INTRODUCTION

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The sodium channel blockers lidocaine and mexiletine have been shown to attenuate reflex bronchoconstriction provoked by an inhalational challenge with histamine (1). At the time of the histamine challenge, lidocaine plasma concentrations ranged at low antiarrhythmic concentrations in this study but still caused mild central nervous side effects in about a third of the volunteers tested. Accordingly, to avoid these systemic side effects, topical application of lidocaine by the inhalational route might be advantageous, since lidocaine inhalation might yield the same or better attenuation of airway constriction at higher airway and lower lidocaine plasma concentrations. In fact, lidocaine inhalation can diminish the response to an inhalational challenge with methacholine, hyperosmolar saline, water, or in exercise-induced bronchoconstriction (2). On the other hand, lidocaine inhalation in patients with asthma may cause an initial bronchoconstriction as well (2).

Therefore, in 15 volunteers with bronchial hyperreactivity in a double-blind randomized study, we tested the hypotheses that (1) baseline lung function is not affected by the inhalation or intravenous administration of lidocaine; (2) the effect of intravenous versus inhaled lidocaine on airway reactivity is not different, and (3) the resulting lidocaine plasma concentrations are not different depending on the route of administration.

	METHODS

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Subjects

After approval of the local ethics committee and informed written consent, 15 subjects (age 34.9 ± 1.4 yr; mean ± SEM; 8 women, 7 men) were enrolled in this randomized, double-blind, placebo-controlled study. The subjects were of normal height (177 ± 2.4 cm) and weight 75 ± 4.6 kg). All subjects had active asthma (n = 9), childhood asthma (n = 1), hay fever (n = 3), or chronic obstructive pulmonary disease (COPD) (n = 2), and symptoms consistent with airway hyperreactivity. Two of the subjects were smokers. Eight subjects inhaled a -adrenergic agonist, three on a regular and five on an as-needed basis, and two used inhaled corticosteroids. None of the subjects received a -adrenergic medication within the last 12 h prior to the measurements, and none of the subjects used theophylline preparations or systemic corticosteroids in the last 3 mo.

Measurements

The same air-conditioned room was used throughout the study. This way humidity was kept constant and room temperature (22° C) varied by ± 1° C. All measurements were performed at the same time of day (± 1 h).

Lung function measurements were performed in a body plethysmograph (Masterlab; Jaeger, Würzburg, FRG) with an integrated spirometer (Jaeger). On the initial screening visit, baseline vital capacity (VC), FEV₁, and airway resistance (Raw) were assessed, followed by an inhalational challenge with histamine to confirm bronchial hyperreactivity (1). Bronchial hyperreactivity was defined when FEV₁ decreased at least 20% from baseline following inhalation of histamine. In these 15 subjects a mean histamine concentration of 7.2 ± 1.31 mg · ml¹ (range, 0.51 to 15.7) was necessary for a 20% decrease of FEV₁ at the screening visit. Five additional volunteers with a history of airway hyperreactivity did respond with a decrease less than 20% in FEV₁ (13 to 17%) to the screening challenge and consequently were not enrolled in the study. During the infusion or inhalation of lidocaine or saline, heart rate (ECG lead II) and blood pressure (oscillometry) were monitored. Venous blood samples were drawn to measure lidocaine and monoethylglycinxylidide (Meg X) plasma concentrations with an immunofluorescence assay (Abbott TDx System; Abbott, Wiesbaden, Germany). The lower level of detection for this method is 0.1 µg · ml¹ for lidocaine and 0.01 µg · ml¹ for Meg X, and the coefficient of variation is less than 3%, as reported previously (10).

Aerosol Challenge

Aerosol inhalation was performed with a DeVilbiss No. 646 nebulizer (DeVilbiss, Somerset, PA) driven by compressed air at 30 psi. The start of nebulization was triggered (Spira Elektro 2 flow meter; Respiratory Care Center, Hämeenlinna, Finland) after inspiration of 500- 750 ml and was maintained for 0.6 s. The subjects were instructed to inspire from FRC to inspiratory capacity at an inspiratory flow rate of less than 0.6 L · s¹. At end inspiration the subjects were advised to hold their breath for 5 s. This maneuver was repeated five times. One to two minutes after inhalation of each aerosol dose FEV₁ and VC were measured a total of three times, and the largest FEV₁ and VC were accepted. The time between the increasing histamine doses was kept constant. Initially the subjects were challenged with aerosolized saline, followed by increasing doses of histamine diphosphate (Sigma-Aldrich GmbH, Deisenhofen, FRG) diluted in saline. The starting concentration of histamine diphosphate was 0.075 mg · ml¹, which was trebled on each subsequent challenge to a maximal concentration of 18 mg · ml¹.

