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Efficacy of Tiotropium Bromide and Rehabilitation Treatment on Pulmonary Function of Patients With Sulfur Mustard Lung Injury

Background: Chronic pulmonary complication is the most common delayed toxic effect of sulfur mustard (SM) and it has no treatment so far. Objectives: To evaluate short-term therapeutic effects of inhaled tiotropium bromide and pulmonary rehabilitation on pulmonary function of patients with SM induced lung injury. Patients and Methods: In a randomized clinical trial, using convenient sampling method, 54 patients with chronic lung disease due to SM exposure were recruited in Baqiyatallah General Hospital, Tehran, Iran for a period of 2-month study. They were randomly divided into 3 groups of 18 participants each. Group 1 received routine drugs (Serevent, Flixotide), pulmonary rehabilitation 30 minutes/2 times a week, and tiotropium bromide 18 µg/day. Group 2 was treated with routine drugs and pulmonary rehabilitation and group 3 was only on the routine drugs. cardiopulmonary exercise test (CPET), plethysmographic measurements, and respiratory symptoms evaluation were performed before and after medical intervention. Results: In group 1, compared to group 3, significant differences were found with regard to symptoms of cough ([difference between the first and last visit in group 1: Diff 1] = -1.6, Diff 3 = -0.3, P = 0.01) and nocturnal dyspnea (Diff 1 = -1.9, Diff 3 = 0.0, P = 0.01), likewise, compared to group 2, significant differences were found with regard to lung function parameters of forced vital capacity (Diff 1 = 3.0, Diff 2 = -3.5, P = 0.03), forced expiratory volume in one second (Diff 1 = 3.9, Diff 2 = -5.6, P = 0.009), maximal mid-expiratory flow rate 25% - 75% (Diff 1 = 1.5, Diff 2 = -3.2, P = 0.007) and peak expiratory flow (Diff 1 = -2.06, Diff 2 = -4.3, P = 0.04). Total lung capacity (Diff 2 = 9.28, Diff 3 = -12.07, P = 0.02) and residual volume (Diff2 = 32.1, Diff3 = -27.6, P = 0.04) were increased in group 2 compared to group 3. There were no significant differences with regard to CPET results among all groups (P > 0.05). Conclusions: Inhalation of tiotropium bromide in combination with pulmonary rehabilitation could improve some plethysmographic lung volumes and clinical outcomes in patients with chronic pulmonary disease due to SM. Short-term prescription of pulmonary rehabilitation has no effect on CPET of patients.


Background
Sulfur mustard (SM) is a potent chemical weapon that was used widely by Iraqi military during Iraq-Iran war (1). Delayed toxic effects of SM involve eyes, skin, nervous system, immune system, and especially respiratory system (2). One of the most significant delayed toxicity of SM (causing disability) is pulmonary disorders in which the main underlying pathology is bronchiolitis obliterans (BO) (3). In the long-term, cough, sputum, and shortness of breath were reported in 80% of Iranian patients after exposure to SM (4). Hemoptysis, feeling of pressure in the thorax, chest pain, and nocturnal dyspnea are other common complications. Clinical findings are often generalized wheezing, crackles, clubbing, and cyanosis (1).
Pulmonary function tests show that obstruction is the most common abnormal pattern and about half of the obstructive cases are reversible after using inhaled bronchodilators. Abnormal spirometry findings tend to increase by passing time (5).
Tiotropium bromide is a long-acting anticholinergic agent, which can improve lung function and exercise tolerance. It also reduces dyspnea, mortality and exacerbations in chronic obstructive pulmonary disease (COPD) (6).
Additionally, respiratory rehabilitation programs are essential tools in the management of COPD (7). Pulmonary rehabilitation is now an established standard of care for patients with COPD who remain symptomatic de-spite bronchodilators therapy (8) .It shows improvement of symptoms and exercise tolerance (9).
There are thousands of such victims without cure with severe respiratory symptoms. However, results of tiotropium bromide and respiratory rehabilitation on patients with isolated BO (as their main pulmonary delayed toxic effects following exposure to SM) have not been determined yet.

