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A Randomized, Placebo-Controlled Trial of Bronchodilators for Bronchoscopy in Patients With COPD^*

^* From the Clinic of Respiratory Medicine and Pulmonary Cell Research University Hospital Basel, Basel, Switzerland.

Correspondence to: Daiana Stolz, MD, Department of Pulmonary, Allergy and Critical Care Medicine, University of Massachusetts Memorial Hospital, 55 Lake Ave N, Worcester, MA 01655; e-mail: stolzd{at}ummhc.org

Abstract

Background: In contrast to asthma, the indication for bronchodilators prior to bronchoscopy in patients with COPD has not been properly investigated. We therefore performed a randomized, double-blind, placebo-controlled trial to determine whether use of a short-acting bronchodilator provides a protective effect in patients with COPD undergoing bronchoscopy.

Methods: One hundred twenty patients undergoing bronchoscopy were included. Patients with COPD were randomized to receive either 200 µg of salbutamol (n = 40) or placebo (n = 40) before bronchoscopy. Control patients (n = 40) did not receive any inhaled medication. Spirometry was performed before and 2 h after bronchoscopy in all patients. Sedative drug requirements and hemodynamic parameters were recorded.

Results: Hemodynamic findings before, during, and after bronchoscopy were similar in patients with COPD randomized to either salbutamol or placebo (p = not significant for all). Compared to prebronchoscopy values, postbronchoscopy percentage of predicted FEV₁ decreased significantly in all three groups: salbutamol (median, – 4.7%; interquartile range [IQR], – 13.3 to 6.6); placebo (median, – 4.8%; IQR, – 19.9 to 8.4); and control subjects (median, – 10.0%; IQR, – 20.2 to – 3.3) [p = 0.023]. The decrease in FEV₁ was similar in all three patient groups (p = 0.432). The relative change in FEV₁ was inversely correlated to the increasing severity of COPD as expressed by Global Initiative for Chronic Obstructive Lung Disease stages (p = 0.01).

Conclusions: Premedication with an inhaled short-acting ß-agonist cannot be recommended in patients with COPD undergoing bronchoscopy.

Key Words: bronchoscopy • COPD • premedication

The prevalence of COPD is increasing worldwide.¹ It is estimated that 1 of every 20 subjects has COPD and every eighth hospital admission is triggered by an exacerbation of COPD.²³ Patients with COPD are prone to undergo flexible bronchoscopy for a variety of reasons. Firstly, patients with COPD have been typically exposed to cigarette smoking, thus sharing a major risk factor for malignancy.⁴⁵ Secondly, interventional bronchoscopy has evolved as a treatment option for tumorous stenosis of the central airways, providing relief of malignant airway obstruction or postobstructive pneumonia.⁶ Thirdly, the treatment of COPD itself may include minimally invasive bronchoscopic techniques, ie, one-way bronchial valves inserted via fiberoptic bronchoscopy and bronchopulmonary fenestrations.⁷ Finally, flexible bronchoscopy has become an integral part of research involving human subjects, especially for the study of chronic pulmonary illnesses such as COPD.⁸

While much interest has been devoted to the safety of bronchoscopic techniques in asthma,^4910111213 little attention has been dedicated to specific requirements in COPD patients. In a study including patients with mild asthma, Rankin et al¹³ showed that the preoperative use of a bronchodilator was associated with no fall in the postoperative FEV_1. Thus, the administration of an inhaled bronchodilator has been recommended prior to flexible bronchoscopy in patients with asthma.¹⁴¹⁵ Bronchoscopy is thought to be safer in patients with COPD than with asthma because of lower levels of bronchial hyperresponsiveness.¹⁶¹⁷ However, there is no consensus regarding the need for administration of bronchodilators prior to the examination in these patients.¹⁴¹⁷¹⁸ To our current knowledge, there are no data evaluating the benefit of administrating bronchodilators before bronchoscopy in patients with COPD. We therefore performed a randomized, double-blind, placebo-controlled trial to determine whether the use of a short-acting bronchodilator prior to flexible bronchoscopy provides a protective effect against bronchoconstriction in COPD patients, thus increasing safety.

