Physiology_Levy

Physiology_Levy. 23.8 ). Two alveoli are ventilated, each of which is supplied by blood from the heart. When ventilation is uniform, half the inspired gas goes to each alveolus, and when perfusion is uniform, half the cardiac output goes to each alveolus. In this normal unit, the ventilation/perfusion ratio in each of the alveoli is the same and is equal to 1. The alveoli are perfused by mixed venous blood that is deoxygenated and contains increased PaCO2. PAO2 is higher than mixed venous O2, and this provides a gradient for movement of O2 into blood. In contrast, mixed venous CO2 is greater than PACO2, and this provides a gradient for movement • Fig. 23.8 Simplified Lung Model of Two Normal Parallel Lung Units. Both units receive equal volumes of air and blood flow for their size. The blood and alveolar gas partial pressures are normal values in a resting person at sea level. PACO2, partial pressure of alveolar carbon dioxide; PAO2, partial pressure of alveolar oxygen; PiCO2, partial pressure of


Physiology_Levy

Physiology_Levy. gas partial pressures are normal values in a resting person at sea level. PACO2, partial pressure of alveolar carbon dioxide; PAO2, partial pressure of alveolar oxygen; PiCO2, partial pressure of inspired carbon dioxide; PiO2, partial pressure of inspired oxygen; PpvCO2, partial pressure of carbon dioxide in portal venous blood; PpvO2, partial pressure of oxygen in portal venous blood; PvCO2, partial pressure of carbon dioxide in mixed venous blood; PvO2, partial pressure of oxygen in mixed venous blood.


Physiology_Levy

Physiology_Levy. of CO2 into the alveolus. Note that in this ideal model, alveolar-arterial O2 values do not differ. An anatomical shunt occurs when mixed venous blood bypasses the gas-exchange unit and goes directly into the arterial circulation (


Physiology_Levy

Physiology_Levy. Fig. 23.9 ). Alveolar ventilation, the distribution of alveolar gas, and the composition of alveolar gas are normal, but the distribution of cardiac output is changed. Some of the cardiac output goes through the pulmonary capillary bed that supplies the gas-exchange units, but the rest of it bypasses the gas-exchange units and goes directly into the arterial circulation. The blood that bypasses the gas-exchange unit is thus shunted, and because the blood is deoxygenated, this type of bypass is called a right-to-left shunt. Most anatomical shunts develop within the heart, and they develop when deoxygenated blood from the right atrium or ventricle crosses the septum and mixes with blood from the left atrium or ventricle. The effect of this right-to-left shunt is to mix deoxygenated blood with oxygenated blood, and it results in varying degrees of arterial hypoxemia.


Physiology_Levy

Physiology_Levy. • Fig. 23.9 Right-to-Left Shunt. Alveolar ventilation is normal, but a portion of the cardiac output bypasses the lung and mixes with oxygenated blood. PaO2 varies according to the size of the shunt. PACO2, partial pressure of alveolar carbon dioxide; PAO2, partial pressure of alveolar oxygen; PiCO2, partial pressure of inspired carbon dioxide; PiO2, partial pressure of inspired oxygen; PpvCO2, partial pressure of carbon dioxide in portal venous blood; PpvO2, partial pressure of oxygen in portal venous blood; PvCO2, partial pressure of carbon dioxide in mixed venous blood; PvO2, partial pressure of oxygen in mixed venous blood.


Physiology_Levy

Physiology_Levy. An important feature of an anatomical shunt is that if an affected individual is given 100% O2 to breathe, the response is blunted severely. The blood that bypasses the gas-exchanging units is never exposed to the enriched O2, and thus it continues to be deoxygenated. The PO2 in the blood that is not being shunted increases and it mixes with the deoxygenated blood. Thus the degree of persistent hypoxemia in response to 100% O2 varies with the volume of the shunted blood. Normally, the hemoglobin in the blood that perfuses the ventilated alveoli is almost fully saturated. Therefore, most of the added O2 is in the form of dissolved O2 (see


Physiology_Levy

Physiology_Levy. The PaCO2 in an anatomical shunt is not usually increased even though the shunted blood has an elevated level of CO2. The reason for this is that the central chemoreceptors (see ) respond to any elevation in CO2 with an increase in ventilation and reduce PaCO2 to the normal range. If the hypoxemia is severe, the increased respiratory drive secondary to the hypoxemia increases the ventilation and can decrease PaCO2 to below the normal range. A physiological shunt (also known as venous admixture) can develop when ventilation to lung units is absent in the presence of continuing perfusion (


Physiology_Levy

Physiology_Levy. Fig. 23.10 ). In this situation, in the two–lung unit model, all the ventilation goes to the other lung unit, whereas perfusion is equally distributed between both lung units. The lung unit without ventilation but with perfusion has a V̇ /Q̇ ratio of 0. The blood perfusing this unit is mixed venous blood; because • Fig. 23.10 Schema of a Physiological Shunt (Venous Admixture). Notice the marked decrease in PaO2 in comparison to PCO2. The alveolar-arterial difference for oxygen (AaDO2) in this example is 85 mm Hg. PACO2, partial pressure of alveolar carbon dioxide; PAO2, partial pressure of alveolar oxygen; PiCO2, partial pressure of inspired carbon dioxide; PiO2, partial pressure of inspired oxygen; PpvCO2, partial pressure of carbon dioxide in portal venous blood; PpvO2, partial pressure of oxygen in portal venous blood; PvCO2, partial pressure of carbon dioxide in mixed venous blood; PvO2, partial pressure of oxygen in mixed venous blood.


Physiology_Levy

Physiology_Levy. there is no ventilation, no gas is exchanged in the unit, and the blood leaving this unit continues to resemble mixed venous blood. The effect of a physiological shunt on oxygenation is similar to the effect of an anatomical shunt; that is, deoxygenated blood bypasses a gas-exchanging unit and admixes with arterial blood. Clinically, atelectasis (which is obstruction to ventilation of a gas-exchanging unit with subsequent loss of volume) is an example of a situation in which the lung region has a V̇ /Q̇ of 0. Causes of atelectasis include mucous plugs, airway edema, foreign bodies, and tumors in the airway. Mismatching between ventilation and perfusion is the most frequent cause of arterial hypoxemia in individuals with respiratory disorders. In the most common example, the composition of mixed venous blood, total blood flow (cardiac output), and the distribution of blood flow are normal. However, when alveolar ventilation is distributed unevenly between the two gas-exchange units (


Physiology_Levy

Physiology_Levy. Fig. 23.11 ) and blood flow is equally distributed, the unit with decreased ventilation has a V̇ /Q̇ ratio of less than 1, whereas the unit with the increased ventilation has a V̇ /Q̇ of greater than 1. This causes the alveolar and end-capillary gas compositions to vary. Both the arterial O2 content and CO2 content are abnormal in the blood that has come from the unit with the decreased ventilation (V̇ /Q̇ , <1). The unit with the increased ventilation (V̇ /Q̇ , >1) has a lower CO2 content and a higher O2 content because it is being overventilated. The actual PaO2 and PaCO2 vary, depending on the relative contribution of each of these units to arterial blood. The alveolar-arterial O2 gradient (AaDO2) is increased because the relative overventilation of one unit does not fully


Physiology_Levy

Physiology_Levy. PlO2 = 150 PlCO2 = 0 PAO2 = 77 PACO2 = 45 PCO2= 45PO2= 77 PAO2 = 105 PACO2 = 36 PpvO2 = 89 PpvCO2 = 40.5 Pulmonary vein Pulmonary artery PvO2 = 40 PvCO2 = 46 – – Anatomic dead space • Fig. 23.11 Effects of Ventilation/Perfusion Mismatching on Gas Exchange. The decrease in ventilation to the one lung unit could be due to mucus obstruction, airway edema, bronchospasm, a foreign body, or a tumor. PACO2, partial pressure of alveolar carbon dioxide; PAO2, partial pressure of alveolar oxygen; PiCO2, partial pressure of inspired carbon dioxide; PiO2, partial pressure of inspired oxygen; PpvCO2, partial pressure of carbon dioxide in portal venous blood; PpvO2, partial pressure of oxygen in portal venous blood; PvCO2, partial pressure of carbon dioxide in mixed venous blood; PvO2, partial pressure of oxygen in mixed venous blood.


Physiology_Levy

Physiology_Levy. compensate (either by the addition of extra O2 or by the removal of extra CO2) for underventilation of the other unit. The failure to compensate is greater for O2 than for CO2, as indicated by the flatness of the upper part of the oxyhemoglobin dissociation curve, in contrast to the slope of the CO2 dissociation curve (see Chapter 24). In other words, increased ventilation increases PAO2, but it adds little extra O2 content to the blood because hemoglobin is close to being 100% saturated in the overventilated areas. This is not the case for CO2, for which the steeper slope of the CO2 curve indicates removal of more CO2 when ventilation increases. Thus inasmuch as CO2 moves by diffusion, then as long as a CO2 gradient is maintained, CO2 diffusion will occur.


Physiology_Levy

Physiology_Levy. The PAO2 is determined by a balance between the rate of O2 uptake and the rate of O2 replenishment by ventilation. Oxygen uptake depends on blood flow through the lung and the metabolic demands of the tissues. If ventilation decreases, PAO2 decreases, and PaO2 subsequently decreases. In addition, VA and PACO2 are directly but inversely related. When ventilation is halved, the PACO2 doubles and thus so does the PaCO2 (see Eq. 23.16 ). Ventilation insufficient to maintain normal levels of CO2 is called hypoventilation. Hypoventilation always decreases PaO2 and increases PaCO2. One of the hallmarks of hypoventilation is a normal AaDO2. Hypoventilation reduces PAO2, which in turn results in a decrease in PaO2. Because gas exchange is normal, the AaDO2 remains normal. Hypoventilation accompanies diseases associated with muscle weakness and is associated with drugs that reduce the respiratory drive. In the presence of hypoventilation, however, areas of atelectasis develop


Physiology_Levy

Physiology_Levy. Ventilation, Perfusion, and Ventilation/Perfusion Relationships rapidly; atelectasis creates regions with V̇ /Q̇ ratios of 0, and when this occurs, the AaDO2 rises.


Physiology_Levy

Physiology_Levy. Abnormalities in diffusion of O2 across the alveolar-capillary barrier could potentially result in arterial hypoxia. Equilibration between alveolar and capillary O2 and CO2 content occurs rapidly: in a fraction of the time that it takes for red blood cells to transit the pulmonary capillary network. Hence, diffusion equilibrium almost always occurs in normal people, even during exercise, when the transit time of red blood cells through the lung increases significantly. An increased AaDO2 attributable to incomplete diffusion (diffusion disequilibrium) has been observed in normal persons only during exercise at high altitude (≥10,000 feet). Even in individuals with an abnormal diffusion capacity, diffusion disequilibrium at rest is unusual but can occur during exercise and at altitude. Alveolar capillary block, or thickening of the air-blood barrier, is an uncommon cause of hypoxemia. Even when the alveolar wall is thickened, there is usually sufficient time for gas diffusion unless the


Physiology_Levy

Physiology_Levy. capillary block, or thickening of the air-blood barrier, is an uncommon cause of hypoxemia. Even when the alveolar wall is thickened, there is usually sufficient time for gas diffusion unless the red blood cell transit time is increased.


