. The goal of lidocaine administration before and during flexible bronchoscopy is to achieve satisfactory topical anesthesia of the upper and lower airways that includes the nares, base of the tongue, pharynx, upper larynx, vocal cords, lower larynx, and trachea. Good anesthesia will help prevent gagging, cough, and patient discomfort. For good topical anesthesia to be achieved, satisfactory anesthesia of cranial nerves V, IX, and X is necessary. It is for this reason that injecting lidocaine into one single site to achieve adequate anesthesia of these individual nerves has proven to be very difficult.10
Although lidocaine has adverse effects related to overdosage, it remains one of the safest topical anesthetics available for airway anesthesia.11 Dosing should be adjusted for poor hepatic blood flow, liver failure, and low cardiac output. Because the half-life of lidocaine is 90 minutes, any second dose administered should be reduced by half and given at least 90 minutes after the first full dose (Ref. 12, p. 46). During bronchoscopy, repeated small aliquots of lidocaine are administered over several minutes, sometimes via nebulization or aerosolization before beginning the procedure, then in gel form to anesthetize the nasal passages, and finally lidocaine in liquid form is sprayed through the working channel directly onto mucosal tissues.
Peak plasma levels occur about 15 minutes after direct topical application to the larynx and trachea and 5 minutes after ultrasonic or other nebulization (eg, using a bulb or Devilbiss atomizer) is employed.13 In most cases, peak plasma levels are also assumed to be reached within 5 minutes after lidocaine is administered to the distal airway mucosa directly through the bronchoscope's working channel (Ref. 12, p. 53) In the bronchoscopy setting, the expected duration of action is 1 hour14 with a total onset of action between 1 and 5 minutes.15,16
Although nebulized lidocaine is frequently used to achieve airway anesthesia, its efficacy has come into question. In a recent randomized, double blind, placebo controlled trial, investigators randomized 150 patients to receive either lidocaine or saline solution as placebo via nebulization. There was no significant difference between the 2 groups in terms of cough score, hemodynamic parameters, discomfort, midazolam dose for additional sedation, or amount of supplemental lidocaine used. In fact, the lidocaine group used significantly more lidocaine compared with the placebo group. The investigators noted that the addition of nebulized lidocaine for airway anesthesia before commencing flexible bronchoscopy offered no benefit when flexible bronchoscopy is performed using combined topical anesthesia and moderate conscious sedation.17
Furthermore, in another study, investigators evaluated patients undergoing flexible bronchoscopy using topical and nebulized lidocaine for anesthesia alone (without additional parenteral administration of moderate conscious sedation drugs). Eighty percent of subjects undergoing procedures using this topical anesthesia protocol rated the adequacy of anesthesia as “very good” or “good.” No complications were observed and specimens could be obtained in all cases. Total lidocaine plasma levels remained below 6 mcg/mL.18
To date, various doses of lidocaine have been used safely during bronchoscopy. Dosage ranges from 400 mg1 or 4 mg/kg11 up to 12 mg/kg and higher.19 A randomized double-blind clinical study found that 1% lidocaine, 0.2 to 0.3 mg/kg at volumes of 10 to 20 mL (100 to 200 mg) was adequate to tolerate bronchoscopy without sustained cough.20 At our own institution, we routinely perform bronchoscopies using maximum doses of 100 to 200 mg using the spray as you go technique instilling 1% lidocaine. Most experts agree that dose will vary with the individual patient, but the bronchoscopist should always strive to use the minimum dose possible to achieve airway anesthesia without causing adverse effects.
LIDOCAINE ALLERGY AND OTHER ADVERSE EVENTS
In most of the cases, lidocaine is safe and efficacious for use as topical anesthesia during flexible bronchoscopy and most procedures are, in fact, performed without reaching toxic blood levels. In rare cases, however, complications have been documented secondary to allergic reactions rather then high plasma levels. To evaluate documented cases of lidocaine allergy, it is necessary to briefly review the various types of allergic reactions possible.
Allergic reactions can be grouped into 5 types. Type 1 (anaphylactic immediate-type hypersensitivity) occurs within 30 to 60 minutes. Exposure to the antigen results in the release of vasoactive substances such as histamine, leukotrienes, and prostaglandins from mast cells or basophils and is usually immunoglobulin E dependent. Clinical features include anaphylaxis, bronchospasm, angioedema, and urticaria. Type 2 (antibody-dependent cytotoxity) occurs when an antigen associated with a cell binds to antibody and triggers cell injury. This type of reaction may result in hemolytic anemia or interstitial nephritis. Type 3 (immune complex) results from antigen-antibody complex deposition in vessels or tissues resulting in serum sickness. Type 4 (cell mediated or delayed hypersensitivity) reactions allow antigen to sensitize T cells, which then mediates tissue injury and often manifest as contact dermatitis. Type 5 reactions (presumed T-cell cytotoxity) are not well described, may take longer than 72 hours, and often result in a maculopapular rash.
