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1 Gas Exchange & Transport RTT 100 Professor Michael Nazzaro You must study BOTH chapter 11 and this supplement Part 1, Pressures and Gradients Supplement to Text, Chapter 11 and Background for Chapter 38 Gas Exchange and Transport: Introduction The chapter begins with the third different definition of respiration found in the text (pg. 150 and 225). Ventilation is the mechanical process that moves ventilatory gases between the atmosphere and the alveoli. • Gas moves by bulk flow in the large airways and by diffusional flow in the small airways. Gas exchange is the movement of gasses (both O2 and CO2) across the A/c membrane in the lungs, across the erythrocyte membrane in the red blood cells (RBC), and across the cell membrane in the tissue cells. • Gas movement between the lungs and the cells occurs by simple diffusion. • Diffusion, like other movement, requires a gradient. Gas transport refers to the mechanisms by which the blood carries oxygen from the lungs to the tissue cells and carbon dioxide from the tissue cells to the lungs. 2 Fig. 11-1 illustrates the diffusion gradients for the oxygen and carbon dioxide cascades. Reference, Note, Text pg. 114, 251, 253 The PACO2 (the partial pressure of CO2 in alveolar gas) comes from the CO2 in the pulmonary capillary blood, not from CO2 inhaled from the atmosphere. PACO2 (the partial pressure of alveolar carbon dioxide) is directly proportional to minute cellular CO2 production (VCO2) and inversely proportional to alveolar minute ventilation (VA). The formula is: PACO2 = VCO2 x 0.863 • • Example:PACO2 = 200 ml x 863 4315 ml = 40 mmHg VAWhere: • VCO2 is minute cellular production of CO2 (normally about 200 ml/min. at rest). • VA (with a dot over the V) is alveolar minute ventilation: ((VT – VD) x RR) • The factor 863 (or 0.863) corrects for several incompatibilities: 1. VCO2 is expressed as a flow of dry gas at ambient pressure (BTPD) and is reported in ml/min. 2. VA is expressed as a saturated gas at body temperature and ambient pressure (BTPS) and is reported in L/min. 3. The factor reconciles the BTPD and BTPS incompatibilities. 4. It also allows the incompatible units of flow and pressure to be expressed as a pressure. • Simple diffusion is the mechanism for movement of O2 molecules from the atmosphere to the mitochondria of the cells. This movement is usually called the Oxygen Cascade1. Fick’s equation identifies the variables in diffusion across biologic membranes such as the A/C membrane: (see Note). • In the physiologic oxygen cascade, a series of pressure gradients run down from a PO2 of about 160 torr in the atmosphere to about 3-5 torr at the tissue cells. • Air contains about 21% O2 (20.95%), 79% N2 (78.08%), and about 1% other gases (0.97%). – Dalton’s Law of Partial Pressure explains gas behavior in mixtures and lets us calculate the pressure of each gas. The total pressure of all atmospheric gases equals 760 torr. • When air is Inhaled into the alveoli the O2 has to share the space with three other gases: nitrogen (N2), water vapor (H2O), and carbon dioxide (CO2). 1. The normal PAN2 ≈ 573 torr. The FN2 is constant in the atmosphere, the alveoli, the blood, and the body tissues. Therefore, there is essentially no diffusion gradient for N2 to move across the A/C membrane (unless the patient is breathing 100% O2). 2. The PAH2O is also constant (47 torr at 370C), and its pressure must be deducted from PB (PB – 47 torr) when calculating alveolar PO2 (the PAO2). 3. Accounting for alveolar CO2 is a little more complicated: – CO2 is continuously diffusing into the alveoli (CO2 excretion) at a rate of 200 ml/min. • That constant diffusion from the capillaries explains the normal PACO2 of 40 torr. – O2 is continuously diffusing out of the alveoli (O2 uptake) at a rate of 250 ml/min. • The Respiratory Exchange ratio (R) is 200/250 = 0.8 (for a normal adult at rest). – R accounts for the dynamic reduction in alveolar O2 and the increase in alveolar CO2 when we use the Alveolar Gas Equation to calculate the pressure of O2 in the alveoli (PAO2). • One message from all this is that if the FIO2 remains constant, the PAO2 will vary INVERSELY with the PACO2 because increased CO2 will take up room in the alveolus and displace O2. Oxygenation: The O2 Cascade 3Reference: Note, Text pg. 117, 251, 253 1Cascade means waterfall or a series of series of small waterfalls. In physiology a cascade is a stepwise process in which the end of one step starts the next step (like falling dominoes). Gas Exchange: Pulmonary Pressure Gradients Pressure (diffusion) gradients (the P1 minus P2 from Fluid Physics) provide the force for O2 and CO2 to move across the A/C membrane: • The average PIO2 is ≈ 160 torr • The average PAO2 is ≈ 100 torr • The average PvO2 is ≈ 40 torr • The average PaO2 is ≈ 100 torr The pressure gradient for O2 diffusion across the A/C membrane is about 60 torr. • The average PACO2 is ≈ 40 torr* • The average PvCO2 is ≈ 46 torr • The average PaCO2 is ≈ 40 torr The pressure gradient for CO2 diffusion across the A/C membrane is 6 torr. • The diffusion gradients are between capillary venous blood (the “Pv” numbers) and alveolar gas. • At rest, erythrocytes transit the alveolus in about 0.75 seconds. • Equilibration O2 and CO2 occurs in about 0.25 seconds. • Dalton’s Law predicts that the sum of the PaO2 and the PaCO2 will be about 140 torr. This helps us evaluate the accuracy of ABG results: – If the PaO2 + the PaCO2 is significantly >140 torr and the PaO2 is greater than about 120 torr, then the patient must be on an FIO2 >.21. 4 Although the pressure gradient for O2 is 10 times higher than the CO2 gradient, CO2 diffuses across the A/C membrane about 20 times faster than O2 because CO2 is about 20 times more soluble in plasma than O2 (Henry’s Law). The P(A-a) O2 is NOT the diffusion gradient for oxygen. Reference: Note, Text pg. 117, 251–5 Pressure gradients for O2 and CO2 between the alveolus, the venous and the arterial circulations. The pressure of nitrogen (the PAN2 and PaN2) are constant. The PO2 of air inhaled into the trachea (the PIO2) equals FIO2 x PB. (At sea level: 0.21 x 760 = 159.6 ≈ 160 torr). *Atmospheric PCO2 is ≈ 0.0004 x 760 = 0.30 torr. (the text, pg. 251, states that it is is 1 torr). Either number is essentially zero physiologically. The PACO2 comes from CO2 diffusing out of the pulmonary capillaries, not from inhaled CO2 . The PAO2 is less than the PBO2 because the other gases in the alveoli (N2, H2O, and CO2)take up space. Pulmonary capillary PvO2 PaO2 PvCO2 PaCO2 Cardiopulmonary Values: R/Q & V/Q • R is the Respiratory Quotient (R/Q) aka the Respiratory Exchange Ratio. • R is the quotient of minute CO2 production (VCO2) over minute O2 uptake (VO2) (there should be dots over the V and the Q). –R corrects for the dynamic nature of gas exchange across the A/C membrane when the Alveolar Air Equation is used to calculate the PAO2. • In normal individuals at rest: –CO2 diffuses out of the pulmonary capillaries into the alveoli at a rate of 200 ml/min. –O2 diffuses out of the alveoli into the pulmonary capillaries at a rate of 250 ml/min. • The normal resting value is: R= 200/250 = 0.8 5 • V/Q is the Ventilation/Perfusion ratio (there should be dots over the V and Q). • It is the ratio of minute alveolar ventilation (VA) over minute cardiac output (Q). • In normal individuals at rest: – VA is about 4 L/min. The normal resting minute alveolar ventilation (minute volume). – Q is about 5 L/min. The normal resting minute cardiac output. • The normal resting value is: V/Q = 4L/5L = 0.8. − other writers use 