of Cardiac Output

Professor of Anesthesiology, Albany Medical College, Albany, NY, USA



Circulation modelsLeft ventricular modelGuyton’s venous return modelCardiac outputWeber’s circulation modelPeripheral resistanceElastic recoilMean circulatory pressureOhm’s lawHeart failure therapyAortic balloon pump

Models are used to simplify a group of observable events into readily understandable concepts. Over the years, numerous models of circulation have been developed in an effort to elucidate fundamental hemodynamic principles. They attest to ingenuity on the part of investigators but also point to the complexity of the subject at hand. Because the heart is the organ which is thought to provide the total hydraulic energy to the blood, the idea of the heart as a pressure-generating pump is implicit in most commonly used models. Just how much of a role the heart plays in blood propulsion and the relative contribution of the peripheral circulation in the regulation of cardiac output continue, however, to be the subjects of the ongoing debate [15]. Because of the multitude of factors which contribute to the regulation of cardiac output, the subject will be approached from the two commonly used perspectives: that of the heart and of the peripheral circulation [6].

14.1 Left Ventricular View of the Circulation

An account of the historical development of ideas, which culminated in the understanding of the heart to be the primary source of blood propulsion, is beyond the scope of this monograph, and for a comprehensive review, the reader is referred to the work by Fuchs [7]. In his seminal work “On the Movement of the Heart and Blood” (1628), William Harvey (1578–1657), the discoverer of the circulation, sought the primary causes for the movement of the blood in the early embryonic circulation. The blood, he maintained, is “the principal portion of the body, prior to its receptacles,” while the heart and vessels are “constructed for the sole purpose of its distribution” [8]. Contrary to the popular opinion, Harvey did not liken the action of the heart to a pump [9, 10], but considered “vital heat” the cause of its inherent (perpetual) motion and “the prime cause” of the pulse of the heart and of the arteries. In a letter addressed to Jean Riolan, the celebrated Parisian anatomist and adherent of Galen, Harvey suggests:

I do not believe that the heart is the fashioner of the blood, neither do I imagine that the blood has powers, properties, motion, or heat as the gift of the heart…for I hold that the part of the pulse which is designated the diastole depends on another cause, different from the systole, and must always and everywhere precede any systole. I hold that the innate heat is the first cause of dilatation and that the primary dilatation is in the blood itself…. [11]

It appears that, for Harvey, the cause of motion is different, for blood entering or leaving the heart. The atria distend (i.e., atrial diastole), under the impetus of the blood’s “innate heat,” whereas the ventricles are “impellers” of the blood that is already in motion … “much like a ball player can strike the ball more forcibly and further if he takes on the rebound” [12].

Harvey, an avid Aristotelian, evidently sought a wider explanation for his newly discovered circulatory phenomena in the Aristotelian concept of circular motion as the archetype of all movement [13].1 According to Pagel, application of analogies between macrocosm and microcosm already had a long tradition as is evident from a statement by Harvey’s contemporary Giordano Bruno in 1590 that “in us blood continually and rapidly moves in a circle” [15]. A similar idea is expressed by Harvey in the following passage: “Which motion (of the blood) we may be allowed to call circular, in the same way as Aristotle says the air and the rain emulate the circular motion of the superior bodies (planets),” or from the statement, “The heart, consequently, is the beginning of life; the sun of the microcosm, even as the sun in his turn might well be designated the heart of the world” [16].

Harvey’s discovery of circulation was based upon two key phenomena, namely that venous blood flows in the direction of the heart (as confirmed by direct observation of blood flow in animals and from the structure and directionality of venous valves) and the fact that far greater volume of blood flows through the heart than can be supplied from absorption of nutrients.2 In support of the latter, Harvey resorted to a thought experiment. He made an estimate of cardiac throughput (by multiplying an estimated ventricular volume by the number of beats per unit time) and had an intuitive insight that the blood must move in circles. Notwithstanding the fact that Harvey’s arguments went against the grain of long-established theories (see Sect. 15.​3), the sheer number of observed phenomena, meticulously documented and supported by a quantitative estimate, were innately consistent and in due course confirmed the proposed theory.

