Anticholinergic therapy has long been a cornerstone of management of chronic obstructive pulmonary disease (COPD) but has not been included in treatment guidelines for asthma. In September 2015, tiotropium bromide was approved for use in adults with asthma; the indication has since been expanded to children ages 6 years and older. This article discusses appropriate patient selection and dosing, and the role of tiotropium bromide in asthma management.

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Introdução: Os pacientes com bronquiolite obliterante (BO) costumam apresentar acometimento importante da função pulmonar que resulta em hipoxemia crônica e limitação da atividade física. Não há terapêutica de grande eficácia na BO, a resposta aos broncodilatadores costuma ser pobre, entretanto, não se conhece a resposta broncodilatadora a um agente anticolinérgico de longa ação como o brometo de tiotrópio (BT). Já se demonstrou eficácia e segurança do BT em adultos com doença pulmonar obstrutiva crônica (DPOC) com resposta broncodilatadora significativa e sustentada em dose única diária. Objetivo: Avaliar se existe melhora do grau de obstrução brônquica e do aprisionamento aéreo, através de medidas funcionais, após o uso de dose única de brometo de tiotrópio por via inalatória comparado a placebo em crianças e adolescentes com BO. Métodos: Ensaio clínico prospectivo, duplo cego, randomizado, placebocontrolado e cruzado em pacientes com BO estáveis na faixa etária de 6 a 16 anos. Espirometrias e pletismografias foram realizadas antes e aos 30, 60, 120, 180 minutos e 24 horas após a inalação de 18 mcg de tiotrópio ou placebo. Após 7-14 dias, os medicamentos foram invertidos e os procedimentos repetidos. As mudanças nos parâmetros de função pulmonar em cada momento foram comparadas com o basal através da análise de variância (ANOVA) e pós-teste de Tukey e as diferenças entre todos os momentos versus o basal nos grupos tiotrópio versus placebo foram comparados usando o teste de Friedman. Resultados: Trinta pacientes participaram do estudo (23 do sexo masculino, 7 do feminino; idade 10,9±2,8a ), com valores basais de função pulmonar (% do previsto) de CVF, VEF1, VEF1/CVF, FEF25-75%, CI, CPT, VR, VR/CPT, resistência das vias aéreas (raw) e condutância (sGaw) de 75±15, 48±14, 59±11, 22±11, 64±23, 120±19, 281±101, 49±13, 250±65 e 23±9, respectivamente. Diferenças estatisticamente significantes foram observadas após inalação do tiotrópio nos seguintes parâmetros comparados ao tempo basal: CVF em 60/120/180 min/24h, VEF1 em 30/60/120/180min, VEF1/CVF em 60/120/180min, FEF25- 75% em 60/120/180min, VR em 30/60/120/180min, CPT em 30/120/180min, VR/CPT em 30/60/120/180min, raw em 30/60/120/180min/24h e sGaw em 30/60/120/180min/24h. Na fase placebo não houve diferença estatisticamente significante em nenhum parâmetro funcional em nenhum momento após a administração. As diferenças entre as medidas funcionais comparando o grupo tiotrópio versus o grupo placebo foram estatisticamente significantes. Conclusões: O brometo de tiotrópio, após dose única, diminuiu agudamente o grau de obstrução e de aprisionamento aéreo por até 24 horas em crianças com BO. Estudos de longo prazo são necessários para se avaliar o papel do BT na terapêutica desses pacientes / Introduction: Patients with bronchiolitis obliterans (BO) usually have severe airflow obstruction that results in chronic hypoxemia and limitation of physical activity. There is no efficient therapy for BO, bronchodilator response is usually poor, however, the bronchodilator response to a long action anticholinergic agent such as tiotropium bromide (TB) is not known. Efficacy and safety of TB with one daily administration has already been shown in chronic obstructive pulmonary disease (COPD) with significant and sustained bronchodilator response. Objective: Verify through functional measurements whether the level of bronchial obstruction and air trapping was improved by the administration of a single dose of TB by inhalation when compared to placebo in children and adolescents with BO. Methods: A randomized, double blind, placebo-controlled, crossover, prospective study in stable BO patients, 6 to 16 years of age. Spirometry and plethysmography were performed before and at 30, 60, 120 and 180 minutes and 24 hours after inhalation of 18 mcg of tiotropium or a placebo. After 7-14 days, the drugs were inverted, and the procedures were repeated. The changes in lung function parameters at each time point were compared to the baseline by analysis of variance (ANOVA) and Tukey\'s post-test and the differences in all time points assessment versus baseline in tiotropium versus placebo groups were compared using the Friedman test. Results: Thirty patients were enrolled in the study (23 male, 7 female; age 10.9±2.8 y) with baseline lung function values (% predicted) of FVC, FEV1, FEV1/FVC, FEF25-75%, IC, TLC, RV, RV/TLC, airway resistance (raw) and conductance (sGaw) of 75±15, 48±14, 