5L/6L, either way the V/Q for healthy people at rest = 0.8. Under normal resting conditions, both the R/Q, and the V/Q will equal 0.8 In order to maintain the R (i.e. the R/Q) and the V/Q equal at 0.8, the body must have a normal cardiopulmonary system that can change its level of alveolar minute ventilation (VA) and cardiac output (Q) to keep pace with the different levels of CO2 production and O2 consumption encountered during exercise, while living at high altitude, and during illness. In cases of ventilatory failure or insufficiency, the cardiovascular system must increase its work to compensate. Reference: Note, Text, pg. 252, 256, 488-90, 990 Note: If the patient is on an FIO2 of ≥ .60 the correction factor R is dropped and the equation becomes: PAO2 = FIO2 x (PB - 47) – PaCO2 Alveolar Air (Gas) Equation: The PAO2 Calculating the partial pressure of O2 in the alveoli (PAO2) is the first step in assessing the adequacy of oxygen delivery across the A/C membrane into the arterial blood. The PAO2 is the driving pressure to get O2 across the A/C membrane and into the plasma. The Clinical (simplified) Alveolar Gas Equation is used to calculate the PAO2: PAO2 = FIO2 (PB-47) - (PaCO2 1/0.8) OR (PaCO2 x 1.25) Either way gives the same answer. • We have seen that five factors determine the PAO2 (Slide 2): 1. The Fractional Inspired O2 Percentage (the ambient FIO2). - Ambient atmospheric FIO2 is always 0.21 at any altitude from sea level to the top of Mount Everest (29,029 ft.) and out to the edge of space. 2. The Barometric Pressure (PB) which is measured with a barometer. - PB at sea level averages about 760 torr. - The PB in cities at higher altitudes will be known, for example; • For example, the PB in Denver is assumed to average 640 torr. 3. Water vapor pressure (PH2O)) in the airways and the alveoli. - PH2O is controlled by body temperature (see vapor pressure in Ch. 6). - At body temperature, 37o C, the PAH2O is always 47 torr. 4. The patient’s PACO2 - PACO2 is difficult to measure, but the PaCO2 is essentially equal to the PACO2, so it is used.. 5. The Respiratory Exchange Ratio (R), the ratio of CO2 excretion to O2 uptake in the alveoli. – Normally R equals 0.8. The equation uses1/R which equals 1.25. 6Reference: Note, Text pg. 119, 252 Hint: For a patient with a normal PaCO2 (40 torr), breathing room at sea level air: FIO2 x (PB - PH2O) = 150 torr, so PAO2 at sea level on room air is simply PAO2 = 150 – (PaCO2 x 1.25) = 100 torr Alveolar Gas Equation: Clinical Problem •The ABG lab reports that a patient on an FIO2 of 0.21 has the following arterial blood gas values: pH 7.42 PaCO2 35 torr PaO2 150 torr. (At this point we are not evaluating acid-base status so the HCO3 is not included) •Your interpretation tells you that this ABG must be in error for at least two reasons: 1.The sum of this patient’s PaO2 and PaCO2 is 185 torr, which violates Dalton’s Law for a room air (FIO2 0.21) ABG (sum of the values in the capillary on Slide 4). –On room air the PaO2 + PaCO2 cannot be much greater than 140 torr. 2. This patient’s PaO2 is reported as 150 torr on room air. –Breathing room air (0 .21 O2) at sea level, the PAO2 would be 150 torr if there was no CO2 in the alveoli to take up space (figure on Slide 4). –This patient’s PaCO2 is 35 torr so his room air PAO2 should be 106 torr: 150 – 44 = 106 torr. (where did the 44 come from? PaCO2 x R.= 35 x 1.25 = 43.75). • A patient with a normal PaCO2 (40 torr) on room air would have a PAO2 of 100 torr (150 - 50 = 100 torr) (Slide 4). –In either case, the lung is not a perfect machine, the small normal shunts and normal V/Q mismatching, prevents the PaO2 from being equal to the PAO2. • In order for the reported PaO2 of150 torr to be correct, the patient would have to be on an FIO2 of about .27, you can work it out for yourself: 0.27 x (760 - 47) – (35 x 1.25) = (.27 x 713) – 44 = 193 – 44 ≈ 150 torr Labs do make mistakes and clinicians have to be able to identify errors. 7 Reference: Text pg. 253 (Rule of Thumb & Mini Clini) Oxygenation: The P(A-a)O2 & the a/A Ratio 1.P(A-a)O2 is simply the difference between the alveolar and arterial PO2. • Since almost all the O2 in the alveoli should diffuse across the A/C membrane, the P(A-a)O2 should be a very low number. • The text says it should be less than 5-10 torr on room air (FIO2 0.21) and ≤ 65 torr on 100% (FIO2 1.0). • Other writers say that the room air P(A-a)O2 should be “less than the patient’s age in years”. • A formula frequently cited in the literature: P(A-a) O2 should be less than the (patient age/4)+4. ̶ For example, a normal 36 YO’s P(A-a O2) should be less than 13 torr: (36/4)+4 = 9+4 = 13 torr. – If her calculated PAO2 was 100 torr, her PaO2 should therefore be greater than 87 torr. • A PaO2 < 87 torr indicates a high P(A-a)O2 and a problem with O2 transfer across the A/C membrane. • The formula also states that P(A-a)O2 may normally increase by 1-3 torr for each decade >20 YO. • In addition, the P(A-a)O2 is expected to increases about 5-7 torr for every 10% increase in FIO2. – On 100% O2 the A-a O2 will be about 60-70 torr (the text says 65 torr). 2.The a/A ratio is another clinical tool used to evaluate the efficiency of O2 transfer from the alveoli into the blood across the A/C membrane. • The a/A is the ratio between arterial and alveolar oxygen pressures. • The arterial oxygen, PaO2, is divided by the alveolar oxygen PAO2: (PaO2 / PAO2). • The normal a/A ratio is ≥ 90% (≥ 0.9). –Normally, more than 90% of alveolar O2 diffuses across the A/C membrane into the blood. • A high P(A-a)O2 and a low a/A ratio are evidence of a diffusion defect. –The factors that determine gas diffusion include the distance the gas has to diffuse. (see Graham’s, Henry’s, and Fick’s Laws, Text pg. 115). • Diffusion defects are conditions that have the effect of increasing the pathway distance for gas diffusion across the A/C membrane, as if the membrane had become thicker. They include conditions such as: – Pulmonary edema, hyaline membrane formation, and conditions that lead to pulmonary fibrosis. 8Reference: Note, Text, pg. 198 -202, 252 (Mini-Clini), 606, 993 (Rule of Thumb) 1164-5 The P(A-a)O2 is commonly referred to as the “A-a Gradient.” This is incorrect because the P(A-a)O2 does not represent a diffusion gradient. The correct term is the “A-a difference.” The difference between the PAO2 and the PaO2 should be very small because it indicates a gas exchange abnormality. Oxygen Dissolved in the Plasma: PaO2 Oxygen is carried in the blood in two forms: Dissolved in the plasma and Bound to the Hb. •The PaO2 is the partial pressure of the oxygen molecules that are dissolved in the arterial blood plasma and in the intracellular fluid of the erythrocytes. – Dissolved O2 molecules move around randomly in the plasma (the Kinetic Theory of gases), generating a pressure which is measured by the O2 electrode of the ABG analyzer. •Once the O2 molecules bind to Hb they no longer exert pressure in the plasma, so bound O2 molecules are not included in the PaO2 measurement. – Just as the PAO2 is the driving pressure to get O2 across the A/C membrane so that it can dissolve in the plasma, the PaO2 is the driving pressure to get O2 across the erythrocyte plasma membrane so it can bind with the hemoglobin. •According to Henry’s Law (Text pg.109 & 252) the solubility coefficient for O2 in plasma at 37oC is 0.00003 ml of O2 per ml of blood per torr (mmHg of O2 pressure). – In clinical practice the deciliter (100 ml) is a more convenient unit than the ml for blood measurement, so the solubility coefficient becomes 0.00003 x 100 = 0.003 ml/dl. • Many writers now use the term volumes percent (vol%) in place of ml/dl (see Note). – Texts state that the average normal PaO2 is 100 torr. •The equation for dissolved O2 is: Dissolved O2 (in ml/dl or vol%) = PaO2 x 0.003. •At a PaO2 of 100 torr, we get the textbook value for dissolved O2 as 0.3 vol% – This tiny amount (< 2% of the total O2 carried) is highly significant because dissolved O2 acts as a reserve to keep the Hb saturated as the blood perfuses the systemic tissue capillaries. •There is a direct, linear relationship between PaO2 and the amount of dissolved O2. – A patient breathing 100% O2 (FIO2 = 1.0) with a normal PaCO2 (40 torr) will have a PaO2 ≈ 600 torr (do the alveolar air equation and then use a P(A-a)O2 of 65 torr to get the PaO2). – A patient on 100% at 3 atm (in a hyperbaric chamber) will have a PaO2 of 2240 torr and have about 6.7 vol% of dissolved O2. 