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The Respiratory System The process of respiration involves the exchange of gases between the atmosphere and different

body cells, as well as the intracellular utilization of O2 and the production of CO2 while deriving energy from nutrient molecules. Thus the process of respiration involves two separate but related processes: 1. The exchange of gases which is also called the external respiration. 2. The intracellular utilization of O2 with the production of CO2 which is also called the internal respiration. The internal respiration or cellular respiration as a subject is usually discussed under the topic of cellular metabolism. Accordingly the physiology of respiration involve the discussion of the topic of external respiration External respiration: The term of external respiration refers to the entire sequence of events in the exchange of O2 and CO2 between the atmosphere (the external environment) and the cells of the body. External respiration occurs in 4 steps: 1. At first air must alternately flows in and out of the lungs so that air can be exchanged between the atmosphere and alveoli of the lungs. This exchange is accomplished by the mechanical act of breathing, or ventilation. 2. Following the process of ventilation for bodys cells to obtain O2 and to eliminate CO2. O2 and CO2are exchanged between air in the alveoli and blood within pulmonary capillaries by the process of diffusion. 3. The blood transports O2 and CO2 between the lung and tissues. Then O2 and CO2 are exchanged between the tissues and blood by the process of diffusion across the tissue capillaries. 4. Regulation of breathing. As the volume of O2 used by bodys cells and the volume of CO2 the cell produce depends on the rate of metabolism. Thus the process of gas exchange requires regulation to match the body need for O2 and for the elimination of the produced CO2. Does the respiratory system accomplish all the steps of external respiration?

Anatomically the respiratory system consists of: 1. Conducting airways: which are tubes that carry air between the atmosphere and the alveoli where gas can be exchange between air and blood. The airways begin with the nasal passages, which open into the pharynx, the trachea, the right and left bronchi. Within the lung, the bronchus continues to branch into progressively, narrower, shorter, and more numerous airways down to the terminal bronchioles (the smallest airways without alveoli). 2. Respiratory zone: made up of the respiratory bronchioles clustered at its end tiny air sacs the alveoli, the alveoli are surrounded by pulmonary capillaries. In this region of the lungs as the air within the alveoli is separated by large surface area of extremely thin structures (the alveolar capillary membrane) from blood within pulmonary capillaries it becomes a suitable site for gas exchange between air and blood across which O2 and CO2 diffuse. Thus only the part of the inspired air that reaches the respiratory zone participates in the process of gas exchange. There are 300 million alveoli in human lungs and the total area of the alveolar walls in contact with capillaries in both lungs is about 70 m2. The two lungs occupy most of the volume of thoracic cavity. A double walled sac, the pleural sac separates each lung from the thoracic wall and other surrounding structures. The two layers of the pleural sac are separated by thin layer of fluid called the intrapleural space. Thus lungs slide easily on the chest wall but resist being pulled away from it in the same way that two moist pieces of glass slide on each other but resist separation. The primary function of the lung is gas exchange. However the respiratory system performs several additional functions that have nothing to do with the process of gas exchange. - The lung metabolizes some compounds passing through the pulmonary circulation: it removes - prostaglandins E2 and F2, serotonin it activates - convert the inactive angiotensin I to the active angiotensin II by the ACE it inactivates bradykinin - filters unwanted material from the circulation, and - acts as a reservoir for blood. These functions are collectively termed the non respiratory functions of the lung.

Movement of air in and out of the lungs and the pressures that cause the movement: Let us at first discuss pressures inside the lungs and how changes in these pressures are produce that consequently resulting in the movement of air between the atmosphere and the lungs. 1. Intrapleural pressure: the chest and lungs are elastic tissues. As the elastic property within a structure constantly tend to return the elastic structure to its natural size when an external deforming force is removed (like a spring). The lung recoil and collapse if the chest wall is opened and if the lung loss its elasticity the thoracic wall expand and move outward. Normally the lungs are occupying the whole thoracic cavity and separated from the chest wall only by the thin intrapleural space. Accordingly neither the thoracic wall nor the lungs are in their natural position when they are held in apposition to each other. Under such condition the stretched lungs tend to pull inward, whereas the compressed thoracic wall tends to move outward. Therefore the closed intrapleural space lies between two forces acting in opposite direction creating a subatmospheric pressure within the space. The subatmospheric intrapleural pressure exerts a force that expands the lungs and pulls inward the chest wall from their resting position to an equilibrium position. Normally there is no communication between the pleural space and either the atmosphere or the alveolar air. However if the chest wall is punctured (for example by a stab wound or broken rib), air flows down its pressure gradient from the higher atmospheric pressure into the pleural space. This abnormal condition is known as pneumothorax. Intrapleural pressure is now equal to atmospheric pressure, with no stretching force on the lung; it collapses to its resting size. Similarly the thoracic wall springs outward to its resting position. Does the intrapleural subatmospheric pressure have the same value around the whole lungs? 2. Alveolar pressure: which is the pressure of air inside the lung alveoli? 3. Transpulmonary pressure: is the difference between alveolar pressures and pleural pressure. As far the movement of air in and out of the lung is concerned, it is known that air tends to flow from a region of higher pressure to a region of lower pressure that is down a pressure gradient. During inspiration air at atmospheric pressure flows inside the lungs thus for inspiration to occur the alveolar pressure that is air pressure inside the

lungs must be less than atmospheric pressure and for expiration to occur alveolar pressure must be greater than atmospheric pressure. Alveolar pressure changes necessary for the induction of inspiration and expiration is accomplished by increasing and decreasing the elastic lungs and chest volumes (Boyles law: states that at any constant temperature, the pressure exerted by a gas varies inversely with the volume of the gas). The changes in chest and lungs volume require active contraction of respiratory muscles to expand (increase in volume) or compressed (decrease in volume) from their resting positions. Muscles of Respiration: The major muscles that contract to produced inspiration during quiet breathing are the diaphragm and external intercostals muscles: the most important muscle of inspiration is the diaphragm. When it contract the abdominal contents are forced downward and forward increasing the vertical dimension of the chest cavity. In normal quiet breathing the level of the diaphragm moves about 1cm. or so, but on forced inspiration and expiration it moves up to 10 cm. the diaphragm is the principle muscle of inspiration, about 75% of the enlargement of thoracic cavity during quiet breathing is produced by contraction of the diaphragm. Thus paralysis of the intercostals alone does not seriously affect breathing, because the diaphragm is so effective. The external intercostal muscles connect the adjacent ribs whose fibers slope downward and forward, when contract enlarges the thoracic cavity in both the lateral and anteroposterior dimensions. When the external intercostals contract, they elevate the ribs and subsequently the sternum upward and outward. Therefore the process of inspiration is an active process as it requires active contraction of inspiratory muscles. The accessory muscles of inspiration: Hyperventilation or deeper inspirations where more air breathed in can be produced by more forceful contraction of the diaphragm and external intercostal muscles in addition to the contraction of the accessory inspiratory muscles for further enlargement in thoracic cavity. These muscles include the scalene muscles which elevate the first two ribs and the sternomastoids which raise the sternum enlarging the upper portion of the thoracic cavity. Consequently further increase in lung volume is produced leading to more dropping in alveolar pressure and a larger inflow of air occurs. Expiration: At the end of inspiration the inspiratory muscles relax ending the effect of the expanding forces on the chest wall and the lungs. The

stretched chest wall and lungs recoil to their preinspiratory position because of their elastic properties. As a result lungs volume becomes smaller, and intraalveolar pressure rises to a level higher than atmospheric pressure. Thus air flows out of the lungs down its pressure gradient until equilibrium between alveolar and atmospheric pressure is reached. Therefore during quiet breathing expiration normally is a passive process produced by elastic recoil of the lungs and does not require active muscle contraction. During deep breaths accompanying exercise and voluntary hyperventilation expiration becomes active to empty the lungs more completely and rapidly than during quiet breathing. The intra-alveolar pressure must be increased even further above atmospheric pressure than that produce during quiet breathing by relaxation of inspiratory muscles and elastic recoil of the lungs. Therefore contraction of expiratory muscles is required to further reduce the thoracic cavity and lungs. The most important muscles of expiration are muscles of the abdominal wall. When these muscles contract intra abdominal pressure is raised pushing the diaphragm further up into the thoracic cavity than its relaxed position, decreasing the thoracic cavity even more. The other expiratory muscles are the internal inter-costal muscles which assist active expiration by pulling the ribs downward and inward, decreasing the thoracic and lungs volumes. In addition they stiffen the intercostals spaces to prevent them from bulging outward during straining. How does the enlargement of the thoracic cage during contraction of the inspiratory muscles enlarge the lungs? Natural breathing in man is accomplished by active contraction of the inspiratory muscles that do not act directly on the lungs to change their volume. Contraction of inspiratory muscles pulling on the chest wall moving it a way from the lungs this made the pleural pressure more subatmospheric increasing its expanding force on the lungs increasing lungs volume decreasing alveolar air pressure allowing the inflow of air into the lungs. At the end of inspiration the chest wall recoil back to its preinspiratory position and the pleural pressure becomes less subatmospheric; as a result its expansion force on the lungs decreases decreasing lungs volume increasing alveolar pressure leading to outflow of air from the lungs.

Cyclic respiratory muscles activity alternately changes pleural and alveolar pressures leading to air flows in and out of the lungs during the act of breathing. Active muscle contraction is needed to provide the force necessary to overcome: 1. the elastic recoil of the lungs and chest wall. 2. the frictional resistance to air flow through the numerous conducting airways. Airway resistance: although air flow in and out of the lungs is determined by the pressure gradient between the alveoli and the atmosphere. It also depends on the resistance to air flow offered by the conducting airways, so air flow: P F = -----R Where: F = air flow P = pressure gradient R = resistance of airways. The primary determinant of resistance to air flow is the radius of the conducting airways. Normally the radius of the conducting airways is large enough that resistance remains extremely low. As the airways offer such low resistance normally, that only very small pressure gradient of 1 to 2 mm Hg needed to achieve adequate rates of flow in and out of the lungs. Normally airway radius is adjusted by the activity of autonomic nervous system. Parasympathetic stimulation produces bronchoconstriction (a reduction in bronchiolar diameter), in contrast sympathetic stimulation causing bronchodilation (an increase in bronchiolar diameter). Thus during period of sympathetic domination, when increased demand for O2 uptake is placed on the body, bronchodilation ensures maximum airflow with minimum resistance. Because of this sympathetic bronchodilation action epinephrine or similar drugs are useful therapeutic agents to counteract airway constriction in patient with bronchial spasm. Resistance becomes an extremely important impediment to airflow when airway lumens become abnormally narrowed by disease. The chronic obstructive pulmonary disease (COPD) is a group of lung diseases characterized by increased airway resistance resulting from narrowing of the lumen of lower airways. When airway resistance increased a large pressure

gradient must be established to maintain even a normal airflow rate. Accordingly patients with COPD must work harder to breath. COPD includes three chronic (long-term) diseases: chronic bronchitis, asthma, and emphysema. When COPD of any type increases airway resistance, expiration is more difficult than inspiration. The smaller airways lacking the cartilaginous rings that hold the large airway open are held open by the transmural pressure gradient. Expansion of the thoracic cavity during inspiration indirectly dilates even further than their expiratory dimensions, so airway resistance is lower during inspiration than during expiration. Thus an asthmatic has more difficulty expiring than inspiring, giving rise to the characteristic wheeze as air is forced out through the narrowed airways. Elastic properties of the lungs: We now know that active muscles contraction expands the lungs indirectly by causing changes in intrapleural pressure which is leading to changes in lungs volume during breathing. Thus a relationship between changes in pleural pressure and changes in lungs volume can be constructed to steady the behavior of the lungs during breathing that is to asses the distensibility or the elastic properties of the lungs. The diagram relating changes in lungs volume to changes in pleural pressure during inspiration and expiration represent the pressure volume curve of the lung. The curve shows that: 1. the lung follows different curves during inspiration and expiration. This behavior is known as hysteresis (failure of coincidence of two associated phenomena). 2. lung volume at any given pressure during expiration is larger than during inspiration. 3. the lung without any expanding pressure has some air inside it. Even when the pressure around the lung is raised above atmospheric pressure some amount of air remains in the lungs due to the closure of small airways and trapping air in the alveoli. The slope of the line that results from plotting the distending pressure against the increase in lung volume serves as a measure of distensibility of the lung or compliance of the lung. Compliance: is the lung volume change per unit change in pressure. From the compliant curve we can see that: In the normal rang of expanding intrapleural pressure of about 2 to 6 (cm H2O) the lung remarkably ditensible or very compliant. The compliance of human lung is about 200 ml/cm H2O

At high expanding pressures, lung compliance is smaller as shown by the flatter slope of the curve. The compliance is reduced: 1. when the pulmonary venous pressure is increased and the lungs become congested with blood. 2. alveolar edema by preventing inflation of some alveoli. 3. when the lungs remain unventilated for a long period. 4. diseases causing fibrosis of the lungs.

