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Therapies for Dynamic Hyperinflation in COPD

Therapies for Dynamic Hyperinflation in COPD. Richard Casaburi PhD, MD Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Torrance, California, USA. Exercise Intolerance. Often the chief complaint of the COPD patient Linked to dynamic hyperinflation

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Therapies for Dynamic Hyperinflation in COPD

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  1. Therapies for Dynamic Hyperinflation in COPD Richard Casaburi PhD, MD Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Torrance, California, USA

  2. Exercise Intolerance • Often the chief complaint of the COPD patient • Linked to dynamic hyperinflation • Physiologically-based strategies to reduce hyperinflation sought • Four interventions to decrease hyperinflation with exercise have now been identified

  3. Hyperinflation at Restvs.Hyperinflation With Exercise

  4. Chest X-Ray Changes With Hyperinflation and Air Trapping Low, Flattened Diaphragm Increased AP Diameter Air Trapping Janssens JP, et al. J Pain Symptom Manage. 2000;19:378-392.

  5. Hyperinflation at Restvs.Hyperinflation With Exercise

  6. X PL PL . . V V Normal COPD Reduced recoil Reduced tethering Increased airways resistance Expiratory flow limitation Increased air trapping

  7. Exercise  TLC Health IC VC EELV RV Exercise  TLC COPD IC VC EELV RV

  8. Exercise  TLC Health IC VC EELV RV Exercise  TLC COPD IC VC EELV RV IRV Decreases in inspiratory capacity and inspiratory reserve volume imply dynamic hyperinflation

  9. Assessing Dynamic Hyperinflation during Exercise 8 6 4 2 0 Rest Exercise 8 6 Volume (L) Volume (L) 4 IC IC 2 0 0 10 20 0 10 20 Time(s) Time(s)

  10. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy • Inhaled Gas Mixtures • Rehabilitative Therapy

  11. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy - Bronchodilators • Inhaled Gas Mixtures • Rehabilitative Therapy

  12. Effect of Tiotropium on Hyperinflation and Exercise Tolerance in COPD • Multi-center double-blinded randomized placebo- controlled study • 198 patients with COPD randomized to 6 weeks of tiotropium (18 µg) once-daily versus placebo • Exercise tolerance determined by serial constant-work rate tests at 75% of initial peak work rate in an incremental exercise test • Hyperinflation during exercise measured by inspiratory capacity maneuvers O’Donnell D et al. ERS, 2004

  13. Study Population Tiotropium Placebo n (m/f) 96 (68/28) 91 (70/21) Age (y) 61.5 59.4 FEV1 (L) 1.25 1.29 FEV1/FVC (%) 45.7 44.6 RV (L) 4.42 4.37 RV (% pred) 206 207 Peak work rate (W)* 78 79 *at day -15 (screening visit)

  14. Inspiratory Capacity at Isotime During Constant-Work Rate Exercise Placebo (n=91) Tiotropium (n=96) * * **  IC STD (mL) =178 Days *P<0.0001 **P<0.0005

  15. Endurance Time in a Constant-Work Rate Exercise Test Placebo (n=91) Tiotropium (n=96) ** * + 105.2 sec + 21.4 % + 66.8 sec + 13.6 % Exercise duration (seconds) 491.7 sec Days *P<0.05 **P<0.01

  16. Tiotropium decreases expiratory airflow resistance, thereby decreasing dynamic lung hyperinflationduring exercise …and improving exercise tolerance

  17. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy • Inhaled Gas Mixtures • Rehabilitative Therapy

  18. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy • Inhaled Gas Mixtures – Oxygen - Heliox • Rehabilitative Therapy

  19. Oxygen Decreases Hyperinflation and Increases Exercise Tolerance Somfay, A., J. Porszasz, S.M. Lee and R. Casaburi. Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxemic COPD patients. Eur. Respir. J. 18:77-84, 2001.

  20. Methods • 10 patients with COPD • Constant work rate exercise to tolerance • Fio2 = 0.21, 0.3, 0.5, 0.75, 1.0 • Dynamic hyperinflation assessed by inspiratory capacity maneuvers

  21. Patient Characteristics • Age: 65 ± 7 years • FEV1: 31 ± 10 % pred. • RV: 200 ± 45% pred. • DLCO: 41 ± 12% pred. • SpO2 (rest): 96 ± 1 % • SpO2 (ex.): 92 ± 3 %

  22. Effect of Oxygen in Patients Performing Constant-Work Rate Exercise (Isotime Values) 32 700 30 600 28 500 26 Respiratory rate (breaths/min) Inspiratory reserve volume (ml) 24 400 22 300 20 18 200 0.2 0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.8 1.0 FIO2 FIO2 Somfay et al. ERJ 2001

  23. Effect of Oxygen in Patients Performing Constant-Work Rate Exercise 14 12 10 Endurance time (min) 8 6 4 2 0.2 0.4 0.6 0.8 1.0 FIO2 Somfay et al. ERJ 2001

  24. Effect of Oxygen in Patients Performing Constant-Work Rate Exercise 14 12 10 Endurance time (min) 8 160% increase 6 4 2 0.2 0.4 0.6 0.8 1.0 FIO2 Somfay et al. ERJ 2001

  25. Supplemental oxygen decreases ventilatory drive and slows breathing, thereby decreasing dynamic lung hyperinflation during exercise …and improving exercise tolerance

  26. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy • Inhaled Gas Mixtures – Oxygen - Heliox • Rehabilitative Therapy

