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.

EKG – Supraventricular Arrhythmias

August 27, 2016 Uncategorized No comments , , , ,

Mechanism for Arrhythmias ("HIS DEBS" rule)

  • Hypoxia
  • Ischemia and irritability
  • Sympathetic stimulaiton
  • Drugs
  • Electrolyte disturbances
  • Bradycardia
  • Stretch

Arrhythmias that originate in the atria or the AV node, the supraventricular arrhythmias. Atrial arrhythmias can consist of a single beat or a sustained rhythm disturbance lasting for a few seconds or many years.

Atrial and Junctional Premature Beats

Screen Shot 2016-08-27 at 1.15.26 PMSingle ectopic supraventricular betas can originate in the atria or in the vicinity of the AV node. The former are called atrial premature beats (or premature atrial contractions, PACs) and the latter, junctional premature beats. These are common phenomena, neither indicating underling cardiac disease nor requiring treatment. They can, however, initiate more sustained arrhythmias.

An atrial premature beat can be distinguished from a normal sinus beat by the contour of the P wave and by the timing of the beat. Because an atrial premature beat originates at an atrial site distant from the sinus node, atrial depolarization does not occur in the usual manner, and the configuration of the resultant P wave differs from that of the sinus P waves. If the site of origin of the atrial premature beta is far from the sinus node, the axis of the atrial premature beat will also differ from that of the normal P waves. An atrial premature beat comes too early; that is, it intrudes itself before the next anticipated sinus wave.

With junctional premature beats, there is usually no visible P wave, but sometimes, a retrograde P wave may be seen. This is just like the case with the junctional escape beats seen with sinus arrest. What is the difference between a junctional premature beat and a junctional escape beat? They look exactly alike, but the junctional premature beat occurs early, prematurely, interposing itself into the normal sinus rhythm. An escape beat occurs late, following a pause when the sinus node has failed to fire.

Both atrial and junctional premature beats are usually conducted normally to the ventricles, and the resultant QRS complex is therefore narrow. Some times, an atrial premature beat may occur sufficiently early that the AV node will not have recovered (i.e., repolarized) from the previous conducted beat and will therefore be unable to conduct the atrial premature beat into the venticles. The EKG may then show only a P wave without an ensuing QRS complex. This beat is then termed blocked atrial premature contraction.

Atrial Fibrillation

In atrial fibrillation, atrial activity is completely chaotic, and the AV node may bebombarded with more than 500 impulses per minute. Whereas in atrial flutter a single constant reentrant circuit is responsible for the regular saw-toothed pattern on the EKG, in atrial fibrillation multiple reentrant circuits whirl around in totally unpredictable fashion. No true P waves can be seen. Instead, the baseline appears flat or undultates slightly. The AV node, faced with this extraordinary blitz of atrial impulses, allow only occasional impulses to pass through at variable intervals, genrating an irregularly irregular ventricular rate, usually between 120 and 180 beats per minute. However, slower or faster ventricular responses can often be seen.

This irregularly irregular appearance of QRS complexes in the absence of discrete P waves is the key to identifying atrial fibrillation. The wavelike forms that may often be seen on close inspection of the undulating baseline are called fibrillation waves.

Carotid message may slow the ventricular rate in atrial fibrillation, but it is rarely used in this setting because the diagnosis is usually obvious.

[Physiology] Regulation of Arterial Pressure

June 21, 2016 Uncategorized No comments

Appropriate systemic arterial pressure is the single most important requirement for proper operation of the cardiovascular system. Without sufficient arterial pressure, the brain and the heart do not receive adequate blood flow, no matter what adjustments are made in their vascular resistance by local control mechanisms. In contrast, unnecessary demands are placed on the heart by excessive arterial pressure (afterload, see thread "Afterload and Its Components" at http://www.tomhsiung.com/wordpress/2015/10/afterload-and-its-components/). Thus, although dramatic changes in peripheral resistance and cardiac function can and do occur normally during the course of our normal daily activities, mean arterial pressure is maintained within a narrow range and is tightly regulated.

Arterial pressure is continuously monitored by various sensors located within the body. Whenever arterial pressure varies from normal, multiple reflex responses are initiated, which cause the adjustments in cardiac output, and total peripheral resistance needed to return arterial pressure to its normal value.

