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(Chest. 2000;118:509-515.)
© 2000 American College of Chest Physicians

Combined Lidocaine and Salbutamol Inhalation for Airway Anesthesia Markedly Protects Against Reflex Bronchoconstriction*

Harald Groeben, MD; Marie-Theres Silvanus, MD; Mechthild Beste and Jürgen Peters, MD

* From the Abteilung für Anästhesiologie und Intensivmedizin (Drs. Groeben, Silvanus, and Peters) and Abteilung für Gastroenterologie (Ms. Beste), Universität Essen, Essen, Germany.

Correspondence to: Harald Groeben, MD, Abteilung für Anästhesiologie und Intensivmedizin, Universität Essen, Hufelandstr 55, 45122 Essen, Germany; e-mail: harald.groeben{at}uni-essen.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Lidocaine inhalation, in subjects with bronchial hyperreactivity, attenuates evoked bronchoconstriction but also irritates airways. Whether salbutamol pretreatment can mitigate airway irritation and whether combined treatment offers more protection than treatment with either drug alone is unknown. Therefore, we evaluated the effects of the inhalation of lidocaine, salbutamol, lidocaine and salbutamol combined, and placebo on an inhalational histamine challenge.

Methods: Fifteen patients with mild asthma were selected by a screening procedure (ie, a provocative concentration of a substance [histamine aerosol of < 18 mg/mL] causing a 20% fall in FEV1 [PC20]). On 4 different days after pretreatment with the inhalation of lidocaine (5 mg/kg), inhalation of salbutamol (1.5 mg), combined treatment, or placebo, the histamine challenge was repeated.

Results: The baseline FEV1 after lidocaine inhalation but prior to the histamine challenge decreased by > 5% in 7 of 15 volunteers, with a mean (± SD) decrease from 3.82 ± 0.90 to 3.54 ± 0.86 L (p = 0.0054). The baseline PC20 for histamine was 6.4 ± 4.3 mg/mL. Both lidocaine and salbutamol inhalation significantly increased PC20 more than twofold (14.9 ± 13.7 and 16.8 ± 10.9 mg/mL, respectively; p = 0,0007) at a lidocaine plasma concentration of 0.7 ± 0.3 µg/mL. Combined treatment quadrupled the PC20 to 29.7 ± 20.3 mg/mL (vs lidocaine, p = 0.002; vs salbutamol, p = 0.003).

Conclusions: Thus, histamine-evoked bronchoconstriction, as a model of reflex bronchoconstriction, can be significantly attenuated by salbutamol or lidocaine inhalation. However, lidocaine inhalation causes significant initial bronchoconstriction. The combined inhalation of salbutamol and lidocaine prevents the initial bronchoconstriction observed with lidocaine alone and offers even more protection to a histamine challenge than either lidocaine or salbutamol alone. Therefore, the combined inhalation of lidocaine and salbutamol can be recommended to mitigate bronchoconstriction when airway instrumentation is required.

Key Words: airway resistance • asthma • bronchospasm • lidocaine • lung


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In patients with asthma and individuals with bronchial hyperreactivity, airway instrumentation such as endotracheal intubation can cause life-threatening bronchospasm, as outlined by the closed claim project of the American Society of Anesthesiologists.1

Lidocaine inhalation attenuates the response to different stimuli evoking bronchoconstriction, like hyperosmolar saline solution, exercise-induced asthma, and histamine.2 3 4 In fact, as we have shown earlier in the same group of volunteers, inhalation of lidocaine attenuates bronchial hyperreactivity as effectively as IV administration.5 However, the use of lidocaine as an aerosol can evoke an initial bronchoconstriction in patients with bronchial hyperreactivity.2 3 4 6 7 8 9

In case awake endotracheal intubation or bronchoscopy in asthmatic patients is required, the topical administration of local anesthetics is obviously unavoidable and the initial airway irritation as well as the subsequent attenuation of bronchial reactivity caused by lidocaine attain clinical relevance.

