Cardiac Anesthesia: Principles and Clinical Practice

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CHAPTER 2: Principles of cardiovascular physiology


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G. J. Crystal: Departments of Anesthesiology and of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois, and Department of Anesthesiology, Illinois Masonic Medical Center, Chicago, Illinois 60657

An understanding of basic principles of cardiovascular physiology is essential for effective and safe patient management in the perioperative period. This information provides a theoretical rationale for the use of drugs and interventions to maintain and optimize the patient's vital organ function.

A primary role of the circulation is to provide sufficient blood flow to satisfy the metabolic demands of the body tissues. The individual factors and relationships determining tissue blood flow are summarized in Fig. 2-1. Tissue blood flow is dependent on activity of both the heart and blood vessels; aortic pressure, one primary determinant of tissue blood flow, is the product of cardiac output and total peripheral resistance, whereas local vascular resistance, the other primary determinant of tissue blood flow, is a function of local vasomotor tone. An appreciation of the relationships presented in Fig. 2-1 is essential for even the most rudimentary understanding of cardiovascular physiology. A major portion of this chapter is devoted to clarifying them.

FIG 2.1. The cardiac and peripheral vascular factors that determine tissue bloow flow and their interrelationships. (Modified from Rothe CF. Cardiodynamics. In: Selkurt EE. Physiology. Boston: Little, Brown, 1971, with permission.)

Additional information on topics presented in the chapter or on related topics can be obtained from the suggested reading list at the end of the chapter.


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Control of cardiac output

Cardiac output (CO) is the volume of blood pumped to the body tissues per minute. It is equal to the product of heart rate (HR) and stroke volume (SV) (Fig. 2-2). Normal values for CO are 5 to 6 L/minute in a 70-kg man, with an HR of 60–80 beats/minute and an SV of 60 to 90 mL/beat. CO varies in proportion to the work demand and oxygen needs of the body.

FIG 2.2. Determinants of cardiac output.

HR is normally determined by the rhythmic, spontaneous depolarizations of the pacemaker cells located in the sinoatrial (SA) node. The rate of these depolarizations is modulated by the autonomic nervous system. Sympathetic stimulation increases activity of the SA node, whereas parasympathetic stimulation (vagus nerve) decreases its activity.

SV is the difference between end-diastolic volume and end-systolic volume (Fig. 2-2). It is augmented by increases in end-diastolic volume (Starling's law) and in myocardial contractility; it is decreased by increases in afterload. These factors are discussed in detail later in this chapter.

The sarcomere is the basic functional unit of the myocardium (Fig. 2-3). The ultrastructural arrangement of the thick (myosin) and thin (actin) myofilaments within sarcomeres and their interaction can explain much of the mechanical behavior of the cardiac muscle. Cardiac muscle contraction is initiated by an increase in intracellular calcium, which results in the formation of cross-bridges between the adjacent actin and myosin filaments. This process tends to draw the thin myofilaments and the Z lines toward the center of the sarcomere. This is the fundamental basis of the sliding filament mechanism for muscle contraction.

FIG 2.3. Contractile machinery and ultrastructure of the cardiac cell. (Modified from Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. Boston: Little, Brown, 1976, with permission.)

The relation between resting sarcomere length and the level of developed tension was originally defined in isolated skeletal muscle fibers (Fig. 2-4). Developed tension is a direct function of the number of cross-bridges pulling in parallel, and therefore of the amount of overlap between the thin and thick filaments before activation. Tension development (and myofilament overlap) is maximum at an inter- mediate sarcomere length and minimum at either extreme.

FIG 2.4. Tension development as a function of sarcomere length and myofilament overlap. (Modified from Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. Boston: Little, Brown, 1976, with permission.)

The length-tension relation provides a basis for Starling's law of the heart, which states that the strength of contraction of the intact heart is proportional to the initial length of the cardiac muscle fibers—that is, the end-diastolic volume (preload). This can be demonstrated with the use of a cardiac function curve, which is a plot of ventricular performance (e.g., SV) as a function of ventricular end-diastolic volume or an index thereof, such as ventricular end-diastolic pressure or pulmonary capillary wedge pressure (Fig. 2-5, top, right). In vivo, the cardiac muscle fibers are stretched by venous inflow. Normally, the volume in the ventricle before contraction (the preload) sets the sarcomere to a suboptimal length; the active tension that can be developed from that length is only about 20% of maximum. Increases in end-diastolic volume due to enhanced venous return cause an improvement in ventricular performance.

FIG 2.5. Top, right: Diagram of a cardiac function curve, relating ventricular end-diastolic volume (EDV) (i.e., stretching of the myocardium) to ventricular performance. Bottom, left: Major factors determining the magnitude of EDV. (From Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. Boston: Little, Brown, 1976, with permission.)

Venous return is augmented by conditions associated with reduced peripheral vascular resistance. These include the opening of an arteriovenous fistula and conditions that mimic it, such as fever (marked dilation of cutaneous beds), pregnancy, or exercise. Other factors affecting venous return are presented in Fig. 2-5 (bottom, left). Rapid, significant reductions in total blood volume reduce the venous return. At any given total blood volume, venous return is a function of the distribution of blood between the intrathoracic and extrathoracic compartments. For example, the assumption of an upright posture, because of the force of gravity, tends to increase extrathoracic volume at the expense of intrathoracic volume, thereby reducing venous return. An elevation of intrathoracic pressure, as occurs during positive-pressure ventilation, pneumothorax, or opening of the chest, has a similar effect. The systemic veins are endowed with smooth muscle in their walls, and they respond to humoral and neural stimuli. Sympathetic nerve stimulation produces venoconstriction, which augments venous return, whereas drugs that interfere with adrenergic nerve function (e.g., ganglionic blockers) and drugs that act directly to relax venous smooth muscle (e.g., nitrates) have the opposite effect. Extravascular compression of veins by contracting muscle increases venous return during exercise. Atrial contraction normally makes a relatively minor contribution to ventricular filling, but it becomes more important at high HRs, when the time available for passive filling of the ventricles is limited. Increases in pericardial pressure, such as occur in cardiac tamponade, limit ventricular filling and SV.

The relation between ventricular volume and pressure during diastole is termed compliance. A stiff or noncompliant ventricle demonstrates impaired diastolic filling and a reduced SV. This condition is associated with a variety of pathologic states, including ischemia, healing or healed myocardial infarction, hypertrophy, and constrictive pericarditis.

Contractility reflects the ability of the myocardium to perform mechanical work at a given preload. It can be shown graphically by a family of cardiac function curves (Fig. 2-6, bottom, left). Changes in contractility can augment cardiac performance (positive inotropic effect) or decrease it (negative inotropic effect). Movement of an entire curve upward or downward signifies a positive or a negative inotropic effect, respectively. Examples of positive inotropic factors are circulating catecholamines and the cardiac sympathetic nerves; examples of negative inotropic factors are severe anoxia or acidosis, pharmacologic depressants (e.g., anesthetics), and loss of myocardium (e.g., myocardial infarction) (Fig. 2-6, top, right).

FIG 2.6. Top, right: Diagram showing major factors affecting myocardial contractility. Bottom, left:Family of cardiac function curves demonstrating the effect of contractility on ventricular performance. (From Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. Boston: Little, Brown, 1976, with permission.)

Afterload may be defined as the tension, force, or stress in the ventricular wall during ventricular ejection. In accordance with the law of Laplace, afterload is directly related to intraventricular pressure and size and inversely related to its wall thickness. Because of changing size and pressure, afterload varies continuously during ventricular ejection. For this reason, it is difficult to quantify with precision. Aortic pressure for the left ventricle and pulmonary artery pressure for the right ventricle usually provide a reasonable estimate of afterload in vivo. In isolated heart preparations, in which preload, inotropic state, and beating rate are controlled, increases in afterload cause reductions in left ventricular output (i.e., SV) (Fig. 2-7). In the intact circulation, this impairment to cardiac performance may be avoided when the level of contractility is high or when venous return and preload increase sufficiently. This is demonstrated in Fig. 2-8, which indicates an almost constant SV when normal hearts are exposed to increased afterload (outflow resistance), but a marked decrease in SV when failing hearts are faced with the same condition. Afterload-reducing vasodilating drugs (e.g., nitroprusside) improve cardiac function in patients with heart failure, but they have minimal effect in normal patients.

