How is blood from the lower extremities returned to the heart?

Venous return refers to the flow of blood from the periphery back to the right atrium, and except for periods of a few seconds, it is equal to cardiac output. Because clinicians and investigators have long observed that factors affecting primarily the venous side of the circulation can have profound influence on cardiac output, mechanisms governing the flow of blood to the heart have been studied in some depth. However, full understanding of the venous side has been challenging because of the complex nature of some of its characteristics.

Guyton recognized the importance of determining the role of both mean systemic pressure and right atrial pressure in controlling venous return, and measuring both accurately proved to be very difficult. Mean systemic pressure can only be measured when pressures throughout the systemic circulation have come to equilibrium after the heart has stopped beating. He and his coworkers developed techniques to temporarily stop the heart by electrical fibrillation or other means while blood was mechanically pumped rapidly through an arterial to venous shunt in order to bring the arterial and venous pressures to equilibrium in less than 7 s [4]. They found that the technique could be repeated many times without affecting the value of mean systemic pressure. Analysis of the effects of changes in the right atrial pressure on venous return required a means to vary the right atrial pressure in a controlled manner. Because right atrial pressure is a function of output from the right atrium into the right ventricle and flow of blood into the atrium from the vena cava, they had to develop a preparation in which outflow could be augmented by mechanically pumping from the atrium through an extracorporal shunt into the pulmonary artery or through a heart lung bypass machine to the aorta. By varying the rate of flow around the atrium, they were able to reduce right atrial pressure in a controlled manner while measuring cardiac output in the systemic circulation, from which they knew the value of venous return. They could also augment flow into the atrium from a reservoir, thereby increasing right atrial pressure. Some of the experiments were conducted with closed chest animals that were breathing again negative pressure as low as –10 mm Hg, lowering the intrathoracic and right atrial pressures to the lowest physiological levels. These extensive series of experiments laid the groundwork for an in-depth understanding of the basic factors controlling venous return.

2.1. Determinants of Venous Return

Everywhere in the body, pressure gradients and resistances determine blood flow rate. When considering venous return, the pressure gradient is mean systemic pressure minus the right atrial pressure, and resistance is the total peripheral vascular resistance. It is probable that some of the difficulties associated with conceptualizing and measuring mean systemic pressure have contributed to the challenges in understanding venous return.

Mean systemic pressure is affected by blood volume and vascular tone. When blood volume is normal, mean systemic pressure is approximately 7 mm Hg [3, 4]. If mean systemic pressure is measured after blood volume has been changed rapidly in steps above and below normal while sympathetic nervous system activity has been blocked, a volume–pressure relationship is obtained. An example of such a curve is illustrated by the solid line in Figure 2.1. Several of its characteristics are significant: first, the relationship is approximately linear within physiological limits, and second, it is highly sensitive to changes in volume, with a 15% reduction in blood volume (approximately 1 L in man) decreasing mean systemic pressure from 7 to 0 mm Hg. The blood volume at which mean systemic pressure is 0 mm Hg is termed the unstressed vascular volume of the system. Reducing blood volume below the unstressed vascular volume does not result in further reduction in mean systemic pressure.

FIGURE 2.1

Relationship between percentage changes in blood volume and mean systemic pressure measured with reflex responses blocked. Unstressed vascular volume is the blood volume at which mean systemic pressure is 0, approximately 85% of normal blood volume. Data (more...)

The sympathetic nervous system and locally acting and circulating vasoactive hormones affect vascular smooth muscle tone. Increasing vascular tone shifts the volume–pressure curve to the left without significantly affecting the slope. When vascular tone increases, unstressed volume decreases and mean systemic pressure increases for each level of blood volume. Conversely, totally blocking the sympathetic nervous system or otherwise reducing vasomotor tone has been shown to shift the curve to the right in a parallel manner.

The vessels on the arterial side have much less capacity and are much less distensible than the veins, and consequently, the characteristics of their volume–pressure relationship differ markedly from those of the venous side; the unstressed arterial vascular volume is approximately 0.4 versus 4.0 L for the venous side, and the arterial slope is 33 versus 7 mm Hg/L. In addition, the arterial vessel wall is more responsive to sympathetic nervous system innervation and vasoactive hormones.