9Reference: Note, Text pg. 252, 258 (Fig.11 -6) Her PAO2 = 150 - (75 x 1.25) = 150 - 94 = 56 torr (remember the Hint on Slide 9). Her a/A ratio (should be >90%) but it actually is 41/56 = 73% Her predicted P(A-a)O2 = (20/4) + 4 = 9 torr. Her actual P(A-a)O2 is 56 - 41 = 14 torr. A high P(A-a)O2 and a low a/A ratio indicate a diffusion defect, in this case it is probably an acute increase in Right to Left shunting secondary to atelectasis or consolidation. PAO2 , P(A-a)O2, & the a/A ratio: Clinical Problem • A 20 YO female with an altered level of consciousness is brought to the ER by her boyfriend. The boyfriend reports that he came home from work and found her “asleep” on the sofa, but when he tried to awaken her she just mumbled. He wonders if this might be caused by her taking too much pain medicine for a sprained ankle she suffered a few days ago. He doesn’t think she takes any other medications or has any drug allergies. • Physical examination reveals the following: – Respiratory rate 8/min. – Room air ABG: pH 7.21, PaCO2 75 torr, PaO2 41 torr. • The ER physician asks you to help identify the probable cause(s) of her hypoxemia, is it: 1. Hypoventilation secondary to a pain medication overdose? 2. A diffusion defect caused by vomiting and aspiration (aspiration pneumonia) which is a common occurrence in people with an altered level of consciousness? • You report to the physician: 1.She is obviously hypoventilating because her PaCO2 of 75 torr is much higher than the normal range (35-45 torr). 2. Based on calculation of her P(A-a)O2 and her a/A ratio, you conclude that she also has a diffusion defect and suggest that the physician order a chest X-Ray to confirm aspiration pneumonia. 10Reference: Slide 8, Text pg. 752 (Mini -Clini) Oxygenation: Erythrocytes (RBCs) • The primary function of the erythrocytes (red blood cells, RBCs) is to carry the hemoglobin (Hb) which carries >98% of the O2 transported by the blood. • Erythrocytes are soft, flexible, biconcave disks about 8 μm in diameter by about 2 μm thick. – Their shape maximizes the surface area for gas exchange and aids in deformability to allow the RBCs to fit through even the smallest capillaries. • RBCs are about 66% water and 33% Hb by volume • They don’t have a nucleus (they can’t divide) and they don’t have mitochondria (they don’t use O2), but they do have all the enzymes needed for anaerobic glycolysis and metabolic activity. – During glycolysis RBCs don’t produce CO2, they produce the organophosphate 2,3-DPG (aka 2,3-BPG). – 2,3-DPG is produced in an amount roughly equal to the RBC’s Hb content. – The level of 2,3-DPG rises when the erythrocyte is metabolically active and falls when activity diminishes. – 2,3-DPG is also essential to Hb’s ability to deliver (unload) O2 at the tissues. – The organophosphate stabilizes Hb in the deoxygenated state. – When the Hb is in the systemic capillaries, the 2,3-DPG present lowers the Hb’s affinity tor O2. – Low affinity for O2 causes the HbO2 to unload O2 and shifts the dissociation curve to the Right (Slide 13). 11Reference: Note, Text pg. 257 -8, 358 Normal adult RBC count: • Males 4.6 – 6.2 x 106 /mm3 • Females 4.2 – 5.4 x 106/mm3 Normal adult Hb: • Males 13.5 – 16.5 g/dl • Females 12.0 – 15.0 g/dl Normal adult hematocrit (Hct): • Males 40% - 54% • Females 38% - 47% (Note, 106 = 1,000,000) This RBC does not contain HbS (sickle cell). Its flexible nature has allowed it to deform in order to pass through a small capillary Normal erythrocytes • Oxygen‘s low solubility in plasma (Slide 9) makes it impossible for the plasma to carry enough dissolved O2 to meet the normal, average, resting adult body’s need for about 250 ml of O2 per minute. • Hb makes adequate blood transport of O2 possible because, in theory, each of our 15 grams of Hb can carry 1.39 ml of O2. – The actual capacity is closer to 1.31 ml/g, but some writers use 1.34 or 1.35. (the Text uses 1.34 ml of O2 per gram of Hb). – In theory, O2 bound to Hb should = 1.39 ml/g x 15 g/dl = 20.1 ml/dl. – In fact, some Hb is defective and some is in shunted blood, so bound O2 = 1.34 x Hb x % SaO2. = 1.34 x 15 x 0.97 ≈ 19.5 ml/dl. • Hb also has several other very important characteristics: 1.Hb can alter (change) its affinity* for O2 . 2.Hb displays cooperative binding and unbinding of O2 – As each molecule of O2 binds or unbinds, it becomes easier for the next molecule to bind or unbind and so the process speeds up. - Binding and releasing O2 causes a conformational (shape) change as the Hb molecule goes from the tense (T) state with LOW affinity for O2 to the relaxed (R) state with HIGH O2 affinity. 3.Hb is an allosteric molecule; it has the four primary binding sites on the hemes, but it has also has secondary binding sites. Atoms bound to secondary sites affect binding at primary sites. 12 Oxygenation: Hemoglobin (Hb) *In chemistry affinity is the strength of the bonds that hold atoms together in compounds. In respiratory physiology, it is the strength of the bond that holds O2 to hemoglobin. • The HbA molecule consists of four protein chains called globins; two alpha chains and two beta chains (shown in different colors) and four porphyrin rings called hemes. • The globin chains are held together by salt bridges. • Each heme contains an iron atom that acts as a binding site for O2. • The four heme groups with their iron atoms are enfolded within the globin chains. • Binding and unbinding causes conformational (shape) changes. • Conformational changes alter the light refractive properties of the Hb and explain its color change. Terms and abbreviations for the Hb types commonly seen in clinical practice: • Normal adult Hb is called HbA. • Oxygenated Hb (oxyhemoglobin) is HbO2. • Deoxygenated (Hb available to carry O2) is Hb. • Carboxyhemoglobin (bound to Co) is HbCO. • Fetal Hb is HbF (abnormal in adults). • Methemoglobin is called metHb • Sickle cell Hb is called HbS. Reference: Note, Text pg. 257, 263 There are many other abnormal variants. See Text, pg. 249-251 for some of the more types. O2 Transport: The Oxyhemoglobin Dissociation Curve 13 The HbO2 curve showing the “Standard” curve and curves shifted Left (increased affinity) and Right (decreased affinity). All three curves are normal, the HbO2 curve shifts back and forth as the blood circulates between the pulmonary and the systemic capillaries. • The steep portion of the curve shows the greatest increase in SaO2 for each incremental increase in PaO2. • The flat portion of the curve shows little or no increase in SaO2 even when PaO2 increases. • Start with the P50 (dashed line), compare the different PaO2 levels and SaO2 points. • Right shift occurs In the systemic capillaries for three reasons: 1. CO2 diffusing in from the cells lowers the pH. 2. The temperature in metabolically active tissues is higher. 