Challenges were discontinued if the subject had symptoms of chest tightness or difficulty in breathing, a decrease in FEV₁ of at least 20% from the prechallenge baseline, or had received the maximal concentration of histamine diphosphate. The histamine threshold concentration necessary for a 20% decrease in FEV₁ was calculated for each subject using previously described methods (11). Subjects who had a decrease of 20% in FEV₁ within the range of histamine diphosphate tested were enrolled in the study. If, on one of the subsequent study days, a subject did not reach a 20% decrease in FEV₁, the threshold was calculated by extrapolation.

For all subsequent challenges the starting concentration for each individual subject was two concentrations lower than the concentration of histamine diphosphate that had caused a 20% decrease in FEV₁ (PC₂₀).

For consistency, all lung function measurements were made by a single investigator (H.G.), who was blind to the drugs administered.

Study Protocol

An 18-gauge cannula was inserted into an antecubital vein for withdrawal of blood samples for measurement of lidocaine serum concentration. For infusion of lidocaine or placebo, a second intravenous line was inserted on the contralateral side. On each day baseline lung function was assessed. Further measurements were postponed if the actual FEV₁ differed by more than 7% from the FEV₁ baseline at the screening visit.

On a total of three visits on three different days, in random order and in double-blind fashion, the subjects received lidocaine as an aerosol, lidocaine intravenously, or placebo intravenously. In detail, the subjects inhaled in one day lidocaine 5 mg · kg¹ in saline (Sigma Chemical Co., St. Louis, MO; prepared preservative-free prior to each testing, final concentration 100 mg · ml¹) with 2 s of nebulization with each breath. The volunteers were advised to perform a 5-s breath-hold at end inspiration. On another day the subjects received lidocaine intravenously (1.5 mg · kg¹ lidocaine over 20 min followed by a constant dose of 3 mg · kg · h¹ in saline to maintain lidocaine plasma concentrations until the end of the histamine challenge). On another day an intravenous infusion of saline (0.15 ml · kg over 20 min, followed by 0.3 ml · kg · h¹ until the end of the histamine challenge) was given. Venous blood samples were processed from 13 subjects. The samples were drawn prior to the start of the intravenous or inhalational administration of lidocaine or saline infusion and every 5 min up to 90 min.

Data Analysis

Data were presented as mean ± SEM. The following a priori null hypotheses were tested: (1) lidocaine inhalation as well as intravenous infusion do not change baseline lung function; (2) compared to placebo, intravenously administered lidocaine or inhaled lidocaine do not change the histamine threshold for a hyperreactive response; and (3) peak lidocaine plasma concentrations and plasma concentrations at the end of the histamine challenge do not differ following inhalation or intravenous administration of lidocaine. Comparisons were made by the Friedman test followed by Wilcoxon signed-rank test with correction for multiple comparisons (Bonferroni). Null hypotheses were rejected and significant statistical differences assumed with an alpha error of p < 0.05.

	RESULTS

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Both intravenous and inhalational administration of lidocaine doubled the histamine threshold from 6.4 ± 1.1 mg · ml¹ to 14.2 ± 2.5 mg · ml¹ and 14.8 ± 3.5 mg · ml¹, respectively (p = 0.0007), despite significant lower lidocaine plasma concentrations following lidocaine inhalation. The thresholds for each volunteer on each study day are presented in Figure 1.

View larger version (16K): [in this window] [in a new window]   Figure 1.   Histamine concentrations (logarithmic scale) inducing a 20% decrease of FEV1 (PC20); placebo versus lidocaine administered intravenously (left panel ), or placebo versus lidocaine aerosol (right panel ). Each pair of symbols represents the response of one volunteer with mean values to the left and right of the individual data. Open symbols represent placebo while closed symbols represent the responses to lidocaine. The inhalational histamine challenges were performed on three different days. Lidocaine administered intravenously or as an aerosol significantly (p = 0.0007) increased the histamine threshold when compared to placebo. There was no statistical difference between the two modes of administration.

In contrast, the histamine threshold (PC₂₀) following administration of placebo (6.4 ± 1.1 mg · ml¹) did not differ significantly from the threshold obtained at the screening visit (7.2 ± 1.3 mg · ml¹).

The lidocaine plasma concentrations following intravenous and inhalational administration are presented in Figure 2. Peak lidocaine plasma concentration at the end of the intravenous "loading dose" of lidocaine was 2.4 ± 0.15 µg · ml¹, while lidocaine inhalation led to a peak plasma concentration of only 1.5 ± 0.14 µg · ml¹ (p = 0.0229). The peak plasma concentration following intravenous administration was maintained over the time of the challenge and did not differ significantly from the concentration at the end of the histamine challenge (2.2 ± 0.14 µg · ml¹ at 20 min and 2.1 ± 0.17 µg · ml¹ at 50 min, respectively).

