THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Pulmonary Circulation and Its DeterminantsChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Perfusion.pptx

3. Aims At the end of this lecture students should be able to • outline factors involved in gas diffusion; • determine alv. pressure gradients for CO2 and O2; • explain why CO2 diffuses much better than O2; • identify factors determining perfusion; • illustrate how gases and chemicals modulate perfusion; • recognise implications of ventilation-perfusion relationship; and • locate anatomical and physiological shunts.

4. Contents • Specializations maximising pulmonary gas exchange • Factors determining gas exchange • Considerations for O2 and CO2 diffusion • Pressure gradients for CO2 and O2 • Perfusion of lung tissue • Gases and chemicals that modulate perfusion • Ventilation-perfusion relationship and its implications • Inhomogeneities in ventilation-perfusion relationship • Anatomical and physiological shunts

5. Alveolar Vascular Sheet • Capillary bed is very tight (frog). • Top: small artery • Bottom: vein • Individual capillary segments are so short that blood forms an almost continuous sheet (“sheet of flowing blood”): Very close proximity of gas and blood. • Gas exchange via “pulmonary membrane”: • Surface area: 70 m2 • Blood content (cap.): 60 - 140 mL • Blood content/m2: 1 - 2 mL≈ 1 µm thickness (fast gas exchange). • Capillary diameter: 5 µm (RBC 7 µm): hardly any plasma space between RBC membrane and endothelium. Guyton & Hall, 2001

6. Alveolar Respiratory Membrane Berne et al., 2004 • Human lung tissue sample at EM level • Short diffusion distances: 0.5 - 4 µm (around a nucleus). • Factors affecting gas diffusion: • Thickness of membrane • Diffusion coefficient • Total surface area of respiratory membrane • Pressure gradients

7. 1. Membrane Thickness • Average distance of diffusion: 0.3 - 0.7 µm • A significant decrease in diffusion is only evident if membrane thickens > 2 - 3 x. • Thickening due to pathological processes • Lung oedema (interstitial and alveolar fluid) • Lung fibrosis (interstitial) due to inflammation

8. 2. Diffusion Coefficient • Gas diffusion rate same as that in water. • Depends on gas solubility in membrane. • Diffusion rate of CO2 23 x better than that of O2, which is about 2 x that of N2. • There are hardly ever diffusion problems for CO2. • O2 diffusion can easily become limited.

9. 3. Total Membrane Surface Area • Some loss of area (70 m2) throughout life. • When loss reaches about ¼ - ⅓ of original total, gas exchange is severely restricted even under resting conditions (reserve, “surgical volume”…). • Changes due to pathological processes: • Emphysema (loss of alveolar surface area): smoker,α1-antitrypsin deficiency, etc. • Lung resections (surgical removal).

10. 4. Pressure Gradients (ΔP) • tContact: 0.3 - 0.8 s • Diffusion time: 0.3 s • Pressure gradient for • O2 is 2.5 x, and for • CO2 is 1.15 x • initial value. Despopoulos & Silbernagl 2003 • Driving force for diffusion is difference in partial pressures in capillary and alveolus (pressures in figure). • Rate of gas exchange dependent on ventilation, perfusion (CO)and haemoglobin concentration.

11. Lung Perfusion ( ) • Globally corresponds to CO. • Low pressure in lung vessels: • Systolic: 25 torr; diastolic: 10 torr (low resistance) • In capillaries: ~10 torr; left atrium ~7 torr • Capillary pressure smaller than colloid-osmotic pressure (plasma, 26 torr): normally lung is dry. • Intrathoracic vessels as capacitive elements: 700 - 900 mL “stored” in vessels and exposed to intrathoracic pressure differences (~10 beats). • Pulsatile flow even in capillaries (different to systemic circulation).

12. Vascular Resistance (RL) • Low resistance in lung vessels: RL = 10 x smaller than that of systemic circulation. • 40% of RL is determined in capillaries (difference to systemic circulation). • Not all capillaries are used under resting conditions: recruitment during high demand with little drop in RL. • Vessel compliance low (C = ΔV / ΔP): volume increase matched with big pressure increase. • Lung volume determines RL (in capillaries): • RL↑ at beginning of expiration (because PA↑). • RL↓ at beginning of inspiration (because PA↓).