It is ironic that Rene Descartes (1596–1650), Harvey’s contemporary, was one of the first natural philosophers to embrace Harvey’s revolutionary circulation theory and widely promoted it, although in altered form, through his writings [17]. Unlike Harvey, known for his meticulous observations and inductive method of investigation, by which sense perceptible phenomena are analyzed in light of primal (Aristotelian) principles, Descartes employs a method of a priori (deductive) reasoning, where scientific truths are derived from what is known “clearly and distinctly” to the intellect.3 Descartes’ physiological and cosmological doctrines are first presented as “hypotheses” which serve as “models” of the universe and of the organism in the modern sense. The blood, for Descartes, is no longer a “vital fluid” but only a mixture of materials and a collection of special food particles which serve as fuel for the fire maintained by the heart. The concept of “vital heat” is reduced to a continuous process of combustion—a mere physical-chemical event. Mechanical analogies, if any, implied by Harvey for the explanation of circulatory phenomena become explicit and central in Descartes’ writings [19]. The ultimate aim of Descartes’ natural philosophy was to identify material causes and define mechanical laws that are applicable with equal measure to an organism as well as to a mechanism. In this sense, “The mechanical no longer represents an element within vital organization; through the paradigm of the automaton, it embraces the organism itself” (emphasis by T. Fuchs) [19].

Thus, according to Descartes’ philosophical view, the body as a physical object has much in common with other objects in nature and as such, the heart functions entirely according to mechanical principles which are fundamentally identical in humans and animals. The certainty, that this is indeed the case, obtained Descartes from his younger contemporary, Blaise Pascal (1623–1662),4 who had proven that physical characteristics of liquids can be determined in terms of pressure. After all, the blood, being liquid and subject to pressure, would make the mechanical concept of the heart into a workable hypothesis. Pascal, well acquainted with Descartes’ views and method of science, was deeply troubled by Descartes’ fundamental notion that bodily organs are mere parts of a sophisticated machine. He believed that Descartes’ model trivialized the nature of human feelings which, arising from the body, would be reduced to the value of arbitrary thoughts.5 Pascal’s foreboding of the Cartesian dogma and its effect it may have for the future of medicine and psychology has been aptly summarized by J. Lynch:

Thus, the heart (and, by extension, the entire body) could no longer be the source of any emotion that could be considered uniquely human, since the bodily mechanics of emotions were obviously quite similar in humans and in animals. [20]

By all accounts, Harvey, too, “despised” the mechanistic philosophy that had facilitated the success of his circulation theory and confronted Descartian and Baconian philosophers head-on by writing his most comprehensive work well over two decades after “De Motu Cordis” (1628). “On Generation of Living Creatures” (1651) contains a summary of Harvey’s life-long research efforts, “a sort of apotheosis on the blood” [21]. In spite of his enormous efforts, Harvey and his adherents were not a match to the advent of the new mechanical-intellectual tide that swept across Europe after the 1640s, which rejected vitalist and Aristotelian principles and sought to interpret the living phenomena through mechanical associations that necessarily follow from the laws of nature.6

Giovanni Borelli (1608–1679), recognized as the father of modern biomechanics, emphasized hydraulic properties of the circulation and proposed that the heart acts like a piston ejecting blood into flexible tubes, the arteries. In a treatise “On the Movement of Animals” (1680), Borelli compared the work of the heart to the skeletal muscle and calculated that the motive force exerted by the heart is equal to supporting an excess of 3000 lb [22]. Others applied an array of mechanical contraptions to explain the circulation, for example, Johannes Bohn (1697) who stated: “What a hydraulic pump or piston achieves, the heart brings about in the living machine and the circulatory movement of all liquids. Just like the former does with water, so the latter gives the blood its first impulse by driving it forward. When the heart and pump stop, the fluids of both also stand still” (cited in [23]).

The first quantitative estimations of arterial pressure were performed by Stephen Hales (1677–1761) by means of inserting glass tubes into the arteries of several species of animals. In a series of papers published in 1733 by the Royal Society as Statical Essays: containing Haemastatics, Hales described the measurement of pressure on the carotid artery of a mare, estimated ventricular volume from wax casts of hearts, and deduced aortic flow velocity in a dog [24]. Needless to say, such interventions almost invariably ended with demise of the experimental animal, and no other method was available for the estimation of arterial pressure for clinicians except by surgical exposure of the artery. Hale’s ability to conceive the blood as a “pressurized liquid” that could be defined in terms of hydraulics is dependent to a large extent on the prior work of Pascal.

