Month: September 2016

Diffusion of Gases

September 28, 2016 Uncategorized No comments , , , , , , , , , , , , ,

Diffusion of a gas occurs when there is a net movement of molecules from an area in which that particular gas exerts a high partial pressure to an area in which it exerts a lower partial pressure. Movement of a gas by diffusion is therefore different from the movement of gases through the conducting airways, which occurs by "bulk flow" (mass movement or convection). During bulk flow, gas movement results from differences in total pressure, and molecules of different gases move together along the total pressure gradient. During diffusion, different gases move according to their own individual partial pressure gradients. Gas transfer during diffusion occurs by random molecular movement. It is therefore dependent on temperature because molecular movement increases at higher temperatures. Gases move in both directions during diffusion, but the area of higher partial pressure, because of its greater number of molecules per unit volume, has proportionately more random "departures." Thus, the net movement of gas is dependent on the partial pressure difference between the 2 areas. In a static situation, diffusion continues until no partial pressure differences exist for any gases in the 2 areas; in the lungs, oxygen and carbon dioxide continuously enter and leave the alveoli, and so such an equilibrium does not take place.

Fick's Law for Diffusion

Oxygen is brought into the alveoli by bulk flow through the conducting airways. When air flows through the conducting airway during inspiration, the linear veocity of the bulk flow decreases as the air approaches the alveoli. This is because the total cross-sectional area increases dramatically in the distal protions of the tracheobronchial tree.

By the time the air reaches the alveoli, bulk flow probably ceases, and further gas movement occurs by diffusion. Oxygen then moves through the gas phase in the alveoli according to its own partial pressure gradient. The distance from the alveolar duct to the alveolar-capillary interface is usually less than 1 mm. Diffusion in the alveolar gas phase is believed to be greatly assisted by the pulsations of the heart and blood flow, which are transmitted to the alveoli and increase molecular motion.

Oxygen the diffuses through the alveolar-capillary interface. It must first, therefore, move from the gas phase to the liquid phase, according to Henry's law. Oxygen must dissolve in and diffuse through the thin layer of pulmonary surfactant, the alveolar epithelium, the interstitium, and the capillary endothelium. It must then diffuse through the plasma, where some remains dissolved and the majority enters the erythrocyte and combines with hemoglobin. The blood then carries the oxygen out of the lung by bulk flow and distributes it to the other tissues of the body. At tissues, oxygen diffuses from the erythrocyte through the plasma, capillary endothelium, interstitium, tissue cell membrane, and cell interior and into the mitochondrial membrane. The process is almost entirely reversed for carbon dioxide.

The factors that determine the rate of diffusion of gas through the alveolar-capillary barrier are described by Fick's law for diffusion, shown here in a simpified form:

Vgas = [A X D X (P1 – P2)] / T [Equation 1]

where Vgas = volume of gas diffusing through the tissue barrier per time, mL/min

A = surface area of the barrier available for diffusion

D = diffusion coefficient, or diffusivity, of the particular gas in the barrier

T = thickness of barrier of the diffusion distance

P1– P2 = partial pressure difference of the gas across the barrier

That is, the volume of gas per unit of time moving across the alveolar-capillary barrier is directly proportional to the surface area of the barrier, the diffusivity, and the difference in concentration between the 2 sides, but is inversely proportional to the barrier thickness.

Surface area of barrier

The surface area of the blood-gas barrier is believed to be at least 70 m2 in a healthy average sized adult at rest. That is, about 70 m2 of the potential surface area is both ventilated and perfused at rest. If more capillaries are recruited, as in exercise, the surface area available for diffusion increase; if venous return falls, for example, because of hemorrhage, or if alveolar pressure is raised by positive-pressure ventilation, then capillaries may be derecruited and the surface available for diffusion may decrease.

Thickness of barrier

The thickness of the alveolar-capillary diffusion barrier is only about 0.2 to 0.5 um. This barrier thickness can increase in interstitial fibrosis or interstitial edema, thus interfering with diffusion. Diffusion probably increase at higher lung volumes as alveoli are stretched, the diffusion distance decreases slightly (and also because small airways subject to closure may be open at higher lung volumes).

Diffusion coefficient/Diffusivity

The diffusivity, or diffusion constant, for a gas is directly proportional to the solubility of the gas in the diffusion barrier and is inversely proportional to the square root of the molecular weight (MW) of the gas:

screen-shot-2016-09-27-at-10-32-14-amThe relationship between solubility and diffusion through the barrier has already been discussed. The diffusivity is inversely propprtional to the square root of the MW of the gas because different gases with equal numbers of molecules in equal volumes have the same molecular energy if they are at the same temperature. Therefore, light molecules travel faster, have more frequent collisions, and diffuse more rapidly. Thus, Graham's law states that the relative rates of diffusion of 2 gases are inversely proportional to the square roots of their MWs, if all else is equal.

Because the difference in MWs of oxygen and carbon dioxide, it should diffuse 1.2 times as fast as carbon dioxide. In hte alveolar-capillary barrier, however, the relative solubilities of oxygen and carbon dioxide must also be considered. The solubility of carbon dioxide in the liquid phase is about 24 times that of oxygen, and so carbon dioxide diffuse about 20 times more rapidly through the alveolar-capillary barrier than does oxygen. For this reason, patients develop problems in oxygen diffusion through the alveolar-capillary barrier before carbon dioxide retention due to diffusion impairment occurs.

Limitations of Gas Transfer

The factors that limit the movement of a gas through the alveolar-capillary barrier, as described by Fick's law for diffusion, can be divided into 3 components: the diffusion coefficient, the surface area and thickness of the alveolar-capillary membrane, and the partial pressure difference across the barrier for each particular gas.

Diffusion Limitation

screen-shot-2016-09-27-at-11-12-59-amAn erythrocyte and its attendant plasma spend an average of about 0.75 to 1.2 seconds inside the pulmonary capillaries at resting cardiac outputs. This time can be estimated by dividing the pulmonary capillary blood volume by the pulmonary blood flow. Some erythrocytes may take less time to traverse the pulmonary capillaries; others may take longer. Figure 6-1 shows schematically the calculated change with time in the partial pressures in the blood of 3 gases: oxygen, carbon monoxide, and nitrous oxide. These are shown in comparision to the alveolar partial pressures for each gas, as indicated by the dotted line. This alveolar partial pressure is different for each of the 3 gases, and it depends on its concentration in the inspired gas mixture and on how rapidly it is removed by the pulmonary capillary blood. The schematic is drawn as though all 3 gases were administered simultaneously, but this is not necessarily the case. Consider each gas as though it were acting independently of the others.

The partial pressure of carbon monoxide in the pulmonary capillary blood rises very slowly compared with that of the other 2 gases in the figure. (Obviously, a low inspired concentration of carbon monoxide must be used for a very short time in such an expirement.) Nevertheless, if the content of carbon monoxide were measured simultaneously, it would be rising very rapidly. The reason for this rapid rise is that carbon monoxide combines chemically with the hemoglobin in the erythrocytes. Indeed, the affinity of carbon monoxide for hemoglobin is about 210 times that of oxygen for hemoglobin. The carbon monoxide that is cheically combined with hemoglobin does not contribute to the partial pressure of carbon monoxide in the blood because it is no longer physically dissolved in it.

Therefore, the partial pressure of carbon monoxide in the pulmonary capillary blood does not come close to the partial pressure of carbon monoxide in the alveoli during the time that the blood is exposed to the alveolar carbon monoxide. (If the alveolar partial pressure of carbon monoxide were great enough to saturate the hemoglobin, the pulmonary capillary partial pressure would rise rapidly.) The partial pressure difference across the alveolar-capillary barrier for carbon monoxide is thus well maintained for the entire time the blood spends in the pulmonary capillary, and the diffusion of carbon monoxide is limited only by its diffusivity in the barrier and by the surface area and thickness of the barrier – that is, the diffusion characteristics of the barrier itself. Carbon monoxide transfer from the alveolus to the pulmonary capillary blood is referred to as diffusion-limited rather than perfusion-limited.

