RESPIRATORY PHYSIOLOGY- Lung mechanics, pulmonary blood flow and O2

respiratory physiology

1. RESPIRATORY SYSTEM PGY 121 Kampolo D. BSc Biol , BSc HB, MBChB , MSc, MMED- Internal Medicine, MASM, Dip MGT, Cert MED UNILUS - SOM

2. respiration can be divided into four major functions : (1) pulmonary ventilation- the inflow and outflow of air between the atmosphere and the lung alveoli; ( 2) diffusion of oxygen and carbon dioxide between the alveoli and the blood; ( 3) transport of oxygen and carbon dioxide in the blood and body fluids to and from the body’s tissue cells; and (4) regulation of ventilation and other facets of respiration.

3. Mechanics of Pulmonary Ventilation Lung Expansion and Contraction The lungs can be expanded and contracted in two ways: ( 1) by downward and upward movement of the diaphragm to lengthen or shorten the chest cavity, (2) by elevation and depression of the ribs to increase and decrease the anteroposterior diameter of the chest cavity

4. inspiration contraction of the diaphragm pulls the lower surfaces of the lungs downward Expiration- the diaphragm relaxes, the elastic recoil of the lungs, chest wall , and abdominal structures compresses the lungs and expels the air In heavy breathing, rapid expiration, is achieved mainly by contraction of the abdominal muscles

5. The second method for expanding the lungs is to raise the rib cage expanding the lungs when the rib cage is elevated, the ribs project directly forward, moving sternum forward, increases anteroposterior diameter of the chest about 20 per cent greater during maximum inspiration than expiration

6. Respiratory Muscles muscles that elevate the chest cage are classified as muscles of inspiration, The most important muscles that raise the rib cage are the external intercostals , ( 1) sternocleidomastoid muscles- lift sternum (2 ) anterior serrati , - lift the upper 5-6 ribs ; (3 ) scaleni ,- lift the first two ribs.

7. The muscles that pull the rib cage downward during expiration are; (1) abdominal recti ,- powerful effect of pulling downward on the lower ribs ( 2) internal intercostals abd muscles also compress the abd contents upward against the diaphragm,

8. Movement of Air In and Out of the Lungs The lung is an elastic structure that collapses like a balloon and expels all its air through the trachea whenever there is no force to keep it inflated. there are no attachments between the lung and the walls of the chest cage, except at its hilum the lung “floats” in thoracic cavity, surrounded by a thin layer of pleural fluid that lubricates it

9. continual suction of excess fluid into lymphatic channels maintains a slight suction between the visceral and parietal pleural of the thoracic cavity. lungs are held to the thoracic wall as if glued there, except they are well lubricated and can slide freely as the chest expands and contracts .

10. Pleural Pressure and Its Changes Pleural pressure(PP) - pressure of the fluid in the thin space between the lung pleura and the chest wall pleura . this is normally a slight suction , giving negative pressure. PP at the beginning of inspiration is about –5 centimetres of water, is the amount of suction required to hold the lungs open to their resting level.

11. in normal inspiration expansion of the chest cage pulls outward on the lungs with greater force and creates more negative pressure An average of about –7.5 centimeters of water. the increasing negativity of the pleural pressure from –5 to –7.5 in inspiration increase in lung volume of 0.5 liter . during expiration, the events are reversed.

12. Alveolar Pressure is the pressure of the air inside the lung alveoli. When the glottis is open and no air is flowing into or out of the lungs , pressures in all the respiratory tree, are equal to atmospheric pressure, i.e. zero(0) centimeters water For inward flow of air into the alveoli during inspiration; the pressure in the alveoli must fall to a value slightly below atmospheric pressure (below 0 ).

13. In inspiration, alveolar pressure decreases to about –1 centimeter of water- slight negative This pressure is enough to pull 0.5 liter of air into the lungs in the 2 seconds required for normal quiet inspiration. During expiration, opposite pressures occur: Thealveolar pressure rises to about +1 centimeter of water, this forces the 0.5 liter of inspired air out of the lungs during the 2 to 3 seconds of expiration

14. Transpulmonary Pressure Is the difference between the alveolar pressure and the pleural pressure. It is the pressure difference between that in the alveoli and that on the outer surfaces of the lungs It is a measure of the elastic forces in the lungs that tend to collapse the lungs at each instant of respiration, called the recoil pressure

15. Compliance of the Lungs Is the extent to which the lungs will expand for each unit increase in transpulmonary pressure Total compliance of both lungs in normal adult human averages about 200 ml of air/cm of water transpulmonary pressure . Every time the transpulmonary pressure increases 1 cm of water, the lung volume, after 10 to 20 seconds, will expand 200 milliliters .

16. The elastic forces of the lungs determine compliance. These can be divided into two parts : (1) elastic forces of the lung tissue itself (2 ) elastic forces caused by surface tension of the fluid that lines the inside walls of the alveoli and other lung air spaces. The elastic forces are determined mainly by elastin and collagen fibers in lung parenchyma .

17. Principle of Surface Tension When water forms a surface with air the water molecules on the surface of the water have an strong attraction for one another . the water surface is always attempting to contract. This is what holds raindrops together : that is, there is a tight contractile membrane of water molecules around the entire surface of the raindrop . In Alveoli, water surface is also attempting to contract. This results in an attempt to force the air out of the alveoli through the bronchi and, in doing so, causes the alveoli to try to collapse. The net effect is to cause an elastic contractile force of the entire lungs- surface tension elastic force.

18. Surfactant greatly reduces the surface tension of water. It is secreted by special surfactant-secreting epithelial cells called type II alveolar epithelial cells Surfactant is a complex mixture of several phospholipids , proteins, and ions. M ost important components are the phospholipid dipalmitoylphosphatidylcholine , surfactant apoproteins , and calcium ions . The dipalmitoylphosphatidylcholine , along with several less important phospholipids, is responsible for reducing the surface tension.

19. Table 3: C omposition of surfactant. Component Percent Composition Dipalmitoylphosphatidylcholine 62 Phosphatidylglycine 5 Other phospholipids 10 Neutral lipids 13 Proteins 8 Carbohydrate 2    

20. Effect of Alveolar Radius on the Pressure Caused by Surface Tension Pressure generated as a result of surface tension in the alveoli is inversely affected by the radius of the alveolus, the smaller the alveolus, the greater the alveolar pressure caused by the surface tension . This is especially significant in small premature babies, many of whom have alveoli with radii less than one quarter that of an adult person. Further, surfactant does not normally begin to be secreted into the alveoli until between the sixth and seventh months of gestation

21. Premature babies have little or no surfactant in the alveoli when they are born their lungs have an extreme tendency to collapse, This causes the condition called respiratory distress syndrome of the newborn .

22. Work of Breathing during normal quiet breathing , all respiratory muscle contraction occurs during inspiration; expiration is almost entirely a passive process caused by elastic recoil of the lungs and chest cage. under resting conditions, the respiratory muscles normally perform “work” to cause inspiration but not to cause expiration. The work of inspiration can be divided into three fractions : ( 1) that required to expand the lungs against the lung and chest elastic forces, called compliance work or elastic work ; (2) that required to overcome the viscosity of the lung and chest wall structures, called tissue resistance work; and (3) that required to overcome airway resistance to movement of air into the lungs, called airway resistance work .

23. Energy Required for Respiration During normal quiet respiration, only 3 to 5 per cent of the total energy expended by the body is required for pulmonary ventilation. during heavy exercise, the amount of energy required can increase as much as 50-fold one of the major limitations on the intensity of exercise that can be performed is the person’s ability to provide energy for the respiratory process

24. Recording Changes in Pulmonary Volume— Spirometry A simple method for studying pulmonary ventilation is to record the volume movement of air into and out of the lungs, a process called spirometry . It consists of a drum inverted over a chamber of water, with the drum counterbalanced by a weight. In the drum is a breathing gas, usually air or oxygen; a tube connects the mouth with the gas chamber . When one breathes into and out of the chamber, the drum rises and falls, and an appropriate recording is made on a moving sheet of paper. events of pulmonary ventilation, the air in the lungs has been subdivided in this diagram into four volumes and four capacities

25. Pulmonary Volumes 1. The tidal volume is the volume of air inspired or expired with each normal breath; it amounts to about 500 milliliters in the adult male. 2. The inspiratory reserve volume is the extra volume of air that can be inspired over and above the normal tidal volume when the person inspires with full force; it is usually equal to about 3000 milliliters . 3. The expiratory reserve volume is the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration; this normally amounts to about 1100 milliliters . 4. The residual volume is the volume of air remaining in the lungs after the most forceful expiration ; this volume averages about 1200 milliliters .