Almost a century later (1828), J. Poiseuille (1797–1869) applied the use of mercury manometer for the measurement of the arterial pressure by connecting a manometer tubing to an arterial cannula filled with an anticoagulant. The insight by Karl Vierordt (1855) that arterial pressure can be measured indirectly by registering the amount of force needed to occlude the artery was a breakthrough. Vierordt’s sphygmomanometer was an ingenious device working on the principle of a scale, with cups and levers attached to a kymograph. The pressure in the radial artery was determined by the amount of weights needed for its occlusion. Several improvements on the method followed which eventually led to S. Riva-Rocci’s invention of a pneumatic cuff applied round the girth of the arm (1896) [25]. Ease of application, accuracy, and harmlessness to the patient ensured widespread popularity and use of the technique. The unintended consequence of the invention was that clinicians increasingly lost appreciation for the nuances of the arterial pulse, which in addition to pressure yielded a number of other qualities about the state of the cardiovascular system (cf. Sect. 22.​1) While hailed by some, an editorial in the British Medical Journal at the time held the view that the use of sphygnomanometer “pauperizes our senses and weakens clinical acuity” [25].

By the middle of the nineteenth century, more sophisticated, though still entirely mechanistic ideas about the circulation abounded. In his treatise on hemodynamics, Volkmann (1855) made the following remark:

If we take the process of the circulation of the blood with the greatest generality, then we are dealing with the movement of the fluid through the tubes, which in a circular way, turn back onto themselves, and with the course of this movement in a certain amount of time. This task is of a purely mechanical nature; nothing prevents the assumption that the heart’s pump, as a mechanical middle, is adequate to solve this task. The heart is a pump and possesses as such enough force to drive the mass of blood in a circular movement through the entire vascular system. (cited in [23])

Understanding of the physical laws governing the flow of fluid through a system of tubes in the eighteenth and nineteenth centuries has been the starting point for the investigation of flow-related phenomena in living systems. Poiseuille’s experiments on a steady flow in the capillary tubes, in combination with Hagen’s observation that flow is proportional to the fourth power of the radius, were given a mathematical formulation in the form of Hagen–Poiseuille’s equation:

$$ \varDelta P=\frac{8\mu LQ}{\pi {r}^4} $$

where ΔP is the pressure gradient along the tube, L is the length of tube, μ is the dynamic viscosity, Q is the volume flow rate, r is the radius, and π is the mathematical constant.

Although the physical conditions under which Poiseuille’s law is applied are implicit in the method by which it was derived experimentally, it was nevertheless applied widely to circulation phenomena and formed the framework for the pressure-propulsion theory [26].

However, the application of Hagen–Poiseuille’s lawfulness to a system of vessels requires—in addition to the knowledge of the physical properties of the fluid such as viscosity and temperature—values for pressure gradient, volume flow rate, and dimension of the vessels. (Blood is a non-Newtonian fluid with viscosity 3–4 times that of water.) It may be conceivable to calculate the dimensions of a small capillary bed and to measure pressures at the inflow and outflow in order to experimentally derive the resistance, but such information for individual organs or for the systemic circulation does not exist. Moreover, the capillary beds are highly dynamic units where, the (revised) Starling’s principle (cf. Sect. 21.​1.​2) [27] of the microvascular fluid exchange plays an active part, so only gross approximations of real-time events are available at best. Therefore, a simplified formulation of equation has been adopted from the Ohm’s law in electricity:

$$ P1-P2=Q\times {R}_{\mathrm{p}} $$

where the pressure gradient (voltage) (P1 − P2) is the difference between pressures of the left ventricle and right atrium, the flow (current ) is cardiac output (CO), and (Rp) is the fluid resistance [26]. Assuming a zero value for right atrial pressure, and if the mean aortic pressure is taken as the average pressure generated by the left ventricle (pressure source), the equation can be re-written as:

$$ {R}_{\mathrm{p}}=\left({P}_{\mathrm{m}}\mathrm{Ao}-{P}_{\mathrm{ra}}\right)/\mathrm{CO} $$

where Rp is peripheral resistance, PmAo is mean aortic pressure and Pra is right atrial pressure. The result is expressed either in standard physical units (dyne × s × cm−5) or in arbitrary units such as PRU (peripheral resistance units). The problem of applying the concept of resistance to biological systems has been aptly summarized by Fishman:

The idea of resistance is unambiguous when applied to rigid tubes perfused by homogenous fluid flowing in a laminar stream…complexities are introduced when these concepts are extended to the pulmonary (as well as to systemic) circulation: the vascular bed is a non-linear, visco elastic, frequency-dependent system, perfused by a complicated non-Newtonian fluid; moreover, the flow is pulsatile, so that the inertial factors, reflected waves, pulse wave velocity, and interconversions of energy become relevant considerations…as a result of many active and passive influences which may affect the relationship between the pressure gradient and flow, the term “resistance” is bereft of its original physical meaning: instead of representing a fixed attribute of blood vessel, it has assumed physiological meaning as a product of a set of circumstances. [28]

Since flow (CO) and pressures are readily obtained by invasive (and noninvasive) methods, this formulation (Ohm’s law for fluids) has found a widespread application among investigators and clinicians alike.7 The presence of such relationship is certainly suggested by experiments where the heart has been replaced by an artificial pump, and an increase in pump flow (output) results in increase in arterial pressure and a simultaneous decrease in central venous pressure [3032] (see also Sect. 16.​7). However, the problem arises when a causal relationship existing between voltage and current which are independently verifiable is transposed on to a complex system of conduits comprising the circulation. Such an oversimplification can give an erroneous idea about the state of organ perfusion in various hyperdynamic circulatory states, where low values of resistance are obtained in the face of decreased organ perfusion, leading to multiple organ failure. For example, in a patient with septic shock, a decrease in arterial pressure down to 50% of control, the vascular resistance may increase in a nonreactive bed such as the skin, but might decrease in the brain, heart, and skeletal muscle with overall resistance unchanged. Another example is about three times increase in cardiac output during dynamic exercise in highly trained athletes, in the face of decreased peripheral resistance to one third of its resting value, while maintaining normal or slightly decreased mean arterial pressures [33]. Since the additional energy for blood propulsion during exercise is supposedly provided by contracting muscles (skeletal muscle pump), application of Ohm’s law to define global cardiovascular function is arguable [34].

It has become apparent over the years that, in fact, a far more complex relationship exists between the heart chamber filling pressures, aortic pressure, and cardiac output as purported by left ventricular (LV) view of the circulation. Numerous studies have failed to demonstrate significant correlation between CVP, pulmonary capillary wedge pressure (PCWP), and CO and call for a better understanding of clinical hemodynamics [3539]. It is little surprising that treatment modalities [39] and classification of heart failure [40] and pulmonary hypertension have undergone through so many revisions [41].

Since its inception in the 1950s, the concept of PCWP has been subject to considerable debate. Among several criteria adopted at the time for deciding whether it is a dependable measure of left atrial pressure, none was found to be consistently reliable [42]. The problems associated with the clinical application of PCWP in heart failure are well known (see [40] for review) and have lost significant ground to more dynamic Doppler studies. There is little appreciation among clinicians of the fact that pulmonary venous wedge pressure (PVWP) is, in fact, slightly higher than pulmonary artery wedge pressure (PAWP) [43] or that the pressure gradient between the mean PA pressure and LA can be as low as 1–2 mmHg [44], raising the question whether the pressure gradient across the pulmonary circuit is the sole driving force for the blood?

Another commonly used formula, by which cardiac output (CO) equals stroke volume (SV) times the heart rate (HR)

$$ \mathrm{CO}=\mathrm{SV}\times \mathrm{HR} $$

is equally problematic, since it implies that the heart is a pump coupled to a closed system of rigid tubes. Only in such a pump-limited system would a volume displaced by a pump at its outflow (aorta) be equal to what returns at the inflow into the pump (right atrium). On the surface this appears to be true, since at a steady-state the output and input volumes are closely matched for systemic as well as for pulmonary circulations. However, this equilibrium is easily upset by a variety of physiological perturbations and pathological states, suggesting a far more dynamic interaction between the heart and the peripheral circulation. For example, artificial pacing of the heart in animals [45] and humans [46, 47] at rates up to four times above baseline show that CO remains the same, or even drops. There is no change in CO even if a technique of paired electrical pacing is employed, in which a second depolarizing stimulus is delivered just after the refractory period, which markedly increases the inotropic state of the heart [48].