Several sites in the vascular system have large reservoir capacities. Portions of the vascular system have a large capacitance, that is, they can gain or lose large volumes of blood with little change in pressure. Therefore, as pressure within other portions of the venous system increases or decreases, large volumes of blood can move into or out of these reservoirs, buffering changes in pressure throughout the vascular system. Smooth muscle of the vascular walls of some of the vessels in these sites can contract in response to sympathetic stimulation and circulating vasoconstrictor substances, significantly decreasing their capacitance and causing additional blood to be translocated to other portions of the circulation. Large veins in the abdomen and thorax are especially effective reservoirs, as are the sinuses of the spleen and liver. The vascular plexuses of the skin can also function as reservoirs. Blood flow into the skin is highly responsive to catecholamines released from the sympathetic nerves innervating the resistance vessels of the skin, the constriction of which decreases blood volume stored in the veins of the skin. All of these reservoir functions can significantly affect mean systemic pressure, as their effective capacitance is altered, and blood is transferred to or from other portions of the vascular system.

The vasopressor hormone angiotensin II is implicated as a causative factor in many forms of hypertension. The renal sodium-retaining effects of angiotensin II are the primary mechanisms contributing to sustained blood pressure elevation, although the peptide has other significant vascular actions. Its effects on mean systemic pressure were analyzed in a series of studies in dogs in which angiotensin II was infused intravenously for 7 days, raising mean arterial blood pressure from the normal level of 100 to 160 mm Hg [5]. Blood volume remained unchanged, while mean systemic pressure rose from 9.5 to 12.6 mm Hg. The effect of the hormone was to increase the vascular tone, causing an increase in filling pressure at a constant blood volume. The increase in mean systemic pressure may have been caused by a decrease in the unstressed vascular volume and /or a decrease in capacitance of the system.

Right atrial pressure is normally approximately 0 mm Hg or atmospheric pressure. At a normal level of right atrial pressure, venous return will be normal as long as mean systemic pressure and resistance are normal. Guyton found that increasing right atrial pressure by 1 mm Hg decreased venous return by 14% in animals whose sympathetic nervous systems had been blocked [6]. Each additional 1 mm Hg increase resulted in a similar decrease in venous return, until atrial pressure reached 7 mm Hg, the mean systemic pressure, at which point flow into the heart ceased. The results of their study are plotted in Figure 2.2.

FIGURE 2.2

Relationship between right atrial pressure between 0 and 7 mm Hg and venous return. As atrial pressure is raised from the normal value of 0 to 7 mm Hg, venous return falls from the normal level to 0. The slope of the relationship is the inverse of the (more...)

When right atrial pressure is reduced below the normal value of 0 mm Hg, a different venous return response pattern is observed. For the first 1 mm Hg reduction in right atrial pressure, venous return increases by 10%. But with subsequent 1 mm Hg increments in pressure reduction, the rate of rise in venous return falls progressively less until it reaches a steady level at pressures below –4 mm Hg. Further right atrial pressure reductions below –4 mm Hg will not increase venous return further. The negative right atrial pressure and venous return data are presented in Figure 2.3. The relationship becomes curved as pressure falls to approximately –2 to –3 mm Hg as the slope decreases progressively with additional reductions in atrial pressure. At approximately –4 mm Hg, the slope becomes 0, and further reductions do not cause additional increases in venous return. Below –4 mm Hg, venous return maintains a plateau at a flow rate of 20–30% above the normal value associated with right atrial pressure of 0 mm Hg.

FIGURE 2.3

Relationship between right atrial pressure between 0 and –8 mm Hg and venous return. The relationship is curvilinear between –2 and –4 mm Hg due to progressively increasing resistance to venous return resulting from collapse of (more...)