Physiology_Levy

Mechanisms of Hypercapnia

Physiology_Levy. Mechanisms of Hypercapnia


Physiology_Levy

Physiology_Levy. Two major mechanisms account for the development of hypercapnia (elevated PCO2): hypoventilation and wasted, or increased, dead space ventilation. As noted previously, alveolar ventilation and alveolar CO2 are inversely related. When ventilation is halved, PACO2 and PaCO2 double. Hypoventilation always decreases PaO2 and increases PaCO2 and thereby results in a hypoxemia that responds to an enriched source of O2. Dead space ventilation is wasted, or increased, when pulmonary blood flow is interrupted in the presence of normal ventilation. This is most often caused by a pulmonary embolus that obstructs blood flow. The embolus halts blood flow to pulmonary areas with normal ventilation (V̇ /Q̇ =∞). In this situation, the ventilation is wasted because it fails to oxygenate any of the mixed venous blood. The ventilation to the perfused regions of the lung is less than ideal (i.e., there is relative “hypoventilation” to this area because in this situation, it receives all the pulmonary


Physiology_Levy

Physiology_Levy. venous blood. The ventilation to the perfused regions of the lung is less than ideal (i.e., there is relative “hypoventilation” to this area because in this situation, it receives all the pulmonary blood flow with “normal” ventilation). If compensation does not occur, PaCO2 increases and PaO2 decreases. Compensation after a pulmonary embolus, however, begins almost immediately; local bronchoconstriction occurs, and the distribution of ventilation shifts to the areas being perfused. As a result, changes in arterial CO2 and O2 content are minimized.


Physiology_Levy

Physiology_Levy. Effect of 100% Oxygen on Arterial Blood Gas Abnormalities One of the ways that a right-to-left shunt can be distinguished from other causes of hypoxemia is for the individual to breathe 100% O2 through a non-rebreathing face mask for approximately 15 minutes. When the individual breathes 100% O2, all of the N2 in the alveolus is replaced by O2. Thus the PAO2, according to the alveolar air equation ( Eq. 23.13), is calculated as follows: Equation 23.20 PAO2 =[1 0. × (Pb − PH2O)]− PaCO2 0 8. =[1 0 × (760 4 . − 47)]− 40 08


Physiology_Levy

Physiology_Levy. In a normal lung, the PAO2 rapidly increases, and it provides the gradient for transfer of O2 into capillary blood. This is associated with a marked increase in PaO2 (see 23.2 ). Similarly, over the 15-minute period of breathing enriched with O2, even areas with very low V̇ /Q̇ ratios develop high alveolar O2 pressure as the N2 is replaced by O2. In the presence of normal perfusion to these areas, there is a gradient for gas exchange, and the end-capillary blood is highly enriched with O2. In contrast, in the presence of a right-to-left shunt, oxygenation is not corrected because mixed venous blood continues to flow through the shunt and mix with blood that has perfused normal units. The poorly oxygenated blood from the shunt lowers the arterial O2 content and maintains the AaDO2. An elevated AaDO2 during a properly conducted study with 100% O2 signifies the presence of a shunt (anatomical or physiological); the magnitude of the AaDO2 can be used to quantify the proportion of the


Physiology_Levy

Physiology_Levy. elevated AaDO2 during a properly conducted study with 100% O2 signifies the presence of a shunt (anatomical or physiological); the magnitude of the AaDO2 can be used to quantify the proportion of the cardiac output that is being shunted.


Physiology_Levy

Physiology_Levy. The regional differences in ventilation and perfusion and the relationship between ventilation and perfusion were discussed earlier in this chapter. The effects of various physiological abnormalities (e.g., shunt, V̇ /Q̇ mismatch, and hypoventilation) on arterial O2 and CO2 levels were also described. In addition, however, it should be noted that because the V̇ /Q̇ ratio varies in different regions of the lung, the end-capillary blood coming from these regions has different O2 and CO2 levels. These differences are shown in


Physiology_Levy

Physiology_Levy. Fig. 23.7 , and they demonstrate the complexity of the lung. First, recall that the volume of the lung at the apex is less than the volume at the base. As previously described, ventilation and perfusion are less at the apex than at the base, but the differences in perfusion are greater than the differences in ventilation. Thus the V̇ /Q̇ ratio is high at the apex and low at the base. This difference in ventilation/perfusion ratios is associated with a difference in alveolar O2 and CO2 content between the apex and the base. The PAO2 is higher and the PACO2 is lower in the apex than in the base. This results in differences in end-capillary contents for these gases. End-capillary PO2 is lower, and, as a consequence, the O2 content is lower in end-capillary blood at the lung base than at the apex. In addition, there is significant variation in blood pH in the end capillaries in these regions because of the variation in CO2 content. During exercise, blood flow to the apex increases and


Physiology_Levy

Physiology_Levy. apex. In addition, there is significant variation in blood pH in the end capillaries in these regions because of the variation in CO2 content. During exercise, blood flow to the apex increases and becomes more uniform in the lung; as a result, the difference between the content of gases in the apex and in the base of the lung diminishes with exercise.


Physiology_Levy

Physiology_Levy. 1. The volume of air in the conducting airways is called the anatomical dead space. Dead space ventilation varies inversely with tidal volume. The total volume of gas in each breath that does not participate in gas exchange is called the physiological dead space. It includes the anatomical dead space and the dead space secondary to ventilated but unperfused alveoli. 2. The sum of the partial pressures of a gas is equal to the total pressure. The partial pressure of a gas (Pgas) is equal to the fraction of the gas in the gas mixture (Fgas) multiplied by the total pressure (Ptotal). The conducting airways do not participate in gas exchange. Therefore, the partial pressures of O2, N2, and water vapor in humidified air remain unchanged in the airways until the gas reaches the alveolus. 3. The partial pressure of O2 in the alveolus is given by the alveolar air equation ( Eq. 23.13 ). This equation is used to calculate the AaDO2, a useful measurement of abnormal arterial O2. 4.


Physiology_Levy

Physiology_Levy. 3. The partial pressure of O2 in the alveolus is given by the alveolar air equation ( Eq. 23.13 ). This equation is used to calculate the AaDO2, a useful measurement of abnormal arterial O2. 4. The relationship between CO2 production and alveolar ventilation is defined by the alveolar carbon Eq. 23.14 ). There is an inverse relationship between the PACO2 and VA, regardless of the exhaled quantity of CO2. In normal lungs, PaCO2 is tightly regulated to remain constant at around 40 mm Hg.


Physiology_Levy

Physiology_Levy. Eq. 23.14 ). There is an inverse relationship between the PACO2 and VA, regardless of the exhaled quantity of CO2. In normal lungs, PaCO2 is tightly regulated to remain constant at around 40 mm Hg. 5. Because of the effects of gravity, there are regional differences in ventilation and perfusion. The ventilation/perfusion (V̇ /Q̇ ) ratio is defined as the ratio of ventilation to blood flow. In a normal lung, the overall ventilation/perfusion ratio is approximately 0.8. When ventilation exceeds perfusion, the ventilation/perfusion ratio is greater than 1 (V̇ /Q̇ > 1), and when perfusion exceeds ventilation, the ventilation/perfusion ratio is less than 1 (V̇ /Q̇ < 1). The V̇ /Q̇ ratio at the apex of the lung is high (ventilation is increased in relation to very little blood flow), whereas the V̇ /Q̇ ratio at the base of the lung is low. In individuals with normal lungs who are breathing room air, the AaDO2 is less than 15 mm Hg; the upper limit of normal is 25 mm Hg.


Physiology_Levy

Physiology_Levy. CHAPTER 23 Ventilation, Perfusion, and Ventilation/Perfusion Relationships 6. The pulmonary circulation is a low-pressure, low-resistance system. Recruitment of new capillaries and dilation of arterioles without an increase in pressure are unique features of the lung and allow for adjustments during stress, as in the case of exercise. Pulmonary vascular resistance is the change in pressure from the pulmonary artery (PPA) to the left atrium (PLA), divided by cardiac output (QT). This resistance is about 10 times less than in the systemic circulation. Leff AR, Schumacker PT. Respiratory Physiology: Basics and Applications. Philadelphia: WB Saunders; 1993. Lumb AB. Nunn’s Applied Respiratory Physiology. 8th ed. St. Louis: Elsevier; 2016. Mead J, Macklem PT, vol eds. American Physiological Society Handbook of Physiology: The Respiratory System. Vol. 3. Mechanics. Bethesda, MD: American Physiological Society; 1986. 7.


Physiology_Levy

Physiology_Levy. Mead J, Macklem PT, vol eds. American Physiological Society Handbook of Physiology: The Respiratory System. Vol. 3. Mechanics. Bethesda, MD: American Physiological Society; 1986. 7. There are four categories of hypoxia (hypoxic hypoxia, anemic hypoxia, diffusion hypoxia, and histotoxic hypoxia) and six mechanisms of hypoxic hypoxia and hypoxemia: anatomical shunt, physiological shunt, decreased FiO2, V̇ /Q̇ mismatching, diffusion abnormalities, and hypoventilation. 8. There are two mechanisms of the development of hypercapnia: increase in dead space ventilation and hypoventilation. Wasserman K, Beaver WL, Whipp BI. Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation. 1990;81(1 suppl):1114-1130. West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed. New York: Blackwell Scientific; 1991. Upon completion of this chapter, the student should be able to answer the following questions: 1.


Physiology_Levy

Physiology_Levy. West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed. New York: Blackwell Scientific; 1991. Upon completion of this chapter, the student should be able to answer the following questions: 1. Describe the basic gas diffusion principles and how they affect O2 and CO2 absorption and expiration. 2. Compare and contrast the chemical transport mechanisms of O2 and CO2 in blood. 3. Describe the basic principles and clinical significances of the O2 and CO2 dissociation curves. 4. Describe the chemical synthesis of H+ ions and their role in the regulation of acid-base balance. 5. Explain why the diffusion of O2 and that of CO2 are considered perfusion limited and that of CO is considered diffusion limited. 6. Compare and contrast factors that shift the oxyhemoglobin dissociation curve. 7. Explain the clinical significance of the differences in the oxyhemoglobin and carboxyhemoglobin dissociation curves. 8.


Physiology_Levy

Physiology_Levy. 7. Explain the clinical significance of the differences in the oxyhemoglobin and carboxyhemoglobin dissociation curves. 8. Compare and contrast the chloride shift and the Haldane effect on CO2 transport.


Physiology_Levy

Physiology_Levy. 8. Compare and contrast the chloride shift and the Haldane effect on CO2 transport. he respiratory and circulatory systems function together to transport oxygen (O2) from the lungs to the tissues to sustain normal cellular activity and to transport carbon dioxide (CO2) from the tissues to the lungs for expiration. CO2, a product of active cellular metabolism, is transported from the tissues via systemic veins to the lungs, where it is expired (Fig. 24.1 ). To enhance uptake and transport of these gases between the lungs and tissues, specialized mechanisms (e.g., binding of O2 and hemoglobin and HCO3 − transport of CO2) have evolved that enable O2 uptake and CO2 expiration to occur simultaneously. Moreover, these specialized mechanisms facilitate uptake of O2 and expiration of CO2. To understand the mechanisms involved in the transport of these gases, gas diffusion properties, as well as transport and delivery mechanisms, must be considered.


Physiology_Levy

Physiology_Levy. Gas movement throughout the respiratory system occurs predominantly via diffusion. The respiratory and circulatory systems contain several unique anatomical and physiological features to facilitate gas diffusion: (1) large surface areas for gas exchange (alveolar to capillary and capillary to tissue membrane) with short distances to travel, (2) substantial partial pressure gradient differences, and (3) gases with advantageous diffusion properties. Transport and delivery of O2 from the lungs to the tissue and vice versa for CO2 are dependent on basic gas diffusion laws. Diffusion of Gases From Regions of Higher to Lower Partial Pressure in the Lungs


Physiology_Levy

Physiology_Levy. Diffusion of Gases From Regions of Higher to Lower Partial Pressure in the Lungs The process of gas diffusion is passive and similar whether diffusion occurs in a gaseous or liquid state. The rate of diffusion of a gas through a liquid is described by Graham’s law, which states that the rate is directly proportional to the solubility coefficient of the gas and inversely proportional to the square root of its molecular weight. Calculation of the diffusion properties for O2 and CO2 reveals that CO2 diffuses approximately 20 times faster than O2. Rates of O2 diffusion from the lungs into blood and from blood into tissue, and vice versa for CO2, are predicted by Fick’s law of gas diffusion ( Fig. 24.2). The ratio AD:T represents the con ductance of a gas from the alveolus to blood. The diffusing capacity of the lung (DL) is its conductance (A•D/T) when considered for the entire lung; thus, with Fick’s equation, DL can be calculated as follows:


Physiology_Levy

Physiology_Levy. Equation 24.1 where V̇ gas = gas diffusion. Fick’s law of diffusion could be used to assess the diffusion properties of O2 in the lungs, except that the capillary partial pressure of oxygen cannot be measured. This limitation can be overcome with the use of carbon monoxide (CO) rather than O2. Because CO has low solubility in the capillary membrane, the rate of CO equilibrium across the capillary is slow, and the partial pressure of CO in capillary blood remains close to 0. In contrast, the solubility of CO in blood is high. Thus the only limitation for diffusion of CO is the alveolar-capillary membrane, and thus CO is a •Fig. 24.1 Oxygen (O2) and Carbon Dioxide (CO2) Transport in Arterial and Venous Blood. Oxygeninarterialbloodistransferredfromarterialcapillariestotissues.TheflowratesforO2andCO2areshownfor1Lofblood.


