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Lidocaine inhalation for local anaesthesia and attenuation of bronchial hyper-reactivity with least airway irritation. Effect of three different dose regimens

Groeben, H*; Growendt, T; Silvanus, M.-T*; Beste, M; Peters, J

European Journal of Anaesthesiology (EJA): November 2000 - Volume 17 - Issue 11 - p 672-679
Original Papers

The inhalation of lidocaine attenuates bronchial hyper-reactivity but also causes airway irritation. However, how lidocaine dose and plasma concentration influence relationships are unknown. Accordingly, we evaluated the effects of three concentrations of lidocaine (1, 4, and 10%, total dose of 0.5, 2.0, and 5.0 mg kg−1, respectively) vs. placebo in 15 mild asthmatic patients, selected by their response to a histamine challenge (decrease in FEV1 > 20% to less than 18 mg mL−1 of histamine [PC20]). Baseline lung function, histamine-induced bronchoconstriction, topical anaesthesia, and lidocaine plasma concentrations were obtained. FEV1 following lidocaine inhalation showed the greatest decrease for the highest dose (from 3.79 ± 0.15-3.60 ± 0.15; P = 0.0012). Lidocaine inhalation increased baseline PC20 (6.1 ± 1.3 mg mL−1) significantly (to 11.8 ± 3.1, 16.1 ± 3.3, and 18.3 ± 4.5 mg mL−1, respectively) with no difference between the two highest doses. The duration of local anaesthesia was not significantly different between lidocaine concentrations of 4% and 10%. Thus, lidocaine inhalation, with increasing concentrations of the aerosolized solution, increases initial bronchoconstriction while significant attenuation of bronchial hyper-reactivity is not further enhanced with increasing concentrations from 4 to 10%. Plasma concentrations of lidocaine were always far below the toxic threshold. In conclusion, when local anaesthesia of the airways is required a lidocaine dose of 2.0 mg kg−1 as a 4% solution can be recommended for local anaesthesia and attenuation of bronchial hyper-reactivity with the least airway irritation.

Departments of *Anaesthesiology and Intensive Medicine and †Gastroenterology, University of Essen, Essen, Germany

Accepted May 2000

Correspondence: H. Groeben, Abteilung für Anästhesiologie und Intensivmedizin, Universität Essen, Hufelandstr. 55, D-45122 Essen, Germany

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Lidocaine inhalation in subjects with bronchial hyper-reactivity attenuates bronchoconstriction in response to a variety of stimuli, but also causes airway irritation [1-4]. However, whether these antagonistic effects relate to inhaled lidocaine concentration and total dose is unknown. In this context the question arises if high concentrations and doses of lidocaine can overcome initial bronchoconstriction and thus lead to direct attenuation of bronchial hyper-reactivity. On the other hand, there are hints that profound upper airway anaesthesia can impair co-ordination of motor function of pharyngeal muscles as visualized by fibreoptic laryngoscopy [5]. If this mechanism indeed causes upper airway obstruction, it might be avoided by the use of lower concentrations of lidocaine.

The main clinical interest is to inhale lidocaine for topical anaesthesia to facilitate fibreoptic bronchoscopy or awake endotracheal intubation. So if an optimal lidocaine concentration can be identified with the least airway irritation and the most attenuation of bronchial reactivity, the question remains how this concentration relates to topical anaesthesia and the resulting lidocaine plasma concentrations?

Therefore, we tested in volunteers with bronchial hyper-reactivity the hypotheses that lidocaine inhalation in three different concentrations and doses: (a) alters baseline lung function; (b) changes maximal inspiratory and expiratory flow rates as a parameter for upper airway obstruction; (c) attenuates the response to an inhalational challenge with histamine; (d). increases topical anaesthesia with increasing concentrations and doses of lidocaine. Finally, lidocaine plasma concentrations during inhalation and the following histamine challenge were determined.