Objectives
This trial was designed to evaluate, for the first time, the role of tiotropium bromide in combination with pulmonary rehabilitation in improvement of pulmonary function of patients with chronic pulmonary lesions following exposure to SM.

Patients and Methods
This study was performed as a randomized clinical trial from March 2011 to January 2013 in pulmonary department of Baqiyatallah Hospital, Tehran, Iran. It is a general, referral, and university affiliated hospital. We enrolled volunteer patients with long-term obstructive respiratory disease compatible with BO following definite exposure to SM. Exclusion criteria were acute bronchiolitis and or pneumonia, history of pulmonary tuberculosis or resection of one or more lobes, history of smoking or exposure to other toxins, and participating in simultaneous clinical trials.
The study protocol and advantages and disadvantages of drugs were explained to patients and written consent form was obtained from all participants before recruitment. The consent forms tell the patients that they can leave the study at any time. This study was registered and confirmed in the Scientific and Ethics Committee of the Baqiyatallah university (the code and date of ethical approval: 2422, February 21, 2010). The study protocol followed the ethical guidelines of the (1975 revision) Declaration of Helsinki.
Considering α = 5%, statistical power of 90%, and d = 1.2, the sample size was calculated as 18 subjects in each group, using the following formula. Considering 20% drop up in sample, we add 3 more samples to the optimal sample size, so we totally considered 18 samples in each group. We used standard protocol for our study. Patients were selected using convenient sampling method from the whole population with medical records of chronic pulmonary diseases due to SM. History of medication, smoking, addiction, and current diseases were recorded. Then, they were randomly divided into 3 groups. All patients were on standard routine respiratory medication and there was not any washing period before study. Group 1 (n = 18) received routine drugs (Serevent, Flixotide), twice-weekly 30-minute pulmonary rehabilitation and tiotropium bromide 18 µg/ day. Group 2 (n = 18) received routine drugs and pulmonary rehabilitation, and group 3 (n = 18) received just routine drugs. The patients were treated for 2 months and visited every 15 days for recording possible clinical adverse effects. Only one observer was recruited for the study. Clinical symptoms assessed by visual analogue scale. Physical examinations, pulmonary function tests, and cardiopulmonary exercise test (CPET), were performed before and after the study period. The exercise test was performed according to the protocol of Wasserman on an electrically-braked cycle ergometer (Sensor Medics 2900). Before each test, calibration of gas analyzers was checked using standard gas provided by the manufacturer (Sensor Medics). Plethysmographic measurements were performed according to the American Thoracic Society and the European Respiratory Society recommendations (10, 11) with daily calibration (ZAN 500 Body II, Meβgrerate GmbH, Germany).
Data were analyzed using SPSS version 19 (SPSS Inc., Chicago, Ill., USA). Continuous variables are presented as the mean (SD), whereas categorical data are presented as frequency and percentages. Independent and paired sample t tests, ANOVA, Mann-Whitney Test, and Kruskal-Wallis Test were used for continuous variables. There was no missing value. Homogeneity of data was assessed using Levene's test, and normal distribution of data was checked using Kolmogorov Smirnov test. Also because of small sample size, we used Bootstrap method. In this study, the probability value of 0.05 or less (P ≤ 0.05) was set the significance level.
There were no significant differences between the groups over time regarding CPET indexes (Table 3).