26. Pulmonary Capacities All pulmonary volumes and capacities are about 20 to 25 per cent less in women than in men, and they are greater in large and athletic people than in small and asthenic people. VC = IRV + VT + ERV VC = IC + ERV TLC = VC + RV TLC = IC + FRC FRC = ERV + RV

27. Functional Residual Capacity, Residual Volume, and Total Lung Capacity The functional residual capacity (FRC), which is the volume of air that remains in the lungs at the end of each normal expiration, is important to lung function. Because its value changes markedly in some types of pulmonary disease The spirometer cannot be used in a direct way to measure the functional residual capacity,

28. The volume of air that can be forcibly expired in the first second is called FEV 1 . Likewise , the cumulative volume expired in 2 seconds is called FEV 2 , and the cumulative volume expired in 3 seconds is called FEV 3 . Normally , the entire vital capacity can be forcibly expired in 3 seconds, so there is no need for "FEV 4 ."

29. FVC and FEV 1 are useful indices of lung disease. Specifically , the fraction of the vital capacity that can be expired in the first second, FEV 1 /FVC, can be used to differentiate among diseases. For example, in a normal person, FEV 1 /FVC is approximately 0.8, meaning that 80% of the vital capacity can be forcibly expired in the first second

30. In a patient with an obstructive lung disease such as asthma, both FVC and FEV 1 are decreased, but FEV 1 is decreased more than FVC is. Thus, FEV 1 /FVC is also decreased, which is typical of airway obstruction with increased resistance to expiratory airflow In a patient with a restrictive lung disease such as fibrosis, both FVC and FEV 1 are decreased, but FEV 1 is decreased less than FVC is. Thus, in fibrosis, FEV 1 /FVC is actually increased

31. MEASUREMENTS OF FRC because the air in the residual volume of the lungs cannot be expired into the spirometer, and this volume constitutes about one half of the functional residual capacity. To measure functional residual capacity, the spirometer must be used in an indirect manner Two methods are used

32. The helium dilution method, T he subject breathes a known amount of helium After a few breaths the helium concentration in the lungs becomes equal to that in the spirometer, which can be measured. The amount of helium that was added to the spirometer and its concentration in the lungs are used to "back-calculate" the lung volume. If this measurement is made after a normal tidal volume is expired, the lung volume being calculated is the FRC.

33. The body plethysmograph employs a variant of Boyle's law, which states that for gases at constant temperature, gas pressure multiplied by gas volume is constant (P × V = constant). I f volume increases, pressure must decrease, and if volume decreases, pressure must increase. To measure FRC, the subject sits in a large airtight box called a plethysmograph . After expiring a normal tidal volume, the mouthpiece to the subject's airway is closed. The subject then attempts to breathe. As the subject tries to inspire, the volume in the subject's lungs increases, and the pressure in his or her lungs decreases. Simultaneously , the volume in the box decreases, and the pressure in the box increases. The increase in pressure in the box can be measured and, from it, the preinspiratory volume in the lungs can be calculated, which is the FRC.

34. Minute Respiratory Volume The minute respiratory volume is the total amount of new air moved into the respiratory passages each minute ; this is equal to the tidal volume times the respiratory rate per minute. The normal tidal volume is about 500 milliliters , and the normal respiratory rate is about 12 breaths per minute. Therefore , the minute respiratory volume averages about 6 L/min. A person can live for a short period with a respiratory rate of only 2 to 4 breaths per minute. The respiratory rate occasionally rises to 40 to 50

35. Alveolar Ventilation The ultimate importance of pulmonary ventilation is to continually renew the air in the gas exchange areas of the lungs, where air is in proximity to the pulmonary blood . These areas include the alveoli, alveolar sacs, alveolar ducts, and respiratory bronchioles . The rate at which new air reaches these areas is called alveolar ventilation.

36. “Dead Space” and Its Effect on Alveolar Ventilation Some of the air a person breathes never reaches the gas exchange areas but simply fills respiratory passages where gas exchange does not occur, such as the nose , pharynx, and trachea . This air is called dead space air because it is not useful for gas exchange .

37. On expiration, the air in the dead space is expired first, before any of the air from the alveoli reaches the atmosphere. Therefore, the dead space is very disadvantageous for removing the expiratory gases from the lungs .

38. The volume of the physiologic dead space is estimated based on the measurement of the partial pressure of CO 2 (P co 2 ) of mixed expired air (P e CO2 ) Three assumptions: 1 All of the CO 2 in expired air comes from exchange of CO 2 in functioning (ventilated and perfused) alveoli; 2 there is essentially no CO 2 in inspired air; and 3 the physiologic dead space (nonfunctioning alveoli and airways) neither exchanges nor contributes any CO 2 .

39. If physiologic dead space is zero, then P e CO2 will be equal to alveolar P co 2 (P a CO2 ). However, if a physiologic dead space is present, then P e CO2 will be "diluted" by dead space air and P e CO2 will be less than P a CO2 by a dilution factor. By comparing P e CO2 with P a CO2 , the dilution factor (i.e., volume of the physiologic dead space) can be measured. A potential problem in measuring physiologic dead space is that alveolar air cannot be sampled directly. Thus , the P co 2 of systemic arterial blood (Pa CO2 ) is equal to the P co 2 of alveolar air (P a CO2 ).

40. the equation states that the volume of the physiologic dead space is the tidal volume (volume inspired with a single breath) multiplied by a fraction. The fraction represents the dilution of alveolar P co 2 by dead space air (which contributes no CO 2 ).

41. Anatomic and Physiologic Dead Space measuring the dead space measures the volume of all the space of the respiratory system other than the alveoli and their other closely related gas exchange areas; this space is called the anatomic dead space. some of the alveoli themselves are non functional or only partially functional because of absent or poor blood flow through the adjacent pulmonary capillaries. Therefore , from a functional point of view , these alveoli must also be considered dead space .

42. When the alveolar dead space is included in the total measurement of dead space - the physiologic dead space In a normal person, the anatomic and physiologic dead spaces are nearly equal because all alveoli are functional in the normal lung, in a person with partially functional or non functional alveoli in some parts of the lungs the physiologic dead space may be as much as 10 times the volume of the anatomic dead space, or 1 to 2 liters .

43. Rate of Alveolar Ventilation Alveolar ventilation per minute is the total volume of new air entering the alveoli and adjacent gas exchange areas each minute. It is equal to the respiratory rate times the amount of new air that enters these areas with each breath. A = Freq • (VT – VD) where A is the volume of alveolar ventilation per minute , Freq is the frequency of respiration per minute , VT is the tidal volume, and VD is the physiologic dead space volume .

44. Thus, with a normal tidal volume of 500 milliliters , dead space of 150 milliliters , and a respiratory rate of 12 breaths per minute, alveolar ventilation equals 12 X (500 – 150), or 4200 ml/min. Alveolar ventilation is one of the major factors determining the concentrations of oxygen and carbon dioxide in the alveoli.

45. Blood flow Pulmonary blood flow is the cardiac output of the right heart. It is ejected from the right ventricle and is delivered to the lungs via the pulmonary artery . The pulmonary arteries branch into increasingly smaller arteries and travel with the bronchi toward the respiratory zones. The smallest arteries divide into arterioles and then into the pulmonary capillaries, which form dense networks around the alveoli. Because of gravitational effects, pulmonary blood flow is not distributed evenly in the lungs.

46. When a person is standing, blood flow is lowest at the apex (top) of the lungs and highest at the base (bottom) of the lungs. When the person is supine (lying down), these gravitational effects disappear. regulation of pulmonary blood flow is accomplished by altering the resistance of the pulmonary arterioles . Changes in pulmonary arteriolar resistance are controlled by local factors, mainly O 2 . Bronchial circulation is the blood supply to the conducting airways (which do not participate in gas exchange) and is a very small fraction of the total pulmonary blood flow

47. Lymphatics Lymph vessels are present in all the supportive tissues of the lung - right thoracic lymph duct . help to prevent pulmonary edema .

48. Pressures in the Pulmonary System The systolic pressure in the right ventricle of The normal human being averages about 25 mm Hg , and the diastolic pressure Normal human being, the diastolic pulmonary arterial pressure is about 8 mm Hg, The mean pulmonary arterial pressure is 15 mm Hg.

49. Pulmonary Capillary Pressure The mean pulmonary capillary pressure is 7 mm Hg. The importance of this low capillary pressure

50. Left Atrial and Pulmonary Venous Pressures The mean pressure in the left atrium and the major pulmonary veins averages about 2 mm Hg in the recumbent human being, Varying from as low as 1 mm Hg to as high as 5 mm Hg. Left atrial pressure can be estimated with by measuring the pulmonary wedge pressure.

51. Blood Flow Through the Lungs and Its Distribution The blood flow through the lungs is essentially equal to the cardiac output. Therefore , the factors that control cardiac output also control pulmonary blood flow. Pulmonary vessels act as passive, distensible tubes that enlarge with increasing pressure and narrow with decreasing pressure . For adequate aeration of the blood it is important for the blood to be distributed to those segments of the lungs where the alveoli are best oxygenated.