  27. Methods • 10 patients with COPD (age = 70 ± 9 years; FEV1=1.2 ± 0.4 L) • Constant work rate exercise to tolerance at 90% of peak work rate in an incremental test • Inhalate: room air vs. 80% He + 20% O2 administered in randomized order • Dynamic hyperinflation assessed by inspiratory capacity maneuvers Goto, et al., ATS Annual Meeting, 2004

  28. Typical Ventilatory Responses Incremental Test Constant Work Rate Test

  29. Changes in Inspiratory Capacity: CWR Exercise Group Response Typical Subject

  30. Air Heliox% increase IRV isotime (l)0.50 0.77 54% VE end (l/min) 36.1 41.4 15% Endurance time (min) 7.8 11.5 47% Effect of Heliox Breathing on Responses to Constant Work Rate Exercise in 10 COPD Patients Goto, et al., ATS Annual Meeting, 2004

  31. Heliox breathing decreases airflow resistance, thereby decreasing dynamic hyperinflation during exercise …and improving exercise tolerance

  32. Improving Exercise Tolerance- Decreasing Hyperinflation in COPD - • Pharmacotherapy • Inhaled Gas Mixtures • Rehabilitative Therapy

  33. Mechanisms by which Exercise Tolerance is Improved by Rehabilitative Exercise • Decreased ventilatory stimulation by lactic acidosis • Decreased muscle fatigue • Decreased hyperinflation

  34. Rehabilitative Exercise Training Decreases Hyperinflation and Increases Exercise Tolerance Porszasz, J, M. Emtner, S. Goto, A. Somfay, B.J. Whipp and R. Casaburi. High intensity training decreases exercise-induced hyperinflation in patients with COPD. Chest. 128:2025-2034,2005.

  35. Methods • 24 patients with COPD (age = 66 ± 8 years; FEV1=35 ± 9% pred.) • Training program: high intensity cycle ergometer exercise, 45 min/session, 3 sessions/week, 7 weeks • Constant work rate exercise to tolerance at 75% of peak work rate in an incremental test • Dynamic hyperinflation assessed by inspiratory capacity maneuvers Porszasz et al. Chest, 2005

  36. VO2 post VEpost VO2pre VE pre Work rate Pre 50 40 Work rate Post 30 20 10 0 0 5 10 15 20 25 30 Time (min) Effect of Exercise Training on Oxygen Uptake and Ventilation During Constant-Work Rate Exercise 120 100 1.0 80 60 0.5 40 20 0 0 0 5 10 15 20 25 30 Time (min) Porszasz et al. Chest, 2005

  37. Post-training Pre-training Effect of Exercise Training on Hyperinflation during Constant-Work Rate Exercise 2.5 2.0 IC (l) 1.5 1.0 -5 0 5 10 15 20 Time (min) Porszasz et al. Chest, 2005

  38. Effect of Exercise Training on Breathing Pattern and Hyperinflation in COPD Porszasz et al., Chest, 2005

  39. Relation of Training-Induced Changes in Breathing Pattern and Hyperinflation Porszasz et al., Chest, 2005

  40. Endurance exercise training reduces ventilatory drive and slows breathing, thereby decreasing dynamic hyperinflation during exercise …and improving exercise tolerance

  41. Improving Exercise Tolerance in COPD:Strategies Demonstrated to Reduce Hyperinflation • Bronchodilator therapy • Heliox breathing • Supplementary oxygen • Endurance exercise training

  42. Improving Exercise Tolerance in COPD:Strategies Demonstrated to Reduce Hyperinflation • Bronchodilator therapy • Heliox breathing • Supplementary oxygen • Endurance exercise training Decreases airflow resistance Decreases ventilatory drive

  43. Improving Exercise Tolerance in COPD:Strategies Demonstrated to Reduce Hyperinflation • Bronchodilator therapy • Heliox breathing • Supplementary oxygen • Endurance exercise training Decreases airflow resistance Decreases ventilatory drive Effects of these Interventions Should be Additive

  44. Improving Exercise Tolerance in COPD:Strategies Demonstrated to Reduce Hyperinflation • Bronchodilator therapy • Heliox breathing • Supplementary oxygen • Endurance exercise training Decreases airflow resistance Decreases ventilatory drive Effects of these Interventions Should be Additive

  45. Improvement in Exercise Tolerance with the Combination of Tiotropium and Pulmonary Rehabilitation in Patients with COPD R Casaburi, D Kukafka, CB Cooper, TJ Witek, S KestenChest 2005;127:809–817

  46. Study Design • Subjects randomized to tiotropium vs. placebo once-daily (double blinded) at 17 sites • Study drug administered 5 weeks prior to, 8 weeks during, and 12 weeks following rehabilitation • Rehabilitation included three 45-min treadmill exercise sessions/week • Primary endpoint was treadmill walking (0% incline) endurance time at 80% of the maximum speed attained during an initial incremental test

  47. Study Participants • 93 participants; 57% male • Age=67 ± 8 years • BMI=29.5 ± 5.2 kg/m2 • FEV1=0.88 ± 0.36 L (34 ± 12% predicted)

  48. 42% 32% 16% Effect of Tiotropium on the Improvement in Exercise Tolerance Resulting from Rehabilitation Study drug * * Rehabilitation *P<0.05

  49. Tiotropium + Exercise Training • The group receiving tiotropium during exercise training demonstrated greater improvements in exercise tolerance and maintained these improvements after rehabilitation than those receiving placebo. • Tiotropium and exercise training have additive effects on exercise tolerance in COPD.

  50. Improving Exercise Tolerance in COPD:Strategies Demonstrated to Reduce Hyperinflation • Bronchodilator therapy • Heliox breathing • Supplementary oxygen • Endurance exercise training Decreases airflow resistance Decreases ventilatory drive Effects of these Interventions Should be Additive

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