Physiology_Levy

Physiology_Levy. •Fig. 24.2 AccordingtoFick’slaw,diffusionofagasacrossasheetoftissue(Vgas)isdirectlyrelatedtothesurfacearea(A)ofthetissue, thediffusionconstant(D)ofthespecificgas,andthepartialpressuredifference(P1− P2)ofthegasoneachsideofthetissue,anditisinverselyrelatedtotissuethickness(T). useful gas for calculating DL. The capillary partial pressure (P2 in Eq. 24.1 ) is essentially 0 for CO, and therefore DL can be measured from the diffusion of carbon monoxide (V̇ CO) and the average partial pressure of CO in the alveolus; that is, Equation 24.2 where DLCO = diffusion capacity of the lung for carbon monoxide. Assessment of DLCO has become a classic measurement of the diffusion barrier of the alveolar-capillary membrane. It is useful in the differential diagnosis of certain obstructive lung diseases, such as emphysema.


Physiology_Levy

Physiology_Levy. Apatientwithinterstitialpulmonaryfibrosis(arestrictivelungdisease)inhalesasinglebreathof0.3%COfromresidualvolumetototallungcapacity.Heholdshisbreathfor10secondsandthenexhales.Afterdiscardingtheexhaledgasfromthedeadspace,arepresentativesampleofalveolargasfromlateinexhalationiscollected.TheaveragealveolarCOpressureis0.1mmHg,and0.25mLofCOhasbeentakenup.ThediffusioncapacityforCOinthispatientis . mL/10 seconds × 0 1. mm Hg = 15 mL/minute/mm Hg ThenormalrangeforDLCOis20to30mL/minute/mmHg.Patientswithinterstitialpulmonaryfibrosishaveaninitialalveolarinflammatoryresponsewithsubsequentscarformationwithintheinterstitialspace.Theinflammationandscarreplacethealveolianddecreasethesurfaceareaforgasdiffusiontooccur,whichresultsindecreasedDLCO.Thisisaclassiccharacteristicofcertaintypesofrestrictivelungdisease. Oxygen and Carbon Dioxide Exchange in the Lung Is Perfusion Limited


Physiology_Levy

Physiology_Levy. Different gases have different solubility factors. Gases that are insoluble in blood (i.e., anesthetic gases such as nitrous oxide and ether) do not chemically combine with proteins in blood and equilibrate rapidly between alveolar gas and blood. The equilibration occurs in less time than the 0.75 seconds that the red blood cell spends in the capillary bed (capillary transit time). The diffusion of insoluble gases between alveolar gas and blood is considered perfusion limited because the partial pressure of gas in the blood leaving the capillary has reached equilibrium with alveolar gas and is limited only by the amount of blood perfusing the alveolus. In contrast, a gas that is diffusion limited, such as CO, has low solubility in the alveolar-capillary membrane but high solubility in blood because of its high affinity for hemoglobin (Hgb). These features prevent the equilibration of CO between alveolar gas and blood during the red blood cell transit time.


Physiology_Levy

Physiology_Levy. The high affinity of CO for Hgb enables large amounts of CO to be taken up in blood with little or no appreciable increase in its partial pressure. Gases that are chemically bound to Hgb do not exert a partial pressure in blood. Like CO, both CO2 and O2 have relatively low solubility in the alveolar-capillary membrane but high solubility in blood because of their ability to bind to Hgb. However, their rate of equilibration is sufficiently rapid for complete equilibration to occur during the transit time of the red blood cell within the capillary. Equilibration for O2 and CO2 usually occurs within 0.25 seconds. Thus O2 and CO2 transfer is normally perfusion limited. The partial pressure of a gas that is diffusion limited (i.e., CO) does not reach equilibrium with the alveolar pressure over the time that it spends in the capillary (


Physiology_Levy

Physiology_Levy. Fig. 24.3 ). Although CO2 has a greater rate of diffusion in blood than O2 does, it has a lower membrane-blood solubility ratio and consequently takes approximately the same amount of time to reach equilibration in blood. Start of End of 0 .25 .50 .75 Time in capillary (sec) •Fig. 24.3 Uptake of Nitrous Oxide (N2O), Carbon Monoxide (CO), and O2in Blood in Relation to Their Partial Pressures and the Transit Time of the Red Blood Cell in the Capillary. Forgasesthatareperfusionlimited(N2OandO2),theirpartialpressureshaveequilibratedwithalveolarpressurebeforeexitingthecapillary.Incontrast,thepartialpressureofCO,agasthatisdiffusionlimited,doesnotreachequilibriumwithalveolarpressure.Inrareconditions,O2uptakecanbecomediffusionlimited. Diffusion limitation for O2 and CO2 would occur if red blood cells spent less than 0.25 seconds in the capillary bed. This is occasionally the case in very fit athletes during vigorous exercise and in healthy subjects who exercise at high altitude.


Physiology_Levy

Physiology_Levy. Oxygen is carried in blood in two forms: dissolved O2 and O2 bound to Hgb. The dissolved form is measured clinically in an arterial blood gas sample as the partial pressure of arterial oxygen (PaO2). Only a small percentage of O2 in blood is in the dissolved form, and its contribution to O2 transport under normal conditions is almost negligible. However, dissolved O2 can become a significant factor in conditions of severe hypoxemia. Binding of O2 to Hgb to form oxyhemoglobin within red blood cells is the primary transport mechanism of O2. Hgb not bound to O2 is referred to as deoxyhemoglobin or reduced Hgb. The O2-carrying capacity of blood is enhanced about 65 times by its ability to bind to Hgb.


Physiology_Levy

Physiology_Levy. Hgb is the major transport molecule for O2. The Hgb molecule is a protein with two major components: four nonprotein heme groups, each containing iron in the reduced ferric (Fe+++) form, which is the site of O2 binding, and a globin portion consisting of four polypeptide chains. Normal adults have two α-globin chains and two β-globin chains (HgbA), whereas children younger than 6 months of age have predominantly fetal Hgb (HgbF), which consists of two α chains and two γ chains. This difference in the structure of HgbF increases its affinity for O2 and aids in the transport of O2 across the placenta. In addition, HgbF is not inhibited by 2,3-diphosphoglycerate (2,3DPG), a product of glycolysis; thus O2 uptake is further enhanced.


Physiology_Levy

Physiology_Levy. Binding of O2 to Hgb alters the ability of Hgb to absorb light. This effect of O2 on Hgb is responsible for the change in color between oxygenated arterial blood (bright red) and deoxygenated venous blood (dark red-bluish). Binding and dissociation of O2 with Hgb occur in milliseconds, thus facilitating O2 transport because red blood cells spend only 0.75 seconds in the capillaries. There are approximately 280 million Hgb molecules per red blood cell, which provides an efficient mechanism to transport O2. Myoglobin, a protein similar in structure and function to Hgb, has only one subunit of the Hgb molecule. It aids in the transfer of O2 from blood to muscle cells and in the storage of O2, which is especially critical in O2-deprived conditions.


Physiology_Levy

Physiology_Levy. Abnormalities of the Hgb molecule occur with mutations in the amino acid sequence (i.e., sickle cell disease) or in the spatial arrangement of the globin polypeptide chains and result in abnormal function. Compounds such as CO, nitrites (nitric oxide), and cyanides can oxidize the •Fig. 24.4 Oxyhemoglobin Dissociation Curve Showing the Relationship Between the Partial Pressure of Oxygen (Po2) in Blood and the Percentage of Hemoglobin (Hgb) Binding Sites That Are Occupied by Oxygen Molecules (Percentage Saturation). Adulthemoglobin(HgbA)isabout50%saturatedwithoxygenataPO2of27mmHg,90%saturatedat60mmHg,andabout98%saturatedat100mmHg.TheP50isthepartialpressureatwhichHgbis50%saturatedwithO2.WhentheO2dissociationcurveshiftstotheright,P50increases.Whenthecurveshiftstotheleft,P50decreases. iron molecule in the heme group and change it from the reduced ferrous state (Fe++) to the ferric state (Fe+++), which reduces the ability of O2 to bind to Hgb.


Physiology_Levy

Physiology_Levy. iron molecule in the heme group and change it from the reduced ferrous state (Fe++) to the ferric state (Fe+++), which reduces the ability of O2 to bind to Hgb. In the alveoli, the majority of O2 in plasma quickly diffuses into red blood cells and chemically binds to Hgb. This process is reversible, so that Hgb quickly gives up its O2 to tissue through passive diffusion (the concentration of O2 in Hgb decreases). The oxyhemoglobin dissociation curve illustrates the relationship between PO2 in blood and the number of O2 molecules bound to


Physiology_Levy

Physiology_Levy. Hgb (Fig. 24.4 ). The S shape of the curve demonstrates the dependence of Hgb saturation on PO2, especially at partial pressures lower than 60 mm Hg. The clinical significance of the flat portion of the oxyhemoglobin dissociation curve (>60 mm Hg) is that a drop in PO2 over a wide range of partial pressures (100 to 60 mm Hg) has a minimal effect on Hgb saturation, which remains at 90% to 100%, a level sufficient for normal O2 transport and delivery. The clinical significance of the steep portion (<60 mm Hg) of the curve is that a large amount of O2 is released from Hgb with only a small change in PO2, which facilitates the release and diffusion of O2 into tissue. The point on the curve at which Hgb is 50% saturated with O2 is called the P50, and it is 27 mm Hg in normal adults.


Physiology_Levy

Physiology_Levy. ˜˜˜˜°°°°Temperature PCO2 2,3-DPG pH Decreased P50 (increased affinity) Temperature PCO2 2,3-DPG pH Increased P50 (decreased affinity) •Fig. 24.5 Factorsthatshifttheoxyhemoglobindissociationcurvetotheright(decreasedaffinityofHgbforO2)ortotheleft(increasedaffinity).2,3-DPG,2,3-diphosphoglycerate;PCO2,partialpressureofcarbondioxide. Physiological Factors That Shift the Oxyhemoglobin Dissociation Curve The oxyhemoglobin dissociation curve can shift in numerous clinical conditions, either to the right or to the left ( Fig. 24.5 ). The curve is shifted to the right when the affinity of


Physiology_Levy


Physiology_Levy

Physiology_Levy. Hgb for O2 decreases, which enhances O2 dissociation. This results in decreased Hgb binding to O2 at a given PO2, which causes the P50 to increase. When the affinity of Hgb for O2 increases, the curve is shifted to the left, which causes the P50 to decrease. In this state, O2 dissociation and delivery to tissue are inhibited. Shifts to the right or left of the dissociation curve have little effect when they occur at O2 partial pressures within the normal range (80 to 100 mm Hg). However, at O2 partial pressures below 60 mm Hg (steep part of the curve), shifts in the oxyhemoglobin dissociation curve can dramatically influence O2 transport.