52. Automatic Control of Pulmonary Blood Flow Distribution. When the concentration of oxygen in the air of the alveoli decreases below normal—below 70 per cent of normal (below 73 mm Hg Po2) The adjacent blood vessels constrict, with the vascular resistance increasing more than fivefold at extremely low oxygen levels. This is opposite to the effect observed in systemic vessels, which dilate rather than constrict in response to low oxygen. Low oxygen concentration causes release of vasoconstrictor substance by the alveolar epithelial cells when they become hypoxic. This substance promotes constriction of the small arteries and arterioles.

53. Effect of low oxygen on pulmonary vascular resistance has an important function: To distribute blood flow where it is most effective. If some alveoli are poorly ventilated so that their oxygen concentration becomes low, the local vessels constrict. This causes the blood to flow through other areas of the lungs that are better aerated , Thus providing an automatic control system for distributing blood flow to the pulmonary areas in proportion to their alveolar oxygen pressures.

54. Regulation of Pulmonary Blood Flow Hypoxic vasoconstriction The major factor regulating pulmonary blood flow is the partial pressure of O 2 in alveolar gas, P a O2 . Decreases in P a O2 produce pulmonary vasoconstriction, i.e., hypoxic vasoconstriction. Initially , this effect may seem counterintuitive, because in several vascular beds decreases in P o 2 produce the exact opposite effect, vasodilation (to increase O 2 delivery to the tissue). In the lungs, however, hypoxic vasoconstriction occurs as an adaptive mechanism, reducing pulmonary blood flow to poorly ventilated areas where the blood flow would be "wasted." Thus , pulmonary blood flow is directed away from poorly ventilated regions of the lung, where gas exchange would be inadequate, and toward well-ventilated regions of the lung, where gas exchange will be better.

55. In certain types of lung disease, hypoxic vasoconstriction serves a protective role because, within limits, blood can be redirected to alveoli that are well oxygenated without changing overall pulmonary vascular resistance. The compensatory mechanism fails, however, if the lung disease is widespread (e.g., multilobar pneumonia); If there are insufficient areas of well-ventilated alveoli, hypoxemia will occur. The mechanism of hypoxic vasoconstriction involves a direct action of alveolar P o 2 on the vascular smooth muscle of pulmonary arterioles. This action can be understood by recalling the proximity of the alveoli to the pulmonary microcirculation. The arterioles and their capillary beds densely surround the alveoli. O 2 is highly lipid-soluble and, therefore, is quite permeable across cell membranes.

56. When P a O2 is normal (at 100 mm Hg), O 2 diffuses from the alveoli into the nearby arteriolar smooth muscle cells, keeping the arterioles relatively relaxed and dilated. If P a O2 is reduced to values between 100 mm Hg and 70 mm Hg, vascular tone is minimally affected. If P a O2 is reduced below 70 mm Hg, the vascular smooth muscle cells sense this hypoxia, vasoconstriction, and reduce pulmonary blood flow in that region. The mechanism whereby alveolar hypoxia causes contraction of nearby vascular smooth muscle is not precisely understood. It is believed that hypoxia causes depolarization of vascular smooth muscle cells; depolarization opens voltage-gated Ca 2+ channels, leading to Ca 2+ entry into the cell and contraction .

57. Hypoxic vasoconstriction can function locally to redirect blood flow to well-ventilated regions of the lung. It also can operate globally in an entire lung, in which case the vasoconstriction will produce an increase in pulmonary vascular resistance. For example, at high altitude or in persons breathing a low O 2 mixture, P a O2 is reduced throughout the lungs, not just in one region. The low P a O2 produces global vasoconstriction of pulmonary arterioles and an increase in pulmonary vascular resistance.

58. In response to the increase in resistance, pulmonary arterial pressure increases. In chronic hypoxia, the increased pulmonary arterial pressure causes hypertrophy of the right ventricle, which must pump against an increased afterload. Fetal circulation is another example of global hypoxic vasoconstriction. Because the fetus does not breathe, P a O2 is much lower in the fetus than in the mother, producing vasoconstriction in the fetal lungs. This vasoconstriction increases pulmonary vascular resistance and, accordingly, decreases pulmonary blood flow to approximately 15% of the cardiac output. At birth, the neonate's first breath increases P a O2 to 100 mm Hg, hypoxic vasoconstriction is reduced, pulmonary vascular resistance decreases, and pulmonary blood flow increases and eventually equals cardiac output of the left side of the heart (as in the adult).

59. Other vasoactive substances. In addition to O 2 , several other substances alter pulmonary vascular resistance. Thromboxane A 2 , a product of arachidonic acid metabolism (via the cyclooxygenase pathway) in macrophages, leukocytes, and endothelial cells, is produced in response to certain types of lung injury. Thromboxane A 2 is a powerful local vasoconstrictor of both arterioles and veins. Prostacyclin (prostaglandin I 2 ), also a product of arachidonic acid metabolism via the cyclooxygenase pathway, is a potent local vasodilator. It is produced by lung endothelial cells. The leukotrienes , another product of arachidonic acid metabolism (via the lipoxygenase pathway), cause airway constriction.

60. Pressure Gradients in the Lungs on Regional Pulmonary Blood Flow the blood pressure in the foot of a standing person can be as much as 90 mm Hg greater than the pressure at the level of the heart. This is caused by hydrostatic pressure The same effect, but to a lesser degree, occurs in the lungs. In the normal, upright adult, the lowest point in the lungs is about 30 cm below the highest point . There is a 23 mm Hg pressure difference, about 15 mm Hg of which is above the heart and 8 below. The pulmonary arterial pressure in the uppermost portion of the lung of a standing person is about 15 mm Hg less than the pulmonary arterial pressure at the level of the heart the pressure in the lowest portion of the lungs is about 8 mm Hg greater

61. pressure differences have profound effects on blood flow through the different areas of the lungs. In the standing position at rest , there is little flow in the top of the lung but about five times as much flow in the bottom. To explain these differences, lung is divided into three zones In each zone, the patterns of blood flow are quite different.

62. Properties of Gases The pressure of a gas is proportional to its temperature and the number of moles per volume: where P = Pressure n = Number of moles R = Gas constant T = Absolute temperature V = Volume

63. Partial Pressures gases expand to fill the volume available to them, the volume occupied by a given number of gas molecules at a given temperature and pressure is (ideally) the same regardless of the composition of the gas. The pressure exerted by any one gas in a mixture of gases (its partial pressure ) is equal to the total pressure times the fraction of the total amount of gas it represents .

64. The composition of dry air is 20.98% O 2 , 0.04% CO 2 , 78.06% N 2 , and 0.92% other inert constituents such as argon and helium. The barometric pressure (PB) at sea level is 760 mm Hg (1 atmosphere). The partial pressure (indicated by the symbol P) of O 2 in dry air is therefore 0.21 x 760, or 160 mm Hg at sea level. The PN 2 and the other inert gases is 0.79 x 760, or 600 mm Hg; and the PCO 2 is 0.0004 x 760, or 0.3 mm Hg.

65. The water vapor in the air in most climates reduces these percentages, and therefore the partial pressures. Air equilibrated with water is saturated with water vapor Inspired air is saturated by the time it reaches the lungs. The Ph 2 O at body temperature (37 °C) is 47 mm Hg. The partial pressures at sea level of the other gases in the air reaching the lungs are PO 2 , 149 mm Hg; PCO 2 , 0.3 mm Hg; and PN 2 (including the other inert gases), 564 mm Hg.

66. Gas diffuses from areas of high pressure to areas of low pressure the rate of diffusion depending on the concentration gradient and the nature of the barrier between the two areas. When a mixture of gases is in contact with and permitted to equilibrate with a liquid, Each gas in the mixture dissolves in the liquid to an extent determined by its partial pressure and its solubility in the fluid . The partial pressure of a gas in a liquid is the pressure that, in the gaseous phase in equilibrium with the liquid, would produce the concentration of gas molecules found in the liquid

67. DIFFUSION OF GASES-FICK'S LAW Transfer of gases across cell membranes or capillary walls occurs by simple diffusion For gases, the rate of transfer by diffusion ( V x ) is directly proportional to the driving force, a diffusion coefficient, and the surface area available for diffusion; it is inversely proportional to the thickness of membrane barrier. Thus,where V x - Volume of gas transferred per unit time D - Diffusion coefficient of the gas A- Surface area ΔP- Partial pressure difference of the gas Δ x Thickness of the membrane

68. (1 ) The driving force for diffusion of a gas is the partial pressure difference of the gas ( Δ P) across the membrane, not the concentration difference. if the P o 2 of alveolar air is 100 mm Hg and the P o 2 of mixed venous blood that enters the pulmonary capillary is 40 mm Hg , then the partial pressure difference, or driving force, for O 2 across the alveolar/pulmonary capillary barrier is 60 mm Hg (100 mm Hg - 40 mm Hg ). (2) The diffusion coefficient of a gas (D) is a combination of the usual diffusion coefficient, which depends on molecular weight and the solubility of the gas. The diffusion coefficient for CO 2 is approximately 20 times higher than the diffusion coefficient for O 2 ; a result, for a given partial pressure difference, CO 2 diffuses approximately 20 times faster than O 2 .

