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51.e2 PART II Scientiﬁc Foundation of Cardiac Intensive Care

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41. Cain SM. Supply dependency of oxygen uptake in ARDS: myth or reality? Am J Med Sci. 1984;288(3):119–124.

42. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med. 1987;13:223–229.

43. Wittenberg BA, Wittenberg JB. Transport of oxygen in muscle. Annu Rev Physiol. 1989;51:857–878.

44. Wittenberg BA, Wittenberg JB. Myoglobin-mediated oxygen delivery to mitochondria of isolated cardiac myocytes. Proc Natl Acad Sci USA. 1987;84:7503–7507.

45. Garry DJ, Ordway GA, Lorenz JN, et al. Mice without myoglobin. Nature. 1998;395(6705):905–908.

46. Kanatous SB, Garry DJ. Gene deletional strategies reveal novel physiological roles for myoglobin in striated muscle. Respir Physiol Neurobiol. 2006;151(2–3):151–158.

47. Wagner PD. Muscle O2 transport and O2 dependent control of metabolism. Med Sci Sports Exerc. 1995;27(1):47–53.

48. Cerretelli P, Marconi C, Pendergast D, et al. Blood ﬂow in exercising muscles by xenon clearance and by microsphere trapping. J Appl Physiol. 1984;56(1):24–30.

49. Gronlund J, Malvin GM, Hlastala MP. Estimation of blood ﬂow distribution in skeletal muscle from inert gas washout. J Appl Physiol. 1989;66(4):1942–1955.

50. Richardson RS, Haseler LJ, Nygren AT, Bluml S, Frank LR. Local perfusion and metabolic demand during exercise: a noninvasive MRI method of assessment. J Appl Physiol. 2001;91:1845–1853.

51. Vogiatzis I, Habazettl H, Louvaris Z, et al. A method for assessing heterogeneity of blood ﬂow and metabolism in exercising normal human muscle by near infrared spectroscopy. J Appl Physiol. 2015;118(6):783–793.

52. Louvaris Z, Habazettl H, Asimakos A, et al. Heterogeneity of blood ﬂow and metabolism during exercise in patients with chronic obstructive pulmonary disease. Respir Physiol Neurobiol. 2017;237:42–50.

53. Piiper J, Meyer M, Scheid P. Dual role of diffusion in tissue gas exchange: blood-tissue equilibration and diffusion shunt. Respir Physiol. 1984;56:131–144.

54. Honig CR, Gayeski TEJ. Precapillary O2 loss and arteriovenous O2 shunt are below limit of detection in myocardium. Adv Exp Med Biol. 1989;247:591–599.

55. Gaehtgens P, Kreutz F Skeletal muscle perfusion, exercise capacity, and the optimal hematocrit. In: Brendez, Zink, editors. High Altitude Physiology and Medicine. 1982:123-128.

56. Piiper J, Haab P. Oxygen supply and uptake in tissue models with unequal distribution of blood ﬂow and shunt. Respir Physiol. 1991;84:261–272.

57. Zapol WM, Falke KJ. Acute Respiratory Failure. New York: Marcel Dekker, Inc; 1985.

58. Pinsky MR, Dhainaut J-FA. Pathophysiologic Foundations of Critical Care. Baltimore: Williams & Wilkins; 1993.

59. Samsel RW, Schumacker PT. Determination of the critical O2 delivery from experimental data: sensitivity to error. J Appl Physiol. 1988;64(5):2074–2082.

60. Cain SM. Peripheral oxygen uptake and delivery in health and disease. Clin Chest Med. 1983;4(2):139–148.

61. Wagner PD. An integrated view of the determinants of maximum oxygen uptake. In: Gonzalez NC, Fedde MR, eds. Oxygen Transfer From Atmosphere to Tissues. Vol. 227. New York: Plenum Press; 1988:245–256.

62. Wilson DF, Erecinska M, Drown C, Silver IA. Effect of oxygen tension on cellular energetics. Am J Physiol. 1977;233: C135–C140.

63. Mik EG, Stap J, Sinaasappel M, et al. Mitochondrial PO2 measured by delayed ﬂuorescence of endogenous protoporphyrin IX. Nat Methods. 2006;3(11):939–945.

64. Schlichtig R. O2 uptake, critical O2 delivery, and tissue wellness. In: Pinsky MR, Dhainaut J-FA, eds. Pathophysiologic Foundations of Critical Care. Baltimore, MD: Williams & Wilkins; 1993:119–139.

65. Cain SM. Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol. 1977;42(2):228–234.

66. Hogan MC, Bebout DE, Wagner PD. Effect of hemoglobin concentration on maximal O2 uptake in canine gastrocnemius muscle in situ. J Appl Physiol. 1991;70:1105–1112.

67. Schaffartzik W, Barton ED, Poole DC, et al. Effect of reduced hemoglobin concentration on leg oxygen uptake during maximal exercise in humans. J Appl Physiol. 1993;75:491–498.