Physiology_Levy

Physiology_Levy. Changes in blood hydrogen ion concentration (pH) shift the oxyhemoglobin dissociation curve. An increase in CO2 production by tissue and its release into blood results in the generation of hydrogen ions (H+) and a decrease in pH. This shifts the dissociation curve to the right, which has a beneficial effect by aiding in the release of O2 from Hgb for diffusion into tissues. The shift to the right in the dissociation curve is due to the decrease in pH and to a direct effect of CO2 on Hgb. Conversely, as blood passes through the lungs, CO2 is exhaled, which results in an increase in pH, which in turn causes the oxyhemoglobin dissociation curve to shift to the left. This effect of CO2 on the affinity of Hgb for O2 is known as the Bohr effect, and it serves to enhance O2 uptake in the lungs and delivery of O2 to tissues. An increase in body temperature, as occurs during exercise, shifts the oxyhemoglobin dissociation curve to the right and enables more O2 to be released to tissues, where


Physiology_Levy

Physiology_Levy. delivery of O2 to tissues. An increase in body temperature, as occurs during exercise, shifts the oxyhemoglobin dissociation curve to the right and enables more O2 to be released to tissues, where it is needed because the demand increases. During cold weather, a decrease in body temperature, especially in the extremities (lips, fingers, toes, and ears), shifts the O2 dissociation curve to the left (higher Hgb affinity). In this instance, PaO2 may be normal, but release of O2 in these extremities is not facilitated.


Physiology_Levy

Physiology_Levy. 2,3-Diphosphoglycerate Mature red blood cells do not have mitochondria, and therefore they depend on anaerobic glycolysis. Large quantities of a metabolic intermediary, 2,3-DPG, are formed in red blood cells during glycolysis, and the affinity of Hgb for O2 decreases as 2,3-DPG levels increase. Thus the oxyhemoglobin dissociation curve shifts to the right. Although the binding sites of 2,3-DPG and O2 differ on the Hgb molecule, binding of 2,3-DPG creates an allosteric effect that inhibits the binding of O2. Conditions that increase 2,3-DPG include hypoxia, decreased Hgb, and increased pH. Decreased levels of 2,3-DPG are observed in stored blood samples and thus may present a problem to transfusion recipients because of the greater affinity of Hgb for O2, which inhibits the unloading of O2 to tissues. As discussed previously, HgbF has a greater affinity for O2 than does adult Hgb, and the oxyhemoglobin dissociation curve thus shifts to the left.


Physiology_Levy

Physiology_Levy. As discussed previously, HgbF has a greater affinity for O2 than does adult Hgb, and the oxyhemoglobin dissociation curve thus shifts to the left. •Fig. 24.6 Theoxyhemoglobinandcarboxyhemoglobindissociationcurvesclearlyillustratetheincreasedaffinitythatcarbonmonoxide(CO)hasforHgb,incomparisonwithO2.100 80 60 40 20 0 0 20 40 60 PO2 (mm Hg) Hemoglobin saturation (%) 80 100 O2 + hemoglobin CO + hemoglobin CO binds to the heme group of the Hgb molecule at the same site as O2 and forms carboxyhemoglobin (HgbCO). A major difference between the ability of CO and that of O2 to bind to Hgb is illustrated by a comparison of the oxyhemoglobin and carboxyhemoglobin dissociation curves. The affinity of CO for Hgb is about 200 times greater than it is for O2 (


Physiology_Levy

Physiology_Levy. Fig. 24.6 ). Thus small amounts of CO can greatly influence the binding of O2 to Hgb. In the presence of CO, the affinity of Hgb for O2 is enhanced. This causes the dissociation curve to shift to the left, which further prevents the unloading and delivery of O2 to tissues. As the PCO of blood approaches 1.0 mm Hg, all of the Hgb binding sites are occupied by CO, and Hgb is unable to bind to O2. This situation is not compatible with life and is the cause of death in cases of CO poisoning. In healthy individuals, HgbCO occupies about 1% to 2% of the Hgb binding sites; however, in cigarette smokers and in individuals who reside in high-density urban traffic areas, occupation of Hgb binding sites can be increased to 10%. Levels above 5% to 7% are considered hazardous. Treatment of individuals with high levels of CO, such as those who have inhaled car exhaust or smoke from a burning building, consists of administering high concentrations of O2 to displace CO from Hgb. Increasing the


Physiology_Levy

Physiology_Levy. with high levels of CO, such as those who have inhaled car exhaust or smoke from a burning building, consists of administering high concentrations of O2 to displace CO from Hgb. Increasing the ambient pressure above atmospheric pressure, through the use of a barometric chamber, substantially increases the O2 tension, which promotes the dissociation of CO from Hgb. Another gas, nitric oxide, has great affinity (200,000 times greater than O2) for Hgb, and it binds irreversibly to Hgb at the same site that O2 does. Endothelial cells synthesize nitric oxide, which has vasodilation properties. Thus nitric oxide is used therapeutically as an inhalant in patients with pulmonary hypertension to reduce pressure. Although nitric oxide poisoning is not common, the clinician should be cautious when administering nitric oxide therapy for long periods. Hgb-bound CO and nitric oxide is referred to as methemoglobin. Under normal conditions, about 1% to 2% of Hgb is bound to CO and nitric oxide.


Physiology_Levy

Physiology_Levy. Oxygen Saturation, Content, and Delivery Each Hgb molecule can bind up to four O2 atoms, and each gram of Hgb can bind up to 1.34 mL of O2. The term O2 saturation (SO2) refers to the amount of O2 bound to Hgb in relation to the maximal amount of O2 (100% O2 capacity) that can bind Hgb. At 100% O2 capacity, the heme groups of the Hgb molecules are fully saturated with O2, and at 75% O2 capacity, three of the four heme groups are occupied. Binding of O2 to each heme group increases the affinity of the Hgb molecule to bind additional O2. The O2 content in blood is the sum of the O2 bound to Hgb and the dissolved O2. Oxygen content is decreased in the presence of increased CO2 and CO and in individuals with anemia ( Fig. 24.7


Physiology_Levy

Physiology_Levy. Fig. 24.7 Oxygen delivery from the lungs to tissues is dependent on several factors, including cardiac output, the Hgb content of blood, and the ability of the lung to oxygenate the blood. Not all of the O2 carried in blood is unloaded at the tissue level. The actual O2 extracted from blood by the tissue is the difference between the arterial O2 content and the venous O2 content, multiplied by cardiac output. Under normal conditions, Hgb leaves the tissue 75% saturated with O2, and only about 25% is actually used by tissues. Hypothermia, relaxation of skeletal muscles, and an increase in cardiac output reduce O2 extraction. Conversely, a decrease in cardiac output, anemia, hyperthermia, and exercise increase O2 extraction.


Physiology_Levy

Physiology_Levy. Tissue hypoxia is a condition in which O2 available to cells is insufficient for maintaining adequate aerobic metabolism. Thus anaerobic metabolism is stimulated and results in the increases in levels of lactate and H+ and the subsequent formation of lactic acid. The net result can lead to a significant decrease in blood pH. In cases of severe hypoxia, the extremities, toes, and fingertips may appear blue-gray (cyanotic) because of lack of O2 and increased deoxyhemoglobin levels. There are four major types of tissue hypoxia (hypoxic hypoxia, circulatory hypoxia, anemic hypoxia, histotoxic hypoxia), discussed in detail in Chapter 23.


Physiology_Levy

Physiology_Levy. Chapter 23. Tissue oxygenation depends on the concentration of Hgb and thus on the number of red blood cells available in the circulation. Red blood cell production (erythropoiesis) in the bone marrow is controlled by the hormone erythropoietin, which is synthesized in the kidneys by cortical interstitial cells. Although Hgb levels are normally very stable, decreased O2 delivery, low Hgb concentration, and low PaO2 stimulate the secretion of erythropoietin. This increases the production of red blood cells. Chronic renal disease damages the cortical interstitial cells and thereby suppresses their ability to synthesize erythropoietin. This causes anemia, along with decreased Hgb because of the lack of erythropoietin. Erythropoietin replacement therapy using epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) effectively increases red blood cell production.


Physiology_Levy

Physiology_Levy. CO2 is produced at a rate of approximately 200 mL/minute under healthy conditions, and typically, 80 molecules of CO2 are expired by the lung for every 100 molecules of O2 that enter the capillary bed. The ratio of expired CO2 to O2 uptake is referred to as the respiratory exchange ratio and, under normal conditions, is 0.8 (80 molecules of CO2 to 100 molecules of O2). This ratio is similar at the tissue to blood compartment, where it is referred to as the respiratory quotient. The body has enhanced storage capabilities for CO2, in comparison with O2, and hence PaO2 is much more sensitive to changes in ventilation than is PaCO2. Whereas PaO2 is dependent on several factors, in addition to alveolar ventilation, arterial PaCO2 is solely dependent on alveolar ventilation and CO2 production. There is an inverse relationship between alveolar ventilation and PaCO2. In blood, CO2 is transported in red blood cells primarily as bicarbonate (HCO3 −) but also as dissolved CO2 and as


Physiology_Levy

Physiology_Levy. In blood, CO2 is transported in red blood cells primarily as bicarbonate (HCO3 −) but also as dissolved CO2 and as H2CO3 = PCO2 ˜ 0.0301 •Fig. 24.8 Mechanisms of CO2Transport in Blood. v. ThepredominantmechanismbywhichCO2istransportedfromtissuecellstothelungisintheformofbicarbonateanion(HCO3−).H2CO3,carbonicacid;HgbO,oxyhemoglobin;NaHCO3,sodiumbicarbonate;RBC,redbloodcell. carbamino protein complexes (i.e., CO2 binds to plasma proteins and to Hgb; Fig. 24.8 ). Once CO2 diffuses through the tissue and enters plasma, it quickly dissolves. The reaction of CO2 with H2O to form carbonic acid (H2CO3) is the major mechanism for the generation of HCO3 − in red blood cells: Equation 24.3


Physiology_Levy

Physiology_Levy. Equation 24.3 The reaction normally proceeds quite slowly; however, it is catalyzed within red blood cells by the enzyme carbonic anhydrase. The HCO3 − diffuses out of the red blood cell in exchange for Cl−, in a process known as the chloride shift, which helps the cell maintain its osmotic equilibrium. This chemical reaction (see Fig. 24.8 ) is reversible and can be shifted to the right to generate more HCO3 − in response to more CO2 entering the blood from tissues, or it can be shifted to the left as CO2 is exhaled in the lungs, which reduces HCO3 − levels. The free H+ is quickly buffered within the red blood cell by binding to Hgb. Buffering of H+ is critical for keeping the reaction moving toward the synthesis of HCO3; high levels of free H+ (low pH) cause the reaction to shift to the left. Regulation of Hydrogen Ion Concentration and Acid-Base Balance


Physiology_Levy

Physiology_Levy. Regulation of Hydrogen Ion Concentration and Acid-Base Balance The H+ concentration (pH) has a dramatic effect on many metabolic processes within cells, and regulation of pH is essential for normal homeostasis. In the clinical setting, blood pH is measured to assess the concentration of H+ . The normal pH range for adults is 7.35 to 7.45 and is maintained by the lungs, kidneys, and chemical buffer systems. In the respiratory system, conversion of CO2 to HCO3 − , illustrated as follows, is a major mechanism of buffering and regulating the H+ concentration (pH): Equation 24.4 As PACO2 changes, so does the concentration of HCO3 − and H2CO3, as well as PaCO2. The Henderson-Hasselbalch equation is used to calculate how changes in CO2 and HCO3 − affect pH: Equation 24.5 where α= solubility. Thus Equation 24.6 log[HCO3 − ]pH = 6 1. + 0 03 × PCO2


Physiology_Levy

Physiology_Levy. Equation 24.5 where α= solubility. Thus Equation 24.6 log[HCO3 − ]pH = 6 1. + 0 03 × PCO2 In these equations, the amount of CO2 is determined from the PCO2 and its solubility (α) in solution. For plasma at 37°C, α has a value of 0.03. Also, pK′ is the negative logarithm of the overall dissociation constant for the reaction and has a logarithmic value of 6.1 for plasma at 37°C. Acute hyperventilation secondary to exercise or anxiety reduces PCO2 and thereby causes an increase in pH (respiratory alkalosis). Conversely, if PCO2 increases because of hypoventilation secondary to an overdose of a respiratory depressant, the pH decreases (respiratory acidosis). Acid-base imbalances are also caused by metabolic disorders such as metabolic acidosis (e.g., lactic acidosis, ketoacidosis, and renal failure) and metabolic alkalosis (e.g., hypokalemia, hypochloremia, vomiting, high doses of steroids).