Short-Term Regulation of Arterial Pressure

Arterial Baroreceptor reflex

The arterial baroreceptor reflex is the single most important mechanism providing short-term regulation of arterial pressure. The efferent pathways of the arterial baroreceptor reflex are the cardiovascular sympathetic and cardiac parasympathetic nerves. The effector organs are the heart and peripheral blood vessels.

Efferent Pathways

In the sympathetic pathways, the cell bodies of the preganglionic fibers are located within the spinal cord (T1-L2). These pregangllionic neurons have spontaneous activity that is modulated by excitatory and inhibitory inputs, which arise from centers in the brainstem and descend in distinct excitatory and inhibitory spinal pathways.

In the parasympathetic system, the cell bodies of the preganglionic fibers are located within the brainstem and spinal cord (S2-S4). Their spontaneous activity is modulated by inputs from adjacent centers in the brainstem.

Afferent Pathways

Screen Shot 2016-06-06 at 9.11.08 PMSensory receptors, called arterial barorecetpros, are found in abundance in the walls of the aorta and carotid arteries. Major concentrations of these receptors are found near the arch of the aorta and at the bifurcation of the common carotid artery into the internal and external carotid arteries on either side of the neck. The receptors themselves are mechanoreceptors that sense arterial pressure indirectly from the degree of stretch of the elastic arterial walls. In general, increased stretch causes an increased action potential generation rate by the arterial baroreceptors. Baroreceptors actually sense not only absolute stretch but also the rate of change of stretch. For this reason, both the mean arterial pressure and the arterial pulse pressure affect baroreceptor firing rate. If arterial pressure remains elevated over a period of several days for some reason, the arterial baroreceptor firing rate will gradually return toward normal. Thus, arterial baroreceptors are said to adapt to long-term changes in arterial pressure. For this reason, the arterial baroreceptor reflex cannot serve as a mechanism for the long-term regulation of arterial pressure.

Action potentials generated by the carotid sinus baroreceptors travel through the carotid sinus nerves (Hering's nerve), which join with the glossopharyngeal nerves (cranial nerve IX) before entering the CNS. Afferent fibers from the aortic baroreceptors run to the CNS in the vagus nerves (cranial nerve X).

Central Integration

Much of the central integration involved in reflex regulation of the cardiovascular system occurs in the medulla oblongata in what are traditionally referred to as the medullary cardiovascular centers. The neural interconnections between the diffuse structures in this area are complex and not completely mapped. Moreover, these strucutures appear to serve multiple functions including respiratory control, for example. What is known with a fair degree of certainty is where the cardiovascular afferent and efferent pathways enter and leave the medulla. And the intermediate processes involved in the actual integration of the sensory information into appropriate sympathetic and parasympathetic responses are not well understood at present. Although much of this integration takes place within the medulla, higher centers such as the hypothalamus are probably involved as well.

The major external influence on the cardiovascular centers comes from the arterial baroreceptors which supply a tonic input to the central integration centers. Increased inputs from the arterial baroreceptors tends to simultaneously 1).inhibit the activity of the spinal sympathetic excitatory tract; 2).stimulate the activity of the spinal sympathetic inhibitory tract, and 3).stimulate the activity of parasympathetic preganglionic nerves. Thus, an increase in the arterial baroreceptor discharge rate (via increased arterial pressure and/or pulse pressure) causes a decrease in the tonic activity of cardiovascular sympathetic nerves and a simultaneous increase in the tonic activity of cardiac parasympathetic nerves.

Operation of The Arterial Baroreceptor Reflex

The arterial baroreceptor reflex is a continuously operating control system that automatically makes adjustments to prevent primary disturbances on the heart and/or vessels from causing large changes in mean arterial pressure. The arterial baroreceptor reflex mechanism acts to regulate arterial pressure in a negative feedback manner that is analogous in many ways to the manner in which a thermostatically controlled home heating system operates to regulate inside temperature despite disturbances such as changes in the weather or open windows. One should recall that nervous control of vessels is more important in some areas such as the kidney, the skin, and the splanchnic organs than in the brain and the heart muscle. Thus, the reflex response to a fall in arterial pressure may, for example, include a significant increase in renal vascular resistance and a decrease in renal blood flow without changing the cerebral vascular resistance or blood flow. The peripheral vascular adjustments associated with the arterial baroreceptor reflex take place primarily in organs with strong sympathetic vascular control.

