Controversy exists regarding the total amount of. Serum Lidocaine Concentrations in Asthmatics Undergoing Research Bronchoscopy*

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1 Serum Lidocaine Concentrations in Asthmatics Undergoing Research Bronchoscopy* Esther L. Langmack, MD; Richard J. Martin, MD, FCCP; Juno Pak, BS; and Monica Kraft, MD, FCCP Study objectives: To determine how often serum lidocaine concentrations (SLC) fall into the potentially toxic range (> 5 mg/l) in asthmatics undergoing research bronchoscopy, and to determine whether subject or procedure characteristics are associated with higher SLC. Design: Prospective, observational study. Setting: Academic research center. Participants: Fifty-one volunteers with mild to moderate asthma enrolled in three separate bronchoscopy protocols to study airway inflammation in asthma. Interventions: Lidocaine was administered topically to the upper airway and tracheobronchial tree to achieve local anesthesia for bronchoscopy. Venous blood was sampled during bronchoscopy, 30 min after upper airway anesthesia was completed (time 1), and 30 min after bronchoscopy was completed (time 2). Measurements and results: The mean total amount of lidocaine administered was mg ( mg/kg). No signs or symptoms of lidocaine toxicity were observed in any of the subjects. SLC ranged between 0.10 and 2.90 mg/l at time 1 and 0.50 and 3.20 mg/l at time 2. SLC was significantly correlated with the total amount of lidocaine (milligrams/kilogram) administered at both points (time 1, r 0.33, p 0.021; time 2, r 0.33, p 0.023). No statistically significant relationship was observed between SLC and subject age, sex, weight, baseline FEV 1, procedure length, or study protocol. No statistically significant relationship was found between subject FEV 1 and either total lidocaine dose or procedure length. Conclusions: An average total dose of 600 mg (8.2 mg/kg) of lidocaine appears to be safe in mild to moderate asthmatics undergoing research bronchoscopy. (CHEST 2000; 117: ) Key words: anesthesia; asthma; bronchoscopy; lidocaine Abbreviations: EBBR endobronchial brushings; EBBX endobronchial biopsies; SLC serum lidocaine concentration *From the Department of Medicine, National Jewish Medical and Research Center, and the University of Colorado Health Sciences Center, Denver, CO. Supported by NHLBI grants HL36577 (Drs. Kraft and Martin) and HL03343 (Dr. Kraft), and the American Lung Association Asthma Research Center Award (Drs. Kraft and Martin). Manuscript received July 13, 1999; revision accepted November 30, Correspondence to: Esther L. Langmack, MD, National Jewish Medical and Research Center, 1400 Jackson Street, J119, Denver, CO 80206; langmacke@njc.org Controversy exists regarding the total amount of lidocaine that can be safely administered to asthmatics undergoing investigative bronchoscopy. The National Institutes of Health guidelines published in 1985 recommended a maximum total dose of 400 mg, 1 but subsequent guidelines recommended only that the total dose be minimized and did not stipulate a maximal dose. 2 The death of a normal volunteer from lidocaine toxicity after research bronchoscopy heightened concerns about potential adverse events associated with use of topical lidocaine for airway anesthesia. 3 Lidocaine is rapidly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream, 4 with peak blood concentrations generally reached at 20 to 40 min after application. 5 8 Lidocaine toxicity is directly correlated with its concentration in the blood. At low blood concentrations of 1 to 5 mg/l, lidocaine is an effective antiarrhythmic agent, and light-headedness and drowsiness are the most common side effects. 4 The risk of more serious toxic effects increases when blood concentrations exceed 5 mg/l, with seizures and hallucinations occurring at concentrations of 8 to 12 mg/l, and cardiorespiratory arrest, at 20 to 25 mg/l. 4 Although most clinical studies have reported nontoxic blood lidocaine concentrations associated with CHEST / 117 / 4/ APRIL,