Physiology_Levy

Physiology_Levy. In contrast to O2, the dissociation curve for CO2 in blood is linear and directly related to PCO2 ( Fig. 24.9). The degree of Hgb saturation with O2 has a major effect on the CO2 dissociation curve. Although O2 and CO2 bind to Hgb 1. Gases (nitrous oxide, ether, helium) that have a rapid rate of air-to-blood equilibration are perfusion limited. Gases (CO) that have a slow air-to-blood equilibration rate are diffusion limited. Under normal conditions, O2 and CO2 exchange are perfusion limited but can be diffusion limited in some situations. 2. The major transport mechanism of O2 in blood is within the red blood cell bound to Hgb, and for CO2, it is within red blood cells in the form of HCO3 − . 3. The reversible reaction of CO2 with H2O to form H2CO3, with its subsequent dissociation to HCO3 − and H+ , is catalyzed by the enzyme carbonic anhydrase within red blood cells and is the major mechanism for generation of HCO3 − . 4.


Physiology_Levy

Physiology_Levy. 4. The O2 dissociation curve is S shaped. In the plateau area (>60 mm Hg), increasing or decreasing PO2 has only a minimal effect on Hgb saturation from 100% •Fig. 24.9 Equilibrium Curves for CO2in Arterial and Venous Blood. VenousbloodcantransportmoreCO2thanarterialbloodcanatanygivenPCO2.IncomparisonwiththeHgbO2equilibriumcurve,theCO2curvesareessentiallystraightlinesbetweenaPCO2of20andaPCO2of80mmHg.Long dashes representthearterialequilibriumcurve;short dashes representthevenousequilibriumcurve.


Physiology_Levy

Physiology_Levy. at different sites, deoxygenated Hgb has greater affinity for CO2 than oxygenated Hgb. Thus deoxygenated blood (venous blood) freely takes up and transports more CO2 than oxygenated arterial blood does. The deoxygenated Hgb more readily forms carbamino compounds and also more readily binds free H+ released during the formation of HCO3 − . The effect of changes in oxyhemoglobin saturation on the relationship of CO2 content to PCO2 is referred to as the Haldane effect and is reversed in the lungs when O2 is transported from the alveoli to red blood cells. This effect is illustrated by a shift to the left in the CO2 dissociation curve in venous blood in comparison with arterial blood. to 90%. This ensures adequate Hgb saturation over a large range of PO2 values. 5. The CO2 dissociation curve is linear and directly related to PCO2. PCO2 is solely dependent on alveolar ventilation and CO2 production. 6.


Physiology_Levy

Physiology_Levy. 5. The CO2 dissociation curve is linear and directly related to PCO2. PCO2 is solely dependent on alveolar ventilation and CO2 production. 6. The CO2 to HCO3 − pathway plays a critical role in the regulation of H+ ions and in maintaining acid-base balance in the body. 7. Tissue oxygenation is dependent on Hgb within red blood cells and subsequently the number (and production) of red blood cells, which is controlled by the hormone erythropoietin. Low O2 delivery, low Hgb concentration, and low PaO2 stimulate the secretion of erythropoietin in the kidneys. 8. Tissue hypoxia occurs when insufficient amounts of O2 are supplied to the tissue to conduct normal levels of aerobic metabolism. Butler JP, Tsuda A. Transport of gases between the environment and alveoli—theoretical foundations. Compr Physiol. 2011;1: 1301-1316. Calverley PMA, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J. 2005;25:186-199.


Physiology_Levy

Physiology_Levy. Calverley PMA, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J. 2005;25:186-199. Hillman SS, Hancock TV, Hedrick MS. A comparative meta-analysis of maximal aerobic metabolism of vertebrates: implications for respiratory and cardiovascular limits to gas exchange. J Comp Physiol [B]. 2013;183:167-179. Hughes JM. Assessing gas exchange. Chron Respir Dis. 2007;4:205-214. Petersson J, Glenny RW. Gas exchange and ventilation-perfusion relationships in the lung. Eur Respir J. 2014;44:1023-1041. Sheel AW, Romer LM. Ventilation and respiratory mechanics. Compr Physiol. 2012;2:1093-1142. Stickland MK, Lindinger MI, Olfert IM, et al. Pulmonary gas exchange and acid-base balance during exercise. Compr Physiol. 2013;3:693-739. Whipp BJ. Physiological mechanisms dissociating pulmonary CO2 and O2 exchange dynamics during exercise in humans. Exp Physiol. 2007;92:347-355.


Physiology_Levy

Physiology_Levy. Whipp BJ. Physiological mechanisms dissociating pulmonary CO2 and O2 exchange dynamics during exercise in humans. Exp Physiol. 2007;92:347-355. Upon completion of this chapter, the student should be able to answer the following questions: 1. Describe the central organization of breathing. 2. Explain the role of central and peripheral chemoreceptors in regulating respiration. 3. Compare and contrast the roles of chemoreceptors and pulmonary mechanoreceptors in regulating respiration. 4. Describe ventilatory control during special circumstances (e.g., exercise and high altitude). 5. Describe the effects of abnormalities in ventilatory control.


Physiology_Levy

Physiology_Levy. eople breathe without thinking, and they can willingly modify their breathing pattern and even hold their breath. Control of ventilation includes the generation and regulation of rhythmic breathing by the respiratory center in the brainstem and its modification by the input of information from higher brain centers and from systemic receptors. The goals of breathing are, from a mechanical perspective, to minimize work and, from a physiological perspective, to maintain and regulate positive pressures of arterial blood O2 (PaO2) and CO2 (PaCO2). Another goal of breathing is to maintain acid-base balance in the brain by regulating PaCO2. Automatic respiration begins at birth. In utero, the placenta, not the lung, is the organ of gas exchange in the fetus. Its microvilli interdigitate with the maternal uterine circulation, and PaO2 transport and PaCO2 removal from the fetus occur by passive diffusion across the maternal circulation. Ventilatory Control: An Overview


Physiology_Levy

Physiology_Levy. Ventilatory Control: An Overview There are four major sites of ventilatory control: (1) the respiratory control center, (2) central chemoreceptors, (3) peripheral chemoreceptors, and (4) pulmonary mechanoreceptors/sensory nerves. The respiratory control center is located in the medulla oblongata of the brainstem and is composed of multiple nuclei that generate and modify the basic ventilatory rhythm. This center consists of two main parts: (1) a ventilatory pattern generator, which sets the rhythmic pattern, and (2) an integrator, which controls generation of the pattern, processes input from higher brain centers and chemoreceptors, and controls the rate and amplitude of the ventilatory pattern. Input to the integrator arises from higher brain centers, including the cerebral cortex, hypothalamus, limbic system including the amygdalae, and cerebellum.


Physiology_Levy

Physiology_Levy. Central chemoreceptors are located in the central nervous system just below the ventrolateral surface of the medulla. These central chemoreceptors detect changes in the PaCO2 and pH of interstitial fluid in the brainstem, and they modulate ventilation. Peripheral chemoreceptors are located on specialized cells in the aortic arch (aortic bodies) and at the bifurcation of the internal and external carotid arteries (carotid bodies) in the neck. These peripheral chemoreceptors sense the PaO2, PaCO2, and pH of arterial blood, and they feed information back to the integrator nuclei in the medulla through the vagus nerves and carotid sinus nerves, which are branches of the glossopharyngeal nerves. Pulmonary mechanoreceptors and sensory nerve stimulation, in response to lung inflation or to stimulation by irritants or release of local mediators in the airways, modify the ventilatory pattern.


Physiology_Levy

Physiology_Levy. The collective output of the respiratory control center to motor neurons located in the anterior horn of the spinal column controls the muscles of respiration, and this output determines the automatic rhythmic pattern of respiration. Motor neurons located in the cervical region of the spinal column control the activity of the diaphragm through the phrenic nerves, whereas other motor neurons located in the thoracic region of the spine control the intercostal muscles and the accessory muscles of respiration.


Physiology_Levy

Physiology_Levy. In contrast to automatic respiration, voluntary respiration bypasses the respiratory control center in the medulla. The neural activity controlling voluntary respiration originates in the motor cortex, and signaling passes directly to motor neurons in the spine through the corticospinal tracts. The motor neurons to the respiratory muscles act as the final site of integration of the voluntary (corticospinal tract) and automatic (ventrolateral tracts) control of ventilation. Voluntary control of these muscles competes with automatic influences at the level of the spinal motor neurons, and this competition can be demonstrated by breath holding. At the start of the breath hold, voluntary control dominates the spinal motor neurons. However, as the breath hold continues, the automatic ventilatory control eventually overpowers the voluntary effort and limits the duration of the breath hold. Motor neurons also innervate muscles 490 SECTION5Berne & Levy Physiology 15 10 5 0 25 35 45 55 65


Physiology_Levy

Physiology_Levy. control eventually overpowers the voluntary effort and limits the duration of the breath hold. Motor neurons also innervate muscles 490 SECTION5Berne & Levy Physiology 15 10 5 0 25 35 45 55 65 PaCO2 (mm Hg) Alveolar ventilation (L/min) Metabolic acidosis Awake normal Sleep Morphine, barbiturates COPD Anesthetic agents •Fig. 25.1 Relationship between Partial Pressure of Arterial Carbon Dioxide (PaCO2) and Alveolar Ventilation in Awake Normal States, during Sleep, after Narcotic Ingestion and Deep Anesthesia, and in the Presence of Metabolic Acidosis. Boththeslopesoftheresponse(sensitivity)andthepositionoftheresponsecurves(threshold,thepointatwhichthecurvecrossesthex-axis[notshown])arechanged,whichindicatesdifferencesinventilatoryresponsesandresponsethresholds.COPD,chronicobstructivepulmonarydisease.


Physiology_Levy

Physiology_Levy. of the upper airway. These neurons are located within the medulla near the respiratory control center. They innervate muscles in the upper airways through the cranial nerves. When activated, they dilate the pharynx and large airways at the initiation of inspiration. Response to Carbon Dioxide Ventilation is regulated by PaCO2, PaO2, and pH in arterial blood. PaCO2 is the most important of these regulators. Both the rate and depth of breathing are controlled to maintain PaCO2 close to 40 mm Hg. In a normal awake individual, there is a linear rise in ventilation as PaCO2 reaches and exceeds 40 mm


Physiology_Levy

Physiology_Levy. Hg (Fig. 25.1 ). The ventilatory drive or response to changes in PaCO2 can be reduced by hyperventilation and by drugs that depress the respiratory center and decrease the ventilatory response to both CO2 and O2, such as morphine, barbiturates, and anesthetic agents. In these instances, the stimulus is inadequate to stimulate the motor neurons that innervate the muscles of respiration. It is also depressed during sleep. In addition, the ventilatory response to changes in PaCO2 is reduced if the work of breathing is increased, which can occur in individuals with chronic obstructive pulmonary disease (COPD). This effect occurs primarily because the neural output of the respiratory center is less effective in promoting ventilation as a result of the mechanical limitation to ventilation.