The explanation for the nonlinear nature of the relationship in the negative pressure range of the right atrial pressure and the plateau below –4 mm Hg is the progressive collapse of veins as the luminal pressure falls below extramural pressure. Within the chest, the pressure averages approximately –4 mm Hg but cycles between values more negative during inspiration to slightly positive during expiration. As right atrial pressure, which is equal to venous pressure anywhere within the thorax, falls below atmospheric pressure, some veins just outside their point of entry into the thorax may collapse during inspiration, as their intraluminal pressure falls below atmospheric pressure. As central venous pressure falls lower, more veins may collapse for longer portions of the respiratory cycle, while below –4 mm Hg, essentially, all veins in the chest remain collapsed until the buildup of upstream blood increases their intraluminal pressure to –4 mm Hg or greater. The collapse of the veins increases resistance to venous return, which is the inverse of the slope of the relationship between flow and right atrial pressure. Ultimately, resistance becomes infinite below –4 mm Hg, preventing any increase in flow above that present at –4 mm Hg. The resistance increases progressively as right atrial pressure falls from approximately –2 to –4 mm Hg, causing the plotted relationship between pressure and flow to be curvilinear in this range.

The pulsations of the right atrium cause a retrograde pressure wave that may progress through the central veins to varying distances. These pulses contribute to the fluctuations in venous closure that occur in the negative right atrial pressure range that are reflected in the curve or splay of the pressure–flow relationship.

Changes in arterial as well as venous resistances affect venous return. In Chapter 1, the progressive blood pressure reductions throughout the vascular system were presented in Table 1.1. The greatest segmental pressure reduction occurs at the arterioles, indicating that arterioles contribute the largest portion of total systemic vascular resistance. Furthermore, the resistance of the arterioles is highly dynamic, capable of increasing or decreasing several folds in a few seconds. The smooth muscle in the arteriole walls responds rapidly to changes in concentrations of circulating vasoactive hormones, local metabolically linked mediators, and input from fibers of the sympathetic nervous system. Angiotensin II and catecholamines in the blood and locally produced endothelin are powerful arteriolar smooth muscle agonists, significantly affecting resistance to venous return.

In the experiment referred to above, in which angiotensin II was infused into dogs for 7 days, venous return remained unchanged while mean systemic pressure increased from 9.5 to 12.6 mm Hg. During this period, right atrial pressure increased slightly from 1.6 to 3.4 mm Hg. Calculating resistance to venous return during the control period from the pressure gradient for venous return (mean systemic pressure–right atrial pressure) and the rate of venous return (cardiac output) yields a value of 2.2 L/min/mm Hg (Figure 2.4). After 7 days of angiotensin infusion, resistance to venous return increased to 3.3 L/min/mm Hg, a 50% increase resulting from the constriction of arterioles and possibly of portions of the venous system as well.

FIGURE 2.4

Cardiovascular effects of angiotensin II. In a study on dogs, after a 7-day control period, angiotensin II was infused intravenously for an additional 7 days. Values of mean systemic pressure (MSP), right atrial pressure (RAP), pressure gradient for venous (more...)

Locally produced and circulating nitric oxide, prostacyclin, and prostaglandin E2 are vascular smooth muscle antagonists, producing arteriolar dilation and reduction of resistance to venous return. Local tissue metabolism, in particular, aerobic metabolism, strongly affects arteriolar resistance. Activity that reduces tissue pO2 especially elicits significant arteriolar dilation and reduction in resistance to venous return.

The linkage between total body tissue oxygen demand and resistance to venous return is a fundamental mechanism governing control of cardiac output. This is the basic mechanism by which the cardiovascular system responds to changes in demand for cardiac output as metabolic rate changes. Other means of cardiovascular control may take part in responses to metabolic changes, but this connection of tissue oxygen demand to resistance to venous return is of overriding significance. Oxygen demand is a strong determinant of resistance to venous return over periods ranging from seconds to hours and in long-term and steady-state conditions. If demand is elevated for extended periods of days or weeks, new microvascular vessels grow through the tissue in need, decreasing local vascular resistance and increasing blood flow. Conversely, if blood flow exceeds demand for periods of several days or more, microvascular vessels will degenerate, reducing vascular density and increasing resistance. This process is termed rarifaction and normally normally takes place in tissues whose use and metabolic activity are reduced. Rarifaction also may occur if arterial blood pressure increases. For example, in the angiotensin II infusion experiment, the infusion resulted in a steady-state increase in arterial blood pressure of 60 mm Hg by affecting renal function, and the peptide had an immediate direct constrictor effect on the arterioles throughout the body. But during the 7-day course of the study, the sustained increase in arterial pressure may have induced microvascular rarifaction throughout the body. The immediate and delayed increases in tissue resistance throughout the body may both have contributed to the increase in observed resistance to venous return during the infusion period.