FIG 2.7. Left ventricular output as a function of left atrial pressure (i.e., filling pressure), plotted at several aortic pressures (afterloads). The increases in aortic pressure cause progressive reductions in left ventricular output at each filling pressure. (From Sagawa K. Analysis of the ventricular pumping capacity as function of input and output pressure loads. In: Reeve EB, Guyton AC, eds. Physical bases of circulatory transport: regulation and exchange. Philadelphia: WB Saunders, 1967, with permission.)

FIG 2.8. Effect of increased afterload on stroke volume in normal and compromised hearts. (Modified from Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. N Engl J Med 1977;297:27, with permission.)

Events of the cardiac cycle

The events of the cardiac cycle are shown in Fig. 2-9. At "O" the heart valve opens, and at "C" it closes. The salient points of this figure are the following: (a) Atrial systole begins after the P wave of the electrocardiogram; ventricular systole begins near the end of the R wave and ends just after the T wave. (b) When ventricular pressure exceeds aortic pressure, the aortic valve opens and ventricular ejection begins. (c) The amount of blood ejected by the ventricle (i.e., the SV) is about 65% of the end-diastolic volume; this is termed the ejection fraction. (d) About 80% of ventricular filling is passive; that is, it occurs before atrial systole. (e) Events on the right side of the circulation are similar to those on the left side, but they are somewhat asynchronous. Right atrial systole precedes left atrial systole, and contraction of the right ventricle begins after that of the left. However, because pulmonary arterial pressure is less than aortic pressure, right ventricular ejection precedes left ventricular ejection.

FIG 2.9. Events of a cardiac cycle. The phases of the cardiac cycle are identified at the bottom as follows: 1, atrial systole; 2, isovolumetric ventricular contraction; 3, ventricular ejection; 4, isovolumetric relaxation; 5, ventricular filling. (From Ganong WF. Review of medical physiology, 19th ed. Stamford, CT: Appleton & Lange, 1999, with permission.)

The ventricular pressure-volume loop

Figure 2-10 presents the relation between ventricular pressure and volume during a cardiac cycle. A similar plot (with a reduced pressure range) could be generated for the right ventricle. For the normal left ventricle (solid lines), diastolic filling starts at A and ends at B, when the mitral valve closes. The increase in ventricular pressure during this period of filling reflects the compliance of the ventricular wall. During isovolumetric contraction (B to C), pressure increases steeply while volume remains constant. At C, ventricular pressure rises to a level that exceeds aortic pressure, the aortic valve opens, and blood is ejected. Ventricular ejection (systole) continues until the ventricular pressure falls below the aortic pressure and the aortic valve closes (D). What follows is the period of isovolumetric relaxation (D to A), which is characterized by a sharp decrease in pressure and no change in volume. The mitral valve opens at A, thus completing one cardiac cycle. Effects of variations in loading conditions and contractile state can be demonstrated with the use of the pressure-volume relation. In Fig. 2-10, the dashed lines show the effect of heart failure (i.e., decreased contractility) on the pressure-volume relation. The area within the pressure-volume loop represents the mechanical work of the heart.

FIG 2.10. Pressure-volume loop of the cardiac ventricle. A–B, Diastolic filling; B–C, isovolumetric contraction; C–D, systolic ejection; D–A, isovolumetric relaxation. A plot for a normal ventricle is shown by the solid line, and one for a failing ventricle by the dashed line.


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Pressure changes in systemic and pulmonary circulations

The heart comprises two parallel pumps, each consisting of an atrium and a ventricle. The right side of the heart supplies the pulmonary circulation, where exchange of oxygen and carbon dioxide occurs in the lung alveoli; the left side of the heart supplies the systemic circulation, which carries oxygenated blood to the body tissues. Figure 2-11 compares the pressure changes as blood flows through the series-coupled components of the systemic and pulmonary circulations—from the large arteries to the arterioles, capillaries, and veins. Important features of this figure are the following: (a) The pressure developed by the right ventricle is approximately one sixth that by the left ventricle. This results in a smaller workload for the right ventricle, which is in keeping with its much thinner wall. (b) Although pressure in the ventricles falls almost to zero during diastole, pressure is maintained in the large arteries. This is possible because a portion of the energy released by cardiac contraction during systole is stored in the distensible large arteries. During diastole, the elastic recoil of the vessels converts this potential energy into forward blood flow, which ensures that capillary flow is continuous throughout the cardiac cycle. (c) The most severe drop in pressure occurs in the arterioles; for this reason, they are often termed the resistance vessels. The diameter of the arteriole is regulated by the contractile activity of the smooth muscle contained in its wall. Variations in arteriolar diameter are a primary determinant of local blood flow and capillary hydrostatic pressure.

FIG 2.11. Pressure changes as blood flows through the series-coupled components of the systemic and pulmonary circulations. (Modified from Folkow B, Neil E. Circulation. New York: Oxford University Press, 1971, with permission.)

Determinants of blood flow: Poiseuille's law

Blood flow (F) is a function of the arteriovenous pressure gradient (Pa – Pv) and local vascular resistance (VR), according to the equation:

This is analogous to Ohm's law in an electrical circuit. Because arterial and venous blood pressures are normally well maintained within narrow limits by homeostatic mechanisms, tissue blood flow usually varies inversely as a function of vascular resistance.

Poiseuille performed studies that yielded an equation describing resistance to flow (R) in a straight, rigid tube of length l and radius r:

where is the viscosity. Of note, flow resistance varies inversely with tube radius (r) raised to the fourth power. Therefore, small changes in tube radius cause large changes in resistance.

Because the length of blood vessels in situ is fixed, geometric changes in blood flow resistance occur through variations in vessel radius. These adjustments are the result of contraction or relaxation of the smooth muscle investing the arterioles. Chemical factors that are linked to the metabolic activity of the tissue (e.g., adenosine) modulate vascular resistance so that blood flow (and oxygen delivery) is commensurate with the prevailing local oxygen demands.

Blood viscosity

Viscosity is the internal friction resulting from the intermolecular forces operating within a flowing liquid. The term internal friction emphasizes that as a fluid moves within a tube, laminae in the fluid slip on one another and move at different speeds. This produces a velocity gradient in a direction perpendicular to the wall of the tube. This velocity gradient is termed the shear rate. In the circulation, shear rate is directly correlated with rate of blood flow. An intuitive understanding of the term viscosity can be gained from the experiment shown in Fig. 2-12. In this experiment, a homogeneous fluid is confined between two closed spaced, parallel plates (analogous to playing cards). Assume that the area of each plate is A, the distance between the plates is Y, and the bottom plate is stationary. If a tangential force (a shear stress) is applied to the upper plate, that plate moves with velocity V in the direction of the applied force, and a velocity gradient (or shear rate) is developed in the fluid. Viscosity is defined as the factor of proportionality relating shear stress and shear rate for the fluid.

FIG 2.12. Relation between shear stress and shear rate when a fluid is sheared between two parallel plates. Details are included in the text. (From Fahmy NR. Techniques for deliberate hypotension: haemodilution and hypotension. In: Enderby GEH, ed. Hypotensive anaesthesia. Edinburgh, Scotland: Churchill-Livingstone, 1985, with permission.)

Newton assumed that viscosity was a constant property of a particular fluid and independent of shear rate. Fluids that demonstrate this behavior are termed Newtonian. The units of viscosity are dynes per second per square centimeter, or poise.

