1. New Advances in Dyspnea management in COPD
Professor Denis E. O’Donnell, MD, FRCPI, FRCPC
Respiratory Investigation Unit
Queen’s University & Kingston General Hospital
Kingston, Ontario
Canada

2. OUTLINE Definition of COPD
Role of lung hyperinflation in morbidity and mortality
Pathophysiology of Lung hyperinflation
Reducing lung hyperinflation
Short term benefits of pharmacological lung deflation
Can we change the clinical course of COPD?

3. Trends in Death Rates for 6 Leading Causes of Death in United States, 1970-2002
Trends in Age-Standardized Death Rates for the 6 Leading Causes of Death in the United States,
Jemal A, et al. JAMA 2005; 294:
Copyright restrictions may apply.

4. COPD Definition:
“Chronic obstructive pulmonary disease (COPD) is a respiratory disorder largely caused by smoking, and is characterized by progressive, partially reversible airway obstruction and lung hyperinflation, systemic manifestations, and increasing frequency and severity of exacerbations.”
Can Respir J 2008;15(Suppl A):1A-8A.

5. COPD Definition:
“Chronic obstructive pulmonary disease (COPD) is a respiratory disorder largely caused by smoking, and is characterized by progressive, partially reversible airway obstruction and lung hyperinflation, systemic manifestations, and increasing frequency and severity of exacerbations.”
Can Respir J 2008;15(Suppl A):1A-8A.

7. age

8. Static lung volumes in COPD (n = 2,952)
TLC (L) 1 2 3 4 5 6 7 8
Normal
predicted
GOLD I
(751)
GOLD II
(1448)
GOLD III
(633)
GOLD IV
(120)
FRC
IC/TLC% IC
43%
37%
28%
46%
20%
Post-bronchodilator value
O’Donnell et al. KGH database

9. Kaplan-Meier survival curves for all causes (A) and for respiratory failure (B) using a 25% IC/TLC threshold
Casanova C, et al. AJRCCM 2005.

10. Morbidity in COPD

11. Health Status Scores at Different COPD Stages (ATS Criteria)
SGRQ score
FEV1 % predicted 10 20 30 40 50 60 70 80
Upper limit
Age-matched normals
Poor health
Good health
Bars indicate SE
Ferrer et al An Intern Med 1997; 127:1702

12. Breathlessness

13. Pathophysiology of Lung Hyperinflation in COPD

14. Histopathologic Features of COPD
Normal
Obstructive Bronchiolitis
Emphysema
Barnes PJ. N Engl J Med. 2000;343: Copyright © 2004 [2000] Massachusetts Medical Society. All rights reserved.

15. . . Normal COPD Reduced recoil Reduced tetheringPL V . PL V .
Reduced recoil
Reduced tethering
Increased airways resistance
Expiratory flow limitation

16. IRV VT
EELV
Normal COPD
EILV
TLC IC

17. To the COPD patient, this is a breathtaking view.

18. EELV is dynamically determined
Normal
COPD +
VE 18 L/min
VT 0.9 L
F 20 /min
TE 1.95 sec
EELV - Vr = VT
eTE/trs -1

19. O’Donnell et al. AJRCCM 2001;164:770-777.
VENTILATION (L/min)
140
120
100 80 60 40 20
VOLUME (%pred TLC)
Normal
(n=25)
COPD
(n=105)
EELV
IRV IC VT
O’Donnell et al. AJRCCM 2001;164:

20. Effects of Dynamic Hyperinflation
 Work of breathing
Inspiratory muscle weakness
Early ventilatory limitation to exercise
Negative effect on cardiac function
 Exertional dyspnea

21. Key Messages
Lung hyperinflation contributes to morbidity and mortality in COPD
There is a solid physiological and clinical rationale for therapeutic lung deflation

22. Expiratory flow limitation Reduced exercise Capacity
Clinical Course of COPD
COPD
Expiratory flow limitation
Air trapping
Exacerbations
Hyperinflation
Breathlessness
HRQoL
Deconditioning
Inactivity
Reduced exercise Capacity

23. Reducing Lung Hyperinflation
Bronchodilators
Reduce Ventilation:
Oxygen
Exercise Training
Heliox
Deflationary breathing techniques
Surgical: LVRS
Valves: Stents / fenestrations /glue