3. The RBCs are actively producing 2,3-DPG. • Left shift occurs in the pulmonary capillaries for three reasons: 1.Capillary pH is higher as CO2 diffuses out of the blood. 2.The temperature in the lungs is lower than in systemic tissue. 3.The RBCs are producing less 2,3-DPG. PaO2 (torr) % Saturation of Hb 27 torr 50% 40 torr 70% 50 torr 80% 60 torr 90% 100 & > 97 - 100% Memorize these correlations between PaO2 and O2 sat from the HbO2 dissociation curve. Please Note: 40 torr is the normal PVO2. 100 torr is the normal PaO2. SaO2 of 100% could represent ANY PaO2 > 100 torr. • Arterial Oxygen Saturation (SaO2) is the ratio between the amount of Hb that is available to carry O2and the amount that is actually carrying O2 (just like the relative humidity formula). The SaO2 formula is: • The HbO2 Curve is a graph of the relationship between PaO2 and SaO2. – The shifted curves show how Hb’s affinity for O2 changes in response to physical (temperature) and chemical (pH and 2,3-DPG) changes in the blood • 2,3-DPG binds to deoxygenated Hb, lowering its affinity for O2 (R shift, which helps O2 unload at the tissues). • The HbO2 curve is sigmoid (S-shaped) because the relationship between SaO2 and PaO2 is not linear like the relationship between PO2 and dissolved O2 which is linear. Reference: Note Text pg. 258, 260 (Mini-Clini), 261-2, 263-4. Changing Hb’s Affinity: The Bohr Effect & 2,3-DPG • Hb’s normal affinity for O2 is so high that it simply wouldn’t release O2 at the tissues. – Hb only works physiologically because it can change its affinity for O2 in response to changes in the environment the RBC is currently in. “Environment” means the particular capillary network the blood containing the RBCs happens to be perfusing. • Hb’s ability to lower (R shift) its affinity for O2 in response to increased CO2 (and the resulting decrease in pH) is called the Bohr effect (discovered by Christian Bohr). − Blood entering the systemic capillaries has a pH about 7.40. In the systemic capillaries, CO2 produced by the metabolically active cells diffuses into the capillaries and dissolves in the plasma lowering the pH to around 7.37. The reaction, which we have seen before, looks like this: CO2+ H2O <-------> H+ + HCO-3 − Hb affinity shifts to the Right because the CO2 and the free (loose) hydrogen ion (H+) bind to sites on the protein globin chain. CO2 binds to valine and produces carbamino compounds. The loose hydrogen ion (H+) binds to (and strengthens) the salt bridges connecting the globin chains together. All this tends to stabilize the globin in the Tense state and promote O2 release. • Obviously, the Bohr effect has a lot to do with CO2 transport in the blood. • Another important modulator of Hb affinity is the organophosphate 2,3-DPG (aka 2,3-BPG). − 2,3-DPG is a byproduct of anaerobic glycolysis (RBCs make it when they are metabolically active). One molecule of 2,3-DPG reacts with one molecule of Hb. Increased temperature raises 2,3-DPG production. • O2 binds loosely to the beta (β) globin chains of the Hb but it binds tightly to the alpha (α) chains. At the tissues, O2 molecules leave the β chains easily, but O2 tends to stay bound to the α chains. − The 2,3-DPG molecule slides into the cavity between the two β chains after they have released their O2, This allosteric binding changes the Hb molecule’s shape and promotes O2 release from the two α chains. That is the mechanism by which 2,3-DPG lowers Hb’s affinity for O2. • Increased DPG makes the Hb more efficient at unloading O2 at the tissues. − DPG production increases in anemia, chronic hypoxia and in chronic cardiopulmonary disease. • Decreased DPG makes the Hb more efficient at picking up O2 in the lungs. − DPG production decreases in chronic acidemia (CO2 retention in COPD) and in stored blood. 14Reference: Text pg. 260, Slide 21. Oxygen Content: CaO2 The significance of the last 14 pages of Text and the last 14 slides is that systemic arterial blood delivers the O2 molecules that the tissue cells need for metabolism. The oxygen is delivered in two ways: dissolved and bound, and there are three clinical measurements of arterial O2. We already covered the first two, the PaO2 and the SaO2. Now we will look at the total oxygen content of arterial blood, the CaO2 . (The CaO2 can be expressed either as ml of O2 per dl or blood or as vol%). To calculate the CaO2 we also have to know the patient’s total hemoglobin (HbTotal). HbTotal can also be expressed either as grams per deciliter (g/dl) or as vol%. • Oxygen content is measured directly by an ABG analyzer or it can be calculated with the oxygen content equation. • The classic version of the equation shown in the text is: CaO2 = PaO2 x (.003 ml O2/mm Hg/dl) + (Hb (in gm/dl) x (1.34 ml O2/gm Hb) x SaO2) • 0.003 ml of O2 will dissolve in each dl (100 ml) of plasma For every mmHg of pressure (Slide 9). • 1.34 ml of O2 can bind to each gram of Hemoglobin (Slide 12). • The clinical version of the equation is: CaO2 = (0.003 ml x PaO2) + (HbTotal x 1.34 x SaO2) • In our average normal healthy adult at rest the CaO2 is predicted to be: CaO2 = (0.003 x 100) + (15 x 1.34 x 0.97) = 0.3 + 19.5 = 19.8 vol%. That means that each deciliter (100 mL) of blood can carry almost 20 mL of O2. 15Reference: Note, Text pg. 259 Oxygen Loading & Unloading: C(a-v)O2 • As the blood circulates through the systemic capillaries, it releases O2 according to the metabolic needs of the cells being perfused. • The C(a-v)O2 is the difference between the O2 content at the arterial end of the capillary and content at the venous end. –The C(a-v)O2 measures the amount of O2 taken up by the tissues. • Normally, in healthy subjects at rest, each dl of arterial blood releases about 5 ml of O2 to the tissues. –That means that the normal C(a-v)O2 is about 5 vol% (or ml/dl). • Remember the structure of the circulation: – Arteries carry blood away from the heart. Veins carry blood back to the heart. Capillaries are the very short, thin-walled exchange vessels that connect arteries and veins. – The term exchange vessels means that the capillaries are where blood arterializes in the pulmonary capillaries and becomes venous again in the systemic capillaries. 16 A relaxed, systematic survey of Fig. 11-9 (Text, pg. 261) reveals that it uses the standard HbO2 dissociation curve to examine the C(a-v)O2 concept. •The X axis plots dissolved O2 (as vol% without values) and PaO2 in torr. •The Y axis plots SbO2 (b = whole blood) as % saturation and CaO2 (in vol%). •Point V is blood just leaving the systemic capillaries and entering the pulmonary capillaries. •Point A is blood just leaving the pulmonary capillaries and heading for the systemic capillaries. •The line marked A-V Po2 difference (should be a-v) is read from the X axis. It shows the PaO2 about 100 torr and the PvO2 about 40 torr. •The A-V Hb difference (again, A should be a) is read from the Y axis. It shows the SO2 of A as about 97% and the SO2 of V as about 72%. Note that at a PO2 of 100 torr the HbO2 dissociation curve flattens out and SO2 no longer increases even though more and more O2 is dissolving in the plasma. Reference: Note, Slide 4 (Figure), Text, pg. 261 Physiological Oxygen Transport: Summary • Clinically, the CaO2 is a much more useful measure of oxygenation than the PaO2. – Healthy people, who have 15 vol% of normal Hb and a PaO2 of 100 torr will have a CaO2 of about 20 vol%. This CaO2 is adequate for a normal level of activity. In normal people a PaO2 of 100 torr by itself can be presumed to produce a normal SaO2 and a normal