2 bronchoscopy, 7 9 several have reported concentrations in the toxic range ( 5 mg/l). 5,6,10 In all of these studies, blood lidocaine concentrations were measured in normal volunteers or patients undergoing bronchoscopy for clinical indications, such as hemoptysis. None of these studies examined blood lidocaine concentrations in a large number of asthmatic subjects. In asthmatics, airway inflammation or disruption of the bronchial mucosa by biopsy forceps or endobronchial brushing could theoretically increase the rate of lidocaine absorption and the risk of lidocaine toxicity. Given the lack of information about blood lidocaine concentrations in asthmatics undergoing investigative bronchoscopy, we set out to determine how often serum concentrations of lidocaine fall into the potentially toxic range in this subject population. In addition, we wished to determine whether there are subject or procedure characteristics associated with higher serum lidocaine concentration (SLC). Subjects Materials and Methods Fifty-one asthmatic volunteers ranging in age from 19 to 62 years ( years; mean SD) were recruited from the general Denver community. All subjects met diagnostic criteria for asthma. 11 Exclusion criteria included any history of significant nonasthmatic pulmonary disease, significant nonpulmonary disease (including cardiac, liver, or kidney disease), pregnancy, and any history of tobacco use during the past 1 year or 5 pack-years of total use. All subjects gave informed consent to all protocols, which were approved by the Institutional Review Board. Subject characteristics are shown in Table 1. Bronchoscopy Asthmatic subjects underwent bronchoscopy as part of three on-going research protocols designed to study various aspects of airway inflammation. In protocol 1, subjects underwent BAL and five endobronchial biopsies (EBBX). Protocol 2 involved BAL with or without four to five EBBX. Protocol 3 consisted of eight EBBX, seven endobronchial brushings (EBBR), and BAL. BAL, EBBX, and EBBR were performed as described previously. 12,13 Twelve, 8, and 31 subjects underwent bronchoscopy in protocols 1, 2, and 3, respectively. On the day of bronchoscopy, subjects had an FEV 1 60% Table 1 Subject Characteristics (N 51) Age, yr Sex, M F Weight, kg Baseline FEV 1, L Baseline FEV 1, % pred Medications Inhaled 2 -agonist 51 Inhaled corticosteroid 23 predicted 15 min after two puffs of albuterol via metered-dose inhaler and had taken nothing po for 6 h. An IV catheter was placed in an upper extremity. Subjects were premedicated with 0.4 mg IV atropine. Lidocaine (4%; Roxane Laboratories, Inc; Columbus, OH) was sprayed in the nose and throat with a handheld atomizer until the gag reflex was extinguished. Just before insertion of the bronchoscope, 2 to 3 ml of 2% viscous lidocaine (Geneva Pharmaceuticals, Inc; Broomfield, CO) was applied to the nose. Two to 6 ml of 1% lidocaine (Elkins-Sinn, Inc; Cherry Hills, NJ), delivered in 2-mL aliquots, was applied to the larynx via the bronchoscope. Additional 1% lidocaine was applied in 2-mL aliquots through the bronchoscope to the tracheobronchial tree, at the discretion of the bronchoscopist, to control cough. Bronchoscopists were advised to keep the total dose of lidocaine 10 mg/kg, if possible. IV midazolam and fentanyl were given in incremental doses to achieve conscious sedation, before and after the insertion of bronchoscope. The mean total amounts (mean SD) of midazolam and fentanyl used in this study were mg and g, respectively. BAL, EBBX, and EBBR were then performed according to the particular study protocol. During the procedure, subjects received supplemental oxygen via nasal cannula. IV crystalloid (5% dextrose in 0.5 N saline solution) was administered at a low flow rate (approximately 25 ml/h) to facilitate administration of IV medications. A nurse monitored the subject s ECG, BP, and pulse oximetry continuously throughout the procedure and during the 1- to 3-h recovery period. Discharge criteria included an FEV 1 within 10% of their prebronchoscopy, postbronchodilator baseline, presence of an intact gag reflex, and stable vital signs. Subjects were taken home by an escort and told not to drive for 24 h. They were provided verbal and written instructions to contact the investigators with any problems after the procedure. In