24. Treatment Strategies
Bronchodilators

25. COPD: Response to BronchodilatorsV . X
Θ tiotropium
Volume
Flow
IC pre-BD
Vmax .
IC post-BD

26. Pharmacological Volume Reduction
(%predicted TLC)
Lung Volume
TLC
FRC IC

27. Bronchodilator-Induced Changes in IC
Change in IC (L)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
O'Donnell (Chest 2006)
Peters (Thorax 2006)
VanNoord (Chest 2006)
Maltais (Chest 2005)
O'Donnell (ERJ 2004)
DiMarco (ERJ 2003)
Celli (Chest 2003)
Newton (Chest 2002)
O'Donnell (AJRCCM 1998)
severe
moderate
SABD
LABA
LABA+ICS
tiotropium
tio+LABA

28. Tiotropium + Formoterol: Effects on Hyperinflation
24-h baseline IC
tiotropium qd + formoterol bid
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2 -2 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
IC (L)
normal
TLC
0.0
9 am
3 pm
9 pm
3 am
JA van Noord, et al. Chest 2006

29. Cardiopulmonary Exercise Testing

30. Operating Lung Volumes during Exercise
Normal COPD
pre-dose post-dose
EELV
IRV VT IC
TLC

31. Bronchodilators Improve Endurance
Tiotropium
Placebo
p<0.01
900
800
700
600
500
400
300
p<0.05
p<0.01
Endurance time
(seconds)
Constant work rate cycle ergometry to symptom limitation at 75%Wmax (2.25 hours after dosing)
[Can Resp Meet ppt. Slides 27]
Maltais F et al. Chest;128:
Baseline Days
Maltais F et al. Chest;128:

32. Responses to Bronchodilators in COPD
Peters M.M., Thorax 2006
O'Donnell D.E., AJRCCM 1999
O'Donnell D.E., Chest 2006
O'Donnell D.E., ERJ 2004b
Maltais F., Chest 2005
O'Donnell D.E., ERJ 2004a 30 60 90
120
150
180
Change in endurance time (sec)
0.1
0.2
0.3
0.4
0.5
Change in IC (L)
SABD
LABA
LAAC
ICS/LABA
■ crossover study
■ parallel group study

33. Triple Therapy for COPD?

34. The Canadian Optimal Trial- Intervention:
Patients with moderate or severe COPD (n=449) were randomized to one of 3 arms for 52 weeks:
Tiotropium plus placebo
Tiotropium plus Salmeterol 25 ug, 2 puffs twice daily.
Tiotropium plus Fluticasone/Salmeterol (500/50 ug daily).
Aaron et al. Annals of Internal Medicine 2007

35. One Year Changes in Lung Function
( L from day 0)
( L from day 0)

36. Optimal Study - Change in Health Status
Worse 52
p = 0.01 for Tio + Fluticasone/Salmeterol vs. Tio + Placebo
p = 0.02 for Tio + Salmeterol vs. Tio+ Placebo 50 48
SGRQ total
score 46
Tiotropium + Placebo 44
Key Points:
The primary outcome measure is the proportion of patients who experienced a respiratory exacerbation in the three treatment groups within 52 weeks of randomization. Other outcomes that have been assessed over the 52-week trial period include: 1) changes in disease-specific quality of life and changes in dyspnea; 2) healthcare utilization; and 3) changes in lung function.1
St George’s Respiratory Questionnaire (SGRQ): the St George's Respiratory Questionnaire is a standardized self-completed questionnaire for measuring impaired health and perceived well-being ('quality of life') in airway disease.1
Reference:
Aaron SD, Vandemheen K, Fergusson D, Fitzgerald M, Maltais F, Bourbeau J, et al. The Canadian Optimal Therapy of COPD Clinical Trial. American Thoracic Society International Conference. 2006: San Diego, CA. (Poster) 42
Tiotropium + Salmeterol
Tiotropium + Fluticasone/
Salmeterol
Better 40 4 20 36 52
Time (weeks)
Aaron S, et al. AIM 2007; 146:

37. Pharmacotherapy In COPD
Increasing Disability and Lung Function Impairment
Mild
Moderate
Severe
Infrequent AECOPD
(an average of
< 1 per year)
Frequent AECOPD
(≥ 1 per year)
SABD prn
LAAC or LABA + SABA prn
LAAC + ICS/LABA + SABA prn
Recommendations
►For patients with symptoms that are only noticeable with exertion and who have relatively little disability, initiation of short-acting bronchodilator therapy, as needed, is acceptable. Options would include short-acting beta2-agonists, short-acting anticholinergics, alone or in combination. The choice of first-line therapy in mild symptomatic COPD should be individualized and based on clinical response and tolerance of side effects. Some such patients may benefit from treatment with a long acting bronchodilator (level of evidence: 3B).
►For patients with more persistent symptoms and moderate to severe airflow obstruction, a long-acting bronchodilator such as tiotropium or salmeterol, should be used to improve dyspnea, exercise endurance and health status and to reduce exacerbation frequency (level of evidence: 1A). Short-acting beta2-agonists should be used as needed for immediate symptom relief. The panel believed that tiotropium was an acceptable first choice long acting bronchodilator in this group given its proven clinical efficacy, convenient once daily dosing regimen and safety profile (level of evidence: 3B).
►For patients with moderate to severe COPD with persistent symptoms but infrequent exacerbations (less than one per year on average, for two consecutive years), a combination of tiotropium 18 µg once daily and a LABA (ie, salmeterol 50 µg twice daily) is recommended to maximize bronchodilation and lung deflation (level of evidence: 3B). Lower dose SALM /FP (50/250 twice daily) could be substituted for salmetrol to maximize bronchodilatation in patients with persistent dyspnea despite combined long-acting bronchodilators (SALM plus tiotropium) (level of evidence:3B.) Short-acting beta2-agonists may be used as needed for immediate symptom relief.
►For patients with moderate to severe COPD with persistent symptoms and a history of exacerbations (1 or more per year on average, for two consecutive years), a combination of tiotropium plus a LABA and ICS therapy product (eg, SALM/FP 50/500 or FM/BUD 12/400, twice daily) is recommended to improve bronchodilation and lung deflation, to reduce the frequency and severity of exacerbations and to improve health status (level of evidence 1A). Short-acting beta2-agonists may be used as needed for immediate symptom relief.
►Inhaled corticosteroids (ICS) should not be used as monotherapy in COPD and when used should be combined with a LABA (level of evidence: 1E).
►In patients with severe symptoms despite use of both tiotropium and a LABA/ICS, a long-acting preparation of oral theophylline may be tried, although monitoring of blood levels, side effects and potential drug interactions is necessary (level of evidence: 3B).
O’Donnell DE, et al. Can Respir J Vol 14 Suppl B September 2007: 5B-32B (16B)
persistent disability
persistent disability
persistent disability
LAAC + LABA + SABA prn
LAAC + SABA prn or
LABA + SABD prn
persistent disability
LAAC + ICS/LABA + SABA prn
Theophylline
LAAC + ICS/LABA* + SABA prn
O’Donnell DE, et al. Can Respir J Vol 14 Suppl B September 2007: 5B-32B (14B)

38. Comprehensive Management of COPD
Surgery
Surgery
Oxygen
Oxygen
Inhaled corticosteroids/LABA
Inhaled corticosteroids
Pulmonary rehabilitation
Pulmonary rehabilitation
Long-acting bronchodilator(s)
Long
Short-acting bronchodilator(s) prn
PRN Rapid
Smoking cessation/exercise/self
Smoking cessation/exercise/self-management education
Lung Function
Mild
Mild
Very Severe
Very Severe
Impairment
MRC Dyspnea
Scale II II V V
Early diagnosis
Prevent/Rx AECOPD
End of Life
Care
(spirometry) +
Follow-up

39. Can we change the clinical course of COPD?

40. TORCH: Rate of Decline in FEV1
1350
1300
1250
1200
1150
1100
Placebo
SAL FP
SFC
–39 mL/yr*†
FEV1 (mL)
–42 mL/yr*
–42 mL/yr*
–55 mL/yr
[Can Resp Meet ppt. Slides 36]
Weeks
No. of patients
*p<0.001 vs. placebo, †p<0.001 vs. SAL and FP
B Celli et al. AJRCCM