Other Cardiovascular Reflexes and Responses

Seemingly in spite of the arterial baroreceptor reflex mechanism, large and rapid changes in mean arterial pressure do occur in certain physiological and pathological situatons. These reactions are caused by influences on the medullary cardiovascular centers other than those from the arterial baroreceptors. These inputs on the medullary cardiovascular centers arise from many types of peripheral and central receptors as well as from "higher centers" in the CNS such as hypothalamus and the cortex.

As discussed before, the analogy was made that the arterial baroreceptor reflex operates to control arterial pressure somewhat as a home heating system acts to control inside temperature. Such as system automatically acts to counteract changes in temperature caused by such things as an open window or a dirty furnace. It does not, however, resist changes in indoor temperature caused by someone's resetting of the thermostat dial – infact, the basic temperature regulating mechanisms copperate wholeheartedly in adjusting the temperature to the new desired value. The temperature setting on a home thermostat's dial has a useful conceptual analogy in cardiovascular physiology often referred to as the "set point" for arterial pressure. Most (but not all) of the influences that are about to be discussed influence arterial pressure as if they changed the arterial baroreceptor reflex's set point for pressure regulation. Consequently, the arterial baroreceptor reflex does not resist most of these pressure disturbances but actually assists in producing them.

Reflexes From Receptors in the Heart and Lungs/Cardiopulmonary Receptors (+)

A host of mechanoreceptors and chemoreceptors that can elicit reflex cardiovascular responses have been identified in atria, ventricles, coronary vessels, and lungs. The role of these cardiopulmonary receptors in neurohumoral control of the cardiovascular system is, in most cases, incompletely understood. One general function that the cardiopulmonary receptors perform is sensing the pressure (or volume) in the atria and the central venous pool. Increased central venous pressure and volume cause receptor activation by stretch, which elicits a reflex decrease in sympathetic activity.

Chemoreceptor Reflexes (+)

Low PO2 and/or high PCO2 levels in the arterial blood cause reflex increases in respiratory rate and mean arterial pressure. These responses appear to be a result of increased activity of arterial chemoreceptors, located in the carotid arteries and the arch of the aorta, and central chemoreceptors, located somewhere within the CNS. Chemoreceptors probably play little role in the normal regulation of arterial pressure because arterial blood PO2 and PCO2 are normally held very nearly constant by respiratory control mechanisms.

  • Arterial PO2 and PCO2
  • Cerebral ischemic response

Reflexes From Receptors in Exercising Skeletal Muscle

Reflex tachycarida and increased arterial pressure can be elicited by stimulation of certain afferent fibers from the skeletal muscle. These pathways may be activated by chemoreceptors responding to muscle ischemia (more accurately, low PaO2 and/or high PaCO2), which occur with strong, sustained static (isometric) exercise. This input may contribute to the marked increase in blood pressure that accompanies such isometric efforts. It is uncertain as to what event this reflex contributes to the cardiovascular responses to dynamic (rhythmic) muscle exercise.

Dive Reflex

Aquatic animals respond to diving with a remarkable bradycardia and intense vasoconstriction in all systemic organs except the brain and the heart. A similar but less dramatic dive reflex can be elicited in humans by simply immersing the face in water (Cold water enhances the response). The response involves the unusual combination of bradycardia produced by enhanced cardiac parasympathetic activity and peripheral vasoconstriction caused by enhanced sympathetic activity. This is a rare exception to the general rule that sympathetic and parasympathetic nerves are activated in reciprocal fashion.

Cardiovascular Responses Associated with Emotion (+)

Cardiovascular responses are frequently associated with certain states of emotion. These responses include blushing, fight or flight, vasovagal syncope, etc., which originate in the cerebral cortex and reach the medullary cardiovascular centers through corticohypothalamic pathways.

Central Command (+)

The term central command is used to imply an input from the cerebral cortex to lower brain centers during voluntary muscle exercise. In the absence of any other obvious causes, central command is at present the best explanation as to why both mean arterial pressure and respiration increase during voluntary exercise.