Physiology_Levy

Physiology_Levy. Changes in PaCO2 are sensed by central and peripheral chemoreceptors, and they transmit this information to the medullary respiratory centers. The respiratory control center then regulates minute ventilation and thereby maintains PaCO2 within the normal range. In the presence of a normal PaO2, ventilation increases by approximately 3 L/minute for each 1 mm Hg rise in PaCO2. The response to an increase in PaCO2 is further increased when the PaO2 is low ( Fig. 25.2, ). With a low PaO2, ventilation is greater for any given PaCO2, and the increase in ventilation for a given increment in PaCO2 is enhanced. The slope of the minute ventilation response as a function of the inspired CO2 is termed the ventilatory response to CO2 and is a test of CO2 sensitivity. It is important to recognize that this relationship is amplified by low O2 (see


Physiology_Levy

Physiology_Levy. Fig. 25.2, B ). The responsiveness to low O2 is enhanced because different mechanisms are responsible for sensing PaO2 and PaCO2 in the peripheral chemoreceptors. Thus the presence of both hypercapnia-elevated CO2 and hypoxemia-low O2 (often called asphyxia when both changes are present) has an additive effect on chemoreceptor output and on the resulting ventilatory stimulation. Control of Ventilation: The Details The Respiratory Control Center When the brain is transected experimentally between the medulla and the pons, periodic breathing is maintained, thus demonstrating that the inherent rhythmicity of breathing originates in the medulla. Although no single group of neurons in the medulla has been found to be the breathing “pacemaker,” two distinct nuclei within the medulla are involved in generation of the respiratory pattern (


Physiology_Levy

Physiology_Levy. Fig. 25.3 ). One nucleus is the dorsal respiratory group (DRG), which is composed of cells in the nucleus tractus solitarius and is located in the dorsomedial region of the medulla. Cells in the DRG receive afferent input from cranial nerves IX •Fig. 25.2 The Effects of Hypoxia and Hypercapnia on Ventilation as the Other Respiratory Gas Partial Pressures Are Varied. A, Atagivenpartialpressureofarterialcarbondioxide(PaCO2),ventilationincreasesmoreandmoreaspartialpressureofarterialoxygen(PaO2)decreases.WhenPaCO2isallowedtodecrease(thenormalcondition)duringhypoxia,thereislittlestimulationofbreathinguntilPaO2fallsbelow60mmHg.Thehypoxicresponseismediatedthroughthecarotidbodychemoreceptors.B, ThesensitivityoftheventilatoryresponsetoCO2isenhancedbyhypoxia.


Physiology_Levy

Physiology_Levy. and X, which originate from airways and the lungs and constitute the initial intracranial processing station for this afferent input. The second group of medullary cells is the ventral respiratory group (VRG), located in the ventrolateral region of the medulla. The VRG is composed of three cell groups: the rostral nucleus retrofacialis, the caudal nucleus retroambiguus, and the nucleus para-ambiguus. The VRG contains both inspiratory and expiratory neurons. The nucleus retrofacialis and the caudally located cells of the nucleus retroambiguus are active during exhalation, whereas the rostrally located cells of the nucleus retroambiguus are active during inspiration. The nucleus para-ambiguus has inspiratory and expiratory neurons that travel in the vagus nerve to the laryngeal and pharyngeal muscles. Discharges •Fig. 25.3 The Respiratory Control Center is Located in the Medulla, the Most Primitive Portion of the Brain.


Physiology_Levy

Physiology_Levy. that travel in the vagus nerve to the laryngeal and pharyngeal muscles. Discharges •Fig. 25.3 The Respiratory Control Center is Located in the Medulla, the Most Primitive Portion of the Brain. Theneuronsaremainlyintwoareas:thedorsalrespiratorygroup(DRG),whichconsistsofthenucleustractussolitarius,andtheventralrespiratorygroup(VRG),whichconsistsoftherostralnucleusretrofacialis,nucleusparaambiguus,andthecaudalnucleusretroambiguus.C1referstothefirstcervicalsignalsegmenttothecaudalborderofthepons.Thefourthventricleofthebrainislocatedbelowthecerebellumandabove,andbetween,theponsandthemedulla.


Physiology_Levy

Physiology_Levy. •Fig. 25.4 Diagram of the Basic Wiring of the Brainstem Ventilatory Controller. Thesignsofthemainoutput(arrows) oftheneuronpoolsindicatewhethertheoutputisexcitatory(+)orinhibitory(−).PoolAprovidestonicinspiratorystimulitothemusclesofbreathing.PoolBisstimulatedbypoolAandprovidesadditionalstimulationtothemusclesofbreathing,andpoolBstimulatespoolC.OtherbraincentersfeedintopoolC(inspiratorycutoffswitch),whichsendsinhibitoryimpulsestopoolA.Afferentinformation(feedback)fromvarioussensorsactsatdifferentlocations:ChemoreceptorsactonpoolA,andintrapulmonarysensoryfibersactviathevagusnervesonpoolB.Apneumotaxiccenterintheanteriorponsreceivesinputfromthecerebralcortex,anditactsonpoolC. from cells in these areas excite some cells and inhibit other cells. At the level of the respiratory control center, inspiration and exhalation involve three phases: one inspiratory and two expiratory (


Physiology_Levy

Physiology_Levy. Fig. 25.4 ). Inspiration begins with an abrupt increase in discharge from cells in the nucleus tractus solitarius, the nucleus retroambiguus, and the nucleus para-ambiguus, followed by a steady ramp-like increase in firing rate throughout inspiration. This leads to progressive contraction of the respiratory muscles during automatic breathing. At the end of inspiration, an “off-switch” event causes neuron firing to decrease markedly, at which point exhalation begins. At the start of exhalation (phase I of expiration), a paradoxical increase in inspiratory neuron firing slows the expiratory phase down by increasing inspiratory muscle tone and expiratory neuron firing. This inspiratory neuron firing decreases and stops during phase II of exhalation. Although many different neurons in the DRG and VRG are involved in ventilation, each cell type appears to have a specific function. For example, the Hering-Breuer reflex is an inspiratory-inhibitory reflex that arises from afferent stretch


Physiology_Levy

Physiology_Levy. and VRG are involved in ventilation, each cell type appears to have a specific function. For example, the Hering-Breuer reflex is an inspiratory-inhibitory reflex that arises from afferent stretch receptors located in the smooth muscles of the airways. Increasing lung inflation stimulates these stretch receptors and results in early exhalation by stimulating the neurons associated with the off-switch phase of inspiratory muscle control. Thus rhythmic breathing depends on a continuous (tonic) inspiratory drive from the DRG and an intermittent (phasic) expiratory drive from the cerebrum, thalamus, cranial nerves, and ascending sensory tracts in the spinal cord.


Physiology_Levy

Physiology_Levy. A chemoreceptor is a receptor that responds to a change in the chemical composition of blood or other fluid around it. Central chemoreceptors are specialized cells on the ventrolateral surface of the medulla. Chemoreceptors are sensitive to the pH of the surrounding extracellular fluid. Because this extracellular fluid is in contact with cerebrospinal fluid (CSF), changes in the pH of CSF affect ventilation by acting on these chemoreceptors CSF is an ultrafiltrate of plasma that is secreted continuously by the choroid plexus and is reabsorbed by the arachnoid villi. Because it is in contact with the extracellular fluid in the brain, the composition of CSF is influenced by the metabolic activity of the cells in the surrounding area and the composition of the blood. Although the origin of CSF is plasma, the composition of CSF is not the same as that of plasma because the blood-brain barrier exists between the two sites (


Physiology_Levy

Physiology_Levy. Fig. 25.5 ). The blood-brain barrier is composed of endothelial cells, smooth muscle, and the pial and arachnoid membranes, and it regulates the movement of ions between blood and CSF. In addition, the choroid plexus also determines the ionic composition of CSF by transporting ions into and out of CSF. The blood-brain barrier is relatively impermeable by H+ and HCO3 − ions, but it is very permeable by CO2. Thus the PCO2 in CSF parallels the arterial PCO2 tension. CO2 is also produced by cells of the brain as a product of metabolism. As a consequence, the PCO2 in CSF is usually a few millimeters of mercury higher than that in arterial blood, and so the pH is slightly more acidic (7.33) in CSF than in plasma (


Physiology_Levy

Physiology_Levy. Table 25.1 •Fig. 25.5 Carbon Dioxide and the Blood-Brain Barrier. PaCO2crossestheblood-brainbarrierandrapidlyequilibrateswithCO2incerebrospinalfluid(CSF).H+ andHCO3− ionscrossthebarrierslowly.Thepartialpressureofarterialcarbondioxide(PaCO2)combineswithCO2generatedbymetabolismtodilatethesmoothmuscle.Incomparisonwitharterialblood,thepHofCSFislowerandthePCO2ishigher,withlittleproteinbuffering. PCO2,partialpressureofcarbondioxide.


Physiology_Levy

Physiology_Levy. PCO2,partialpressureofcarbondioxide. The carotid and aortic bodies are peripheral chemoreceptors that respond to changes in PaO2 (not the O2 content), PaCO2, and pH, and they transmit afferent information to the central respiratory control center. The peripheral chemoreceptors are the only chemoreceptors that respond to changes in PaO2. The peripheral chemoreceptors are also responsible for approximately 40% of the ventilatory response to PaCO2. These chemoreceptors are small, highly vascularized structures. They consist of type I (glomus) cells that are rich in mitochondria and endoplasmic reticulum. They also have several types of cytoplasmic granules (synaptic vesicles) that contain various neurotransmitters, including dopamine, acetylcholine, norepinephrine, and neuropeptides. Afferent nerve fibers synapse with type I cells, and they transmit information to the brainstem through the carotid sinus nerve (carotid body) and vagus


Physiology_Levy


Physiology_Levy

Physiology_Levy. ChangesinPaCO2thatresultfromalterationsinpHactivatehomeostaticmechanismsthatreturnthepHbacktowardanormalvalue.Theblood-brainbarrierregulatesthepHofCSFbyadjustingtheioniccompositionand[HCO3 −]ofCSF.ThesechangesinCSF[HCO3−],however,occurslowly,overaperiodofseveralhours,whereaschangesinCSFPCO2canoccurwithinminutes.ThuscompensationforchangesinthepHofCSFrequireshourstodevelopfully. Several reflexes that arise from the chest wall and lungs affect ventilation and ventilatory patterns (


Physiology_Levy

Physiology_Levy. Several reflexes that arise from the chest wall and lungs affect ventilation and ventilatory patterns ( Table 25.2 ). The Hering-Breuer inspiratory-inhibitory reflex is stimulated by increases in lung volume, especially those associated with an increase in both ventilatory rate and tidal volume. This stretch reflex is mediated by vagal fibers, and when nerve (aortic body). Type I cells are the cells primarily responsible for sensing PaO2, PaCO2, and pH. In response to even small decreases in PaO2, there is an increase in chemoreceptor discharge, which enhances respiration. The response is robust when PaO2 decreases below 75 mm Hg. Thus ventilation is regulated by changes in arterial and CSF pH through effects on peripheral and central chemoreceptors (


Physiology_Levy

Physiology_Levy. Fig. 25.6 •Fig. 25.6 The Ventilatory Response to Partial Pressure of Arterial Carbon Dioxide (PaCO2) is Affected by the Concentration of Hydrogen ([H+]) in Cerebrospinal Fluid (CSF) and Brainstem Interstitial Fluid. Duringchronicmetabolicacidosis(e.g.,diabeticketoacidosis),the[H+]inCSFisincreased,andtheventilatoryresponsetoinspiredPaCO2isincreased(steeperslope).Conversely,duringchronicmetabolicalkalosis(arelativelyuncommoncondition),the[H+]inCSFisdecreasedandtheventilatoryresponsetoinspiredPaCO2isdecreased(reducedslope).Thepositionsoftheresponselinesarealsoshifted,whichindicatesalteredthresholds.


Physiology_Levy

Physiology_Levy. ImagineflyingfromNewYorkCitytoDenver.ThebarometricpressureinNewYorkisapproximately760mmHg,whereasinthemountainssurroundingDenver,Colorado,itis600mmHg.Atsealevel,thePaO2isapproximately95mmHgandPAO2= [(760− 47)× 0.21]− [40/0.8]= 100mmHg(accordingtothealveolarairequation;see ).Ifthealveolar-arterialPO2difference[AaDO2]is5mmHg,PaO2= 100mmHg− 5mmHg= 95mmHg.IntheCSF,pHwouldbeapproximately7.33,PaCO2wouldbe44mmHg(PaCO2+ CO2producedbymetabolismofbraincells),andHCO3− wouldbeapproximately22mEq/L.