14.1.1 Heart Failure Therapy

The trends in pharmacologic therapy of acute heart failure syndromes are an eloquent example of a shift from treatment modalities in the 1960s and 1970s, which primarily support the pressure propulsion concept of heart’s action, such as the use of potent sympathomimetic amines (epinephrine, isoproterenol, and dopamine) [49, 50], to a ubiquitous use of vasodilators. In fact, the use of inotropes (dobutamine and milrinone) is currently reserved for the treatment of a minority of patients with severe systolic dysfunction who do not tolerate vasodilators due to hypotension [51]. For example, data from ADHERE (Acute Decompensated Heart Failure national Registry) [52] trial showed that of 150,000 patients with acute heart failure, the systolic blood pressure was lower than 90 mmHg in fewer than 3% of patients, suggesting harmful effect. Of note, mortality in those treated with inotropes was higher (19%), in comparison with the group not receiving the inotropes (14%) [53]. Accordingly, the clinical practice guidelines of the Heart Failure Society of America (HFSA), the American College of Cardiology Foundation/American Heart Association (ACCF/AHA), as well as the European Society of Cardiology (ESA) recommend the use of vasodilators and deemphasize the use of inotropes in the management of acute heart failure syndromes [54]. From the range of available inotropes, dobutamine and milrinone are chosen for their significant vasodilatory effect. Of further interest is the fact that, in addition to standard treatment (diuretics and ACE inhibitors), the use of β-blockers is universally recommended in all patients with stable, mild, moderate, and severe heart failure with ischemic or nonischemic cardiomyopathies and reduced LV ejection fraction [55]. Surely, such pharmacotherapy is counterintuitive, if the heart is supposed to be a pressure propulsion pump! According to this model, the β-blockers would further weaken the failing heart (pump), and the vasodilators decrease the pressure head needed by the pump in order to drive the blood around the circuit more effectively.

Ever since the introduction into clinical practice by Kantrowitz and colleagues in 1968, the intra-aortic balloon pumps (IABP) have been widely used in patients with myocardial infarction complicated by cardiogenic shock with the goal of improving coronary perfusion by afterload reduction, with concomitant increase in CO and perfusion to vital organs [56]. The purported hemodynamic effect of IABPs was evidently based on the “heart as a pump model,” and over the years, the insertion of IABPs has become a standard of care (class I recommendation), in spite of several outcome studies showing their limited effectiveness [57]. It is hardly surprising that recently published results of IABP-SHOCK II trial found no difference in 30-day mortality or hemodynamic improvement in patients in cardiogenic shock and early revascularization procedure, with or without the IABP [58]. In the editorial accompanying this landmark study, O’Connor and Rogers question continued use of the IAPB and call for “development of novel and innovative strategies to treat this condition.” They further note that “The results of IABP-SHOCK II trial parallel those from many recent outcome trials that have challenged our understanding of the management of acute and chronic heart failure, including those regarding the use of pulmonary artery catheters and the role of revascularization in ischemic cardiomyopathy.” [57]. On the basis of collective evidence, the joint American College of Cardiology, the American Heart Association, and the European Society of Cardiology downgraded recommendations and level of evidence for the use of IAPB in the treatment of cardiogenic shock from class Ib (should be used) to class IIb (may/can be used) [59]. Finally, Su et al. in a 2015 meta-analysis of 17 studies examined the effectiveness of IABPs in the total of 3266 patients with acute myocardial infarction, with or without cardiogenic shock. Again, no significant difference in short- and/or long-term mortality was shown between patients receiving IABP support and controls. The presence or absence of cardiogenic shock did not influence the results [60].

Chronic heart failure is a global health problem affecting 30–50 million patients worldwide [61]. In the Unites States alone, 5.1 million people are affected by chronic heart failure, with an additional 825,000 cases of newly diagnosed cases each year amounting to 1 million hospital admissions at an estimated cost of $30 billion [62]. In spite of significant advances in the treatment of acute coronary syndromes in the past 30 years, the 5-year overall mortality of chronic heart failure patients of around 50% remains unacceptably high [63]. Surprisingly, the development of new drugs for chronic heart failure has diminished to a fraction in comparison to that in the 1990s. According to Packer, the investment in large clinical trials has declined because the promising results of phase II clinical trials are rarely confirmed by definitive large-scale trials. This dire situation has arisen, in part, due to the fact that the “primary mechanisms of the disorder are poorly understood” [64].

In view of the forgoing, several authors have questioned the single-organ concept of heart failure based on the traditional hemodynamic view. Schulze proposed that in view of the complex systemic neurohormonal response activated in chronic heart failure, the validity of the heart-as-a-pump paradigm can no longer be supported [65]. In a recent review of circulation models, Alexander moreover suggested that the current impasse in new therapies of heart failure may have arisen on account of the deeply entrenched pressure propulsion paradigm and submitted that “superseding of the pressure-propulsion model may steer researchers away from pharmacological and device blind alleys and lead them instead to wide avenues of discovery and progress in therapy” [66]. Similar arguments were raised in a recent review of circulation models [67].