59±11, 22±11, 64±23, 120±19, 281±101, 49±13, 250±65 and 23±9, respectively. Statistically significant differences were observed after tiotropium inhalation in the following parameters compared to baseline: FVC at 60/120/180min/24h, FEV1 at 30/60/120/180min, FEV1/FVC at 60/120/180min, FEF25-75% at 60/120/180min, RV at 30/60/120/180min, TLC at 30/120/180min, RV/TLC at 30/60/120/180min, raw at 30/60/120/180min/24h and sGaw at 30/60/120/180min/24h. For the placebo group, no significant differences were observed in any lung function parameters at any time. The differences between the functional measurements comparing the tiotropium versus placebo groups were statistically significant. Conclusions: Tiotropium bromide, after a single dose, acutely decreased airway obstruction and air trapping for up to 24 hours in children with BO. Long-term studies are necessary to evaluate the role of BT in the management of these patients

Introdução: Os pacientes com bronquiolite obliterante (BO) costumam apresentar acometimento importante da função pulmonar que resulta em hipoxemia crônica e limitação da atividade física. Não há terapêutica de grande eficácia na BO, a resposta aos broncodilatadores costuma ser pobre, entretanto, não se conhece a resposta broncodilatadora a um agente anticolinérgico de longa ação como o brometo de tiotrópio (BT). Já se demonstrou eficácia e segurança do BT em adultos com doença pulmonar obstrutiva crônica (DPOC) com resposta broncodilatadora significativa e sustentada em dose única diária. Objetivo: Avaliar se existe melhora do grau de obstrução brônquica e do aprisionamento aéreo, através de medidas funcionais, após o uso de dose única de brometo de tiotrópio por via inalatória comparado a placebo em crianças e adolescentes com BO. Métodos: Ensaio clínico prospectivo, duplo cego, randomizado, placebocontrolado e cruzado em pacientes com BO estáveis na faixa etária de 6 a 16 anos. Espirometrias e pletismografias foram realizadas antes e aos 30, 60, 120, 180 minutos e 24 horas após a inalação de 18 mcg de tiotrópio ou placebo. Após 7-14 dias, os medicamentos foram invertidos e os procedimentos repetidos. As mudanças nos parâmetros de função pulmonar em cada momento foram comparadas com o basal através da análise de variância (ANOVA) e pós-teste de Tukey e as diferenças entre todos os momentos versus o basal nos grupos tiotrópio versus placebo foram comparados usando o teste de Friedman. Resultados: Trinta pacientes participaram do estudo (23 do sexo masculino, 7 do feminino; idade 10,9±2,8a ), com valores basais de função pulmonar (% do previsto) de CVF, VEF1, VEF1/CVF, FEF25-75%, CI, CPT, VR, VR/CPT, resistência das vias aéreas (raw) e condutância (sGaw) de 75±15, 48±14, 59±11, 22±11, 64±23, 120±19, 281±101, 49±13, 250±65 e 23±9, respectivamente. Diferenças estatisticamente significantes foram observadas após inalação do tiotrópio nos seguintes parâmetros comparados ao tempo basal: CVF em 60/120/180 min/24h, VEF1 em 30/60/120/180min, VEF1/CVF em 60/120/180min, FEF25- 75% em 60/120/180min, VR em 30/60/120/180min, CPT em 30/120/180min, VR/CPT em 30/60/120/180min, raw em 30/60/120/180min/24h e sGaw em 30/60/120/180min/24h. Na fase placebo não houve diferença estatisticamente significante em nenhum parâmetro funcional em nenhum momento após a administração. As diferenças entre as medidas funcionais comparando o grupo tiotrópio versus o grupo placebo foram estatisticamente significantes. Conclusões: O brometo de tiotrópio, após dose única, diminuiu agudamente o grau de obstrução e de aprisionamento aéreo por até 24 horas em crianças com BO. Estudos de longo prazo são necessários para se avaliar o papel do BT na terapêutica desses pacientes / Introduction: Patients with bronchiolitis obliterans (BO) usually have severe airflow obstruction that results in chronic hypoxemia and limitation of physical activity. There is no efficient therapy for BO, bronchodilator response is usually poor, however, the bronchodilator response to a long action anticholinergic agent such as tiotropium bromide (TB) is not known. Efficacy and safety of TB with one daily administration has already been shown in chronic obstructive pulmonary disease (COPD) with significant and sustained bronchodilator response. Objective: Verify through functional measurements whether the level of bronchial obstruction and air trapping was improved by the administration of a single dose of TB by inhalation when compared to placebo in children and adolescents with BO. Methods: A randomized, double blind, placebo-controlled, crossover, prospective study in stable BO patients, 6 to 16 years of age. Spirometry and plethysmography were performed before and at 30, 60, 120 and 180 minutes and 24 hours after inhalation of 18 mcg of tiotropium or a placebo. After 7-14 days, the drugs were inverted, and the procedures were repeated. The changes in lung function parameters at each time point were compared to the baseline by analysis of variance (ANOVA) and Tukey\'s post-test and the differences in all time points assessment versus baseline in tiotropium versus placebo groups were compared using the Friedman test. Results: Thirty patients were enrolled in the study (23 male, 7 female; age 10.9±2.8 y) with baseline lung function values (% predicted) of FVC, FEV1, FEV1/FVC, FEF25-75%, IC, TLC, RV, RV/TLC, airway resistance (raw) and conductance (sGaw) of 75±15, 48±14, 59±11, 22±11, 64±23, 120±19, 281±101, 49±13, 250±65 and 23±9, respectively. Statistically significant differences were observed after tiotropium inhalation in the following parameters compared to baseline: FVC at 60/120/180min/24h, FEV1 at 30/60/120/180min, FEV1/FVC at 60/120/180min, FEF25-75% at 60/120/180min, RV at 30/60/120/180min, TLC at 30/120/180min, RV/TLC at 30/60/120/180min, raw at 30/60/120/180min/24h and sGaw at 30/60/120/180min/24h. For the placebo group, no significant differences were observed in any lung function parameters at any time. The differences between the functional measurements comparing the tiotropium versus placebo groups were statistically significant. Conclusions: Tiotropium bromide, after a single dose, acutely decreased airway obstruction and air trapping for up to 24 hours in children with BO. Long-term studies are necessary to evaluate the role of BT in the management of these patients

<p><strong>Abstract:</strong><strong> </strong></p> <p><em>Introduction:</em></p> <p>Because the relationship between pulmonary function and exercise tolerance is highly variable in COPD, other contributing factors were investigated. Physiological factors that contribute to exercise tolerance must contribute to the symptoms limiting exercise, thus the symptoms limiting exercise in COPD and their contributing factors were explored, including an investigation of novel mechanisms to explore the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD.</p> <p><em>Methods:</em></p> <p>We conducted a retrospective, cross-sectional analysis of 4,424 COPD patients and 4,221 healthy subjects; referred to McMaster University Medical Center for exercise testing. Multiple linear regression, ridge regression, and MANOVA were utilized to determine the factors contributing to exercise tolerance, important symptoms limiting exercise, and factors contributing to dyspnea.</p> <p>A randomized, double-blind, placebo-controlled, crossover study of 20 COPD subjects was performed. Repeated measures ANOVA was utilized to determine effects of 3 weeks tiotropium bromide vs. 3 weeks placebo on cardiac output and efficiency of gas exchange during exercise.</p> <p><em> </em></p> <p><em>Results:</em></p> <p>MBC, DL_CO, and quadriceps strength were the three major, independent, contributors to exercise capacity (MPO = -206.3 + 5.1*Quadriceps Strength + 1.8*MBC + 10.0*DL_CO, r² = 0.677). MANOVA further illustrated this.</p> <p>Dyspnea, alone or in equal combination with leg effort, was the most important symptom limiting exercise in COPD. V_E and MBC were the two major, independent, contributors to dyspnea (Dyspnea = 0.95 + 0.08*V_E + -0.01*MBC, r² = 0.457). The increase in dyspnea with V_E was much greater than the decrease with MBC.</p> <p>Tiotropium bromide did not significantly (p = 0.72) improve the efficiency of gas exchange for oxygen, significantly worsened (p = 0.005) the efficiency of gas exchange for carbon dioxide, and did not improve cardiac output.</p> <p><em>Conclusion:</em></p> <p>We concluded the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD is not mediated through improvements in gas exchange efficiency and/or cardiac output.</p> <p><strong><br /></strong></p> / Doctor of Philosophy (Medical Science)

Asthma is a chronic inflammatory airway disease, and its treatment is frequently challenging despite detailed national and international guidelines. While basic antiinflammatory therapy usually consists of inhaled corticosteroids in doses adapted to the asthma severity, add-on treatment with bronchodilators is essential in more severe asthma. Only recently, the long-acting anticholinergic tiotropium was introduced into the GINA guidelines. This review reports on the studies that have been performed with tiotropium in adult asthmatic patients. Following early proof-of-concept studies, several studies with tiotropium as an add-on therapy to inhaled corticosteroids (ICS), with or without a long-acting beta agonist (LABA), demonstrated convincing clinical benefit for patients. Important lung function parameters and quality of life scores significantly improved shortly after onset of the add-on therapy with tiotropium, and some studies even demonstrated non-inferiority against salmeterol. All studies reported an excellent safety profile of tiotropium. The still growing body of tiotropium studies, both in adults and children, will help to identify the position of tiotropium in future asthma guidelines and might also indicate which patients benefit most from an add-on therapy with tiotropium.