Perfusion Limitation

The partial pressure of nitrous oxide in the pulmonary capillary blood equilibrates very rapidly with the partial pressure of nitrous oxide in the alveolus because nitrous oxide moves through the alveolar-capillary barrier very easily and because it does not combine chemically with the hemoglobin in the erythrocytes. After only about 0.1 of a second of exposure of the pulmonary capillary blood to the alveolar nitrous oxide, the partial pressure difference across the alveolar-capillary barrier has been abolished. From this point on, no further nitrous oxide transfer occurs from the alveolus to that portion of the blood in the capillary that has already equilibrated with the alveolar nitrous oxide partial pressure; duirng the last 0.6 to 0.7 of a second, no net diffusion occurs between the alveolus and the blood as it travels through the pulmonary capillary. Of course, blood just entering the capillary at the arterial end will not be equilibrated with the alveolar partial pressure of nitrous oxide, and so nitrous oxide can diffuse into the blood at the arterial end. The transfer of nitrous oxide is therefore perfusion-limited. Nitrous oxide transfer from a particular alveolus to one of its pulmonary capillaries can be increased by increasing the cardiac output and thus reducing the amount of time the blood stays in the pulmonary capillary after equilibration with the alveolar partial pressure of nitrous oxide has occurred. (Because increasing the cardiac output may recruit previously unperfused capillaries, the total diffusion of both carbon monoxide and nitrous oxide may increase as the surface area for diffusion increases.)

Diffusion of Oxygen

As can be seen in Figure 6-1, the time course for oxygen transfer falls between those for carbon monoxide and nitrous oxide. The partial pressure of oxgen rises fairly rapidly (note that it starts at the PO2 of 40 mm Hg, rather than at zero), and equilibration with the alveolar PO2 of about 100 mm Hg occurs within about 0.25 of a second, or about one third of the time the blood is in the pulmonary capillary at normal resting cardiac outputs. Oxygen moves easily through the alveolar-capillary barrier and into the erythrocytes, where it combines chemically with hemoglobin. The partial pressure of oxygen rises more rapidly than the partial pressure of carbon monoxide (at very low partial pressure carbon monoxide that would be used). Nonetheless, the oxygen chemically bound to hemoglobin (and therefore no longer physically dissolved) exerts no partial pressure, and so the partial pressure difference across the alveolar-capillary membrane is initially well maintained and oxygen transfer occurs. The chemical combination of oxygen and hemoglobin, however, occurs rapidly (within hundredths of a second), and at the normal alveolar partial pressure of oxygen, the hemoglobin becomes nearly saturated with oxygen very quickly. As this happens, the partial pressure of oxygen in the blood rises rapidly to that in alveolus, and from that point, no further oxygen transfer from the alveolus to the quilibrated blood cna occur. Therefore, under the conditions of normal alveolar PO2 and a normal resting cardiac output, oxygen transfer from alveolus to pulmonary capillary is perfusion-limited.

screen-shot-2016-09-27-at-4-10-29-pmFigure 2-6A shows similar graphs of calculated changes in the partial pressure of oxygen in the blood as it moves through a pulmonary capillary. The alveolar PO2 is normal. During exercise, blood moves through the pulmonary capillary much more rapidly than it does at resting cardiac outputs. In fact, the blood may stay in the "functional" pulmonary capillary on an average of only about 0.25 of a second during strenuous exercise, as indicated on the graph. Oxygen transfer into the blood per time will be greatly increased because there is little or no perfusion limitation of oxygen transfer. (Indeed, that part of the blood that stays in the capillary less than the average may be subjected to diffusion limitation of oxygen transfer.) Of course, total oxygen transfer is also increased during exercise because of recruitment of previously unperfused capillaries, which increases the surface area for diffusion, and because of better matching of ventilation and perfusion. A person with an abnormal alveolar-capillary barrier due to a fibrotic thickening or interstitial edema may approach diffusion limitation of oxygen transfer at rest and may have a serious diffusion limitation of oxygen transfer during strenuous exercise, as can be seen in the middle curve in Figure 2-6A. A person with an extremely abnormal alveolar-capillary barrier might have diffusion limitation of oxygen transfer even at rest, as seen on the right in the figure.

The effect of a low alveolar partial pressure of oxygen on oxygen transfer from the alveolus to the capillary is seen in Figure 6-2B. The low alveolar PO2 sets the upper limit for the end-capillary blood PO2. Because the oxygen content of the arterial blood is decreased, the mixed venous PO2 is also decreased. The even greater decrease in the alveolar partial pressure of oxygen, however, causes a decreased alveolar-capillary partial pressure gradient, and the blood PO2 takes longer to equilibrate with the alveolar PO2. For this reason, a normal person exerting himself or herself at high altitude might be subject to diffusion limitation of oxygen transfer.

Diffusion of Carbon Dioxide

screen-shot-2016-09-27-at-9-35-45-pmThe time course of carbon dioxide transfer from the pulmonary capillary blood to the alveolus is shown in Figure 6-3. In a normal person with a mixed venous partial pressure of carbon dioxide of 45 mm Hg an dan alveolar partial partial pressure of carbon dioxide of 40 mm Hg, an equilibrium is reached in a little more than 0.25 of a second, or about the same time as that for oxygen. This may seem surprising, considering that the diffusivity of carbon dioxide is about 20 times that of oxygen, but the partial pressure gradient is normally only about 5 mm Hg for carbon dioxide, whereas it is about 60 mm Hg for oxygen. Carbon dioxide transfer is therefore normally perfusion-limited, although it may be diffusion-limited in a person with an abnormal alveolar-capillary barrier, as shown in the figure.

Measurement of Diffusing Capacity

If is often useful to determine the diffusion characteristics of a patient's lungs during their assessment in the pulmonary function laboratory. It may be particularly important to determine whether an apparent impairment in diffusion is a result of perfusion limitation or diffusion limitation.

The diffusion capacity (or transfer factor) is the rate at which oxygen or carbon monoxide is absorbed from the alveolar gas into the pulmonary capillaries (in  milliliters per minute) per unit of partial pressure difference (in millimeters of mercury). The diffusing capacity of the lung (for gas x), DLx, is therefore equal to the uptake of gas x, Vx, divided by the difference between the alveolar partial pressure of gas x, PAx, and the mean capillary partial pressure of gas x, Pcx:


The mean partial pressure of oxygen or carbon monoxide is, as already discussed, affected by their chemical reactions with hemoglobin, as well as by their transfer through the alveolar-capillary barrier. For this reason, the diffusing capacity of the lung is determined by both the diffusing capacity of the membrane (both the alveolar-capillary membrane and the plasma membrane of the erythrocyte), DM, and the reaction with hemoglobin, expressed as 𝜃 X Vc, where 𝜃 is the volume of gas in mililiters per minute taken up by the erythrocytes in 1 mL of blood per millimeter of mercury partial pressure gradient between the plasma and the erythrocyte and Vc is the capillary blood volume in milliliters. (The units of 𝜃 X Vc are therefore mL/min/mm Hg.) The diffusing capacity of the lung, DL, can be shown to be related to DM and 𝜃 X Vc as follows:


DA, or diffusion through the alveolus, is normally very rapid and usually can be disregarded; however, in conditions such as alveolar pulmonary edema or pneumonia it may be a major problem.