69. FORMS OF GASES IN SOLUTION In alveolar air, there is one form of gas expressed as a partial pressure. in solutions such as blood, gases are carried in additional forms. In solution, gas may be dissolved, it may be bound to proteins, or it may be chemically modified. total gas concentration in solution is the sum of dissolved gas plus bound gas plus chemically modified gas.

70. Dissolved gas Henry's law gives the relationship between the partial pressure of a gas and its concentration in solution For a given partial pressure, the higher the solubility of the gas, the higher the concentration of gas in solution. In solution, only dissolved gas molecules contribute to the partial pressure. bound gas and chemically modified gas do not contribute to the partial pressure. Of the gases found in inspired air, nitrogen (N 2 ) is the only one that is carried only in dissolved form, and it is never bound or chemically modified. N 2 is used for certain measurements in respiratory physiology

71. Bound gas. O 2 , CO 2 , and carbon monoxide (CO) are bound to proteins in blood . O 2 and CO bind to hemoglobin inside red blood cells and are carried in this form. CO 2 binds to hemoglobin in red blood cells and to plasma proteins. Chemically modified gas. The most significant example of a chemically modified gas is the conversion of CO 2 to bicarbonate (HCO 3 - ) in red blood cells by the action of carbonic anhydrase. most CO 2 is carried in blood as HCO 3 - , rather than as dissolved CO 2 or as bound CO 2 .

72. GAS TRANSPORT IN THE LUNGS the pulmonary capillaries are perfused with blood from the right heart (the equivalent of mixed venous blood). Gas exchange then occurs between alveolar gas and the pulmonary capillary: O 2 diffuses from alveolar gas into pulmonary capillary blood, and CO 2 diffuses from pulmonary capillary blood into alveolar gas. The blood leaving the pulmonary capillary is delivered to the left heart and becomes systemic arterial blood.

73. In dry inspired air, the P o 2 is approximately 160 mm Hg , computed by multiplying the barometric pressure times the fractional concentration of O 2 , 21% (760 mm Hg × 0.21 = 160 mm Hg ) In humidified tracheal air, the air becomes fully saturated with water vapor . At 37°C, P h 2 o is 47 mm Hg. Thus , in comparison to dry inspired air, P o 2 is reduced, since the O 2 is "diluted" by water vapor . R ecall that partial pressures in humidified air are calculated by correcting the barometric pressure for water vapor pressure, then multiplying by the fractional concentration of the gas. Thus, the P o 2 of humidified tracheal air is 150 mm Hg ([760 mm Hg - 47 mm Hg] × 0.21 = 150 mm Hg). Since there is no CO 2 in inspired air, the P co 2 of humidified tracheal air also is zero. The humidified air enters the alveoli, where gas exchange occurs.

74. In alveolar air, the values for P o 2 and P co 2 are changed substantially when compared with inspired air. The notations for partial pressures in alveolar air use the modifier "A"; P a O2 is 100 mm Hg, which is less than in inspired air, and P a CO2 is 40 mm Hg, which is greater than in inspired air. These changes occur because O 2 leaves alveolar air and is added to pulmonary capillary blood, and CO 2 leaves pulmonary capillary blood and enters alveolar air. Normally , the amounts of O 2 and CO 2 transferred between the alveoli and pulmonary capillary blood correspond to the needs of the body. Thus , on a daily basis, O 2 transfer from alveolar air equals O 2 consumption by the body, and CO 2 transfer to alveolar air equals CO 2 production.

75. Blood entering the pulmonary capillaries is essentially mixed venous blood. This blood has been returned from the tissues, via the veins, to the right heart. It is then pumped from the right ventricle into the pulmonary artery, which delivers it to the pulmonary capillaries. The composition of this mixed venous blood reflects metabolic activity of the tissues: The P o 2 is relatively low, at 40 mm Hg, because the tissues have taken up and consumed O 2 ; the P co 2 is relatively high, at 46 mm Hg, because the tissues have produced CO 2 and added it to venous blood

76. The blood that leaves the pulmonary capillaries has been arterialized (oxygenated) and will become systemic arterial blood. The arterialization is effected by the exchange of O 2 and CO 2 between alveolar air and pulmonary capillary blood. Because diffusion of gases across the alveolar/capillary barrier is rapid, blood leaving the pulmonary capillaries normally has the same P o 2 and P co 2 as alveolar air - there is complete equilibration Hence , Pa O2 is 100 mm Hg and Pa CO2 is 40 mm Hg, just as P a O2 is 100 mm Hg and P a CO2 is 40 mm Hg. This arterialized blood will now be returned to the left heart, pumped out of the left ventricle into the aorta, and begin the cycle again.

77. DIFFUSION-LIMITED AND PERFUSION-LIMITED GAS EXCHANGE Gas exchange across the alveolar/pulmonary capillary barrier is described as either diffusion-limited or perfusion-limited. Diffusion-limited gas exchange means that the total amount of gas transported across the alveolar-capillary barrier is limited by the diffusion process. In these cases, as long as the partial pressure gradient for the gas is maintained, diffusion will continue along the length of the capillary. Perfusion-limited gas exchange means that the total amount of gas transported across the alveolar/capillary barrier is limited by blood flow (i.e., perfusion) through the pulmonary capillaries. In perfusion-limited exchange, the partial pressure gradient is not maintained, and in this case, the only way to increase the amount of gas transported is by increasing blood flow.

78. CO is a diffusion-limited gas and nitrous oxide (N 2 O) is a perfusion-limited gas CO or N 2 O diffuse out of alveolar gas into the pulmonary capillary, Pa for the gas increases along the length of the capillary and approaches or reaches the value for P a . If the value for Pa reaches the value of P a , then complete equilibration has occurred. Once equilibration occurs, there is no longer a driving force for diffusion (i.e., there is no longer a partial pressure gradient) unless blood flow increases - more blood enters the pulmonary capillary

79. Diffusion-Limited Gas Exchange Diffusion-limited gas exchange - the transport of CO across the alveolar/pulmonary capillary barrier It is also illustrated by the transport of O 2 during strenuous exercise and in pathologic conditions such as emphysema and fibrosis.

80. net diffusion of CO into the pulmonary capillary depends on the magnitude of the partial pressure gradient which is maintained because CO is bound to hemoglobin in capillary blood. Thus , CO does not equilibrate by the end of the capillary. In fact, if the capillary were longer, net diffusion would continue indefinitely, or until equilibration occurred.

81. Perfusion-limited O 2 transport In the lungs of a normal person at rest, O 2 transfer from alveolar air into pulmonary capillary blood is perfusion -limited (although not to the extreme that N 2 O is perfusion-limited) P a O2 is constant at 100 mm Hg. At the beginning of the capillary, Pa O2 is 40 mm Hg, reflecting the composition of mixed venous blood. There is large partial pressure gradient for O 2 between alveolar air and capillary blood, which drives O 2 diffusion into the capillary. As O 2 is added to pulmonary capillary blood, Pa O2 increases. The gradient for diffusion is maintained initially because O 2 binds to hemoglobin , which keeps the free O 2 concentration and the partial pressure low. Equilibration of O 2 occurs about one third of the distance along the capillary, at which point Pa O2 becomes equal to P a O2 , and unless blood flow increases, there can be no more net diffusion of O 2 . Thus , under normal conditions, O 2 transport is perfusion-limited. perfusion-limited O 2 exchange is to say that pulmonary blood flow determines net O 2 transfer. increases in pulmonary blood flow (e.g., during exercise) will increase the total amount of O 2 transported, and decreases in pulmonary blood flow will decrease the total amount transported.