Venous resistance makes up about 15% of total vascular resistance and is not regulated as actively as arterial resistance. The relatively large diameter of central veins presents little resistance to flowing blood, although they are easily compressed and flattened by surrounding tissue. When they are compressed, they create significant resistance. For example, many veins entering the thorax over the first ribs are partially compressed by the sharp angle of the path over the bone. In the abdomen, the weight of the viscera may flatten the great veins, and in the neck, atmospheric pressure prevents the jugular veins from assuming a rounded shape when a person is upright. Within the thorax, the veins may collapse if central venous pressure falls much lower than the atmospheric pressure. Even considering these impediments to blood flow, venous resistance is a relatively minor component of resistance to venous return. Arterial resistance, especially that portion resulting from the arterioles, makes up the greatest portion of total vascular resistance. It is this portion that is most actively regulated in response to changes in demand of the circulatory system.

2.2. The Venous Return Curve

If right atrial pressure were changed in steps over the entire range of possible atrial pressures and venous return were measured at each point, plotting the data set would yield a complete venous return curve, which is presented in Figure 2.5. As mentioned earlier, such measurements would have to be made during total blockade of the autonomic nervous system so that circulatory reflexes would be normal. Notice that, at the normal right atrial pressure value (0 mm Hg), venous return is 100%, which is 5 L/min in man. Venous return falls progressively as right atrial pressure increases, until right atrial pressure reaches 7 mm Hg, the normal value for mean systemic pressure. At that point, venous return is 0 because the pressure gradient for venous return is 0. As right atrial pressure falls below 0, the venous return curve increases at a progressively declining rate until flow reaches a plateau at approximately –4 mm Hg. As discussed above, the reason for the curvilinear nature in this portion of the relationship, termed the transition zone, is the progressive increase in vascular resistance due to the collapse of increasing numbers of veins as right atrial pressure becomes more negative.

FIGURE 2.5

The complete venous return curve over the range of right atrial pressure from –8 to 8 mm Hg. Venous return values are for humans.

Such a function curve can reveal important characteristics of the circulation. First, the value of cardiac output or venous return at a given level of right atrial pressure can be read directly from the curve. Similarly, the value of mean systemic pressure is easily determined from the value of the x-axis intercept. For a given level of right atrial pressure, the pressure gradient for venous return can be calculated from the difference between the mean systemic pressure and the value of right atrial pressure. The resistance to venous return can also be calculated from the pressure gradient for venous return and rate of venous return at any level of right atrial pressure. Finally, the lower limit of right atrial pressure that will affect venous return, the plateau pressure, can be determined from inspection of the graph. These circulatory characteristics are key elements in understanding the regulation of cardiac output.

2.3. Alterations of the Venous Return Curve

The characteristics of the venous return curve can be altered dramatically within seconds by rapidly acting physiological mechanisms and for indefinitely extended periods by long-acting responses of the circulatory control system. The curve can also be affected by many pathological circumstances. However, all factors modifying the curve act by altering one or more of its basic characteristic: mean systemic pressure, plateau, slope, and right atrial pressure.

Changes in mean systemic pressure resulting from alteration of either blood volume or vascular tone cause parallel shifts in the venous return curve. Guyton and associates extensively analyzed the relationship between blood volume and mean systemic pressure in anesthetized, open-chest canine preparations in which the sympathetic nervous system activity was blocked by total spinal anesthesia, but a constant level of sympathetic tone was maintained by continuous intravenous infusion of very small amounts of epinephrine [7, 8]. Their results from one animal are presented in Figure 2.6. By removing or adding blood, mean systemic pressure was changed over the range 4.7–10.6 mm Hg, and other data points describing the venous return curves were obtained.

FIGURE 2.6

Effect on the venous return curve of changes in mean systemic pressure resulting from alterations in blood volume from one dog. The anesthetized animal had all autonomic reflexes blocked. Changes in mean systemic pressure resulted in parallel shifts in (more...)