Carbon monoxide is most frequently used in determinations of the diffusing capacity because the mean pulmonary capillary partial pressure of carbon monoxide is virtually zero when nonlethal alveolar partial pressures of carbon monoxide are used:


Several different methods are used clinically to measure the carbon monoxide diffusing capacity and involve both single-breath and steady-state techniques, sometimes during exercise. The DLco is decreased in diseases associated with interstitial or alveolar fibrosis, such as idiopathic pulmonary fibrosis, sarcoidosis, scleroderma, and asbestosis, or with conditions causing interstitial or alveolar pulmonary edema. It is also decreased in conditions causing a decrease in the surface area available for diffusion, such as emphysema, tumors, a low cadiac output, or a low pulmonary capillary blood volume, as well as in conditions leading to ventilation-perfusion mismatch, which effectively decreases the surface area available for diffusion.

Ventilation-Perfusion Relationships

September 26, 2016 Cardiology, Mechanical Ventilation, Pulmonary Medicine, Respirology No comments , , , , , , , , , , , , , , ,

Gas exchange between the alveoli and the pulmonary capillary blood occurs by diffusion. Diffusion of oxygen and carbon dioxide occurs passively, according to their concentration differences across the alveolar-capillary barrier. These concentration differences must be maintained by ventilation of the alveoli and persusion of the pulmonary capillaries.

Alveolar ventilation brings oxygen into the lung and removes carbon dioxide fro it. Similarly, the mixed venous blood brings carbon dioxide into the lung and takes up alveolar oxygen. The alveolar PO2 and PCO2 are thus determined by the relationship between alveolar ventilation and pulmonary capillary perfusion. Alterations in the ratio of ventilation to perfusion, called the (VA/QC), will result in changes in the alveolar PO2 and PCO2, as well as in gas delivery to or removal from the lung.

Alveolar ventilation is normally about 4 to 6 L/min and pulmonary blood flow (which is equal to cardiac output) has a similar range, and so the V/Q for the whole lung is in the range of 0.8 to 1.2. However, ventilation and perfusion must be matched on the alveolar-capillary level, and the V/Q for the whole lung is really of interest only as an approximation of the situation in all the alveolar-capillary units of the lung. For instance, suppose that all 5 L/min of the cardiac output went to the left lung and all 5 L/min of alveolar ventilation went to the right lung. The whole lung V/Q would be 1.0, but there would be no gas exchange because there could be no gas diffusion between the ventilated alveoli and the perfused pulmonary capillaries.

Consequences of High and Low V/Q

Oxygen is delivered to the alveolus by alveolar ventilation, is removed from the alveolus as it diffuses into the pulmonary capillary blood, and is carried away by blood flow. Similarly, carbon dioxide is delivered to the alveolus in the mixed venous blood and diffuses into the alveolus in the pulmonary capillary. The carbon dioxide is removed from the alveolus by alveolar ventilation. At resting cardiac outputs the diffusion of both oxygen and carbon dioxide is normally limited by pulmonary perfusion. Thus, the alveolar partial pressures of both oxygen and carbon dioxide are determined by the V/Q. If the V/Q in an alveolar-capillary unit increases, the delivery of oxygen relative to its removal will increase, as will the removal of carbon dioxide relative to its delivery. Alveolar PO2 will therefore rise, and alveolar PCO2 will fall. If the V/Q in an alveolar-capillary unit decreases, the removal of oxygen relative to its delivery will increase and the delivery of carbon dioxide relative to its removal will increase. Alveolar PO2 will therefore fall, and alveolar PCO2 will rise.

Consider these three conditions: 1) A normal V/Q ratio; 2) a V/Q ratio equals to 0; and 3) a V/Q ratio of infinite. With a normal V/Q ratio, inspired air enters the alveolus with a PO2 of about 150 mm Hg and a PCO2 of nearly 0 mm Hg. Mixed venous blood enters the pulmonary capillary with a PO2 of about 40 mm Hg (SvO2 of 75%) and a PCO2 of about 45 mm Hg. This results in an alveolar PO2 of about 100 mm Hg and an alveolar PCO2 of about 45 mm Hg. The partial pressure difference for oxygen diffusion from alveolus to pulmonary capillary is thus about 100 to 40 mm Hg, or 60 mm Hg; the partial pressure gradient for CO2 diffusion from pulmonary capillary to alveolus is only about 45 to 40, or 5 mm Hg.

With a V/Q ratio of 0, the airway supplying has become completely occluded. Its V/Q ratio is zero. As time goes on, the air trapped in the alveolus equilibrates by diffusion with the gas dissolved in the mixed venous blood entering the alveolar-capillary unit (If the occlusion persists, the alveolus is likely to collapse). No gas exchange can occur, and any blood perfusion this alveolus will leave it exactly as it entered it.

With a V/Q ratio of infinite (dead space), the blood flow is blocked by a pulmonary embolus, and the alveolar-capillary unit is therefore completely unperfused. Because no oxygen can diffuse from the alveolus into pulmonary capillary blood and because no carbon dioxide can enter the alveolus is approximately 150 mm Hg and its PCO2 is approximately zero. That is, the gas composition of this unperfused alveolus is the same as that of inspired air. If this condition is due to the fact that the alveolar pressure exceeds its precapillary pressure (pulmonary arterial pressure, Pa), then it would aslo correspond to part of zone 1.

screen-shot-2016-09-21-at-9-11-53-amConditions 2 and 3 represent the 2 extremes of a continuum of ventilation-perfusion ratios. The V/Q ratio of a particular alveolar-capillary unit can fall anywhere along this continuum. The alveolar PO2 and PCO2 of such units will therefore fall between the two extremes shown in the figure: Units wtih low V/Q ratios will have relatively low PO2s and high PCO2s; units with high V/Q ratios will have relatively high PO2s and low PCO2s. This is demonstrated graphically in an O2-CO2 diagram such as that seen in Figure 5-2. The diagram shows the results of mathematical calculations of alveolar PO2s and PCO2s for V/Q ratios between zero and infinity (for inspired air). The resulting curve is known as the ventilation-perfusion ratio line. This simple O2-CO2 diagram can be modified to include correction lines for other factors, such as the respiratory exchange ratios of the alveoli and the blood or the dead space. The position of the V/Q ratio line is altered if the partial pressures of the inspired gas or mixed venous blood are altered.

Evaluation of the Ventilation-Perfusion Mismatch

Physiologic Shunts

Physiologic shunt = Anatomic Shunt + Intrapulmonary shut (absolute + shuntlike)

Anatomic shunts

Anatomic shunts consist of systemic venous blood entering the left ventricle without having entered the pulmonary vasculature. In a normal healthy adult, about 2% to 5% of the cardiac output, including venous blood from the bronchial veins, the besian veins, and the pleural veins, enters the left side of the circulation directly without passing through the pulmonary capillaries. Therefore, the output of the left venticle is normally greater than that of the right venticle in adults.

Absolute intrapulmonary shunts

Mixed venous blood perfusing pulmonary capillaries assocaited with totally unventilation or collapsed alveoli constitutes an absolute shunt (like the anatomic shunts) because no gas exchange occurs as the blood passes through the lung. Absolute shunts are sometimes also referred to as true shunts.

Shuntlike states

Alveolar-capillary units with low V/Q also act to lower the arterial oxygen content because blood draining these units has a lower PO2 than blood from units with well-matched ventilation and perfusion.

The Shunt Equation

The shunt equation conceptually divides all alveolar-capillary units into two groups: those with well-matched ventilation and perfusion and those with ventilation-perfusion ratios of zero. Thus, the shunt equation combines the areas of absolute shunt and the shuntlike areas into a single conceptual group. The resulting ratio of shunt flow to the cardiac output, often referred to as the venous admixture, is the part of the cardiac output that would have to be perfusing absolutely unventilated alveoli to cause the systemic arterial oxygen content obtained from a patient. A much larger portion of the cardiac output could be overperfusion poorly ventilated alveoli and yield the same ratio.

