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Pathophysiology of COPD
Miltos Vassiliou 2009
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smoking
Epidemiology Statistics
Pathology Biochemistry Molecular biology Genetics
COPD
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• Genetic pre-disposition.
• Early disposal to cigarette smoke
• Infections of the childhood.

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Inflammation Chronic bronchitis Chronic
bonchiolitis (small airways disease) Pulmonary
emphysema.
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Chronic
lung
Chronic Bronchitis
Pulmoary Emphysema
Inflammation obstruction
Disease
Obstructive
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• Chronic Obstructive Lung Disease (COPD) is
  characterized by reduction of airflow, which is
  not completely reversible.
• Airflow reduction
• Is progressively installed.
• It is related with inflammatory response to
  noxious gases or particles.

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There is a mechanical event and a mechanical
result
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Terminal Bronchiole
Respiratory Bronchiole
Central airway
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Asthma early chronic bonchitis
Terminal Bronchiole
Respiratory Bronchiole
Central airway
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Chronic asthma advanced chronic bronchitis
Terminal Bronchiole
Respiratory Bronchiole
Central airway
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chronic bronchitis pulmonary emphysema
Terminal Bronchiole
Respiratory Bronchiole
Central airway
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Airway lumen reduction
Contraction of bronchial wall smooth muscles
mainly asthma Lumen stenosis by excessively
produced mucous mainly chronic
bronchitis Alveoli destruction because of
chronic or recurrent airway lumen stenosis
mainly emphysema
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105
104
103
Total surface of airways (cm2)
102
101
100
4.0
2.0
1.0
0.4
Internal diameter of each airway (cm)
0.2
0.1
0.04
0.02
0
4
8
12
16
20
24
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airways generartion
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The distance alveolar duct-terminal alveoli (2
mm) is traveled for ?2 and CO2 with Brownian
molecular movements (diffusion in monophasic
system).
?2
C?2
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Chronic Bronchitis
Emphysema
Asthma
reversibility
Sputum production
Alveolar damage
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Chronic bronchitis Quantitative qualitative
mucus changes

• Multiplication of mucus cells and new cell
  creation (acid mucins)
• Mucus metaplasia

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• Chronic obstructive disease of small airways
  (diameter lt2-3 mm)
• Very early damage, demanding little smoke
  exposure
• epithelial denudation
• Goblet cells metaplasia
• Oedema
• Smooth muscle fibers hypertrophy
• Peribronchial fibrosis

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Chronic obstructive disease of small airways
(diameter lt2-3 mm)

• Silent zone. The functional damage is not
  detected by FEV1.
• Contemporary and/or more detailed functional
  tests are necessary (Closing Volume, FO in
  middle frequencies, frequency dependence of
  compliance.)

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Emphysema permanent dilatation of the airways
distally to the terminal bronchioles with
alveolar destruction without evident fibrosis.
Preliminary indication disturbance of elastic
fibers and loss of elastic recoil.
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Alveolar hypoxia
Pulmonary vascular involvement
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Noxious particles gases
Lung Inflammation
Anti-oxidative factors
Antiproteases

Oxidative Stress
Proteases
?pa?????t???? µ??a??sµ??
COPD Pathology
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Leucocytosis CD4/CD8 reduction CD8 increase
Smoking
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Respiratory system
Thoracic wall
Lungs
TLC
VC
FRC
RV
Pressure (hPa)
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RV
FRC
TLC
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Respiratory system
Thoracic wall
Lungs
TLC
VC
FRC
RV
Pressure (hPa)
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RV
FRC
TLC
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?V1gt ?V2
C1gt C2
150
?mphysema
?V1
Normal
100
?P
Pulmonary Volume ( TLC)
?V2
50
?P
Transpulmonary pressure (PL)
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Elastic Radial Traction