The increase in blood volume raised mean systemic pressure and shifted the venous return curve to the right in a parallel manner. Notice that, at each level of right atrial pressure, the rate of venous return was greater at higher levels of mean systemic pressure, due to the greater pressure gradient for venous return. In addition, previously in this presentation, the venous pressure plateau was stated to begin at approximately –4 mm Hg; in this figure, it is at 0 mm Hg because it was an open-chest preparation.

When blood volume is increased very rapidly even in areflexic preparations, the immediate change in mean systemic pressure begins to wane almost immediately. The effect is the result of stress relaxation of the walls of the large capacitance vessels, although fluid transudation out of the vascular space into the interstitium undoubtedly contributes gradually to the phenomenon as well. In one study, Guyton and associates rapidly infused 35% of the blood volume of a dog and then followed mean systemic pressure over the following minutes [9]. Mean systemic pressure reached its maximum (24 mm Hg) at the conclusion of the 1-minute infusion and then began immediately to decline asymptotically toward a steady-state value somewhat above the initial level with an estimated half-time of 2–4 min. Their estimate of the time course of change in mean systemic pressure following a large infusion is presented in Figure 2.7.

FIGURE 2.7

Effect of vascular stress relaxation on the value of mean systemic pressure following a large infusion of blood into an anesthetized areflexic dog. The half-time of the response appears to be between 2 and 4 min. From reference [9].

They reported similar findings in the opposite direction following step decreases in blood volume, although possibly with longer response times. In either case, the effect of volume change on cardiac output is consistent with the changes in pressure gradient for venous return resulting from the change induced in mean systemic pressure.

Changes in vasomotor tone affect mean systemic pressure by altering vascular capacitance and unstressed vascular volume. Guyton’s laboratory analyzed the quantitative effects of vasomotor tone on mean systemic pressure and venous return in anesthetized animals prepared with total spinal anesthesia and, therefore, with all autonomic vasomotor reflexes abrogated. To simulate increasing levels of vasomotor activity, epinephrine was infused intravenously at a rate of up to 3.5 μg/kg/min [4]. With all reflexes blocked and no epinephrine infusion, mean systemic pressure fell from 7 to 5 mm Hg and arterial pressure to 41 mm Hg. Increasing epinephrine infusion to a maximal level [3.5 μg/kg/min) raised mean systemic pressure to 19 mm Hg and blood pressure to 184 mm Hg. They obtained data for four venous return curves across this range of epinephrine infusion, which are illustrated in Figure 2.8.

FIGURE 2.8

Shifts in venous return curves caused by varying epinephrine infusion rate in areflexic dogs. The rates of infusion were designed to mimic the effects of the complete range of autonomic nervous system activity on the vascular system. From reference [4]. (more...)

The effect of increasing autonomic reflex replacement was to elevate mean systemic pressure and shift the venous return curve upward and to the right in an approximately parallel manner, similar to that described for volume increases. The range of simulated vasomotor activity in theses studies appears to span the range of naturally occurring activity, as judged by comparisons with mean systemic pressure and arterial blood pressure during several manipulations known to be associated with stimulation of vasomotor reflexes [4, 10, 11]: eliciting the maximal carotid sinus reflex increases mean systemic pressure to about 10 mm Hg; the Cushing reflex, which is believed to elicit the most intense naturally occurring sympathetic nervous system reflexes, raises mean systemic pressure to 17 mm Hg; and infusion of a maximal dose of norepinephrine increases mean systemic pressure to 15 mm Hg.

Changes in conditions outside the vascular system can affect mean systemic pressure and venous return. In particular, factors that compress portions of the vascular system, thereby decreasing capacitance, will increase mean systemic pressure.

Abdominal compression can occur during nearly any whole body physical exercise, such as walking or running, athletic events of all types, weight bearing exercises, and movements that require balance. The “core” muscles are activated in all movements involving simultaneous movement of several body parts, and the abdominal muscles make up a large portion of the core muscles. Contraction of the musculature surrounding the abdominal contents increases pressure throughout the abdomen, including the pressure around the large veins, the liver, spleen, and other structures having large capacitance. Consequently, blood is transferred from these structures into the rest of the circulation, raising mean systemic pressure. Compression of the abdomen with the hands can double mean systemic pressure in anesthetized dogs [10], and the effect of forceful contraction of all the muscles that make up the walls of the abdominal cavity may raise the pressure even higher. The effects of increasing abdominal pressure on mean systemic pressure are nearly immediate, occurring in within 1 s.