The compliance of the lung is increased by: 1. aging (physiological process). 2. emphysema (pathological condition). In both instances an alteration in the elastic tissue of the lung is probably responsible. In the upright lungs which is better ventilated the apex or the base of the lung? And what is its significance? The characteristics of the lung pressure volume curve or the compliance diagram are determined by the elastic forces of the lungs. What is responsible for the elastic forces of the lung that is its tendency to return to its resting volume after distention? One factor is the presence of elastic connective tissue; fibers of elastin and collagen among lung parenchyma. Another more important factor in the pressure volume behavior of the lung is the surface tension of the thin liquid film lining the alveoli. It arises at air liquid interface because the forces between the molecules of the liquid are much stronger than those between the liquid and gas. This unequal attraction produces a force known as surface tension that tends to shrink of the liquid surface area to as small as possible size. Thus the surface tension of the liquid lining the alveoli tends to reduce alveolar size, squeezing in on the air inside and opposes expansion of the alveoli. Accordingly the greater the surface tension is the less compliant the lungs. The first evidence that surface tension might contribute to the pressure volume behavior of the lungs was obtained following the observation that saline inflated lungs are easier to distend ( have a much higher compliance) than air inflated lungs. The force of surface tension of liquid lining the alveoli if it is unopposed it would be so great that greater muscular efforts are required to produce stretching and inflation of the alveoli during inspiration. Thus under this

abnormal condition the work of breathing is increased and breathing becomes difficult. However under normal condition the lungs synthesized a substance by the Type II alveolar cells known as the surfactant. The process of surfactant synthesis started in the developing fetal lungs late in pregnancy. What are the physiological advantages of the surfactant? 1. surfactant lowers the alveolar surface tension, by decreasing the alveolar surface tension, it increases the pulmonary compliance and reducing the work of inflating the lungs. 2. surfactant prevents the development of areas of alveolar collapse within the lungs. At first we have to understand that under normal conditions in the same lung the alveoli have different sizes and the adjacent alveoli are interconnected. Thus fresh air can spread between interconnected small and large alveoli. The force of surface tension pulls the alveolar wall inward squeezing in on the air in the alveoli, generating a pressure. If we consider the alveoli as spherical bubbles the pressure can be calculated by applying LaPlace law: 2T P= r Where: p = pressure T = surface tension r = radius of alveolus From law of LaPlace the magnitude of the pressure is directly proportional to the surface tension and inversely proportional to the radius of the alveolus. Accordingly, if two alveoli of unequal size but the same surface tension are connected, the smaller alveolus because it generates a larger collapsing pressure empty its air into the large alveolus and collapse. However the surfactant not only lowers the surface tension, it modified the surface tension according to surface area. The surfactant reduces the surface tension to a greater degree in small alveoli than in large alveoli thus offset the effect of their smaller radius in determining the air pressure. Accordingly the surfactant prevents the development of alveolar collapse, maintaining stability of alveoli. As mentioned earlier that the surface tension tends to decrease the size of the alveoli to a smaller possible size by pulling on alveolar wall inward. In this way the surface tension act as a force of suction on the alveolar wall assist in

the oozing of fluid from the pulmonary capillaries surrounding the alveoli. This abnormal accumulation of fluids in the alveoli a condition called alveolar edema. However under normal condition the alveoli are dry, due to the presence of surfactant. Surfactant reduces the force of surface tension preventing the development of alveolar edema. What the other factor that is also responsible for dryness of the alveoli under normal condition? What are the consequences of surfactant deficiency? 1. The surface tension is high thus requiring more forceful inspiratory muscles contraction than normal to expand the poorly compliant lungs increasing the work of breathing. 2. The development of areas of collapse within the lungs, increases further the work of breathing and interferes with the process of gas exchange. 3. The development of alveolar edema which decreases lung compliance increasing the work of breathing as well as it interfere with the process of gas exchange. The collection of these symptoms is known as the respiratory distress syndrome. This condition occurs in new born infant especially in prematurely born infants, as the lungs cannot synthesize surfactant until late in pregnancy. Work of breathing: During normal quit breathing inspiration requires active muscles contraction, while expiration is a passive process. As mentioned earlier muscles contraction is required to overcome the elastic recoil of the chest and lungs as well as to overcome the airway resistance to movement of air into the lungs. Under normal conditions the lungs are highly compliant and airways resistance is low, so only 3 5% of the total energy expended by the body is for pulmonary ventilation. The work of breathing may be increased when: 1. pulmonary compliance is decreased. 2. airways resistance is increased OPD. 3. elastic recoil is decreased. 4. there is a need for increased ventilation, during exercise. During exercise the increased amount of energy required to power pulmonary ventilation still represent only about 5%. In contrast in patients with poorly compliant lungs as in OPD energy of breathing at rest may be

increased up to 30% of the total energy expenditure. In such individual exercise ability is severely limited. Lungs volume and Capacities: A simple method for studying pulmonary ventilation is to record the volume movement of air into and out of the lung, a process called spirometry. A spirometre consist of an air filled drum floating in water filled chamber. As the person breath air in and out of the drum through a tube connecting the mouth to the air chamber, the drum rises and falls in the water chamber. This rise and fall can be recorded as spirogram, which is calibrated to volume changes. Inspiration is recorded as upward deflection and expiration as a downward deflection. Lung volumes: 1. Tidal volume (TV): the volume of air that inspired or expired during a single breath at rest. Its average value = 500 ml. 2. Inspiratory reserve volume (IRV): the extra volume of air that can be inspired using maximal inspiratory efforts from the end of the resting inspiratory tidal volume; it is usually equal to 3000 ml. 3. Expiratory reserve volume (ERV): is the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration, and normally it is about 1100 ml. 4. Residual volume (RV): is the volume of air remaining in the lungs at the end of maximal expiration it average about 1200 ml. Lung capacities: A lung capacity is the sum of two or more lung volumes. 1. Inspiratory capacity (IC): the maximum volume of air that can be inspired at the end of a normal quit expiration (IC = IRV + TV). Average value = 3500 ml. 2. Functional residual capacity (FRC): the volume of air in the lung at the end of a normal passive expiration (FRC = ERV + RV) about 2300 ml. 3. Vital capacity (VC): the maximal volume of air that can be expired after maximal inspiration (VC = IRV + TV + ERV) about 4600 ml. 4. Total lung capacity (TLC): the maximum volume of air contained within the lung after maximal inspiration (TLC = VC + RV) about 5800 ml. RV is the only lung volume that can not measured by direct simple spirometer. RV is measured indirectly by the gas dilution method. A spirometer of known volume is filled with air mixed with helium at a known concentration. Helium is chosen as it is poorly taken up by the blood. The

measurement started immediately at the end of quit of expiration the person connected to the spirometer and allowed to make a few breaths. After a few breaths the helium becomes diluted as it now distributed between the spirometer and the lungs. The RV can be calculated from the degree of the dilution of helium using the following formula. C1 x V1 = C2 x V2 Where: C1 = initial helium concentration (in the spirometer). V1 = initial spirometer volume (initial helium volume). C2 = diluted helium concentration (after few breaths). V2 = is the volume of the spirometer + FRC

C1xV1 FRC = ------------C2 RV = FRC ERV. Ventilation: The major function of the respiratory system is to maintain at optimal levels the partial pressure of O2 and CO2 in the pulmonary alveoli and in the arterial blood. This it does by ventilation a cyclic process of inspiration and expiration in which a fresh air at atmospheric pressure enters the alveoli and then nearly an equal volume of alveolar gas leaves them. The pulmonary or minute ventilation is the volume of air breathed in and out in one minute, this is equal to the tidal volume times the respiratory rate per minute. Pulmonary ventilation = TV x respiratory rate. At an average TV of 500 ml/breath and respiratory rate of 12 breath/min, pulmonary ventilation is 6000 ml/min of air breath in or out in one minute under resting condition. Does all the inspired air participate in the process of gas exchange? At the end of inspiration the TV fills the lungs, occupying both the conducting airways and the alveolar region. The volume of the conducting airways in an adult averages about 150 ml. Since no gas exchange occurs in the conducting airways, the volume of inspired air that remains behind in the

conducting airways is considered anatomic dead space because it is useless or ineffective as far as the process of gas exchange is concerned. Thus the volume of the fresh inspired air that reaches the alveolar region and available for gas exchange each minute is equal to: Alveolar ventilation = (TV dead space volume) x rate of breathing. This is called alveolar ventilation, it represent the volume of fresh air entering the alveolar region that is available for gas exchange. Therefore dead space greatly affects the efficiency of pulmonary ventilation. Since out of the 500 ml of air that are moved in and out with each breath, only 350 ml is actually exchange with the alveoli, because 150 ml of air remains behind in the conducting airways. At the end of inspiration the air remains behind in the conducting airways because it does not participate in gas exchange process, it has a similar gas composition to that of the atmospheric air. During subsequent expiration, the first 150 ml expired are the fresh air that remains behind in the conducting airways that is never used. This is followed by the 350 ml of alveolar air that involves in gas exchange with the blood. At the end of expiration the conducting airways is filled with alveolar gas. This alveolar gas is drawn back into the alveoli during the early part of the next inspiration. It does not raise alveolar PAO2 nor lower alveolar PACO2, only the fresh air that enter beyond the conducting airways into the alveoli raises alveolar PAO2 and lowers alveolar PACO2. Which are more important to the process of gas exchange, an increase in TV or an increase in rate of breathing (pattern of breathing)? During quite breathing at rest pulmonary ventilation is equal to: 500 ml x 12 breath/min = 6000mi/min. and alveolar ventilation is equal to: (500 150) ml x 12 breath/min = 4200 ml/min. If a person voluntarily breaths deeply (tidal volume is increased to 1200 ml) and slowly (breathing rate decrease to 5 breath/min.) Pulmonary ventilation = 1200 x 5 = 6000 ml/min. and Alveolar ventilation = (1200 150) x 5 = 5250 mi/min. the pulmonary ventilation is the same as during quite breathing, but alveolar ventilation increases to 5250 ml/min compared to the resting rate of 4200 ml/min. on the other hand if the rate of breathing is voluntarily increased (shallow breathing) to 40 breath/min and the TV to 150 ml, pulmonary ventilation would still be 6000 ml/min; however alveolar ventilation would be zero.