Materials and Methods

A total of 120 patients undergoing diagnostic flexible bronchoscopy at the University Hospital Basel (Basel, Switzerland) between June and October 2005 were recruited for this study. This study was approved by the Ethic Committee of the University Hospital Basel.

Subjects
After obtaining written informed consent, 80 consecutive patients with chronic obstructive pulmonary classified according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines¹⁹ and 40 consecutive patients without evidence of COPD were included in this study. Eligible COPD patients were men or women (age range, 40 to 80 years; current or ex-smokers with > 10 pack-year smoking history; with FEV₁/FVC ratio < 70%). Eligible subjects without COPD (control group) were men or women (age range, 40 to 80 years; no history of COPD; with FEV₁/FVC ratio > 70%). Patients with a history of asthma, bronchiectasis, or cystic fibrosis were not eligible for the study.

During the study period, 383 patients underwent flexible bronchoscopy. A total of 295 underwent diagnostic bronchoscopy and were considered for the study. No patients refused to participate in the study. We have excluded patients undergoing therapeutic bronchoscopies, those who were intubated or administered propofol (mainly IV drug abuser), and patients in whom endobronchial ultrasound examination was performed. In addition, those who were unable to provide informed consent were not included in the trial.

Study Design
On arrival at the waiting room of the bronchoscopy suite, patients underwent baseline pulmonary function testing, including FVC, FEV₁, and FEV₁/FVC, by spirometer (Spirovit SP-10; Schiller; Baar, Switzerland) according to American Thoracic Society guidelines.²⁰ The higher of two values for FEV₁, repeatable within 100 mL, was recorded and the percentages of predicted values were calculated.²¹

Patients satisfying the criteria for the COPD group were randomly assigned to either 200 µg of inhaled salbutamol (two puffs at 100 µg per puff) or identical placebo delivered by a 1-L spacer device in a triple-blind fashion 15 min before commencement of bronchoscopy. Every patient assignment occurred in the waiting room of the bronchoscopy suite by a research nurse. Randomization was through arbitrarily allocation to one of the two treatment groups based on a computer-generated random list (GraphPad Software; San Diego, CA). The recruiting research nurse, bronchoscopists, nursing staff, and patients were unaware of the group assignment due to the identical appearance of both salbutamol and placebo canisters. Patients in the control group did not receive any inhaled medication. Pulmonary function testing was repeated from 2 to 3 h after the end of the bronchoscopy, immediately preceding discharge from the recovery room, once safe swallowing has been established.

Collected data included the following: demographics; use and time of regular inhaled medication for COPD, such as short-term and long-acting ß₂ agonists, anticholinergics, and inhaled steroids; lung function parameters prior and following bronchoscopy; hemodynamic data prior, during, immediately after the procedure, and at discharge; cough severity during bronchoscopy as perceived by bronchoscopist, nursing staff, and patients; requirements of midazolam and lidocaine during the procedure; bronchoscopic procedures; as well as duration of the bronchoscopy. Moreover, historical lung function data from the lung function laboratory at the University Hospital Basel were reviewed to assess the presence of partial reversibility in the group of patients with COPD.

Bronchoscopy
Bronchoscopy was performed transnasally with the patients in the semirecumbent position by a total of four pulmonary fellows under close supervision of four pulmonary attendings. Pulse oximetry was recorded continuously during the procedure, and automated noninvasive BP was monitored every 5 min. Supplemental oxygen was administered at 4 L/min via nasal cannula to all patients. In case of oxygen desaturation 90%, oxygen delivery was increased to 6 L/min.²²

Nasal anesthesia was achieved by spraying 10% lidocaine in the nasopharynx (four times) and oropharynx (two times). One percent lidocaine in 3-mL aliquots was instilled via the bronchoscope as judged by the bronchoscopist. Instilled lidocaine doses were recorded for each patient. No inhaled lidocaine was administered prior to the procedure.²³

