1. Mar del Plata, 10-13 Octubre 2014 R Rodriguez-Roisin UNIVERSITAT DE BARCELONA Utilidad clínico-terapéutica de la investigación del intercambio gaseoso en la EPOC

2. Técnica de eliminación de gases inertes múltiples (MIGET) Wagner PD et al. JAP 1974;36:588-99 Estima cualitativa y cuantitativamente las distribuciones de flujo sanguíneo pulmonar y de ventilación alveolar (relaciones V A /Q). Cuantifica el shunt intrapulmonar, el desequilibrio de las relaciones V A /Q y la limitación de la difusión de oxígeno, componentes esenciales de la diferencia alveolo-arterial de oxígeno (AaPO 2 ). Estima la interacción de los factores pulmonares y no-pulmonares determinantes del intercambio gaseoso.

3. 3 Dead Space Shunt V A /Q ratio distributions in normal individuals Log SDQ Log SDV

4. Arterial Hypoxemia: Ventilation-perfusion mismatching Increased intrapulmonary shunt Diffusion limitation to oxygen Alveolar hypoventilation Arterial Hypercapnia: Alveolar hypoventilation Ventilation-perfusion mismatching Causes of abnormal PaO 2 & PaCO 2

5. Arterial Hypoxemia: Ventilation-perfusion mismatching Increased intrapulmonary shunt Diffusion limitation to oxygen Alveolar hypoventilation Arterial Hypercapnia: Alveolar hypoventilation Ventilation-perfusion mismatching Causes of abnormal PaO 2 & PaCO 2

6. Factors governing PaO 2 & PaCO 2

7. FACTORS GOVERNING PaO 2 & PaCO 2 VENTILATION-PERFUSION IMBALANCE SHUNT DIFFUSION LIMITATION INSPIRED OXYGEN ALVEOLAR VENTILATION CARDIAC OUTPUT OXYGEN UPTAKE

8. COPD: structure & function Alveolar Wall Destruction Air Spaces Enlargement Alveolar Attachments Loss HIGH V A /Q RATIOS Capillary Network Reduction Small Airways Narrowing-Distortion Nonhomogeneous Inspired Air Distribution LOW V A /Q RATIOS Reduced Ventilation In Dependent Alveoli AIRFLOW LIMITATION GAS TRAPPING- LUNG HYPERINFLATION Rodríguez-Roisin R & MacNee W. ERM 2006;38:177-200 AIRFLOW LIMITATION GAS TRAPPING LUNG HYPERINFLATION

9. 9 0 0.30 0.50 0.70 0.90 1.10 1.30 1.50 Grades V A /Q mismatching by GOLD grades 1234 LOG SDQ & LOG SDV Rodríguez-Roisin R et al. JAP 2009;106:1902-8

10. COPD & V A /Q Patterns 0.0010.010.1110100 0.0 0.1 0.2 0.3 0.4 0.0010.010.1110100 0.0 0.1 0.2 0.3 0.4 0.5 VENTILATION (l) AND BLOOD FLOW (l), L/min VENTILATION-PERFUSION RATIO Broadly Unimodal ‘Low’ ‘High’‘Low & High’ Log SDQ Log SDV 42% 21% 23% 5%

11. Effects of 100% oxygen breathing in COPD exacerbations Santos C et al. AJRCCM 2000;161:26-31 Further V A /Q worsening while breathing 100% oxygen in COPD points to a very active hypoxic pulmonary vasoconstriction reversion COPD ARDS

12. Mechanisms of V A /Q worsening in COPD exacerbation Hypoxic vasoconstriction reversion Airflow limitation Mucus hypersecretion Gas trapping-lung hyperinflation Increased cardiac output.. Increased oxygen uptake

13. FACTORS GOVERNING PaO 2 & PaCO 2 VENTILATION-PERFUSIONIMBALANCE SHUNT DIFFUSIONLIMITATION INSPIREDOXYGEN ALVEOLARVENTILATION CARDIAC OUTPUT OXYGENUPTAKE

14. Effects of 100% oxygen breathing in COPD exacerbations Santos C et al. AJRCCM 2000;161:26-31 Further V A /Q worsening while breathing 100% oxygen in COPD points to a very active hypoxic pulmonary vasoconstriction reversion COPD ARDS

15. Alveolar gas equation for carbon dioxide = Alveolar Ventilation PaCO 2 CO 2 Production. K

16. FACTORS GOVERNING PaO 2 & PaCO 2 VENTILATION-PERFUSIONIMBALANCE SHUNT DIFFUSIONLIMITATION INSPIREDOXYGEN ALVEOLARVENTILATION CARDIAC OUTPUT OXYGENUPTAKE

17. CaO 2 - Cardiac Output Oxygen Consumption CvO 2 = Cardiac Output CaO 2 - CvO 2 = Oxygen Consumption Fick Principle

18. CaO 2 - Cardiac Output Oxygen Consumption CvO 2 = Cardiac Output CaO 2 - CvO 2 = Oxygen Consumption Fick principle

19. I V A /Q.. PaO 2 v

20. Mixed venous PO 2 (mm Hg) 100 90 80 70 60 50 40 30 15 20 25 30 40 45 35 Arterial PO 2 (mm Hg) Mixed venous and arterial PO 2 interplay 0.9 1.2 1.5 1.8 COPD patients 0.30.6 Healthy subjects