68. Samsel RW, Nelson DP, Sanders WM, Wood LDH, Schumacker PT. Effect of endotoxin on systemic and skeletal muscle O2 extraction. J Appl Physiol. 1988;65(3):1377–1382.

69. Samsel RW, Cherqui D, Peitrabissa A, et al. Hepatic oxygen and lactate extraction during stagnant hypoxia. J Appl Physiol. 1991;70:186–193.

70. Nelson DP, Samsel RW, Wood LDH, Schumacker PT. Pathological supply dependency of systemic and intestinal O2 uptake during endotoxemia. J Appl Physiol. 1988;64:2410–2419.

71. Matuschak GM, Martinez LH. Sepsis syndrome: pathogenesis, pathophysiology, and management. In: Pinsky MR, Dhainaut J-FA, eds. Pathophysiologic Foundations of Critical Care. Baltimore: Williams & Wilkins; 1993:170–187.

72. Archie JP Jr. Mathematic coupling of data: a common source of error. J Appl Physiol. 1980;193:296–303.

73. Block ER. Oxygen therapy. In: Fishman AP, ed. Pulmonary Diseases and Disorders. New York: McGraw-Hill; 1988:2317–2330.

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Regulation of Cardiac Output

Sándor J. Kovács

OUTLINE

Arteriovenous Oxygen Difference, 52 Reﬂex Control of Cardiac Output, 53 Left Ventricular Performance, 54

Pressure-Volume Loop, 54 Effect of Alterations in Preload on the Pressure-Volume

Loop, 54

End-Systolic Pressure-Volume Relationship, 54

Effect of Changes in Contractile

State, 55

Effect of Afterload Change, 55

Pressure-Volume Approach Applied to Pathologic

Conditions, 56

Acute Systolic Dysfunction, 56 Diastolic Dysfunction, 57 Aortic Stenosis, 57 Mitral Stenosis, 58 Valvular Regurgitation, 58 Dilated Cardiomyopathy, 58

Limitation of the Pressure-Volume Approach, 59 Conclusion, 59

The cardiovascular system includes the four-chambered heart, arteries, veins, and lymphatics. Pulsatile arterial ﬂow supplies tissues with oxygen and metabolic substrates, and nonpulsatile venous ﬂow removes carbon dioxide and other metabolic products. The lymphatics ensure conservation of volume at the microvascular level. The functional integration of all these active and passive components (venous circulation, right heart, lungs and pulmonary vascular system, left heart and arterial circulation) generates the cardiac output.

The most useful conceptual framework for quantifying cardiac

output (CO) is the physiologic analog of Ohm’s law (V = IR; with V meaning voltage, I, current, and R, resistance) expressed as Pressure (mm Hg) = CO (L/min) × Resistance (mm Hg min/L). In the clinical setting, CO is usually measured using indicator dilution techniques. A common approach during right heart catheterization is to inject a bolus of cold 5% dextrose into the right atrium through the proximal port of a multilumen (Swan-Ganz) catheter and measure the resulting transient drop in blood temperature downstream, in the pulmonary artery, using a thermistor on the tip of the catheter. The recorded (temperature as a function of time) thermodilution curve obeys the Stewart-Hamilton equation and allows computation of CO. Alternatively, CO can be measured using the Fick principle. Oxygen consumption rate can be measured by collecting expired gases or, less accurately, assuming a consumption value using a standard nomogram based on height, weight, and age. The difference in arterial and pulmonary venous oxygen content (A-VO2

difference, in milliliters of O2/100 mL of blood) is measured. CO is calculated as:

O2, the oxygen content of blood can be obtained as: O2 content

= Hb[g/dL] × 1.34 (mL of O2/g of Hb) × O × PO2 (torr). Normally, arterial blood is 99% saturated and venous

blood is 75% saturated; hence arterial blood contains about 200 mL of O2/L and venous blood contains 150 mL O2/L.

as the cardiac index (CI). Normal CI at rest ranges from 2.5 to

4.2 L/min per m2. CO can decline by almost 40% without deviat-

ing from normal limits. A low resting CI of less than 2.5 L/min per m2 usually indicates a marked abnormality in cardiovascular performance and is almost always clinically apparent. Although resting CO or CI is an insensitive measure of cardiovascular performance in response to demand, resting values are valuable for decision making in critically ill patients.

ARTERIOVENOUS OXYGEN DIFFERENCE

Maintenance of adequate tissue oxygenation depends on the integrated function of the heart, the central and peripheral vasculature, lungs, blood, and metabolism.2 According to the Fick principle, the oxygen extracted from the circulation and consumed by the body is equal to the product of the CO and the

CO OconsumptionA-Vodifference=

Since each gram of hemoglobin (Hb) can carry 1.34 mL of

saturation fraction

CO is usually normalized for body surface area and expressed

(1)

+ 0.0032

CHAPTER 5 Regulation of Cardiac Output 53

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A-VO2 difference. Under normal circumstances at rest, oxygen delivery exceeds consumption, so that adequate tissue oxygenation is provided with an A-VO2 difference of 40 ± 10 mL/L. If CO decreases, tissues extract a greater fraction of oxygen from the arterial blood, and mixed venous oxygen saturation decreases. If arterial oxygen tension and serum hemoglobin are normal, a mixed venous oxygen saturation of 70% or more is observed, indicating that oxygen delivery is sufﬁcient to meet the physiologic need.