Thus the increase in TV is more important for effective alveolar ventilation than the increase in rate of breathing, since the increase in TV goes to ventilate the alveolar region. Physiological (Total) dead space: Matching between the inspired air and pulmonary capillary blood is important for the process of gas exchange. A perfect gas exchange is obtained at an equal equilibration between the inspired air and pulmonary blood. However under normal conditions not all alveoli are equally ventilated with air and perfused with blood. Some alveoli are hyperventilated (receiving more air than receiving blood); other alveoli are receiving inadequate blood flow (underperfused). Under such situations some volume in the alveoli is in excess of that necessary to arterialize the blood in alveolar capillaries which becomes part of the dead space (nonequilibrating) gas volume. The volume of air that reaches the gas exchange region but does not equilibrate with blood plus the anatomical dead space volume represent the physiological dead space (it is the volume of gas that not equilibrating with blood). In healthy individual the two spaces are identical, but in several types of pulmonary diseases resulting in abnormal inequality of ventilation and perfusion, the physiological dead space may be as much as 10 times the volume of anatomical dead space. Pulmonary Circulation: The pulmonary vascular bed resembles the systemic except that the walls of the pulmonary artery and its large branches are about 30% as thick as the wall of the aorta, and the small arterial vessels and arterioles unlike the systemic arterioles are endothelial tubes with relatively little muscles in their walls. They are thin with large diameters. These facts made the pulmonary arterial tree distensible and give the arterial tree a large compliance. The pulmonary capillaries are large with multiple anastomoses, so that each alveolus sits in a capillary basket. The pulmonary vasculature because of its large compliance can accommodate the output of the right ventricle which is almost equal to that of all the other organs in the body with two quantitatively minor exceptions, the bronchial and coronary blood flow. Bronchial vessels: blood also flows to the lungs through small bronchial arteries that originate from the systemic circulation a bout 1-2 % of the total cardiac output. The bronchial arterial blood is oxygenated blood in contrast to the partially deoxygenated blood in the pulmonary arteries. It supplies the small and large bronchi, and lung connective tissues. There are anastomoses between the bronchial capillaries and the pulmonary capillaries and veins;

although some of the bronchial blood enters the bronchial veins some enter the pulmonary capillaries and veins by passing the right atrium. Other exception is the blood that flows from the coronary arteries into the chamber of the left side of the heart. Physiological shunt is created by these two exceptions. Pressure in the pulmonary circulation: the entire pulmonary vascular system is a distensible low pressure system. the systolic pressure in the right ventricle of the normal human beings average about 25 mm Hg, and diastolic pressure average 0 1 mm Hg, values that are only one fifth those for the left ventricle. During systole the pressure in the pulmonary artery is equal to the pressure in the right ventricle and diastolic pulmonary artery pressure is equal to 8 mm Hg, and means pulmonary artery pressure is 15 mm Hg. The pressure in the left atrium is about 8 mm Hg during diastole so the pressure gradient in the pulmonary system is 7 mm Hg, compared with a gradient of a bout 90 mm Hg in the systemic circulation. The mean pulmonary capillary pressure is about 7 mm Hg. Blood volume of the lungs: The blood volume of the lungs is about 450 ml. because the pulmonary vascular system is a distensible low pressure system. Under various physiological and pathological conditions, the quantity of blood in the lungs can vary from as little as one half normal up to twice normal. For instance when a normal person lies down, the pulmonary blood volume increases up to 400 ml, and when stand up this blood is discharge to the general circulation. This shift is the cause of the decrease in VC in the supine position and is responsible for the occurrence of orthopnea in heart failure. Pulmonary blood flow is important as the inspired air for the process of gas exchange. For adequate aeration of the blood to occur, it is important for the blood to be distributed to those segments of the lung where the alveoli are best oxygenated. This is achieved by both active and passive factors. There are extensive autonomic innervations of the pulmonary vessels. The vessels also respond to circulating humoral agents such as AII. Passive factors such as cardiac output and gravity also have significant effects on pulmonary blood flow. The blood flow through the lungs is essentially equal to the cardiac output. Therefore the factors that control the cardiac output also control pulmonary blood flow. With exercise the cardiac output increases and the pulmonary arterial pressure rises proportionately. During heavy exercise the blood flow through the lungs increases fourfold to sevenfold. Because of the

distensibility, and low resistance characteristics of the pulmonary vascular system it can accommodates large volume of blood with little rises in pulmonary artery pressure. The little increases in pulmonary artery pressure putting less working load on the right side of the heart as well as prevent a significant rise in pulmonary capillary pressure, thus preventing the development of pulmonary edema. Capillaries dilate, and previously underperfused capillaries are recruited (increasing the number of opened capillaries) to carry blood. The net effect is a marked increase in pulmonary blood flow with few if any alteration in autonomic outflow to the pulmonary vessels. Failure of the left side of the heart or increase resistance to blood flow through the mitral valves as a result of valve stenosis or regurgitation, causes blood to damp up in the pulmonary circulation associated with a large increase in the pulmonary vascular pressure. Because the volume of the systemic circulation is about 9 times that of the pulmonary system, a shift of blood from one system to the other affect the pulmonary circulation greatly but usually has only mild systemic circulatory effect. As a result in left side heart failure, the left atrial pressure can rises up to 40 or 50 mm Hg. The initial rise in atrial pressure up to about 7 mm Hg has very little effect on pulmonary circulatory function. Further increases in left atrial pressure above these level cause almost equally great increases in pulmonary arterial pressure. When the left atrial pressure is increased to above 30 mmHg, causing similar increases in pulmonary capillary pressure, pulmonary edema is likely to develop. Effect of gravity: in the normal upright adult lungs (in sitting or standing positions) the lowest point in the lungs is about 30 cm below the highest point. Consequently there is a relatively marked pressure gradient in the pulmonary arteries from the top to the bottom of the lungs, because of the effect of gravity on the weight of blood in the blood vessels. It has been calculated that a changes in arterial pressure per cm changes in the vertical distance of the body as 0.77 mmHg/cm. accordingly this difference represent a 23 mm Hg pressure difference (0.77 x 30), about 15 mm Hg above the heart and 8 mm Hg below the heart. That is the pulmonary arterial pressure in the upper most portions of the lungs is about 10 mm Hg and at the lowest regions is about 33 mm Hg, resulting in linear increases in pulmonary blood flow from the apex to the base of the lungs. These differences in blood flow can be explained by looking at the pressure gradients that are responsible for the blood flow through the pulmonary capillaries. Similar to other capillary bed the pulmonary arterial venous pressure difference is responsible for

pulmonary capillary flow. However in the lungs the pulmonary capillaries are subjected to compression by the alveolar air pressure. Therefore, any time the lung alveolar air pressure becomes greater than the capillary blood pressure, the capillary closes and there is no flow of blood during both systolic and diastolic phases of the cardiac cycle (this is called zone 1). Zone 1 blood flow pattern occurs in the lungs only under abnormal conditions. It exists when the pulmonary arterial pressure is reduced as might occurs after sever blood loss, or if alveolar pressure is increased as in expiration against resistance. Under such circumstances no blood flow in the lung apex would be expected. Under these conditions there is no gas exchange in the affected alveoli and they become part of the physiological dead space. In Zone 2 occurs in lung regions if the pulmonary systolic arterial pressure but not the diastolic pressure exceeds the alveolar pressure during the cardiac cycle. Under these conditions blood flow is determined by the pulmonary arterial alveolar pressure difference rather than by the pulmonary arterial pulmonary venous difference, resulting in intermittent blood flow. Zone 2 normally exists in the apex of the upright lungs the pulmonary arterial pressure at the apex is about 15 mm Hg less than the pressure at the level of the heart. The systolic right ventricular pressure is equal to 25 mm Hg. Therefore the apical systolic pressure is 10 mm Hg, which is greater than the zero alveolar air pressure. While during diastole the right ventricular pressure is equal to 8 mm Hg which is not sufficient to push the blood up the 15 mm Hg hydrostatic pressure gradient required to cause diastolic capillary flow. So blood flow through the apex of the lungs is intermittent, blood flow during systole, with cessation of blood flow during diastole. Zone 3 : the type of continuous blood flow. In the lower region of the lungs the pulmonary arterial pressure because of the effect of gravity remains greater than the zero alveolar air pressure during both systole and diastole. The circulation of blood in zone 3 is thus determined by the arterial venous pressure difference. Under normal conditions the lungs have only zone 2 and zone 3 blood flow. Which type of blood flow does exist within the lungs when a person is lying down? During exercise there much greater increases in blood flow in the top of the lungs than in the lower regions of the lungs. This difference is due to the increase in pulmonary arterial pressure during exercise that convert lung apex from zone 2 to zone 3 pattern of blood flow.


Effect of diminished alveolar O2 on local alveolar blood flow automatic control of pulmonary blood flow distribution. Alveolar capillary flow can be controlled by adjusting the resistance to blood flow through specific pulmonary arterioles. If the concentration of O2 in the air of alveoli is decreased below normal values, the adjacent blood vessels constrict increasing the vascular resistance. This is opposite to the effect observed in systemic vessels, which dilate rather than constrict in response to low O2. Capillary Exchange of Fluid in the Lungs, and Pulmonary Interstitial Fluid Dynamics The dynamics of fluid exchange across the lung capillary membranes are the same as for peripheral tissues. However there are important differences, as follow: 1. The pulmonary capillary pressure is low about 7 mm Hg in comparison to about 17 mm Hg in peripheral tissues capillary. 2. The interstitial fluid pressure in the lung is slightly more negative than that in the peripheral subcutaneous tissue. 3. The colloid osmotic pressure of the pulmonary interstitial fluid is higher than that in peripheral tissues. 4. The alveolar walls are very thin allowing the accumulation of fluid into the alveoli from the interstitial space when its pressure becomes greater than alveolar air pressure. Pulmonary edema: pulmonary capillary pressure is about 7 mm Hg whereas the pulmonary capillary colloid osmotic pressure is 28 mmHg, so that there is an inward directed pressure gradient which keeps the alveoli free of fluid. Any factor that causes the pulmonary interstitial pressure to rise from the negative state into the positive range will cause rapid filling of the interstitial spaces and alveoli with large amounts of free fluid. The most common causes of edema are: 1. left-side heart failure or mitral valve disease, with greater increases in pulmonary venous pressure and pulmonary capillary pressure. 2. damage to the pulmonary blood capillary membranes caused by infection or by breathing noxious substances such as chlorine gas or sulfur dioxide gas causing rapid leakage of both plasma proteins and fluid out of the capillaries into both the interstitial spaces and alveoli. With a normal colloid osmotic pressure of 28 mm Hg, the pulmonary capillary pressure must rises from the normal

level of 7 mm Hg to more than 28 mm Hg to cause pulmonary edema in acute cases. In acute left-sided heart failure in which the pulmonary capillary pressure usually rise to 50 mm Hg death frequently occurs in less than 30 minutes from acute pulmonary edema. When the pulmonary capillary pressure remains elevated chronically, the lungs become even more resistance to pulmonary edema because the lymph vessels expand greatly, increasing their capability for carrying fluid away from the interstitial spaces perhaps as much as 10 fold. Therefore in patient with chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured without the development of lethal pulmonary edema. Physical principles of gas exchange; Diffusion of O2 and CO2 through the respiratory membrane After alveolar ventilation which provides a continual supply of fresh O2 to be taken by the blood and constantly eliminate CO2 that brought by the blood. The next step in the respiratory process is diffusion of O 2 from the alveolar air into pulmonary capillary blood and diffusion of CO2 in the opposite direction. The diffusion of O2 and CO2 at the pulmonary capillaries is a simple passive process, which does not require active transport mechanisms. The rate of diffusion of a gas is directly proportional to the partial pressure of that gas. What is the partial pressure? Partial pressures: Atmospheric air is a mixture of gases. The dry air contain about 78.62 % N2, 20.84% O2, 0.04% CO2, and 0.50% H2O at sea level. Altogether these gases exert a total atmospheric pressure of 760 mm Hg at sea level. This total pressure is equal to the sum of the pressure that each gas in the mixture partially contributed. The pressure exerted by a particular gas is directly proportional to the percentage of that gas in the total mixture. Every gas molecule, no matter what its size, exerted the same amount of pressure, for example, N2 molecule exerts the same amount of pressure as an O2 molecule. Because 78.62% of the air consists of N2 molecules, 78.62% of the 760 mm Hg atmospheric pressure or 596.0 mm Hg is exerted by N2 molecules. Similarly because O2 represents 20.84% of the atmosphere, 20.84% of the 760 mm Hg atmospheric pressure or 159.0 mm Hg is exerted by O2. The individual pressure exerted independently by a particular gas within a mixture of gases is known as its partial pressure. The partial pressures of

