Symposium on Response to Infection and Injury I
Adequate Circulatory Responses or Cardiovascular Failure Herbert B. Hechtman, M.D. *
The function of the cardiovascular system is to supply oxygenated blood and substrates to the tissues and organs of the body in accord with their metabolic requirements. The circulation is ordinarily subjected to an enormous variety of stresses. An understanding of the manner in which this system responds is of importance to clinicans since the clinical manifestations of most cardiovascular disorders arise from an impairment of these responses. Under usual physiologic conditions each tissue and organ receives almost exactly the blood flow required for adequate nutrition. Metabolic needs vary greatly from moment to moment. During heavy exercise, a twenty-fold increase in total oxygen consumption may take place in the course of several seconds. The reserves of the cardiovascular system are large and adapt rapidly to such changing needs. Normally cardiac output increases in proportion to the increase in oxygen consumption. An integrated response of the heart and peripheral vascular bed must occur to provide these increments of oxygen and to distribute them to the appropriate tissues. Oxygen consumption is the key physiologic determinant of the cardiovascular system. Normal, abnormal, and inadequate responses of this system to changing tissue -demands for oxygen form the substance of this article.
OXYGEN AVAILABILITY The amount of oxygen presented to tissues is, in the first instance, a function of blood flow and oxygen content. Oxygen in capillary blood then diffuses into tissues and becomes available to mitochondria. The diffusion process is dependent upon the difference between blood and tissue oxygen tensions. A certain amount of oxygen is extracted by each *Associate Professor of Surgery, Boston University Medical Center, Boston, Massachusetts Supported in part by National Institute of General Medical Sciences Grant, #5P01-GM17366-05 and the U.S. Army Research and Development Command Contract, #DADA17-67-C-7149.
Surgical Clinics of North America- Vol. 56, No.4, August 1976
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tissue or organ such that a predictable end capillary or venous oxygen tension is reached. Normally mixed venous oxygen tension is 35 mm Hg but this composite figure averages a wide range of venous tensions from different organs. Thus, coronary sinus tensions are about 23 mm Hg. In order to meet increased oxygen requirements the body will normally respond by increasing blood flow. The reserve option of increasing oxygen extraction is available to many tissues but not the heart where end capillary or venous PO z is so low that the driving force for diffusion has virtually been exhausted. Chronic adaptations to low flow states, such as chronic heart failure, probably involve multiple intracellular adjustments to allow survival with normal total body oxygen consumption, despite low capillary and tissue oxygen levels. These chronic adjustments are poorly defined and are not necessarily available to patients suffering acute trauma and sepsis.
REGULATION OF CARDIAC OUTPUT Providing cardiac pumping ability is normal, peripheral tissues themselves regulate their own blood flow. It is this regulation of local flow that ordinarily is the dominant factor in determining total cardiac output. The arteriolar network, usually in a state of partial contraction, functions as the primary regulator of blood flow to tissues. Opposing vasodilator influences, as a general rule, arise from the surrounding tissue. As a result of these chemical, neural, and physical stimuli, resting arteriolar tone is modified in accordance with local tissue needs. If metabolic requirements are constant, most organs have an intrinsic tendency to maintain constant blood flow despite changes in arterial perfusion pressure. This autoregulation is accomplished by changing vascular resistance and has been observed in kidney, skeletal muscle, brain, intestine, myocardium, and liver. A general reduction in tissue and organ metabolic requirements will lead to a decrease in cardiac output by virtue of a relaxation in venous smooth muscle and increase in capacitance. Peripheral venous pressure decreases and blood pools in these capacitance vessels. The volume of blood returned to the right atrium will fall as a consequence of the decrease in venous pressure returning blood to the heart. When tissue requirements are high, the reverse occurs. As long as the pumping ability of the heart is normal, the actual adjustment of cardiac output to the metabolic level required by tissues is executed by the peripheral vasculature. Normally the heart plays a permissive role in the regulation of cardiac output. Multiple factors may limit this normal tissue regulation of venous return and cardiac output. Vasoactive agents, anesthetics and drugs, may dilate or constrict portions of the peripheral vasculature independent of tissue metabolic requirements. Other stresses may induce varied flow patterns. The reduction in vascular volume and venous return following hemorrhage leads to low tissue perfusion. Autonomic controls
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CARDIAC RESPONSE TO PEEP 6
Figure 1. As positive end expiratory pressure (PEEP) rises, there frequently is a decrease in thoracic venous return unless extrathoracic venous pressure rises. This animal study demonstrates a fall in cardiac output related to the level of applied PEEP. The transmural CVP (central venous minus intrapleural pressure) must be used to measure right ventricular preload under conditions where pleural pressure varies. Oleic acid was used to induce pulmonary edema. The hemodynamic consequences of PEEP were similar under these circumstances. PEEP may also reduce cardiac output by inducing right ventricular failure. This phenomenon is discussed in the text.