Reflex Responses to Pain (+)

Pain can have either a positive or a negative influence on arterial pressure. Generally, superficial or cutaneous pain causes a rise in blood pressure in a manner similar to that associated with the alerting response and perhaps over many of the same pathways. Deep pain from receptors in the viscera or joints, however, often causes a cardiovascular response similar to that which accompanies vasovagal syncope, that is, decreased sympathetic tone, increased parasympathetic tone, and a serious decrease in blood pressure. This response may contribute to the state of shock that often accompanies crushing injuries and/or joint displacement.

  • Cutaneous pain
  • Deep pain

Temperature Regulation Reflexes

Temperature regulation responses are controlled primarily by the hypothalamus, which can operate through the cardiovascular centers to discretely control the sympathetic activity to regulate vasoconstriction of cutaneous vessels and thus skin blood flow. The sympathetic activity to cutaneous vessels is extremely responsive to changes in hypothalamic temperature.

Long-Term Regulation of Arterial Pressure

Long-term regulation of arterial pressure is a topic of extreme clinical relevance because of the prevalence of hypertension in our society. The most long-standing and generally accepted theory of long-term pressure regulation is that it crucially involves the kidneys, their sodium handling, and ultimately the regulation of blood volume. This theory is sometimes referred to as the "fluid balance" model of long-term arterial blood pressure control. In essence, this theory asserts that in the long term, mean arterial pressure is whatever it needs to be to maintain an appropriate blood volume through arterial pressure's direct effects on renal function.

Circulating blood volume can influence arterial pressure because:

Blood volume (decreases) –> peripheral venous pressure (down) –> left shift of venous function curve –> CVP (down) –> SV (decreases) –> CO (decreases) –> arterial pressure (down)

A fact yet to be considered is that arterial pressure has a profound influence on urinary output rate and thus affects total body fluid volume. Because blood volume is one of the components of the total body fluid, blood volume alterations accompany changes in total body fluid volume. The mechanisms are such that an increase in arterial pressure causes an increase in urinary output rate (due to decreased ADH secretion) and thus a decrease in blood volume. But decreased blood volume tends to lower arterial pressure. Thus, the complete sequence of events that are initiated by an increase in arterial pressure can be listed as follows:

Arterial pressure (increases) –> urinary output rate (up) –> fluid volume (decreases) –> blool volume (decrease) –> cardiac output (down) –> arterial pressure (decreases)

Note the negative feedback nature of this sequence of events: increased arterial pressure leads to fluid volume depletion, which tends to lower arterial pressure. Conversely, an initial disturbance of decreased arterial pressure would lead to fluid volume expansion, which would tend to increase arterial pressure. Because of negative feedback, these events constitute a fluid volume mechanism for regulating arterial pressure.

Remember that the arterial baroreceptor reflex is very quick to counteract disturbances in arterial pressure, but for fluid volume mechanism hours or even days may be required before a change in urinary output rate produces a significant accumulation or loss of total body fluid volume. Whatever this fluid volume mechanism lacks in speed, however, it more than makes up for that in persistence. As long as there is any inequality between fluid intake rate and the urinary output rate, fluid volume is changing and this fluid volume mechanism has not completed its adjustment of arterial pressure. The fluid volume mechanism is in equilibrium only when the urinary output rate exactly equals the fluid intake rate. In the long term, the arterial pressure can only be that which makes the urinary output rate equal to the fluid intake rate.

Medical Statistics – Charting Continuous Metric Data

December 23, 2015 Uncategorized No comments

Screen Shot 2015-12-23 at 7.30.00 PMThe Histogram

A continuous metric variable can take a very large number of values, so it is usually impractical to plot them without first grouping the values. The grouped data is plotted using a frequency histogram, which has frequency plotted on the vertical axis and group size on the horizontal axis.

A histogram looks like a bar chart but without any gaps between adjacent bars. This emphasises the continuous nature of the underlying variable. If the groups in the frequency table are all of the same width, then the heights of the bars in the histogram will be proportional to their frequency.

One limitation of the histogram is that it can represent only one variable at a time (as in the case of the pie chart), and this can make comparisons between two histograms difficult because if you try to plot more than one histogram on the same axes, invariably parts of one chart will overlap the other.

