The maximum amount of topical lidocaine used for airway anesthesia to provide patient comfort during flexible bronchoscopy (FB) remains an ongoing question. An early survey of nearly 25,000 FBs noted 6 patients with complications (respiratory arrest, seizures) related to airway anesthesia and only 1 patient with methemoglobinemia.1 The National Institutes of Health (NIH) published guidelines in 1985 recommending a maximum cumulative lidocaine dose of 400 mg for asthmatics undergoing research FB, but subsequent guidelines published in 1991 only indicated minimizing the dose to avoid potential toxicity.2,3 Langmack et al4 conducted a definitive study in 2000 that demonstrated safety of lidocaine doses up to 8.2 mg/kg in an asthma population undergoing FB. In 2001, the British Thoracic Society (BTS) guidelines for routine FB recommended 8.2 mg/kg based primarily on this study.5 However, other studies demonstrated the safety of lidocaine in much higher doses.6–8 A small study of 19 elderly patients revealed no serious lidocaine toxicity or elevated serum levels greater than 5 μg/mL despite using a mean dose of 1200 mg (19 mg/kg) of topical lidocaine.6
A typical airway preparation for FB includes the application of 2% viscous lidocaine for the nasal mucosa, nebulized 4% topical lidocaine for oral inhalation, and 1% topical lidocaine for additional upper and lower airway mucosal anesthesia to control coughing. This airway preparation is approximately 500 mg of topical lidocaine. The amount of 1% lidocaine used is variable and physician dependent with approximately 100 mg used for direct application to the vocal cords and carina and additional lidocaine used for lower airway anesthesia to suppress coughing. Lidocaine is a very effective topical anesthetic with rapid mucosal absorption. Serious effects of lidocaine toxicity (seizures, methemoglobinemia, respiratory failure, and cardiac arrhythmias) are reported to begin at serum levels >5 μg/mL.9 Milder side effects such as drowsiness, dizziness, paresthesias, euphoria, nausea, and vomiting can occur at lower serum concentrations. Serum lidocaine clearance can be decreased in the elderly, patients with cardiac or liver disease, and those patients taking certain medications such as β-blockers, cimetidine, or verapamil.10
The experience with FB at our institution for the past 10 years has not demonstrated increased complications related to either lidocaine toxicity or methemoglobinemia despite an average topical lidocaine dose of 12 mg/kg given routinely. No large study has been conducted evaluating toxicity or methemoglobinemia related to high dose lidocaine in FB patients.
Consecutive patients undergoing FB in the Pulmonary Clinic were recruited to participate in this study approved by the hospital Institutional Review Board. After obtaining informed consent, patients were given a handout during their nursing preprocedure assessment that explained the study protocol and asked about baseline symptoms. They were specifically asked not to discuss the handout questions with their pulmonologist who was blinded to the study procedure. Current medication use and past medical history were documented along with a baseline weight.
Standard operating procedure for our bronchoscopy suite included intravenous access with continuous heart rate, blood pressure, and pulse oximetry monitoring during the airway preparation and during the FB. A standard dose of 5 to 10 mL of 4% lidocaine was given via a hand-held nebulizer and 10 to 20 mL of 2% viscous lidocaine was inserted nasally. During this airway preparation, the bronchoscopy technician recorded the amount of 4% lidocaine used during the airway nebulization and the amount of 2% viscous lidocaine administered to anesthetize the nasal mucosa. All patients were given supplemental oxygen starting at 2L/min before the procedure to maintain oxygen saturations greater than 92%. Intravenous midazolam and fentanyl were given in incremental doses to achieve conscious sedation before insertion of bronchoscope and during the procedure. During the FB, 1% lidocaine was given as 5 mL aliquots routinely to anesthetize the vocal cords and carina. The technician recorded the amount of 1% lidocaine administered throughout the entire procedure as requested by the bronchoscopist. The bronchoscopist was not informed of the lidocaine amount used or asked to limit the amount during the procedure. All cardiac arrhythmias were recorded by nursing personnel per the conscious sedation guidelines and the total FB procedure time was documented. Serum lidocaine and blood methemoglobin (MetHb) levels were drawn 45 minutes after the last dose of lidocaine was administered. A repeat symptom questionnaire was completed at 2 hours postprocedure when the patient had adequately recovered from conscious sedation.
Serum concentration of lidocaine was analyzed on the COBAS INTEGRA 400 (Roche Diagnostics, Indianapolis, IN) using a fluorescence polarization assay containing an antilidocaine polyclonal antibody and a fluorescein-labeled lidocaine derivative. Serum concentrations were determined by measuring the differences between polarization of unbound and lidocaine-bound fluorescein. Serum MetHb concentrations were determined on the 800 Series Blood Gas Critical Analyte System (Ciba Corning Diagnostics, Norwood, MA) by spectrophotometric analysis of hemoglobin and its derivatives.