The viscosity of blood varies as a direct function of hematocrit (Fig. 2-13): the greater the hematocrit, the more friction there is between successive layers. Plasma is a Newtonian fluid, even at high protein concentrations. However, because blood consists of erythrocytes suspended in plasma, it does not behave like a homogeneous Newtonian fluid; the viscosity of blood increases sharply with reductions in shear rate (Fig. 2-13). This non-Newtonian behavior of blood has been attributed to changes in the behavior of erythrocytes at low flow rates: (a) Erythrocytes lose their axial position in the stream of blood (Fig. 2-14). (b) Erythrocytes lose their ellipsoidal shape. (c) Erythrocytes form aggregates; this tendency toward aggregation appears to depend on the plasma concentration of large protein molecules (e.g., fibrinogen), which form cell-to-cell bridges. (d) Erythrocytes adhere to the endothelial walls of microvessels. Figure 2-15 demonstrates that non-Newtonian behavior is localized in vivo on the venous side of circulation because of its lower shear rates, but that this behavior can be blunted or abolished by hemodilution.

FIG 2.13. Viscosity of whole blood at various hematocrits as a function of shear rate. Hematocrit was varied by the addition of dextran and packed red blood cells. Viscosity increases with hematocrit, and these increases are greatest at the lower shear rates. (Modified from Messmer K. Hemodilution. Surg Clin North Am 1975;55:662, with permission.)

FIG 2.14. Diagram representing various features of streamline and turbulent flow. (From Keele CA, Neil E. Samson Wright's applied physiology. London: Oxford University Press, 1971, with permission.)

FIG 2.15. Graphic representation of the level of blood viscosity in the various vascular compartments. Under normal condition (hematocrit = 45%), viscosity increases in postcapillary venules because of reduced shear rate. Hemodilution can blunt or even eliminate this regional variation in viscosity. (From Messmer K, Sunder-Plassman L. Hemodilution. Prog Surg 1974;12:208, with permission.)

The tendency for an increased hematocrit to increase the blood viscosity is attenuated when blood flows through tubes of capillary diameter (Fig. 2-16). Because erythrocytes are normally very deformable and have a diameter similar to that of the capillary, they can squeeze through the vessel lumen in single file with minimal extra force required. Therefore, the rate at which erythrocytes pass through the capillary has little influence on blood viscosity there; viscosity remains close to that of plasma.

FIG 2.16. The effect of hematocrit on viscosity of blood in tubes of varying radius. In wide tubes, increasing the hematocrit raises viscosity; in narrow tubes, it has no effect. (From Feigl EO. Physics of the cardiovascular system. In: Ruch TC, Patton HD ed. Physiology and biophysics II: circulation, respiration, and fluid balance. Philadelphia: WB Saunders, 1974, with permission.)

Blood viscosity varies inversely with temperature. This is an important consideration during hypothermic cardiopulmonary bypass. After circulatory arrest, the shear stress required to reinitiate flow and to break up red cell aggregates is likely to be high. Additional rheologic benefit may be gained by a further decrease in hematocrit.

Turbulent flow

A condition of Poiseuille's law is that flow must be laminar. Above a critical flow rate, the laminae break down into eddies that move in all directions. Such flow is said to be turbulent (Fig. 2-14). The tendency for turbulence is given by the Reynolds number (Re):

where V = linear velocity, D = diameter, = density, and = viscosity. Re is dimensionless because it is the ratio of inertial and cohesive forces. The former tend to disrupt the stream, whereas the latter tend to maintain them. In long straight tubes, turbulence occurs when Re exceeds a value of approximately 2,000. However, the critical Re in vivo is much less because of pulsatile flow patterns and complicated vascular geometries. When flow is turbulent, a greater portion of the total fluid energy is dissipated as heat and vibration; therefore the pressure drop is greater than what would be predicted from the Poiseuille equation (Fig. 2-17). The vibrations associated with turbulent flow can often be heard as a murmur during physical examination.

FIG 2.17. The linear relation between pressure gradient and flow. Beyond a critical velocity, turbulence begins and the relation between pressure and flow is no longer linear. (From Feigl EO. Physics of the cardiovascular system. In: Ruch TC, Patton HD, ed. Physiology and biophysics II: circulation, respiration, and fluid balance. Philadelphia: WB Saunders, 1974, with permission.)

Major vessel types: structure and function

The various vessel types have structural and geometric features (Fig. 2-18) that correlate with their functional characteristics and roles within the circulation (Fig. 2-19). The large conduit arteries are predominantly elastic structures, allowing them to convert intermittent CO into continuous peripheral flow. Because the cross-sectional area of these vessels is small, the velocity of flow in them is high. The resistance to flow in the arteries is small, and therefore the pressure drop is also small. The arterioles and the terminal arterioles have significant smooth muscle in their walls, which permits active changes in vascular diameter and modulation of local vascular resistance and blood flow. The capillaries have a very large aggregrate cross-sectional area (which decreases the flow velocity) and a thin wall, two features that favor blood-tissue exchange. The veins and venules have the greatest volume, which makes them an appropriate site for blood storage.

FIG 2.18. Dimensions and structural attributes of the various vessel types. (Modified from Berne RM, Levy MN. Principles of physiology. St. Louis: CV Mosby, 1990, with permission.)

FIG 2.19. Velocity, cross-sectional area, blood volume, and pressure within the various vessel types. AO, aorta; LA, large arteries; SA, small arteries; ART, arterioles; CAP, capillaries; VEN, venules; SV, small veins; LV, large veins; VC, vena cavae. (Modified from Berne RM, Levy MN. Principles of physiology. St. Louis: CV Mosby, 1990, with permission.)

Factors influencing the balance between capillary filtration and absorption: mechanisms of edema

Mechanisms of capillary-tissue fluid exchange are portrayed in Fig. 2-20. Because the capillary wall is highly permeable to water and to almost all the solutes of the plasma (with the exception of the plasma proteins), it acts like a porous filter through which protein-free plasma moves by bulk flow under the influence of a hydrostatic pressure gradient. Transcapillary filtration is defined by the equation:

where CF = capillary filtration coefficient, Pcap = capillary hydrostatic pressure, PIF = interstitial fluid hydrostatic pressure, cap = capillary oncotic pressure IF = interstitial fluid oncotic pressure. Pcap and IF are forces of filtration. Pcap is determined by arterial pressure, venous pressure, and the ratio of postcapillary to precapillary resistance. Increases in each of these parameters raise the value for Pcap. Pcap is approximately 35 mm Hg at the arterial end of the capillaries and approximately 15 mm Hg at the venous end. IF is a result of plasma proteins that have passed through the capillary wall and is normally very low compared to Pcap. Therefore, Pcap is normally the major force of filtration. PIF and cap are forces favoring absorption. PIF is determined by the volume of fluid and the distensibility of the interstitial space and is normally almost equal to zero. cap is caused by the plasma proteins (most predominantly albumin) and has a value of approximately 25 mm Hg. cap is normally the major force for absorption. The direction and magnitude of capillary bulk flow is essentially a function of the ratio of Pcap to cap. Filtered fluid that reaches the extravascular spaces is returned to the circulatory system via the lymphatic network. Under normal conditions (Fig. 2-20, panel A), filtration dominates at the arterial end of the capillary, and absorption at the venous end, because of the gradient of hydrostatic pressure; there is a small net filtration, which is compensated by lymph flow. Edema is a condition of excess accumulation of fluid in the interstitial space. It occurs when net filtration exceeds drainage via the lymphatics. This can be caused by (a) increased capillary pressure, (b) decreased plasma protein concentration, (c) accumulation of osmotically active substances in the interstitial space, (d) increased capillary permeability, or (e) inadequate lymph flow. Conditions resulting in edema are diagramatically depicted in Fig. 2-20, panels B through D.