addition, they were telephoned by a nurse 24 h after bronchoscopy to assess their status. The total dose of lidocaine was calculated by adding the total amounts of 4% lidocaine and 1% lidocaine administered. Because the absorption of intranasal lidocaine gel is 50%, 14 the 2% viscous lidocaine was not included in this calculation. No attempt was made to quantitate the amount of lidocaine suctioned from the airways or swallowed. Measurement of SLC Five milliliters of venous blood was drawn from the IV catheter at two times: 30 min after upper airway anesthesia was completed, during bronchoscopy (time 1), and 30 min after the bronchoscopy was completed (time 2). Serum samples were analyzed by a reference laboratory (Quest Diagnostics, Inc; Denver, CO), using a commercial fluorescence polarization immunoassay. For this laboratory, the therapeutic range for lidocaine was 1.5 to 5.0 mg/l. Statistical Analysis Descriptive statistics were calculated for both SLC and for the continuous independent variables. Frequencies and percents were calculated for the categorical variables. In addition, descriptive statistics for SLC were calculated for each level of the categorical independent variable. Relationships between SLC and each independent variable were examined using correlation methods for the continuous predictors and t tests or Kruskal- Wallis tests for the categorical predictors. Relationships between selected independent variables were evaluated using Pearson correlation coefficients. All statistical tests for regression, analysis of variance, and correlation were two-sided and conducted using a significance level of 5% (ie, 0.05). In addition, a 95% 1056 Clinical Investigations

3 one-sided, upper confidence interval was calculated for the percent of subjects with potentially toxic concentrations using the method defined by Hanley and Lippman-Hand. 15 Analyses were performed using SAS version 6.12 (SAS Institute; Cary, NC) on a personal computer running under Windows NT (Microsoft Corp.; Redmond, WA). Data are expressed as the mean SD. Results Clinical Evidence of Lidocaine Toxicity Among the 51 subjects who underwent bronchoscopy, there were no observed signs or symptoms of CNS, cardiac, or respiratory lidocaine toxicity, nor were there any significant adverse events reported during the 24 h after the procedure. Amount of Lidocaine Administered The mean total amount of lidocaine administered, as calculated by adding the amount of 4% and 1% lidocaine given to the subject for the entire procedure, was mg. The total amount of lidocaine administered ranged between 320 and 880 mg. Expressed per subject s body weight, the mean total lidocaine dose was mg/kg, with a range of 4.3 to 14.3 mg/kg. On average, mg of 4% lidocaine was used to anesthetize the upper airway, and mg of 1% lidocaine was applied through the bronchoscope to the larynx and tracheobronchial tree. These data are shown in Table 2. SLC For each point, SLCs were available for 48 of 51 subjects. As shown in Table 3, none of the subjects had SLC 5.0 mg/l, the upper limit of the therapeutic range (1.5 to 5.0 mg/l). During bronchoscopy, 30 min after upper airway anesthesia was complete (time 1), SLC was mg/l, with a range of 0.10 to 2.90 mg/l. Thirty minutes after the bronchoscope was withdrawn at the end of the procedure (time 2), SLC was , with a range of 0.5 to 3.20 mg/l. The highest SLC, 3.20 mg/l, was observed in a 26-year-old, 80.5-kg male in protocol 3, who received a total dose of 700 mg (8.7 mg/kg). This subject had an uneventful procedure Table 2 Amount of Lidocaine Administered* Procedure Lidocaine, mg Lidocaine, mg/kg 4% lidocaine (before bronchoscopy) % lidocaine (during bronchoscopy) Total Range *Values given as mean SD. Table 3 Serum Lidocaine Concentrations Time Mean SD and no signs or symptoms of lidocaine toxicity. For the six subjects for whom only one SLC was available, SLC fell within the ranges observed for the larger group, at time 1 (1.1, 1.3, and 0.9 mg/l) and time 2 (0.7, 0.7, and 0.6 mg/l). The one-sided 95% upper confidence limit for the expected number of events (in this case SLC 5 mg/l) was 3 of 51 (0.059 or 6%). Thus, we conclude that we are 