Lecture 8 Gas Diffusion Exchange PDF

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PHYL 4504/5404: Gas Diffusion and Gas Exchange

At the end of this lecture, the student should be able to: 1.Define the respiratory quotient 2.Name and define a series of gas laws: Boyle’s. Dalton’s, Henry’s and Fick’s 3.Know the normal values for PO2 and PCO2 at various sites around the body 4.Diagram, and be able to explain, diffusion-, and perfusion-limited gas exchange and compare how pulmonary fibrosis and being at altitude affects oxygen diffusion 5.Be able to explain lung diffusion capacity and give examples of when it might be increased or decreased 6.List causes of an increased Aa gradient

By the end of this lecture, you should be able to answer the following questions. 1. The illustration on the bottom left of the title slide (go back one) illustrates which gas law? 2. Where in the body can the PO2 potentially reach as low as 1 mmHg? 3. Which gas can be used to model perfusion-limited gas exchange? 4. Does the lung diffusion capacity increase or decrease in emphysema? 5. What is the typical value for the PCO2 in the mixed venous blood before it enters the lungs?

Remember to input your answers on Brightspace in the section: Quick Quiz: Gas diffusion and Gas exchange (Sept 28) before midnight on Oct 4th This material will be tested in the unit quiz on October 26th

Overview of Oxygen transport

• Function of respiratory system is to supply the tissues with oxygen to satisfy their metabolic demands • Also eliminates CO2 generated as a consequence of metabolic activity • O2 is transferred from alveolar gas into the pulmonary capillary bed via diffusion • Carried around the body and delivered to the tissues, where it diffuses out of the systemic capillary blood into cells • CO2 travels in the opposite direction • The ratio of CO2 production to O2 consumption is the Respiratory exchange ratio, R, which at rest is approximately 0.80. Also referred to as the RQ (respiratory quotient)

- 8 molecules of CO2 for every 10 molecules of O2 consumed

Berne and Levy, Physiology 6th Edition

Gas Laws General Gas Law:

PV = nRT

where P = pressure (mmHg); V = volume (L); n = Moles (mol); R = gas constant; T = temperature (K) In gas phase, BTPS is used and in the liquid phase (dissolved in blood) STPD is used. BTPS = body temperature (37°C or 310K), ambient pressure, and gas saturated with water vapor STPD = standard temperature (0°C or 273K), standard pressure (760mmHg) and dry gas To convert gas volume at BTPS to gas volume at STPD: multiply the vol. (at BTPS) by 273/310 x (Ps – 47)/760 where PB is barometric pressure and 47 mmHg is water vapor pressure at 37°C

Simplifies to 273 310

x 713 760

= 0.826

Boyle’s Law At a given temp. the product of pressure multiplied by volume for a gas is constant

P1V1 = P2V2

Dalton’s Law of Partial Pressures Dalton’s Law: “In a mixture of non-reacting gases, the total pressure exerted is the sum of each of the partial pressures of the individual gases.” Pressure of each individual gas is the partial pressure P. P is the total pressure x fractional content of dry gas:  Each gas acts independently Px = PB x F For humidified gas, we need to correct the barometric pressure for water vapor pressure: Px = (PB – PH2O) x F Px = partial pressure of gas (mmHg); PB = barometric pressure (mmHg); PH2O = water vapor pressure at 37°C (47 mm Hg) ; F = fractional concentration of gas (no units) % of gases at barometric pressure of 760 mmHg : O2 = 21%; N2 = 79%; CO2 = 0% What is PO2 in dry, inspired air and humidified tracheal air at 37°C? Dry air: PO2 = 760 mmHg x 0.21 = 160 mmHg Humidified tracheal air = (760 mmHg - 47 mmHg) x 0.21 = 713 mmHg x 0.21 = 150 mmHg

Alveolar Gas Composition When inspired air reaches alveolus, O2 is transported across alveolar membrane and CO2 added from capillary bed. FO2 + FN2 + FH20 + FCO2 + Fargon + F other gases = 1. As a consequence of gas exchange, FO2 (therefore partial pressure) decreases in the alveolus while the FCO2 increases. N2 and argon are inert, so no change FH2O no change (gas remains fully saturated) Alveolar gas equation describes the PO2 in the alveolus. A = arterial, I = inspired PAO2

= PIO2

- PACO2 or PAO2= (Pb – PH2O) X FIO2 - PACO2 R R R is the respiratory quotient, ie the ratio of CO2 excreted to O2 taken up. R is dependent on calorific intake and varies between 0.7 (fatty acid metabolism) and 1 (carbohydrate metabolism). Normally assumed to be 0.8.