FIG 2.20. Mechanisms of capillary-tissue fluid exchange: A depicts normal condition, while B–D depict conditions favoring edema. Upward arrows indicate filtration, and downward arrows indicate absorption. The area of the shaded triangles reflects the magnitude of filtration and absorption under each condition. (Modified from Friedman JJ. Microcirculation. In: Selkurt EE, ed. Physiology. Boston: Little, Brown, 1971, with permission.)

Baroreceptor control of the circulation

Arterial blood pressure is maintained within narrow limits by a negative feedback system. The major components of this system are as follows (Fig. 2-21): (a) an afferent limb composed of the baroreceptors in the carotid and aortic arch and their respective sensory nerves, the glossopharyngeal and vagus nerves; (b) the cardiovascular centers in the medulla, which receive and integrate the sensory information; and (c) an efferent limb composed of the sympathetic nerves to the heart and blood vessels and the parasympathetic (vagus) nerves to the heart. Figure 2-22 presents the neural relationships of the arterial baroreceptor reflex. The baroreceptors are stimulated by stretch of the vessel wall, which results from an increase in transluminal pressure. Impulses originating in the baroreceptors tonically inhibit discharge of the sympathetic nerves to the heart and blood vessels and tonically facilitate discharge of the vagus nerves to the heart. A rise in arterial pressure reduces baroreceptor afferent activity, resulting in further inhibition of the sympathetic nerves and facilitation of the vagus nerves. This produces vasodilation, venodilation, and reductions in SV, HR, and CO, which tend to normalize arterial pressure. A decrease in arterial pressure has opposite effects. The cardiovascular centers in the medulla are also under the influence of neural factors arising in the arterial chemoreceptors, hypothalamus, and cerebral cortex, and of local changes in the partial pressures of carbon dioxide and oxygen (PCO2 and PO2, respectively). Anesthetics have been demonstrated to inhibit baroreceptor control of the cardiovascular system, although this effect seems to vary from agent to agent (1). This effect may be either an advantage or a disadvantage, depending on the clinical circumstances. For example, an agent that preserves baroreflex function would be advantageous in the presence of a systemic circulatory stress, such as hypovolemia. On the other hand, an agent that blunts baroreflex function would be advantageous in the clinical management of coronary artery disease, where reflex tachycardia (and increased myocardial oxygen demand) would be undesirable.

FIG 2.21. Diagram of arterial baroreceptor reflex loop. (Modified from Rothe CF, Friedman JJ. Control of the cardiovascular system. In: Selkurt EE, ed. Physiology. Boston: Little, Brown, 1971, with permission.)

FIG 2.22. Effect of changes in arterial pressure on carotid sinus nerve discharge and impulse rate of efferent nerves. (Modified from Rushmer RF. Cardiovascular dynamics, 3rd ed. Philadelphia: WB Saunders, 1970, with permission.)


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Oxygen serves as an electron acceptor in oxidative phosphorylation, permitting production of adenosine triphosphate (ATP) along efficient aerobic pathways. The high-energy phosphate bonds of ATP provide energy for functional and biochemical processes within the cell, such as the contraction of muscle proteins or the metabolic activity of enzymes.

The cardiovascular system acts in concert with the respiratory system to transport oxygen from the environmental air to tissue mitochondria. Oxygen transport is composed of a series of steps, each corresponding to a transport process with a PO2 cost, the so-called oxygen cascade (Fig. 2-23). The objective of the oxygen transport system is to maintain PO2 in the vicinity of all mitochondria at 0.1 mm Hg, which is the level required for unimpaired O2 use (Fig. 2-24). The only function of higher PO2 values is to provide for diffusion of oxygen to mitochondria remote from capillaries.

FIG 2.23. On the left is the oxygen cascade, with partial oxygen pressure (PO 2) decreasing from the level in the ambient air to the level in the mitochondria. On the right are listed the factors influencing PO 2 at various steps in the cascade. (From Nunn JF. Nunn's applied respiratory physiology. Oxford: Butterworth Heinemann, 1993, with permission.)

FIG 2.24. Oxygen consumption O2 of isolated mitochondria as a function of partial oxygen pressure (PO 2). (From Honig CR. Modern cardiovascular physiology. Boston: Little, Brown, 1981, with permission.)

The amount of oxygen carried from the lungs to tissues by circulating blood—that is, the convective systemic oxygen delivery (DO2), is given by the equation:

where CO is cardiac output in liters per minute and CaO2 is the arterial oxygen content in volume percent (vol%). The determinants of CO have already been discussed. What follows is a discussion of the factors affecting CaO2.

Oxygen carriage in the blood: oxyhemoglobin dissociation curve

CaO2 comprises oxygen bound to hemoglobin and oxygen dissolved in plasma. The human hemoglobin molecule is composed of two basic portions. The protein or globin portion is made up of identical polypeptide chains: two and two chains. The polypeptide chains are folded and assembled as a tetramer. Each of these chains contains one heme group, which serves as an iron-containing, reversible carrier of one molecule of oxygen. Therefore, each molecule of hemoglobin can bind four molecules of oxygen. The amount of oxygen bound is a function of hemoglobin concentration (Hb), the oxygen saturation of hemoglobin (SaO2), and the oxygen carrying capacity for hemoglobin (1.39 mL O2 per gram of hemoglobin), according to the equation:

SaO2 is a function of PO2 and the oxyhemoglobin dissociation curve (Fig. 2-25). The sigmoid shape of this curve reflects the fact that the four binding sites on a given hemoglobin molecule interact with each other. When the first site has bound a molecule of oxygen, the binding of the next site is facilitated, and so forth. The result is a curve that is steep up to a PO2 of 60 mm Hg and then becomes more shallow, approaching 100% saturation asymptotically. At a PO2 of 100 mm Hg to which human arterial blood is equilibrated, the hemoglobin saturation (SaO2) is approximately 97%; at 40 mm Hg, a typical value for the mixed venous oxygen tension (PO2) in a resting person, the saturation is about 75%.

FIG 2.25. The oxyhemoglobin dissociation curve. The oxygen content of blood has two components: oxygen binding to hemoglobin follows an S-shaped curve up to full saturation; the amount of oxygen in solution increases linearly with the partial oxygen pressure (PO 2) without limit. (From West JB. Respiratory physiology: the essentials. Baltimore: Williams & Wilkins, 1974, with permission.)

The shape of the oxyhemoglobin dissociation curve has important physiologic implications. The flatness of the curve beyond a PO2 of 80 mm Hg ensures a relatively constant oxyhemoglobin saturation for arterial blood despite wide variations in alveolar oxygen pressure. The steep portion of the curve between 20 and 60 mm Hg permits unloading of oxygen from hemoglobin at relatively high PO2 values, which allows the delivery of large amounts oxygen into the tissue by diffusion.

The oxygen binding properties of hemoglobin are influenced by a number of factors, including pH, PCO2, and temperature (Fig. 2-26). These factors cause shifts of the oxyhemoglobin dissociation curve to the right or left without changing the slope of the curve. For example, an increase in temperature or a decrease in pH, such as may occur in active tissues, decrease the affinity of hemoglobin for oxygen and shift the oxyhemoglobin dissociation curve to the right. Therefore, a higher PO2 is required to achieve a given saturation, which facilitates unloading of oxygen at the tissue. To quantify the extent of a shift in the oxyhemoglobin dissociation curve, the so-called P50 is used; this is the PO2 required for 50% saturation. The P50 of normal adult hemoglobin at 37°C and normal pH and PCO2 is 26 to 27 mm Hg.

FIG 2.26. Effects of variations in pH, partial carbon dioxide pressure (PCO 2), and temperature on the oxyhemoglobin dissociation curve. (From Weibel ER. The pathway for oxygen. Cambridge, MA: Harvard University Press, 1984, with permission.)