TRANSMURAL 4 PRESSURE (mmHg) 2
o ·2
CARDIAC OUTPUT (L/min)
3
2
v
PEEP 10 (em H2 0)
o
redistribute this lowered flow away from skin, muscle, and the splanchnic region to the brain and heart. This homeostatic redistribution of flow is appropriate for limited periods of time. In addition to these smooth muscle effects, mechanical factors may playa determinant role in the regulation of venous return. The use of mechanical ventilation with high tidal volumes and positive end expiratory pressure may increase intrathoracic pressure and reduce venous return. The reduction in venous return is a consequence of the narrowing of the pressure differential between the intra- and extrathoracic veins (Fig. 1). Similar reductions in venous return may attend elevations in intraabdominal pressure. Finally, despite appropriate tissue and vascular regulation of venous return, the pumping activity of the heart may be insufficient. It has only been in recent years that the separate contributions and functional limitations of peripheral and cardiac hemodynamics have been appreciated and defined.
SHOCK The imprecise term shock is defined clinically as a syndrome of acute onset, associated with arterial hypotension and oliguria with various and inconstant manifestations of sympathetic overactivity including restlessness, cool moist skin, and pallor. The syndrome is most apt to be observed during hemorrhagic hypotension, but may accompany other forms of trauma or sepsis. Resuscitative measures frequently reverse this clinical state but may not prevent the subsequent development of multiple systems failure and death. Thus, the average time from the occurrence of septic hypotension to death has been observed to range from 9 to 21 days.24 There is a general consensus that complex transport and intracellular biochemical changes occur during the relatively brief shock period. The severity of the basic injury in-
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curred may in part be judged by the duration and degree of shock as well as by the subsequent abnormalities noted in the days following resuscitation. Trauma and severe sepsis are often accompanied by a characteristic pattern of tissue and organ failure. This fact is well documented although pathophysiologic mechanisms remain poorly understood. Functional abnormalities include impaired phagocytosis and bacterial lysis, defects in delayed hypersensitivity, reduction in clotting factors, and thrombocytopenia. Organ failure is exemplified by superficial gastric ulcerations as well as abnormalities in lung, liver, and kidney function. With such multisystem derangements, it is not surprising that the adequacy of cardiac function has been called into question. The observation that following severe stress such as hemorrhage or sepsis, the cardiac output and oxygen consumption tend to be normal or increased has been interpreted to mean that the cardiovascular system is not impaired. However, within the past 10 to 15 years a number of authors have drawn attention to the fact that "normal" flows and oxygen consumption in severely ill patients are inadequate, and are associated with a poor prognosis. 4 A growing body of evidence argues that cardiac reserves are frequently insufficient to provide the requirements of supernormal perfusion and oxygenation in these seriously ill patients. I. 13
PROGNOSTIC INDICATORS Physiologic variables developed by Shoemaker18 which predict survival of critically ill patients relate directly and indirectly to tissue oxygenation. Thus, early in the patient's course, oxygen consumption below 80 ml per min per m 2 and oxygen availability':' below 400 ml per min per m 2 are associated with death. On the other hand, oxygen consumption above 200 ml per min per m 2 and availability above 450 ml per min per m 2 are uniformly favorable indicators. Factors which relate to venous return and tissue perfusion are also predictive. A blood volume deficit greater than 1500 mlleads to death presumably because venous return, cardiac output, and oxygen availability are reduced to very low levels. Similarly, death is associated with a systemic vascular resistance above 3500 dyn ·sec per cm5 ·m2 because of the severe inhibition of tissue perfusion. Cardiac output, whether limited by venous return or by cardiac failure, leads to death when its value is below 1.8 liters per min per m 2 while a uniformly favorable prognosis is noted with outputs above 4.5 liters per min per m 2 • Diminution in cardiac reserves is not well tolerated in these ill patients who require abundant flows and oxygen availability. Thus, relative cardiac failure and the associated flow limitations might be expected to predict death. The following measures of cardiac performance are illustrative. Death is predictable if: the systolic ejection rate is less than 80 ml per min per m2, the tension time index is less than 700, the central venous pressure is above 13 mm Hg, or the right ventricular stroke work is less than 4 gm·m per m 2 • "'The product of cardiac index and arterial oxygen content.