Discussion
Our findings show that tiotropium bromide with pulmonary rehabilitation could improve clinical symptoms and some plethysmographic lung volumes of patients with SM lung injury. Although tiotropium has lots of advantages in patients with COPD, it has not been tested for BO patients after exposure to SM. Despite exercise intolerance, results of this study showed that combination of tiotropium bromide with pulmonary rehabilitation had considerable effect in this setting. Bronchodilators are the first line of treatment in COPD. After adding pulmonary rehabilitation, better treatment results could be achieved (12). Bronchodilators reduce dynamic hyperinflation and shortness of breath and improve air flow. Inhaled anticholinergic drugs like ipratropium are considered as an effective treatment of COPD (13). Tiotropium is a new anticholinergic drug and because of its prolonged blockage of muscarinic receptors, has a long duration of action and can be used only once a day (14). Up to now, many studies have been carried out on the effectiveness of either tiotropium or pulmonary rehabilitation alone. In their 1-year study, Vincken et al. have shown that tiotropium improves dyspnea and pulmonary function. In this study, tiotropium led to better results compared to ipratropium in the treatment of COPD (15). After 4 years study on the effects of tiotropium in COPD, Tashkin et al. have found that treatment with this drug improves pulmonary function and reduces the exacerbations (16). A 1-year study on the comparison of tiotropium and salmeterol effects showed that tiotropium was better than salmeterol in the management of COPD exacerbations (17).
Exercise practices are the main parts of pulmonary rehabilitation in patients with chronic pulmonary problems and improve exercise tolerance of these patients (7). Many studies have been performed on the effectiveness of pulmonary rehabilitation in patients with COPD. Porszasz et al. (18), Plankeel et al. (19), Farid et al. (20), Casaburi et al. (21) and Puente-Maestu et al. (22) all reported the positive effect of pulmonary rehabilitation on lung volumes and improvement in exercise tolerance in chronic pulmonary diseases. In another study, Casaburi et al. evaluated the exercise tolerance changes by using tiotropium and pulmonary rehabilitation in pulmonary obstructive diseases. Their results revealed significant improvements in shortness of breath and health condition of the patients compared to use of pulmonary rehabilitation alone (23).
In our study, for the first time, we focused on the effectiveness of tiotropium and pulmonary rehabilitation together and also the effectiveness of pulmonary rehabilitation alone on pulmonary function and symptoms of the patients exposed to SM. Our results of using combination of tiotropium and pulmonary rehabilitation are in consistent with the study of Casaburi et al. on patients with COPD (23). Similar to report of Pitta et al. (24), pulmonary rehabilitation practices alone did not show significant changes in lung volumes. Our results on rehabilitation could be explained by dynamic hyperinflation and increase of air trapping related to exercise in BO. Dynamic hyperinflation reduces expiratory flow limitation during exercise but increases the inspiratory loading. It also has effects on hemodynamic and results in shallow and rapid breathing and progressive drop in dynamic lung compliance. This process finally leads to exercise intolerance (25). As it is shown in Table 1, even residual volume has been increased in group 2 after rehabilitation compared to group 3 without exercise program. It should be considered that identification of patients with COPD who develop dynamic hyperinflation is important, because of the association between dynamic hyperinflation, dyspnea, and exercise limitation.
However, unchanged plethysmographic lung volumes in this study is related to underlying physiopathology of lung after exposure to SM that leads to a group of irreversible and progressive pulmonary diseases (26) as well as irreversible anatomical changes in the lung tissue. Consequently the possibility of reversibility and improvement in indexes and pulmonary capacities in these patients is low (27,28). Furthermore, it has been shown that improvement in exercise tolerance and dyspnea was not accompanied by significant changes in FEV1. That may be related to the fact that rehabilitation intervenes with other outcomes of COPD patients such as muscle dysfunction, reduced physical activities, and depression (29). The slight changes in plethysmographic lung volumes and pulmonary volumes in some findings (FVC, FVE1, MMEF 25%-75%, and FEV1/FVC) may be due to the strength and endurance of respiratory muscles and as a result reduction in resistance of airways.
Our study has some limitations. The sample size was small and there was not placebo control for comparing the results. Performing the molecular and cellular assays were not feasible in this study, as well.
Tiotropium bromide in combination with pulmonary rehabilitation could improve clinical symptoms and some plethysmographic lung volumes of patients with sulfur mustard lung injury. However, the patients with dynamic hyperinflation had a low cardiopulmonary response to rehabilitation alone in our protocol. Further studies are warranted addressing improvements with long-term and different exercise protocols. Shohrati, Bita Najafian; critical revision of the manuscript for important intellectual content: Mostafa Ghanei, Ali Amini Harandi statistical analysis: Ali Amini Harandi; administrative, technical, and material support: Maryam Jalili, Homa Afshar, Meysam Zaeri; study supervision: Mostafa Ghanei.
Funding/Support:This study was financially supported by Baqiyatallah university of Medical Sciences, Tehran, Iran.