The shunt equation can be derived as follows: Let Qt represent the total pulmonary blood flow per minute (i.e., the cardiac output), and let Qs represent the amount of blood flow per minute entering the systemic arterial blood without receiving any oxygen (the "shunt flow"). The volume of blood per minute that perfuses alveolar-capillary units with well-matched ventilation and perfusion then equals Qt – Qs.

The total volume of oxygen per time entering the systemic arteries is therefore

Qt x CaO2

where CaO2 equals oxygen content of arterial blood in milliliters of oxygen per 100 mL of blood. This total amount of oxygen per 100 mL of blood. This total amount of oxygen per time entering the systemic arteries is composed of the oxygen coming from the well-ventilated and well-perfused alveolar-capillary units:

(Qt – Qs) x CcO2

where CcO2 equals the oxygen content of the blood at the end of the ventilated and perfused pulmonary capillaries, plus the oxygen in the unaltered mixed venous blood coming from the shunt, Qs x CvO2 (where CvO2 is equal to the oxygen content of the mixed venous blood). There is normally a substantial amount of oxygen in the mixed venous blood. That is,

Qt x CaO2 = (Qt – Qs) x CcO2 + Qs x CvO2

After some mathematical rearranagement, the Qs/Qt is expressed as,

Qs/Qt = (CcO2 – CaO2) / (CcO2 – CvO2) [Equation 1]

The shunt fraction Qs/Qt is usually multiplied by 100% so that the shunt flow is expressed as a percentage of the cardiac output.

The arterial and mixed venous oxygen contents can be determined if blood samples are obtained from a systemic artery and from the pulmonary artery (for mixed venous blood), but the oxygen content of the blood at the end of the pulmonary capillaries with well-matched ventialtion and perfusion is, of course, impossible to measure directly. This must be calculated from the alveolar air equation and the patient's hemoglobin concentration.

Physiologic Dead Space

The use of the Bohr equation to determine the physiologic dead space was discussed in detail in thread "Mechanics of Breathing – Alveolar Ventilation" at If the anatomic dead space is subtracted from the physiologic dead space, the result (if there is a difference) is alveolar dead space, or areas of infinite V/Qs. Alveolar dead space also results in an arterial-alveolar CO2 difference; that is, the end-tidal PCO2 is normally equal to the arterial PCO2. End-tidal PCO2 is used as an estimate of the mean PCO2 of all ventilated alveoli. An arterial PCO2 greater than the end-tidal PCO2 usually indicates the presence of alveolar dead space.

Alveolar-Arterial Oxygen Difference

The alveolar and arterial PO2s are treated as though they are equal. However, the aterial PO2 is normally a few mm Hg less than that alveolar PO2. This is normal alveolar-arterial oxygen difference, the (A-a)DO2, is caused by the normal anatomic shunt, some degree of ventilation-perfusion mismatch, and diffusion limitation in some parts of the lung. Of these, V/Q mismatch is usually the most important, with a small contribution from shunts and very little from diffusion limitation. Larger-than-normal differences between the alveolar and arterial PO2 may indicate significant ventilation-perfusion mismatch; however, increased alveolar-arterial oxygen differences also can be caused by anatomic intrapulmonary shunts, diffusion block, low mixed venous PO2s, breathing higher than normal oxygen concentrations, of shifts of the oxy-hemoglobin dissociation curve.

The alveolar-arterial PO2 difference is normally about 5 to 15 mm Hg in a young healthy person breathing room air at sea level. It increases with age because of the progressive decrease in arterial PO2 that occurs with aging. The normal alveolar-arterial PO2 difference increases by about 20 mm Hg between the ages of 20 and 70. A person's age/4 + 4 mm Hg is a good clinical estimate of the normal alveolar-arterial PO2 difference.

Another useful clinical index in addition to the alveolar-arterial oxygen difference is the ratio of arterial PO2 to the fractional concentration of oxygen in the inspired air. The PaO2/FiO2 should be greater than or equal to 200; a PaO2/FiO2 less than 200 is seen in acute respiratory distress syndrome.

Single-Breath Carbon Dioxide Test

The expired concentration of carbon dioxide can be monitored by a rapid-response carbon dioxide meter in a manner similar to that used in the single-breath tests utilizing a nitrogen meter. The alveolar plateau phase of the expired carbon dioxide concentration may show signs of poorly matched ventilation and perfusion if such regions empty asynchronously with other regions of the lung.

Lung Scans After Inhaled and Infused Markers

Lung scans after both inhaled and injected markers can be used to inspect the location and amount of ventilation and perfusion to the various regions of the lung.

Multiple Inert Gas Elimination Technique

A more specific graphic method for assessing ventilation-perfusion relationships in human subjects is called the multiple inert gas elimination technique. This technique uses the concept that the elimination via the lungs of different gases dissolved in the mixed venous blood is affected differently by variations in the ventilation-perfusion ratios of alveolar-capillary units, according to the solubility of each gas in the blood. At a ventilation-perfusion ratio of 1.0, a greater volume of a relatively soluble gas would be the case with a relatively insoluble gas. Thus, the retention of any particular gas by a single alveolar-capillary unit is dependent on the blood-gas partition coefficient of the gas and the ventilation-perfusion ratio of the unit. Gases with very low solubilities in the blood would be retained in the blood only by units with very low (or zero) V/Qs. Gases with very high solubilities in the blood would be eliminated mainly in the expired air of units with very high V/Qs.

Regional V/Q Differences and Their Consequences in the Lung

screen-shot-2016-09-26-at-8-27-08-pmThe regional variations in ventilation in the normal upright lung were discussed in thread "Mechanics of Breathing – Alveolar Ventilation" at Gravity-dependent regions of the lung receive more ventilation per unit volume than do upper regions of the lung when one is breathing near the FRC. The reason for this is that there is a gradient of pleural surface pressure, which is probably caused by gravity and the mechanical interaction of the lung and the chest wall. The pleural surface pressure is more negative in nondependent regions of the lung, and so the alveoli in these areas are subjected to greater transpulmonary pressures. As a result, these alveoli have larger volumes than do alveoli in more dependent regions of the lung and are therefore on a less steep portion of their pressure-volume curves. These less-compliant alveoli change their volume less with each breath than do those in more dependent regions.

The right side of Figure 5-6 shows that the more gravity-dependent regions of the lung also receive more blood flow per unit volume than do the upper regions of the lung, as discussed in thread "Blood flow to the lung – general and pulmonary vascular resistance" at The reason for this is that the intravascular pressure in the lower regions of the lung is greater because of hydrostatic effects. Blood vessels in more dependent regions of the lung are therefore more distended, or more vessels are perfused because of recruitment so there is less resistance to blood flow in lower regions of the lung.

Regional Differences in the Ventilation-Perfusion Ratios in the Upright Lung

screen-shot-2016-09-26-at-8-39-33-pmSimplified graphs of the differences of ventilation and perfusion from the bottom to the top of normal upright dog lungs are shown plotted on the same axis in Figure 5-7. The ventilation-perfusion ratio was then calculated for several locations.

Figure 5-7 shows that the difference of perfusion from the bottom of the lung to the top is greater than the difference of ventialtion. Because of this, the ventilation-perfusion ratio is relatively low in more gravity-dependent regions of the lung and greater in upper regions of the lung. If pulmonary perfusion pressure is low, for example, because of hemorrhage, or if alveolar pressure is high because of positive-pressure ventilation with positive end-expiratory pressure (PEEP), or if both factors are present, then there may be areas of zone 1 with infinite ventilation-perfusion ratios in the upper parts of the lung.