All patients received 5 mg of IV hydrocodone immediately before flexible bronchoscopy.²⁴ Thereafter, conscious sedation was achieved initially with 2 mg of midazolam followed by an additional 1 to 2 mg of IV midazolam boluses during the procedure at the discretion of the endoscopist.²⁴ The total dose of midazolam was documented. Diagnostic procedures, ie, brushing, washings, biopsy, BAL, endobronchial and transbronchial biopsies, were performed depending on the clinical indication. Hemodynamic parameters, sedation, duration of bronchoscopy, bronchoscopic procedures, and complications were noted during the procedure in a form specifically designed for the study. Major complications were defined as follows: major bleeding, need to abort bronchoscopy, need for noninvasive or invasive ventilation, hemodynamic instability requiring vasoactive drugs, pneumothorax, and death. Cough was not regarded as a complication. Oxygen desaturation was only regarded as a major complication if early discontinuation of the procedure or noninvasive or invasive mechanical ventilation was required.

At the end of the procedure, bronchoscopists and nursing staff charted their perception of cough during the procedure on a 10-cm visual analog scale (VAS). Similarly, 2 to 3 h after bronchoscopy, patients were also asked to record their perception of cough related to the procedure on a 10-cm VAS. In the scale, 0 denoted no cough and 10 represented incessant cough. Hemodynamic monitoring was performed immediately before, during, and shortly after the procedure (after removal of the bronchoscope), and before transfer from the bronchoscopy suite to the recovery room. Moreover, BP and heart rate were monitored for up to 3 h after bronchoscopy until discharge.

Data Analysis
Power and sample sizes were calculated based on the percentage of patients showing an FEV₁ deterioration 5% of predicted after bronchoscopy as the primary outcome variable.²⁵ Considering that the use of a bronchodilator could reduce the incidence of a deterioration in FEV₁ 5% of predicted by one third, 40 patients would be needed in each arm to achieve a significance level of < 0.05 with a power of 0.85.

To compare the difference in FEV₁ change between the study groups taking into account the baseline FEV₁ percentage of predicted, analysis of variance with subsequent pair-wise comparisons using the Bonferroni correction was performed. Differences in dichotomous variables were evaluated using the ² test. Correlation analyses between physicians and nursing staff VAS were performed using Spearman rank correlation. All other continuously distributed parameters were evaluated using the nonparametric Mann-Whitney U test or Kruskal-Wallis test, as appropriate.

Statistical software (Version 13 for Windows, SPSS; Chicago, IL) was used. All tests were two tailed; a p value of < 0.05 was considered significant. Results are expressed as median (interquartile range [IQR]) unless otherwise stated.

Results

Demographic and lung function parameters are presented in Table 1 . Patients with COPD randomized to salbutamol and placebo groups were similar in regard to age, gender distribution, and spirometric findings. The majority of the patients with COPD had moderate (43%) or severe (32.5%) disease, according to the GOLD stage classification.¹⁹ Historical data from the lung function laboratory were available for 66 of the subjects (82.5%) with COPD. Lung function testing was performed at a median interval of 6 days (IQR, 2 to 38 days) prior to bronchoscopy. While all patients fulfilled the postbronchodilator criteria for COPD diagnosis according to the GOLD guidelines, a partial reversibility (FEV₁ improvement by at least 12% and 200 mL) was present in 15 cases (22.7%), and median postbronchodilator FEV₁ improvement was 7.5% (IQR, 1.1 to 14.1%).

The diagnostic procedures performed during bronchoscopy in the three patient groups are shown in Table 2 . Most common procedures performed were BAL in 50 cases (42%) and transbronchial needle aspiration in 39 cases (33%). In summary, inspection only was performed in 9 patients (8%), one procedure performed in 57 patients (48%), two procedures in 33 patients (28%), three procedures in 16 patients (13%), four procedures in 4 patients (3%), and five procedures in 1 patient (1%). The median duration of the procedure was similar for patients in the salbutamol group (median, 18 min; IQR, 11 to 27 min), in the placebo group (median, 20 min; IQR, 13 to 29 min), and in the control group (median, 22 min; IQR, 17 to 26 min) [p = 0.324].