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After approval of the local ethics committee and informed written consent, 15 subjects (age 31.8±2.1 years; mean ± SEM) were enrolled in this randomized, double-blinded, placebo-controlled study. The subjects were of normal height (178±2 cm) and weight (74±4.1 kg). Nine of the subjects were women, six were men. All subjects had active asthma (n = 10) or significant hay fever (n = 5) and symptoms consistent with airway hyper-reactivity. None of the subjects was a smoker. Eight subjects used a β-adrenergic inhaler, four on a regular and five on an 'as needed' basis, two inhaled corticosteroids. None of them received β-adrenergic medication within the last 12h prior to the measurements and none of the subjects had used theophylline preparations or systemic corticosteroids in the last 3 months. A total number of 60 studies in 15 volunteers were performed.

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Lung function measurements were performed in a body plethysmograph (Masterlab Jaeger, Würzburg, Germany) with an integrated spirometer (Jaeger, Würzburg, Germany) in each subject at the same time of day (± 1 h). On the initial screening visit, baseline vital capacity (VC), forced expiratory volume in 1 second (FEV1), maximal expiratory flow at 50% of the vital capacity (MEF50), maximal inspiratory flow at 50% of the vital capacity (MIF50), and airway resistance (Rtot) were assessed. This was followed by an inhalational challenge with histamine to confirm bronchial hyper-reactivity. Bronchial hyper-reactivity was defined by a decrease of FEV1 of at least 20% from baseline following the inhalation of histamine in a concentration less than 18 mg mL−1. Three additional volunteers were not enrolled in the study despite a history of airway hyper-reactivity because they did not respond to histamine with a decrease in FEV1 of 20% or more (11, 14, and 15%).

Venous blood was drawn from an antecubital vein to measure lidocaine plasma concentrations using an immunofluorescence assay (Abbott TDx System, Abbott Wiesbaden, Germany). The lower level of detection is 0.1 μg mL−1 and the coefficient of variation is less than 3% [6].

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Aerosol challenge

Aerosol inhalation was performed with a nebulizer driven by compressed air at 30 psi (207 kPa) (DeVilbiss no. 646, DeVilbiss, Somerset, PA, USA) using a mouth piece and a nose clip. The subjects were instructed to inspire from functional residual capacity (FRC) to inspiratory capacity at an inspiratory flow rate of less than 0.6 L s−1. At end-inspiration the subjects were advised to hold their breath for five seconds. Nebulization was triggered by inspiration starting after the first 500-750 mL of inspiration and was maintained for 0.8 s (Spira Elektro 2 flowmeter; Respiratory Care Center, Hämeenlinna, Finland). This manoeuvre 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.

Initially the subjects were challenged with aerosolized saline, followed by increasing doses of histamine diphosphate (Sigma-Aldrich GmbH, Deisenhofen, Germany) diluted in saline. The starting concentration of histamine diphosphate was 0.075 mg mL−1, which was trebled on each subsequent challenge up to a maximal concentration of 18 mg mL−1. The time interval between inhalations of increasing histamine concentrations was kept constant. Trebling doses of histamine diphosphate were chosen instead of the usual doubling dose with respect to the half-life of lidocaine, the number of challenges, and to minimize possible tachyphylaxis of the histamine effect.

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 [7].

For each individual, two histamine concentrations lower than the concentration that had caused a 20% decrease in FEV1 (PC20) was considered the starting concentration for all subsequent challenges. If a subject in one of the subsequent histamine challenges did not reach a 20% decrease in FEV1 PC20 was calculated by extrapolation [7].

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

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Lidocaine inhalation

Lidocaine was diluted in saline without additives. A nebulizer driven by compressed air at 30 psi (207 kPa) (DeVilbiss no. 646, Somerset, PA, USA), produced aerosol. The start of nebulization was triggered (Spira Elektro 2 flowmeter) after inhalation of 100 mL air.

The volunteers took deep tidal breaths with a nebulization time of 2 s with each breath and they were advised to perform a 5-s breath hold at the end of each inspiration. The inhalation was continued until the complete solution was aerosolized. Topical anaesthesia was tested by touching the uvula and the posterior pharyngeal wall with a cotton swab. The response was judged by eliciting gag reflex and the volunteer's sensation.

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On each study day baseline lung function was assessed and further measurements were postponed, if the actual FEV1 differed by more than 7% from the initial baseline obtained on the day of the screening visit.