The Consequences of Regional Ventilation-Perfusion Differences in the Normal Upright Lung

The effects of the regional differences in V/Q on the alveolar PO2 and PCO2 can be seen in Figure 5-8. The lung was arbitrarily divided into 9 imaginary horizontal sections, and the V/Q was calculated for each section. These sections were then positioned on the ventilation-perfusion line of the O2-CO2 diagram, and the PO2 and PCO2 of the alveoli in each section could be estimated. Under normal circumstances the blood in the pulmonary capillaries equilibrates with the alveolar PO2 and PCO2 as it travels through the lung, and so the effects of regional differences in V/Q on the regional gas exchange could be predicted. As can be seen from the figure, the upper sections have relatively high PO2 and low PCO2; the lower sections have relatively low PO2 and high CO2.

Figure 5-7 and 5-8 demonstrate that the lower regions of the lung receive both better ventilation and better perfusion than do the upper portions of the lung. However, the perfusion difference is much steeper than the ventilation difference, and so the ventilation-perfusion ratio is higher in the apical regions than it is in the basal regions. As a result, the alveolar PO2 is greater and the alveolar PCO2 is less in upper portions of the lung than they are in lower regions. This means that the oxugen content of the blood draining the upper regions is greater and the carbon dioxide contnet is less than that of the blood draining the lower regions. However, these contents are based on milliliters of blood, and there is much less blood flow to the upper most sections than there is to the bottom sections. Therefore, even though the uppermost sections have the greatest V/Q and PO2 and the lowest PCO2, there is more gas exchange in the more basal sections.

Pressure-Volume Relationships in the Respiratory System

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screen-shot-2016-09-15-at-3-04-48-pmThe relationship between changes in the pressure distending the alveoli and (transmural pressure) changes in the lung volume is important to understand because it dictates how easily the lung inflates with each breath. The alveolar-distending pressure is often referred to as the transpulmonary pressure. Strictly speaking, the transpulmonary pressure is equal to the pressure in the trachea minus the intrapleural pressure. Thus, it is the pressure difference across the whole lung. However, the pressure in the alveoli is the same as the pressure in the airways – including the trachea – at the beginning or end of each normal breath, that is, end-expiratory or end-inspiratory alveolar pressure is 0 cm H2O. Therefore, at the beginning or end of each lung inflation, alveolar-distending pressure can be referred to as the transpulmonary pressure.

Compliance of the Lung and the Chest Wall

Reference range: The total compliance of a nromal person near the FRC is about 0.1 L/cm H2O. The compliance of the lungs is about 0.2 L/cm H2O; that of the chest wall is also aobut 0.2 L/cm H2O.

Figure 2-6 shows that as the transpulmonary pressure increases, the lung volume increases. This relationship is not a straight line: The lung is composed of living tissue, and although the lung distends easily at low lung volumes, at high volumes the distensible components of alveolar walls have already been stretched, and large increases in trnaspulmonary pressure yield only small increases in volume.

The slope between 2 points on a pressure-volume curve is known as the compliance. Compliance is defined as the change in volume divided by the change in pressure (transmural pressure). Lungs with high compliance have a steep slope on their pressure-volume curves; that is, a small change in distending pressure will cause a large change in volume. It is important to remember that compliance is the inverse of elastance, elasticity, or elastic recoil. Compliance denotes the ease with which something can be stretched or distorted; elastance refers to the tendency for something to oppose stretch or distortion, as well as to its ability to return to its original configuration after the distorting force is removed.

There are several interesting things to note about the lung pressure-volume curve. From Figure 2-6 there is a difference between the pressure-volume curve for inflation and the deflation, as shown by the arrows. Such a difference is called hysteresis. One possible explanation for this hysteresis is the stretching on inspiration and the compression on expiration of the film of surfactant that lines the air-liquid interface in the alveoli. Surfactant has less effect on decreasing surface tension during inspiration than during expiration because of movement of surfactant molecules from the interior of the liquid phase to the surface during inspiration. Another explanationis that some alveoli or small airways may open on inspiration (recruitment) and close on expiration (decrecruitment); the recruitment of collapsed alveoli or small airways requires energy and may be responsible for the lower inflection point seen on  some inspiratory pressure-volume curves. Finally, it is helpful to think of each alveolus as having its own pressure-volume curve like that shown in Figure 2-6, although some researchers believe that lung volume changes primarily by recruitment and decrecruitment of alveoli rather than by volume changes of individual alveoli.

Clinical Evaluation of the Compliance of the Lung and the Chest Wall

The compliance of the lung and the chest wall provides very useful data for the clinical evaluation of a patient's respiratory system because many diseases or pathologic states affect the compliance of the lung, of the chest wall, or both. The lung and the chest wall are physically in series with each other, and therefore their compliances add as reciprocals:

screen-shot-2016-09-20-at-9-50-53-amConversely, the elastances of the lung and chest wall add directly.

Compliances in parallel add directly. Therefore, both lungs together are more compliant than either one alone; 2 alveoli in parallel are similarly more compliant than 1 alone.

Representative static compliance curves for the lungs are shown in Figure 2-7. Note that these curves correspond to the expiratory curve in Figure 2-6. Many pathologic states shift the curve to the right (i.e., for any increase in transpulmonary pressure there is less of an increase in lung volume). A proliferation of connective tissue called fibrosis may be seen in sarcoidosis or after chemical or thermal injury to the lungs. Such changes will make the lungs less compliant, or "stiffer," and increase alveolar elastic recoil. Conversely, emphysema increases the compliance of the lungs because it destroys the alveolar septal tissue that normally opposes lung expansion.

screen-shot-2016-09-20-at-10-26-47-amFor patients wtih decreased lung compliance, they must generate greater transpulmonary pressures to breath in the same volume of air. Therefore they must do more work to inspire than those with normal pulmonary compliance.

The compliance of the chest wall is decreased in obese people, for whom moving the diaphragm downward and the rib cage up and out is much more difficult. People suffering from a musculoskeletal disorder that leads to decreased mobility of the rib cage, such as kyphoscoliosis, also have decreased chest wall compliance. Similarly, people wtih decreased chest wall compliance must do more muscular work than people with normal chest wall compliance.

Lung Elastic Recoil and Alveoli Surface Tension

The elastic recoil of the lungs is partly due to the elastic properties of the pulmonary parenchyma itself. Elastin is more compliant or distensible and is important at low or normal lung volumes. Collagen is less compliant or distensible and is not usually stressed until lung volume is large. However, there is another component of the elastic recoil of the lung besides the elastin, collagen, and other constituents of the lung tissue. That other component is the surface tension at the air-liquid interface in the alveoli.

Surface tension is a force that occurs at any gas-liquid interface and is generated by the cohesive forces between the molecules of the liquid. These cohesive forces balance each other within the liquid phase but are unopposed at the surface of the liquid. Surface tension is what causes water to bead and form droplets. It causes a liquid to shrink to form the smallest possible surface area. The unit of measurement of surface tension is dynes per centimeter (dyn/cm).

Because the lung is inflated with air, an air-liquid interface is present in the lung, and surface tension forces contribute to alveolar elastic recoil. If all the gas is removed from the lung, and it is inflated again, but with saline instead of with air, the surface tension forces are absent because there is no air-liquid interface. In this circumstance, the elastic recoil is due only to the elastic recoil of the lung tissue itself. Thus, the hysteresis disappears under this condition.