Physiology_Levy

Physiology_Levy. WhenyouarriveinDenver,thereisanabruptdecreaseinthepartialpressureofinspiredO2(PiO2):PiO2= (600− 47)× 0.21= 116mmHg;therearealsodecreasesinthepartialpressuresofalveolarandarterialO2:PAO2= 116− (40/0.8)= 66mmHg,andPaO2= 61mmHgifthereisnochangeinAaDO2).ThisdecreaseinarterialO2stimulatestheperipheralchemoreceptorsandtherebyincreasesventilation.TheincreaseinventilationdecreasesPaCO2andelevatesarterialpH.TheresultofthisincreaseinventilationistominimizethehypoxemiabyincreasingPAO2.Forexample,assumethatPACO2decreasesto30mmHg.ThenPAO2= [(600− 47)× 0.21]− [30/0.8]= 78mmHg,a12–mmHgincreaseinPAO2.


Physiology_Levy

Physiology_Levy. elicited, it results in cessation of inspiration by stimulating the off-switch neurons in the medulla. This reflex is inactive during quiet breathing and appears to be most important in newborns. Stimulation of nasal or facial receptors with cold water initiates the diving reflex. When this reflex is elicited, apnea, or cessation of breathing, and bradycardia occur. This reflex protects individuals from aspirating water in the initial stages of drowning. Activation of receptors in the nose is responsible for the sneeze reflex.


Physiology_Levy

Physiology_Levy. The aspiration or sniff reflex can be elicited by stimulation of mechanical receptors in the nasopharynx and pharynx. This is a strong, short-duration inspiratory effort that brings material from the nasopharynx to the pharynx, where it can be swallowed or expectorated. The mechanical receptors responsible for the sniff reflex are also important in swallowing by inhibiting respiration and causing laryngeal closure. For anatomical reasons, only newborns can breathe and swallow simultaneously, which allows more rapid ingestion of nutrients. The larynx contains both superficial and deep receptors. Activation of the superficial receptors results in apnea, cough, and expiratory movements that protect the lower respiratory tract from aspirating foreign material. The deep receptors are located in the skeletal muscles of the larynx, and they control muscle fiber activation, as in other skeletal muscles.


Physiology_Levy

Physiology_Levy. Three major types of sensory receptors located in the tracheobronchial tree respond to a variety of different stimuli, and those responses result in changes in the lung’s mechanical properties, alterations in the respiratory pattern, and the development of respiratory symptoms. Inhaled dust, noxious gases, and cigarette smoke stimulate irritant receptors in the trachea and large airways that transmit information through myelinated vagal afferent fibers. Stimulation of these receptors results in an increase in airway resistance, reflex apnea, and coughing. These receptors are also known as rapidly adapting pulmonary stretch receptors. Slowly adapting pulmonary stretch receptors respond to mechanical stimulation, and they are activated by lung inflation. They also transmit information through myelinated, vagal afferent fibers. The increase in lung volume in people with COPD stimulates these pulmonary stretch receptors and delays the onset of the next inspiratory effort. This explains


Physiology_Levy

Physiology_Levy. myelinated, vagal afferent fibers. The increase in lung volume in people with COPD stimulates these pulmonary stretch receptors and delays the onset of the next inspiratory effort. This explains the long, slow expiratory effort in affected individuals, and it is essential to minimize dynamic, expiratory airway compression.


Physiology_Levy

Physiology_Levy. In addition, specialized sensory receptors located in the lung parenchyma respond to chemical or mechanical stimulation in the lung interstitium. These receptors are called juxta-alveolar, (or J) receptors. They transmit their afferent input through unmyelinated, vagal C fibers. They may be responsible for the sensation of dyspnea (abnormal shortness of breath) and the rapid, shallow ventilatory patterns that occur in interstitial lung edema and some inflammatory lung states. VO2 (L/min) . 1 1.5 2 VCO2 . PaCO2 pH Ventilation PaO2 Lactate •Fig. 25.8 The Two Main Categories of Sleep Apnea. A, Obstruc-tivesleepapnea,thepleuralpressureoscillationsincreaseasCO2levelrises.Thisindicatesthatresistancetoairflowisveryhighasaresultofupperairwayobstruction.B, Centralsleepapneaischaracterizedbynoattempttobreathe,asdemonstratedbynooscillationsinpleuralpressure.


Physiology_Levy

Physiology_Levy. •Fig. 25.7 Oxygen Consumption (V̇ O2) as a Function of the Metabolic Changes That Occur During Exercise. Theanaerobicthreshold(arrow) isthepointatwhichtheillustratedvariableschangeandisduetolacticacidosis.PaCO2,partialpressureofarterialcarbondioxide;PaO2,partialpressureofarterialoxygen;VCO2,carbondioxide consumption. Somatic receptors are also located in the intercostal muscles, rib joints, accessory muscles of respiration, and tendons, and they respond to changes in the length and tension of the respiratory muscles. Although they do not directly control respiration, they do provide information about lung volume and play a role in terminating inspiration. They are especially important in individuals with increased airway resistance and decreased pulmonary compliance because they can augment muscle force within the same breath. Somatic receptors also help minimize the chest wall distortion during inspiration in newborns, who have very compliant rib cages.


Physiology_Levy

Physiology_Levy. The ability to exercise depends on the capacity of the cardiac and respiratory systems to increase delivery of O2 to tissues and remove CO2 from the body. Ventilation increases immediately when exercise begins, and this increase in minute ventilation closely matches the increases in O2 consumption and CO2 production that accompany exercise ( Fig. 25.7 ). Ventilation is linearly related to both CO2 production and O2 consumption at low to moderate levels (see Fig. 25.7 ). During maximal exercise, a physically fit individual can achieve an O2 consumption of 4 L/minute with a minute ventilation volume of 120 L/minute, which is almost 15 times the resting level.


Physiology_Levy

Physiology_Levy. Exercise is remarkable because of the lack of significant changes in blood gases. Except at maximal exertion, changes in PaCO2 and PaO2 are minimal during exercise. Arterial pH remains within normal values during moderate exercise. During strenuous exercise, arterial pH begins to fall as lactic acid is liberated from muscles during anaerobic metabolism. This decrease in arterial pH stimulates ventilation that is out of proportion to the level of exercise. The level of exercise at which sustained metabolic (lactic) acidosis begins is called the anaerobic threshold (see Fig. 25.7 Abnormalities in the Control of Breathing


Physiology_Levy

Physiology_Levy. Fig. 25.7 Abnormalities in the Control of Breathing Changes in the ventilatory pattern can occur for both primary and secondary reasons. During sleep, approximately one third of normal individuals have brief episodes of apnea or hypoventilation that have no significant effects on PaO2 or PaCO2. The apnea usually lasts less than 10 seconds, and it occurs in the lighter stages of slow-wave and rapid eye movement (REM) sleep. In sleep apnea syndromes, the duration of apnea is abnormally prolonged, and it changes PaO2 and PaCO2. There are two major categories of sleep apnea ( Fig. 25.8 ). The first, obstructive sleep apnea (OSA), is the most common of the sleep apnea syndromes, and it occurs when the upper airway (generally the hypopharynx) closes during inspiration. Although the process is similar to what happens during snoring, it is more severe, inasmuch as it obstructs the airway and causes cessation of airflow.


Physiology_Levy

Physiology_Levy. The second sleep apnea syndrome is central sleep apnea. This variant of apnea occurs when the ventilatory drive to TheclinicalhistoriesofindividualswithOSAareverysimilar.Aspouseusuallyreportsthattheaffectedindividualsnores.Thesnoringbecomeslouderandlouderandthenstopswhiletheindividualcontinuestomakevigorousrespiratoryefforts(see Fig.25.8 ).Theindividualthenawakens,fallsbacktosleep,andcontinuesthesameprocessrepetitivelythroughoutthenight.IndividualswithOSAawakenwhenthearterialhypoxemiaandhypercapniastimulatebothperipheralandcentralchemoreceptors.Respirationisrestoredbrieflybeforethenextapneiceventoccurs.IndividualswithOSAcanhavehundredsoftheseeventseachnightthatinterruptsleep.ComplicationsofOSAincludesleepdeprivation,polycythemia,right-sidedcardiacfailure(corpulmonale),andpulmonaryhypertensionsecondarytotherecurrent,hypoxicevents.OSAiscommoninindividualswithobesityandinthosewithexcessivecomplianceofthehypopharynx,upperairwayedema,andstructuralabnormalitiesoftheupperairway.


Physiology_Levy

Physiology_Levy. the respiratory motor neurons decreases. Individuals with central sleep apnea have repeated episodes of apnea, during which time they make no respiratory effort, every night (see Fig. 25.8 ). The degree of hypercapnia and hypoxemia in individuals with central sleep apnea is less than that in individuals with OSA, but the same complications (e.g., polycythemia) can occur when central sleep apnea is recurrent and severe. Cheyne-Stokes ventilation is another abnormality of breathing that is characterized by varying tidal volume and ventilatory frequency (


Physiology_Levy

Physiology_Levy. Cheyne-Stokes ventilation is another abnormality of breathing that is characterized by varying tidal volume and ventilatory frequency ( Fig. 25.9 ). After a period of apnea, tidal volume and respiratory frequency increase progressively over several breaths, and then they progressively decrease until apnea recurs. This irregular breathing pattern is seen in some individuals with central nervous system diseases, head trauma, and increased intracranial pressure. It is also present on occasion in normal individuals during sleep at high altitude. The mechanism underlying Cheyne-Stokes respiration is not known. In some individuals, it appears to be due to slow blood flow in the brain in association with periods of overshooting and undershooting ventilatory effort in response to changes in PCO2.


Physiology_Levy

Physiology_Levy. Central alveolar hypoventilation, alsoknownasOndine’s curse, isararediseaseinwhichvoluntarybreathingisintactbutabnormalitiesinautomaticityexist.Itisthemostsevereofthecentralsleepapneasyndromes.Asaresult,peoplewithcentralalveolarhypoventilationcanbreatheaslongastheydonotfallasleep.Fortheseindividuals,mechanicalventilationor,morerecently,bilateraldiaphragmaticpacing(similartoacardiacpacemaker)canbelifesaving. Apneustic breathing is another abnormal breathing pattern that is characterized by sustained periods of inspiration separated by brief periods of exhalation ( Fig. 25.10, C •Fig. 25.9 In Cheyne-Stokes Breathing, Tidal Volume and, as a Consequence, Arterial Blood Gas Levels Wax and Wane. Ingeneral,Cheyne-Stokesbreathingisasignofvasomotorinstability,particularlylowcardiacoutput.PaCO2,partialpressureofarterialcarbondioxide;PaO2,partialpressureofarterialoxygen.


Physiology_Levy

Physiology_Levy. Lung volumeRemove input from cortex, thalamus, and vagus nerves A B Remove sensory input from lungs •Fig. 25.10 Some Patterns of Breathing. A, Normalrateofbreathingisintherangeof12to20breathsperminute.B, Whensensoryinputisremovedfromvariouslungreceptors(mainlystretch),eachbreathingcycleislengthenedandtidalvolumeisincreased,sothatalveolarventilationisnotsignificantlyaffected.C, Wheninputfromthecerebralcortexandthalamusisalsoeliminated,togetherwithvagalblockade,theresultisprolongedinspiratoryactivitybrokenafterseveralsecondsbybriefexpirations(apneusis). The mechanism underlying this ventilatory pattern appears to be a loss of inspiratory-inhibitory activities that results in augmentation of the inspiratory drive. The pattern sometimes occurs in individuals with central nervous system injury.


