1. CS 2015 Pulmonary Circulation and Its Determinants Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/Perfusion.pptx Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/Perfusion.pptx THE AUSTRALIAN NATIONAL UNIVERSITY

2. CS 2015

3. Aims At the end of this lecture students should be able to outline factors involved in gas diffusion; determine alveolar pressure gradients for CO 2 and O 2 ; explain why CO 2 diffuses much better than O 2 ; identify factors determining perfusion; illustrate how gases and chemicals modulate perfusion; recognise implications of ventilation-perfusion relationship; and locate anatomical and physiological shunts.

4. CS 2015 Contents Specializations maximising pulmonary gas exchange Factors determining gas exchange Considerations for O 2 and CO 2 diffusion Pressure gradients for CO 2 and O 2 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. CS 2015 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 m 2 –Blood content (cap.): 60 - 140 mL –Blood content/m 2 : 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. CS 2015 Human lung tissue sample at EM level Short diffusion distances: 0.5 - 4 µm (around a nucleus). Factors affecting gas diffusion: 1.Thickness of membrane 2.Diffusion coefficient 3.Total surface area of respiratory membrane 4.Pressure gradients Berne et al., 2004 Alveolar Respiratory Membrane

7. CS 2015 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. CS 2015 2. Diffusion Coefficient Gas diffusion rate same as that in water. Depends on gas solubility in membrane. Diffusion rate of CO 2 23 x better than that of O 2, which is about 2 x that of N 2. There are hardly ever diffusion problems for CO 2. O 2 diffusion can easily become limited.

9. CS 2015 Some loss of area (70 m 2 ) 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, α 1 -antitrypsin deficiency, etc. –Lung resections (surgical removal). 3. Total Membrane Surface Area

10. CS 2015 4. Pressure Gradients (ΔP) Driving force for diffusion is the difference in partial pressures in capillary and alveolus (pressures in figure). Rate of gas exchange dependent on ventilation, perfusion (CO) and haemoglobin concentration. Despopoulos & Silbernagl 2003 t Contact : 0.3 - 0.8 s Diffusion time: 0.3 s Pressure gradient for - O 2 is 2.5 x, and for - CO 2 is 1.15 x initial value.

11. CS 2015 Lung Perfusion ( ) Overall, 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 (10 torr) < 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. CS 2015 Vascular Resistance (R L ) Low resistance in lung vessels: R L = 10 x smaller than that of systemic circulation. –40% of R L is determined in capillaries (different to systemic circulation). –Not all capillaries are used under resting conditions: recruitment during high demand with little drop in R L. –Vessel compliance low (C = ΔV / ΔP): volume increase matched with big pressure increase. Lung volume determines R L (in capillaries): –R L ↑ at beginning of expiration (because P A ↑). –R L ↓ at beginning of inspiration (because P A ↓).

13. CS 2015 Hydrostatic Considerations Human lung: about 30 cm from base to apex; ΔP orthostatic ~ 30 cm H 2 O = 22 torr. –within range of capillary pressure. Countering P Cap (~10 torr) are ΔP orthostatic and P A : P Cap at apex can be ≤ 0 → collapsed capillaries → no/minimal perfusion. Perfusion is best at base and worst at apex. Despopoulos & Silbernagl 2003

14. CS 2015 Modulation of Pulmonary Flow Vasoconstrictors –Low –α-adrenergic action –Thromboxane A 2 –Angiotensin –Leukotrienes –Neuropeptides –Serotonin –Endothelin –Histamine –Prostaglandins Vasodilators –High –β-adrenergic action –Nitric oxide –Prostacyclin –Acetylcholine –Bradykinin –Dopamine –Adenosine Pulmonary blood flow is NOT much dependent on. Global hypoxia increases R L (mountain climber; people in Andes with right ventricular hypertrophy). 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 increase in R L is measured.

15. CS 2015 Ventilation - Perfusion Relationship

16. CS 2015 THE PAS-DE-DEUX IS DETERMINED BY ALVEOLAR GASES: and

17. CS 2015 Relationship For optimal function, ventilation and perfusion need to be matched; if mismatched, O 2 and CO 2 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. CS 2015 and Gas Partial Pressures 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. Despopoulos & Silbernagl 2003

19. CS 2015 and Homeostasis Poorly ventilated lung areas are poorly perfused: ↑, ↓ → R L ↑ Alveolo-vascular effect Poorly perfused lung areas are poorly ventilated: ↑, ↓ → R AW ↑ Alveolo-bronchiolar effect

20. CS 2015 Ventilation – Perfusion Summary

21. CS 2015 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 ( ): R L ↓; R AW ↑ –at base relative hypoventilation ( ): R L ↑; R AW ↓ Homeostatic principle to keep within limits. Modified after Despopoulos & Silbernagl 2003

22. CS 2015 Impairment of Gas Exchange 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. –O 2 therapy does not help here, because shunted blood never “sees” O 2. Physiological shunt = venous admixture: atelectasis caused by mucus plugs in airways, airway oedema, foreign bodies and tumours. Despopoulos & Silbernagl 2003

23. CS 2015 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 CO 2 is much better than that of O 2. 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. CS 2015 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? Standing & restingRunning A Upper < middle < lower B Upper = middle = lower C Upper < middle < lowerUpper > middle > lower D Upper = middle = lowerUpper > middle > lower E Upper < middle < lower

25. CS 2015 That’s it folks…

26. CS 2015 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? Standing & restingRunning A Upper < middle < lower B Upper = middle = lower C Upper < middle < lowerUpper > middle > lower D Upper = middle = lowerUpper > middle > lower E Upper < middle < lower