41. What About Progression of Disease?
1.2
post hoc analysis
Tiotropium (n=518)
1.1
-12.4 mL/year*
Trough FEV1 (L)
1.0
Placebo (n=328)
-58.0 mL/year
0.9 18
344
Day
*p=0.005 tiotropium vs placebo (mean regression slopes)
Anzueto A et al. Pulm Pharm Ther 2005;18:75-81

42. Reducing Lung Hyperinflation
Reduce work of breathing
Improve inspiratory muscle strength
Improve ability to exercise.
Improve cardiac function
Reduce exertional dyspnea
Reduce frequency of AECOPD
?Delay disease progression and improve survival

43. LVRS improves survival in some patients
A survival benefit with LVRS is seen only in patients with predominantly upper lobe emphysema and low exercise capacity
No. at risk
Surgery
Medical therapy
Months after randomisation
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probability of death
p=0.005
139
151
121
120 93 85 61 43 17 13
Fishman et al. N Engl J Med 2003

44. Static lung volumes (%TLC)
The Natural History of Hyperinflation
Static lung volumes (%TLC) 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Normal
GOLD I
GOLD II
GOLD III
GOLD IV
FRC IC
LVRS
pharmacologic volume reduction
Post-bronchodilator value
O’Donnell et al. KGH database

45. Clinical Course of COPD
Expiratory flow limitation
Exacerbations
Air trapping
Hyperinflation
Breathlessness
HRQoL
Deconditioning
Inactivity
In patients with COPD, there is a cycle of airflow limitation, dyspnea, and reduced exercise endurance.
The physiological impairment in COPD is characterized by airflow limitation, air trapping, and hyperinflation.
These physiologic abnormalities lead to dyspnea (or breathlessness).
Dyspnea in itself is unpleasant, and it also severely limits the amount of activity a patient can undertake. Often patients will avoid situations that demand physical activity.
Avoiding exercise leads to deconditioning and worsening of the disease and, ultimately, the patient’s health-related quality of life suffers.
COPD is often associated with acute exacerbations of symptoms.
Exacerbations are periodic worsenings of disease that are often triggered by respiratory tract infections.
As COPD worsens, patients are more likely to experience exacerbations, which become more severe.
Exacerbations may have a long-term impact on the disease and can contribute to premature mortality.
Reduced exercise Capacity
Systemic (muscle wasting, CV disease, osteoporosis, insulin resistance, etc)
Disability
Disease Progression
Death

46. Clinical Course of COPD
Reduce exacerbations
Expiratory flow limitation
LAAC+ LABS/ICS
Improve airflow limitation (FEV1),
Reduce air-trapping & hyperinflation (IC) 
Relieve Breathlessness
Maintain physical condition
HRQoL
Increase activity
In patients with COPD, there is a cycle of airflow limitation, dyspnea, and reduced exercise endurance.
The physiological impairment in COPD is characterized by airflow limitation, air trapping, and hyperinflation.
These physiologic abnormalities lead to dyspnea (or breathlessness).
Dyspnea in itself is unpleasant, and it also severely limits the amount of activity a patient can undertake. Often patients will avoid situations that demand physical activity.
Avoiding exercise leads to deconditioning and worsening of the disease and, ultimately, the patient’s health-related quality of life suffers.
COPD is often associated with acute exacerbations of symptoms.
Exacerbations are periodic worsenings of disease that are often triggered by respiratory tract infections.
As COPD worsens, patients are more likely to experience exacerbations, which become more severe.
Exacerbations may have a long-term impact on the disease and can contribute to premature mortality.
Improve exercise Capacity
Systemic (muscle wasting, CV disease, osteoporosis, insulin resistance, etc) 
Disability
Disease Progression
Death

47. Summary
To achieve clinical benefits in COPD, we need to address the central pathophysiologic abnormalities of airflow limitation and lung hyperinflation.
Modern pharmacotherapy has consistently demonstrated sustained impacts on key outcome parameters: airflow limitation, lung hyperinflation, exercise tolerance, exacerbations and health-related quality of life.
International Guidelines recognize the value of long term treatment with “triple therapy” in treating moderate to severe COPD.
Long term treatment with “triple therapy” has the potential to improve the clinical course of COPD and to increase survival.