Phol 480: Pulmonary Physiology SectionSession 2: Gas Exchange

Instructor Jeff Overholte-mail: jxo@po.cwru.eduphone: 8962location: E616 Medical School

Text: Berne and Levy, Fourth ed. Chapters 34 and 35

Brief review of mechanics:

Compliance: the ease with which the lungs can be distended. Can be derived from the slope of pressure vs lung volume, mathematically V/P.

The resting point of the system (FRC) is determined by the recoil pressure of the lung to collapse, opposed by the pressure of the chest wall to expand. At FRC the lung and the chest wall are recoiling in equal and opposite directions.

Alveolar Ventilation:The most important aspect of breathing is to maintain

an optimal concentration of O2 and CO2 in the alveolar gas.

Anatomical dead space: space taken up by airway structures that do not participate in gas exchange

Physiological dead space: Due to non-functioning alveoli. Is the ADS + volume of air in non-functional alveoli.

Gas Diffusion:

• Once air is in the lungs, due to the pressure differences between alveolar gas and pulmonary blood, O2 and CO2 can move by diffusion.•Diffusion depends on the driving force (the difference in the partial pressure of the gases) and on distance.•Partial pressure: each gas in a mixture exerts a certain amount of pressure proportional to it’s concentration, i.e. in air O2 is 21%, atmospheric pressure is 760 mmHg (at sea level), thus the O2 partial pressure (PO2) is 0.21 x 760=160 mmHg.

Partial Pressure of Alveolar Gases:

•Alveolar air does not have the same concentration as gases in the atmosphere.

a. Alveolar air only partially replaced each breath (dead space, FRC).

-FRC=2400 ml, VT=500 ml, VA=350 ml, therefore only 350 of 2900 ml (1/8) is exchanged each breath. Many breaths are required to completely exchange the air. This slow change helps to prevent sudden, cyclical changes in alveolar gases each breath.

b. O2 is constantly being absorbed from the alveolar air

c. CO2 is constantly diffusing into the alveolar air (dilutes the other gases such as O2)

d. Dry atmospheric air is humidified in the conducting passages of the airways. Water expands the volume of air and therefore dilutes the other gases. Adds a partial pressure to the mix (~47 mmHG).

•O2 concentration controlled by the rate of absorption into the blood (body need) and the rate at which O2 is brought into the alveoli. That is, the O2 concentration is directly related to ventilation.

-Even with the greatest ventilatory effort you can not go above 149 mmHg (the partial pressure of O2 in humidified air)

• CO2 dynamic is the opposite. Increase CO2 in proportion to excretion in the blood and the CO2 concentration is inversely related to ventilation.

Respiratory Unit•Consists of respiratory bronchioles, alveolar ducts and alveoli, in normal adult human about 300 million with an average diameter of 0.25µM (70 m2)•Alveolar gases in very close proximity to capillaries (very thin alveolar membrane)•Diffusion occurs through the membranes of the terminal portion of the lungs, the respiratory membranes.

1. Thin layer of fluid (with surfactant)2. Thin layer of alveolar epithelium3. Epithelial basement membrane4. Interstitial space5. Capillary basement membrane6. Endothelial lining of capillary** Total is very thin 0.2-0.5µM and blood is spread very

thin over the 70 m2 of capillary surface area.

*Gases are very soluble in the lipid membrane, therefore the limiting factor for diffusion is the rate of diffusion through the water portions of the membrane

Factors determining diffusion1. The thickness of the membrane2. Surface area3. Solubility of the gas (in H2O, since this is where it

is limiting)4. Pressure difference

Diffusion Equation:

2CO2AO2

O2 L

)PA(P x DV

Where VO2 is the volume flow of gas by diffusion, D is a diffusion factor, A is the alveolar surface area. And PAO2 and PCO2 are the partial pressures of O2 in the alveoli and capillary, respectively. PAO2-PCO2 is the driving force or pressure difference.

•Notice L (length), as length increases, diffusion decreases as the square of the length. Therefore, length is the most important factor.

-certain diseases can increase the length, thereby decreasing diffusion

Diffusion (cont’d):

It follows that the most efficient way to improve O2 delivery is to decrease the distance for diffusion by recruiting more capillaries. Increase surface area, decrease diffusion distance.• CO2 is 20X as diffusible as O2, so diffusion of

CO2 is usually not a problem

Transit time:Another factor that influences diffusion is the time the blood spends in the capillary exposed to the high oxygen content of the alveoli.

At an average HR of 80/min., the blood remains in the capillary for only a fraction of a second (0.75 s).

This usually isn’t a problem as diffusion occurs fairly quickly, and remember from the pulmonary anatomy that one capillary usually spans more than one alveoli, thereby increasing the exposure time of the blood to the alveolar oxygen supply.