View larger version (26K): [in this window] [in a new window]   Figure 2.   Time course of lidocaine and monoethylglycinxylidide (Meg X) (lower panel ) plasma concentrations following intravenous (upper panel ) or inhalational (middle panel ) administration of lidocaine in 13 volunteers (mean ± SEM). With continuous infusion of lidocaine after the loading dose, a stable concentration was maintained during the inhalational challenge. There is no significant difference of the lidocaine concentration at the end of the loading dose and at the end of the inhalational challenge. In contrast, inhalation of lidocaine leads to an initial concentration peak after 15 min and a steady decline to about half of the initial peak values. A third of the peak plasma concentrations is observed following intravenous administration at the time of the maximal inhalational challenge. Irrespective of the lidocaine administration route, peak plasma concentrations of lidocaine are below the toxic range of 5 µg · ml1. Of note, despite similar attenuation of bronchoconstriction, lidocaine plasma concentrations following lidocaine inhalation were significantly lower than after lidocaine infusion. Meg X plasma concentrations increase to a plateau 15 min after termination of intravenous lidocaine infusion, but still increase up to 50 min following lidocaine inhalation. Therefore, a prolonged local absorption of lidocaine from the airways can be assumed.

In contrast, lidocaine plasma concentration following inhalation of lidocaine declined over the duration of the histamine challenge. In fact, the concentration at the end of the challenges (0.7 ± 0.08 µg · ml¹) was significantly different from the respective peak concentration (1.5 ± 0.14 µg · ml¹, p = 0.0015) and the lidocaine plasma concentration at the time of the maximal challenge during intravenous administration (2.1 ± 0.17 µg · ml¹, p = 0.0022).

Meg X plasma concentrations reached a peak for intravenous as well as inhalational administration (221 ± 29 ng · ml¹ and 126 ± ng · ml¹, respectively) after 65 min and showed a plateau following both treatments for 50 to 90 min (Fig. 2).

Baseline FEV₁ and VC were assessed on each study day and compared to the FEV₁ and VC following treatments with lidocaine and placebo. FEV₁ and VC significantly decreased following lidocaine inhalation, while both placebo and intravenous administration of lidocaine did not alter FEV₁ and VC (Table 1).

Heart rate and arterial blood pressure were not affected by the loading dose or the continuous infusion of lidocaine, nor by lidocaine inhalation. During intravenous administration of lidocaine, 3 of 15 volunteers mentioned lightheadedness and slight vertigo, which was also mentioned during both intravenous placebo as well as inhalational lidocaine administration by 1 of 15 volunteers.

	DISCUSSION

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Bronchial hyperreactivity was significantly attenuated by both intravenous as well as inhalational administration of lidocaine, while inhaled lidocaine excited the same attenuation despite significantly lower plasma concentrations. However, inhalation of lidocaine also led to an initial significant decrease of FEV₁. This indicates that intravenous administration can be recommended as the preferred route for attenuation of bronchial hyperreactivity if local anesthesia of the airways is not required.

These results emerged from evaluation of 15 volunteers with moderate bronchial hyperreactivity, all of which were in a stable clinical condition under their current medication or during their symptom-free interval (12). Bronchial hyperreactivity was confirmed and tested by an inhalational histamine challenge (1). Compared to challenge protocols using methacholine, histamine stimulates smooth muscle cells not only directly, but also may provoke reflex bronchoconstriction similar to a mechanical stimulation during endotracheal intubation or bronchoscopy (13, 14). The challenge was performed with control of inspiratory flow, a 5-s breath-hold at end inspiration, a defined time of nebulization during inspiration (15), and a fixed number of breaths to assure a high reproducibility of the challenge. Histamine challenges were performed on three different days using FEV₁, with its small day-to-day variability, to analyze the responses (16).

While intravenous administration of lidocaine did not alter baseline lung function, a decrease in FEV₁ following lidocaine inhalation has been described previously. Overall, both a decrease in FEV₁ as well as an increase in a minority of subjects have been reported following lidocaine inhalation, with a mean decrease ranging from 2.5% to 23.4% (4). In one study individual responses ranged from a 28.2% increase to a 42.1% decrease (7). These effects are observed independent from the use of additives or the extent of underlying bronchial hyperreactivity (4, 7). Moreover, in these studies a lidocaine concentration of 4% was used instead of 10%, with comparable airway irritation, so that the concentration does not seem to have a relevant influence as well.

Although the mean decrease in FEV₁ of 6.7% in our study is statistically significant, a clinically relevant change can be assumed in subjects with obstructive airway disease only with a decrease in FEV₁ by 15 to 17% (16). Therefore, results of the subsequent histamine challenge are not expected to be significantly altered by this small baseline shift.