The compound 2,3-diphosphoglycerate (2,3-DPG) is an intermediate in anaerobic glycolysis (the biochemical pathway by which red blood cells produce ATP) that binds to hemoglobin. Increases in intraerythrocytic 2,3-DPG concentration reduce the affinity of hemoglobin for oxygen (i.e, they shift the oxyhemoglobin dissociation curve to the right), whereas decreases have an opposite effect. Several factors have been found to influence the red cell 2,3-DPG concentration. For example, after storage in a blood bank of only 1 week, the 2,3-DPG concentration is one-third normal, resulting in a shift to the left of the oxyhemoglobin dissociation curve. On the other hand, conditions associated with chronic hypoxia, such as living at high altitude or chronic anemia, stimulate production of 2,3-DPG, causing a rightward shift of the oxyhemoglobin dissociation curve.

Dissolved oxygen is linearly related to PO2 (Fig. 2-25). At 37°C it is defined by the equation:

Dissolved oxygen normally accounts for only 1.5% of total oxygen, but this contribution increases when the bound component is reduced during hemodilution. Because hemoglobin is essentially saturated at a PO2 of 100 mm Hg, increases in PaO2 to levels greater than 100 mm Hg increase the CaO2 by raising the dissolved oxygen component.

Characteristic values for parameters of oxygen delivery

For an individual with normal values for Hb (15 g/100 mL), PaO2 (100 mm Hg), PO2 (40 mm Hg), and CO (5 L/minute):

CO2 is mixed venous oxygen content.

Diffusion of oxygen to tissues: capillary-to-cell oxygen delivery

The final step in the delivery of oxygen to tissue mitochondria is diffusion from the capillary blood. According to the law of diffusion, this process is determined by the capillary-to-cell PO2 gradient and the diffusion parameters, capillary surface area and blood-cell diffusion distance. In 1919, Krogh formulated the capillary recruitment model to describe the processes underlying oxygen transport in tissue (2). The basic model was later expanded and refined (3). Although Krogh's model is limited by multiple simplifying assumptions, it has value as a tool for appreciating the role of vascular control mechanisms in the transport of oxygen to tissue.

The model consists of a single capillary and the surrounding cylinder of tissue that it supplies (Fig. 2-27). Two interrelated oxygen gradients are involved: a longitudinal gradient within the capillary, and a radial oxygen gradient extending into the tissue. Most oxygen in capillary blood is bound to hemoglobin and cannot leave the capillary. This bound oxygen is in equilibrium with the small amount of oxygen dissolved in the plasma. The consumption of oxygen by the tissue (O2) creates a transcapillary gradient for oxygen. Diffusion of oxygen into the surrounding tissue shifts the equilibrium between bound and dissolved oxygen, so that more oxygen is released from hemoglobin. By this mechanism, oxygen dissociation from hemoglobin is controlled by O2.

FIG 2.27. Longitudinal and radial oxygen gradients within tissue in accordance with the Krogh cylinder model. Details are provided in the text. O 2, oxygen consumption; , blood flow; [CaO 2 – CO 2], arteriovenous oxygen content difference; rc, capillary radius; R, tissue cylinder radius; A, arterial end of capillary; V, venous end of capillary; x, point within tissue cylinder; PcapO 2, oxygen tension of capillary blood; D, diffusion coefficient for oxygen. (From Honig CR. Modern cardiovascular physiology. Boston: Little, Brown, 1981, with permission.)

The longitudinal oxygen gradient within the capillary is created by the extraction of oxygen by tissue as blood passes from the arterial to the venous end of the capillary. The arteriovenous oxygen difference is equivalent to the ratio of O2 to blood flow (Fick equation). An increase in O2 or a decrease in blood flow (or both) steepens the longitudinal oxygen gradient. Proportional changes in O2 and blood flow are required to maintain the longitudinal oxygen gradient constant.

A corresponding value for capillary PO2 (PcO2) can be estimated from the value for capillary O2 content, taking into account the Hb and the oxyhemoglobin dissociation curve. The shape of the longitudinal gradient in PO2 within the capillary is approximately exponential because of the influence of the oxyhemoglobin dissociation curve. The PcO2 is the driving force for diffusion of O2 into the tissue. Because PcO2 is minimal at the venous end of the capillary, the mitochondria in this region are most vulnerable to oxygen deficits.

At the bottom of Fig. 2-27 is Krogh's original equation for estimating PO2 at a specific point (x) in the surrounding tissue cylinder. This equation was later simplified to provide a value for mean tissue PO2 (PtO2) (3):

where PcO2 is blood oxygen tension at a midway point in the capillary, A is a constant representing the relation between capillary radius and tissue cylinder radius, O2 is oxygen consumption of the tissue cylinder, r is the radius of the tissue cylinder (half of the intercapillary distance), and D is the oxygen diffusion coefficient. The value for r is determined by the number of capillaries perfused with red blood cells per volume of tissue and is controlled by the precapillary sphincters. The favorable influence of capillary recruitment on tissue PO2 is evident in the Fig. 2-27 (lower panel). If only capillaries 1 and 3 are open, the diffusion distance is so large that PO2 falls to zero toward the center of the tissue cylinder. The low tissue PO2 causes relaxation of the precapillary sphincter controlling capillary 2. Perfusion of capillary 2 decreases the diffusion distance and increases tissue PO2 to an adequate level throughout the tissue.

Mean PtO2 is a reflection of the overall balance between oxygen supply and demand within a particular tissue. An increase in blood flow without a change in oxygen demand (i.e., luxuriant perfusion) raises the mean PtO2, whereas a reduction in blood flow without a change in oxygen demand lowers it. If mean PtO2 falls below a critical level, O2 becomes impaired. Measurements of mean PtO2 have been obtained in laboratory animals in various tissues, including the myocardium and skeletal muscle, by use of a polarographic technique involving bare- tipped platinum electrodes (4,5). The invasiveness of this technique has curtailed the use of mean PtO2 measurements in patients. Measurements of local venous PO2 provide an approximation for average end-capillary PO2, and although they neglect the radial PO2 gradient, they generally show a reasonable correlation to mean PtO2 (6).

Oxygen consumption and other measurable variables in vivo

In a clinical setting, there are several methods to measure O2 of the whole body (7,8): (a) oxygen loss or replacement into a closed breathing system, (b) subtraction of expired from inspired volume of oxygen, and (c) use of the Fick principle.

The first method, oxygen loss or replacement into a closed breathing system, is the most fundamental, is well validated, and has an accuracy well in excess of clinical requirements. However, it is cumbersome and requires meticulous attention to detail to be used safely during intensive care. The second method, subtraction of expired from inspired volume of oxygen, is a difficult and potentially inaccurate method to determine O2. The major problem is that O2 is a small number that is calculated as the difference between two large numbers.

Under steady state conditions, the Fick equation can be used to calculate systemic O2:

In this technique, CO is usually measured by thermodilution using a Swan-Ganz catheter situated in the pulmonary artery. Samples of blood are collected from an artery and from the pulmonary artery (mixed venous sample) and analyzed for oxygen content. Using the normal values for CO and (CaO2 – CO2) described earlier, systemic O2 can be calculated:

The Fick technique is popular in the intensive care setting, probably because the necessary arterial and pulmonary artery catheters are frequently already placed in critically ill patients. An important advantage of this method is that it also provides a measurement of DO2 (Eq. 2-6), which permits analysis of the relation between DO2 and O2. A drawback of the Fick technique is that it excludes O2 of the lungs. Although this component is negligible in the case of normal lungs, simultaneous measurements of O2 by the Fick and gasometric methods indicate that it may be significant (as much as 20% of total O2) in critically ill patients (9). It has been proposed that the increased O2 in the lung is related to production of the superoxide free radical and, in turn, the hydroxyl free radical, hydrogen peroxide, and hypochlorous acid (10).