CaO2. • Unfortunately, in disease, it is possible for a patient to have a normal PaO2 and still be severely hypoxic, and the reported PaO2 value may not indicate the level of tissue hypoxia. – With adequate pulmonary ventilation none of the factors that lower CaO2 will show up in the PaO2 (O2 crosses the A/C membrane and dissolves in the plasma producing the Pressure that we read as PaO2). Factors that lower CaO2 without affecting PaO2 include: • Anemia* (reduction in Hb), HbCO (CO poisoning), metHb (methemoglobin), and various conditions that cause an excessive and permanent shift in the HbO2 curve. – The paradox of hypoxia with a normal PaO2 most often happens in one of two ways: Either there is a reduction in the amount of Hb or there is an abnormality in Hb’s affinity for O2. • On the other hand, a hypoxemic (low PaO2) patient may still have an adequate CaO2. – A defect in gas transfer across the A/C membrane can cause a low PaO2. But if the patient has an adequate supply of normal Hb he may be able to maintain an adequate CaO2. – For example, a patient with a PaO2 of 55 torr will have an SaO2 of 88% (see the HbO2 curve, Text, pg. 246,& Slide 13). If the patient has a normal Hb of 15 vol% we can calculate his CaO2: (15 x 1.34 X .88) + (0.003 x 55) ≈ 18 vol%. – The normal CaO2 ≈ 20 vol%. As long as our hypoxemic patient can increase his cardiac output he can avoid hypoxia and oxygenate his tissue cells even though his PaO2 is low. 17 *Note that anemia does NOT affect either the PaO2 nor the SaO2. It reduces the CaO2 and we have to know the actual HbTotal to do the CaO2 calculation. Reference, Text, pg. 271 18 Gas Exchange & Transport RTT 100 Professor Michael Nazzaro You must study BOTH chapter 11 and this supplement Part 2, Carbon Dioxide Transport Supplement to Text, Chapter 11 and Background for Chapter 38 CO2 Transport: Essential Terminology Acid-Base physiology will be covered in depth during RTT 210, however there are some acid-base chemistry terms and concept that are essential to understanding CO2 transport: •Acid: any substance that donates a hydrogen ion proton (H+)* when hydrolyzed in an aqueous solution (aqueous means that water is the solvent in the solution). •Base: any substance that donates a hydroxyl ion (OH-) and is able to accept a H+ proton when hydrolyzed in an aqueous (water based) solution (alkaline and alkalinity are synonyms). –The terms strong and weak acids and bases refer to how completely the substance disassociates (ionizes) in an aqueous solution, not to the substance’s concentration. •pH: acidity (or basicity) of an aqueous solution is defined as the logarithm of the reciprocal of the hydrogen ion concentration (the negative logarithm of H+). In 1909 Sørenson suggested using the lower case letter “p” to denote the H+. There are all kinds of explanations for what “p” stands for, the one I like best is the power (in both its mathematical and physical sense) of H+. •Buffer (buffer system, buffering, etc.): In the body, buffers are substances in the blood that prevent large, rapid changes in pH when H+ or OH- ions are added. •Acid-base balance: refers to the physiological mechanisms to keep the H+ concentration in body fluids within a range compatible with survival (pH 7.35 – 7.45). 19 Definitions based on the BrØnsted-Lowry theory used in physiology *Chemists know that H+ (free hydrogen ion protons) do not exist in aqueous solutions, because the protons combine with water to form hydrated hydronium ions (H3O+). Medical textbook writers know this as well, but they use H+ as a convenient shorthand for acids in the body. Reference: Note, Text, pg. 264-6, 294, 1344 Physiologic Gas Transport: CO2 Transport 20 •Blood transport of CO2 is much more complicated than O2 transport. Unfortunately, some writers manage to make it look even more complicated than it actually is. •CO2 is produced by the body cells during metabolism; the conversion of food to energy. Most texts state that normal tissue cell CO2 production is about 200 ml/min with a normal range of about 120 to 280 ml/min depending on body size and metabolic rate. The standard physiologic value for CO2 production (in health, at rest) is 2.4 ml/kg/min. •The CO2 is carried from the cells to the alveoli by the blood and excreted by ventilation. The blood carries a volume of about 45-55 ml/dl of CO2 in three forms in the blood. – CO2 transport operates in a reverse cascade of increasing pressures from the cellular level where PCO2 is high to the atmosphere where PCO2 is low. – CO2 diffuses into capillary blood because CO2 pressure in the interstitial fluid is about 46- 47 torr while capillary PCO2 is about 40 torr (see Note). This diffusion raises the capillary PvCO2 to the 46 or 47 torr shown in Fig.11-3 on pg. 255 of the Text. •CO2 is about 20 times more soluble in plasma than O2, so a larger portion (5 - 10%) is simply carried dissolved in the plasma and in the RBC intracellular fluid. The rest is carried as reversible chemical combinations in the RBC and the plasma. These are two types of reversible combinations: carbamate compounds and bicarbonate. – Carbamates bound to plasma proteins are called carbamino compounds and those bound to Hb within the RBC are called carbaminohemoglobin (which is NOT carboxyhemoglobin). • Three modes of CO2 transport: 1. Dissolved in the plasma: about 5-10% (the Text uses 8%). 2. Bound as carbamates (mostly carbaminohemoglobin): about 12-22% (the Text uses 12%). 3. As bicarbonate ions both in the RBC and in plasma: about 80-90% (the Text uses 80%). Reference,: Note, Text, pg. 264 CO2 Transport: Chemical Events in the Blood A relaxed, systematic survey of Fig. 11-13 reveals the following information: • The left edge of the figure represents the tissue interstitial space (the tissue space). • CO2 diffuses into the capillary from the tissue space and O2 diffuses out of the capillary into the tissue space. Binding to protein (the globin in Hb) buffers H+ and changes Hb’s affinity for O2 and CO2 21 Figure 11-13, pg. 265 clearly sums up the chemical events in CO2 transport in the blood. • The Bohr effect (discovered by Christian Bohr) shows how high CO2 and H+ levels In metabolically active tissues lower Hb’s affinity for O2 (R shift) and increase Hb’s affinity for CO2. − Bohr speeds up unloading of O2; and deoxygenated Hb has a high affinity for CO2. • The Haldane effect (discovered by John Scott Haldane) describes how high levels of O2 in the lungs increase Hb’s affinity for O2 (L shift) and decrease its affinity for CO2. − Haldane speeds up of loading of O2 and oxygenated Hb (HbO2) has a low affinity for CO2. During all these rapid chemical changes in the plasma and the erythrocytes, chloride ions (Cl-) shift into the RBC to maintain electrolytic equilibrium (discovered by Hertog Jakob Hamburger). A reverse chloride shift occurs in the pulmonary capillaries. Reference: Note, Text, pg. 264-6, Slide 13 – About 10% of the CO2 enters the plasma, of which: • 5% simply dissolves in the plasma. • 5% slowly ionizes to bicarbonate (HCO3-) and a free hydrogen ion (H+) • <1% combines with the free amino groups (NH2) of protein molecules in the plasma to form carbamino compounds (the prot-NHCOO- + H+ in the figure) and a free hydrogen ion (H+). – About 90% of the CO2 enters the erythrocyte, of which: • 5% simply dissolves in the erythrocyte intracellular fluid. • 63% quickly ionizes to HCO3- because erythrocytes have the enzyme carbonic anhydrase (CA) that makes the reaction almost instantaneous (actually it takes about 2 milliseconds). • 21% forms the carbamino compound carbaminohemoglobin when it binds to amino groups on the