95% confident that the chance of potential lidocaine toxicity, as indicated by SLC 5 mg/l, is 6% in this population. Relationship Between SLC and Procedure and Subject Characteristics As shown in Figure 1, the total amount of lidocaine administered was significantly correlated with SLC at both time 1 and time 2 (time 1, r 0.34, p 0.020; time 2, r 0.37, p 0.010). The total amount of lidocaine expressed per subject s body weight was also significantly correlated with SLC at both points (time 1, r 0.33; p 0.021; time 2, r 0.33, p 0.023). No statistically significant relationship was found between SLC and subject age, weight, sex, baseline FEV 1, or procedure length at either time (Table 4). There were no statistically significant differences in SLC among study protocols or bronchoscopists at either time (Table 4). Relationship of FEV 1 to Total Lidocaine Dose and Procedure Length There was no statistically significant relationship between subject baseline FEV 1 (percent predicted) and total lidocaine administered (milligram) (r 0.14, p 0.320) or total lidocaine expressed per body weight (r 0.19, p 0.176). Lower baseline FEV 1 (percent predicted) tended to be associated with longer procedure length (r 0.24, p 0.090). Discussion SLC, mg/l Range Time 1 (n 48) Time 2 (n 48) In this group of young, otherwise healthy volunteers with mild to moderate asthma, SLC measured during bronchoscopy, 30 min after upper airway anesthesia, and 30 min after bronchoscopy did not fall into the potentially toxic range ( 5 mg/l) for CHEST / 117 / 4/ APRIL,

4 Figure 1. Relationship between the total amount of lidocaine administered and SLC. The total amount of lidocaine administered is expressed in milligrams (A and C) and in milligrams per kilogram subject body weight (B and D). A and B: SLC from time 1 (30 min after upper airway anesthesia, during bronchoscopy). C and D: SLC from time 2 (30 min after the end of bronchoscopy). any of the subjects. This was true even though the average total amount of lidocaine administered, mg, exceeded the 400-mg total dose limit previously recommended for investigative bronchoscopy. 1 None of the subjects displayed signs or symptoms of lidocaine toxicity. Our findings suggest that the previously recommended dose is too restrictive and that 600 mg (8.2 mg/kg) of lidocaine given to mild to moderate asthmatics undergoing investigative bronchoscopy is acceptable. Table 4 Relationship of Subject and Procedure Characteristics to SLC Time 1 Time 2 Characteristic r Value p Value r Value p Value Age* Weight* Baseline FEV 1 * Procedure length* Sex Study protocol Bronchoscopist *p value from univariate regression for SLC vs age, weight, FEV 1, or procedure length. p value from analysis of variance for comparison of mean SLC across sex. p value from Kruskal-Wallis test for comparison of median SLC across study protocol or bronchoscopist Clinical Investigations

5 Of the procedure characteristics studied, only the total dose of lidocaine administered was significantly related to SLC. This finding is consistent with previously published data 5 and the known pharmacokinetics of the drug. 4 Interestingly, performance of EBBR, in addition to BAL and EBBX, did not seem to influence SLC, although this sampling technique could theoretically increase lidocaine absorption by disrupting the bronchial mucosa. BAL, EBBX, and EBBR were performed in protocol 3, compared with only BAL and EBBX in protocols 1 and 2, yet SLCs were not significantly greater for protocol 3. This observation suggests that the amount of mucosal disruption does not necessarily increase SLC. Subject age, sex, baseline FEV 1, and body weight were not related to SLC. These characteristics likely cannot be used to predict SLC in this subject population. In addition, no significant relationship was observed between baseline FEV 1 and either total lidocaine dose or procedure length. These findings suggest that in mild to moderate asthmatics, subjects with relatively reduced lung function do not require significantly greater amounts of lidocaine for topical airway anesthesia or longer times to complete the bronchoscopy. There was considerable variability in SLC even among subjects