Normal composition of Respiratory Gases

Effect of changes in ventilation on alveolar PO2 The level of alveolar PO2 (PAO2) is determined by a balance between the rate of removal of O 2 by the blood (determined by the metabolic demands of the tissue) and the rate of replenishment of O2 by alveolar ventilation. So, if alveolar ventilation was low, PAO2 falls and PACO2 rises (remember alveolar ventilation equation?) The relationship between the fall in PO2 and the rise in PCO2 that occurs with changes in decreased ventilation (and vice versa) can be obtained from the alveolar gas equation if we know the composition of inspired gas and the RQ If alveolar ventilation is halved, PCO2 will double. And the fall in alveolar PO2 will be slightly greater than the increase in PCO2. Remember, the relationship between PACO2 and PAO2 will change if the respiratory quotient changes.

Henry’s Law for Concentrations of Dissolved Gases Henry’s Law: Deals with gases dissolved in solution (e.g. blood) “That the amount of dissolved gas in a liquid is proportional to its partial pressure above the liquid” To calculate a gas conc in the liquid phase, the partial pressure in the gas phase is first converted to the partial pressure in the liquid phase. Second, partial pressure in liquid is converted to concentration in liquid. At equilibrium, the partial pressure of a gas in the liquid phase equals the partial pressure of the gas in the gas phase. Therefore, if alveolar air has a PO2 = 100 mmHg, then the capillary blood that equilibrates with it will also have a PO2 of 100 mmHg. Henry’s Law: used to convert partial pressure of gas in liquid phase to CONCENTRATION in liquid phase E.g. For blood, Cx = Px x solubility, where: CX = concentration of dissolved gas (ml gas/100 ml blood) Px = partial pressure of gas (mm Hg) solubility = solubility of gas in blood (ml gas/100 ml blood/ mmHg) Applies only to dissolved gas that is free in solution. We need to talk about partial pressures of gases not just the concentrations, because the conc. of a gas in a liquid is proportional to its concentration and its solubility- so if a liquid is exposed to 2 gases with the same partial pressure, the concentrations will differ depending on their solubilities.

Question: If arterial PO2 is 100 mmHg, what is the concentration of dissolved O2 in blood, given that the solubility of O2 is 0.003 mL O2/100mL blood/mmHg? [O2] = PO2 x solubility = 100 mmHg x 0.003 mL O2/100 ml blood/mm Hg = 0.3 mL/100 mL blood

Fick’s Law Simplistically, “a solute will move from a region of high concentration to a region of low concentration down a concentration gradient.” Transfer of gases across cell membranes and capillary walls occurs by diffusion, described by Fick’s Law VX = AxDxΔP T VX = volume of gas transferred per unit time; A = surface area; D = diffusion coefficient of that gas; ΔP = partial pressure difference of the gas; T = thickness of the membrane Important parameters for efficient gas exchange in lungs: 1. Large driving force = partial pressure gradient, ΔP 2. Large surface area 3. Distance needs to be small Diffusion coefficient, D ∝ Sol/√MW D for CO2 is approx. 20 times higher than for O2 CO2 elimination not affected by diffusion problems

Berne and Levy Physiology 6th ed. Fig 23-2.