13. Hydrostatic Considerations Despopoulos & Silbernagl 2003 • Human lung: about 30 cm from base to apex;ΔPorthostatic ~ 30 cm H2O = 22 torr. • within range of capillary pressure. • Countering PCap (~10 torr) are ΔPorthostatic and PA: PCap at apex can be ≤ 0→collapsed capillaries →no/minimal perfusion. • Perfusion is best at base and worst at apex.

14. Vasoconstrictors Low α-adrenergic action Thromboxane A2 Angiotensin Leukotrienes Neuropeptides Serotonin Endothelin Histamine Prostaglandins Vasodilators High Nitric oxide β-adrenergic action Prostacyclin Acetylcholine Bradykinin Dopamine Adenosine Modulation of Pulmonary Flow • Pulmonary blood flow is NOT much dependent on . • Hypoxic vasoconstriction is local (shutting down/shifting blood flow to other areas): only massive pneumonia impacts on gas exchange globally. • >20% of vessels need to be hypoxic before a increase in RLis measured. • Global hypoxia increases RL (mountain climber; people in Andes with right ventricular hypertrophy).

15. Ventilation - Perfusion Relationship

16. THE PAS-DE-DEUX IS DETERMINED BY ALVEOLAR GASES: and

17. Relationship • For optimal function, ventilation and perfusion need to be matched; if mismatched, O2 and CO2 exchange are impaired. • can be defined at the level of • total lung ( ) • group of alveoli • single alveolus ( ) • For normal resting individuals with ≈ 4 L/min and CO ≈ 5.0 L/min, . • If ventilation > perfusion: (relative hyperventilation) • If ventilation < perfusion: (relative hypoventilation) • In patients with cardiopulmonary disease, mismatching of ventilation and perfusion is the most frequent cause of systemic arterial hypoxaemia ( ↓). • Typically improves under exercise (see previous lecture).

18. and Gas Partial Pressures Despopoulos & Silbernagl 2003 • If not ventilated, alveolar partial pressures reach those in blood (hypoventilated): • Vessels: vasoconstriction(“shut problem area off”…) • Bronchi dilate→improves ventilation. • If not perfused, alveolar partial pressures reach those in trachea (hyperventilated): • Vessels: vasodilation (“open area up”…). • Bronchi constrict→limits ventilation.

19. and Homeostasis • Poorly ventilated lung areas are poorly perfused: ↑, ↓→RL↑ Alveolo-vascular effect • Poorly perfused lung areas are poorly ventilated: ↑, ↓→RAW↑ Alveolo-bronchiolar effect

20. Local Relationships • Ventilation increases from apex to base of lung. • Perfusion increases also, but more than ventilation. • If , then • From apex to base, ↓ (read horizontally): • at apex relative hyperventilation ( ): RL↓; RAW↑ • at base relative hypoventilation ( ): RL↑; RAW↓ • Homeostatic principle to keep within limits. Modified after Despopoulos & Silbernagl 2003

21. Ventilation – Perfusion Summary

22. Impairment of Gas Exchange Despopoulos & Silbernagl 2003 • Anatomical shunt (extra-alveolar shunt): 2 - 3% of CO. • Bronchial/mediastinal veins, thebesian vessels in left myocardium (drainage directly into ventricle); biggest shunt occurs in the heart. • O2 therapy does not help here, because shunted blood never “sees” O2. • Physiological shunt = venous admixture: atelectasis caused by mucus plugs in airways, airway oedema, foreign bodies and tumours.

23. Take-Home Messages • Unique property of lung with dual circulation and ability to accommodate large volume of blood. • Hypoxia causes pulmonary vessels constriction (“paradoxical”). • Bronchi constrict due to hypocapnia limiting . • Diffusion of CO2 is much better than that of O2. • CO and haemoglobin concentration are non-ventilatory factors affecting gas exchange. • Upright, and ↑ from apex to base. • Apex is relatively hyper-, base hypoventilated. • Hypoxaemia can result from: anatomical shunt, physiological shunt ( mismatching, hypoventilation), and change in gas mixture.

24. MCQ Which of the following statements best describes the relative differences in blood flow among the upper, middle and lower portions of the lung during resting conditions (standing) and during exercise in a running person?

25. That’s it folks…

26. MCQ Which of the following statements best describes the relative differences in blood flow among the upper, middle and lower portions of the lung during resting conditions (standing) and during exercise in a running person?