82. Diffusion-limited O 2 transport In certain pathologic conditions (e.g., fibrosis ) and during strenuous exercise, O 2 transfer becomes diffusion limited. For example, in fibrosis the alveolar wall thickens, increasing the diffusion distance for gases and decreasing D l This increased diffusion distance slows the rate of diffusion of O 2 and prevents equilibration of O 2 between alveolar air and pulmonary capillary blood. In these cases, the partial pressure gradient for O 2 is maintained along the entire length of the capillary, converting it to a diffusion-limited process (although not as extreme as in the example of CO; Because a partial pressure gradient is maintained along the entire length of the capillary, It may seem that the total amount of O 2 transferred would be greater in a person with fibrosis than in a person with normal lungs

83. O 2 transport at high altitude Ascent to high altitude alters some aspects of the O 2 equilibration process. At high altitude, barometric pressure is reduced, and with the same fraction of O 2 in inspired air, the partial pressure of O 2 in alveolar gas also will be reduced. P a O2 is reduced to 50 mm Hg, compared with the normal value of 100 mm Hg. Mixed venous P o 2 is 25 mm Hg (as opposed to the normal value of 40 mm Hg). Therefore, at high altitude, the partial pressure gradient for O 2 is greatly reduced compared with sea level Even at the beginning of the pulmonary capillary, the gradient is only 25 mm Hg (50 mm Hg - 25 mm Hg), instead of the normal gradient at sea level of 60 mm Hg (100 mm Hg - 40 mm Hg). This reduction of the partial pressure gradient means that diffusion of O 2 will be reduced, equilibration will occur more slowly along the capillary, and complete equilibration will be achieved at a later point along the capillary (two-thirds of the capillary length at high altitude, compared with one third of the length at sea level). The final equilibrated value for Pa O2 is only 50 mm Hg, because P a O2 is only 50 mm Hg (it is impossible for the equilibrated value to be higher than 50 mm Hg). The slower equilibration of O 2 at high altitude is exaggerated in a person with fibrosis. Pulmonary capillary blood does not equilibrate by the end of the capillary, resulting in values for Pa O2 as low as 30 mm Hg, which will seriously impair O 2 delivery to the tissues

84. Oxygen Transport in Blood FORMS OF O 2 IN BLOOD O 2 is carried in two forms in blood: dissolved and bound to hemoglobin . Dissolved O 2 alone is inadequate to meet the metabolic demands of the tissues; thus, a second form of O 2 , combined with hemoglobin , is needed Dissolved O 2 is free in solution and accounts for approximately 2% of the total O 2 content of blood. Dissolved O 2 is the only form of O 2 that produces a partial pressure, which, in turn, drives O 2 diffusion. (In contrast, O 2 bound to hemoglobin does not contribute to its partial pressure in blood. The concentration of dissolved O 2 is proportional to the partial pressure of O 2 ; the proportionality constant is simply the solubility of O 2 in blood, 0.003 mL O 2 /100 mL blood/mm Hg. Thus , for a normal Pa O2 of 100 mm Hg, the concentration of dissolved O 2 is 0.3 mL O 2 /100 mL (100 mm Hg × 0.003 mL O 2 /100 mL blood/mm Hg).

85. At this concentration, dissolved O 2 is grossly insufficient to meet the demands of the tissues. For example, in a person at rest, O 2 consumption is about 250 mL O 2 /min. If O 2 delivery to the tissues were based strictly on the dissolved component, then 15 mL O 2 /min would be delivered to the tissues (O 2 delivery = Cardiac output × dissolved O 2 concentration, or 5 L/min × 0.3 mL O 2 /100 mL = 15 mL O 2 /min). Clearly , this amount is insufficient to meet the demand of 250 mL O 2 /min. An additional mechanism for transporting large quantities of O 2 in blood is needed-that mechanism is O 2 bound to hemoglobin .

86. O 2 Bound to Hemoglobin The remaining 98% of the total O 2 content of blood is reversibly bound to hemoglobin inside the red blood cells. Hemoglobin is a globular protein consisting of four subunits. Each subunit contains a heme moiety, which is an iron-binding porphyrin , and a polypeptide chain, which is designated either α or β. Adult hemoglobin ( hemoglobin A) is called α 2 β 2 ; two of the subunits have α chains and two have β chains. Each subunit can bind one molecule of O 2 , for a total of four molecules of O 2 per molecule of hemoglobin . When hemoglobin is oxygenated, it is called oxyhemoglobin ; when it is deoxygenated, it is called deoxyhemoglobin . For the subunits to bind O 2 , iron in the heme moieties must be in the ferrous state (i.e., Fe 2+ ).

87. Methemoglobin If the iron component of the heme moieties is in the ferric, or Fe 3+ , state (rather than the normal Fe 2+ state), it is called methemoglobin . Methemoglobin does not bind O 2 . Methemoglobinemia has several causes, including oxidation of Fe 2+ to Fe 3+ by nitrites and sulfonamides . There is also a congenital variant of the disease in which there is a deficiency of methemoglobin reductase , an enzyme in red blood cells that normally keeps iron in its reduced state.

88. Fetal hemoglobin - HbF In fetal hemoglobin , the two β chains are replaced by γ chains, giving it the designation of α 2 γ 2 . The physiologic consequence of this modification is that hemoglobin F has a higher affinity for O 2 than hemoglobin A, facilitating O 2 movement from the mother to the fetus . Hemoglobin F is the normal variant present in the fetus and is replaced by hemoglobin A within the first year of life. Hemoglobin S. Hemoglobin S is an abnormal variant of hemoglobin that causes sickle cell disease. In hemoglobin S, the α subunits are normal and the β subunits are abnormal, giving it the designation α A 2 β S 2 . In its deoxygenated form, hemoglobin S forms sickle-shaped rods in the red blood cells, distorting the shape of the red blood cells (i.e., sickling them). This deformation of the red blood cells can result in occlusion of small blood vessels. The O 2 affinity of hemoglobin S is less than the O 2 affinity of hemoglobin A

89. O 2 -BINDING CAPACITY AND O 2 CONTENT O 2 transported in blood is reversibly bound to hemoglobin , The O 2 content of blood is primarily determined by the hemoglobin concentration and by the O 2 -binding capacity of that hemoglobin The O 2 -binding capacity is the maximum amount of O 2 that can be bound to hemoglobin per volume of blood Hemoglobin A can bind 1.34 mL O 2

90. The normal concentration of hemoglobin A in blood is 15 g/100 mL. The O 2 -binding capacity of blood is therefore 20.1 mL O 2 /100 mL blood (15 g/100 mL × 1.34 mL O 2 /g Hb). The O 2 content is the actual amount of O 2 per volume of blood. The O 2 content can be calculated from the O 2 -binding capacity of Hb

91. O 2 DELIVERY TO TISSUES The amount of O 2 delivered to tissues is determined by blood flow and the O 2 content of blood. Blood flow is considered to be cardiac output. O 2 content of blood, is the sum of dissolved O 2 (2%) and O 2 -hemoglobin (98%).

92. O 2 -HEMOGLOBIN DISSOCIATION CURVE O 2 combines reversibly and rapidly with hemoglobin , binding to heme groups on each of the four subunits of the hemoglobin molecule. Each hemoglobin molecule, therefore, has the capacity to bind four molecules of O 2 . In this configuration, saturation is 100%. If less than four molecules of O 2 are bound to heme groups, then saturation is less than 100 %. For example, if, on average, each hemoglobin molecule has three molecules of O 2 bound, then saturation is 75%; If, on average, each hemoglobin has two molecules of O 2 bound, then saturation is 50% If only one molecule of O 2 is bound, saturation is 25%

93. Percent saturation of hemoglobin is a function of the P o 2 of blood O 2 -hemoglobin dissociation curve- this curve is its sigmoidal shape. In other words, the percent saturation of heme sites does not increase linearly as P o 2 increases. Rather , percent saturation increases steeply as P o 2 increases from zero to approximately 40 mm Hg, and it then levels off between 50 mm Hg and 100 mm Hg.

94. The shape of the steepest portion of the curve is the result of a change in affinity of the heme groups for O 2 as each successive O 2 molecule binds: Binding of the first molecule of O 2 to a heme group increases the affinity for the second O 2 molecule, binding of the second O 2 molecule increases the affinity for the third O 2 molecule, and so forth. Affinity for the fourth, and last, molecule of O 2 is highest and occurs at values of P o 2 between approximately 60 and 100 mm Hg - where saturation is nearly 100 % This phenomenon is described as positive cooperativity

95. A significant point on the O 2 -hemoglobin dissociation curve is the P 50 . By definition, P 50 is the P o 2 at which hemoglobin is 50% saturated (i.e., where two of the four heme groups are bound to O 2 ). A change in the value of P 50 is used as an indicator for a change in affinity of hemoglobin for O 2 . An increase in P 50 reflects a decrease in affinity, and a decrease in P 50 reflects an increase in affinity

96. Loading and Unloading of O 2 The sigmoidal shape of the O 2 -hemoglobin dissociation curve helps to explain why; O 2 is loaded into pulmonary capillary blood from alveolar gas and unloaded from systemic capillaries into the tissues. At the highest values of P o 2 (i.e., in systemic arterial blood), the affinity of hemoglobin for O 2 is highest; at lower values of P o 2 (i.e., in mixed venous blood), affinity for O 2 is lower)

97. Alveolar air, pulmonary capillary blood, and systemic arterial blood all have a P o 2 of 100 mm Hg. A P o 2 of 100 mm Hg corresponds to almost 100% saturation, with all heme groups bound to O 2 , and affinity for O 2 at its highest value due to positive cooperativity . Mixed venous blood has a P o 2 of 40 mm Hg A P o 2 of 40 mm Hg corresponds to approximately 75% saturation and a lower affinity of hemoglobin for O 2 . Thus , the sigmoidal shape of the curve reflects changes in the affinity of hemoglobin for O 2 , These changes in affinity facilitate loading of O 2 in the lungs where P o 2 and affinity are highest) and unloading of O 2 in the tissues (where P o 2 and affinity are lower

98. In the lungs, Pa O2 is 100 mm Hg. Hemoglobin is nearly 100% saturated (all heme groups are bound to O 2 ). Due to positive cooperativity , affinity is highest and O 2 is most tightly bound Also , because O 2 is so tightly bound to hemoglobin in this range, relatively less O 2 is in the dissolved form to produce a partial pressure; By keeping the P o 2 of pulmonary capillary blood lower than the P o 2 of alveolar gas, O 2 diffusion into the capillary will continue. The flat portion of the curve extends from 100 mm Hg to 60 mm Hg, means that humans can tolerate substantial decreases in alveolar P o 2 to 60 mm Hg (e.g., caused by decreases in atmospheric pressure) without significantly compromising the amount of O 2 carried by hemoglobin . In the tissues, P[ vbar ] O2 is approximately 40 mm Hg, much lower than it is in the lungs. At a P o 2 of 40 mm Hg, hemoglobin is only 75% saturated and the affinity for O 2 is decreased. O 2 is not as tightly bound in this part of the curve, which facilitates unloading of O 2 in the tissues.