Comparison of mean values (age, lidocaine dose, lidocaine level, and MetHb level) by sex was performed using a Student paired t test. Comparison of mean values (age, lidocaine dose, lidocaine level, and MetHb level) by age group and indication was performed using a 1-way analysis of variance with a Bonferroni correction. P values less than 0.05 were considered significant. Analysis was performed on commercially available software (SPSS for Windows, version 11.5).
A total of 154 consecutive patients were enrolled in the protocol and completed the study procedures (no patients declined to participate in the study). There were 93 males (60%) and 61 females (40%) with a mean age of 64.3±13.7 years (range, 18 to 80 y). Indications for FB included evaluation of a pulmonary mass in 93 patients (60%), interstitial lung disease in 19 (12%), hemoptysis in 17 (11%), infection in 17 (11%), and other indications in 8 (5%). Concomitant medication use included 48 patients taking β-blockers, 8 patients taking verapamil, and 1 patient taking cimetidine. Review of past medical history indicated no patients with significant congestive heart failure or chronic liver disease. The mean length of FB was 33.5±18.9 minutes (range, 5 to 100 min). Bronchoalveolar lavage was performed in 64% of patients, transbronchial biopsy in 43%, transbronchial fine needle aspirate in 30%, cytology brushing in 25%, endobronchial biopsy in 18%, airway survey only in 11%, and other procedures in 3%. Mild symptoms were reported in 66.2% of all patients (85.3%—euphoria, 11.8%—dizziness, 1%—headache, 1%—drowsiness) and were more common in females (72.1%) than males (62.4%). No patients had cardiac arrhythmias, seizures, or respiratory failure attributable to lidocaine toxicity.
Total lidocaine dose, mean serum lidocaine levels, and mean blood MetHb levels for the overall group are shown in Table 1. The mean lidocaine dose was 1.17±0.20 g (range, 0.80 to 1.60 g). When adjusted for body weight, the mean lidocaine dose was 15.4±4.5 mg/kg (range, 7.1 to 32.5 mg/kg). The mean length of time until blood was drawn for lidocaine and MetHb levels was 51.1±11.8 minutes (range, 23 to 135 min). Mean serum lidocaine levels were 1.55±0.67 μg/mL with peak level of 5.1 μg/mL. Only 1 patient had a serum lidocaine level greater than 5 μg/mL. Mean blood MetHb levels were 0.69±0.26 μg/mL (range, 0.1 to 1.9 μg/mL). The normal range for our laboratory is 0.4 to 1.2 μg/mL; only 3 patients had a MetHb level greater than 1.2 μg/mL.
A further analysis of the values listed above was first completed by sex as shown in Table 1. There is a significant difference in lidocaine dose only by body weight, 14.3±3.8 mg/kg for males and 16.9±4.9 mg/kg for females with a P=0.0003. There were no differences in serum lidocaine or blood MetHb levels demonstrated. Comparison of lidocaine levels by indication for FB is shown in Table 2. Shorter FB procedures such as evaluation for infectious etiologies or airway survey for hemoptysis in which there is less manipulation of the airway did show a significant difference (P=0.027) in total lidocaine dose. This was not significant when adjusted for body weight or by lidocaine or MetHb levels. Similar findings are shown in Table 3 where comparisons were made on the basis of age group. There is less overall lidocaine used in older patients (P=0.029), but by body weight, there is no difference shown. No significant differences are shown in either lidocaine or MetHb levels. Patients with mild symptoms (n=102) versus no symptoms (n=52) showed no differences in lidocaine levels (1.53±0.58 μg/mL vs. 1.56±0.82 μg/mL, P=0.33) or MetHb levels (0.71±0.24 μg/mL vs. 0.66±0.30 μg/mL, P=0.79). β-blocker use (n=48) versus no β-blocker use (n=106) also showed no significant differences in lidocaine levels (1.58±0.81 μg/mL vs. 1.53±0.59 μg/mL, P=0.65) or MetHb levels (0.65±0.30 μg/mL vs. 0.71±0.24 μg/mL, P=0.19).
This is the largest study to date that assesses blood levels of lidocaine and the potential toxicity of high dose topical lidocaine in FB, although many numerous studies using smaller overall doses previously indicated the relative safety of lidocaine. Concern has been elucidated about the potential toxicities of lidocaine absorption during FB to include seizures, cardiac arrhythmias, respiratory arrest, and methemoglobinemia. These potential complications are more concerning for the elderly and patients with decreased hepatic clearance.11 This study has demonstrated that the routine use of high dose (>12 mg/kg) lidocaine in FB does not cause high serum lidocaine or blood MetHb levels, and does not predispose patients to complications from lidocaine toxicity. Lidocaine doses were significantly higher in females when adjusted for weight, but were not higher when comparing age or indication for FB.