There are four studies describing in patients with asthma the tolerance of bronchoscopy performed with topical lidocaine anesthesia, sometimes with the need for repeated lidocaine administration, but without antiobstructive treatment with a ß-adrenergic aerosol prior to the procedure.10 11 12 13 In all of these studies, an initial irritation by lidocaine inhalation is mentioned, while the attenuation of bronchial hyperreactivity by lidocaine inhalation is completely ignored.10 11 12 13 Although there are no studies to our knowledge that have compared the effect of lidocaine inhalation with a ß-adrenergic aerosol, the tolerance of the asthmatic patients to the mechanical irritation of bronchoscopy may simply be explained by the protective effect of lidocaine inhalation.

To test the hypothesis that lidocaine inhalation attenuates bronchial hyperreactivity in a manner that is comparable to salbutamol as a standard prophylactic treatment, volunteers with bronchial hyperreactivity were challenged with histamine following pretreatment with inhalation of lidocaine or salbutamol vs placebo. Furthermore, to assess whether salbutamol can mitigate any irritation evoked by lidocaine inhalation, the effect of a combined lidocaine and salbutamol inhalation also was evaluated. Finally, salbutamol pretreatment might hasten lidocaine absorption and increase peak lidocaine plasma concentrations toward the toxic threshold.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
After approval of the local ethics committee and receiving informed written consent from the patients, 15 subjects ([mean ± SD] age 34.9 ± 6.4 years) were enrolled in this randomized, double-blinded, placebo-controlled study, which is the third part of an extended work consisting of three study arms. The results of the first study arm (IV lidocaine vs salbutamol) and the second study arm (lidocaine inhalation vs IV lidocaine) have already been published.5 14 The subjects were of normal height (177 ± 9.3 cm) and weight (75 ± 17.7 kg). Eight of the subjects were women, and 7 were men. Of the 15 subjects, 9 had active asthma, 1 had childhood asthma, 3 had significant hay fever, and 2 had COPD. All subjects had symptoms consistent with airway hyperreactivity. Two of the subjects were smokers. Eight subjects used a ß-adrenergic inhaler, three on a regular basis and five on an as-needed basis, two inhaled corticosteroids. None of them had received a ß-adrenergic medication within the last 12 h prior to the measurements, and none of the subjects had used theophylline preparations or systemic corticosteroids in the previous 3 months.

Measurements
Lung function measurements were performed in a body plethysmograph (Masterlab; Jaeger; Würzburg, Germany) with an integrated spirometer (Jaeger) in each subject at the same time of day (± 1 h). On the initial screening visit, baseline vital capacity (VC), FEV1, and airway resistance were assessed, followed by an inhalational challenge with histamine to confirm bronchial hyperreactivity. Bronchial hyperreactivity was defined by the administration of a provocative concentration of a substance (histamine in a concentration of < 18 mg/mL) causing a 20% fall in FEV1 (PC20) from baseline. Five additional volunteers were not enrolled in the study, despite a history of airway hyperreactivity, because they did not respond to histamine with a decrease in FEV1 of >= 20% (change, 13 to 17%).

To measure lidocaine serum concentrations in antecubital venous blood (18-G cannula), an immunofluorescence assay was used (TDx System; Abbott; Wiesbaden, Germany). The lower level of detection is 0.1 µg/mL, and the coefficient of variation is < 3%.15 Blood samples were processed from 13 of 15 volunteers.

During interventions, heart rate (ECG lead II) and arterial BP (oscillometry) were monitored in 5-min intervals.

Aerosol Challenge
Aerosol inhalation was performed with a nebulizer (model No. 646; DeVilbiss; Somerset, PA) driven by compressed air at 30 lb/square inch using a mouthpiece and a nose clip. The subjects were instructed to inspire from functional residual capacity to inspiratory capacity at an inspiratory flow rate of < 0.6 L/s. At end-inspiration, the subjects were advised to hold their breath for 5 s. Nebulization was triggered by inspiration (Spira elektro 2 flowmeter; Respiratory Care Center; Hämeenlinna, Finland) starting after the first 500 to 750 mL of inspiration and was maintained for 0.6 s. This maneuver was repeated five times. One to 2 min after the 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 solution, followed by increasing doses of histamine diphosphate (Sigma-Aldrich GmbH; Deisenhofen, Germany) diluted in saline solution. The starting concentration of histamine diphosphate was 0.075 mg/mL, which was trebled on each subsequent challenge up to a maximal concentration of 18 mg/mL. 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 because of the half-life of lidocaine, the number of challenges, and the need 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 PC20 histamine threshold concentration was calculated for each subject.16