99. The partial pressure gradient for O 2 diffusion into the tissues is maintained in two ways: First , the tissues consume O 2 , keeping their P o 2 low. Second , the lower affinity for O 2 ensures that O 2 will be unloaded more readily from hemoglobin ; unbound O 2 is free in blood, creates a partial pressure, and the P o 2 of blood is kept relatively high. Because the P o 2 of the tissue is kept relatively low, the partial pressure gradient that drives O 2 diffusion from blood to tissues is maintained

100. The O 2 -hemoglobin dissociation curve can shift to the right or shift to the left Such shifts reflect changes in the affinity of hemoglobin for O 2 and produce changes in P 50 . Shifts can occur with no change in O 2 -binding capacity, In which case the curve moves right or left, but the shape of the curve remains unchanged. A right or left shift can occur in which the O 2 -binding capacity of hemoglobin also changes and, in this case, the shape

101. Shifts to the Right Shifts of the O 2 -hemoglobin dissociation curve to the right occur when there is decreased affinity of hemoglobin for O 2 A decrease in affinity is reflected in an increase in P 50 , which means that 50% saturation is achieved at a higher-than-normal value of P o 2 . When the affinity is decreased, unloading of O 2 in the tissues is facilitated. It is advantageous to facilitate unloading of O 2 in the tissues

102. Increases in P co 2 and decreases in pH. When metabolic activity of the tissues increases, the production of CO 2 increases; The increase in tissue P co 2 causes an increase in H + and decrease in pH. Together , these effects decrease the affinity of hemoglobin for O 2 , Shift the O 2 -hemoglobin dissociation curve to the right, and increase the P 50 , all of which facilitates unloading of O 2 from hemoglobin in the tissues. This mechanism helps to ensure that O 2 delivery can meet O 2 demand (e.g., in exercising skeletal muscle). The effect of P co 2 and pH on the O 2 -hemoglobin dissociation curve is called the Bohr effect. Increases in temperature. Increases in temperature also cause a right shift of the O 2 -hemoglobin dissociation curve and an increase in P 50 , facilitating unloading of O 2 in the tissues

103. Increases in 2,3-diphosphoglycerate (2,3-DPG) concentration 2,3-DPG is a byproduct of glycolysis in red blood cells. 2,3-DPG binds to the β chains of deoxyhemoglobin and reduces their affinity for O 2 . This decrease in affinity causes the O 2 -hemoglobin dissociation curve to shift to the right and facilitates unloading of O 2 in the tissues. 2,3-DPG production increases under hypoxic conditions. For example, living at high altitude causes hypoxemia, which stimulates the production of 2,3-DPG in red blood cells. In turn, increased levels of 2,3-DPG facilitate the delivery of O 2 to the tissues as an adaptive mechanism

104. Shifts to the Left Shifts of the O 2 -hemoglobin dissociation curve to the left occur when there is increased affinity of hemoglobin for O 2 An increase in affinity is reflected in a decrease in P 50 , which means that 50% saturation occurs at a lower-than-normal value of P o 2 . When the affinity is increased, unloading of O 2 in the tissues is more difficult

105. Decreases in P co 2 and increases in pH The effect of decreases in P co 2 and increases in pH is the Bohr effect again. When there is a decrease in tissue metabolism, there is decreased production of CO 2 , decreased H + concentration, and increased pH, resulting in a left shift of the O 2 -hemoglobin dissociation curve. When the demand for O 2 decreases, O 2 is more tightly bound to hemoglobin , and less O 2 is unloaded to the tissues. Decreases in temperature. Decreases in temperature cause the opposite effect of increases in temperature-the curve shifts to the left. When tissue metabolism decreases, less heat is produced and less O 2 is unloaded in the tissues.

106. Decreases in 2,3-DPG concentration Decreases in 2,3-DPG concentration also reflect decreased tissue metabolism, causing a left shift of the curve and less O 2 to be unloaded in the tissues. Hemoglobin F As previously described, hemoglobin F is the fetal variant of hemoglobin The β chains of adult hemoglobin ( hemoglobin A) are replaced by γ chains in hemoglobin F This modification results in increased affinity of hemoglobin for O 2 , A left shift of the O 2 -hemoglobin dissociation curve, and decreased P 50 . The mechanism of the left shift is based on the binding of 2,3-DPG. 2,3-DPG does not bind as avidly to the γ chains of hemoglobin F as it binds to the β chains of hemoglobin A. When less 2,3-DPG is bound, the affinity for O 2 increases. This increased affinity is beneficial to the fetus , whose Pa O2 is low (approximately 40 mm Hg

107. Carbon Monoxide The effect of CO is different: It decreases O 2 bound to hemoglobin and also causes a left shift of the O 2 -hemoglobin dissociation curve CO binds to hemoglobin with an affinity that is 250 times that of O 2 to form carboxyhemoglobin When the partial pressure of CO is only 1/250 that of O 2 , equal amounts of CO and O 2 will bind to hemoglobin ! O 2 cannot bind to heme groups that are bound to CO, the presence of CO decreases the number of O 2 -binding sites available on hemoglobin . The implications for O 2 transport are obvious: This effect alone would reduce O 2 content of blood and O 2 delivery to tissues by 50%

108. CO also causes a left shift of the O 2 -hemoglobin dissociation curve Those heme groups not bound to CO have an increased affinity for O 2 . Thus , P 50 is decreased, making it more difficult for O 2 to be unloaded in the tissues

109. Together, these two effects of CO on O 2 binding to hemoglobin are catastrophic for O 2 delivery to tissues. Not only is there reduced O 2 -binding capacity of hemoglobin , The remaining heme sites bind O 2 more tightly

110. Carbon Dioxide Transport in Blood FORMS OF CO 2 IN BLOOD CO 2 is carried in the blood in three forms: As dissolved CO 2 , as carbaminohemoglobin (CO 2 bound to hemoglobin ), and as bicarbonate (HCO 3 - ) which is a chemically modified form of CO 2 . By far, HCO 3 - is quantitatively the most important of these forms As with O 2 , a portion of the CO 2 in blood is in the dissolved form. The concentration of CO 2 in solution is given by Henry's law, which states that the concentration of CO 2 in blood is the partial pressure multiplied by the solubility of CO 2 . The solubility of CO 2 is 0.07 mL CO 2 /100 mL blood/mm Hg; thus, the concentration of dissolved CO 2 in arterial blood, as calculated by Henry's law, is 2.8 mL CO 2 /100 mL blood (40 mm Hg × 0.07 mL CO 2 /100 mL blood/mm Hg), which is approximately 5% of the total CO 2 content of blood. Recall that because of the lower solubility of O 2 , compared with CO 2 , dissolved O 2 is only 2% of the total O 2 content of blood.

111. Carbaminohemoglobin CO 2 binds to terminal amino groups on proteins (e.g., hemoglobin and plasma proteins such as albumin). When CO 2 is bound to hemoglobin , it is called carbaminohemoglobin , which accounts for about 3% of the total CO 2 . HCO 3 -

112. Transport of carbon dioxide (CO 2 ) in the blood CO 2 and H 2 O are converted to H + and HCO 3 - inside red blood cells. H + is buffered by hemoglobin (Hb-H) inside the red blood cells. HCO 3 - exchanges for Cl - Almost all of the CO 2 carried in blood is in a chemically modified form, HCO 3 - , Accounts for more than 90% of the total CO 2 . The reactions that produce HCO 3 - from CO 2 involve the combination of CO 2 and H 2 O to form the weak acid H 2 CO 3 . This reaction is catalyzed by the enzyme carbonic anhydrase, which is present in most cells. In turn, H 2 CO 3 dissociates into H + and HCO 3 - . Both reactions are reversible, and carbonic anhydrase catalyzes both the hydration of CO 2 and the dehydration of H 2 CO 3 .