The Box (and Whisker) Plot

Figure 3.17 shows an example of what is known as a box plot, or more precisely, a box and whisker plot. This form of chart can be used with either ordinal data or metric data, but it is more common with the latter, as in this example, which shows sperm concentration among survivors of childhood cancer and a control (non-cancer) group.Screen Shot 2015-12-23 at 7.42.10 PM

The bottom and top of the box mark what are called the 25th and 75th percentiles, respectively. The 25th percentile is the value below which 25 percent of the values in the sample lie (and thus 75 percent exceed this value) – about 50×106/mL for the control group. The 75th percentile is the value above which 25 percent of the sample lie (and 75 percent below) – about 120×106/mL. The line across the inside of the box (not necessarily in the middle) marks the value which divides the sample into two equal numbers of values – 50 percent below this value and 50 percent above it, about 85×106/mL here, is the 50th percentile. The bottom and top of each whisker mark the smallest and the largest values in the sample, respectively.

Proximal Tubule Reabsorption and Secretion – Organic Solutes

November 5, 2015 Uncategorized No comments , , , , , , , , , , ,

1920px-JointcolorsA major function of the kidneys is the excretion of organic waste, forerign chemicals and their metabolites. As the kidneys excrete these substances they also filter large amounts of organic substances that they do not excrete, such as gllucose and amino acids. Therefore, the kidneys msut discriminate between what to keep and what to discard. The handling of small organic solutes by the kidney has several generalizations, including:

  • Many transporters on renal tubule are promiscuous, accepting multiple solutes, sometimes over 100 different ones. This allows the kidneys to operate without expressing a separate transporter for each and every solute.
  • Most organic solutes are transported only in the proximal tubule. Those that are secreted or escape reabsorption in the proximal tubule end up being excreted (an exception is when charged species become neutral as a result of changes in tubular pH and are reabsorbed passively in regions beyond the proximal tubule).
  • Transport involves a cascade of interrelated transport events always beginning with active extrusion of sodium across the basolateral membrane by the Na-K-ATPase. Neutral or negatively charged organic solutes then enter via symporters with sodium, while cations enter via uniporters driven by the netagive membrane potential. The resulting intracellular accumulation of the solute in question establishes a favorable gradient for its efflux. The accumulated solutes then leave through a variety of pathways across the opposite membrane from which they entered or couple via an antiporter to the influx of another organic solute.

Proximal Reabsorption of Organic Nutrients

Most of the useful organic nutrients in the plasma that should not be lost in the urine are freely filtered. These include glucose, amino acids, acetate, Krebs cycle intermediates, some water-soluble vitamins, lactate, acetoacetate, beta-hydroxybutyrate, and many others. The proximal tubule is the major site for reabsorption of the large quantities of these organic nutrients filtered each day by the renal corpuscles.


Under most circumstances, it would be deleterious to lose glucsoe in the urine, particularly in conditions of prolonged fasting. Thus the kidneys nromally reabsorb all the glucose that is filtered. A typical plasma glucose level is about 90 mg/dL. It rises transiently to well over 100 mg/dL during meals and falls somewhat during fasting. Usually all the filtered glucose is reabsorbed in the proximal tubule. This involves taking up glucose from the tubular lumen across the apical membrane via sodium-glucose symporters, followed by its exit across the basolateral membrane into the interstitium via a GLUT uniporter. Most of the glucose is reabsorbed by a high-capacity, low-affinity sodium-glucose symporter (SGLT-2) that has a stoichiometry of 1 sodium per glucose. Then the last remaining glucose is taken up in the late proximal tubule (S3 segment) by a low-capacity, high-affinity transporter (SGLT-1) that transports 2 sodium ions per glucose. This 2-for-1 stoichiometry provides additional energy to move glucose up its concentration gradient in the  region where the luminal concentration is nromally very low. Unlike the case for sodium and many other solutes, the tight junctions are not significantly permeable to glucose. Therefore, as glucose is removed from the lumen and the luminal concentration falls, there is no back-leak, resulting in virtually complete reabsorption.Screen Shot 2015-11-05 at 10.09.58 PM

Because the sodium-glucose symporters are saturable (Tm systems), abnromally high-filtered loads overwhelm the reabsorptive capacity (exceed the Tm). This occurs when plasma glucose approaches 200 mg/dL, a situation often found in untreated diabetes mellitus. In very sever cases, plasma glucose can exceeed 1000 mg/dL, or over 55 mmol/L, leading to a significant loss of glucose.