Scheme of O2 partial pressures from air to tissues. Reminder Scheme showing how the PO2 falls as the gas moves from the atmosphere to the mitochondria. PO2 of air is 21% of the total dry gas pressure At sea level, barometric pressure is 760 mmHg and at 37ºC, the water vapour pressure of moist inspired gas (fully saturated with water) is 47mmHg (76047) X 0.21 = 150 mmHg By the time the O2 reaches the alveoli, PO2 is 100mmHg PO2 of alveolar gas is determined by the balance of O2 removal into capillary blood and replenishment by ventilation. When systemic arterial blood reaches tissue capillaries, O2 diffuses into mitochondria, where the PO2 is much lower (potentially as low as 1 mmHg). Hypoventilation will decrease PO2 in alveolar and therefore arterial PO2. West Respiratory Physiology Fig 5.1

Values for PO2 and PCO2 throughout the Respiratory System (760 mm Hg x 0.21 = 160)

(760 - 47 mm Hg x 0.21 = 150)

A = alveolar a = arterial

*

Mixed venous blood enters the capillary; O 2 is added to pulmonary capillary blood and CO 2 is removed via diffusion across the alveolar/capillary barrier.

*

(* not really…) Costanzo 5th ed fig 5-16, 5-17

Venous Admixture Approx. 98% of blood that enters left atrium from lungs has passed through alveolar capillaries and become oxygenated to PO2 = 100mmHg Remaining 2% “shunted” from aorta through bronchial circulation- never enters gas exchange areas On leaving the lungs, PO2 of shunted blood is same as normal systemic venous blood, 40 mmHg Shunted blood combines with oxygenated blood venous admixture of blood Result is PO2 of blood exiting heart via aorta to be pumped around body is lower than PAO2, between 95-100mmHg

Guyton and Hall Fig 40-2

Diffusion-Limited Gas Exchange The total amount of gas transported across the alveolar capillary barrier is limited by diffusion. As long as the partial pressure gradient for the gas is maintained, diffusion will continue along the full length of the capillary. CO is an ideal gas to illustrate this model. PACO is constant along length of capillary. Initially, no CO in blood, so PaCO is zero Largest partial pressure gradient at beginning of capillary = largest driving force for CO to diffuse from alveolar air into blood. As CO diffuses into blood, PaCO rises. However, PaCO only rises slightly as blood moves along capillary because CO binds tightly to hemoglobin- not free in solution, so not contributing to the partial pressure. Only dissolved gas contributes to partial pressure. So binding of CO to Hb keeps the free CO concentration (PaCO) low, and the gradient for diffusion continues along the entire length of capillary. Net CO diffusion is limited by the magnitude of the partial pressure gradient, and CO does not equilibrate by capillary end. (Longer capillary = diffusion continue) Costanzo 5th ed fig 5-18

Perfusion-Limited Gas Exchange The total amount of gas transported across the alveolarcapillary barrier is limited by blood flow. Partial pressure gradient is not maintained and the only way to increase the amount of gas transported is by increasing blood flow. N2O is an ideal gas to illustrate this model. Does not bind to Hb- all free in solution PAN2O is constant, PaN2O initially zero Initially, large partial pressure gradient for diffusion and N2O rapidly diffuses into blood. All N2O remains free and contributes to partial pressure, so PaN2O increases rapidly. Full equilibration after first 1/5th capillary. No more partial pressure gradient = no more diffusion Only way to increase net diffusion of N2O is to add more new blood to the pulmonary capillary, so net gas transfer is limited by perfusion.

Costanzo 5th ed fig 5-18

Oxygen Diffusion: Normal versus Fibrosis Normally, O2 transport into pulmonary capillaries is perfusion-limited, but can shift to diffusion-limited, eg strenuous exercise and fibrosis. PAO2 is constant at 100mmHg. Blood entering has PaO2 of 40mmHg = large partial pressure gradient for diffusion of O2 from alveolar air into capillary blood. PaO2 increases as O2 is added along capillary length Gradient for diffusion initially maintained because O2 binds to Hb, which keeps free O2 and PaO2 low. But PaO2 will increase until full equilibration occurs approx 1/3rd distance along capillary. No more net diffusion of O2 unless blood flow increases. Fibrosis increases alveolar wall thickness, increasing barrier for diffusion. Prevents equilibration. Partial pressure gradient is maintained along entire capillary = now diffusion-limited Total O2 transfer reduced, no equilibration = decreased PaO2 in systemic arterial blood Costanzo 5th Ed fig 5-19

Oxygen Diffusion: Normal versus Fibrosis at Altitude Barometric pressure reduced at high altitude, so PAO2 also reduced PAO2 50 mmHg; blood entering capillary has PaO2 25 mmHg = partial pressure gradient now reduced to 25 mmHg (was 60 at sea level) Reduction in partial pressure gradient results in decrease in O2 diffusion, and equilibation occurs more slowly- now 2/3rds capillary length Maximum PaO2 for blood leaving is 50 mmHg Exaggerated in fibrosis- pulmonary capillary blood does not equilibrate by end of capillary resulting in even lower PaO2 . Impaired O2 delivery to the tissues.