On a total of four tests on four different study days, in random order, and in a double-blind fashion, the subjects inhaled lidocaine either as a 1, 4, or 10% solution vs. placebo. The total doses of lidocaine were 0.5, 2.0, or 5.0 mg kg−1, respectively. Directly after the inhalation of lidocaine or placebo lung function was measured. Subsequently, the histamine challenge was repeated. Venous blood was drawn from an antecubital vein prior to the start of the inhalation and every five minutes for up to 75 min

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Data analysis

Data are presented as means ±SEM. The following a priori null hypotheses were tested: (a) lidocaine inhalation does not change baseline lung function regardless of the used concentration; (b) lidocaine inhalation does not cause upper airway obstruction; (c) lidocaine inhalation does not change the response to a histamine challenge compared to placebo; and (d) all three concentrations of lidocaine lead to the same duration of local anaesthesia. Comparisons were made by the Friedman test followed by Willcoxon signed rank test with Bonferroni correction of the α-error for multiple comparisons. Null hypotheses were rejected and significant differences assumed with P < 0.05 as indicated.

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Lidocaine inhalation significantly decreased FEV1 in a dose- and concentration-dependent fashion. Subsequently, histamine-induced bronchoconstriction was significantly attenuated by inhalation of all three lidocaine concentrations with no significant difference between inhalation of lidocaine as a 4 (2.0 mg kg−1) or 10% (5.0 mg kg−1) solution.

Inhalation of saline (placebo) did not alter FEV1 (3.73±0.14 L vs. 3.65±0.15 L), while lidocaine inhalation in increasing concentrations decreased FEV1 from 3.72±0.17 L to 3.60±0.17 L (1%, 0.5 mg kg−1), from 3.69±0.15 L to 3.58±0.14 L (4%, 2.0 mg kg−1), and from 3.79±0.15 L to 3.60±0.15 L (10%, 5.0 mg kg−1; P = 0.0012) as shown in Fig. 1. The inhalation of lidocaine did not change the ratio of maximal expiratory over inspiratory flow at 50% of the vital capacity (Table 1), independent of concentration.

Fig. 1

Fig. 1

Table 1

Table 1

Inhalational administration of lidocaine in increasing concentrations significantly raised histamine thresholds to 11.8±3.1 mg mL−1, 16.1±2.3 mg mL−1, and 18.3±4.5 mg mL−1, respectively (Fig. 2). Histamine threshold (PC20) following administration of placebo (6.1±1.3 mg mL−1 histamine) did not differ significantly from the threshold obtained at the screening visit (7.0±1.3 mg mL−1).

Fig. 2

Fig. 2

Peak lidocaine plasma concentrations following the inhalation of all three lidocaine concentrations were far below the toxic threshold of 5.0 μg mL−1 and significantly different from one another as well as at the time of the maximal histamine challenge (Fig. 3). The duration of local anaesthesia was significantly longer following inhalation of 4% (2.0 mg kg−1) and 10% lidocaine solution (5.0 mg kg−1; 27.7 vs. 31.5 min) compared to lidocaine 1% (0.5 mg kg−1; 15.3 min), but not between the effect of the 4 and 10% solution (Fig. 4). Eleven of 15 volunteers spontaneously mentioned a less intense topical anaesthesia of the 1% lidocaine solution compared to the other two solutions.

Fig. 3

Fig. 3

Fig. 4

Fig. 4

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Attenuation of bronchial hyper-reactivity and duration of local anaesthesia following inhalation of three different lidocaine concentrations reached a maximal effect with the lidocaine solution of 4% and were not further increased by the 10% solution. In contrast, FEV1 decreased as a sign of airway irritation in a concentration dependent fashion with the most irritation induced by the 10% solution.

These results emerged in 15 volunteers with moderate bronchial hyper-reactivity, all in stable clinical condition under current medication or during their symptom free interval. The same investigator made all measurements at the same time of day. To maximize reproducibility of the histamine challenge during the four study days, a 5-s breath hold at end-inspiration was requested, a fixed time of nebulization during inspiration and a fixed number of breaths were defined. Furthermore, inspiratory flow was controlled to prevent uneven aerosol distribution and to minimize turbulent airflow [8]. Because of its low day to day variability FEV1 was chosen to analyse the response to the histamine challenges on the different study days [9-12].