Initial guidelines for lidocaine dosing in healthy asthmatics undergoing FB published by the NIH in 1985 recommended no more than 400-mg cumulative dose of lidocaine; no reference for this recommendation was cited.2 The updated guidelines on FB in asthmatics from an NIH workshop in 1991 simply stated the lowest topical anesthetic dose possible should be used.3 Despite these published guidelines, apprehension was justifiably raised in 1996 when a 19-year-old healthy volunteer died from lidocaine toxicity after undergoing a research FB.12 When the BTS published guidelines for FB in 2001, their recommendations were based primarily on 2 studies.5 One study of 48 asthmatics undergoing research FB demonstrated safety with a mean dose of 8.2 mg/kg of lidocaine as the upper limit of normal for these patients.4 Another smaller study by Milman et al13 of 16 patients undergoing FB recommended a maximum dosage of 6 to 7 mg/kg. Even current textbooks on FB do not stipulate a maximum dose of lidocaine despite the numerous published reports and guidelines.14
Despite the few references used by the BTS to develop their FB guidelines, the current medical literature contains a substantial collection of studies evaluating serum lidocaine levels during FB. A list of the 20 studies with lidocaine dosing and serum lidocaine levels is shown in Table 4.4,6–8,15–27 Two of these studies compared different dosages of lidocaine and 4 studies evaluated lidocaine in different patient populations (elderly vs. young, spraying vs. ultrasonic nebulization, upper vs. lower respiratory tract, presence of hepatic metastases).6,7,9,11,19,23 These studies included a total of 457 patients whose mean age was 47.4±23.7 years (not reported in 9 studies). The mean total dose of lidocaine was 488±463 mg (11 studies) or equivalent of 7.0 mg/kg in a 70 kg person. The mean lidocaine dose (reported as adjusted for weight) was 9.7±5.0 mg/kg (8 studies). Only 6 studies gave a lidocaine dose greater than 8.2 mg/kg or total dose greater than 600 mg. None of the studies reported an average peak lidocaine level >5.0 mg/kg, whereas only 3 of the 21 studies reported a maximum lidocaine level >5.0 mg/kg. This cumulative data of nearly 500 patients do not suggest a trend towards lidocaine toxicity with higher lidocaine levels.
Several studies have demonstrated the safety of higher doses of lidocaine during FB. In the earliest study in 1979, 12 FB patients received an average of 600 mg of topical lidocaine. The maximum lidocaine level was found to be 3.79 μg/mL in a patient with hepatic metastases who only received 420 mg topical lidocaine.18 A follow-up study in 1982 by Efthimiou et al20 of 41 FB patients used a similar mean lidocaine dose (9.3±0.5 mg/kg); mean peak levels were 2.9±0.5 μg/mL and 2 patients had a lidocaine level >5 μg/mL with no complications. Ameer et al6 compared an elderly group of 14 patients (mean age of 67 y) with a young group of 5 patients (mean age of 42 y). Both groups received total lidocaine doses of nearly 1200 mg without significant toxicity. No difference in mean or peak serum lidocaine was found between groups. As part of a study evaluating the effect of lidocaine on endobronchial cultures, Berger et al24 studied 8 patients who received an average total lidocaine dose greater than 2000 mg. The mean serum level was 2.7 μg/mL and the peak level in 1 patient was 5.5 μg/mL; no toxicity was reported. In 1997, Gjonaj et al7 evaluated 8 mg/kg versus 4 mg/kg of nebulized 2% lidocaine in a pediatric population and found no evidence of toxicity. The total lidocaine dose for the high dose group was 10.13±1.26 mg/kg with mean serum lidocaine levels of 1.17±0.54 μg/mL and peak levels of 2.27 μg/mL. The most recent studies by Loukides et al26 (mean lidocaine dose of 622±20 mg) and Sucena et al8 (mean lidocaine dose of 11.6±3.1 mg/kg) also found no toxicities with these doses. Notably, 5 of 30 patients studied by Sucena et al8 had serum levels greater than 5 μg/mL but no clinical toxicity.
Although elevated MetHb levels are another potential concern with the use of higher lidocaine doses, there is scant information supporting this as a significant clinical issue. The 1974 FB survey only noted symptoms related to methemoglobinemia in a single patient who received tetracaine.1 Karim et al28 reported 3 patients and received topical lidocaine who developed clinical evidence of methemoglobinemia; 1 patient was undergoing FB and was taking trimethoprim-sulfamethoxazole. Most methemoglobinemia cases have been in association with benzocaine used in combination with lidocaine or as the sole topical anesthetic.29–32 A study of intravenous lidocaine in 40 patients with arrhythmias also failed to show clinically significant elevated MetHb levels.33 Our cohort had 3 patients with MetHb levels slightly above normal but none were clinically significant.
There is sufficient prospective evidence from this study that higher doses of topical lidocaine for airway anesthesia during FB are well tolerated and safe in the majority of patients. We did not demonstrate a higher level of complications owing to lidocaine toxicity despite a mean dose nearly twice the BTS guidelines. Likewise, there was no evidence of higher serum lidocaine or blood MetHb levels owing to these high dose lidocaine doses. More importantly, the size of this study population confirms the safety of topical lidocaine as an adjunct in providing a comfortable and well-tolerated FB.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
lidocaine; flexible bronchoscopy; toxicity; methemoglobin