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Change in FEV1 comparing prebronchoscopic values to postbronchoscopic values in 120 patients.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Correlation between patient’s cough during the procedure as perceived by the bronchoscopists and nursing staff (r = 0.822, p < 0.0001, Spearman test).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. FEV1 beforeand after bronchoscopy in the three patient groups (analysis of variance, p = 0.432).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 4.. Correlation between the change in FEV1 and the prebronchoscopic FEV1 (r = –0.314, p = 0.001, Spearman test).

This study demonstrates that there is no benefit of inhaled short-acting ß-agonists prior to bronchoscopy in patients with COPD. The inhalation of salbutamol neither improved safety nor prevented decrease in FEV₁. Thus, routine inhalation of a short-acting ß-agonist cannot be recommended as a premedication for bronchoscopy in COPD patients.

Most of the literature regarding the investigative use of bronchoscopy relates to its use in asthma.¹¹ There is a more pronounced postbronchoscopic fall in FEV₁ in asthma patients (26 ± 17%) compared to normal subjects (9 ± 4.7%) [mean ± SD].^11121326 In asthma, the postbronchoscopic fall in FEV₁ is directly correlated to the preoperative concentration of methacholine needed to achieve a significant fall in FEV₁.¹¹²⁷ The use of an inhaled bronchodilator prior to the procedure has been shown to reduce the change in lung volumes, the incidence of wheezing, and oxygen desaturation in this population.¹¹¹³²⁸ Therefore, asthmatic patients should be premedicated with a ß-agonist (inhaled or nebulized) before bronchoscopy, except if there are contraindications.¹⁴¹⁵¹⁸

Although considered a safe procedure, bronchoscopy has been associated with serious adverse events.⁸ Thereby, uniform procedural standards for bronchoscopy in patients with COPD have not been established.⁸ A previous report¹⁶ suggested that bronchoscopy with BAL and endobronchial biopsy can be safely performed after inhalation of salbutamol in a group of 57 patients with COPD. All patients received midazolam as needed during the procedure. The incidence of adverse events requiring hospital treatment was 2%. In contrast, in the present study, a variety of bronchoscopic procedures were performed under combined sedation with IV midazolam and hydrocodone. This combination has proved safe and effective in suppressing cough during flexible bronchoscopy.²⁴ Similar to the previous study,¹⁶ we have also found a very low incidence of adverse events and no major complications related to the procedure. This is particularly important to know, because thus far data on the safety of transbronchial biopsy and transbronchial needle aspiration in patients with COPD were not available. The use of an opiate combined with a benzodiazepine for sedation was not associated with excessive oxygen desaturation in COPD patients as compared to control subjects, and might, therefore, be a safe option for sedation in this population. Conversely, the use of a short-acting bronchodilator was not beneficial in diminishing sedative drug requirements or improving cough scores as judged by bronchoscopists, nurse staff, or patients themselves.

Bronchoscopic procedures have been shown to cause a decrease in lung volumes in normal individuals.²⁹³⁰ The cause of these changes in lung volumes remains mostly speculative. There is some evidence suggesting that topical anesthetics and/or systemic sedation may enhance the mechanic effects of the bronchoscope, leading to decrease both in FEV₁ and FVC. A few studies^29–32 have suggested a protective effect of different premedications in regard to lung function in healthy subjects. The use of aerosolized isoproterenol before topical anesthesia for bronchoscopy improved postbronchoscopic FEV₁ significantly in control subjects.²⁹ Similarly, ipratropium bromide has shown to have a protective effect on lung function decline against the deleterious effects of the topical lidocaine anesthesia or the bronchoscopic examination itself in patients undergoing bronchoscopy.³⁰ Finally, two other small trials³¹³² have proposed a beneficial effect of atropine sulfate both administered by aerosol and IM routes on pulmonary function tests.