Lidocaine inhalation led to peak mean lidocaine plasma concentrations of 1.4 μg mL−1 which is far below the toxic threshold of 5.0 μg mL−1 and did not cause even mild systemic side-effects. Lidocaine plasma concentrations measured after inhalation were well within the range of plasma concentrations reported after inhaling 1.5-3.0 mg kg−1 lidocaine (0.25-1.7 μg mL−1) [13-17].

A decrease in FEV1 (by a mean of 2.5-23.4%) following lidocaine inhalation is described in the literature and in accordance with our results [2-8]. These effects are observed independent from the use of additives or the extent of underlying bronchial hyper-reactivity [1,14].

Two main mechanisms may explain the decrease in FEV1 observed following lidocaine inhalation. First, upper airway anaesthesia may impair upper airway motility by either blocking partially the efferent input to the musculature or the perception of inspiration and expiration, or both. In fact, altered co-ordination of upper airway and laryngeal musculature during inspiration was directly visualized during fibreoptic laryngoscopy and was suspected to cause upper airway obstruction [5]. Upper airway obstruction alters predominantly inspiratory rather than expiratory maximal flow rates [18,19]. Therefore, significant upper airway obstruction should be revealed by a shift in the ratio of maximal expiratory flow over maximal inspiratory flow rates. However, this flow ratio as a marker of extrathoracic airway obstruction [18,19], remained unaltered even following inhalation of the highest concentration of lidocaine.

Second, lidocaine inhalation leads to an initial bronchoconstriction as visualized by high resolution computererized tomography in dogs [20]. When cross-sections of different airway generations, before and after administration of lidocaine aerosol, were analysed, a 27% mean decrease from baseline was observed that could be prevented by intravenous (i.v.) lidocaine pretreatment [20].

Overall, since initial bronchoconstriction was not associated with changes of the ratio of maximal inspiratory and expiratory flow rates and was abolished by i.v. lidocaine the effect of inhaled lidocaine is probably mostly due to airway irritation rather than alteration of upper airway motility.

Following initial airway irritation lidocaine inhalation led to an attenuation of the response to the histamine challenge. Two main mechanisms, direct effects on smooth muscle cells and neural blockade of vagal pathways, or both, may explain this protective effect of lidocaine inhalation [21,22].

Lidocaine (20-200 μg mL−1) on pig trachealis muscle strips attenuates contraction of smooth muscle cells evoked by acetylcholine and potassium [21]. Although these lidocaine concentrations exceed 10-100-fold plasma concentrations observed in this study, lidocaine inhalation can be expected to provide local airway concentrations in that range. Thus, direct effects of lidocaine on airway smooth muscle may significantly contribute to the beneficial effect of lidocaine inhalation on bronchial hyper-reactivity.

On the other hand, lidocaine, in concentrations of approximately 10 μg mL−1, attenuates or even abolishes different reflexes in animals following i.v. administration in clinically relevant plasma concentrations [22-24]. Moreover, in humans undergoing general anaesthesia i.v. lidocaine effectively suppressed reflex-induced cough and, in awake volunteers with bronchial hyper-reactivity, dose-dependently attenuated the response to histamine inhalation [25-27]. Thus, suppression of reflex bronchoconstriction is the main mechanism to explain the systemic effects of i.v. lidocaine.

However, lidocaine inhalation led to plasma concentrations that were only a third of the concentrations required for the systemic effects. Furthermore, increasing the inhaled lidocaine concentration from 4 to 10% led to an increase in the resulting plasma concentrations but not to a further increase in PC20. Therefore, systemic effects following lidocaine absorption are not a likely explanation for the observed effects. Hence, we assume that direct effects on airway smooth muscle cells most likely explain the effect of lidocaine inhalation and that reflex suppression via systemic effects only contributes to the protective effects of lidocaine inhalation.

Finally, the question remains how these effects relate to the local anaesthetic effect of the aerosols. Increasing lidocaine concentration from 4 to 10% (2.0 to 5.0 mg kg−1) does not provide significant longer lasting or more profound local anaesthesia. Accordingly, when lidocaine is used for topical airway anaesthesia in subjects with bronchial hyper-reactivity a concentration of 4% (2.0 mg kg−1) can be recommended. This concentration of lidocaine can be expected to provide (a) significant attenuation of bronchial hyper-reactivity (b) profound topical anaesthesia, with (c) the least minimal airway irritation.

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