A wide A-VO2 difference and reduced mixed venous oxygen saturation may result from reduced CO, a defect in blood oxygen-carrying capacity, or pulmonary disease (impairment of gas exchange). Once tissue is no longer able to increase its extraction of oxygen, tissue hypoxia results. Under these conditions, anaerobic metabolism manifests by a precipitous increase in venous lactate levels.

During exercise, oxygen consumption can increase 18-fold. This demand for increased oxygen delivery is met by a sixfold increase in CO (from 3 to 18 L/min per m2), and a concomitant threefold increase in the A-VO2 difference (from 40 to 120 mL/L), resulting in a mixed venous oxygen saturation decrease from 75% to 25%. Since CO = SV (stroke volume) × HR (heart rate), the six-fold increase in CO is not accompanied by a sixfold increase in HR, indicating that SV must increase as HR increases in response to increased demand.

The resting myocardium nearly maximally desaturates oxygenated (99% saturated) blood. Hence, coronary sinus oxygen saturation is low (<40%), and therefore an increase in oxygen extraction as a compensatory mechanism for inadequate coronary nutritive ﬂow cannot be utilized by the myocardium.

REFLEX CONTROL OF CARDIAC OUTPUT

Under normal conditions, the heart has a large functional reserve; it is usually not the limiting factor in determining CO. The arterial (perfusion) pressure and CO adjust to meet the needs of the body as they vary with posture and activity. The regulatory mechanisms involve sensory and effector components. The sensory components include peripheral receptors that react to changes in blood pressure (e.g., baroreceptors in aortic arch and carotid sinuses), blood volume (e.g., stretch receptors in the atria, Bainbridge reﬂex), and ventilation (e.g., carotid chemoreceptors). In addition, there are loci in the cortex, hypothalamus, and diencephalon of the brain that react to emotions, anxiety, anticipation, exercise, hypoxia, and temperature. CO (as described by Ohm’s law) is modulated through changes in HR, SV, and vasomotor tone (peripheral resistance) that are mediated by direct parasympathetic and sympathetic neural pathways and by circulating catecholamines. Other humoral factors—such as adrenocortical steroids, thyroid hormones, insulin, and glucagons—have been shown to have an effect on cardiac function, requiring longer time scales; the importance of these hormones for regulation of CO is unclear. It should be noted that the heart is also an endocrine organ—by virtue of the fact that the atria function as volumetric strain gauges in response to being distended (increased volume), by generating atrial natriuretic peptide (ANP), and by increasing sodium and water excretion to achieve volume control by targeting the kidney.

Direct sympathetic neural stimulation and circulating catecholamines exert a powerful stimulatory effect, increasing HR and contractile state, whereas vagal stimulation decreases HR and contractile state. The sympathetic and parasympathetic systems interact with each other in a complex fashion to inﬂuence cardiovascular performance. In general, two types of interactions exist: accentuated antagonism and reciprocal excitation.5 Accentuated antagonism refers to the ﬁnding that the negative inotropic and chronotropic effects of vagal stimulation are more pronounced when vagal stimulation occurs in the presence of an increased adrenergic tone. Reciprocal excitation refers to the paradoxical effects of stimulation by one division on the autonomic nervous system, which results in effects normally expected from stimulation by the opposite autonomic division. The most common example of this is the production of positive inotropic effects by vagal stimulation or acetylcholine administration under experimental conditions.

The factors that inﬂuence CO are summarized in Table

5.1. The CO regulatory system can become dysfunctional and

result in syncope as a result of enhanced atrial and peripheral baroreceptor sensitivity, autonomic dysfunction, or complete heart block. In a critically ill cardiac patient, the normal regulatory/ compensatory mechanisms are usually saturated by maximal sympathetic and catecholamine stimulation. Under these conditions, the major CO determinants are no longer the normal neurohormonal regulatory pathways but rather the interaction between pump function and load, that is, peripheral vasculature.

TABLE 5.1 Factors That Inﬂuence

Cardiac Output

Factor Effects

Sympathetic tone ↑ Contractile state, ↑ heart rate Vagal tone ↓ Contractile state Right vagus ↓ Sinus node activity, sinus

bradycardia

Left vagus ↓ Atrioventricular conduction Volume load ↑ Heart rate (Bainbridge reﬂex) Baroreceptor stimulation (aortic

arch, carotid sinus)

Calcium administration ↑ Contractile state Hormones (epinephrine, glucagon,

thyroxine)

Drugs

Positive Inotropes

Phosphodiesterase inhibitors

(milrinone, amrinone, theophylline)

Digitalis glycosides ↑ Contractile state, ↓ atrioventricular

Adrenergic stimulants (dopamine,

dobutamine)

Negative Inotropes

β-adrenergic antagonists ↓ Contractile state, ↓ heart rate Calcium channel blockers ↓ Contractile state, ↓ atrioventricular

↓ Contractile state

↑ Contractile state, ↑ heart rate

conduction

↑ Contractile state, ↑ heart rate

conduction

54 PART II Scientiﬁc Foundation of Cardiac Intensive Care

LV volume

LV pressure

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The determinants of ventricular pump function are of paramount importance.