Pleural Pressure


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...static hyperinflation progresses as FEV1
deterioration.
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Dynamic hyperinflation
(reversible)
Trransient Air trapping
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autoPEEP
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Respiratory system
Thoracic wall
Lungs
Dynamic Hyperinflation (auto-PEEP)
TLC
VC
FRC
RV
Pressure (hPa)
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Airflow limitation is a main contributing
factor...
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When EFL is installed
Pressure increase does not result in flow increase
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Expiratory part of flow-volume curve
Expiratory flow limitation
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Spontaneous quite expiration is passive because
Ersinsp x VT Rrsexp x Vexp
Stored elastic energy during inspiration
Work to overcome frictional resistance

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If Ersinsp x VT lt Rrsexp x Vexp then

• Expiratory muscles are activated
• Pleural Pressure becomes positive
• EFL is installed

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• The degree of dynamic hyperinflation is
  determined by
• ?he degree of EFL.
• ?he respiratory frequency.

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EFL dignosis is more difficult and more crucial
during mechanical ventilation.
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?egative Expiratory Pressure technique
EFL
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Valta P, Corbeil C, Lavoie A, Campodonico R,
Koulouris N, Chasse M, Braidy J, MiIic-Emili
J.(1994) Detection of Expiratory Flow Limitation
During Mechanical Ventilation. Am. J. Respir.
Crit. Care. Med. 150-1311-1317
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Analytical methods for EFL detection offer the
possibility of non-interventional continuous
monitoring during mechanical ventilation
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Forced oscillations
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Vassiliou M, Peslin R, Saunier C, Duvivier C.
Expiratory flow limitation during mechanical
ventilation detected by the forced oscillation
method. Eur Respir J 9779-786, 1996
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Tidal Volume dependence of respiratory system
resistance
Paw EEP Ers.V Rs.V k3.V.V
r 0.92
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M. Vassiliou, C. Saunier, C. Duvivier, P.
Behrakis, R. Peslin. Volume dependence of
Respiratory System Resistance during Artificial
Ventilation in Rabbits. Intensive Care Med 27
896-904, 2001.
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44
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M.P. Vassiliou. A. Amygdalou, C. Leontaridi, S.
Katsenos, C. Psarakis, P.K. Behrakis, R. Peslin.
NON-INTERVENTIONAL DETECTION OF EXPIRATORY FLOW
LIMITATION DURING MECHANICAL VENTILATION. 13th
European Respiratory Society Annual Congress,
Vienna, Austria, September 27 October 1, 2003
(2453).
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Increased work of breathing