The oxygen extraction ratio (EO2), as a percentage, is defined by the equation:

Combining equations and rearranging terms, it can be demonstrated that EO2 is also equal to the ratio of O2 to DO2 and, therefore, reflects the balance between systemic oxygen demand and delivery. Measurements of EO2, as well as of PO2, are frequently used clinically to assess the overall adequacy of DO2 in critically ill patients (11–13).

Critical oxygen delivery

At rest, DO2 greatly exceeds O2 (in our examples, they are 1,025 and 235 mL/minute, respectively); therefore EO2 is relatively modest (approximately 25%), resulting in a substantial reserve for increased EO2. This results in a biphasic relation between DO2 and O2 (Fig. 2-28) (14). At normal or high levels of DO2, O2 is constant and independent of DO2 (Fig. 2-28, panel A). As DO2 is gradually reduced, an increased EO2 maintains the O2 (panel B). Eventually a point is reached at which EO2 cannot increase adequately. Below this threshold, the so-called critical DO2, O2 is limited by the supply of oxygen. In anesthetized dogs, the critical DO2 was found to be approximately 10 mL/minute/kg (15). The normal biphasic DO2-O2 relationship has been demonstrated in patients without respiratory failure undergoing coronary artery bypass surgery (16), whereas a direct linear relationship between DO2 and O2 has been demonstrated in patients with acute adult respiratory distress syndrome (17,18), implying a pathologic impairment to tissue extraction of oxygen in these patients. A decrease in DO2 can follow a reduction in any one of its major factors (Hb, SaO2, or CO) or a small reduction in more than one of these factors, such as may occur in critical illness. Old terminology referred to the conditions of hypoxia resulting from reductions in Hb, SaO2, and CO, as anemic, hypoxic, and stagnant hypoxia, respectively.

FIG 2.28. Changes in systemic oxygen consumption (A) and oxygen extraction ratio (B) during progressive reduction in oxygen delivery. An increased oxygen extraction ratio maintains oxygen consumption at a constant level until oxygen delivery is lowered to a critical value (DO 2crit). The dashed line demonstrates the theoretical increase in oxygen extraction required to maintain oxygen consumption for levels of oxygen delivery below DO 2crit.  (Modified from Schumacker PT, Cain SM. The concept of critical oxygen delivery Intensive Care Med 1987;13;223, with permission.)

Equations 2-6, 2-10, and 2-12 can be applied to individual tissues by substituting local blood flow for CO and local venous oxygen measurements for mixed venous oxygen measurements. The individual body tissues vary widely with respect to the relation between baseline DO2 and VO2, and therefore also in their baseline EO2 (Table 2-1). For example, in the left ventricle baseline EO2 is 70% to 75%, whereas in the kidney it is 5% to 10%. The high baseline EO2 of the left ventricle renders it extremely dependent on changes in blood flow to maintain adequate oxygen transport.


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Control of coronary blood flow

Blood flow to the myocardium, like that to other vascular beds, is a function of the arteriovenous pressure gradient and the local vascular resistance. In the left ventricular wall, coronary vascular resistance is determined by the throttling effect caused by extravascular compressive forces during systole and by active changes in the tone of arteriolar smooth muscle (Fig. 2-29). The mechanical impediment to coronary blood flow is most prominent in the subendocardial layers of the left ventricular wall. This factor means that blood flow in the left coronary circulation occurs predominantly during diastole, rather than during systole, as is the case elsewhere, including the right coronary circulation. The pressure gradient for blood flow in the left ventricular wall is approximated by the difference between aortic diastolic pressure and left ventricular end-diastolic pressure. Local metabolic mechanisms predominate in the active control of coronary vasomotor tone. These mechanisms provide a close coupling between coronary blood flow and myocardial oxygen demand, which serves to maintain myocardial PO2 (and coronary sinus PO2) an an almost constant level. Adenosine, a breakdown product of ATP, is a potent endogenous vasodilator that is thought to play a central role in the metabolic regulation of coronary perfusion. However, other chemical factors may also contribute, including oxygen, hydrogen ions, carbon dioxide, and nitric oxide (released from the vascular endothelium). The term autoregulation refers to the intrinsic capability of the coronary circulation to maintain a relatively constant coronary blood flow over a wide range of perfusion pressures, by metabolic and/or myogenic mechanisms. A myogenic response refers to the intrinsic tendency of vascular smooth muscle to contract in response to increased distending pressure and to relax in response to decreased distending pressure. The higher tissue pressures in the subendocardium result in a reduced autoregulatory capability in the subendocardium compared with the subepicardium. This contributes to the greater vulnerability of that region to infarction during coronary insufficiency. The coronary arterioles are endowed with - (constricting) and 2- (dilating) adrenergic receptors and with muscarinic receptors, and they are supplied by sympathetic and parasympathetic (vagus) nerves. These autonomic pathways normally play a secondary role in coronary vascular regulation.

FIG 2.29. Factors influencing coronary vascular resistance. (Modified from Rubio R, Berne RM. Progress in cardiovascular diseases. New York: Grune & Stratton, 1975;18:105, with permission.)

Coronary reserve assessed by analysis of the reactive hyperemic response

The transient increase in blood flow above the control rate that follows an interval of arterial occlusion is termed a reactive hyperemia (Fig. 2-30). The temporal characteristics of this response have been explained by the concept that metabolites produced in the ischemic tissue first dilate the resistance vessels and then are washed out during reperfusion. A coronary occlusion of 60 seconds is usually required to maximally dilate the coronary circulation and therefore to assess the coronary reserve. Longer occlusions only increase the duration of the reactive hyperemic response. Coronary reserve in the normal right and left ventricular walls is appreciable (500% to 600%), but it is reduced in a variety of conditions, including left ventricular hypertrophy, coronary obstruction, and hemodilution (19) (Fig. 2-30). A diminished coronary reserve renders the myocardium more vulnerable to ischemia secondary to increases in cardiac work or reductions in perfusion pressure.

FIG 2.30. Coronary reserve assessed by analysis of the reactive hyperemia response in the right coronary circulation of a dog. Graded hemodilution was associated with a progressive diminution of this response. (From Crystal GJ, Kim S-J, Salem MR. Right and left ventricular O2 uptake during hemodilution and -adrenergic stimulation. Am J Physiol 1993:265:H1769, with permission.)

Determinants of myocardial oxygen consumption

The heart is a continuously active organ that normally depends almost exclusively on aerobic metabolism to meet its energy demands. Although the heart constitutes less than 0.5% of the weight of the body, it accounts for approximately 7% of the body's basal oxygen consumption. The utilization of substrates by the heart depends on their availability as well as the heart's nutritional status and hormonal influences. Various substrates—including glucose, fatty acids, lactate, pyruvate, acetate, ketone bodies, and amino acids—can serve as energy sources, although under physiologic conditions glucose and fatty acids are the major substrates. The most important determinants of myocardial oxygen consumption are contractility, HR, and wall tension (Fig. 2-31). Other points worthy of mention are the following: (a) Wall tension is directly proportional to the pressure and radius of the heart and inversely proportional to the wall thickness (law of Laplace); the area beneath the left ventricular pressure pulse per minute, the time-tension index (TTI), bears a direct relation to myocardial oxygen consumption. (b) When external work (pressure x SV) is considered, pressure work has a much greater oxygen cost than does flow work. Muscle shortening per se has only a small influence on myocardial oxygen consumption. (c) Basal metabolism reflects ATP-requiring processes not directly related to contraction, such as activity of cell membrane Na+,K+-ATPase for maintaining the ionic environment, and other cellular processes such as protein synthesis. (d) The oxygen cost of activation comprises two components: electrical activation, and release and uptake of calcium by the sarcoplasmic reticulum.