Assume that the glucose Tm is 375 mg/min (a typical value). With a glomerular filtration rate (GFR) of 125 mL/min (1.25 dL/min) and a normal plasma glucose of 90 mg/dL, the filtered load is 1.25 dL/min X 90 mg/dL = 112.5 mg/min, well below the Tm of 375 mg/min. Thus the kidneys easily reabsorb the entire filtered load. When plasma glucose reaches 200 mg/dL, the filtered load becomes 1.25 dL/min X 200 mg/dL = 250 mg/min. At this point, some individual nephrons have reached the upper limit of what they can reabsorb, and a little glucose begins to spill into the urine. Further increases in plasma glucose saturate the remaining transporters and any amount filtered above 375 mg/min is excreted. This leads to loss of glucose and an unwanted osmotic diuresis.

Proteins and Peptides

Although we sometimes say the glomerular filtrate is protein free, it is not truly free of all protein; it just has a total protein concentration much lower than plasma. First, peptides and smaller proteins (e.g., angiotensin, insulin), although present at low concentrations in the blood, are filtered in considerable quantities. Second, while the movement of large plasma proteins across the glomerular filtration barrier is extremely limited, a small amount does make it through into Bowman's space. For albumin, the plasma protein highest concentration in the blood, the concentration in the filtrate is normally about 1 mg/dL, or roughly 0.02% of the plasma ablumin concentration (5 g/dL). Because of the huge volume of fluid filtered per day, the total filtered amount of protein is not negligible. Normally all of these proteins and peptides are reabsorbed completely, although not in the conventional way. They are enzymatically degraded into their constituent amino acids, which are then returned to the blood.

For the larger proteins, the initial step in revovery is endocytosis at the apical membrane. This energy-requiring process is triggered by the binding of filtered protein molecules to specific receptors on the apical membrane. The rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation, and thus, the Tm for protein uptake is reached. The pinched-off intracellular vesicles resulting from endocytosis merge with lysosomes, whose enzymes degrade the protein to low-molecular-weight fragments, mainly individual amino acids. These end products then exit the cells across the basolateral membrane into the interstitial fluid, from which they gain entry to the peritubular capillaries.

To understand the potential problem associated with a failure to take up filtered protein, remember that for a healthy young adult,

Total filtered protein = GFR X concentration of protein in filtrate = 180 L/day X 10 mg/L = 1.8 g/day

If this protein was not removed from the lumen, the entire 1.8 g would be lost in the urine. In fact, most of the filtered protein is endocytosed and degraded so that the excretion of protein in the urine is normally only 100 mg/day. The endocytic mechanism by which protein is taken up is easily saturated, so a large increase in filtered protein resulting from increased glomerular permeability causes the excretion of large quantities of protein.

Discussions of the renal handling of protein logically tend to focus on albumin because it is, by far, the most abundant plasma protein. There are, of course, many other plasma proteins. Although present in lower levels than albumin, they are smaller and thus more easily filtered. For eample, growth hormone (molecular weight, 22,000 Da) is approximately 60% filterable, and the smaller insulin is 100% filterable. The total mass of these filtered hormones is insignificant; however, because even tiny levels in the plasma have importnat signaling functions in the body, renal filtration becomes an important influence on concentrations in the blood. Relatively large fractions of these smaller plasma proteins are filtered and then degraded in tubular cells. The kidneys are major sites of catabolism of many plasma proteins including peptide hormones. Decreased rates of degradaton occuring in renal disease may result in elevated plasma hormone concentrations.

Very small peptides are catabolized into amino acids or di- and tri-peptides within the proximal tubular lumen by peptidases located on the apical surface of the plasma membrane. These products are then reabsorbed by the same transporters that normally reabsorb filtered amino acids.

Finally, in certain types of renal damage, proteins released from damaged tubular cells may appear in the urine and provide important diagnostic information.

Proximal Secretion of Organic Cations

There are many organic cations that does excrete, both endogenously produced waste products and foreign chemicals. Many of these organic cations are filterable at the renal corpuscles, with proximal secretion adding to the amount filtered. Others are extensively bound to plasma proteins and undergo glomerular filtration only to a limited extent; accordingly, proximal tubular secretion constitutes the only significant mechanism for their excretion.