14.2 Regulation of Cardiac Output by the Periphery

Because the venous return (VR) model (see Sect. 14.3) is based on the concept of mean circulatory pressure (MCP), it would serve us well to take a short detour and examine its development. As is often the case, the original idea was not conceived out of research on the circulation but from a related field. In the early part of the nineteenth century, brothers Ernest-Heinrich Weber, a physiologist, and Wilhelm Eduard Weber, a noted physicist, investigated the rate of wave propagation in distensible tubes [68]. In order to better represent the behavior of blood vessels, E.H. Weber constructed a model in which two segments of ileum, with an intact ileocecal valve, were sown together on one end to serve as unidirectional valves of the heart. The opposite ends of the gut were joined over a glass tube (which prevented propagation of fluid waves from arterial to venous compartments) occluded with a sponge which was to simulate the capillaries [69] (Fig. 14.1). The system was filled with water and when rhythmically squeezed at the level of the “heart,” a pulsatile flow was observed in the limb of the circuit before the glass segment. When the rate of pumping increased, the water moved progressively into the “arterial” compartment, but the flow was limited by collapse of the gut on the “venous” side. Weber carefully measured luminal pressures at different segments of the circuit during no-flow state, when the pressures equilibrated and called it the “mean hydrostatic pressure.” The pressures during pumping were designated as “hydrokinetic.” To his surprise, the mean pressure during intermittent contractions was the same as during no-flow state. The only way to increase the hydrostatic and hydrokinetic pressures was to add more fluid to the system. The mean pressure, concluded Weber, does not depend on the action of the heart, but on the amount of fluid in the model.


Fig. 14.1

Weber’s circulation model. Two ends of the gut with intact ileocecal valves are sewn together to simulate heart valves. The sponge represents the microcirculation. Compression of the gut (arrows) causes water to flow in one direction. Pressures at different points of the circuit are measured at rest (hydrostatic mean pressure) and during pumping (hydrokinetic mean pressure). (Reproduced from ref. [70], used with permission of Springer Nature)

Several decades later, Bayliss and Starling were investigating the role of microcirculation in the genesis of peripheral edema in heart failure at the time when, in their view, undue importance was given to the heart and to the arterial pressure in the overall control of cardiac output [71]. To support their hypothesis, they experimented on a series of dogs in which the autonomic reflexes were abolished by high spinal cord transaction and in which the action of the heart was excluded by opening of the chest leading to asphyxia and cardiac arrest. The effect of various circulatory interventions was then tested, such as intravenous infusion of saline or blood and occlusion of the aorta, inferior vena cava, or the portal vein. They introduced a novel technique of simultaneous measurements of pressure in the limb artery and at different points in the venous system [72]. Judging by the opening paragraph of their paper, Bayliss and Starling left no doubt that a significant insight into the riddle of the circulation had been had:

The experimental results which we wish to bring forward are largely such as might be predicted by anyone with a knowledge of elementary principles of circulation. Our justification in bringing them forward however is that they have not been so predicted, and it was only after obtaining the results that we asked ourselves why they had not occurred to us before. In fact they seem to form part of a forgotten or disregarded chapter in the physiology of the circulation, although they are of great importance for the question of pressure in the capillaries of the abdominal organs and therefore of the physiological processes of secretion and transudation which take place in these organs. [72]

In the Theoretical Considerations of their paper, Bayliss and Starling stated that the “forgotten chapter” in physiology is, in fact, Weber’s work “whose experimentation is confirmed by the whole of our observations.” They reproduced the diagram of Weber’s model and quoted his conclusions as the summary of their own work, namely

We see on the simplified model of the circulation that the pump (the heart) cannot increase the mean pressure exerted on the walls of the system of the tubes by the fluid contained within them. It can in fact only give rise to unequal distribution of the pressure, by diminishing the pressure in the veins by pumping fluid out of them and increasing the pressure in the arteries to a corresponding extent by pumping the fluid into them. The mean pressure of the fluid in this model can only be increased by distending the tubes to a larger extent by the injection of more fluid into them. [72]