LEFT VENTRICULAR PERFORMANCE

Pressure-Volume Loop

Although the integrity of left ventricular (LV) and right ventricular (RV) function and pulmonary and peripheral circulations is important, most cardiovascular dysfunction in adults is the result of impaired LV function. The performance of the LV can be understood by examining the relationship between LV pressure and volume during a single cardiac cycle in the pressure-volume plane (Fig. 5.1). Instantaneous intraventricular pressure is plotted on the y axis and simultaneous ventricular volume is plotted on the x axis. At end diastole (point a), ventricular pressure is relatively low and ventricular volume is relatively high. The segment ab is due to isovolumic contraction (typically <90 ms), with an increase in intraventricular pressure but no ejection. Point b represents the start of ejection, coincident with the opening of the aortic valve when ventricular pressure exceeds aortic pressure (AoP). Note that after peak AoP is reached and AoP begins to decline—the aortic valve (AoV) is still open and LV volume is decreasing. At end systole (point c), the AoV closes, and isovolumic relaxation (typically <90 ms) commences (segment cd). The mitral valve opens at point d, when ventricular pres- sure decreases to less than atrial pressure, and ventricular ﬁlling commences. By deﬁnition, the slope (dP/dV) of the end-diastolic pressure volume relationship (EDPVR) at a given end-diastolic volume is the chamber stiffness. Note that left ventricular pressure (LVP) continues to decrease until minimum LVP is reached after mitral valve opening, In other words, as LV volume increases, LV pressure continues to drop (dP/dV<0) until minimum LV pressure is reached.

The difference between the end-diastolic and end-systolic

volumes (aortic SV) or end-systolic and end-diastolic volumes

Stroke volume

Fig. 5.1 For a single cardiac cycle, instantaneous left ventricular

(LV) pressure is plotted against LV volume. Point a represents end diastole and the start of isovolumic contraction. Ventricular pressure increases without any change in volume until ejection starts at point b, which represents the opening of the aortic valve. During ejection, ventricular volume decreases. Point c represents end systole and the start of isovolumic relaxation. Aortic valve closure occurs near end systole. Ventricular pressure continues to decrease until ventricular ﬁlling starts with the opening of the mitral valve at point d. Ventricular pressure increases very slightly during diastolic ﬁlling.

(diastolic ﬁlling volume) deﬁnes the SV. The ratio of SV to end-diastolic volume (EDV) is the LV ejection fraction (LVEF). The LVEF is a clinically useful index of systolic and diastolic function. LVEF = SV/LVEDV is interpreted as a systolic function index. Its role as a diastolic function index is easily appreciated when rewritten as LVEF = [E-wave volume + A-wave volume]/ [LV diastatic volume + A-wave volume]. In atrial ﬁbrillation, this reveals that LVEF = [E-wave volume]/[LV volume at diastasis], underscoring the physiologic importance of LV volume at diastasis as the equilibrium volume of the LV.6 In the absence of aortic stenosis, the LV pressure at end systole is the same as the pressure in the proximal aorta and approximates systolic blood pressure (actually the pressure at the dicrotic notch in the aortic pressuretime course). The pressure-volume (PV) loop provides a useful way to analyze the effects of contractile state, preload, and afterload on CO. The area of the PV loop is the external work of the ventricle.

Effect of Alterations in Preload on the Pressure-Volume Loop

Preload (in sinus rhythm) is deﬁned as the stretch of the myocardium by atrial systole before activation and is readily indexed by end-diastolic volume. Within physiologic ranges, the greater the stretch on the myocardium, the stronger the ensuing contraction; this is known as the Frank-Starling relationship.7 This prestretch is absent in atrial ﬁbrillation. From studies in isolated heart preparations in which preload, afterload, and contractile state were controlled, it has been shown that an increase in preload, produced by an increase in end-diastolic volume, results in an increase in the end-systolic pressure and SV of the ensuing beat.

8–10

Three PV loops under three different preload conditions are shown in Fig. 5.2. For clarity, it is assumed that HR, contractile state, and afterload remain constant. Baseline conditions are represented by the shaded loop. A decrease in preload as a result of loss of blood volume, if not associated with any other change in afterload or contractile state, results in a smaller EDV and a smaller PV loop that is shifted to the left. Conversely, a volume load results in a larger PV loop that is shifted to the right. An isolated increase in preload without any change in afterload or contractile state results in increases in SV and end-systolic pressure if HR, afterload, and contractile state are unchanged. These idealized conditions do not apply precisely in vivo. Isolated changes in preload, afterload, contractile state, or HR occur rarely because these changes are usually a response to, or in themselves result in, compensatory neurohormonal reﬂexes, which simultaneously inﬂuence all of these variables in a complex fashion. It may be useful, however, for an understanding of cardiovascular dynamics to analyze these factors separately.