globin chains of deoxygenated Hb. Gas Exchange Abnormalities: Introduction •The primary purpose of breathing is gas exchange. –Adequate breathing requires a level of VA that is sufficient to take in enough O2 and eliminate enough CO2 to meet the body’s physiological needs. •It is important to remember that what appears to be normal breathing (“normal” tidal volume and respiratory rate) does not automatically guarantee adequate oxygenation. –In fact, hyperventilation is one of the first signs of hypoxemia and hypoxia. •Oxygen delivery to the tissues ( DO2) is the product of O2 content (CaO2) and Cardiac Output ( Q). The DO2 formula is: If Hb =15 vol%, SaO2 = 97%, PaO2= 100 torr, and CO ( Q) = 5 l/min, then DO2 ≈ 990 ml/min 𝐃O2 = ((15 x 1.34 x .97) + (0.003 x 100)) x 5 x 10 = 990 (multiplying by 10 converts ml/dl to ml/L). •When DO2 is inadequate to meet tissue needs, the result is hypoxia. •When the PaO2 is below the predicted normal for the patient’s age, the result is hypoxemia. •Since hypoxia and hypoxemia have a range of causes that often require different forms of treatment, the clinician has to understand the underlying pathologies of hypoxia, for example: –A patient who is hypoventilating will have hypoxemia. Normobaric O2 therapy will correct the hypoxemia (but it will not correct the cause of the hypoventilation). –A patient with a low V/Q (< 1 but > 0) will need O2 under positive pressure to correct the hypoxemia by opening collapsed alveoli. –A patent foramen ovale (the opening between the right and left atria in the fetal heart) that doesn’t close spontaneously after birth will require surgery to close the hole. 22Reference: Text, pg. 267, Slide16 The CO2 Dissociation and the Haldane Effect The Bohr effect and the Haldane effect are examples of heterotrophic interactions: where the presence of one molecule (CO2) affects the binding of a second molecule (O2) to a third molecule (Hb). • The Haldane effect describes how high levels of O2 in the lungs increase (L shift) Hb’s affinity for O2 and thereby decrease its affinity for CO2. Blood in the pulmonary capillaries is in a high O2 environment. − Haldane’s effect describes how high O2 levels speed up loading of O2 onto Hb at the lungs, producing saturated Hb (HbO2). − HbO2 has a low affinity for CO2, so unloading of CO2 and loading of O2 are simultaneously speeded up at the lungs. − Haldane’s effect also works at the tissues but to a lesser degree. • The Bohr effect (Slide 13) describes how high levels of CO2 and H+ in the tissues decrease (R shift) Hb’s affinity for O2 and thereby increase its affinity for CO2. – Blood in the systemic capillaries is in a high CO2 and H+ environment. – Bohr’s effect describes how high CO2 and H+ levels speed up unloading of O2 at the tissue cells, producing deoxygenated Hb. – Deoxygenated Hb has a high affinity for CO2 so loading of CO2 and unloading of O2 are simultaneously speeded up at the tissues. – Bohr’s effect also works at the lungs, but to a lesser degree. • During all of these rapid chemical changes in the plasma and the erythrocytes, chloride ions (Cl-) shift into the RBC to maintain electrolytic equilibrium (a phenomenon named after its discoverer, Hertog Jakob Hamburger). 23 The bottom half of Fig. 11-14, pg. 266. The CO2 Dissociation Curve graphs the Haldane effect. The colored curves represent SaO2. The PCO2 (x axis) and CO2 content (y axis) are shown at two physiologic SaO2 values and an extreme value for comparison. • Point a on the 97.5% saturated curve shows a PCO2 of 40 torr and a CO2 content of 48 vol%. • Point v is on the 70% saturated curve shows a PCO2 of 46 torr and a CO2 content of 52 vol%. • CO2 content increases as O2 saturation decreases. Reference: Slide 4 (Figure), Text pg. 266 24 RTT 100 Professor Michael Nazzaro Supplement to Text, Chapter 11 Background for Chapter 38 You must study BOTH chapter 11 and this supplement Part 3, Gas Exchange Abnormalities Abnormalities of Oxygenation: Hypoxemia • Hypoxemia is defined as a PaO2 lower than the predicted value for the patient’s age (from the equation for older adults on pg. 269): PaO2 = 100.1 − (0.323 x age in years). • Hypoxemia is classified as: – Mild (PaO2 60 torr, which is somewhat < than normal), – Moderate (PaO2 49-59 torr). – Severe (PaO2 <40 torr). • There are two basic causes of hypoxemia: 1. An inadequate amount of oxygen is reaching the alveoli which causes a low PAO2. Likely causes include: inadequate breathing producing a low alveolar minute volume (VA) which may result from: ̶ Overall hypoventilation: • The PAO2 is down because the PaCO2 is up. • The P(A-a)O2 will remain normal because blood perfusing the underventilated alveoli will have a low PaO2 that equilibrates with the low PAO2. ̶ Tachypnea: • Rapid, shallow breathing increases deadspace ventilation because a higher proportion of the lower VT ventilates the fixed amount of anatomic deadspace (remember, Ve ≠ VA from Ch. 10). 2. An inadequate amount of oxygen is crossing the A/C membrane into the blood. Likely causes include: • Low PB causing a low PIO2 , (e.g. mountain climbing, aircraft depressurization, etc.). • Low FIO2 (e.g. being in a closed room with a combustion heater). ̶ Textbook descriptions of diffusion defects across the A/C membrane can be confusing because anything that reduces O2 transfer across the A/C membrane can be classified as a diffusion defect; anything from low PIO2, all the way to circulatory failure. ̶ Mixing of low PO2 blood with high PO2 blood is also potentially confusing because of the diverse terminology used in textbooks. –Both diffusion defects and shunts will be covered separately. 25 Reference: Text pg. 269, 270 (Fig. 11-17), 388, 1164 Gas Exchange Abnormalities: V/Q Imbalance 1 • The formal physiological expression for the ventilation/perfusion ratio is 𝑽𝑨/ 𝑸𝑪Where 𝑽𝑨 stands for minute alveolar ventilation and 𝑸𝑪 stands for minute blood flow through the alveolar capillaries. • The actual normal V/Q is 0.8, but for convenience writers consider the normal V/Q to be one (1). –Abnormalities that lower perfusion with ventilation unchanged will increase the V/Q to a number >1. –Abnormalities that lower ventilation with perfusion unchanged will decrease the V/Q to a number <1. 26 • The term V/Q imbalance means that the distribution of ventilation and/or perfusion in the lung is abnormal and no longer displays a 1:1 match. • Either some ventilation, some perfusion, or both will be wasted (not participate in gas exchange). Think of the black oval in the figure as a slide switch to control V/Q distribution in the model*. At the far right there is no perfusion but full ventilation. •V/Q equals a whole number divided by zero which equals infinity. •This represents pure dead space ventilation (VA = VD). •In pure dead space, alveolar gas pressures equal atmospheric. At the far left there is full perfusion but no ventilation. •V/Q equals zero divided by a whole number which equals zero. •This represents an absolute shunt . •In absolute shunt alveolar gas pressures equal capillary venous gas pressures. The far left and right positions are extremes shown for comparison. • In the normal lung the switch moves back and forth slightly (toward, not to) the extremes depending on a number of factors, including posture and exercise level. • Whatever degree of V/Q mismatching the patient with cardiopulmonary disease is experiencing will have to be identified by the clinician and treated accordingly. Reference: Note, Text, pg. 255-6 27 Gas Exchange Abnormalities: V/Q Imbalance 2 Reference: Text pg. 1162 Absolute Shunt Unit Normal Unit Absolute Dead Space Unit Perfusion (Q) Ventilation (V) V/Q Ratio Alveolar Capillary Blood: PaO2 100 mmHg PaCO2 45 mmHg O2 = 100 CO2 = 40 Atmospheric air: PO2 150 mmHg PCO2 0 mmHg Alveolar air: PAO2 100 mmHg PACO2 40 mmHg This is another way of looking at the information in the figure on Slide 26, with alveolar and capillary gas values found in the three different V/Q states. A relaxed, systematic survey of Fig.11-20 (pg. 272) reveals the following information: • Arterial partial pressure of both gases is shown on the x axis. • Arterial content of both gases in shown on the y axis. • The drawing in the upper right represents alveolar/capillary units displaying both low V/Q (V/Q) and high V/Q (V/Q). • Point “a” on both curves indicates the normal arterial blood value for partial pressure and total content of both gases. − Point a on the O2 curve (midway between the extremes) shows a normal PaO2 of 90 torr and a CaO2 of 19.5 vol%. − Point a on the CO2 curve (midway between the extremes) is also normal, PaCO2 35 torr and a CaCO2 of 48 vol%. • V/Q imbalances are more likely to reduce PaO2 than they are to increase PaCO2 − This primarily results from to the great difference in solubility between O2 and CO2 and the fact that a low PaO2 stimulates increased ventilation. • In general, low V/Q units produce both increased CO2 and reduced O2 . Low V/Q indicates hypoventilation (point x). • In general, high V/Q units produce a low CO2 and a high O2 (point V/Q on both curves). Gas Exchange Abnormalities: V/Q Imbalance 2 28 V/Q imbalances that are below the extremes of pure deadspace ventilation and absolute shunt perfusion will still have an affect on oxygenation and CO2 elimination • In order to survive, patients with a low V/Q (underventilated alveoli due to lung disease) have to compensate for the low O2 by increasing VA. – They do this by increasing their VA. • These patients will have both hypoxemia and a normal or even a low PaCO2 (hypocapnia). • Patients who cannot increase VA will have both hypoxemia and hypercapnia. • Hypoxemic patients will also attempt to compensate by increasing cardiac output. • The “Guy In The Chair” is probably only able to compensate at a very low level. Reference, Text, pg. 272-3 Poor Oxygenation: Ischemia, Shock, & Dysoxia Additional causes of tissue hypoxia involve cardiovascular inadequacies and cellular toxicity 1. Ischemia is the term for a temporary local reduction of oxygenated blood flow to a particular tissue or organ. – Occlusion of a blood vessel will reduce blood flow in the tissue being perfused. If a coronary artery is occluded the result may be a myocardial infarction. If the vessel is in the brain the result may be a stroke. 2. Shock is the term for generalized circulatory failure characterized by excessively low blood pressure. – Shock occurs when the cardiovascular system cannot adequately perfuse the body’s tissue cells. This may result from failure of the heart as a pump, inadequate blood volume, or inability of the blood vessels to produce sufficient muscle tone to maintain pressure. 3. Dysoxia (aka histotoxic hypoxia, hypoxidosis) is a condition in which the cells are unable take up and use O2 normally. In these cases the PaO2, CaO2, SaO2, and O2 transport are all normal, but venous blood returns to the heart with virtually the same PO2 it had when it returned to the left atrium from the lungs. −The classic illustration for dysoxia is cyanide poisoning. • Cyanide inhibits the intracellular enzyme cytochrome oxidase • Cytochrome oxidase is essential to allow the mitochondria to use O2. • Dysoxia is also seen in Adult Respiratory Distress Syndrome (ARDS), now usually called Acute Respiratory Distress Syndrome. Dysoxia is also seen in septic shock. – Septic shock reduces blood flow past the peripheral chemoreceptors (cells located in the aorta and carotid arteries that respond to low O2 levels). This low blood flow causes an increase in the ventilatory drive. • Cyanide alters the neural conductivity of the peripheral receptors and produces a brief period (lasting seconds to minutes) of hyperpnea before death. 29Reference: Note, Text, pg. 270 -1 Diffusion Hypoxia: Clinical Problem 1.An 18 YO male patient is in the recovery room after an uncomplicated appendectomy. He is awake and alert and breathing normally, but the nurse reports that his SpO2 is 88%. You put the patient on a simple O2 mask at 8 L/min (FIO2 ≈ .6) and within several minutes his SpO2 increases to 99%. What caused the low SpO2 and why did the O2 mask correct the problem? – The patient’s condition is diffusion hypoxia which often happens after anesthesia with nitrous oxide (N2O). – Nitrous oxide anesthesia (N2O) is administered by inhalation, so it diffuses across the A/C membrane into the bloodstream where it reaches the CNS and produces anesthesia. – After surgery, the residual N2O diffuses out of the blood into the alveoli and is excreted through the lungs. – During the time it takes to clear the N2O from the blood, the gas displaces O2 in the alveoli and causes a mild hypoxia. – Giving the patient O2 displaces some of the nitrogen (N2) in the alveoli and increases the PAO2 by allowing more room for O2. • If we could measure the patient’s PaN2O we could calculate his actual PAO2 and then calculate his P(A-a)O2. • Since we aren’t able to do those calculations, we have to treat empirically, that is the treatment has to be based on clinical signs (the low SaO2) and our clinical intuition and judgment. 30Reference, Note 31 Pulmonary Physiology:Pulmonary Shunting True Shunts can be anatomic or capillary shunts. True shunts are refractory to oxygen therapy •Anatomic Shunts occur when blood passes from the right side of the circulation to the left side without entering the pulmonary capillaries. – The normal anatomic shunt (about 2-5% of cardiac output) arises from the portion of bronchial, pleural, and coronary venous blood that empties directly into the pulmonary veins and the left atrium. – Many pathological conditions can cause anatomic shunts including congenital heart defects, and tumors of the pulmonary vasculature to name two. •Capillary Shunts occur when blood from the right circulation passes through the pulmonary capillaries but no gas exchange occurs. – The most common cause of capillary shunts is atelectasis. Shunt-like Effect occurs when pulmonary perfusion exceeds alveolar ventilation. • Most common causes of shunt- like effect are hypoventilation, uneven distribution of ventilation, and A/C diffusion defects. • Shunt-like effect is usually responsive to oxygen therapy. • Venous Admixture is the final result of all types of shunting. Venous admixture is just a fancy way of saying that various aliquots of deoxygenated blood mix with oxygenated blood and lower the overall O2 content of the arterial blood. A Shunt occurs when volumes of oxygenated and deoxygenated blood mix. Terminology for shunts is confusing: True Shunt (absolute shunt) and Shunt-like Effect are names for broad categories: Reference, Text pg. 255, 267-8, 991 32 Alveolar ventilation: ( VA) VA = (VT - VD) x Respiratory Rate. Normal = (0.5 L- 0.15L) x 12/min. = 4.2 L/min. = 4.2L of air /4.9L of blood ≈ 0.8 VA Q Pulmonary Physiology: Normal V/Q Ratio Pulmonary Venule When the V/Q relationship is normal, alveolar ventilation and pulmonary capillary perfusion are well matched resulting in optimal oxygenation of arterial blood. If ventilation decreases, the V/Q ratio will become lower. If perfusion decreases, the V/Q ratio will become higher. Alveolar ventilation: ( VA) VA = (VT - VD) x Respiratory Rate. Normal = (0.5 L- 0.15L) x 12/min. = 4.2 L/min. Ventilation Alveolar