21. SCENARIO # 1: Arterial Hypoxemia & COPD Exacerbations

22. Ventilation-Perfusion Worsening 46% COPD Exacerbations: Determinants of Hypoxemia Barberà JA et al. ERJ 1997;10:1285-91 Low Mixed Venous PO 2 26% Increased Oxygen Consumption 28%

23. PaO 2 FALL INCREASED VO 2 DECREASED Mixed Venous PO 2 DECREASED PaO 2 WORSENING V A /Q MISMATCH COPD EXACERBATION

24. SCENARIO # 2: NIV & COPD Exacerbations

25. COPD EXACERBATION AND NIMV (  SD) BL15 min30 minPOST NIMV 35 30 25 20 15 10 * * f (min -1 ) BL15 min30 minPOST NIMV 700 600 500 400 300 200 * * V T (ml) BL15 min30 minPOST NIMV 10.0 8.0 6.0 4.0 * * Q T (L/min). Diaz O et al. AJRCCM 1997;156:1840-5

26. COPD EXACERBATION AND NIMV (  SD) Diaz O et al. AJRCCM 1997;156:1840-5 80 70 60 50 40 BL15 min30 minPOST NIMV PaO 2 PaCO 2 (mm Hg) * * * 7.50 7.40 7.30 7.20 BL15 min30 minPOST NIMV pH * * 25 20 15 10 BL15 min30 minPOST NIMV V A /Q MISMATCH..

27. PaO 2 COPD Exacerbation & NIV MINUTE VENTILATION PaO 2 CARDIAC OUTPUT PvO 2 UNCHANGED V A /Q MISMATCH

28. SCENARIO # 3: SABAs & COPD Exacerbations

29. INCREASED Q T (Vasodilatation?) BRONCHODILATION INCREASED Arterial PO 2 INCREASED Mixed venous PO 2 FINAL Arterial PO 2 WORSENING V A /Q MISMATCH DECREASED Arterial PO 2 COPD Exacerbation & SABAs ?

30. Baseline30 min90 min FEV 1 (% Predicted) 15 25 35 45 55 ACUTE STABLE * * * * COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5 +16% +15%

31. Baseline30 min90 min IC (Liters) 1.25 1.75 2.25 2.75 * * ACUTE STABLE p<0.03 * * p<0.02 COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5 +14% +12%

32. Baseline30 min90 min Minute Ventilation (L/min) 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 ACUTE STABLE p<0.05 COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5

33. Baseline30 min90 min Cardiac Output (L/min) 5 6 7 8 * * ACUTE STABLE COPD Exacerbation & Convalescence: Salbutamol Response +12% * * +23% Polverino E et al. AJRCCM 2007;176:350-5

34. Baseline30 min90 min 200 220 240 260 O 2 Uptake (mL/min) ACUTE STABLE COPD Exacerbation & Convalescence: Salbutamol Response * +10% Polverino E et al. AJRCCM 2007;176:350-5

35. Baseline30 min90 min PaO 2 (mm Hg) 55 60 65 70 75 80 ACUTE STABLE COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5 p<0.01 * * p<0.05 -7.5 mmHg

36. Baseline30 min90 min PaCO 2 (mm Hg) 38 40 42 44 46 48 ACUTE STABLE COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5

37. Baseline30 min90 min V A /Q Mismatch (DISP R-E*) 10 12 14 16 18 20 ACUTE STABLE.. COPD Exacerbation & Convalescence: Salbutamol Response Polverino E et al. AJRCCM 2007;176:350-5 p<0.05 * * +29% + 6%

38. UNCHANGED PaO 2 INCREASED Q T (Vasodilatation?) INCREASED mixed venous PO 2 UNCHANGED V A /Q MISMATCH UNCHANGED PaO 2 Bronchodilation Increased PaO 2 COPD: SABAs & Exacerbation ?

39. Inflammatory Mediators airway lumen Inflammatory Mediators leaky epithelium leaky post-capillary venule Bronchial Circulation

40. Inflammatory Mediators  2 -agonist  2 -receptors

41. COPD: SABAs & Convalescence Bronchodilation Increased PaO 2 INCREASED VO 2 DECREASED mixed venous PO 2 PaO 2 FALL DECREASED PaO 2 INCREASED Q T (Vasodilatation?) INCREASED mixed venous PO 2 WORSENING V A /Q MISMATCH

42. 42 BDs de ACCIÓN CORTA: Mejoran los síntomas y aumentan el FEV 1 (1ª t - Línea) No hay diferencias entre sus diferentes clases Las combinaciones no aportan ningún beneficio complementario No hay diferencias entre el empleo de los MDI y los nebulizadores Se deben aumentar las dosis y/o su frecuencia ¿ Qué sabemos de los broncodilatores? Rodríguez-Roisin R. Thorax 2006;61:535-44

43. + +   +  Bronchodilators Glucocorticoids Antibiotics Oxygentherapy Mechanical Ventilation Fluid Restriction Diuretics Inotropics Gas Exchange & COPD Exacerbation: Therapeutical Implications V A /Q MISMATCH MINUTE VENTILATION OXYGEN CONSUMPTION CARDIAC OUTPUT.. Rodríguez-Roisin R. Thorax 2006;61:535-44