END-SYSTOLIC PRESSURE-VOLUME RELATIONSHIP

In Fig. 5.2, the end-systolic points of all three PV loops fall on a straight line. This line is termed the end-systolic PV relationship (ESPVR) and is constant for a given contractile state.11 A similar but nonlinear relationship can be constructed for the end-diastolic points—EDPVR. Note that in atrial ﬁbrillation diastasis deﬁnes

CHAPTER 5 Regulation of Cardiac Output 55

=−()

LV volume

increase

LV pressure

LV volume

Increased

contractility

LV pressure

https://t.me/medicina_free

Volume

ESPVR

Volume

decrease

EDPVR

Fig. 5.2 Three different pressure-volume (PV) loops are shown

representing beats at three different preloads. Control conditions are represented by the shaded PV loop. An increase in preload (e.g., a large volume load) is associated with an increase in diastolic ﬁlling and a shift in the end-systolic PV point to the left. The added stretch causes a stronger contraction and an increase in the pressure developed during systole and in stroke volume. The PV loop is larger and shifted to the right (broken lines). Conversely, a decrease in preload, such as a loss of blood volume, results in a smaller PV loop that is shifted to the left (broken lines). The end-systolic points of the three variably loaded beats fall on a straight line. This line represents the end-systolic PV relationship (ESPVR). A similar but curvilinear relationship is formed by the end-diastolic PV points—the end-diastolic PV relationship (EDPVR). LV, Left ventricular.

end diastole; therefore the EDPVR and the diastatic pressure volume relation (DPVR) are the same. In contrast, in sinus rhythm the DPVR and the EDPVR are distinct from each other.12 The ESPVR and EDPVR have been shown to be relatively load independent at a given contractile state

13,14

; however, the ESPVR is not absolutely load independent, probably because of the positive and negative inotropic effects of ejection.

15–17

For practical purposes, at a given contractile state, the cardiac PV loop is always bound by the ESPVR and the EDPVR. For a given contractile state, the ESPVR can conveniently be expressed as follows (see Fig. 5.2):

es es es o

(2)

where Pes is end-systolic pressure, Ves is end-systolic volume, Vo is the volume axis intercept, and Ees is the slope of the ESPVR. Because of its relative load independence, Ees has been proposed

8,11,18

as an index of contractility.9 Vo is interpreted as the volume at which the ventricle can no longer generate force. This “dead volume” is a function of heart size. In actuality, the linear ESPVR often crosses the P = 0 axis at negative values of volume. The explanation is that the actual ESPVR is always curvilinear, thereby avoiding negative Vo values; the linear ESPVR should be viewed as valid only in the physiologic range of SVs.

Effect of Changes in Contractile State

The contractile state of the heart refers to the intrinsic ability of the myocardium at a given load to generate contractile force. The myocardial contractile state is inﬂuenced by several endogenous and

contractility

Depressed

Fig. 5.3 Effect of an increase in contractile state on the pressure-

volume loop and the end-systolic pressure-volume relationship. LV, Left ventricular.

exogenous factors (see Table 5.1). In the PV plane, an increase in contractile state results in an increase in force development—that is, higher pressure—at any given ventricular volume. Conversely, the “dead volume” of the ventricle is unchanged because heart size has not changed. These changes manifest in the PV plane as an increase in the slope of the ESPVR without a change in Vo.11 In Fig. 5.3, preload, afterload, and HR are assumed to be constant. Under these conditions, an increase in contractile state results in an increase in SV and end-systolic pressure. Conversely, in the absence of any compensatory mechanisms, a reduction in myocardial contractility results in a reduction in systolic pressure and SV. Some common compensatory mechanisms are discussed later; ﬁrst, the effect of changes in afterload must be considered.

Effect of Afterload Change

Afterload is the load that the ventricle must overcome to eject volume and, in the absence of valve disease, is determined mainly by the properties of the arterial system. An increase in afterload results in an increase in end-systolic pressure at the expense of ejection. The effect on the PV loop is shown schematically in

Fig. 5.4. SV, EF, and, assuming no change in HR, CO are decreased

despite a constant contractile state. This is a good illustration of the load dependence and limitations of CO and EF as clinical indices of contractile state. As shown in Fig. 5.4, an increase in afterload without a change in contractile state results in changes in the shape of the PV relationship, but the end-systolic points do not deviate signiﬁcantly from the ESPVR. This is an idealized ﬁgure; as stated previously, the end-systolic points are load dependent, allows the conceptual expression of the interaction between LV function and the arterial system.