In our previous study, intravenous administration of lidocaine (2.0 mg · kg¹ over 30 min followed by 4.0 mg · kg¹ · h¹) had caused significant attenuation of bronchial hyperreactivity as well as mild central nervous side effects in 40% of the volunteers (1). Accordingly, in the present study we decreased slightly both the loading dose and subsequent lidocaine infusion rate, resulting in decreased lidocaine peak plasma concentrations as well as a decreased number of volunteers with mild side effects. Continuous lidocaine infusion led to a plateau of the lidocaine plasma concentration during inhalational challenge (Figure 2) well below the toxic range of 5.0 µg · ml¹. Thus, we consider this dose of intravenous lidocaine as both appropriate and safe.

Lidocaine administration to the airways leads to variable plasma concentrations, depending on mode of delivery and dose. In accordance with our results (1.5 µg · ml¹ ± 0.14), inhalation of lidocaine (1.5 to 3.0 mg · kg¹) over more than 10 min led to peak lidocaine plasma concentrations between 0.25 µg · ml¹ and 1.7 µg · ml¹ (2, 19).

Peak plasma concentrations following lidocaine inhalation were significantly lower than those following intravenous administration. In fact, due to the continuous decrease in lidocaine plasma concentration during the challenge sequence, plasma concentrations at the time of the maximal histamine challenge were only a third of the concentrations achieved with continuous infusion. Nevertheless, despite this concentration difference, both intravenous as well as inhalational administration of lidocaine led to the same attenuation of bronchial hyperreactivity. Similar attenuation of bronchial hyperreactivity at different lidocaine plasma concentrations strongly suggests differences in mechanisms involved following the inhalational or intravenous route of administration.

Two main mechanisms, neural blockade of vagal reflex pathways and direct effects on smooth muscle cells, may explain the effect of lidocaine on bronchial hyperreactivity (23- 25). Constriction of rat-tail arteries induced via sympathetic nerve stimulation is blocked at a lidocaine concentration of approximately 10 µg · ml¹, but not constriction due to direct stimulation of smooth muscle cells by potassium or norepinephrine (25). Moreover, intravenous lidocaine attenuates different reflexes in animals (26, 27) as well as in humans undergoing general anesthesia, where intravenous lidocaine effectively suppressed reflex-induced cough (28, 29). Therefore, we assume that reflex suppression is the main mechanism to explain the protective effect of intravenous lidocaine in awake volunteers with bronchial hyperreactivity.

Lidocaine also significantly attenuates the response to direct stimulation of smooth muscle cells by acetylcholine or potassium in vitro (24). However, since concentrations of local anesthetics used in these experiments (20-200 µg · ml¹) exceeded 10- to 100-fold the plasma concentrations observed during clinical use, direct attenuation of bronchial smooth muscle tone is not a likely explanation for attenuation of bronchial hyperreactivity following intravenous lidocaine. In contrast to lidocaine infusion, inhalation of lidocaine yields much higher airway concentrations with lower plasma concentrations (24). Accordingly, direct smooth muscle effects may contribute to attenuation of bronchoconstriction following lidocaine inhalation.

Bulut and colleagues (30) demonstrated in dogs with hyperreactive airways (Basenji greyhounds) that an intravenous lidocaine bolus given prior to lidocaine inhalation can prevent bronchoconstriction due to lidocaine inhalation. The results of this study clearly underline the effect of intravenous lidocaine on reflex bronchoconstriction, but the fast systemic absorption of inhaled lidocaine would add to the peak plasma concentrations following intravenous administration of lidocaine, which already led to central nervous side effects in some subjects. Therefore, we did not test the combination and cannot recommend giving an intravenous bolus of lidocaine prior to inhalation of lidocaine.

Plasma concentrations of Meg X, the first metabolite of lidocaine, showed a much longer-lasting plateau following lidocaine inhalation than following intravenous administration, suggesting prolonged lidocaine absorption from the airway into the bloodstream. In fact, Meg X plasma concentrations still increased for 40 min after completion of inhalation, while peak Meg X concentrations were already reached 10 min after termination of lidocaine infusion. Accordingly, although not specifically tested in this study, lidocaine inhalation is likely to have a longer-lasting effect on bronchial hyperreactivity than intravenous administration and might even offer an alternative treatment for airway hyperreactivity. In fact, Hunt and coworkers (31) reported a steroid-sparing effect in patients with severe asthma with inhalation of 40 mg lidocaine three times a day.

In summary, lidocaine both when administered intravenously or as an aerosol significantly attenuates bronchial hyperreactivity in a quantitatively similar fashion, but with lower plasma concentrations following inhalation. On the other hand, inhalation of lidocaine leads to an initial decrease in FEV₁ in the majority of the volunteers. Accordingly, when prevention of reflex bronchoconstriction, e.g., prior to airway instrumentation is required, intravenous lidocaine seems to be the safer and more reliable alternative.