It has been well established that reactions to ester anesthetics are more common then reactions to amides. This is primarily because esters undergo hydrolysis to form the highly antigenic p-aminobenzoic acid.21 Furthermore, esters show cross-reactivity, making it unsafe to use other agents of this class if a known ester allergy exists. Cross-reactivity among amides, however, is poorly documented22 and is probably quite rare, although type 1 and type 4 reactions to lidocaine have been uncommonly documented.
The most common adverse reaction to lidocaine seems to have been described after application of hemorrhoid cream preparations.23 Other lidocaine preparations known to cause type 4 reactions are sunburn relief creams, skin injection for dermatologic and rheumatologic procedures, and dental injections. True allergic reactions to local anesthetics are rare, however, and account for <1% of adverse reactions to these anesthetic preparations.24 In addition, many documented adverse reactions are more likely related to antioxidants, preservatives, or metabolites present in the preparation, rather than to the anesthetic agent itself.21
Although rare, dangerous type 1 reactions to lidocaine have been documented. A well known case is that of a 4-year-old boy who developed anaphylactic shock 15 minutes after a dental procedure during which an intrapulpal injection of 2% lidocaine hydrochloride was used for anesthesia.25 Allergic reactions to lidocaine dental cartridges and reusable vials can also occur because of the presence of preservatives.26 Preservatives such as parabens, for example, are known to be used in reusable vials and dental cartridges to ensure sterility. They can also denature proteins and have an antimetabolite effect.27 In this particular case report, the lidocaine used did not contain paraben as a preservative, but did contain sodium sulfite as a reducing agent. Sodium sulfite is not yet known to cause anaphylactic reactions.25
An example of type 4 reaction was described in the case of a 55-year-old woman who developed redness, itching, and swelling within days of undergoing dermatologic skin biopsies and excisions on multiple occasions. The patient underwent patch testing and was found to have a positive reaction to lidocaine, but negative reactions to tetracaine, benzocaine, procaine, prilocaine, carbocaine, dibucaine, and menthol.22
Although a search of allergic reactions to lidocaine during bronchoscopy yielded no such evidence, in 1 case report the development of muscle twitching and agitation (responding to 5 mL of intramuscular midazolam) after administration of 150 mg of lidocaine was reported during flexible bronchoscopy.27 The mechanism of action was thought to be secondary to blocking of central inhibitory pathways.
In our review of the literature using the PubMed search engine and the key words lidocaine and bronchoscopy, lidocaine allergy, and lidocaine allergy and bronchoscopy, we found several publications describing type 1 and type 4 reactions to lidocaine used for dermatologic and dental procedures, but none describing adverse events due to the use of topical lidocaine during bronchoscopy. In fact, adverse reactions to lidocaine during bronchoscopy seem primarily related to lidocaine toxicity rather than to lidocaine allergy. Nevertheless, the documentation of allergy to lidocaine during nonpulmonary procedures and in a patient who presented with a possible or questionable history of allergy to lidocaine should be enough to prompt bronchoscopists to investigate more thoroughly such a history and to use alternative methods for anesthesia. A medical work-up is also indicated to determine more precisely underlying causes of any adverse event. Under these circumstances, patch testing to an anesthetic allergen series, and if positive, confirmatory intradermal challenge with the suspected antigen has thus been advocated.28 In addition, because many anesthetic preparations contain preservatives, it may be useful to add paraben (most common preservative) containing preparations to the testing panel.29
If an allergy is identified to a local anesthetic belonging to the ester class, then generally speaking, an anesthetic from the amide class may be used and vice versa. Furthermore, allergen testing with an anesthetic allergen series might accurately determine what anesthetics are safe to use and possibly identify cross reactivity among anesthetics of the same class, such as that documented with mepivacaine and lidocaine.30 In other cases, topical anesthesia might be avoided altogether, and bronchoscopy can be performed using intravenous anesthetics, such as propofol, and careful, atraumatic bronchoscopic technique.
In conclusion, lidocaine used as topical anesthesia for bronchoscopy is generally safe when adequate precautions are taken to minimize the risk of toxicity and identify potential allergic responses. Although it is true that adverse events caused by true lidocaine allergy have been very rarely reported; in fact, 2 of the larger studies of safety of bronchoscopy did not report any allergic reactions,10,31 we believe that a precise patient history including directed inquiry regarding previous exposures to topical and local anesthetics is always warranted. Patients should also be informed of the potential risks of topical anesthesia as part of the informed consent process, as this might trigger a patient's memory regarding prior exposures or adverse events. True anaphylactic reactions to the topical anesthetic form of lidocaine used during bronchoscopy have not been documented. If a questionable history of allergy to lidocaine is discovered, however, safe alternatives to lidocaine administration should be considered or procedures can be postponed until the results of patch testing performed under the supervision of an experienced physician are available.
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