To understand ventriculoarterial coupling, it is useful to view the arterial system also in terms of PV or pressure-SV relationships, as proposed by Sunagawa and colleagues.19 In this study, the relationship between SV and arterial ESP is linear, and it is assumed that the relationship passes through the origin (Fig.

5.5). The slope of this relationship is termed the arterial elastance

15,17

but a simpliﬁed view sufﬁces for illustration and

56 PART II Scientiﬁc Foundation of Cardiac Intensive Care

LV volume

LV pressure

Stroke volume

AoP

LV volume

Increased

Decreased

LV pressure

systolic pressure

LV pressure

reduced

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Increased

afterload

Decreased

afterload

Fig. 5.4 Effect of changes in afterload is shown in three beats

at different afterloads. An increase in afterload results in an increase in end-systolic pressure but a decrease in stroke volume. A decrease in afterload has opposite effects. The end-systolic pressure-volume points do not deviate signiﬁcantly from the end-systolic pressure-volume relationship (ESPVR). The ESPVR is insensitive to changes in afterload.

Fig. 5.6 The arterial elastance (Ea; end-systolic pressure divided

by stroke volume) is superimposed on the pressure-volume loops for three variably afterload beats. An increase in afterload is represented by an increase in the slope of the arterial elastance. LV, Left ventricular.

Increased afterload

Depressed contractility

Fig. 5.5 The systolic pressure-volume relationship of the arterial

system. The volume of this system at any given time is a function of the stroke volume, which determines the volume increase during systole, and of the vascular resistance to blood ﬂow out of the arterial system and into the venous system. The change in pressure for a given change in volume is a function of the effective compliance of the arterial system. For a given cardiac cycle and assuming constant afterload, aortic end-systolic pressure (AoP

) is linearly related to stroke volume. The slope of this

relationship is termed the arterial elastance (E of afterload.

) and is the ESP divided by the SV. Ea can be expressed in the

) and is an index

ventricular PV plane (Fig. 5.6). Ea is represented by the slope of a line connecting the EDV on the volume axis and the upper left corner of the PV loop. This approach is simpliﬁed and not absolutely correct because the arterial PV relationship probably does not truly pass through the origin.20 The concept of Ea and the ESPVR can be used, however, to predict analytically the effect of changes in afterload on ESP and CO.

Constant

LV volume

Stroke

volume

Fig. 5.7 Acute myocardial infarction results in a reduction in

contractile state owing to a loss of muscle mass. This results in a decrease in the slope of the end-systolic pressure-volume relationship (ESPVR). The volume axis intercept (V

) increases

by the theoretical volume enclosed by the dead muscle, shifting the ESPVR to the right. Compensatory mechanisms result in an increase in end-diastolic volume and afterload. These changes result in a reduction in stroke volume and an increase in ﬁlling pressures.

PRESSURE-VOLUME APPROACH APPLIED TO PATHOLOGIC CONDITIONS

Acute Systolic Dysfunction

The previously described PV framework allows conceptualization of the interaction among cardiac function, preload, and afterload.

Fig. 5.7 represents a hypothetical situation in a patient with an

acute myocardial infarction (MI). Acute MI results in the loss

CHAPTER 5 Regulation of Cardiac Output 57

LV volume

mal

LV pressure

LV volume

Diastolic dysfunction

ESPVR shifts to left secondary to hypertrophy

LV pressure

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of a segment of functioning myocardium, while the rest of the chamber is preserved. Assuming for simplicity that ischemia or neurohormonal stimuli do not alter the contractile state of the surviving myocardium, the ventricle can be modeled as two compartments: one with a normal ESPVR and one with an ESPVR that moves closer to the EDPVR.21 The combined effect is to reduce the slope of the ESPVR (Ees), representing a reduction in overall myocardial contractility, an increase in LVEDV, a reduction in SV, and an increase in the volume intercept (Vo). The increase in Vo represents the contribution of the volume of the nonfunctioning segment of the ventricle to the dead volume.

As a result of these changes, the heart is able to maintain an adequate systemic perfusion pressure, but at the expense of an increase in EDV and EDP. The increases in EDV and EDP are mediated by neurohormonal reﬂexes that result in ﬂuid retention and an increase in vascular resistance. The increase in vascular resistance is reﬂected in the PV plane as an increase in Ea. The clinical syndrome of heart failure as a result of acute systolic dysfunction results from the increase in end-diastolic ﬁlling pressure, which causes pulmonary congestion or peripheral edema and the reduction in SV that is the result of the decrease in Ees and the increase in Ea. To some extent, an increase in HR may compensate for the reduction in SV to maintain cardiac output.