-The O2 partial pressures take only a fraction of the time (about 0.25 s) to equilibrate compared to the time the blood spends in the capillary (0.75 s)

Alveolar pressure differences:

Gas partial pressures in the pulmonary artery are similar to systemic mixed venous.

In the alveoli, O2 is taken up by the blood in the capillaries and CO2 is removed.• Alveolar O2 high (104 mmHg), CO2 low (40

mmHg)Arterial O2low (40 mmHg), P.D. (104-40) 64

mmHg into blood. Arterial CO2 high (45 mmHg), P.D. (45-40) 5 mmHg into alveoli.

Pulmonary venous gas concentrations very similar to systemic arterial concentrations

Tissues Pressure Differences In the pulmonary capillaries PO2 rises in blood to

equal the alveolar PO2 (104 mmHg).• PO2 in aorta is only about 95 mmHg due to

venous admixture (right to left shunt) and mixing of blood through poorly ventilated alveoli.

Opposite of what happens in the pulmonary capillaries

• Interstitial tissue O2 low (40 mmHg), CO2 high (45 mmHg)

Arterial O2 high (95 mmHg), P.D. (95-40) 55 mmHg into tissue, arterial CO2 low (40 mmHg) P.D. (45-40) 5 mmHg into blood

Venous gas concentrations very similar to interstitial tissue concentrations

Metabolic use of O2 (cellular respiration)•Inside the cell PO2 is much less, partially dependent upon the distance between the cells and the interstitial solution

-5-60 mmHg intracellular PO2 avg. 23 mmHg, fortunately mitochondrial respiratory enzymes only need 1-5 mmHg PO2

Therefore O2 is usually not the limiting factor, ADP is. Increase ADP concentration increases usage. Under normal conditions the rate of O2 utilization by the cell is determined by the rate of energy expenditure which is reflected in the ADP concentration.

O2 Transport Two critical steps in O2 transport•Diffusion of O2 from alveolar gas to blood in lung capillaries.•Diffusion of O2 from blood to mitochondria in capillaries of peripheral tissues.•But, how do we get O2 from lung to tissue in blood?

One liter of plasma holds only 3 ml of O2 (at PO2 of 100 mmHg). If O2 transport relied solely on dissolved O2, cardiac output would have to be 80L/min to support the normal O2 consumption of 250 ml/min.

Therefore higher organisms developed a special molecule to aid in O2 transport in the blood.

Hemoglobin:Hematocrit: the fraction of blood that contains RBC’s, optimal is 40-50%.•Four O2 binding heme molecules. Iron containing porphyrin rings. Therefore each hemoglobin molecule can bind 4 O2 molecules.

-iron is normally in the reduced ferrous (Fe++) form-certain compounds can oxidize to the non-functional ferric state (Fe+++) methemoglobinemia

Binding of O2 is reversible.•The rate of movement of O2 on and off hemoglobin is very fast (ms)

-blood is in pulmonary capillaries less than 1 sec (75/min.=0.8 sec)

1. Hemoglobin=free form, no O2 bound2. Oxyhemoglobin=form with O2 boundHemoglobin concentration is regulated by erythropoietin.Produced in kidney in response to decrease O2. Stimulates erythropoiesis in bone marrow.

•Binding is cooperative: binding of one O2 changes structure of hemoglobin slightly in such a way that makes it easier for the next O2 to bind (enhanced affinity). This gives hemoglobin it’s sigmoidal saturation curve.

•Saturation curve: the ratio of oxygen bound to the total binding capacity.

Flat upper portion reflects the fact that hemoglobin is saturated above 70-80 mmHg PO2.

-This means that PO2 can fall to 70-80 mmHg (as in high altitude) and still not change arterial O2 saturation much.

Steep part of curve reflects the range of PO2‘s over which hemoglobin will release O2.

The hemoglobin saturation curve can be modified by a number of factors.

•Most factors affect the position of the curve along the PO2 axis.•PCO2 H+, temperature and 2,3 DPG

-When any of these factors increase the curve is shifted to the right, the affinity of Hb for O2 decreases (favors delivery to the tissues).

-P50 the PO2 at which Hb is half saturated. The P50 increases.

-When any of these decrease, the curve is shifted to the left, affinity of Hb for O2 increases (the P50) decreases.

-2,3 DPG is produced in RBC’s as a side reaction to glycolysis.

One major physiological advantage of this is that it enhances delivery and uptake of O2 in the lung and tissues.

-in the tissue, CO2 is added to blood, which shifts the curve to the right and enhances delivery of O2 to the tissues (decreases the affinity of Hb for O2). P50=29 mmHg.