individual gas in a mixture are designated by the symbols PO2, PCO2, PN2, PH2O, and so forth. Alveolar PO2 and PCO2 its relation to atmospheric air: Alveolar air is not of the same composition as inspired atmospheric air, for the following reasons: as soon as atmospheric air enters the respiratory passages, exposure to the moist airways saturates it with H2O like any other gas water vapor exerts a partial pressure. At body temperature the partial pressure of H2O vapor is 47 mm Hg. Because the sum of the partial pressures must total the atmospheric pressure of 760 mm Hg. In humidified air, PH2O = 47 mm Hg, PN2 = 563.4 mmHg, and PO2 = 149.3 mm Hg. Alveolar PO2 is lower than atmospheric PO2, because fresh inspired air is mixed with large volume of air that remained in the dead space and in the lungs at the end of the preceding expiration (FRC). At the end of inspiration only 350 ml of fresh air mix with and dilute the large volume of air remained in the lungs at the end of expiration. As a result of humidification and the small turnover of alveolar air the average alveolar PO2 is 104 mm Hg compared to the atmospheric PO2 of 159 mm Hg. Small fluctuations in alveolar PO2 from its average value occur during the respiratory cycle. It increases during inspiration and decreases during expiration. Because only small volume of inspired high PO2 air is mixed with much larger retained low PO2 air, the level of total alveolar PO2 is slightly elevated. Additionally the O2 reaching the alveoli in the newly inspired air simply replaces the O2 that diffusing out of the alveoli into the pulmonary capillary blood. CO2 which is continually produced by body tissues as a metabolic waste product is constantly added to the blood at the level of systemic capillaries. In the pulmonary capillaries CO2 diffuses down its partial pressure gradient from the blood into the alveoli and is subsequently removed from the body during expiration. As with O2 alveolar PCO2 remains fairly constant throughout the respiratory cycle but at a lower value of 40 mm Hg. PO2 and PCO2 gradients across the pulmonary capillaries: The blood that retained to the right side of the heart following gas exchange with tissues is low in O2, with a PO2 of 40 mm Hg, and is relatively high in CO2, with a PCO2 of 46 mm Hg. This blood is pumped by the right ventricle to the lungs through the pulmonary arteries, entering the pulmonary capillaries where it exposed to alveolar air. Because the alveolar PO2 at 104 mm Hg is higher than the PO2 of 40 mm Hg in the blood entering the lungs, O2 diffuses down its partial pressure gradient from the alveoli into the blood until no further gradient exists. As blood leaves the pulmonary capillaries

and enters the systemic circulation in the aorta it has a slightly lower PO2 than alveolar PO2 because of the physiological shunt. The partial pressure gradient for CO2 is in the opposite direction. Blood entering the pulmonary capillaries has a PCO2 of 46 mm Hg, whereas alveolar PCO2 is 40 mm Hg. CO2 diffuses from the blood into the alveoli until blood PCO2 equilibrate with alveolar PCO2. Thus blood leaving the pulmonary capillaries has a PCO2 of 40 mm Hg. The PO2 of the systemic venous blood is 40 mm Hg thus blood returning to the lungs from tissues contains O2, and blood leaving the lungs contains CO2 ( PCO2 of the systemic arterial blood is 40 mm Hg). The extra O2 carried in the blood beyond that normally given up to the tissues represents O2 reserve that can be used by tissue cells whenever their O2 demands increase. The amount of O2 picked up in the lungs matches the amount extracted and used by the tissues. The CO2 remaining in the blood even after passage through the lungs through the lungs plays an important role in the acid base balance of the body and in driving respiration.

PO2 and PCO2 in the expired air: Expired air is a mixture of the air that remains behind in the conducting airway at the end of inspiration and dose not participate in the process of gas exchange with the alveolar air. At the end of expiration the dead space is filled with alveolar air. Therefore Expired PO2 = 120 mmHg, and PCO2 = 27 mm Hg. At what time during the respiratory cycle a sample of air can be collected that represent alveolar air? Factors that influence the rate of gas diffusion through the respiratory membrane (alveolocapillary membrane): In addition to the gas partial pressure gradient, the diffusion rate of a gas through the membrane also depends on the surface area and thickness of the membrane through which the gas is diffusing and on the diffusing coefficient of the particular gas. Changes in the rate and direction of gas exchange normally are determined primarily by changes in partial pressure gradient between blood and alveoli, because these factors are relatively constant under resting conditions. However, under conditions when other factors do change, these changes alter the rate of gas diffusion. The thickness of the respiratory membrane:

The alveocapillary membrane through which gases are diffused between the alveoli and blood in pulmonary capillaries is a thin membrane with a large surface area thus is a suitable site for gas exchange. This membrane is composed of: 1. a layer of fluid lining the alveoli, which containing the surfactant. 2. the alveolar epithelium. 3. epithelial basement membrane. 4. a thin interstitial space between the alveolar epithelium and capillary membrane. 5. the capillary endothelium. Despite the large number of layers, the overall thickness of the respiratory membrane in most areas is as little as 0.2 micrometer, and its average is 0.6 micrometer. The total surface area of the respiratory membrane is 70 square meter. Because the rate of diffusion is inversely proportional to the square of the distance through which a gas diffuse, any factor that increases the thickness to more than two to three times normal can interfere significantly with normal respiratory gas exchange. Thickness increases in pulmonary edema fluid in the interstitial space between the alveoli and pulmonary capillaries caused by pulmonary inflammation or left sided heart failure. Membrane thickness also increases in pulmonary fibrosis which involving replacement of the delicate lung tissue with thick fibrous tissue in response to certain chronic irritants. The surface area of the respiratory membrane: Several conditions can greatly reduce pulmonary surface area and in turn decrease the rate of gas exchange. For instance removal of an entire lung, also in emphysema surface area is reduced because many alveolar walls are lost, resulting in large but fewer alveolar chambers, reducing the total surface area of the respiratory membrane. Effect of diffusion coefficient on gas exchange: The rate of gas transfer is directly proportional to the diffusion coefficient a constant value related to the solubility of a particular gas in the lung tissues and to its molecular weight. The diffusion coefficient for CO2 is 20 times that of O2 because CO2 is much more soluble in body tissue than O2 is. The rate of CO2 diffusion through the respiratory membrane is therefore is 20 times more rapid than that of O2 for a given partial pressure gradient. This offset the smaller partial pressure gradient for CO2 (6 mm Hg, compared to the O2 gradient of 60 mm Hg) thus approximately equal amounts of CO2 and O2 are transferred across the membrane. Normally a given volume of blood spends 0.75 of a second passing through the pulmonary capillary bed PO2 and PCO2 are usually equilibrated with alveolar partial pressures by the time the

blood has traversed only one third the length of the pulmonary capillaries. This means that the lung normally has large diffusion reserves, which becomes very important during heavy exercise. The time the blood spends in the pulmonary capillaries is decreased as pulmonary blood flow increases during exercise. Even when less time is available for exchange, blood PO2 and PCO2 are normally able to equilibrate with alveolar levels because of the lungs diffusion reserves. During heavy exercise normally both pulmonary blood flow and alveolar ventilation are greatly increased, leading to about three times increase in O2 diffusing capacity than under resting condition. This increase is caused by opening up of many dormant pulmonary capillaries or to greater dilation of the already dilated open capillaries, thereby increasing the surface area for diffusion, and to a better match between pulmonary blood flow and alveolar ventilation. In diseased lung in which diffusion is impaired because the surface area is decreased or the blood air barrier is thickened, O2 transfer is usually more affected than CO2 transfer, because of the large CO2 diffusion coefficient, CO2 can diffuse more rapidly through the respiratory membrane.

Diffusion of O2 and CO2 from the systemic capillaries into the tissue fluid: When the arterial blood reaches the peripheral tissues its PO2 in the capillaries is 99 mm Hg less than the alveolar PO2 of 104 mm Hg and its PCO2 is 40 mm Hg the same as the alveolar PCO2. This slight decrease in the arterial PO2 is due to mixing of small volume of venous blood (its PO2 = 40 mmHg) that does not pass through the gas exchange area of the lung with the blood that leaving the alveolar region (its PO2 = 104 mmHg). This is called physiological shunting as it exists normally. At the tissue level cells constantly consume O2 and produce CO2 through oxidative metabolism. Cellular PO2 average about 40 mm Hg and PCO2 46mm Hg, although these values are highly variable, depending on cellular metabolic activity, and rate of tissue blood flow. O2 moves by diffusion down its partial pressure gradient into the interstitial fluid that surrounds tissue cells. The reverse situation exists for CO2, which rapidly diffuses down its partial pressure gradient out of the cells into capillary blood until equilibrium is reached. Therefore PO2 and PCO2 of venous blood leaving the systemic capillaries are equal to tissue PO2, and PCO2. The venous blood returns to the heart which pumped to the lungs as the cycle repeats itself.

Ventilation Perfusion Ration and its effect on Alveolar gas concentration: Gas exchange and the level of alveolar PO2 and PCO2 are determined by matching of the total alveolar ventilation with the pulmonary capillary blood perfusing whole alveoli. This is the concept of ventilation perfusion ratio and in quantitative terms it is expressed as VA/Q. The ratio of pulmonary ventilation to pulmonary blood flow for the whole lung at rest is about 0.8 (4.2 L/min ventilation divided by 5 L/min blood flow). However, there are relatively marked differences in the VA/Q in various part of the normal lung as a result of the effect of gravity, and local changes in the VA/Q are common in disease. If the ventilation to an alveolus is reduced relative to its perfusion the PO2 in the alveolus is falls because less O2 is delivered to it and the PCO2 rises because less CO2 is expired. Conversely if perfusion is reduced relative to ventilation the PCO2 falls because less CO2 is delivered and the PO2 rises because less O2 enters the blood. Ventilation as well as perfusion in the upright position decline in a linear fashion from the bases to the apices of the lungs; however blood flow is decreased considerably more than ventilation and VA/Q is higher in the upper portions of the lung than the ideal value. This causes a moderate degree of physiological dead space in the upper part of the lung. At the bases of the lung there is slightly less ventilation in relation to blood flow with lower VA/Q than the ideal value. In this area a small fraction of the blood failed to become normally oxygenated and this represents a physiological shunt. Whenever VA/Q is below normal, there is inadequate ventilation to provide the O2 needed to fully oxygenate the blood flowing through the alveolar capillaries. Therefore a certain fraction of the venous blood passing through the pulmonary capillaries does not become oxygenated and is called shunted blood. Also some additional blood flows through bronchial vessels by passing the gas exchange zone is unoxygenated shunted blood. The total quantitative amount of shunted blood per minute is called the physiological shunt. The greater the physiological shunt the greater the amount of blood that fails to be oxygenated as it passes through the lungs. When ventilation of some alveoli is greater than the alveolar blood flow there is more available O2 in the alveoli than can be transported by the flowing blood. Thus the ventilation of these alveoli is said to be wasted and the ventilation of the anatomical dead space is also wasted. The sum of these two types of wasted ventilation is called the physiological dead space. The transport of oxygen by the blood:

O2 is carried in the blood in two forms: 1. dissolved O2, and 2. in combination with hemoglobin. Blood can carry any gas in solution the amount dissolved is controlled by Henrys law which states that the amount of the gas dissolved is directly proportional to the partial pressure. Because O2 is poorly soluble in body fluids the amount of O2 dissolved in blood under a normal alveolar PO2 is very small. It has been found that at alveolar PO2 of 100 mmHg, only 3 ml of O2 can dissolved in 1 litter of blood. Thus only 15 ml O2/min can dissolve in the normal pulmonary blood flow of 5 L/min (the resting cardiac output). Under resting condition, the cells consume 250 ml O2/min therefore if O2 could only be transported in dissolved form, the cardiac output would have to be 83.3 L/min instead of 5 L/min. 1. Does the dissolved O2 conceder as an effective method of O2 transport? 2. What is the inspired PO2 during breathing pure O2? 3. What is the amount of dissolved O2 in arterial blood during breathing? pure O2? Fortunately the blood contains hemoglobin which is more effective and essential method for transport O2 to the tissues as it permits the whole blood to take up 65 times as much O2 as that dissolved in plasma at a PO2 of 100 mm Hg. The dissolved O2 represents 1.5% of the whole O2 transported by the blood, while O2 bound to hemoglobin represent 98.5% 0f the O2 carried by the blood. The blood O2 content include the dissolved O2 plus that bound to hemoglobin. Only the dissolved O2 represents the partial pressure of O2 in the blood. The combination of oxygen to hemoglobin: Hemoglobin an iron-bearing protein molecule contained within the red blood cells. Oxygen forms an easily reversible combination with hemoglobin to give oxyhemoglobin. Hb + O2 HbO2