Diastolic Dysfunction

Inasmuch as LV systolic function represents the role of the chamber as a simultaneous pressure and volume pump, diastolic function is best viewed as the role of the chamber as a volume (suction) pump. The chamber stores elastic strain in systole (via titin and other extracellular matrix components) that is recovered in diastole by generating mechanical recoil that aspirates atrial blood into the LV. The rate of crossbridge uncoupling (relaxation) modulates the recoil (suction) process and explains the shape of clinically observed E-waves and their relation to chamber stiffness.22 Normal diastolic function is deﬁned as adequate ﬁlling of the LV without exceeding a pulmonary venous pressure of 12 mm Hg.23 From the PV approach, both the DPVR and the EDPVR are functions of diastatic and end-diastolic volume, respectively. Systolic dysfunction that increases EDV and EDP also meets this deﬁnition and clearly illustrates that systole and diastole are coupled. In this case, the abnormality is primarily in systole; however, if systole is deﬁned as adequate ejection, given adequate ﬁlling, diastolic dysfunction manifests as an increase in LVEDP.

Isolated diastolic dysfunction commonly can result from impaired ventricular distensibility, external compression of the LV or obstruction to ﬁlling of the LV. as a result of chronic hypertension is a common cause of diastolic dysfunction and is represented in the PV plane as a steep or left-shifted EDPVR (Fig. 5.8). With signiﬁcant diastolic dysfunction, adequate ﬁlling sufﬁcient to maintain SV is achieved only at the expense of an elevated end-diastolic ﬁlling pressure. Diastolic dysfunction, without any systolic dysfunction, can produce symptoms of pulmonary congestion and congestive heart failure.

25,27

The effect of external compression, such as pericardial tamponade or constriction, similarly results in a leftward shift of the EDPVR by reducing capacitance.

24–26

Impaired distensibility

Diastolic dysfunction

Nor

Fig. 5.8 Diastolic dysfunction resulting from impaired distensibility

manifests in the pressure-volume plane as an increase in the slope or leftward shift of the end-diastolic pressure-volume relationship. The ventricle requires a higher ﬁlling pressure to distend sufﬁciently to receive an adequate end-diastolic volume. LV, Left ventricular.

Aortic valve gradient

secondary to hypertrophy

Normal

Fig. 5.9 Aortic stenosis imposes an added afterload on the left

ventricle, which must generate an increased end-systolic pressure to overcome the aortic valve gradient. Concentric left ventricular hypertrophy results in a leftward shift in the end-systolic pressurevolume relationship (ESPVR) with a small increase in the slope of the ESPVR. Hypertrophy also results in diastolic dysfunction, with a steeper end-diastolic pressure-volume relationship. These changes result in a reduction in stroke volume and an increase in ﬁlling pressures. LV, Left ventricular.

Aortic Stenosis

Aortic stenosis is a special form of systolic dysfunction. The stenosed aortic valve imposes a resistance to ejection that must be overcome by the ventricle to maintain an adequate SV and systemic perfusion pressure. The resistance to ejection results in a pressure gradient across the valve. The effect on the ventricle is an increase in the effective E the stenotic valve and does not reﬂect pure arterial properties. The increase in ESP results in an increase in end-systolic ventricular wall stress. Over time, the LV compensates by concentric hypertrophy, which reduces the wall stress. The effect of this hypertrophy is to shift the ESPVR to the left. Concentric hypertrophy that ultimately remodels the chamber so that it is stiffer in diastole is also a common cause of diastolic dysfunction and manifests as an elevated EDPVR (Fig. 5.9).

that, in this case, incorporates

28,29

58 PART II Scientiﬁc Foundation of Cardiac Intensive Care

LV volume

LAEDP

LV pressure

Effective

LV volume

LV pressure

LV volume

LV pressure

https://t.me/medicina_free

LVEDP

Fig. 5.10 Mitral stenosis imposes a resistance to left ventricular

(LV) ﬁlling. This results in a diastolic pressure gradient between the left atrium and left ventricle. Adequate ventricular ﬁlling is maintained at the expense of an increase in left atrial end-diastolic pressure (LAEDP). LVEDP, Left ventricular end-diastolic pressure.

Mitral Stenosis

Mitral stenosis is a special form of diastolic dysfunction. The stenotic mitral valve imposes a resistance to left ventricular ﬁlling, which results in a pressure gradient between the left atrium and the LV. The increased atrial pressure is reﬂected into the pulmonary venous system and can result in symptoms of pulmonary congestion and congestive heart failure. This is best visualized in the PV plane by plotting end-diastolic left atrial pressure superimposed on the ventricular pressure (Fig. 5.10). Atrial pressure exceeds ventricular diastolic pressure throughout diastole by an amount that depends on the effective mitral valve area and the ﬂow across the valve.

Valvular Regurgitation

Mitral and aortic regurgitation result in increased ventricular ﬁlling in diastole, with an increase above normal in EDV that results in an increase in total SV. The effective SV is the difference between total SV and regurgitant volume. In acute valvular regurgitation, the increase in ventricular ﬁlling results in high ﬁlling pressures as the ventricle is forced to operate on the steep portion of its EDPVR; this can result in acute pulmonary edema. Over time, the ventricle can adapt its systolic and diastolic properties and dilate to accommodate the increase in EDV while limiting the increase in ﬁlling pressure. This shifts the ESPVR and EDPVR rightward. pensated, chronic valvular regurgitation. Ventricular dilation results in an increase in Vo. In the compensated phase, the contractile state is preserved and the slope of the ESPVR does not change signiﬁcantly, but shifts to a higher operating volume. Chronic severe regurgitation, if uncorrected, can lead to systolic dysfunction, resulting in a dilated cardiomyopathy.