Increased activity of respiratory muscles
Respiratory failure
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Neuromechanical dissociation disturbance of the
proportional relationship between respiratory
effort and result.
It is due to the upward transport of V-P curve
(non-linear part).
It is measured by VT/FVC or Pes/Pimax.
It is strongly related with dyspnoea (Borg score)
and to dynamic hyperinflation (EEVL/TLC)
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Increase of Airway resistance (Raw)
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CVRVCC
CV/VC, CC/TLC
Vital Capacity
IV
III
? ?2 750-1250
II
???
Closing Volume
I
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Combination of decreased FEV1 and disturbed
??2() may predict a serious functional
deterioration due to smoking.
Stanescu D, Sanna A, Veriter C, Robert A.
Identification of smokers susceptible to
development of chronic airflow limitation a
13-year follow-up. Chest. 1998 Aug114(2)416-25.
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P2
P (hPa)
P1
V (l/s)
V1
V2
V (l)
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1.0
Cdyn/Cstsat
Small airway disease
0.5
0.0
0 15 30 45 60
75 90
Frequency
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Frequency dependence of dynamic compliance
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Forced oscillations
N.Pappas, C.Katsanos, C.Koubaniou,
M.Psiloutsikou, O.Karabali, P.K.Behrakis, S.H.
Constantopoulos and M.P. Vassiliou. 14th ERS
ACONTRIBUTION OF THE FORCED OSCILLATIONS
TECHNIQUE IN THE DETECTION OF EXPIRATORY FLOW
LIMITATION DURING SPONTANEOUS RESPIRATION Annual
Congress Glascow, UK, 4-8/9/2004.
... Impedance at 4 Hz and Reactance at 16 Hz
permit the diagnosis of obstructive functional
disturbance.
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Forced Spirometry
FEV1/FVC is the critical index
FEV1
FEV1
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0.5
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Forced Spirometry Flow-Volume curve
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Expiratory part of flow-volume curve
Expiratory flow limitation
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Expiratory part of flow-volume curve
Expiratory flow limitation
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Forced spirometry and bronchodilatation
Full response
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Forced spirometry and bronchodilatation
Flow response
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Forced spirometry and bronchodilatation
Vexp
Volume response
FEF75
V
Vinsp
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RV
Aex V.dV
TLC
The expiratory flow-volume surface area as index
of bronchodilatation response. Psiloutsikou M.
Katsenos S, Gogali A, Matthaiou M, Jatsanos C.,
Koubaniou C. Constantopoulos S. Vassiliou M. 13th
3Panhellenic Congress of Thoracic Diseases, Patra
2-4/12/2004. ... The ?EX changes present the
more frequent and the strongest relationships to
the changes of all indices, classically used to
evaluate the bronchodilatation response.
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• Increased RV, FRC, TLC
• RV change after bronchodilatation indicates
  reversibility