-in the lung, removal of CO2 shifts the curve to the left and enhances uptake of O2 by the blood (increased affinity of Hb for O2). P50=26 mmHg. 3 mmHg shift.

O2 is not the only gas molecule with high affinity binding to Hb

CO (carbon monoxide) and NO (nitric oxide) both have higher affinity Hb

-CO binds 250X better than O2 -does not dissociate unless CO is low (fresh air

or O2 for CO inhalation)-PCO in alveoli of only 0.5 (1/210 of O2) can

compete equally with O2 for binding-as low as 0.7 mmHg can be lethal

-NO binds 200,000 times more strongly than O2 -binding is so strong it is irreversible

The dissociation curve does not reflect changes in capacity.

If the amount of Hb decreases, the PO2 saturation curve would be unchanged since it depends on the % Hb that has O2 bound (50/100 is same as ½).

Therefore, the absolute concentration of O2 is important (O2 /L)

-anemia: compensated for by increasing cardiac output

-CO poisoning: decrease in ability of blood to carry O2. CO is bound to Hb, so O2 can’t bind.

Partial Pressures and Saturation do no tell the whole story

O2 Content (vol% or ml O2/100 ml blood)• Normal hemoglobin can bind 1.34 ml O2/g• Normal adult male 15 g/dl (100ml) blood

Therefore with an arterial O2 saturation of 100%• 1.34 * 15 = 20.1 vol% O2 carried by Hb in the

blood

Total arterial O2 Content:• Total arterial O2 content=O2 carried by Hb + O2

physically dissolved in plasma• 20.1 + 0.3 = 20.4 ml O2/100 ml or 20.4 vol%

• As PO2 goes above 100 mmHg the amount of dissolved O2 can increase significantly because hemoglobin is already saturated. Too high a pressure can cause O2 poisoning (too much tissue O2).

• O2 poisoning can not occur with hemoglobin since it is designed to release O2 at PO2 below 60 mmHg

Utilization coefficient: fraction of blood that gives up it’s O2. Normally 25%•Remaining O2 serves as a reservoir for use in increased demand.•During increased demand, such as during exercise can increase to 75-85%.

3X increase in utilization coefficient and cardiac output can increase 5X,

3 X 5=15X increase in O2 delivery during times of need.

Transport of CO2:

•CO2 is formed in cells where it reaches a value above the PCO2 of arterial blood entering capillaries.•CO2 has a big effect on acid-base balance in the blood.•Diffusion of CO2 is 20X greater than for O2 so it readily diffuses into the blood in tissue capillaries.•CO2 is transported in three forms.

1. Dissolved in plasma (~7%)2. Combines with hemoglobin to form carbaminohemoglobin (~25%)•dissociates very easily

3. In RBC combines with H2O to form carbonic acid (weak acid), normally a very slow reaction. (~70%).•RBC’s contain carbonic anhydrase, which speeds up the reaction•carbonic acid rapidly dissociates into HCO3

- and H+. H+ is taken up by Hb and HCO3

- is exchanged for Cl- in the plasma.

CO2 Transport (cont’d):

The Haldane effect: combination of O2 with Hb in the lungs causes Hb to become a stronger acid. More O2 bound less room for CO2.

• More acidic Hb has less tendency to combine with CO2 to form carbaminHb

• The increased acidity causes Hb to dump H+, this drives the carbonic acid reaction in the opposite direction. H+ + HCO3

- H2CO3, which can dissociate into water and carbon dioxide to be released from the blood in the alveoli.

Acid-Base Balance:

•The pK is the pH at which a buffer system is half dissociated. A buffer system is strongest (addition of acid or base has the smallest effect on the pH) when operating at a pH close to its pK.•The pK (6.1) of the bicarbonate buffer system is far away from the normal pH (7.35)

Acid-Base Balance (cont’d):

•However, the system is still an effective buffer, because the concentration of the reactants can be regulated. That is, ventilation can regulate pH by adjusting the concentration of CO2.•Remember, blood CO2 content is inversely related to minute ventilation i.e., increased breathing causes decreased CO2 in the blood.•The formation of carbonic acid is reversed, removing an acid:

3222 COH CO OH

•From Henderson-Hasselbach, pH depends on the ratio of:

][CO]CO[H

2

-32

•Therefore, remove CO2, increase the ratio (increase pH, more basic

•In addition, the kidneys also contribute to acid-base balance by regulating the circulating concentrations of H+, HCO3

-, and NH4+

Pulmonary blood flowFlow of blood in the pulmonary circulation.• Right ventricle (mixed venous blood) alveolar wall

capillaries (site of gas exchange) pulmonary veins (oxygenated) left atrium• Low resistance: large number of pulmonary arteries

and capillary beds (parallel flow, just as in airways)• Low vascular tone: vessels are normally in the

dilated state.Equally as important as ventilation in maintaining proper gas exchange.