FIG 2.31. Determinants of myocardial oxygen consumption. (From Marcus ML. The coronary circulation in health and disease. New York: McGraw-Hill, 1983, with permission.)

Conditions having detrimental influence on myocardial oxygen balance: mechanisms of myocardial ischemia

When the vasodilator reserve of the coronary bed is limited by a proximal stenosis (or by hypoxemia or anemia), the myocardium, especially the subendocardium, becomes vulnerable to ischemia (i.e., oxygen demands exceeding oxygen delivery). The factors tending to promote this condition are presented on Fig. 2-32. An increase in HR is especially detrimental to oxygen delivery/demand balance because it decreases coronary blood flow (via a shortening of the diastolic period) while also increasing myocardial oxygen demand. An increase in preload also reduces coronary blood flow by compromising the pressure gradient, and it increases myocardial oxygen demand via an increase in wall tension. Although an increase in aortic pressure tends to augment coronary blood flow by increasing driving pressure, it also increases myocardial oxygen demand via an increase in wall tension. Therefore, its net effect depends on the balance between these factors. Under conditions of restricted coronary vasodilator reserve, the most favorable hemodynamic situation is characterized by a low HR and preload, a normal aortic pressure, and a normal to moderate inotropic state (20).

FIG 2.32. Conditions having detrimental influence on myocardial oxygen balance: mechanisms of myocardial ischemia.

In the early 1970s, Hoffman and Buckberg (21) proposed the endocardial viability ratio (EVR) as an index to detect subendocardial ischemia. The EVR reflects the relationship between indices of oxygen supply (blood flow) and oxygen demand in subendocardium. The diastolic pressure-time index (DPTI) is used an index for blood flow to subendocardium. This index is based on the proposition that blood flow to the subendocardium occurs primarily during diastole and therefore is dependent on the integrated pressure difference between the aorta and left ventricle. The time-tension index (TTI) is used as an estimate for oxygen demand in the subendocardium:

A normal value for EVR is 1.0 or greater. An EVR lower than 0.7 is considered to reflect subendocardial ischemia. The reliability of EVR as an index for detecting subendocardial ischemia intraoperatively is open to debate. Marcus (22) has criticized EVR on the basis that DPTI does not take into account a host of factors, including pathologic changes (e.g., cardiac hypertrophy), drugs, and neural stimuli, that have potential independent effects on the transmural distribution of left ventricular perfusion, and that TTI ignores important determinants of myocardial oxygen demand (e.g., changes in contractility and ventricular wall thickness, such as occurs in hypertrophy).

Two other indices are used clinically as estimates of myocardial oxygen demand. The rate-pressure product (RPP) is obtained by multiplying the systolic arterial pressure (SAP) by the HR:

The triple index (TI) adds an estimate of left ventricular end-diastolic volume, the pulmonary capillary wedge pressure (PCWP), to the index of myocardial oxygen demand:

Determinants of coronary steal

Coronary steal refers to the phenomenon in which small-vessel dilation and an increase in flow to an area of already well-perfused myocardium leads to a decrease in flow to another area of myocardium with borderline perfusion and limited coronary reserve. Coronary steal can occur between two arteries connected by collateral vessels (intercoronary steal) or from subendocardium to subepicardium distal to a coronary stenosis (transmural steal). A schematic diagram demonstrating the hemodynamic basis of vasodilator-induced intercoronary steal is shown in Fig. 2-33. Under the control condition (panel A) in this hypothetical situation, (a) the left anterior descending coronary artery (LAD) is completely occluded, and the myocardium in its perfusion territory receives flow via collateral vessels originating at the circumflex artery (CX); (b) the CX has a significant stenosis; (c) collateral flow to the LAD bed is equal to antegrade flow to the CX bed; and (d) resistance vessels in the LAD bed are maximally dilated, so blood flow in this region is pressure-dependent. On the other hand, resistance vessels in the CX bed retain a significant vasdilator reserve capacity. Coronary steal occurs (panel B) when a vasodilator, either a drug or a physiologic factor such as hypercapnia, reduces vascular resistance in the distal CX bed, which increases the rate of blood flow through the CX. This steepens the pressure drop within this artery, resulting in a reduced pressure at the source of the collateral vessels and a decrease in collateral flow to the pressure-dependent LAD bed.

FIG 2.33. Mechanism of coronary steal. A: Control condition. B: Vasodilator-induced coronary steal.

Transmural steal occurs because the subepicardium has a greater capacity for autoregulation than does the subendocardium. This is probably the result of the higher tissue pressures in the subendocardium. Coronary steal can precipitate myocardial ischemia if the decrease in flow is not accompanied by a proportional decrease in myocardial oxygen demand.

Nitric oxide: its source, release, and functions in the cardiovascular system

In 1980, Furchgott and Zawadzki observed that acetylcholine-induced relaxation of isolated arterial segments required an intact endothelium (23). This observation led to their conclusion that acetylcholine was acting on the muscarinic receptors located on the endothelial membrane to cause release of a vasodilating substance, which they termed endothelium-derived relaxing factor (EDRF). In 1987, EDRF was identified as nitric oxide (NO) (24). It is now known that NO is a ubiquitous molecule that has important roles in the circulation system and elsewhere, including roles in immunologic reactions and as a neurotransmitter in the central nervous system (24).

Figure 2-34 shows the signal-transduction pathway for endothelium-derived NO.

FIG 2.34. Diagram showing the signal-transduction pathway for endothelium-derived nitric oxide.

NO is a free radical produced in the vascular endothelium from the amino acid L-arginine in a reaction requiring the constitutive enzyme nitric oxide synthase (NOS) (24). NOS activity is stimulated by increases in intracellular calcium concentration, which occur in response to the interaction of a chemical agent in the blood (e.g., bradykinin, acetylcholine) with its specific membrane receptor or by increases in shear stress. Constitutive NOS produces small quantities of NO (picomoles) over short periods (seconds). Endothelium-derived NO diffuses into the underlying vascular smooth muscle, where it stimulates production of cyclic guanosine monophosphate (cGMP), thereby causing vascular relaxation. In the circulation, NO is rapidly scavenged by hemoglobin. Inhibitors of NOS have been shown to produce hypertension in animals, implying that basally released NO maintains a tonic vasodilator tone in the systemic resistance vessels (25).

NO has important physiologic roles in the circulation, in addition to its vasodilating effect. It is a potent inhibitor of platelet aggregation and adhesion to the endothelial surface (24,26). Furthermore, platelets that do aggregrate release serotonin and adenosine diphosphate, which in turn act on the endothelium to cause massive release of NO, resulting in vasodilation and a flushing out of the developing thrombus. NO also inhibits leukocyte activation and proliferation of vascular smooth muscle cells. Recent evidence suggests that constitutive NOS is normally expressed in tissues other than the vascular endothelium, including the endocardial endothelium, myocytes, and neurons in the myocardium (27,28).

NO may influence cardiac function indirectly by affecting vascular tone and directly by influencing the cGMP pathway in the myocytes themselves. With respect to the indirect mechanisms, coronary endothelial dysfunction may impair cardiac function by compromising coronary blood flow and oxygen delivery. Furthermore, changes in peripheral arterial tone may influence cardiac function via variations in ventricular afterload, whereas changes in peripheral venous tone and capacitance may alter cardiac function via variations in preload (Starling mechanism). Evidence for the former mechanism are the decreases in SV and CO that characteristically accompany the peripheral vasoconstriction caused by NOS inhibitors (25).

Studies in various in vitro cardiac preparations have demonstrated that both endogenous NO and NO donors may have direct cGMP-mediated negative inotropic actions (27,28). However, results obtained in vivo suggest that these actions do not apply to the normal, in situ heart exposed to physiologically relevant levels of NO (29). NO release from the vascular endothelium is inhibited in a number of pathologic conditions, including atherosclerosis, diabetes mellitus, and hypercholesterolemia (30). Vascular endothelial dysfunction may promote coronary vasospasm.