ventilation: ( VA) VA = (VT - VD) x Respiratory Rate. Normal = (0.5 L- 0.15L) x 12/min. = 4.2 L/min. Perfusion Cardiac output: CO Q Q = Stroke Volume x Heart Rate. Normal = (0.07 L) x 70/min. = 4.9 (≈ 5)L/min. . . Reference: Text pg. 260, 272 The Fick equation for cardiac output Qt = VO2 / [C(a-v)O2 x 10] The ventilation perfusion ratio formula 33 Hypoxic vasoconstriction reduces blood flow to hypoxic alveoli Physiology: Response to Pulmonary Shunt When ventilation to a lung region decreases: • The PCO2 in the alveoli will increase and PO2 will decrease. • Sensors in the pulmonary capillaries will cause smooth muscle cells to contract, • This will reduce blood flow through the capillary to reestablish the V/Q balance. Reference: Text, pg. 178 & Ch. 8 PPT Slide 70, pg. 260, 272 Hypoxic pulmonary vasoconstriction diverts blood away from the underventilated unit to the well ventilated alveolus. Pulmonary capillary distension helps keep vascular resistance low. PO2 PCO2 Blood flow to hypoxic alveoli does not participate in gas exchange (shunted). Blood flows equally to the well ventilated and the underventilate (hypoxic) alveoli. Blood perfusing the hypoxic unit mixes with oxygenated blood and lowers the overall PaO2. 34 Zone 1: Has high transmural pressure which collapses the capillaries. • Little or no blood flows to these alveoli, and their ventilation does not participate in gas exchange (they add to alveolar dead space). Zone 2: Pulmonary arterial pressure increases but pulmonary venous pressure is still lower than alveolar pressure. • Blood flow is determined by the relationship between arterial and alveolar pressure instead of arterial and venous pressure. • This is an example of the Starling resistor or waterfall effect. Zone 3: Pulmonary venous pressure is greater than alveolar pressure and blood flow is determined by the arterial-to-venous pressure difference. • Capillary distension and recruitment play a role in this increased blood flow. Pulmonary Physiology:West’s Three Zone Concept 1 Low flow High flow In the upright lung, blood flow decreases nearly linearly from the bottom to the top. Dr. West developed a three zone model to explain this phenomenon. Note: these zones are physiologic, NOT anatomic. Pulmonary vascular pressure (right ventricle) ≈25 mmHg. Lung height, 30 cm. (30 cmH2O ≈ 23 mmHg). Reference: Note, Text pg. 179, 198-199, 256 35 Pulmonary Physiology:West’s Concept 2 • Zone 1 does not occur under normal conditions because pulmonary artery pressure is just high enough to raise blood to the top of the lung. • If arterial pressure is reduced, for example by severe blood loss (hemorrhage) or alveolar pressure is raised (positive pressure ventilation) a Zone 1 Condition will occur. – That statement means there will be increased Alveolar Dead Space. Some physiologists think that the pressure/ flow relationships in these vessels is not described by Poiseuille’s Law but resemble the p/f relationships of a waterfall: • The driving pressure for flow through the intraalveolar vessels may not always be the ∆P between capillary inflow and outflow pressure. • Flow may be controlled by the difference between the inflow pressure and the vessel’s critical closing pressure (the transmural pressure which is controlled by alveolar pressure) Reference: Note The relationship between alveolar pressure (distension) and pulmonary capillary perfusing pressure controls blood flow in different regions of the lung. 36 Pulmonary Physiology:Alveolar Dead Space Alveolus A is ventilated but not perfused because it is located above the hydrostatic pressure head of the right ventricle (see West’s Zone 1). Such alveoli are usually near the apex of the upright lung. Alveolus B represents a normal condition, where ventilation is closely matched to perfusion, the ideal situation. Alveolus C has normal ventilation, but blood flow is blocked by an embolus. Thus, it is ventilated, but perfusion is limited and it contributes to the Alveolar Dead space. Alveolus D is characteristic of emphysema Where the septa between adjacent alveoli break down to form large air sacs that are ventilated but poorly perfused. Alveolus E has adequate ventilation, but blood flow is diminished by pre-capillary vasoconstriction. All of the above conditions, except Alveolus B, increase the alveolar dead space and add to the physiological dead space. Alveolar dead space occurs both normally and with certain lung diseases. Alveolus E has reduced perfusion because of hypoxic pulmonary vasoconstriction. Reference: Text pg. 246-7 37 A: Normal. B; Normal during exercise, note the increased V & Q). C: Asthma & Bronchitis, note the partial alveolar collapse and compressed capillaries due to pulsus paradoxus. D: Emphysema, note the destruction of alveolar septa and capillaries with severe reduction in gas exchange surface area. E: Reduced perfusion. F: Mitral valve stenosis, note the capillary engorgement. G: Pulmonary Edema, alveoli 1 & 2 are compressed by edema fluid. Fluid has entered alveolus 3 reducing gas exchange surface area and increasing alveolar surface tension. Alveolus 4 is flooded and is no longer able to participate in gas exchange. A B C D E F G Pulmonary Physiology:Altered Respiratory Mechanics 38 Diffusion Across the AC Membrane 1 Gas molecules move in and out of the alveoli by diffusion Air moves in and out of the airway by Bulk Flow Air Exchange (Ve) and Gas Exchange Erythrocytes spend about 0.75 seconds in the alveolar capillary. Hemoglobin saturation occurs in approximately 0.25 seconds. Detail on next slide 39 Diffusion Across The AC Membrane 2 O2 O2 O2 O2 O2O 2 O2 O2 O2 O2O2O2 O2 O2 O2O2 Is the PaO2 Dissolved O2 Attached to Hb: SaO2 SaO2 O2 Attached to Hb is not part of the PaO2 Pulmonary Capillary Alveoli example of the Starling resistor or waterfall effect. Zone 3: Pulmonary venous pressure is greater than alveolar pressure and blood flow is determined by the arterial-to-venous pressure difference. • Capillary distension and recruitment play a role in this increased blood flow. Pulmonary Physiology:West’s Three Zone Concept 1 Low flow High flow In the upright lung, blood flow decreases nearly linearly from the bottom to the top. Dr. West developed a three zone model to explain this phenomenon. Note: these zones are physiologic, NOT anatomic. Pulmonary vascular pressure (right ventricle) ≈25 mmHg. Lung height, 30 cm. (30 cmH2O ≈ 23 mmHg). Reference: Note, Text pg. 179, 198-199, 256 35 Pulmonary Physiology:West’s Concept 2 • Zone 1 does not occur under normal conditions because pulmonary artery pressure is just high enough to raise blood to the top of the lung. • If arterial pressure is reduced, for example by severe blood loss (hemorrhage) or alveolar pressure is raised (positive pressure ventilation) a Zone 1 Condition will occur. – That statement means there will be increased Alveolar Dead Space. Some physiologists think that the pressure/ flow relationships in these vessels is not described by Poiseuille’s Law but resemble the p/f relationships of a waterfall: • The driving pressure for flow through the intraalveolar vessels may not always be the ∆P between capillary inflow and outflow pressure. • Flow may be controlled by the difference between the inflow pressure and the vessel’s critical closing pressure (the transmural pressure which is controlled by alveolar pressure) Reference: Note The relationship between alveolar pressure (distension) and pulmonary capillary perfusing pressure controls blood flow in different regions of the lung. 36 Pulmonary Physiology:Alveolar Dead Space Alveolus A is ventilated but not perfused because it is locat