Therefore, it is very important to match ventilation V and pulmonary blood flow Q and there are important mechanisms to adjust both to insure proper matching.

Matching Ventilation and Perfusion, V/Q ratio:

Inequalities in the distribution of V/Q ratios are the most common cause of inefficient O2 and CO2 exchange.• Normal VA is 4.2 L/min (12 x 350) and pulmonary

blood flow is 5L/min (75 x 70), thus V/Q=4.2/5=0.84

Matching Ventilation and Perfusion, V/Q ratio:

Factors affecting perfusion:•Right to left shunt (venous admixture) blood that bypasses lungs without being oxygenated

a. Occurs in normal condition, arises from the bronchial system (bronchopulmonary venous anastomoses) and the intracardiac thebesian vessels.b. Reduces systemic arterial oxygen tension (pulmonary capillary 102, aorta 95 mmHg).c. Can be greatly affected by disease.d. Venous admixture is the blood flow equivalent of wasted ventilation.

•Left to right shunta. Does not affect the systemic arterial PO2

b. Affects O2 of pulmonary circulationc. Pulmonary blood flow exceeds systemic by the amount of the shunt

Matching Ventilation and Perfusion, V/Q ratio:

Wasted ventilation: pulmonary artery is obstructed, thus part of the lung is not perfused. Decreases the overall efficiency of the lungs because energy is being expended to ventilate a non-perfused part of the lung. V/Q=

Ventilation compensates and shifts to useful part of the lung.

1)Fast: Local PCO2 falls (increase pH) causes constriction of airway smooth muscle and diverts ventilation away from non-perfused area.

2)Slow: Impaired alveolar cells slow production of surfactant causing an increase in compliance

Matching Ventilation and Perfusion, V/Q ratio (cont’d):•Venous admixture: obstruction of the airway, part of the lung is not ventilated.V/Q=0.•The other part of the lung receives all of the ventilation (hyperventilation). V/Q, PCO2 and PO2 , however, due to the saturation of hemoglobin at PO2 greater than 70 mM Hg, the blood can not compensate by carrying more O2. Therefore, overall PO2 and not much effect on CO2 (because it’s concentration in blood is not saturated).•Pulmonary circulation shifts to better ventilated areas.

-The effect of hypoxia (low O2) on pulmonary vasculature is opposite to it’s effect on systemic vasculature. Low alveolar O2 causes pulmonary vasoconstriction to divert blood away from poorly ventilated areas. The effects are mostly on the arterioles and small muscular arteries.

Matching Ventilation and Perfusion, V/Q ratio (cont’d):

•There are also chemical factors that affect perfusion.

a. thromboxane A2 (arachidonic acid metabolism) strong constrictor of pulmonary arteriole and venous smooth muscle. Is produced during acute lung injury.

b. prostacyclin (prostaglandin I2 ;also AA metabolism) vasodilator from endothelial cells.

c. Nitric Oxide (NO) gaseous molecule, very localized, vasodilator; bound by hemoglobin very rapidly. Possible therapeutic use in pulmonary hypertension because it can be directly delivered to the lung by inhalation.

Distribution of alveolar ventilation:• It is reasonable to assume that alveolar ventilation is distributed evenly throughout the lungs. However, this is not the case.•Alveoli in the lower regions of the lung receive more ventilation/breath than alveoli in the upper regions.•The intrapleural pressure is less negative in the lower regions of the lung.•Caused by gravity and by mechanical interactions between the lung and chest wall

For each cm of vertical displacement down the lung, the intrapleural pressure increases by 0.2 to 0.5 cmH2O. (Alveolar pressure=0 throughout lune, but transpulmonary pressure (alveolar-pleural) is greater in upper regions.

Distribution of perfusion:•As with ventilation, it would be reasonable to assume that pulmonary blood flow is distributed evenly throughout the lungs. However, this would lead to V/Q inequalities since ventilation is not distributed evenly throughout the lungs.

-There is greater blood flow per alveoli in the lower regions of the lung than in the upper regions.

-Caused by gravity.The intravascular pressure is greater in lower regions of the lung, therefore resistance is also lower due to recruitment and distension

Alveolar ventilation=(TV-dead space) x Rate:(500-150) x 12=4.2L

• The quantity of fresh air moved into and out of the alveoli each minute.

• The large FRC (~2.4 L) relative to the small alveoalar ventilation (350 ml) acts as a buffer to maintain the O2 and CO2 in alveolar gas constant