For each individual, two histamine concentrations lower than the 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, the PC20 was calculated by extrapolation.16

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

Inhalation of Salbutamol and Lidocaine
Salbutamol (1.5 mg in 1.5 mL saline solution) and lidocaine (5 mg/kg in a concentration of 100 mg/mL) were diluted in saline solution without additives. Aerosol was produced by a nebulizer (model No. 646; DeVilbiss) driven by compressed air at 30 lb/square inch. The start of nebulization was triggered by a flowmeter (Spira elektro 2 flowmeter; Respiratory Care Center) after the 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 end-inspiration. The inhalation was continued until the solution was aerosolized.

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

On four different study days, in random order and in a double-blinded fashion, the subjects received salbutamol aerosol, placebo, placebo followed by lidocaine aerosol, or salbutamol aerosol followed by lidocaine aerosol. In this way, they received in a random fashion on the first day only salbutamol, on the second day only placebo, on the third day placebo and lidocaine, and on the fourth day salbutamol and lidocaine. Randomization was performed with respect to the other two study arms.

Lung function measurements, medication inhalation, and histamine challenges were performed in direct sequence without any interruption. Venous blood was drawn prior to the start of the inhalation and every 5 min for up to 90 min.

Data Analysis
Data are presented as mean ± SD. The following a priori null hypotheses were tested: (1) lidocaine inhalation as well as salbutamol inhalation do not change baseline lung function; (2) lidocaine or salbutamol inhalation as well as the combination of salbutamol and lidocaine inhalation do not change the histamine threshold compared to placebo inhalation. Comparisons were made by the Friedman test followed by Wilcoxon signed rank test with correction of the {alpha}-error for multiple comparisons (Bonferroni correction). Null hypotheses were rejected, and significant differences were assumed, with p < 0.05, as indicated.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Lidocaine inhalation decreased FEV1 and VC significantly, while both salbutamol and combined salbutamol and lidocaine inhalation improved lung function.

The inhalation of saline solution (placebo) did not alter either FEV1 (3.78 ± 0.92 L; p = 0.6701) or VC (4.88 ± 1.31 L; p = 0.1118). Lidocaine inhalation significantly decreased FEV1 by 7.1% from 3.82 ± 0.90 to 3.54 ± 0.86 L (p = 0.0054), but not VC (4.84 ± 1.12 to 4.70 ± 1.07 L [2.9%]; p = 0.3109). Salbutamol inhalation significantly improved FEV1 (3.79 ± 0.86 to 3.97 ± 0.84 L; p = 0.0083) and VC (4.78 ± 1.12 to 4.87 ± 1.13; p = 0.0098). Salbutamol and lidocaine combined had a significant effect on baseline FEV1 (3.76 ± 0.85 to 3.95 ± 0.96 L; p = 0.0070) (Fig 1 ) and VC (4.75 ± 1.10 to 4.91 ± 1.27 L; p = 0.0083).



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  		Figure 1. The effect of inhalation of lidocaine (left, A), salbutamol (middle left, B), combined lidocaine and salbutamol (middle right, C), and saline solution placebo (right, D) compared to baseline FEV1 on each day. Each pair of symbols represents the response of one volunteer. Mean ± SD are presented to the left and right of the individual data. Lidocaine inhalation leads to a significant decrease of FEV1 prior to the histamine challenge, while salbutamol inhalation significantly increases FEV1. Combined treatment with salbutamol and lidocaine attenuates the initial bronchoconstriction evoked by lidocaine inhalation. * = p < 0.05 vs baseline; ns = not significant.

 
Subsequently, evoked bronchoconstriction was significantly attenuated by both salbutamol and lidocaine inhalation. The inhalation of salbutamol and lidocaine in sequence even further attenuated bronchial hyperreactivity.