113. In the tissues, CO 2 generated from aerobic metabolism is added to systemic capillary blood, converted to HCO 3 - by the reactions described previously, and transported to the lungs. In the lungs, HCO 3 - is reconverted to CO 2 and expired .

114. In the tissues, CO 2 is produced from aerobic metabolism. CO 2 then diffuses across the cell membranes and across the capillary wall, into the red blood cells. The transport of CO 2 across each of these membranes occurs by simple diffusion Driven by the partial pressure gradient for CO 2

115. Carbonic anhydrase is found in high concentration in red blood cells. It catalyzes the hydration of CO 2 to form H 2 CO 3 . In red blood cells, the reactions are driven to the right by mass action because CO 2 is being supplied from the tissue. In the red blood cells, H 2 CO 3 dissociates into H + and HCO 3 - . The H + remains in the red blood cells, where it will be buffered by deoxyhemoglobin , and the HCO 3 - is transported into the plasma in exchange for Cl - (chloride).

116. If the H + produced from these reactions remained free in solution, It would acidify the red blood cells and the venous blood. Therefore , H + must be buffered so that the pH of the red blood cells (and the blood) remains within the physiologic range. The H + is buffered in the red blood cells by deoxyhemoglobin and is carried in the venous blood in this form. Deoxyhemoglobin is a better buffer for H + than oxyhemoglobin : By the time blood reaches the venous end of the capillaries, Hemoglobin is conveniently in its deoxygenated form (i.e., it has released its O 2 to the tissues).

117. There is a useful reciprocal relationship between the buffering of H + by deoxyhemoglobin and the Bohr effect. The Bohr effect states that an increased H + concentration causes a right shift of the O 2 -hemoglobin dissociation curve, Which causes hemoglobin to unload O 2 more readily in the tissues; thus, the H + generated from tissue CO 2 causes hemoglobin to release O 2 more readily to the tissues. In turn, deoxygenation of hemoglobin makes it a better buffer for H + . The HCO 3 - produced from these reactions is exchanged for Cl - across the red blood cell membrane (to maintain charge balance), and the HCO 3 - is carried to the lungs in the plasma of venous blood. All of the reactions occur in reverse in the lungs . H + is released from its buffering sites on deoxyhemoglobin , HCO 3 - enters the red blood cells in exchange for Cl - , H + and HCO 3 - combine to form H 2 CO 3 , and H 2 CO 3 dissociates into CO 2 and H 2 O. The regenerated CO 2 and H 2 O are expired by the lungs.

118. REGULATION OF RESPIRATION The volume of air inspired and expired per unit time is tightly controlled, Both with respect to frequency of breaths and to tidal volume Breathing is regulated so the lungs can maintain the Pa O2 and Pa CO2 within the normal range

119. Breathing is controlled by centers in the brain stem There are four components to this control system: ( 1) chemoreceptors for O 2 or CO 2 , ( 2) mechanoreceptors in the lungs and joints, ( 3) control centers for breathing in the brain stem (medulla and pons), and ( 4) the respiratory muscles Activity is directed by the brain stem centers Voluntary control can also be exerted by commands from the cerebral cortex e.g ., breath-holding or voluntary hyperventilation, which can temporarily override the brain stem

120. BRAIN STEM CONTROL OF BREATHING Breathing is an involuntary process that is controlled by the medulla and pons of the brain stem The frequency of normal, involuntary breathing is controlled by three groups of neurons or brain stem centers: the medullary respiratory center, the apneustic center, and the pneumotaxic center The medullary respiratory center is located in the reticular formation and is composed of two groups of neurons that are distinguished by their anatomic location: - the inspiratory center (dorsal respiratory group) - the expiratory center (ventral respiratory group).

121. Inspiratory center The inspiratory center is located in the dorsal respiratory group of neurons Controls the basic rhythm for breathing by setting the frequency of inspiration. This group of neurons receives sensory input from peripheral chemoreceptors via; - the glossopharyngeal (CN IX) - Vagus (CN X) nerves and - From mechanoreceptors in the lung via the vagus nerve The inspiratory center sends its motor output to the diaphragm via the phrenic nerve. Inspiration can be shortened by inhibition of the inspiratory center via the pneumotaxic center

122. Expiratory center The expiratory center is located in the ventral respiratory neurons Is responsible primarily for expiration Since expiration is normally a passive process, these neurons are inactive during quiet breathing. During exercise when expiration becomes active, this center is activated

123. Apneustic Center Apneusis is an abnormal breathing pattern with prolonged inspiratory gasps, followed by brief expiratory movement. Stimulation of the apneustic center in the lower pons produces this breathing pattern Stimulation of these neurons apparently excites the inspiratory center in the medulla, Prolonging the period of action potentials in the phrenic nerve, and Thereby prolonging the contraction of the diaphragm

124. Pneumotaxic Center The pneumotaxic center turns off inspiration, limiting the burst of action potentials in the phrenic nerve. In effect, the pneumotaxic center, located in the upper pons, limits the size of the tidal volume, and secondarily, it regulates the respiratory rate A normal breathing rhythm persists in the absence of this center

125. CEREBRAL CORTEX Commands from the cerebral cortex can temporarily override the automatic brain stem centers For example, a person can voluntarily hyperventilate (i.e., increase breathing frequency and volume ) The consequence of hyperventilation is a decrease in Pa CO2 , which causes arterial pH to increase Hyperventilation is self-limiting, however, because the decrease in Pa CO2 will produce unconsciousness and the person will revert to a normal breathing pattern Although more difficult, a person may voluntarily hypoventilate (i.e., breath-holding). Hypoventilation causes a decrease in Pa O2 and an increase in Pa CO2 , both of which are strong drives for ventilation . A period of prior hyperventilation can prolong the duration of breath-holding.

126. CHEMORECEPTORS The brain stem controls breathing by processing sensory (afferent) information and sending motor (efferent) information to the diaphragm Of the sensory information arriving at the brain stem, the most important is that concerning Pa O2 , Pa CO2 , and arterial pH

127. Central Chemoreceptors The central chemoreceptors, located in the brain stem, are the most important for the minute-to-minute control of breathing. These chemoreceptors are located on the ventral surface of the medulla, Near the point of exit of the glossopharyngeal (CN IX) and vagus (CN X) nerves and Only a short distance from the medullary inspiratory center. Central chemoreceptors communicate directly with the inspiratory center . The brain stem chemoreceptors are exquisitely sensitive to changes in the pH of cerebrospinal fluid (CSF). Decreases in the pH of CSF produce increases in breathing rate (hyperventilation ) Increases in the pH of CSF produce decreases in breathing rate (hypoventilation

128. The medullary chemoreceptors respond directly to changes in the pH of CSF and indirectly to changes in arterial P co 2 In the blood, CO 2 combines reversibly with H 2 O to form H + and HCO 3 - by the familiar reactions. Because the blood-brain barrier is relatively impermeable to H + and HCO 3 - , these ions are trapped in the vascular compartment and do not enter the brain. CO 2 , however, is quite permeable across the blood-brain barrier and enters the extracellular fluid of the brain. 2. CO 2 also is permeable across the brain-CSF barrier and enters the CSF. 3. In the CSF, CO 2 is converted to H + and HCO 3 - . Thus , increases in arterial P co 2 produce increases in the P co 2 of CSF, which results in an increase in H + concentration of CSF (decrease in pH). 4 and 5. The central chemoreceptors are in close proximity to CSF and detect the decrease in pH . A decrease in pH then signals the inspiratory center to increase the breathing rate (hyperventilation).

129. The goal of central chemoreceptors is to keep arterial P co 2 within the normal range, if possible. Thus , increases in arterial P co 2 produce increases in P co 2 in the brain and the CSF, which decreases the pH of the CSF. A decrease in CSF pH is detected by central chemoreceptors for H + , which instruct the inspiratory center to increase the breathing rate. When the breathing rate increases, more CO 2 will be expired and the arterial P co 2 will decrease toward

130. Peripheral Chemoreceptors There are peripheral chemoreceptors for O 2 , CO 2 , and H + in the carotid bodies In the aortic bodies Information about arterial P o 2 , P co 2 , and pH is relayed to the medullary inspiratory center via CN IX and CN X, Which orchestrates an appropriate change in breathing rate.

131. Decreases in arterial P o 2 The most important responsibility of the peripheral chemoreceptors is to detect changes in arterial P o 2 . The peripheral chemoreceptors are relatively insensitive to changes in P o 2 : They respond when P o 2 decreases to less than 60 mm Hg . If arterial P o 2 is less than 60 mm Hg, the breathing rate increases in a very steep and linear fashion. In this range of P o 2 , chemoreceptors are exquisitely sensitive to O 2 ; In fact , they respond so rapidly that the firing rate of the sensory neurons may change during a single breathing cycle. Increases in arterial P co 2 . The peripheral chemoreceptors also detect increases in P co 2 , but the effect is less important than their response to decreases in P o 2 . Detection of changes in P co 2 by the peripheral chemoreceptors also is less important than detection of changes in P co 2 by the central chemoreceptors.