Positive pressure breathing increases pressure throughout the thorax, decreasing the blood volume contained in the vascular structures within it. The volume of the heart and pulmonary veins as well as the blood vessels of the lungs all decrease during positive pressure breathing. In addition, the muscular work required to breath against positive pressure requires forceful involvement of the abdominal muscles. Together, these effects can at least double the mean systemic pressure [10].

Contraction of any muscle increases the pressure within the sheath of connective tissue surrounding it. This forces blood from the muscle into the rest of the circulation. When many large muscles contract at the same time, as during standing from a sitting position, running, weight- bearing exercise, or any action requiring coordinated movement of several body parts, the movement of blood volume out of the muscles can significantly raise mean systemic pressure. Electrical stimulation of muscles of the hind legs and abdomen can increase mean systemic pressure to as high as 30 mm Hg within 1 s of the start of contraction [12].

Peripheral edema can increase interstitial fluid pressure to as high as 10 mm Hg, which compresses peripheral veins and elevates mean systemic pressure [4]. Similarly, ascites fluid accumulation in the abdominal cavity can increase pressure on the capacitance structures within the abdomen.

Increasing resistance to venous return decreases the slope of the venous return curve. Although an increase in resistance alone will not alter the mean systemic pressure, venous return will be reduced at each level of right atrial pressure, and the plateau value will be decreased. Reducing resistance to venous return will have the opposite effects on the curve. Examples of venous return curves at normal resistance (100%), at 50%, and 200% are illustrated in Figure 2.9.

FIGURE 2.9

Effect on the venous return curve of altering resistance to venous return.

Resistance to venous return can be manipulated experimentally by opening and closing a large shunt connecting the arterial and venous systems. The venous return curves for a group of dogs prepared with such a shunt are presented in Figure 2.10 [13].

FIGURE 2.10

Shift in the venous return curve associated with opening a large arterial to venous shunt. From reference [13].

The mean systemic pressure was approximately the same in both conditions, although when the shunt was opened and resistance to venous return was sharply reduced, the slope was much greater. Venous return also increased at each level of right atrial pressure, and the plateau was elevated.

The quantitative effects on venous return of changes in venous resistance are much greater than proportionally similar changes in arterial resistance. Ohm’s law can be useful in understanding flow of fluid through rigid tubes, but because the circulatory system is made up of compliant vessels, modification of the law can be made in order to make it more useful in analysis of flow through the cardiovascular system. Instead of using one simple term for systemic resistance, arterial and venous resistances can be weighted separately according to the capacitances of the two segments of the vascular system. The importance of venous resistance is even more striking when viewed in light of the experimental data, indicating that the ratio of venous to arterial capacitance may be as large as 18:1 [3]. The derivation of the modified equation is presented in Chapter 4.

2.4. Summary

Venous return and, consequently, cardiac output are functions of the pressure gradient for venous return and the sum of the resistances of the arterial and venous segments. The pressure gradient is affected by factors that increase or decrease mean systemic pressure and/or right atrial pressure. Resistance to venous return is affected by factors that cause changes in smooth muscle tone of resistance vessels or changes in pressure in the tissue surrounding thin-walled venous structures.

The implications of these statements are broad and significant and include the following:

Cardiac output is very sensitive to the pressure gradient for venous return. An increase in mean systemic pressure of only a few mm Hg, such as those occurring in muscular activity or with an increase in blood volume, will result in immediate increases in cardiac output. Conversely, even small increases in right atrial pressure of a few mm Hg, such as those occurring in acute heart failure following myocardial infarction, will result in significant reductions in cardiac output. Furthermore, the most that right atrial pressure can possibly increase is to a level approaching mean systemic pressure.

Cardiac output is affected by systemic vascular resistance, which is the sum of capacitance- weighted arterial and venous resistances, with an increase in total systemic resistance resulting in a reduction in cardiac output. Changes in venous resistance will have a much greater effect on total systemic resistance than equivalent percentage changes in arterial resistance.

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How does blood return from our feet back to our heart is it high or low pressure?

What structure is blood from the lower extremities returned to and what chamber of the heart does it go into?