A second isoform of NOS, so-called inducible NOS, has been identified (24,31,32). Inducible NOS is not normally present and has no physiologic role, but it is expressed after stimulation by microbial products (e.g., endotoxin) or by inflammatory mediators, including the cytokines, interleukin-1 (IL-1), IL-2, IL-6, and tumor necrosis factor. Activity of inducible NOS is not sensitive to calcium concentration. Inducible NOS was originally described in macrophages but subsequently identified in the vascular endothelium, vascular smooth muscle, and myocardial cells. Inducible NOS is generally activated by induction of transcription over several hours. It can produce large quantities of NO (nanomoles) over extended periods (hours). It can have cytotoxic effects either directly or via reaction with superoxide anion (O2) to form peroxynitrite (OONO), which is a potent oxidant capable of causing significant cellular damage. Formation of peroxynitrite has been demonstrated in tissue during inflammation, hypoxia-reoxygenation, and ischemia-reperfusion (33,34). The expression of inducible NOS is inhibited by glucocorticoids. The inducible NOS isoform is responsible for the uncontrolled, excessive vasodilation associated with septic shock, and it may be involved in acute myocarditis, dilated cardiomyopathy, and cardiac transplant rejection (31,32).

The vasodilating effects of sodium nitroprusside and nitroglycerin have been explained by their ability to provide exogenous NO (35). Inhaled NO has been shown to be a potent and selective pulmonary vasodilator that may have a role in the treatment of adult respiratory distress syndrome, pulmonary hypertension, and asthma (36,37).


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  1. Segard JL, Bosnjak ZJ, Hopp FA Jr, et al. Cardiovascular effects of general anesthetics. In: Covino BJ, , Fozzard HA, , Rehder K,, et al., eds. Effects of anesthesia. Bethesda, MD: American Physiological Society, 1985:149.
  2. Krogh A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol (London) 1919;52:409.
  3. Kety SS. Determinants of tissue oxygen tension. Fed Proc 1957;16:666.
  4. Crystal GJ, Weiss HR.VO2 of resting muscle during arterial hypoxia: role of reflex vasoconstriction. Microvasc Res 1980;20:30.
  5. Crystal GJ, Downey HF, Bashour FA. Small vessel blood and total coronary blood volume during intracoronary adenosine infusion. Am J Physiol 1981;241:H194.
  6. Tenny SM. Theoretical analysis of the relationship between venous blood and mean tissue oxygen pressure. Respir Physiol 1975;20:283.
  7. Nunn JF, Makita K, Royston B. Validation of oxygen consumption measurements during artificial ventilation. J Appl Physiol 1989;67:2129.
  8. Makita K, Nunn JF, Royston B. Evaluation of metabolic measuring instruments for use in critically ill patients. Crit Care Med 1990;18:638.
  9. Smithies MN, Royston B, Makita K, et al. Comparison of oxygen consumption measurements: indirect calorimetry versus the reversed Fick method. Crit Care Med 1991;19:1401.
  10. Webster NR, Nunn JF. Molecular structure of free radicals and their importance in biological reactions. Br J Anaesth 1988;60:98.
  11. Astiz ME, Rackow EC, Kaufman B, et al. Relationship of oxygen delivery and mixed venous oxygenation and to lactate acidosis in patients with sepsis and acute myocardial infarction. Crit Care Med 1988;16:655.
  12. Pinsky MR. Assessment of adequacy of oxygen transport in the critically ill. Appl Cardiopulm Pathophysiol 1990;3:271.
  13. Levy PS, Chavez RP, Crystal GJ, et al. Oxygen extraction ratio: a valid indicator of transfusion need in limited coronary vascular reserve? J Trauma 1992;32:769.
  14. Schumacker PT, Cain SM. The concept of critical oxygen oxygen delivery. Intensive Care Med 1987;13:223.
  15. Cain SM. Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol 1977;42:228.
  16. Shibutani K, Komatsu T, Kubal K, et al. Critical level of oxygen delivery in anesthetized man. Crit Care Med 1983;11:640.
  17. Danek SJ, Lynch JP, Weg JG, et al. The dependence of oxygen uptake on oxygen delivery in the adult respiratory distress syndrome. Am Rev Respir Dis 1980;122:387.
  18. Mohsenifar Z, Goldbach P, Tachkin DP, et al. Relationship between O2 delivery and O2 consumption in the adult respiratory distress syndrome. Chest 1983;84:267.
  19. Crystal GJ, Kim S-J, Salem MR. Right and left ventricular O2 uptake during hemodilution and -adrenergic stimulaton. Am J Physiol 1993;265:H1769.
  20. Hug CC Jr, Shanewise JS. Anesthesia for adult cardiac surgery. In: Miller RD, , ed. Anesthesia, 4th ed, vol 2. New York: Churchill Livingstone, 1994:1757.
  21. Hoffman JIE, Buckberg GD. Regional myocardial ischemia: causes, prediction and prevention. Vasc Surg 1974;8:115.
  22. Marcus ML. The coronary circulation in health and disease. New York: McGraw-Hill, 1983.
  23. Furchgott RF, Zawadzki JV. Obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (London) 1980;288:373.
  24. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109.
  25. Crystal GJ, Zhou X, Halim AA, et al. Nitric oxide does not modulate whole-body oxygen consumption in anesthetized dogs. J Appl Physiol 1999;86:1944.
  26. Vanhoutte PM, Scott-Burden T. The endothelium in health and disease. Tex Heart Inst J 1994;21:62.
  27. Shah AM, Grocott-Mason RM, Pepper CB, et al. The cardiac endothelium: cardioactive mediators. Prog Cardiovasc Dis 1996;39:263.
  28. Kelly RA, Balligand J-L, Smith TW. Nitric oxide and cardiac function. Circ Res 1996;79:363.
  29. Crystal GJ, Gurevicius J. Nitric oxide does not modulate myocardial contractility acutely in in situ canine hearts. Am J Physiol 1996;270:H1568.
  30. Searle NR, Sahab P. Endothelial vasomotor regulation in health and disease. Can J Anaesth 1992;39:838.
  31. Birks EJ, Yacoub MH. The role of nitric oxide and cytokines in heart failure. Coron Artery Dis 1997;8:389.
  32. De Belder AJ, Ramdomski MW, Martin JF, et al. Nitric oxide and the pathogenesis of heart muscle disease. Eur J Clin Invest 1995;25:1.
  33. Lefer AM, Lefer DJ. Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. Ann Rev Pharmacol Toxicol 1993;33:71.
  34. Xie Y-W, Wolin MS. Role of nitric oxide and its interaction with superoxide in the suppression of cardiac muscle mitochondrial respiration: involvement in response to hypoxia/reoxygenation. Circulation 1996;94:2580.
  35. Anderson TJ, Meredith IT, Ganz P, et al. Nitric oxide and nitrovasodilators: similarities, differences, and potential interactions. J Am Col Cardiol 1994;24:555.
  36. Conti CR. Nitric oxide as a therapeutic agent. Clin Cardiol 1994;17:227.
  37. Lowson SM, Rich GF, McArdle PA, et al. The response to varying concentrations of inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesth Analg 1996;82:574.

Suggested Readings

Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. Boston: Little, Brown, 1976.

Edwards JD, Shoemaker WC, Vincent J-L, eds. Oxygen transport: principles and practice. London: WB Saunders, 1993.

Feigl EO.Coronary physiology. Physiol Rev 1983;63:1.

Honig CR. Modern cardiovascular physiology. Boston: Little, Brown, 1981.

Nunn JF. Nunn's applied respiratory physiology. Oxford: Butterworth-Heinemann, 1993.

Weibel ER. The pathway for oxygen. Cambridge: Harvard University Press, 1984.