Starling went on to refine the concept of the mean systemic pressure by further experimentation and delivered a series of lectures on heart failure in 1897, where he proposed that, “Somewhere in the circulation there must be a point where the pressure is neither raised nor lowered and where, therefore, the pressure is independent of cardiac activity” [71]. The location of this point would be of great significance in the genesis of heart failure; should it be located in arterioles (upstream of the capillaries), the capillary pressure would rise and the filtration of fluid into interstitium would increase. If, on the other hand, the point was in the veins (downstream of the capillaries), the pressure would fall, as the (left) heart failed. This occurs, reasoned Starling, due to resistance in the vessels which incurs a loss of energy of the flowing blood, as dictated by the law of conservation of energy. In the capillaries with a large total cross section, the flow is very slow, but the pressure is relatively large. In the veins, on the other hand, the flow velocity is greater but occurs at a lower pressure. “It thus follows,” concluded Starling, “that the neutral point in the vascular system, where the mean systemic pressure is neither raised nor lowered by the inauguration of the circulation, lies considerably on the venous side of the capillaries—at any rate, in most parts of the body” [71]. Starling stressed the importance of mean systemic pressure (MSP) and, in turn, of venous circulation on CO by experimenting on a mammalian heart-lung preparation. Together with the “law of the heart,” the concept of MSP became an essential component of the pressure propulsion model of circulation [73].

The significance of mean circulatory pressure was reexamined by Starr and Rawson who constructed a mechanical model of circulation in order to simulate various forms of heart failure. The model predicted that an increase in MSP (termed “static pressure” in their study) was brought on as a compensatory mechanism in congestive heart failure and not as a result of it [74]. To verify the theory, Starr performed direct measurements of “dead pressure” on “recently deceased patients” suffering with congestive heart failure (CHF) and concluded that “systemic venous congestion of the congestive heart failure is not fully explained as the direct mechanical consequence of weakness of either right or the whole heart.” Clearly, other factors such as the hypothetical “static pressure” play an important role [75].

14.3 Guyton’s Venous Return Model

The model conceived by Weber and Starling was fully developed by Guyton and his co-workers, who systematically investigated the importance of peripheral circulation in the control of cardiac output. The sheer volume of their work, spanning over several decades, has shaped the basic understanding of cardiovascular physiology for generations of students, researchers, and clinicians.

The starting point for Guyton’s work was the familiar cardiac function curves, first generated by Frank on isolated frog heart in 1895 and later by Patterson and Starling on the mammalian heart-lung preparation [76] (Fig. 14.2). While cardiac function curves represented the ability of the heart to eject the blood at various values of right atrial pressure, they only poorly reflected the function of the peripheral circulation. To complete the picture, a method was sought by Guyton and his collaborators which would characterize the systemic circulation in terms of blood returning to the heart. In order to achieve such measurements under controlled conditions, it was necessary to “break” the continuity of the vascular loop and use a mechanical pump in place of the heart. The first “venous return” curves were obtained on “recently dead” dogs [78] in which the vasomotor reflexes were abolished by total spinal anesthesia, and the arterial pressure was supported by the infusion of epinephrine [79]. A number of experiments were run to study the response of venous circulation at different levels of right atrial pressure (RAP) which was controlled by varying the height of collapsible tubing (Starling resistor) inserted between the right atrium and the bypass pump, replacing the right ventricle [7880]. Guyton plotted the results in the form of the well-known “venous return curves” which show the dependence of venous return (pump flow) on right atrial pressure (Fig.14.3). It is evident from Guyton’s graphic analyses that as the RAP decreases, venous return increases. Further decrease in atrial pressure (brought about by an increase in pump flow rate) would result in leveling off the flow at a certain maximal rate due to collapse of the great veins. Elevation of the RAP, on the other hand, results in a rapid decrease in venous return, approaching zero value when the pressure reaches about 7 mmHg. The zero flow pressure is equivalent to MCP. It should be noted parenthetically that elevation of right atrial pressure to levels by which venous return falls to near zero (intersect on the abscissa) for more than a few seconds proved “extremely traumatic to the preparation,” evidently due to overstretching of the right ventricle beyond its optimal working point, resulting in its failure [79]. It was demonstrated in these experiments that the right atrial pressure essentially presents an impedance to blood returning from the systemic circulation, i.e., to venous return.


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May 1, 2020 | Posted by in CARDIOLOGY | Comments Off on of Cardiac Output
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