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V/Q inhomogeneity

• capillary and/or airway destruction (COPD)
  hypoxia associated with
• Increased PAO2 - PaO2
• Decreased PaO2 / PAO2
• Hypercapnia in advanced damage (e.g. FEV1lt1.2 L)

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Diffusion disturbance

• Increased distance alveolar ducts alveoli.
• Drestruction of the alveolo-capillary membrane.

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What determines the exercise capacity limitation
in COPD ?
Is it the hypoxemia degree ?
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Any relationship between hypoxemia degree and
traveled distance is not proved in COPD
Spence DP, Hay JG, Carter J, Pearson MG,
Calverley PM. Oxygen desaturation and
breathlessness during corridor walking in chronic
obstructive pulmonary disease effect of
oxitropium bromide. Thorax 19934811451150.
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FEV1 is a strong predicting index of the
exercising capacity in COPD. The same is true
for the respiratory muscle strength
Dillard TA, Piantadosi S, Rajagopal KR.
Determinants of maximum exercise capacity in
patients with chronic airflow obstruction. Chest
198996267271.
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The respiratory muscles strength is decisively
influenced by hyperinflation (shortened
inspiratory muscles and flatted diaphragm)
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It seems that hyperinflation is the main
etiological mechanism. But not always...
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Certain COPD patients did not present increased
end-expiratory volume during exercise (euvolumic
patients).
Aliverti A, Stevenson N, Dellaca RL, Lo MA,
Pedotti A, Calverley PM. Regional chest wall
volumes during exercise in chronic obstructive
pulmonary disease. Thorax 200459210216.
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Thorax
Thorax
Thorax
Abdomen
Abdomen
Abdomen
End-expiration (euvolumic COPD patients)
End-expiration (most COPD patients)
End-expiration (normal)
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Percentage change of death rates in USA
(1965-1998)
3.0
Coronary Artery disease
Stroke
Othet Cardio- vascular
COPD
Other causes
2.5
2.0
1.5
1.0
0.5
59
64
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163
7
0
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
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better understanding better treating
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For further reading -Stanescu D, Veriter C, Van
de Woestijne KP. Maximal inspiratory flow rates
in patients with COPD. Chest. 2000
Oct118(4)976-80 - Hogg JC, Macklem PT,
Thurlbeck WM. Site and nature of airway
obstruction in chronic obstructive lung disease.
N Engl J Med. 1968 Jun 20278(25)1355-60. -Woolco
ck AJ, Vincent NJ, Macklem PT. Frequency
dependence of compliance as a test for
obstruction in the small airways. J Clin Invest.
1969 Jun48(6)1097-106. -Stanescu D, Sanna A,
Veriter C, Robert A. Identification of smokers
susceptible to development of chronic airflow
limitation a 13-year follow-up. Chest. 1998
Aug114(2)416-25. -Vassiliou M, Peslin R,
Saunier C, Duvivier C. Expiratory flow limitation
during mechanical ventilation detected by the
forced oscillation method. Eur Respir J. 1996
Apr9(4)779-86. -Vassiliou MP, Amygdalou A,
Psarakis CJ, Dalavanga Y, Vassiliou PM, Mandragos
KE, Constantopoulos SH, Behrakis PK. Volume and
flow dependence of respiratory mechanics in
mechanically ventilated COPD patients. Respir
Physiol Neurobiol. 2003 Apr 15135(1)87-96.
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• For further reading
• Rossi A, Brandolese R, Milic-Emili J, Gottfried
  SB. The role of PEEP in patients with chronic
  obstructive pulmonary disease during assisted
  ventilation. Eur Respir. J 1990 3 818822.
• Sarir H, Mortaz E, Karimi K, Kraneveld AD, Rahman
  I, Caldenhoven E, Nijkamp FP, Folkerts G.
  Cigarette smoke regulates the expression of TLR4
  and IL-8 production by human macrophages. J
  Inflamm (Lond). 2009 May 1612.
• Burger CD. Pulmonary hypertension in COPD a
  review and consideration of the role of arterial
  vasodilators. COPD. 2009 Apr6(2)137-44.
• Cooper CB, Celli B. Venous admixture in COPD
  pathophysiology and therapeutic approaches. COPD.
  2008 Dec5(6)376-81.
• Stockley RA. Progression of chronic obstructive
  pulmonary disease impact of inflammation,
  comorbidities and therapeutic intervention. Curr
  Med Res Opin. 2009 May25(5)1235-45
• Maury G, Marchand E. Thoracic hyperinflation and
  COPD. Beyond respiratory mechanics and dyspnea.
  Rev Mal Respir. 2009 Feb26(2)153-65.
• Mador MJ, Krawza M, Alhajhusian A, Khan AI,
  Shaffer M, Kufel TJ. Interval training versus
  continuous training in patients with chronic
  obstructive pulmonary disease. J Cardiopulm
  Rehabil Prev. 2009 Mar-Apr29(2)126-32.