Besides the surfactant's impact on elastic recoil, it has another critical importance, which would be described below. According to the Laplace's law, the transmural pressure of two alveoli with different radius would be different in the absence of surfactant (the surface tension of most liquids is constant and not dependent on the surface area of the air-liquid inteface). Consider what this would mean in the lung, where alveoli of different sizes are connected to each other by common airways and collateral ventilation pathways. If 2 alveoli of different sizes (radius) are connected by a common airway and the surface tension of the 2 alveoli is equal, then the pressure in the small alveolus must be greater than that in the larger alveolus and the smaller alveolus will empty into the larger alveolus. If surface tension is independent of surface area, the smaller the alveolus with smaller radius becomes, the higher the pressure in it. Thus, if the lung were composed of interconnected alveoli of different sizes with a constant surface tension at the air-liquid interface, it would be expected to be inherently unstable with a tendency for smaller alveoli to collapse into larger ones. Normally, this is not the case, which is fortunate because collapsed alveoli require very great distending pressures to reopen, partly because of the cohesive forces at the liquid-liquid interface of collapsed alveoli. At least two factors cause the alveoli to be more stable than this prediction based on constant surface tension. The first factor is a substance called pulmonary surfactant, which is produced by specialized alveolar cells, and the second is the structrual interdependence of the alveoli.

Mechanism of Pulmonary Edema

September 13, 2016 Cardiology, Critical Care, Hemodynamics, Physiology and Pathophysiology, Pulmonary Medicine, Respirology No comments , , , , , , , , ,

screen-shot-2016-09-12-at-8-32-24-pmPulmonary edema is the extravascular accumulation of fluid in the lung. This pathologic condition may be caused by one or more physiologic abnormalities, but the result is inevitably impaired gas transfer. As the edema fluid builds up, first in the interstitium and later in alveoli, diffusion of gases – particularly oxygen – decreases.

The capillary endothelium is much more permeable to water and solutes than is the alveolar epithelium. Edema fluid therefore accumulates in the interstitium before it accumulates in the alveoli.

The Starling equation describes the movement of liquid across the capillary endothelium, see the figure above. This equation describes the basic parameters that determine the net fluid movement between the vessel and the interstitium. On the other hand, the lymphatic drainage is another important factor which relieves the interstitial fluid accumulation by simply drainage – removing fluid from the interstitium. Any fluid that makes its way into the pulmonary interstitium must be removed by the lymphatic drainage of the lung. The pulmonary lymphatic vessels are mainly located in the extra-alveolar interstitium. The volume of lymph flow from the human lung is now believed to be as great as that from other organs under normal circumstances, and it is capable of increasing as much as 10-fold under pathologic conditions. It is only when this large safety factor is overwhelmed that pulmonary edema occurs.

screen-shot-2016-09-12-at-8-58-50-pmConditions That May Lead to Pulmonary Edema

The Starling equation provides a useful method of categorizing most of the potential causes of pulmonary edema.

Permeability (Kf)

Infections, circulating or inhaled toxins, oxygen toxicity, and other factors that destroy the integrity of the capillary endothelium can lead to localized or generalized pulmonary edema.

Capillary Hydrostatic Pressure (Pc)

The capillary hydrostatic pressure is estimated to be about 10 mm Hg under normal conditions. If the capillary hydrostatic pressure increases dramatically, the filtration of fluid across the capillary endothelium will increase greatly, and enough fluid may leave the capillaries to exceed the lymphatic drainage. The pulmonary capillary hydrostatic pressure often increases secondary to problems in the left side of the circulation, such as infarction of the left venticle, left ventricular failure, or mitral stenosis. As left atrial pressure and pulmonary venous pressure rise because of accumulating blood, the pulmonary capillary hydrostatic pressure also increases. Other causes of elevated pulmonary capillary hydrostatic pressure include overzealous administration of intravenous fluids by the physician and disease that occlude the pulmonary veins.

Interstitial Hydrostatic Pressure (Pis)

Some investigators believe the interstitial hydrostatic pressure of the lung to be slightly positive, whereas others have shown evidence that it may be in the range of -5 to -7 mm Hg. Conditions that would decrease the interstitial pressure would increase the tendency for pulmonary edema to develop. These include forced inspiration against an upper airway obstruction and potential actions of the physician, such as rapid evacuation of chest fluids or reduction of pneumothorax. Situations that increase alveolar surface tension, for example, when decreased amounts of pulmonary surfactant are present, could also make the interstitial hydrostatic pressure more negative and increase the tendency for the formation of pulmonary edema. Note that as fluid accumulates in the interstitium, the interstitial hydrostatic pressure increases, which helps limit further fluid extravasation.

The Reflection Coefficient (σ)

Any situation that permits more solute to leave the capillaries will lead to more fluid movement out of the vascular space.

Plasma Colloid Osmotic Pressurepl )

Decreased in the colloid osmotic pressure of the plasma, which helps retain fluid in the capillaries, may lead to pulmonary edema. Plasma colloid osmotic pressure, normally in the range of 25 to 28 mm Hg, falls in hypoproteinemia or over administration of intravenous solutions.

Interstitial Colloid Osmotic Pressureis)

Increased concentration of solute in the interstitium will pull fluid from the capillaries.

Lymphatic Insufficiency

Conditions that block the lymphatic drainage of the lung, such as tumors or scars, may predispose patients to pulmonary edema.

Other Conditions Associated with Pulmonary Edema

Pulmonary edema is often seen associated with head injury, heroin overdose, and high altitude. The causes of the edema formation in these conditions are not known, although high-altitude pulmonary edema may be partly caused by high pulmonary artery pressures secondary to the hypoxic pulmonary vasoconstriction.

[Respiration][Circulation] Blood Flow to the Lung – General and Pulmonary Vascular Resistance

September 11, 2016 Cardiology, Critical Care, Hemodynamics, Mechanical Ventilation, Physiology and Pathophysiology, Pulmonary Medicine, Respirology No comments , , , , , , , , , , , ,

The lung receives blood flow via both the bronchial circulation and the pulmonary circulation. Bronchial blood flow constitutes a very small portion of the output of the left ventricle and supplies part of the tracheobronchial tree with systemic arterial blood. Pulmonary blood flow (PBF) constitutes the entire output of the right venticle and supplies the lung with the mixed venous blood draining all the tissues of the body.

There is about 250 to 300 mL of blood per square meter of body surface area in the pulmonary circulation. About 60 to 70 mL/m2 of this blood is located in the pulmonary capillaries.

Gas exchange starts to take place in smaller pulmonary arterial vessels, which are not truly capillaries by histologic standards. These arterial segments and successive capillaries may be thought of as functional pulmonary capillaries.

About 280 billion pulmonary capillaries supply approximately 300 million alveoli, resulting in a potential surface area for gas exchange estimated to be 50 to 100 m2.

Bronchial Circulation

The bronchial arteries arise variably, either directly from the aorta or from the intercostal arteries. They supply arterial blood to the tracheobronchial tree and to other structures of the lung down to the level of the terminal bronchioles. They also provide blood flow to the hilar lymph nodes, visceral pleura, pulmoonary arteries and veins, vagus, and esophagus. The bronchial circulation may be important in the "air-conditioning" of inspired air. The blood flow in the bronchial circulation constitutes about 2% of left ventricle output of the left ventricle. Blood pressure in the bronchial arteries is the same as that in other systemic arteries.

The venous drainage of the bronchial circulation is unusual. Although some of the bronchial venous blood enters the azygos and hemiazygos veins, a substantial portion of bronchial venous blood enters the pulmonary veins. Therefore, the bronchial venous blood entering the pulmonary venous blood is part of the normal anatomic right-to-left shunt. Histologists have also identified anastomoses, or connections, between some bronchial capillaries and pulmonary capillaries and between bronchial arteries and branches of the pulmonary artery. Thse connections probably play little role in a healthy person but may open in pathologic states, such as when either bronchial or PBF to a protion of lung is occluded. For example, if PBF to an area of the lung is blocked by a pulmonary embolus, bronchial blood flow to that area increases.