The main factor determines the amount of O2 that bound to hemoglobin is the arterial PO2. A higher PO2 forces more O2 molecules to combine with hemoglobin, while exposure of the blood to a low PO2 decreases the force that keeps O2 bound to hemoglobin resulting in dissociation and release of O2 from hemoglobin. As in any other reversible reaction the reaction can move in either direction depending on the concentration of substances on

both side of the equation. Increases in blood PO2 as in the pulmonary capillaries driven the reaction toward the right side of the equation, increasing the formation of HbO2. When blood PO2 decreases as in the systemic capillaries the reaction is driven toward the left side of the equation and O2 is released from Hb (dissociation of HbO2). The O2 Hb dissociation curve: The equilibration between O2 and Hb or the characteristic of the combination of Hb with O2 is described by the O2 Hb dissociation curve in which the blood PO2 is plotted against the percent Hb saturation (%Hb). The %Hb is a measure of the extent to which the Hb present in combination with O2 can vary from 0% to 100%. O2 combined with Hb % Hb = ------------------------------ X 100 O2 capacity of Hb The O2 capacity is the maximal amount of O2 that can combine with Hb when blood is exposed to high PO2. The capacity varies with the number of grams of Hb/100 ml of blood, as 1 gram of Hb when fully loaded with O2 combine with 1.34 ml of O2. The relation between blood PO2 and % Hb saturation is not a linear. Rather, the relation between these variables follows an S shaped curve, the O2 dissociation (or saturation) curve: at the upper end of the curve or the association part of the curve where blood is exposed to normally existing alveolar and arterial blood PO2 the Hb is 97.4 % saturated with O2, and the Hb in 100 ml of blood combines with 19.5 ml O2. On passing through tissue capillaries about 5 ml of O2 under normal conditions are transported from the lungs to the tissues by each 100 ml of blood flow, leaving 14.4 ml O2 as a reserve. At the upper end of the curve breathing air at sea level results normally in nearly full saturation of Hb with O2 (97.4%). When blood exposed to a PO2 greater than 100 mmHg, Hb can not accept much more O2. Hb is fully saturated (100%) when the PO2 is about 250 mmHg, the saturation increase only by 2.6% and O2 associated with Hb can increase only by 0.5 ml/100 ml no matter how high the PO2 of alveolar air or blood is raised. Maximal hyperventilation with air rarely raises alveolar PO2 to more than 130 mm Hg, it cannot add more O2 to the blood. at the upper part of the curve between a blood PO2 of 60 and 100 mm Hg, the curve flattens off. What is the significance of the flat portion of

O2 Hb curve?. It can be seen from the curve with greater decreases in alveolar PO2 and consequently in arterial PO2 the Hb is still highly saturated with O2. A decreases in alveolar or arterial PO2; from 100 to 90 mmHg decreases % Hb saturation from 97.4 to 96.9% from 100 to 80 mmHg decreases % Hb saturation from 97.4 to 95.9% from 100 to 70 mmHg decreases % Hb saturation from 97.4 to 94.1% from 100 to 60 mmHg decreases % Hb saturation from 97.4 to 89 %. With the decrease in alveolar or arterial PO2 down to 60 mmHg, the arterial Hb is still 89% saturated with O2 and the tissues still remove about 5 ml O2 from each 100 ml of blood passing through the tissues. Thus the tissue PO2 hardly changes despite the marked fall in alveolar PO2. This means that a healthy man can live at reasonably high altitude - where the inspired PO2 is lower than at sea level which consequently lowers alveolar and arterial PO2 - without much reduction in the uptake of O2 by Hb. Also in patients with pulmonary diseases that are associated with a low arterial PO2 of 70 or 60 mmHg due to inadequate ventilation or defective gas exchange, the uptake of O2 by Hb is not significantly affected. the steep middle and lower parts of the curve or the dissociation part of the curve occurs in the blood PO2 range that exists at the systemic capillaries, where O2 is unloading from Hb. In the systemic capillaries the blood equilibrates with surrounding tissue cells at an average PO2 of 40 mm Hg. Because the PO2 determines the amount of O2 that Hb can hold, the oxyhemoglobin in systemic capillaries dissociates and releases O2. At a PO2 of 40 mm Hg holds only 75% of its O2, and 25% of HbO2 dissociates and release O2 that diffuse down its partial pressure gradient into tissue cells. If the tissue metabolic rate is increased, the PO2 of systemic capillary blood falls below 40 mm Hg because the cell consuming O2 more rapidly. Because the range of fall in PO2 operating in the steep portion of the curve, only a small drop in systemic capillary PO2 can automatically make a large amount of O2 available to meet the O2 need of more actively metabolizing cells. If PO2 fall to 30 mm Hg the % Hb saturation is 57.5%. If PO2 fall to 20 mm Hg the % Hb saturation is 32%. If PO2 fall to 10 mm Hg the % Hb saturation is 9.6%. Therefore the flat upper part of the curve protects the body by enabling the blood to load O2 despite a large decrease in PO2. The steep middle and lower portion of the curve protect

the tissue by enabling them to withdraw large amount of O2 from blood for relatively small decreases in PO2. Hb promotes the net transfer of O2 at both alveolar and tissue levels: The blood O2 content include the dissolved O2 pulse that combined with Hb. At the alveolar level O2 enters the blood down its partial pressure gradient in solution as a dissolved O2 which only contribute to PO2, as combined O2 cannot contribute to PO2. Because Hb combined rapidly with O2 as it enters the blood from alveolar air, Hb keeps blood PO2 low and prologs the existences of partial pressure gradient so that a large net transfer of O2 into the blood can take place. Until Hb is maximally saturated all the O2 transferred into the blood remained dissolved and directly contribute to the PO2, which then equilibrate rapidly with alveolar PO2. The reverse situation occurs at the tissue level. As blood entering the systemic capillaries, O2 immediately diffuses into tissues lowering blood PO2. When blood PO2 falls the %Hb saturation is reduced, releasing combined O2. The released O2 dissolved in the blood, increasing blood PO2 to a higher level than that of the surrounding tissues. This allows further movement of O2 out of the blood until Hb can no longer release any more O2 in solution. Thus Hb plays an important role in the total quantity of O2 that the blood can pick up in the lungs and deliver it to tissue cells. Factors that shift the oxygen-hemoglobin dissociation curve Their importance for oxygen transport: The shape of the O2 Hb curve is not constant; it can be shifted to the right or to the left. At first what a shift in the curve means? The main factor determining the % Hb saturation is the PO2 of the blood. At the tissue capillaries because O2 diffuses into tissues from the blood, lowering blood PO2, which consequently reduces the %Hb saturation, releases more O2 to the tissues until state of equilibrium is reached. At equilibrium state the blood PO2 is 40 mm Hg comparable to that of interstitial fluid PO2. For the tissues to obtain more O2 from the blood, tissues and consequently blood PO2 have to decrease further lower than 40 mmHg. However a shift in the curve to the right from the control curve for the same PO2 ( without further decreases in PO2) the Hb will hold less O2, that is %Hb decreases and more O2 is released to diffuse into the tissues. While a shift in the curve to left increases the affinity of Hb to combine with O2, thus decreases the release of the combined O2. The other factors that can affect the affinity or bond strength between Hb and O2, and shift the curve are CO2, pH, temperature, and 2,328

biphosphoglycerate (2,3 BPG). The control curve is taken at the blood normal values of these factors as at pulmonary level. Effect of CO2 on % Hb saturation: An increase in PCO2 shifts the O2 Hb curve to the right. The % saturation is still depends on PO2, but for any given PO2 less Hb and O2 can combined. This effect is important, because the PCO2 of the blood increases in the systemic capillaries as CO2 diffuses down its gradient from the cells into blood. The presence of this additional CO2 in the blood decreases the affinity of Hb for O2, so Hb unloads more O2 at the tissue level than it would if the reduction in PO2 in the systemic capillaries were the only factor affecting the % Hb saturation. Effect of acid on % Hb saturation: An increase in acidity also shifts the curve to the right. Because CO2 form carbonic acid (CO2 + H2O H2CO3), the blood becomes more acidic at the systemic capillaries as it loaded with CO2 from the tissues. This helps to release even more O2 at the tissue level for a given PO2. In actively metabolizing cells such as exercising muscles, not only more carbonic acid is formed but lactic acid may also produce if the cells use anaerobic metabolism. The resultant local elevation of acid in working muscles helps further unloading of O2 in tissues where it mostly needed. The influence of CO2 and acid on the release of O2 is known as Bohr Effect. Effect of temperature on % saturation of Hb: In a similar manner a rise in temperature shift the O2 Hb curve to the right. An exercising muscle or actively metabolizing cell produces heat. The resulting local rise in temperature enhances O2 release from Hb for use by more active tissues. Comparison of these factors at the tissues and pulmonary levels: Increases in CO2, acidity, and temperature at the tissue level are associated with increased cellular metabolism and increased O2 consumption, enhancing the effect of a drop in PO2 in facilitating the release of O2 from Hb. These effects are reversed at the pulmonary level, where the extra acid forming CO2 is eliminated and the local environment is cooler. Therefore Hb has a higher affinity for O2 in the pulmonary capillaries enhancing the effect of raised PO2 in loading O2 onto Hb.

Effect of 2,3-biphosphoglycerate on % Hb saturation: the 2,3-biphosphoglycerate (BPG) is a constituent of red blood cells (RBCs), while the above mentioned changes occur outside the RBCs. This substance which produced during RBC metabolism can bind reversibly with Hb and reduce its affinity for O2 just as CO2, and H+ do. Thus an increased level of BPG shifts the O2 Hb curve to the right, enhancing O2 unloading as the blood flow through the tissues. BPG production by RBCs gradually increases whenever Hb in the arterial blood is chronically undersaturated that is when arterial HbO2 is below normal. This condition may occur in people living at high altitudes or in patients suffering from certain types of circulatory or respiratory diseases or anemia. The increased BPG maintain O2 availability for tissue use even though arterial O2 is chronically reduced. However unlike the other factors which normally present only at tissue level and thus shift the O2 Hb curve to the right only in the systemic capillaries. BPG is present in RBCs throughout the circulatory system and accordingly shifts the curve to the right to the same degree in both the tissues and lungs. As a result, BPG decreases the ability to load O2 at the pulmonary level. Combination of hemoglobin with carbon monoxide displacement of oxygen: Carbon monoxide (CO) and O2 compete for the same binding sites on Hb, but the Hb affinity for CO is about 250 times that of its affinity for O2. The combination of CO and Hb is known as carboxyhemoglobin. Therefore a CO partial pressure of 0.4 mm Hg in the alveoli, 1/250 that of normal alveolar O2 (100 mm Hg PO2), allows the CO to compete equally with O2 for combination with Hb and causes half the Hb in the blood to combine with CO instead of with O2. Even though the blood oxygen content is greatly reduced in carbon monoxide poisoning, the Hb concentration and PO2 are normal. This makes exposure to CO especially dangerous, because the blood is bright red and there are no obvious signs of hypoxemia, such as bluish color (cyanosis) of the fingertips or lips. Also PO2 is not reduced and the feedback mechanism that usually stimulates increased respiration rate in response to lack of O2, the person may become disoriented and unconscious before becoming aware of the danger. Transport of carbon dioxide in the blood: The process of CO2 transport starts at the tissue level where it is continually form as a result of active cellular metabolism. This increases tissues PCO2

above that of the systemic capillary blood, allowing CO2 to diffuse passively down its partial pressure gradient from the tissues into the plasma of capillary blood. In the blood (plasma and RBCs) CO2 is carried in three forms: 1. as dissolved CO2. 2. as bicarbonate. 3. in combination with proteins. Most of the CO2 so added to plasma diffuses into the RBCs, but some enter into the three reactions in the plasma. The dissolved CO2 present at first in simple solution in plasma which responsible for the partial pressure of CO2 in the blood. From the dissolved form CO2 enters into other reactions in both plasma and inside the RBCs. These reactions delay the rapid equilibration of blood PCO2 with the tissues PCO2, allowing more diffusion of CO2 into the blood. Like the dissolved O2, the amount of physically dissolved CO2 in the blood depends on the PCO2. Because CO2 is more soluble than O2, a greater proportion of the total CO2 than of O2 in the blood is physically dissolved. Even so only about 7 % of the blood total CO2 content is carried this way at the normal systemic venous PCO2 level. Transport of CO2 in the form of bicarbonate ion: the dissolved CO2 in plasma and inside the RBCs associates with water to form carbonic acid through a reversible reaction. The carbonic acid then dissociates into H+ and bicarbonate ion HCO3. CO2 + H2O H2CO3 H+ + HCO3 .