receiving the same total lidocaine dose. Such variability has been observed in previous studies of SLC during bronchoscopy 5 and is believed to reflect primarily individual differences in lidocaine absorption and metabolism. The amount of lidocaine suctioned from the airway, swallowed, or expectorated, as well as the timing of lidocaine administration during the procedure, may also contribute to the observed variability in SLC. In our study, despite the variability in SLC, SLC still did not exceed 5 mg/l, the upper limit of the therapeutic range for lidocaine. There are several limitations to this study. It is possible that sampling blood at only two times missed the true maximal blood concentration of lidocaine, although we selected these times on the basis of the timing of previously reported peaks in blood lidocaine concentration during bronchoscopy. 5 8 Absorption from the trachea can be very rapid in some individuals, with peak concentrations reached within 5 to 15 min. 6 In addition, midazolam and fentanyl given for conscious sedation may have prevented subjects from reporting milder symptoms of lidocaine toxicity, such as light-headedness, tinnitus, or paresthesias. Midazolam, a benzodiazepine, could theoretically have suppressed seizures, although seizure activity at SLC 5 mg/l would be expected to be quite rare. Finally, by choosing to exclude the amount of 2% viscous lidocaine from the calculation of total lidocaine dose, we have certainly underestimated the total lidocaine dose by approximately 40 to 60 mg for each subject. Absorption through the nasal mucosa is estimated to be approximately 50% 14 and could be enhanced by nasal trauma associated with the procedure or rhinosinusitis (a common condition in asthmatics). Nonetheless, the fact that SCL did not exceed 5 mg/l in any subject, despite the fact that we excluded the 2% viscous lidocaine from the total dose, supports our contention that higher total doses of lidocaine may be used for research bronchoscopy in asthmatics than previously recommended. The total lidocaine doses administered in our study fall within the range of total doses reported in previous studies, several of which exceeded 400 mg without detection of blood lidocaine concentrations in the potentially toxic range. 8,9 The data from these studies, in conjunction with our own, would support the use of 400 mg of lidocaine for research bronchoscopy. However, these results from other studies must be considered with caution, as these studies did not include asthmatics undergoing procedures such as EBBX, BAL, and EBBR. Moreover, the methods of lidocaine administration and timing of blood sampling vary greatly. Our observations and conclusions may not apply to other subject and patient populations, or research settings, for several reasons. First, aside from mild to moderate asthma, our subjects were otherwise healthy adults. They were not acutely ill, nor did they have congestive heart failure or liver disease, factors that have been associated with higher SLC. 16 They did not require positive-pressure ventilation, which has been shown to enhance lidocaine absorption. 17 Second, they were relatively young, and likely had normal rates of lidocaine clearance, compared with elderly individuals. 18 In addition, our observations may not apply when different methods (eg, nebulization, laryngotracheal spraying) are used to anesthetize the airway, inasmuch as the method of lidocaine delivery has been shown to influence SLC. 19 Lastly, the bronchoscopists, nurses, and research assistants involved in this study had considerable experience performing and monitoring bronchoscopy in asthmatic subjects, which may have influenced how lidocaine was administered during the procedure. Taking all of these factors into account, in the described research population and setting, we recommend that total lidocaine doses up to 600 mg (8.2 mg/kg) can be given safely. References 1 National Institutes of Health Workshop Summary. Summary and recommendations of a workshop on the investigative use of fiberoptic bronchoscopy and bronchoalveolar lavage in CHEST / 117 / 4/ APRIL,

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