Inhalational administration of salbutamol or lidocaine each significantly increased the histamine threshold to 16.8 ± 10.9 mg/mL and 14.9 ± 13.7 mg/mL, respectively (p = 0.0007) (Fig 2 ). The combined treatment with salbutamol and lidocaine even further increased the histamine threshold significantly to 29.7 ± 20.3 mg/mL (p = 0.0007; Fig 2 ). The histamine threshold for PC20 following placebo inhalation (6.4 ± 4.3 mg/mL) did not differ significantly from the threshold at the screening visit (7.2 ± 4.9 mg/mL; p = 0.4432).



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  		Figure 2. Inhaled PC20 (log scale) levels before and after inhalation of lidocaine (left), salbutamol (middle), and salbutamol/lidocaine combined (right), respectively. Data are from 60 inhalational challenges with histamine performed on 4 different days in 15 individuals with bronchial hyperreactivity. Each pair of symbols represents the response of individual subjects, while the mean response is shown to the left and right of the individual responses. Lidocaine and salbutamol both significantly increase the histamine threshold compared to placebo, with no statistical difference between the effects of lidocaine and salbutamol. Salbutamol and lidocaine combined even further increase the histamine threshold significantly.

 
Peak lidocaine plasma concentrations and the plasma concentrations at the time of the maximal histamine challenge following the inhalational administration of lidocaine with and without salbutamol pretreatment are presented in Figure 3 . There was no difference in the peak and the time course of lidocaine plasma concentrations with or without salbutamol pretreatment.



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  		Figure 3. Time course of lidocaine serum concentration with ({blacksquare}) and without (•) salbutamol pretreatment (mean ± SD). Peak lidocaine concentrations are far below the toxic range of 5 µg/mL. Following the inhalation of lidocaine, plasma concentrations reach a peak directly after the end of inhalation with a continuous decrease during the inhalational challenge. There is no significant difference between the plasma concentrations with or without salbutamol pretreatment.

 
Heart rate and arterial BP were not affected significantly by the inhalation of lidocaine or salbutamol. However, one subject showed a reproducible increase in heart rate by 11 to 15 beats/min following salbutamol inhalation with no increase in heart rate following placebo or lidocaine inhalation.

One of 15 volunteers mentioned mild CNS symptoms such as lightheadedness and slight vertigo during lidocaine inhalation.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Lidocaine inhalation significantly attenuated bronchial hyperreactivity as much as the inhalation of salbutamol in awake humans. Salbutamol and lidocaine combined attenuated bronchial hyperreactivity even further. Furthermore, lidocaine inhalation evoked a significant initial decrease of FEV1, which was completely prevented by salbutamol pretreatment. Salbutamol pretreatment had no influence on lidocaine absorption and the resulting plasma concentrations.

These results emerged in 15 volunteers with moderate bronchial hyperreactivity. They were all in a stable clinical condition under their current medication or during their symptom-free interval. Measurements were made by the same investigator at the same time of day. Because of its low day-to-day variability, FEV1 was chosen as a measurement to analyze the response to the histamine challenges on 4 study days.17 18 19 In this way, a high reproducibility of the test results could be assumed, and the risk of unpredictable adverse responses to the histamine challenge was minimized.20

Inspiratory flow was controlled during the challenge to prevent uneven aerosol distribution and to minimize turbulent air flow. A 5-s breath hold at end-inspiration, a defined time of nebulization during inspiration, and a fixed number of breaths assured a high reproducibility of the challenge during the 4 study days.21 The inhalation of histamine not only directly stimulates smooth muscle cells, like methacholine does, but also provokes reflex bronchoconstriction.22 23 This is an important feature when adverse or protective effects prior to endotracheal intubation or bronchoscopy are assessed.

A salbutamol dose of 1.5 mg was chosen to avoid cardiac side effects while achieving bronchial protection. In fact, the response to histamine was significantly attenuated by salbutamol, and no increase in heart rate was observed, although a single subject showed a reproducible mild increase in heart rate. Thus, the salbutamol dose chosen for pretreatment attenuates bronchial hyperreactivity and carries a low risk for cardiac complications.