The proximal tubules possess several closely related transport systems for organic cations. Because there are a number of different transporters that are relatively nonselective as to which solute species they accept, a substantial number of foreign and endogenous organic cation species are transported. Although the transporters manifest Tm limitation, in many cases over 90% of a given cation species entering the renal circulation is removed, indicating that the transport capacity is high. The process begins with the Na-K-ATPase, which establishes a potassium concentration gradient and resulting negative membrane potential. Organic cations enter across the basolateral membrane via one of several uniporters, members of the OCT family (Organic Cation Transporter) driven energetically by the negative membrane potential. This raises the cytosolic concentration of the cation well above that in the interstitium. The cations then exit into the lumen via an antiporter that exchanges a proton for the organic cation. Because this antiporter exchanges 2 univalent cations, it is electroneutral and unaffected by the membrane potential.

Proximal Secretion of Organic Anions

The active secretory pathway for many organic anions in the proximal tubule uses the recycling of alpha-ketoglutarate (alphaKG) as a tool. First, alphaKG, which is a divalent anion, is actively taken up from both the lumen and interstitium by a sodium-alphaGK symporter (stoichiometry of 3 sodium per alphaKG), which raises the cellular levels of alphaKG. Then alphaKG effluxes across the basolateral membrane via an antiporter that imports an organic anion that is destined to be secreted. This antiporter is a member of the QAT family (Organic Anion Transporter) of basolaeral membrane proteins. The alphaKG keeps recycling, entering with sodium and effluxing back to the interstitium in exchange for the other organic solute. Finally, the second organic solute is secreted across the apical membrane via one of several pathways, including the multidrug resistance protein MDR-2, which is an ATPase that drives the efflux of many different organic anions.

Screen Shot 2015-11-05 at 10.25.46 PMAnalogous to the transporters for cations, the basolateral membrane of proximal convoluted tubule epithelial cells contains several QAT species, each one accepting multiple solutes to be transported. The proximal tubule thus has the capacity to secrete many organic anions. These organic anions are not sinificantly permeable through tight junctions or lipid membranes, and their transport is characterized by Tm. If the plasma concentration of an organic anion is too high, it will not be efficiently removed from the blood by the kidneys.

Metabolic transformations in the liver are very important, where many foreign (and endogenous) substances are conjugated with either glucuronate or sulfate. The addition of these groups renders the parent molecule far more water-soluble. These conjugates are actively transported by the organic anion secretory pathway.


An increase in the plasma concentration of urate can cause gout and is thought to be involved in some forms of heart disease and renal disease; therefore, its removal from the blood is important. However, instead of excreting all the urate it can, the kidneys actually reabsorb most of the filtered urate. Urate is freely filterable. Almost all the filtered urate is reabsrobed early in the proximal tubule, primarily via antiporters (URAT1) that exchange urate for another organic anion. Further on in the proximal tubule urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. Because the total rate of reabsorption is normally much breater than the rate of secretion, only a small fraction of the filtered load is excreted.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimualted, thereby increasing urate excretion.

Given these mechanisms of renal urate handling, you should be able to deduce the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: 1.decreased filtraton of urate secondary to decreased GFR, 2.excessive reabsorption of urate, and 3.diminished secretion of urate.

pH Dependence of Passive Reabsorption or Secretion

Many of the organic solutes handled by the kidney are weak acids or bases and exist in both, neutral and ionized forms. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. Neutral solutes are more permeable than ionized solutes. As water is reabsorbed from the tubule, any substance remaining in the tubule becomes progressively more concentrated. Because the luminal pH may change substantially during flow through the tubules, both the progressive concentration of organic solutes and change in pH strongly influence the degree to which they are reabsorbed by passive diffusion through regions of tubule beyond the proximal tubule.

At low pH weak acids are predominantly neutral (acid form), while at high pH they dissociate into an anion and a proton. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, acidification converts much of the acid to the neutral form and therefore, increases kts pe2meability. This favors diffusion out of the lumen (reabsorption). High acidic urine (low pH) tends to increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just the opposite. At low pH they are protonated cations (trapped in the lumen). As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted.

Some organic solutes, although more membrane permeable in the neutral form, are less soluble in aqueous solution and tend to precipitate. This specifically applies to urate. The combination of excess plasma urate and low urinary pH, which converts urate to the neutral uric acid, often leads to the formation of uric acid kidney stones.