Pulmonary Circuation

The pulmonary vessels offer much less resistance to blood flow than do the systemic arterial tree. They are also much more distensible than systemic arterial vessels. These factors lead to much lower intravascular pressures than those found in the systemic arteries, which makes them more compressible. The pulmonary vessels are located in the thorax and are subject to alveolar and intrapleural pressures that can change greatly. Therefore, factors other than the tone of the pulmonary vascular smooth muscle may have profound effects on pulmonary vascular resistance (PVR). The transmural pressure difference across vessel walls is therefore a major determinant of PVR.

Because the right and left circulations are in series, the outputs of the right and left venticles must be approximately equal to each other over the long run. If the 2 outputs are the same and the measured pressure drops across the systemic circulation and the pulmonary circulation are bout 98 and 10 mm Hg, respectively, then the PVR must be about one tenth that of the systemic vascular resistance (SVR). Again, the low resistance to blood flow offered by the pulmonary circulation is due to the structural aspects of the pulmonary circulation.

The resistance is fairly evenly distributed among the pulmonary arteries, the pulmonary capillaries, and the pulmonary veins (from 15 mm Hg to 12 mm Hg, from 12 mm Hg to 8 mm Hg, from 8 mm Hg to 5 mm Hg, respectively). At rest, about one third of the resistance (PVR) is located in the pulmonary arteries, about one third is located in the pulmonary capillaries, and about one third is located in the pulmonary veins.


screen-shot-2016-09-11-at-3-44-33-pmThe relative small amounts of vascular smooth muscle, low intravascular pressures, and high distensibility of the pulmonary circulation lead to a much greater importance of extravascular effects ("passive factors") on PVR. Gravity, body position, lung volume, alveolar and intrapleural pressures, intravascular pressures, and right ventricular output all can have profound effects on PVR without any alteration in the tone of the pulmonary vascular smooth muscle.

Transmural Pressure On PVR

For distensible-compressible vessels, the transmural pressure difference is an important determinant of the vessel diameter. As the transmural pressure difference (which is equal to pressure inside minus pressure outside) increases, the vessel diameter increases and resistance falls; as the transmural pressure difference decreases, the vessel diameter decreases and the resistance increases. Negative transmural pressure differences lead to compression or even collapse of the vessel.

Lung Volume on PVR

Screen Shot 2016-09-06 at 12.48.46 PMTwo different groups of pulmonary vessels must be considered when the effects of changes in lung volume on PVR are analyzed: those vessels that are exposed to the mechanical influences of the alveoli and the larger vessels that are not – the alveolar and extraalevolar vessels.

As lung volume increases during a normal negative-pressure inspiration, the alveoli increase in volume. While he alveoli expand, the vessels found between them, mainly pulmonary capillaries, are elongated. As these vessels are stretched, their diameters decrease, just as stretching a rubber tube causes its diameter to narrow. Resistance to blood flow through the alveolar vessels increases as the alveoli expand because the alveolar vessels are longer (resistance is directly proportional to length) and because their radii are smaller (resistance is inversely proportional to radius to the fourth power). At high lung volumes, then, the resistance to blood flow offered by the alveolar vessels increases greatly; at low lung volumes, the resistance to blood flow offered by the alveolar vessels decreases.

One group of the extraalveolar vessels, the larger arteries and veins, is exposed to the intrapleural pressure. As lung volume is increased by making the intrapleural pressure more negative, the transmural pressure difference of the larger arteries and veins increase and they distend. Another factor tending to decrease the resistance to blood flow offered by the extraalveolar vessels at higher lung volumes is radial traction by the connective tissue and alveolar septa holding the larger vessels in place in the lung. Thus, at high lung volumes, the resistance to blood flow offered by the extraalveolar vessels decreases. During a forced expiration to low lung volumes, however, intrapleural pressure becomes very positive. Extraalveolar vessels are compressed, and as the alveoli decrease in size, they exert less radial traction on the extraalveolar vessels. The resistance to blood flow offered by the extraalveolar vessels increase greatly.

Because the alveolar and extraalveolar vessels may be thought of a 2 groups of resistances in series with each other, the resistances of the alveolar and extraalveolar vessels are additive at any lung volume. Thus, the effect of changes in lung volume on the total PVR gives the U-shape cruve. PVR is lowest near the functional residual capacity and increases at both high and low lung volumes.

There is another type of extraalveolar vessel called corner vessel, or extraalveolar capillary. Although these vessels are found between alveoli, their locations at junctions of alveolar septa give them different mechanical properties. Expansion of the alveoli during inspiration increases the wall tension of the alveolar septa, and the corner vessels are distended by increased radial traction, whereas the alveolar capillaries are compressed.

Also note that during mechanical positive-pressure ventilation, alveolar pressure (PA) and intrapleural pressure are positive during inspiration. In this case, and the resistance to blood flow offered by both alveolar and extraalveolar vessels increases during lung inflation. This is especially a problem during mechanical positive-pressure ventilation with positve end-expiratory pressure (PEEP). During PEEP, airway pressure (and thus alveolar pressure) is kept positive at end expiratory to help prevent atelectasis. In this situation, alveolar pressure and intrapleural pressure are positive during both inspiration and expriation. PVR is elevated in both alveolar and extraalveolar vessels throughout the respiratory cycle. In addition, because intrapleural pressure is always positive, the other intrathoracic blood vessels are subjected to decreased transmural pressure differences; the venae cavae, which have low intravascular pressure, are also compressed. If cardiovascular reflexes are unable to adjust to this situation, cardiac output may fall precipitously because of decreased venous return (for the reason see thread "Effects of Pressure Outside the Heart on Cardiac Output" at and high PVR.

Recruitment and Distention

During exercise, cardiac output can increase several-fold without a correspondingly great increase in MPAP. Although the MPAP does increase, the increase is only a few millimeters of mercury, even if cardiac output has doubled or tripled. Since the pressure drop across the pulmonary circulation is proportional to the cardiac output times the PVR, this must indicate a decrease in PVR.

Like the effects of lung volume on PVR, this decrease appears to be passive – that is, it is not a result of changes in the tone of pulmonary vascular smooth muscle caused by neural mechanisms or humoral agents. In fact, a fall in PVR in response to increased blood flow or even an increase perfusion pressure can be demonstrated in a vascularly isolated perfused lung. There are two different mechanisms that can explain this decrease in PVR in response to elevated blood flow and perfusion pressure: recruitment and distention.


At resting cardiac outputs, not all the pulmonary capillaries are perfused. A substantial proportion of capillaries, perhaps as large as one half to two thirds, is probably not perfused because of hydrostatic effects. Others may be unperfused because they have a relatively high critical opening pressure. That is, these vessels, because of their high vascular smooth muscle tone or other factors such as positive alveolar pressure, require a higher perfusion pressure than that solely necessary to overcome hydrostatic forces. Under normal circumstances, it is not likely that the critical opening pressures for pulmonary blood vessels are very great because they have so little smooth muscle. Increased blood flow increases the MPAP, which opposes hydrostatic forces and exceeds the critical opening pressure in previously unopened vesels. This series of events opens new parallel pathways for blood flow, which lowers the PVR. This opening of new pathways is called recruitment. Note that decreasing the cardiac output or pulmonary artery pressure can result in a derecruitment of pulmonary capillaries.


As perfusion pressure increases, the transmural pressure gradient of the pulmonary blood vessels increases, causing distention of the vessels. This increases their radii and decreases their resistance to blood flow.

Control of Pulmonary Vascular Smooth Muscle

Pulmonary vascular smooth muscle is responsive to both neural and humoral influences. These produce "active" alterations in PVR, as opposed to those "passive" factors discussed in the previous section.

The pulmonary vasculature is innervated by both sympathetic and parasympathetic fibers of the autonomic nervous system. The innervation of pulmonary vessels is relatively sparse in comparsion with that of systemic vessels. There is relatively more innervation of the larger vessels and less of the smaller, more muscular vessels. There appears to be no innervation of vessels smaller than 30 um in diameter. There does not appear to be much innervation of intrapulmonary veins and venules.