Lidocaine inhalation led to peak lidocaine plasma concentrations of 1.5 ± 0.5 µg/mL. These concentrations are far below the toxic threshold of 5 µg/mL and did not cause even mild systemic side effects such as those reported following IV administration. The lidocaine plasma concentrations measured were well within the range of plasma concentrations reported after inhaling 1.5 to 3.0 mg/kg lidocaine (range, 0.25 to 1.7 µg/mL).6 7 24 25 26

A decrease in FEV1 (range, 2.5 to 23.4%) following lidocaine inhalation is well-described and is in accordance with our results (mean decrease, 7.1%).2 3 4 6 7 8 9 In one study, individual responses ranged from a 28.2% increase to a 42.1% decrease.7 These effects were observed to be independent of the use of additives or the extent of underlying bronchial hyperreactivity.2 7 The observed mild initial airway irritation of 7.1% is close to the reproducibility of the method and is unlikely to have a significant impact on our inhalational challenge, which required a change in FEV1 of at least 20%.17 18 19

The main mechanism that explains the decrease in FEV1 following lidocaine inhalation is reflex bronchoconstriction due to airway irritation.

Initial bronchoconstriction following lidocaine inhalation was visualized by high-resolution CT scanning in dogs.27 Analyzing cross-sections of different airway generations before and after the administration of lidocaine aerosol, a 27% decrease from baseline was observed that could be prevented by IV lidocaine pretreatment.27 In our study, salbutamol pretreatment prior to lidocaine inhalation completely abolished the decrease in FEV1, while salbutamol alone led to a slight increase of FEV1 compared to baseline (Fig 2) .

Subsequently, lidocaine inhalation led to an attenuation of the response to the histamine challenge. Two main mechanisms, direct effects on smooth muscle cells and/or neural blockade of vagal pathways, may explain this protective effect.28 29

Direct effects on smooth muscle cells are described using lidocaine concentrations of 20 to 200 µg/mL.28 Although these lidocaine concentrations exceed the 10- to 100-fold plasma concentrations that were observed in this study, lidocaine inhalation likely provides higher local airway concentrations. Thus, the direct effects of lidocaine on airway smooth muscle may explain the beneficial effect of lidocaine inhalation on bronchial hyperreactivity.

Lidocaine plasma concentrations of approximately 10 µg/mL can block nerve conduction and different reflexes in animals following the systemic administration of lidocaine.29 30 31 Furthermore, in humans undergoing general anesthesia, IV lidocaine administration effectively suppressed reflex-induced cough as well as the response to histamine inhalation in awake volunteers with bronchial hyperreactivity, with lidocaine plasma concentrations of about 2 to 3 µg/mL.14 32 33 34

However, lidocaine inhalation led to plasma concentrations that are only a third of the concentrations required for these systemic effects. With similar attenuation of bronchial hyperreactivity at only a third of the plasma concentrations, both mechanisms might be involved. Although the local concentration in the bronchial tissue is unknown, it has to be much higher than the resulting plasma concentrations. Therefore, direct effects on airway smooth muscle cells can be assumed to be as important as systemic effects to explain the effect of lidocaine inhalation.

In summary, lidocaine inhalation significantly attenuates bronchial hyperreactivity, and to the same extent as salbutamol inhalation. Furthermore, lidocaine inhalation initially evokes a significant decrease in FEV1 in the majority of subjects, but this effect can be blocked by salbutamol pretreatment. This combined inhalation of salbutamol and lidocaine in sequence markedly attenuates reflex bronchoconstriction, and to a significantly greater extent than pretreatment with either drug alone. Pretreatment with salbutamol did not alter systemic lidocaine absorption.

Accordingly, when lidocaine is used for topical airway anesthesia in subjects with bronchial hyperreactivity, it should be preceded by pretreatment with a ß-adrenergic aerosol. Subsequently, a profound protective effect of both lidocaine and a ß-adrenergic aerosol can be expected to attenuate reflex bronchoconstriction.


   Footnotes
 
Abbreviations: PC20 = provocative concentration of a substance causing a 20% fall in FEV1; VC = vital capacity

Presented in part at the Annual Meeting of the American Thoracic Society, Chicago, IL, April 24 to 29, 1998.

Received for publication September 28, 1999. Accepted for publication March 8, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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