132. Decreases in arterial pH Decreases in arterial pH cause an increase in ventilation, mediated by peripheral chemoreceptors for H + This effect is independent of changes in the arterial P co 2 and is mediated only by chemoreceptors in the carotid bodies (not by those in the aortic bodies). Thus , in metabolic acidosis, in which there is decreased arterial pH the peripheral chemoreceptors are stimulated directly to increase the ventilation rate the respiratory compensation for metabolic acidosis

133. OTHER RECEPTORS Addition to chemoreceptors, several other types of receptors are involved in the control of breathing, including lung stretch receptors, joint and muscle receptors, irritant receptors, and juxtacapillary (J) receptor Lung stretch receptors Mechanoreceptors are present in the smooth muscle of the airways . When stimulated by distention of the lungs and airways, mechanoreceptors initiate a reflex decrease in breathing rate called the Hering -Breuer reflex. The reflex decreases breathing rate by prolonging expiratory time

134. Joint and muscle receptors Mechanoreceptors located in the joints and muscles detect the movement of limbs and instruct the inspiratory center to increase the breathing rate. Information from the joints and muscles is important in the early (anticipatory) ventilatory response to exercise. Irritant receptors. Irritant receptors for noxious chemicals and particles are located between epithelial cells lining the airways. Information from these receptors travels to the medulla via CN X and causes a reflex constriction of bronchial smooth muscle and an increase in breathing rate

135. J receptors Juxtacapillary (J) receptors are located in the alveolar walls and, therefore, are near the capillaries Engorgement of pulmonary capillaries with blood and increases in interstitial fluid volume may activate these receptors and produce an increase in the breathing rate For example, in left-sided heart failure, blood "backs up" in the pulmonary circulation, and J receptors mediate a change in breathing pattern, including rapid shallow breathing and dyspnea

136. Integrative Functions

137. RESPONSES TO EXERCISE The response of the respiratory system to exercise is remarkable. As the body's demand for O 2 increases, more O 2 is supplied by increasing the ventilation rate: Excellent matching occurs between O 2 consumption, CO 2 production, and the ventilation rate For example, when a trained athlete is exercising, his O 2 consumption may increase from its resting value of 250 mL/min to 4000 mL/min, His ventilation rate may increase from 7.5 L/min to 120 L/min. Both O 2 consumption and ventilation rate increase more than 15 times the resting level!

138. Remarkably, mean values for arterial P o 2 and P co 2 do not change during exercise. An increased ventilation rate and increased efficiency of gas exchange ensure that there is neither a decrease in arterial P o 2 nor an increase in arterial P co 2 . ( The arterial pH may decrease, however, during strenuous exercise because the exercising muscle produces lactic acid .)

139. Venous P co 2 The P co 2 of mixed venous blood must increase during exercise Because skeletal muscle is adding more CO 2 than usual to venous blood. However , since mean arterial P co 2 does not increase, the ventilation rate must increase sufficiently to rid the body of this excess CO 2

140. Cardiac Output and Pulmonary Blood Flow

141. ADAPTATION TO HIGH ALTITUDE Ascent to high altitude is one of several causes of hypoxemia. The respiratory responses to high altitude are the adaptive adjustments a person must make to the decreased P o 2 in inspired and alveolar air The decrease in P o 2 at high altitudes is explained as follows: At sea level, the barometric pressure is 760 mm Hg; at 18,000 feet above sea level, the barometric pressure is one-half that value, or 380 mm Hg. To calculate the P o 2 of humidified inspired air at 18,000 feet above sea level, correct the barometric pressure of dry air by the water vapor ressure of 47 mm Hg, then multiply by the fractional concentration of O 2 , which is 21%. Thus , at 18,000 feet, P o 2 = 70 mm Hg ([380 mm Hg - 47 mm Hg] × 0.21 = 70 mm Hg). A similar calculation for pressures at the peak of Mount Everest yields a P o 2 of inspired air of only 47 mm Hg

142. Hyperventilation The most significant response to high altitude is hyperventilation, an increase in ventilation rate. For example, if the alveolar P o 2 is 70 mm Hg, then arterial blood Which is almost perfectly equilibrated, also will have a P o 2 of 70 mm Hg, which will not stimulate peripheral chemoreceptors. However , if alveolar P o 2 is 60 mm Hg, then arterial blood will have a P o 2 of 60 mm Hg, In which case the hypoxemia is severe enough to stimulate peripheral chemoreceptors in the carotid and aortic bodies. In turn, the chemoreceptors instruct the medullary inspiratory center to increase the breathing rate

143. Consequence of the hyperventilation is that "extra" CO 2 is expired by the lungs and arterial P co 2 decreases, producing respiratory alkalosis. The decrease in P co 2 and the resulting increase in pH will inhibit central and peripheral chemoreceptors and offset the increase in ventilation rate. These offsetting effects of CO 2 and pH occur initially, but within several days HCO 3 - excretion increases, HCO 3 - leaves the CSF, and the pH of the CSF decreases toward normal. Thus , within a few days, the offsetting effects are reduced and hyperventilation resumes The respiratory alkalosis that occurs as a result of ascent to high altitude can be treated with carbonic anhydrase inhibitors (e.g., acetazolamide ). These drugs increase HCO 3 - excretion, creating a mild compensatory metabolic acidosis

144. Polycythemia The stimulus for polycythemia is hypoxemia, which increases the synthesis of erythropoietin in the kidney . Erythropoietin acts on bone marrow to stimulate red blood cell production Ascent to high altitude produces an increase in red blood cell concentration ( polycythemia ) and, as a consequence, an increase in hemoglobin concentration. The increase in hemoglobin concentration means that the O 2 -carrying capacity is increased, Which increases the total O 2 content of blood in spite of arterial P o 2 being decreased. Polycythemia is advantageous in terms of O 2 transport to the tissues, but it is disadvantageous in terms of blood viscosity. The increased concentration of red blood cells increases blood viscosity, which increases resistance to blood flow

145. 2,3-DPG and O 2 -Hemoglobin Dissociation Curve One of the most interesting features of the body's adaptation to high altitude is an increased synthesis of 2,3-DPG by red blood cells. The increased concentration of 2,3-DPG causes the O 2 hemoglobin dissociation curve to shift to the right. This right shift is advantageous in the tissues, since it is associated with increased P 50 , decreased affinity, and increased unloading of O 2 . However , the right shift is disadvantageous in the lungs because it becomes more difficult to load the pulmonary capillary blood with O 2

146. Pulmonary Vasoconstriction At high altitude, alveolar gas has a low Po 2 , Which has a direct vasoconstricting effect on the pulmonary vasculature As pulmonary vascular resistance increases, pulmonary arterial pressure also must increase to maintain a constant blood flow. The right ventricle must pump against this higher pulmonary arterial pressure May hypertrophy in response to the increased afterload

147. Acute Altitude Sickness The initial phase of ascent to high altitude is associated with a constellation of complaints, including headache , fatigue, dizziness , nausea , palpitations , and insomnia. The symptoms are attributable to the initial hypoxia and respiratory alkalosis, Which abate when the adaptive responses are established

148. Hypoxemia and Hypoxia Hypoxemia is defined as a decrease in arterial P o 2 Hypoxia is defined as a decrease in O 2 delivery to, or utilization by, the tissues Hypoxemia is one cause of tissue hypoxia, although it is not the only cause HYPOXEMIA Hypoxemia, a decrease in arterial P o 2 , has multiple causes,

149. Table 5-5. Causes of Hypoxemia Cause Pa O2 A - a Gradient Supplemental O 2 Helpful? High altitude (↓ P b ; ↓ P i O2 ) Decreased Normal Yes Hypoventilation (↓ P a O2 ) Decreased Normal Yes Diffusion defect (e.g., fibrosis) Decreased Increased Yes V/Q defect Decreased Increased Yes Right-to-left shunt Decreased Increased Limited

150. HYPOXIA Table 5-6. Causes of Hypoxia Cause Mechanism Pa O2 ↓ Cardiac output ↓ Blood flow - Hypoxemia ↓ Pa O2 ↓   ↓ O 2 saturation of hemoglobin     ↓ O 2 content of blood   Anemia ↓ Hemoglobin concentration -   ↓ O 2 content of blood   Carbon monoxide poisoning ↓ O 2 content of blood Left shift of O 2 -hemoglobin curve - Cyanide poisoning ↓ O 2 utilization by tissues

151. Hypoxia is decreased O 2 delivery to the tissues. Since O 2 delivery is the product of cardiac output and O 2 content of blood Hypoxia is caused by decreased cardiac output (blood flow) or decreased O 2 content of blood

152. END