The effects of stimulation of the sympathetic innervation of the pulmonary vasulature are somewhat controversial. Some investigators have demonstrated an increase in PVR with sympathetic stimulation of the innervation of the pulmonary vasculature, whereas others have shown only a decreased distensibility with no change in calculated PVR. Stimulation of the parasympathetic innervation of the pulmonary vessels generally causes vasodilation, although its physiologic function is not known.

The catecholamines epinephrine and norepinephrine both increase PVR when injected into the pulmonary circulation. Histamine, found in the lung in mast cells, is a pulmonary vasoconstrictor. Certain prostaglandins and related substances, such as PGF2alpha, PGE2, and thromboxane, are also pulmonary vasoconstrictors, as is endothelin, a 21-amino acid peptide synthesized by the vascular endothelium. Alveolar hypoxia and hypercapnia also cause pulmonary vasoconstriction. Acetylcholine, the beta-adrenergic agonist isoproterenol, nitric oxide (NO), and certain prostaglandins, such as PGE1, and PGI2 (prostacyclin), are pulmonary vasodilators.

Gravity's Impact on PVR

Determinations of the regional distribution of PBF (see discussion below) have shown that gravity is another important "passive" factor affecting local PVR and the relative perfusion of different regions of the lung (see discussion below). The interaction of the effects of gravity and extravascular pressures may have a profound influence on the relative perfusion of different areas of the lung.

The Regional Distribution of Pulmonary Blood Flow

Interaction of Gravity and Extravascular Pressure

Experiments done on excised, perfused, upright animal lungs have demonstrated the same gradient of increased perfusion per unit volume from the top of the lung to the bottom. When the experiments were done at low pump outputs so that the pulmonary artery pressure was low, the uppermost regions of the lung received no blood flow. Perfusion of the lung ceased at the point at which alveolar pressure (PA) was just equal to pulmonary arterial pressure (Pa). Above this point, there was no perfusion because alveolar pressure exceeded pulmonary artery pressure, and so the transmural pressure across capillary walls was negative. Below this point, perfusion per unit volume increased steadily with increased distance down the lung.

screen-shot-2016-09-12-at-1-51-11-pmThus, under circumstances in which alveolar pressure is greater than pulmonary artery pressure in the upper parts of the lung, no blood flow occurs in that region, and the region is referred to as being in zone 1, as shown in Fingure 4-9. Any zone 1, then, is ventilated but not perfused. It is alveolar dead space. Fortunately, during normal, quiet breathing in a person with a normal cardiac output, pulmonary artery pressure, even in the uppermost regions of the lung, is greater than alveolar pressure, and so there is no zone 1. Some experiments have also demonstrated perfusion of the corner vessels under zone 1 conditions.

The lower portion of the lung in Figure 4-9 is said to be in zone 3. In this region, the pulmonary artery pressure and the pulmonary vein pressure (Pv) are both greater than alveolar pressure. The driving pressure for blood flow through the lung in this region is simply pulmonary artery pressure minus pulmonary vein pressure. Note that this driving pressure stays constant as one moves further down the lung in zone 3 because the hydrostatic pressure effects are the same for both the arteries and the veins.

The middle portion of the lung in Figure 4-9 is in zone 2. In zone 2, pulmonary artery pressure is greater than alveolar pressure, and so blood flow does occur. However, because alveolar pressure is greater than pulmonary vein pressure, the effective driving pressure for blood flow is pulmonary artery pressure minus alveolar pressure in zone 2. Notice that in zone 2 the increase in blood flow per distance down the lung is greater than it is in zone 3. This because the upstream driving pressure, the pulmonary artery pressure, increases according to the hydrostatic pressure increase, but the effective downstream pressure, alveolar pressure, is constant throughout the lung at any instant.

It is important to realize that the boundaries between the zones are dependent on physiologic conditions – they are not fixed anatomic landmarks. Alveolar pressure changes during the course of each breath. During eupneic breathing these changes are only a few centimeters of water, but they may be much greater during speech, exercise, and other conditions. A patient on a positive-pressure ventilator with PEEP may have substantial amounts of zone 1 because alveolar pressure is always high. Similarly, after a hemorrhage or during general anesthesia, PBF and pulmonary artery pressure are low and zone 1 conditions are also likely. During exercise, cardiac output and pulmonary artery pressure increase and any existing zone 1 should be recruited to zone 2. The boundary between zones 2 and 3 will move upward as well. Pulmonary artery pressure is highly pulsatile, and so the borders between the zones probably even move up a bit with each contraction of the right ventricle.

Changes in lung volume also affect the regional distribution of PBF and will therefore affect the boundaries between zones. Finally, changes in body position alter the orientation of the zones with respect to the anatomic locations in the lung, but the same relationships exist with respect to gravity and alveolar pressure.

Hypoxic Pulmonary Vasoconstriction

Alveolar hypoxia or atelectasis causes an active vasoconstriction in the pulmonary circulation. The site of vascular smooth muscle constriction appears to be in the arterial (precapillary) vessels very close to the alveoli.

The mechanism of hypoxic pulmonary vasoconstriction is not completely understood. The response occurs locally, that is, only in the area of the alveolar hypoxia. Connections to the central nervous system are not necessary: An isolated, excised lung, perfused with blood by a mechanical pump with a constant output, exhibits an increased perfusion pressure when ventilated with hypoxic gas mixtures. This indicates that the increase in PVR can occur without the influence of extrinsic nerves. Thus, it is not surprising that hypoxic pulmonary vasoconstriction persists in human patients who had received heart-lung transplants. Hypoxia may cause the release of a vasoactive substance from the pulmonary parenchyma or mast cells in the area. Histamine, serotonin, catecholamines, and prostaglandins have all been suggested as the mediator substance, but none appears to completely mimic the response. Decreased release of a vasodilator such as nitric oxide may also be involved in hypoxic pulmonary vasoconstriction. Possibly several mediators act together. More recent studies have strongly indicated that hypoxia acts directly on pulmonary vascular smooth muscle to produce hypoxic pulmonary vasoconstriction.

Physiologic Function of Hypoxic Pulmonary Vasoconstriction

The function of hypoxic pulmonary vasoconstriction in localized hypoxia is fairly obvious. If an area of the lung becomes hypoxic because of airway obstruction or if localized atelectasis occurs, any mixed venous blood flowing to that area will undergo little or no gas exchange and will mix with blood draining well-ventilated areas of the lung as it enters the left atrium. This mixing will lower the overall arterial PO2 (PaO2) and may even increase the arterial PCO2 (PaCO2). The hypoxic pulmomary vasoconstriction diverts mixed venous blood flow away from poorly ventilated areas of the lung by locally increasing vascular resistance. Therefore, mixed venous blood is sent to better-ventilated areas of the lung. The problem with hypoxic pulmonary vasoconstriction is that it is not a very strong response because there is so little smooth muscle in the pulmonary vasculature. Very high pulmonary artery pressures can interfere with hypoxic pulmonary vasoconstriction, as can other physiologic disturbances, such as alkalosis.

In hypoxia of the whole lung, such as might be encountered at high altitude or in hypoventilation, hypoxic pulmonary vasoconstriction occurs throughout the lung. Even this may be useful in increasing gas exchange because greatly increasing the pulmonary artery pressure recruits many previously unperfused pulmonary capillaries. This increases the surface area available for gas difusion and improves the matching of ventilation and perfusion. On the other hand, such a whole-lung hypoxic pulmonary vasoconstriction greatly increases the workload on the right venticle, and the high pulmonary artery pressure may overwhelm hypoxic pulmonary vasoconstriction in some parts of the lung, increase the capillary hydrostatic pressure in those vessels, and lead to pulmonary edema.