A previous report³³ suggested that bronchoscopy consistently impairs lung mechanics and gas exchange in a selected group of COPD patients. To our knowledge, this is the first trial to evaluate the effectiveness of an inhaled ß-agonist in preserving lung volumes in patients with COPD undergoing bronchoscopy. Inhaled salbutamol was not effective in reducing the postbronchoscopic fall in FEV₁. Interestingly and in contrast to asthma, the postbronchoscopic change in lung volumes correlated inversely to the severity of COPD. Thus, it can be hypothesized that in patients with COPD without respiratory distress, the source of an eventual major complication during bronchoscopy is unlikely to be bronchospasm.

This study has several limitations. Although this is the largest study performed on safety of bronchoscopy in patients with COPD, it was not powered to detect an effect on rare events, for instance death. However, common outcomes such as oxygen desaturation during the procedure, requirement for sedative drugs, and cough scores were very similar between the groups. Another point to take into consideration is the fact that lung function tests were repeated only 2 h after the procedure and not at an earlier stage. Due to sedation, much more sophisticated methods would have been needed to assess lung function in semiconscious patients. Moreover, as most patients undergoing uneventful bronchoscopy are usually discharged 2 h after the procedure, the assessment of lung function parameters at this time point was thought to be clinically relevant. In addition, the patient’s cough perception may have been influenced 2 h after the procedure because of the amnesic effect of midazolam. However, according to several previous studies, wake up time for combined sedation with an opiate and benzodiazepine seems to be between 35 to 60 min and discharge time 75 to 120 min after the procedure.³⁴³⁵³⁶ Thus, we believe that it is fair to assume that patients were able to estimate their cough related to the procedure after 2 h.

This study was designed to assess the value of a short-acting ß₂-agonist immediately prior to the procedure. Thus, in a subgroup of patients who were already receiving inhaled medications on a regular basis, salbutamol represented additional treatment on top of a combination therapy of long-acting B₂ agonist, anticholinergics, and/or inhaled steroids. While no additional benefit could be demonstrated in either case, our results do not allow any inference about the protective effect of a long-term inhaled therapy with steroids or long-acting ß₂-agonist in potentially decreasing bronchial hyperreactivity prior to bronchoscopy. Finally, reversibility to bronchodilators was not assessed immediately prior to the procedure. However, historical data were available in the vast majority (82.5%) of the cases and confirmed the diagnosis of COPD in all of them. Even though we cannot exclude the presence of superimposed asthma in the few cases without historical data on bronchodilator response, considering that patients with asthma are likely to benefit from bronchodilators in this setting, this would lead to a conservative bias. Thus, it would be more probable to find statistically significant results, although the null hypothesis was true. As we did not find a difference between both groups, this bias is not considered to be a serious limitation in interpreting the data. In conclusion, in contrast to asthma, our data suggest that patients with COPD do not need to be premedicated with inhaled short-acting ß-agonists prior to bronchoscopy.

Acknowledgements

We are deeply grateful to the endoscopy staff (Esther Gysin, Dusan Jovic, Bjorn Fehrke, Monika Kohler, Sylvie Groelly, Michael Ortmann, Beatrice Lehner, Brigitte Koch, Margot Brenneisen) for their collaboration; to Anja Meyer, RN, for her enthusiastic cooperation in data collection; and to Andy Schoetzau for statistical assistance.

Footnotes

Abbreviations: GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range; VAS = visual analog scale

This work was funded by the Clinic of Respiratory Medicine, University Hospital Basel.

The authors have no conflicts of interest to disclose.

Received for publication September 20, 2006. Accepted for publication November 7, 2006.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Stolz, D. Articles by Tamm, M. Search for Related Content PubMed PubMed Citation Articles by Stolz, D. Articles by Tamm, M.