By far the most form of CO2 transport is as bicarbonate, with 70% of the CO2 being converted into HCO3 by the above reaction, which takes place within the RBCs. In the first step, CO2 associates with water to form carbonic acid. The rate of this reaction is a slow one. The rate of association of CO2 and water can be speed up by the enzyme carbonic anhydrase (CA). This enzyme present inside the RBCs but not in plasma. Thus CO2 associates with water at a much rapid rate inside the RBCs than in plasma, as a result more carbonic acid is formed inside the RBCs than in plasma. As is characteristic of acids, carbonic acid molecules spontaneously dissociate into H+ and HCO3. Even with the presence of the enzyme CA the increase in the concentration of H+ and HCO3 on the right side of the equation slows down or stops the association of more CO2 and water as a state of equilibrium between both

sides of the equation is reached. However if by some means the concentration of substances on the right side of the equation is reduced more CO2 is going to associate with water, leading to increase CO2 transport by the blood. In fact most of the H+ that formed inside the RBCs is taken by Hb, because the Hb protein is a powerful acid-base buffer. It has about 6 times greater buffering capacity than that of plasma proteins still the unoxygenated Hb has a greater buffering capacity than HbO2 does (what this does mean). As the reaction proceeds, HCO3 and H+ start to accumulate within the RBCs in the systemic capillaries. The RBC membrane has a HCO3 - Cl carrier that passively facilitates the diffusion of these ions in opposite directions across the membrane. The membrane is relatively impermeable to H+. Consequently HCO3 but not H+ diffuses down its concentration gradient out of the RBCs into the plasma. Because HCO3 is a negatively charged ion, the efflux of HCO3 unaccompanied by a comparable outward diffusion of positively charged ions creates an electrical gradient. Cl the dominant plasma anions diffuse into the RBCs down this electrical gradient to restore electrical neutrality. This inward diffusion of Cl in exchange for the efflux of HCO3 generated by CO2 is known as the chloride shift. Transport of CO2 in combination with Hb and plasma protein: About 23% of all CO2 carried by the blood combine with the globin portion of Hb, in contrast to O2 which combines with the heme portion. The combination of CO2 with Hb form carbamino hemoglobin. The unoxygenated Hb has a greater affinity to combine with CO2 than the HbO2 does. Thus the unloading of O2 from Hb in the tissue capillaries helps the blood to transport more CO2. Haldane Effect: As with the affinity to CO2, unoxygenated Hb has a greater affinity for H+ than oxyhemoglobin does. Therefore the unloading of O2, helps Hb to load more CO2-generate H+. The fact that removing O2 from Hb increases the ability of Hb to pickup CO2 and CO2-generated H+ is known as the Haldane effect. The Haldane effect and Bohr effect work in synchrony to facilitate O2 release and the uptake of CO2 and CO2-generatyed H+ at the tissue level. Increased CO2, and H+ cause increased release of O2 from Hb by Bohr effect, increased O2 release from Hb in turn causes increased CO2 and H+ up take by Hb through the Haldane effect. The reactions at tissue level are reversed once the blood reaches the pulmonary capillaries. Through the Haldane effect , the combination of O2 with Hb in the lungs causes the Hb to become stronger acid. This eliminate CO2 from the blood in two ways (1) the more highly acidic Hb has less

tendency to combine with CO2 releasing much of CO2 present in the blood. (2) the increased acidity of Hb also causes it to release an excess of H+ which bind with bicarbonate H+ + HCO3 H2CO3 CO2 + H2O

To form carbonic acid, this then dissociates into water and CO2 and CO2 is released from blood into alveoli and finally eliminated into the air. Regulation of Respiration Breathing must occur in a continuous cyclic pattern to sustained life processes. Inspiratory muscles must rhythmically contract and relax to alternately fill the lungs with air and empty them. By these activities the respiratory system does not only perform its main function of gas exchange also maintains normal levels of PO2, and PCO2 in arterial blood inspite of changing demand for O2 uptake and CO2 output. The regulation of gas exchange is possible because the level of ventilation is so carefully controlled. The respiratory control system is an example of negative feed back mechanism consists of the following elements: 1. sensor: which gather information about changes in the body fluids PO2 and PCO2 and send these information to, 2. the respiratory control centers in the brain which coordinate these information and send the appropriate order to, 3. the effectors, (the respiratory muscles) changing ventilation. The respiratory control centers: Respiration is an automatic involuntary activity that without any thought on our part mange to bring just enough air into the pulmonary alveoli to maintain PO2 and PCO2 of alveolar or arterial blood at optimal levels. However the respiratory muscles are skeletal muscles, possess no inherent rhythm. They do not contract if they are separated from the central nervous system by cutting the motor nerve innervating them. The rhythmic pattern of breathing is established by cyclic neural activity to the respiratory muscles that arise from the respiratory control centers in the brain. Unlike nerve supply to cardiac and smooth muscles which regulate their inherent rhythmic contraction. Nerve supply to respiratory muscles is essential in maintaining breathing and in reflex adjusting the level of ventilation to match changing needs for O2 uptake and CO2 removal. In

addition respiration unlike other involuntary automatic activities is subjected to a limited voluntary control. The respiratory activity can be voluntarily modified to accomplish speaking, whistling, holding breath while swimming or hyperventilation. Neural control of respiration - the respiratory centers: The periodic nature of inspiration and expiration is generated by collection of several groups of neurons located in the medulla and pons of the brain steam which are called the respiratory centers. Three main groups of neurons are recognized: 1. the medullary respiratory center: consists of several collection of neuronal cell bodies within the medulla that provide output to the inspiratory muscles, the diaphragm and external intercostals muscles, supplied by the phrenic nerve and intercostal nerves respectively. The cell bodies for the neuronal fibers forming these nerves are located in the spinal cord. Impulses originating in the medullary center end on these motor neuron cell bodies. When these motor neurons are activated, they in turn stimulate the inspiratory muscles, leading to inspiration, when these neurons are not firing, the inspiratory muscles relax and expiration takes place. The medullary respiratory center consists of two neuronal groups known as the dorsal respiratory group and the ventral respiratory group. The dorsal respiratory group (DRG): most of its neurons are located within the nucleus of the tractus solitarius, which is the sensory termination of the vagal and glossopharyngeal nerves that transmit sensory signals into the respiratory center from peripheral chemoreceptors, baroreceptors, and several types of receptors in the lungs. The DRG consists mostly of inspiratory neurons whose descending fibers terminate on the motor neurons that supply the inspiratory muscles. When the DRG insiratory neurons fire, inspiration takes place when they cease firing, expiration occurs. The DRG has interconnections with the venteral respiratory group. The venteral respiratory group (VRG): is composed of inspiratory and expiratory neurons, both of which remain inactive during normal quite breathing. This region is called into play by the DRG during periods when demands for ventilation are increased. It is especially important in active expiration. No impulses are generated in the descending pathways from the expiratory neurons during quite breathing.


2. Pneumotaxic and Apneustic centers: these centers are located in the pons they influence the activity of the medullary center to produce normal smooth inspirations and expirations. The pneumotaxic center sends impulses to the DRG that helps switch off the inspiratory neurons, limiting the duration of inspiration. In contrast the apneustic center prevents the inspiratory neurons from being switched off, thus prolonged inspiration. The pneumotaxic center dominates over the apneustic center ending inspiration and letting expiration occur normally. Without the pneumotaxic brakes, the breathing pattern consists of prolonged inspiratory gasps abruptly interrupted by very brief expiration. This abnormal breathing pattern is known as apneusis, thus the center that promotes this type of breathing is the apneustic center. The Hering Breuer inflation reflex: In addition to the central nervous system respiratory control mechanisms operating entirely within the brain stem, sensory nerve signals from the lungs also help control respiration. Most important, are the stretch receptors that located in the muscular portions of the wall of the bronchi and bronchioles throughout the lungs. The pulmonary stretch receptors are activated by stretching the lungs at large tidal volumes. Signals from these receptors travel through the vagi into the dorsal respiratory group of neurons and inhibit the inspiratory neurons. This negative feedback response from the highly stretched lungs that cut inspiration short before the lungs become over inflated is called the Hering Breuer reflex. Therefore this reflex is mainly a protective mechanism for preventing excess lung inflation rather than an important part in the normal control of ventilation. Chemical control of respiration: Arterial blood gases are maintained within the normal range inspite of changing demand by varying the level of ventilation to match the body needs for O2 uptake and CO2 removal. The medullary respiratory center receives information about the body needs for gas exchange. It responds by sending appropriate signals to the motor neurons supplying the respiratory muscles adjusting ventilation to meet those needs. Thus the two signals that increase the ventilation are a decreased arterial PO2 or increased arterial PCO2. Also a third factor H+ influences the level of ventilation. Information about changes in arterial PO2, PCO2, and H+ that affect ventilation is gathered by chemoreceptors (sensors). The chemoreceptors are receptors that respond to changes in the chemical composition of the blood or other body fluid around them. The chemoreceptors involved in the control of ventilation are of two types, peripheral and central chemoreceptors.

Peripheral chemoreceptors for the control of respiratory activity: The peripheral chemoreceptors are located outside the brain in the carotid bodies and aortic bodies. Most of the chemoreceptors are in the carotid bodies which located bilaterally at the bifurcations of the common carotid arteries. Their afferent nerve fibers pass through Herings nerves to the glossophrangeal nerves and then to the dorsal respiratory area of the medulla. The aortic bodies are located along the arch of the aorta, their afferent fibers pass through the vagi also to the medullary respiratory area. The peripheral chemoreceptors are especially important for detecting changes in O2 in the blood, although they respond to a lesser extent to changes in CO2 and H+ concentrations. They are responsible for all the increase of ventilation which occurs in man in response to a decrease in arterial PO2. Stimulation of the chemoreceptors by decreased arterial oxygen: The peripheral chemoreceptors are not sensitive to moderate reduction in arterial PO2. The arterial PO2 must fall below 60 mmHg before the peripheral chemoreceptors respond by sending afferent impulses to the medullary inspiratory neurons thereby reflexly increasing ventilation. Because arterial PO2 falls below 60 mm Hg only in the unusual conditions of sever pulmonary disease or reduced atmospheric PO2, it does not play a role in the normal moment by moment regulation of respiration. Each of the chemoreceptors bodies receives its blood supply directly from the adjacent trunk. Further blood flow through these bodies is extreme, 20 times the weight of the bodies themselves each minute. The dissolved O2 which represents the blood PO2 is quite enough to provide the chemoreceptors demand for O2, thus the peripheral chemoreceptors respond to the PO2 of the blood. In conditions where the arterial blood content (dissolved O2 + O2 combined to Hb) is reduced such in anemic states, in which O2-carrying capacity is reduced, or in CO poisoning, where the functional Hb is reduced. In both cases the arterial PO2 is normal so respiration is not stimulated, even though O2 supply to tissues is greatly reduced. The control of respiratory center activity by CO2: The peripheral chemoreceptors are only weakly responsive to changes in arterial PCO2, so they play a minor role in stimulating respiration in response to an elevation in arterial PCO2. Yet stimulation by way of peripheral chemoreceptors occurs as much as five times as rapidly as central stimulation. The most important receptors involved in the adjustment of

ventilation in response to increased arterial PCO2 are the central chemoreceptors, located in the medulla near the respiratory center. The central chemoreceptors are not stimulated directly by CO2; however they are sensitive to changes in H+ concentration induced by CO2 of the interstitial of the medulla and CSF that baths them. Movement of materials across the brain capillaries into the CSF is restricted by the blood-brain barrier. Because this barrier is readily permeable to CO2, any increase in arterial PCO2 causes a similar rise in the CSF as CO2 diffuses down its pressure gradient from the cerebral blood capillaries into the CSF. In CSF CO2 immediately associates with water to form H+ CO2 + H2O H2CO3 HCO3 + H+