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For further reading -Voynow JA, Rubin BK.
Mucins, mucus, and sputum. Chest. 2009
Feb135(2)505-12 -Kelly PT, Swanney MP, Stanton
JD, Frampton C, Peters MJ, Beckert LE. Resting
and exercise response to altitude in patients
with chronic obstructive pulmonary disease. Aviat
Space Environ Med. 2009 Feb80(2)102-7. -Weitzenb
lum E, Canuet M, Kessler R, Chaouat A. Pulmonary
function tests in chronic obstructive pulmonary
disease. Presse Med. 2009 Mar38(3)421-31 -A.
Aliverti, M. Quaranta, B. Chakrabarti, A. L. P.
Albuquerque, and P. M. Calverley. Paradoxical
movement of the lower ribcage at rest and during
exercise in COPD patients. Eur Respir J 2009
3349-60. -Au DH, Bryson CL, Chien JW, Sun H,
Udris EM, Evans LE, Bradley KA. The Effects of
Smoking Cessation on the Risk of Chronic
Obstructive Pulmonary Disease Exacerbations. J
Gen Intern Med. 2009 Apr24(4)457-63 -Moore R,
Berlowitz D, Pretto J, Brazzale D, Denehy L,
Jackson B, McDonald C. Acute effects of hyperoxia
on resting pattern of ventilation and dyspnoea in
COPD. Respirology. 2009 Mar 12. -van Durme YM,
Verhamme KM, Stijnen T, van Rooij FJ, Van
Pottelberge GR, Hofman A, Joos GF, Stricker BH,
Brusselle GG. Prevalence, Incidence and Lifetime
Risk for the Development of COPD in the Elderly.
The Rotterdam Study. Chest. 2009
Feb135(2)368-77.
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For further reading -Walker PP, Hadcroft J,
Costello RW, Calverley PM. Lung function changes
following methacholine inhalation in COPD. Respir
Med. 2009 Apr103(4)535-41. -Woo Jin Kim, Craig
P. Hersh, Dawn L. DeMeo, John J. Reilly and Edwin
K. Silverman. Genetic association analysis of
COPD candidate genes with bronchodilator
responsiveness. Respir Med. 2009
Apr103(4)552-7 -Zhen Wang, Smith Jean, Thaddeus
Bartter. Lung Sound Analysis in the Diagnosis of
Obstructive Airway Disease. Respiration.
200977(2)134-8. -Chaouat A, Savale L, Chouaid
C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset
B, Brandt C, Le Corvoisier P, Weitzenblum E,
Eddahibi S, Adnot S. Role for Interleukin-6 in
COPD-Related Pulmonary Hypertension. Chest. 2009
Apr 6. -Borghi-Silva A, DI Thommazo L, Pantoni
CB, Mendes RG, DE Fátima Salvini T, Costa D.
Non-invasive ventilation improves peripheral
oxygen saturation and reduces fatigability of
quadriceps in patients with COPD. Respirology.
2009 Apr 5. -Bhowmik A, Chahal K, Austin G,
Chakravorty I. Improving mucociliary clearance in
chronic obstructive pulmonary disease. Respir
Med. 2009 Apr103(4)496-502 -Cosio BG, Iglesias
A, Rios A, Noguera A, Sala E, Ito K, Barnes PJ,
Agusti A. Low dose theophylline enhances the
anti-inflammatory effects of steroids during
exacerbations of chronic obstructive pulmonary
disease. Thorax. 2009 May64(5)424-9.
79
For further reading -Krieger BP. Hyperinflation
and Intrinsic Positive End-Expiratory Pressure
Less Room to Breathe. Respiration.
200977(3)344-50 -Chaouat A, Naeije R,
Weitzenblum E. Pulmonary hypertension in COPD.
Eur Respir J. 2008 Nov32(5)1371-85. -Casanova
C, Cote C, Marin JM, Pinto-Plata V, de Torres JP,
Aguirre-Jaíme A, Vassaux C, Celli BR. Distance
and Oxygen Desaturation During the 6-min Walk
Test as Predictors of Long-term Mortality in
Patients With COPD. Chest. 2008
Oct134(4)746-52 -Rodríguez E, Ferrer J, Martí
S, Zock JP, Plana E, Morell F. Impact of
Occupational Exposure on Severity of COPD. Chest.
2008 Dec134(6)1237-43 -Martinez FD. The Origins
of Asthma and Chronic Obstructive Pulmonary
Disease in Early Life. Proc Am Thorac Soc. 2009
May 16(3)272-7 -Garcia-Aymerich J, Serra I,
Gómez FP, Farrero E, Balcells E, Rodríguez DA, de
Batlle J, Gimeno E, Donaire-Gonzalez D,
Orozco-Levi M, Sauleda J, Gea J, Rodriguez-Roisin
R, Roca J, Agustí AG, Antó JM.Physical Activity
and Clinical and Functional Status in COPD.
Chest. 2009 Mar 2. -Chiappa GR, Queiroga F Jr,
Meda E, Ferreira LF, Diefenthaeler F, Nunes M,
Vaz MA, Machado MC, Nery LE, Neder JA. Heliox
Improves Oxygen Delivery and Utilization During
Dynamic Exercise in Patients with COPD. Am J
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