Costanzo 5th ed Fig 5-19

Lung Diffusing Capacity, DL From Fick’s Law, we know that the amount of gas transferred (Vgas)

=

A x D x (P1 –P2) T

Not possible to measure area and thickness in patient, so equation simplified to: Vgas = DL x (P1 – P2) Diffusing capacity, DL, combines area, thickness and diffusion properties of gas. Measures diffusion barrier of the alveolar-capillary membrane. Can be measured with CO since transfer of this gas is entirely governed by diffusion DLco = VCO P1 – P2 or DLco = VCO because partial pressure of CO in capillary blood is so small, we can ignore PACO Diffusing capacity of the lung for CO is the volume of CO transferred in millimeters per minute per mmHg of alveolar partial pressure.

Lung Diffusing Capacity, DL (2) Usually measured by the single-breath test. Single inspiration of CO (low concentration) made and the rate of CO disappearance from the alveolar gas is measured during a 10-second breath hold. Analyze concentrations of CO in inspired versus expired air. Helium also added to the inspired gas to give a measurement for lung volume Normal range for DLCO at rest is 20 to 30 mL/min/mm Hg Increases 2-3 times this on exercise due to addition of extra capacity in the pulmonary capillaries Exercise = DL increases (capillary recruitment) Changes in pulmonary disease: Emphysema = DL decreases (less surface area) Fibrosis = DL decreases (membrane thickness increases) Anemia = DL decreases (less Hb in red blood cells)

A – a gradient •

Describes the difference in PO2 between alveolar gas (PAO2) and systemic arterial blood (PaO2) • Has there been equilibration of O2 between alveolar gas and pulmonary arterial blood (systemic arterial blood)?

•

HYPOXEMIA is a decrease in arterial PO2 (PaO2) A – a gradient = PAO2 – PaO2 where PAO2 can be calculated from: Pa PAO2 = PIO2 - PACO2 R (where PIO2= P inspired O2;R = respiratory quotient)

•

Ideally, should be as close to zero as possible, but sometimes increased, signifying a defect in O2 equilibration

Causes of increased A – a gradient 1. Diffusion defects, eg. fibrosis, pulmonary edema. Increase diffusion distance or decrease surface area. O2 equilibration is impaired. Supplemental O2 will raise PaO2 via PAO2, increasing driving force for diffusion 2. V/Q defects (more later): Always cause hypoxemia. Supplemental O2 helpful, it raises PO2 of low V/Q regions where blood flow is highest. 3. Shunts: (more later) blood completely passes ventilated alveoli and cannot be oxygenated. Supplemental O2 is of limited use as it only increases PO2 of non-shunted blood

Summary Fick’s Law of Diffusion • The rate of diffusion of a gas through a tissue is proportional to the area • The rate of diffusion of a gas through a tissue is proportional to the partial pressure difference • The rate of diffusion of a gas through a tissue is inversely proportional to the thickness Oxygen Diffusion at alveolar-capillary membrane:

• At rest the PO2 of the blood normally equilibrates with alveolar gas after about 1/3rd of its time in the capillary • Blood spends only about 0.75 second in the capillary • During exercise, this time is reduced to approx 0.25 second, so less time for equilibration to occur • Diffusion is challenged by exercise, thickening of the blood-gas barrier (fibrosis) and alveolar hypoxia (altitude) Measurement of Diffusing Capacity • Carbon monoxide is used because the uptake of this gas is diffusion limited • Normal diffusing capacity is about 25 ml.min-1mmHg-1 • Diffusing capacity increases on exercise...