Physiology_Levy

Physiology_Levy. Sudden infant death syndrome (SIDS)isthemostcommoncauseofdeathininfantsinthefirstyearoflifeaftertheperinatalperiod.AlthoughthecauseofSIDSisnotknown,abnormalitiesinventilatorycontrol,particularlyin 1. Ventilatory control is composed of the respiratory control center, central chemoreceptors, peripheral chemoreceptors, and pulmonary mechanoreceptors/ sensory nerves. PaCO2 is the major factor that influences ventilation. 2. The respiratory control center is composed of the dorsal respiratory group and the ventral respiratory group. Rhythmic breathing depends on a continuous (tonic) inspiratory drive from the dorsal respiratory group and on intermittent (phasic) expiratory input from the cerebrum, thalamus, cranial nerves, and ascending spinal cord sensory tracts. The peripheral and central chemoreceptors respond to changes in PaCO2 and pH. The peripheral chemoreceptors (carotid and aortic bodies) are the only chemoreceptors that respond to changes in PaO2.


Physiology_Levy

Physiology_Levy. Calverley PMA, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J. 2005;25:186-199. Canning BJ. Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. Otolaryngol Clin N Am. 2010;43:15-25. Leff AR, Schumacker PT. Respiratory Physiology: Basics and Applications. Philadelphia: WB Saunders; 1993. Nishino T. Dyspnoea underlying mechanisms and treatment. Br J Anaesth. 2011;106:463-474. CO2responsiveness,havebeenimplicated.Placinginfantsontheirbackstosleep(whichreducesthepotentialforCO2rebreathing)hasdramaticallydecreased(butnoteliminated)therateofdeathfromthissyndrome. 3. Acute hypoxia and chronic hypoxia affect breathing differently because the slow adjustments in CSF [H+] in chronic hypoxia alter sensitivity to CO2. 4.


Physiology_Levy

Physiology_Levy. 3. Acute hypoxia and chronic hypoxia affect breathing differently because the slow adjustments in CSF [H+] in chronic hypoxia alter sensitivity to CO2. 4. Irritant receptors protect the lower respiratory tract from particles, chemical vapors, and physical factors, primarily by inducing cough. C fiber J receptors in the terminal respiratory units are stimulated by distortion of the alveolar walls (by lung congestion or edema). 5. The two most important clinical abnormalities of breathing are obstructive and central sleep apnea. 6. PaO2, PaCO2, and pH remain within normal limits during moderate exercise; however, during strenuous exercise, pH falls, which stimulates ventilation, whereas PaO2 and PaCO2 remain relatively normal. Otis AB. A perspective of respiratory mechanics. J Appl Physiol. 1983;54:1183-1187. Sheel AW, Romer LM. Ventilation and respiratory mechanics. Compr Physiol. 2012;2:1093-1142.


Physiology_Levy

Physiology_Levy. Otis AB. A perspective of respiratory mechanics. J Appl Physiol. 1983;54:1183-1187. Sheel AW, Romer LM. Ventilation and respiratory mechanics. Compr Physiol. 2012;2:1093-1142. Wasserman K, Beaver WL, Whipp BI. Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation. 1990;81(1 suppl):1114-1130. Wine JJ. Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system. Auton Neurosci. 2007;133:35-54. Upon completion of this chapter, the student should be able to answer the following questions: 1. Describe the components of the mucociliary clearance system and their role in the removal of xenobiotic substances and particulates. 2. Explain how particle characteristics and properties influence their deposition and clearance. 3. Compare and contrast the major mechanisms of particle deposition. 4. Compare and contrast the mucosal and systemic immune responses. 5.


Physiology_Levy

Physiology_Levy. 3. Compare and contrast the major mechanisms of particle deposition. 4. Compare and contrast the mucosal and systemic immune responses. 5. Describe unique features of immunoglobulin A and why it is well suited for the mucosal environment and protection. 6. Compare and contrast adaptive and innate immune cells in the respiratory system. 7. Describe the various metabolic processes in the lung. n addition to their primary function of gas exchange, the lungs act as a primary barrier between the outside world and the inside of the body, with host defense functions. They are also active organs in the metabolism of xenobiotic and endogenous compounds. To cope with the inhalation of foreign substances, the respiratory system and, in particular, the conducting airways have developed unique structural features: the mucociliary clearance system and specialized adaptive and innate immune response mechanisms.


Physiology_Levy

Physiology_Levy. The mucociliary clearance system protects the conducting airways by trapping and removing inhaled pathogenic viruses and bacteria, in addition to nontoxic and toxic particulates (e.g., pollen, ash, mineral dust, mold spores, and organic particles), from the lungs. These particulates are inhaled with each breath and must be removed. The three major components of the mucociliary clearance system are two fluid layers, referred to as the sol (periciliary fluid) and gel (mucus) layers, and cilia, which are positioned on the surface of bronchial epithelial cells ( Fig. 26.1 ). Inhaled material is trapped on the viscoelastic (sticky) mucus layer, whereas the watery periciliary fluid allows the cilia to move freely and establish an upward flow to clear particulates from the lung. Effective clearance requires both ciliary activity and the appropriate balance of periciliary fluid and mucus.


Physiology_Levy

Physiology_Levy. The periciliary fluid layer is composed of nonviscous serous fluid, which is produced by the pseudostratified ciliated columnar epithelial cells that line the airways. These cells have the ability to either secrete fluid, a process that is mediated by activation of cystic fibrosis transmembrane regulator (CFTR) chloride (Cl−) ion channels (Na+ secretion follows passively between cells across the tight junctions) or reabsorb fluid, a process that is mediated by activation of epithelial sodium channels (ENaC; Cl− absorption follows passively between cells across the tight junctions). NaCl secretion or reabsorption temporarily establishes an osmotic gradient across the pseudostratified epithelium, which provides the driving force for passive water movement. The balance between CFTR-mediated Cl− secretion and ENaC-mediated Na+ absorption is regulated by a variety of hormones and determines the volume of the periciliary fluid, which in the healthy lung is 5 to 6 µm deep, a level that is


Physiology_Levy

Physiology_Levy. Cl− secretion and ENaC-mediated Na+ absorption is regulated by a variety of hormones and determines the volume of the periciliary fluid, which in the healthy lung is 5 to 6 µm deep, a level that is optimal for rhythmic beating of the cilia and mucociliary clearance.


Physiology_Levy

Physiology_Levy. The mucus layer lies on top of the periciliary fluid layer and is composed of a complex mixture of macromolecules and electrolytes. Because the mucus layer is in direct contact with air, it entraps inhaled substances, including pathogens. The mucus layer is predominantly water (95% to 97%), 5 to 10 µm thick and exists as a discontinuous blanket (i.e., islands of mucus). Mucus has low viscosity and high elasticity and is composed of glycoproteins with groups of oligosaccharides attached to a protein backbone. Healthy •Fig. 26.1 Overview of the Epithelial Lining and Innervation of the Tracheobronchial Tree. Theciliaoftheepithelialcellresideinthepericiliaryfluidlayer,andthemucuslayerisontop.Interspersedbetweentheciliatedepithelialcellsaresurfacesecretory(goblet)cellsandsubmucosalglands.Sympatheticandparasympatheticnervefibersdescendintothesubmucosalglandsandsmoothmuscles.


Physiology_Levy


Physiology_Levy

Physiology_Levy. DetailedstudyofthedifferentCFTR mutationshasresultedinanunderstandingofvariousdisease-relatedphenotypes,someofwhichareassociatedwithmilderdiseaseandsomewithmoreseveredisease.Sincethe1980s,researchfindingshaveelucidatedhowmanyofthemostcommonmutationsintheCFTR genecauseCF,andthishasledtothedevelopmentofdrugsthattargetspecificmutationsandreversethe individuals produce approximately 100 mL of mucus each day. Four cell types contribute to the quantity and composition of the mucus layer: goblet cells and Clara cells within the tracheobronchial epithelium, and mucous cells and serous cells within the tracheobronchial submucosal glands. Goblet cells, also referred to as surface secretory cells, represent approximately 15% to 20% of the tracheobronchial epithelium, and are found in the tracheobronchial tree up to the 12th division. In many respiratory diseases, goblet cells appear further down the tracheobronchial tree; thus the smaller airways are more susceptible to obstruction


Physiology_Levy

Physiology_Levy. tracheobronchial tree up to the 12th division. In many respiratory diseases, goblet cells appear further down the tracheobronchial tree; thus the smaller airways are more susceptible to obstruction progressivereductioninlungfunction.Forexample,inonemutation(G551D-CFTR,whichaffects≈5%ofpatientswithCF),theCFTRCl− channelreachestheplasmamembraneofairwayepithelialcellsbutdoesnotsecreteCl− .Throughprecisionmedicine,adrug,ivacaftor(Kalydeco),hasbeenfoundtostimulateCl− secretionviatheG551D-CFTR,therebyimprovinglungfunctionanddecreasingtherateofdiseaseprogression.WhentheallelesarehomozygousfortheΔF508CFTRmutation(whichaffects≈50%ofpatientswithCF),theCFTRCl− channeldoesnotreachtheplasmamembraneofairwayepithelialcells.


Physiology_Levy

Physiology_Levy. In2015,theU.S.FoodandDrugAdministrationapprovedacombinationdrugtherapy,lumacaftor/ivacaftor(Orkambi),thathasbeenshowntocorrectthegenedefect,increasetheamountofΔF508-CFTRintheplasmamembrane,andimproveCl− transport.Clinically,bothivacaftorandlumacaftor/ivacaftorhavebeenshowntoimprovelungfunctionsignificantlyandtodecreasetherateofdeclineinlungfunction. by mucus plugging. Goblet cells secrete neutral and acidic glycoproteins rich in sialic acid in response to chemical stimuli. In the presence of infection or cigarette smoke or in patients with chronic bronchitis, goblet cells can increase in size and number, extend above the 12th division of the tracheobronchial tree, and secrete copious amounts of mucus. Injury and infection increase the viscosity of the mucus secreted by goblet cells, which reduces mucociliary clearance of inhaled particles and pathogens.


Physiology_Levy

Physiology_Levy. Submucosal tracheobronchial glands are present wherever there is cartilage in the upper regions of the conducting airways, and they secrete water, ions, and mucus into the airway lumen through a ciliated duct (see Fig. 26.1 ). Although both mucous and serous cells secret mucus, their cellular structure and mucus composition are distinctly different (


Physiology_Levy

Physiology_Levy. Fig. 26.1 ). Although both mucous and serous cells secret mucus, their cellular structure and mucus composition are distinctly different ( Table 26.1 ). In several lung diseases, including chronic bronchitis, the number and size of submucosal glands are increased, which leads to increases in mucus production, alterations in chemical composition of mucus (i.e., increased viscosity and decreased elasticity), and the formation of mucus plugs that cause airway obstruction. Mucus secretion from submucosal tracheobronchial glands is stimulated by parasympathetic (cholinergic) compounds such as acetylcholine and substance P and inhibited by sympathetic (adrenergic) compounds such as norepinephrine and vasoactive intestinal polypeptide. Local inflammatory mediators such as histamine and arachidonic acid metabolites also stimulate mucus production.


Physiology_Levy

Physiology_Levy. Clara cells, located in the epithelium of bronchioles, also contribute to the composition of mucus through secretion of a nonmucinous material containing carbohydrates and proteins. These cells play a role in bronchial regeneration after injury. As noted previously, the respiratory tract to the level of the bronchioles is lined by a pseudostratified, ciliated columnar epithelium (see


Physiology_Levy

Physiology_Levy. As noted previously, the respiratory tract to the level of the bronchioles is lined by a pseudostratified, ciliated columnar epithelium (see Fig. 26.1 ). These cells maintain the level of the periciliary fluid in which cilia and the mucociliary transport system function. Mucus and inhaled particles are removed from the airways by the rhythmic beating of the cilia. There are approximately 250 cilia per airway epithelial cell, and each is 2 to 5 µm in length. Cilia are composed of nine microtubular doublets that surround two central microtubules held together by dynein arms, nexin links, and spokes. The central microtubule doublet contains an adenosine triposphatase (ATPase) that is responsible for the contractile beat of the cilium. Cilia beat with a coordinated oscillation in a characteristic, biphasic, and wave-like rhythm called metachronism. They beat at approximately