Fig. 5.11 shows these effects for com-

Total SV

increased

Fig. 5.11 Chronic mitral or aortic regurgitation imposes a chronic

volume load on the left ventricle owing to the added burden of the regurgitant volume (RV). The increase in preload results in an increase in total stroke volume (SV), although effective stroke volume usually is unchanged. In acute regurgitation, ﬁlling pressures are markedly increased, but with chronic regurgitation, the ventricle dilates and the end-systolic pressure-volume relationship and end-diastolic pressure-volume relationship shift to the right, enabling the heart to accommodate the added volume load with smaller increases in ﬁlling pressures. LV, Left ventricular.

Increased

Fig. 5.12 Severe chronic systolic dysfunction results in the

development of a dilated cardiomyopathy. The slope of the end-systolic pressure-volume relationship (ESPVR) is reduced, and the ESPVR and end-diastolic pressure-volume relationship are displaced to the right because of ventricular dilation. LV, Left ventricular; SV, stroke volume.

Reduced

contractile

state

SV reduced

Dilated Cardiomyopathy

Chronic, severe systolic dysfunction can result from coronary ischemia, valvular regurgitation, or other causes of chronic volume overload and intrinsic myocardial pathology. The common pathophysiology is that the ventricle dilates to compensate for chronic volume overload. The ventricular dilation—imposed by regurgitation, shunts, or other abnormalities of the peripheral

circulation or in primary myocardial disease—is the only way that the heart can maintain an adequate perfusion pressure. The changes in the PV plane are characterized by a reduction in the slope of the ESPVR as a result of a decrease in contractile state and a right shift in the ESPVR and EDPVR secondary to dilation of the LV (Fig. 5.12).

CHAPTER 5 Regulation of Cardiac Output 59

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LIMITATION OF THE PRESSURE-VOLUME APPROACH

For clinicians, the practical value of the PV approach lies in the conceptual framework that it provides to understand the physiologic and pathologic determinants of cardiac function and hemodynamics. Invasive and noninvasive determination of the ESPVR and EDPVR in conscious animals and humans has been described diagnosis or therapy for several reasons. In a single heart, it is simple to interpret a change in the baseline ESPVR, but comparisons between populations or individuals are difﬁcult because the slope and intercept of the ESPVR depend on cardiac size.

size makes it difﬁcult to deﬁne a normal range for the Ees. This difﬁculty is compounded by the fact that Vo cannot be measured directly in vivo but rather is determined by extrapolation and is subject to large errors.34 In addition, the timing of end systole is not always clear cut. End systole is deﬁned as the upper left corner of the PV loop, but this does not always correspond with either aortic valve closure or maximal ventricular elastance, especially in mitral regurgitation.35 Apart from difﬁculties in comparing PV relationships, the determination of these relationships in vivo requires alterations in loading conditions over a wide range. The changes in loading conditions themselves may directly affect the slope of the ESPVR through reﬂex alterations in contractile state and HR.

with a slope and an intercept that are readily determined. Several studies have suggested, however, that the ESPVR becomes

8,31–33

but has not been implemented routinely in clinical

The lack of a universally acceptable correction for cardiac

Last, ESPVR is depicted in this chapter as a linear relationship

nonlinear at high contractile states and with heart failure. This nonlinearity may make a slope measurement sensitive to the range of data collection and complicate comparison. These limitations do not diminish the effectiveness of the PV relationship as a conceptual framework and an analytical tool to understand the physiologic and pathophysiologic determinants of cardiac output.

36–39

CONCLUSION

The function of the cardiovascular system is to provide adequate metabolic substrate delivery and tissue oxygenation by the circulation of oxygenated blood. Mixed venous oxygen saturation is determined by the balance between oxygen delivery and metabolism and activity-dependent oxygen consumption. Under normal conditions, the heart has a large functional reserve and cardiac output is regulated by neurohormonal mechanisms to meet the body’s needs in response to posture and activity so that, at rest, mixed venous oxygen saturation is at least 70%. LV dysfunction is a common cause of cardiovascular insufﬁciency. In this setting, regulatory and compensatory mechanisms are characterized by maximal sympathetic autonomic stimulation; hence, CO becomes limited by LV performance. Ventricular performance and its coupling to the vasculature can be analyzed within the PV plane. This approach provides a clinically useful, mechanistic conceptual framework for understanding integrated cardiovascular function in critically ill patients.

The full reference list for this chapter is available at

ExpertConsult.com.

CHAPTER 5 Regulation of Cardiac Output 59.e1

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