An elevation in H+ concentration in the CSF directly stimulates the central chemoreceptors, which in turn increases ventilation by stimulating the respiratory center. As the excess CO2 is subsequently eliminated the arterial PCO2 and PCO2 and H+ concentration of CSF return to normal. Conversely a decrease in arterial PCO2 below normal is paralleled by a fall in PCO2 and H+ in CSF leading to a decrease in ventilation. Unlike CO2, H+ cannot readily permeate the blood- brain barrier, so H+ in the plasma cannot gain excess to the central chemoreceptors. Accordingly the central chemoreceptors respond only to H+ generated within the CSF as a result of CO2 entry. Because CO2 diffuses easily through the blood-brain barrier, and CSF has lower protein concentration than plasma, for the same PCO2 the CSF will have greater changes in its pH than plasma. So an increase in the arterial PCO2 will produce rapid and greater increase in CSF H+, which produces a potent stimulatory effect on the central chemoreceptors. For these reasons respiratory center activity is increased very strongly by changes in blood CO2, therefore: 1. Which is more important in the regulation of ventilation under normal? condition changes in PO2 or changes in PCO2? 2. can you hold your breath for unlimited period of time? 3. can you voluntarily perform hyperventilation or unlimited period? Loss of sensitivity to chronic increase in PCO2: Excitation of the respiratory center by CO2 is great the first few hours after the CO2 first increases, but then it is gradually declines over the next few days.(1)Parts of this decline results from renal adjustment of the H+ concentration in the circulating blood back toward normal after the CO2 first increases H+ concentration. The kidneys achieve this by increasing the

formation and absorption of bicarbonate through their role in acid-base balance, the bicarbonate binds with the H+ in the blood and CSF to reduce their concentration.(2) More important with time HCO3 diffuses slowly through the blood-brain barrier into the CSF combines with H+ so that it no longer contributes to free H+. Under these conditions CSF pH returns to normal although arterial blood and CSF PCO2 remain high, and the increased PCO2 loss its effect on the peripheral and central chemoreceptors through changes in arterial blood and CSF pH. The central chemoreceptors no longer reflexly stimulate the respiratory center in response to the elevated CO2. Thus in patient with chronic respiratory failure 1.how respiration is regulated? 2. Is it safe to administered pure O2 to a patient with chronic respiratory failure? Adjustment in ventilation in response to changes in arterial H+ : Changes in arterial H+ concentration cannot influence the central chemoreceptors because H+ does not readily cross blood-brain barrier. However the peripheral chemoreceptors are highly responsive to changes in arterial H+ concentration, in contrast to their weak sensitivity to changes in arterial PCO2 and their unresponsiveness to arterial PO2 until it falls to 40% below normal. Changes in arterial PCO2 brings about corresponding changes in the H+ concentration of the blood as well as of the CSF. These CO2-induced changes in the arterial blood are detected by the peripheral chemoreceptors, which reflexly change ventilation. However these changes in ventilation are less important than the powerful central chemoreceptor mechanism. The peripheral chemoreceptors do play a major role in adjusting ventilation in response to changes in arterial H+ concentration unrelated to changes in PCO2. Arterial H+ concentration can be changed by the addition or loss of noncarbonic acid as in diabetes mellitus. Composite effect of PCO2, pH, and PO2 on alveolar ventilation: interactions between the various stimuli occur. Thus increases in chemoreceptor sensitivity to decreases in arterial PO2 are potentiated by increases in PCO2 and decreases in pH. Other factors that can affect respiration: 1. voluntary control of respiration. 2. effect of irritant receptors in the airways: the epithelium of the trachea, bronchi, and bronchioles is supplied with sensory nerve

endings called pulmonary irritant receptors that when stimulated cause sneezing and coughing. 3. function of lung J receptors a few sensory nerve endings have been described in the alveolar walls in juxtaposition to the pulmonary capillaries hence the name J receptors. They are stimulated especially when the pulmonary capillaries become congested with blood, or when pulmonary edema occurs as in heart failure. Although the functional role of J receptors is not clear, their excitation may give the person a feeling of dyspnea. 4. effect of brain edema: the activity of the respiratory center may be depressed or inactivated by a cute brain edema. 5. anesthesia: the most prevalent cause of respiratory depression andrespiratory arrest is overdosage of anesthetic or narcotics. The role of the respiratory system in acid balance: The cells of complex multicellular organism are able to survive and function only within a very narrow range of composition of the ECF, the internal environment that baths the cells. H+ similar to other ECF constituents requires regulation. Only slight changes in H+ concentration from its normal range can cause marked alterations in the rate of chemical reactions of virtually all cells and body functions. For this reason the regulation of H + concentration is one of the most important aspects in homeostasis. Hydrogen ions concentration; pH: Compared with other ions, the concentration of free H+ ions in the body fluids is very low about 40x109 Eq/L. To avoid dealing with small numbers, the symbol pH has used for expressing the concentration of H+ ion, and pH is the negative logarithm to the base of 10 of the H+ ion concentration, therefore: 1 pH = log = log (H+). [H+] If the H+ concentration = 40 x 109 Eq/L Then pH = log (40 x 109 ) pH = log 40 log 109 pH = 1.6 9 pH = 7.4 From this formula two important points should be noted:

a. a high [H+] corresponds to a low pH, and a low [H+] corresponds to a high pH. b. every unit change in pH represents a 10-folds change in [H+] because of the logarithmic relationship. The pH of the arterial blood is 7.4, whereas the pH of the venous blood and interstitial fluid is about 7.35, because of the extra amount of CO2 released from the tissues to form H2CO3in these fluids. Because the normal pH of the arterial blood is 7.4, a person is considered to have acidosis when the pH falls below this value and to alkalosis when the pH rises above 7.4. The lower limit of pH at which a person can live more than few hours is about 6.8 and the upper limit is about 8.0. Hydrogen ions are continually added to the body fluids as a result of metabolic activities: A small amount of acid capable of dissociating to release H+ is taken in with food, such as the weak citric acid found in oranges. Most H+ in the body fluids is generated internally from metabolic activities. Normally H+ is continually being added to the body fluids from the three following sources: 1. Aerobic metabolism leading to carbonic acid formation: the major source of H+ is through H2CO3 formation from metabolically produced CO2. Cellular oxidation of nutrients gives energy with CO2 and H2O as end products. Catalyzed by the enzyme carbonic anhydrase (ca), CO2 and H2O form H2CO3, which then partially dissociates into free H+ and HCO3. 2. Inorganic acids produced during breakdown of nutrients: dietary proteins Found abundantly in meat contain a large quantity of sulfur and phosphorus. Metabolic breakdown of these nutrient molecules, sulfuric acid and phosphoric acid are produced as by-products. 3. incomplete or anaerobic metabolism of fat and carbohydrate can yield lactic acid, pyruvic acid, and acetoacetic acid as in diabetes mellitus. Thus the input of H+ is unstopping, highly variable, and unregulated. Accordingly H+ is kept at balance or within its normal range through the regulation of its output or elimination from the body. Excess H+ ion is excreted from the body by the respiratory and renal systems. H+ ion formed during cellular metabolism must be gain excess from tissue cells to interstitial fluid and blood before it reaches the lungs and kidneys to be removed, yet the concentration of free H+ in body fluids remains stable in health. Therefore there must be ways or mechanisms by which the body maintains the concentration of free H+ very stable. The first line that resists changes in body fluids pH is the buffer systems of the body fluids which

react within a fraction of a second and tied up free H+ to minimize pH changes. The second line of defense against changes in pH, the respiratory system also acts within a few minutes to eliminate CO2 and therefore H2CO3 from the body. Respiratory control cannot return the H+ concentration all the way back to normal when a disturbance outside the respiratory system has altered the pH. The respiratory mechanism for controlling H+ concentration has effectiveness between 50 and 75 %. The third line of defense, the kidneys although relatively slow to respond over a period of hours to several days, they are the most powerful of the acid-base regulatory systems. The importance of body fluid buffers is realized from the presence of low H+ concentration in the body fluids inspite of relatively large amounts of acid produced by the body each day. About 80 mEq of H+ either ingested or produced each day by metabolism, whereas the H+ concentration of body fluids normally is only 0.00004 mEq/L.

Bicarbonate buffer system: The bicarbonate buffer system is the most important buffer system in the ECF for buffering pH changes brought about by causes other than changes in CO2 generated H2CO3. The bicarbonate buffer system consists of water solution of a weak acid H2CO3 and its weak base the bicarbonate salt such as NaHCO3. H2CO3 is formed in the body from: CO2 + H2O H2CO3.

H2CO3 ionized weakly to form small amount of H+ and HCO3 H2CO3 H+ + HCO3

The second component of the system in the ECF is NaHCO3, which ionized completely to form: NaHCO3 Na + HCO3

When a strong acid (ionized rapidly) such as HCl is added to the bicarbonate buffer solution, the increased H+ released from the acid (HCl H+ + Cl) is buffered by HCO3 .

H+ + HCO3


CO2 + H2O

As a result more H2CO3 is formed, causing increased CO2 and H2O production. The total amount of H+ in the solution is not changed, but the H+ released rapidly from the strong acid HCl reacts with HCO3 to form the very weak acid H2CO3 (releases H+ slowly). The excess CO2 formed as a result of buffering of the strong acid stimulates respiration which eliminates the CO2 from the body. The opposite reaction takes place when a strong base such as sodium hydroxide (NaOH) is added to the bicarbonate buffer solution. NaOH + HCO3 NaHCO3 +H2O Thus the weak base NaHCO3 replaces the strong base NaOH. At the same time the concentration of H2CO3 decreases because it reacts with NaOH, causing more CO2 to combine with H2O to replace the H2CO3. The net result is a decrease in the level of CO2 and increase in HCO3 of the blood. As CO2 is transported mainly in the form of bicarbonate, where CO2 associates with water to form H2CO3.This method of CO2 transport involve the generation of H+ (CO2 + H2O H2CO3), and through the elimination of CO2 the respiratory system actually regulates body fluid pH. Further more. In addition the buffering of the H+ added to body fluids from any source other than CO2 by the bicarbonate buffer system results finally in the formation of CO2 which is removed by the lungs (H+ + HCO3 H2CO3 CO2 + H2). + Accordingly the added H is eliminated from the body in the form of CO2. These points show the important role of the respiratory system in the regulation of acid- balance of the body. The pH resulting from the solution of CO2 in body fluids and the consequent dissociation of carbonic acid is given by the Henderson Hasselbalch Equation: All acids, including H2CO3 are ionized to some extent. The concentrations of H+ and HCO3 are proportional to the concentration of H2CO3. H2CO3 H+ + HCO3

The law of mass action states that, the concentration of the acid relative to its dissociated ions is defined by the dissociation constant KA . H+ x HCO3 KA= ---------------------42

H2CO3 Where KA is the ionization constant of carbonic acid, at equilibrium no further changes in occur in the concentration of H+, HCO3, or H2CO3. Since the concentration of carbonic acid is proportional to concentration of dissolved CO2 we can write the equation as:

H+ x HCO3 KA = -------------------CO2 HCO3 Taking logarithm log KA = log H+ + log ---------CO2 HCO3 Transporting log H+ = log KA + log ---------CO2 + Since pH is defined as pH = log H . The dissociation constant can be expressed in a similar manner. HCO3 pH = pKA + log --------------CO2 The amount of CO2 in the blood is a linear function of PCO2 times the solubility coefficient for CO2, under physiological condition the solubility coefficient for CO2 is 0.03mmol/mm Hg, thus the concentration of CO2 in mM/L can be replaced by (PCO2 x 0.03). The normal concentration of HCO3 in arterial blood is 24 mM/L. For the bicarbonate buffer system, the pKA is 6.1, and the equation cab be rewritten as: 24 pH = 6.1 + log ------------0.03 x 40 pH = 6-1 + log 20 pH = 6.1 + 1.3

pH = 7.4 Note that as long as the ratio of bicarbonate CO2 remains equal to 20, the pH will remains at 7.4. From the Henderson Hasselbalch equation, it is apparent that an increase in HCO3 concentration causes the pH to rise shifting the acid base balance toward alkalosis. An increase in PCO2 causes the pH to decrease, shifting the acid base balance toward acidosis. The bicarbonate concentration is regulated by the kidneys, whereas the PCO2 in the ECF is controlled by the level of ventilation. Normal physiological acid base homeostasis result from the coordinated functions of both the lungs and kidneys. Clinical causes of Acid-Base Disorders: Respiratory acidosis: this disorder is caused by an increase in PCO2 which reduces the HCO3 /CO2 ratio and thus decreases the pH leading to acidosis. It is caused by inability of the lungs to eliminate CO2 as rapidly as it form as in pneumonia, emphysema, obstruction of the conducting airways, decreased pulmonary membrane surface area, and any factor that interferes with the gas exchange at the lungs or depression of the respiratory center by drug or disease. In respiratory acidosis, the compensatory responses available are, the buffers of body fluids, and the kidneys which respond by increasing the formation and reabsorption of HCO3 increasing its concentration in body fluids, which moves the HCO3/CO2 ratio back up toward its normal level, correcting the pH. The kidneys require several days to compensate for the disorder. Respiratory alkalosis: the primary defect in respiratory alkalosis is excess loss of CO2 from the body as a result of hyperventilation. The decrease in PCO2 increases the HCO3/CO2 ratio and thus elevates the pH. Psychoneurosis can occasionally cause hyperventilation. A physiological type of respiratory alkalosis occurs when a person ascend to high altitude. The low oxygen content of the air stimulates respiration which causes excess loss CO2 and development of mild alkalosis. The main means of compensation are the chemical buffers of the body fluids and ability of the kidneys to increase HCO3 excretion. Metabolic acidosis: the term metabolic acidosis refers to all other types of acidosis besides those caused by excess CO2 in the body fluids. Metabolic acidosis can result from several general causes: (1) failure of the kidneys to excrete metabolic acid normally formed in the body, (2) formation of excess

quantities of metabolic acids in the body, (3) addition of metabolic acids in the body by ingestion or infusion of acids, and (4) loss of base from the body fluids which has the same effect as adding acids to the body fluids. Metabolic acidosis is the type of acid base disturbance most frequently encountered, most common causes are: 1. Sever diarrhea is probably the most frequent cause of metabolic acidosis. The cause of this acidosis is the loss of large amounts of NaHCO3 into the feces. During digestion the gastrointestinal secretions normally contain large amounts of bicarbonate which latter reabsorbed back into the plasma. Because of the loss of HCO3, less HCO3 is available to buffer H+, leading to more free H+ in the body fluids. 2. Diabetes mellitus: in the absence or insufficient insulin secretion, the normal use of glucose for metabolism is prevented. Instead some fats are split into acetoacetic acid, which metabolized by tissues for energy in place of glucose. With sever diabetes mellitus blood acetoacetic acid levels can rise very high causing sever metabolic acidosis. 3. Vomiting of intestinal contents: vomiting of gastric contents alone cause loss of acid and a tendency toward alkalosis because the stomach secretions are highly acidic. However vomiting large amounts from deeper in the gastrointestinal cause loss of bicarbonate and results in metabolic acidosis in the same way that diarrhea causes acidosis. 4. Chronic renal failure: with the marked decline in renal function, the kidneys cannot remove from the body even the normal amount of H+ generated from noncarbonic acids formed by ongoing metabolic processes, so H+ starts to accumulate in the body fluids. Also the kidneys cannot form and reabsorb an adequate amount of HCO3 for buffering the normal acid load. 5. Renal tubular acidosis: this type of acidosis result from a defect in renal secretion of H+ or in the reabsorption of HCO3 or both. Clinical analysis of acid-base disorders: Appropriate therapy of acid-base disorders requires proper diagnosis. The above mentioned simple acid-base disorders can be diagnosed by analysis of three measurements from the arterial blood sample; pH, plasma HCO3 concentration, and PCO2. Normal values of pH = 7.4, HCO3 = 24 mEq/L, and PCO2 = 40 mm Hg. - the expected values for a simple respiratory acidosis would be reduced plasma pH, increased PCO2, and plasma HCO3 concentration after partial

renal compensation. - in simple metabolic acidosis one would expect to find a low pH, a low plasma HCO3, and a reduction in PCO2 after partial respiratory compensation. - in simple respiratory alkalosis one would expect to find increased pH, decreased PCO2, and plasma HCO3 concentration. - in simple metabolic alkalosis one would expect to find increased pH, increased plasma HCO3 concentration, and increased PCO2. Complex acid-base disorder and the use of acid-base normogram for diagnosis: this means that there are 2 or more underlying causes for the o acid-base disturbance. For example a patient with low pH, and low HCO3 concentration are associated with elevated PCO2, one would suspect a respiratory component to the acidosis as well as a metabolic component. This could occur in a patient with acute diarrhea (metabolic acidosis) who also has emphysema (respiratory acidosis). Acid-base normogram in which pH, HCO3 concentration, and PCO2 values intersect according to the Henderson Hasselbalch equation, can be used to determine the type of acidosis or alkalosis as well as its severity. When using this diagram, sufficient time for full compensatory response has elapsed, which is 6 to 12 hours for the ventilatory compensation in primary metabolic disorders and 3 to 5 days for the metabolic compensations in primary respiratory disorders. If a value within the shaded area, this suggests that there is a simple acid-base disturbance. Conversely if the values of pH, HCO3, or PCO2 lie outside the shaded area, this suggests that there may be a mixed acid-base disorder. An important point that an acid-base value within the shaded area does not always mean that there is a simple acid-base disorder. With this point in mind the acid-base diagram can be used as quick means of determining the specific type and severity of an acid-base disorder. For example, the arterial plasma of a patient gives the following values: pH 7.3, HCO3 12.0 mEq/L, and PCO2 25 mm Hg. From the diagram this represents a simple metabolic acidosis with appropriate respiratory compensation. In a second sample with the following values: pH 7.15, HCO3 7 mEq/L, and PCO2 50 mm Hg. This is a case of acidosis with a metabolic component because of the decreased plasma HCO3, the respiratory compensation that would normally reduce PCO2 is absent and the PCO2 increases above normal value. This is consistent with a mixed acid-base disturbance consisting of metabolic acidosis as well as respiratory component. In a clinical setting, the patients history and other physical

findings also provide a clue concerning the cause and treatment of acid-base disorders. Hypoxias: is oxygen deficiency at the tissue level, it can be classified according to the causes as: 1. Inadequate oxygenation of blood in the lung because of extrinsic reasons a. deficiency of O2 in the inspired air (normal individuals at high altitudes) b. hypoventilation (neuromuscular disorders) 2. Pulmonary disease a. hypoventilation caused by increased airways resistance or decreased pulmonary compliance. b. abnormal VA/Q (including either increased physiologic dead space or increased physiologic shunt) c. diminished respiratory membrane diffusion 3. Venous-to-arterial shunt (right to left cardiac shunts) 4. Inadequate oxygen transport to the tissues by the blood a. anemia b. carbon monoxide poisoning c. general circulatory deficiency d. localized circulatory deficiency 5. Inadequate tissue capability of using O2 a. poisoning of cellular oxidation enzymes b. diminished cellular metabolic capacity for using O2 as in vitamin B deficiency. Oxygen therapy in different types of hypoxia: The value of O2 therapy is depending on the basic physiological principle of the type of hypoxia. O2 administration is of very limited value in hypoxia caused by anemia (anemic hypoxia), circulatory deficiency (stagnant hypoxia), or shunting of unoxugenated venous blood past the lungs, because normal O2 is already available in the alveoli. The problem is that one or more of the mechanisms for transporting O2 from the lungs to the tissues are deficient. All that can be accomplished by the administration of O2 is an increase in the amount of dissolved O2 in the arterial blood, as O2 transported by Hb is hardly altered. However the small extra amount of dissolved O2 may be a life saving. In hypoxia caused by inadequate tissue use of O2 (histotoxic hypoxia) the abnormality is not in the pickup of O2 by the lungs or in its transport to the tissues. Instead the tissue metabolic enzyme system is incapable of using O2. Therefore O2 therapy is of hardly any measurable benefit.

In atmospheric hypoxia (hypoxic hypoxia), hypoventilation hypoxia, and hypoxia caused by impaired alveolar membrane diffusion, O2 therapy is of great benefit. As breathing pure O2 (100% O2) increase the O2 pressure gradient for diffusion from the alveoli to the blood to more than 800%. Cyanosis: mean bluish discoloration of the tissues which appears when the deoxygenated Hb concentration of the blood in capillaries is more than 5 grams in each 100 ml of blood. The occurrence of cyanosis depends upon the - total amount of Hb in the blood, - the degree of Hb unsaturation, and - the state of the capillary circulation. Cyanosis is most easily seen in nail beds, mucous membrane, in the ear lobes, lips, and fingers where the skin is thin. Cyanosis does not occur in anemia because there is not enough Hb for 5 grams to be deoxygenated in 100 ml of arterial blood. Conversely in polycythemia vera, the great excess of available Hb that can be deoxygenated leads frequently to cyanosis even under otherwise normal conditions. In CO poisoning because the color of the reduced Hb is obscured by the cherry-red color of the carbonmonoxy hemoglobin. Hypercapnia: means excess of CO2 in body fluids. Respiratory conditions that cause hypoxia would not necessarily causing hypercapnia. Hypercapnia usually occurs in association only with hypoxia caused by hypoventilation, or circulation deficiency. Hypoxia caused by decreased PO2 in the inspired air, anemia, or poisoning of the oxidative enzymes, that hypercapnia is not a concomitant of these type of hypoxia. In hypoxia resulting from poor diffusion through the pulmonary membrane or through the tissues, hypercapnia usually does not occur at the same time because CO2 diffuse 20 times as rapidly as O2. If hypercapnia does begin to occur, it stimulates ventilation which corrects the hypercapnia but not necessarily the hypoxia. Conversely, in hypoxia caused by hypoventilation, CO2 transfer between the alveoli and the atmosphere is affected as much as O2 transfer. And in circulatory deficiency, diminished flow of blood decreases CO2 removal from the tissues, resulting in tissue hypercapnia and hypoxia. Hypercapnia is exacerbated when CO2 production is increased. For example in febrile patients there is a 13% increase in CO2 production for each 1 C rise in temperature, and a high carbohydrate intake increases CO2 production.


Dyspnea: a sensation of shortness of breath and suffocation. People who have dyspnea have the subjective sensation that they not getting enough air; that is they fell short of breath. Dyspnea is the mental anguish associated with hunger desire for more adequate ventilation. It often accompanies the labored breathing characteristic of obstructive lung disease, or the pulmonary edema associated with congestive heart failure. In contrast during exercise a person can breathe very hard without experiencing dyspnea, because such exertion is not accompanied by a sense of anxiety over the adequacy of ventilation. Surprisingly dyspnea is not directly related to chronic elevation of arterial PCO2 or reduction in PO2. the subjective feeling of air hunger may occur even when alveolar ventilation and the blood gases are normal. Some people experience dyspnea when they feel that they are short of air even though this is not actually the case, people who have a fear of not being able to receive a sufficient quantity of air, such as on entering small or crowded rooms.