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Pulmonary vascular resistance above 500 dyn·sec per cm5 ·m2 predicts death while a value below 250 dyn·sec per cm5 ·m2 predicts survival. The presence of a high pulmonary vascular resistance may limit flow and therefore survival because of right ventricular failure. A clinical setting where this phenomenon is observed is in patients with pulmonary difficulties who require mechanical ventilation and end-expiratory pressure. These patients suffer reductions in cardiac output not only because venous return may be lower, but more often because of increases in pulmonary vascular resistance 12 (see Fig. 1). The elevated resistance is secondary to high alveolar pressures and obstruction of the pulmonary capillary bed. Other causes of increased pulmonary vascular resistance relate to neurohumoral factors. Most other investigators agree with the importance of the variables which Shoemaker has selected, although the quantitative values which he gives must be viewed as tentative. 19 In addition, the optimal levels of these cardiovascular variables remain unknown. Other variables of predictive value relate to the arterial oxygen content, an important determinant of oxygen availability. Thus, if arterial oxygen tension is below 60 mm Hg or hemoglobin concentration is below 9.0 gm per 100 mI, death is predictable. 1s Factors which either affect or reflect oxygen transport from capillaries to tissues, such as the 02-oxygen-hemoglobin affinity state and mixed venous oxygen tensions will be discussed later. It should be emphasized that these empiric correlations with survival do not necessarily define underlying etiologic factors and only in part explain the pathophysiologic alterations of the cardiovascular system.
CARDIAC RESERVES A number of the prognostic indicators relate to intrinsic cardiac function. Frequently it is difficult to separate intrinsic function from extrinsic factors which may reduce flow. Thus, a low cardiac output may relate to a decrease in venous return or to cardiac failure. The normal heart responds to an increase in venous return by increasing cardiac output, which is the product of heart rate and stroke volume. The response to exercise in conditioned athletes is an increase in both rate and stroke volume. Both share equally as mechanisms for flow increase. Heart rate is regulated by neurohumoral mechanisms and normally represents a major reserve mechanism. Most seriously ill patients have a sinus tachycardia. In such patients increases in cardiac output subsequent to fluid loading are characteristically the result of increases in stroke volume. Heart rate usually does not playa major role. On occasion a bradycardic patient with low flow may be significantly improved with chronotropic agents or pacing. The determinants of stroke volume are: (1) preload, which in general terms may be described by the end-diastolic ventricular filling pressures, central venous and left atrial, for the right and left hearts respectively. The force of contraction is directly related to preload and is
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described by Starling's law of the heart. (2) Afterload is the force-resisting fiber shortening and is equivalent to pulmonary or systemic arterial pressure for right and left ventricles respectively. The force of contracture is inversely related to afterload. (3) The contractile state of the heart relates to factors such as beta-adrenergic agonists and antagonists which can change the force of contraction independent of preload and afterload. 3
CARDIAC WORK When pulse and afterload are constant, the Starling mechanism is the major determinant of stroke volume and cardiac output. Thus, in severe sepsis, vasodilatation and sequestration of volume in capacitance vessels lead to a reduction in venous return. There is a resultant lowering of right and then left ventricular filling pressures or preloads. This leads to a fall in cardiac output. Therapy involves the infusion of fluids to increase venous return, preload, and flow. However, when afterload also changes, the reserve function of the heart is more difficult to describe. Figure 2 demonstrates that fluid loading increases cardiac output in mild sepsis and that for equivalent preloads the septic subject has a higher flow. In this case the Starling mechanism is operating normally while contractility appears to be increased. This "hyperdynamic" state is common. The cardiac work performed in the septic group, however, remains unchanged (right panel, Fig. 2). The decrease in arteriolar resis-
THREE HOURS AFTER E. COLI FLUID CHALLENGE _ _ SEPTIC
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Figure 2. Following a moderate but not lethal E. coli bacteremia, septic animals become hyperdynamic. The left panel shows that when the animals were volume loaded, the cardiac index was increased in the septic group at all levels of mean pulmonary arterial wedge pressure (MPAWP). Flow was significantly higher than controls at a MPAWP between 14 and 17 mm Hg. This increased flow is an advantage to peripheral tissues because of increased oxygen availability. However, the function of the heart itself is best described by left ventricular stroke work, which is the product of stroke volume and the difference between afterload and preload. The right panel shows that intrinsic cardiac function is unchanged by nonlethal sepsis.
935
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tance in sepsis leads to systemic hypotension (lowered afterload), such that work which is the product of flow and systemic minus left atrial pressure remains constant. High flow states are characteristic of septic patients who survive. It appears that the septic patient may exchange flow for pressure work, thus increasing oxygen availability. The experiment shown in Figure 2 illustrates the importance of evaluating cardiac work, not simply stroke volume, when attempting to describe intrinsic myocardial function.
AFTERLOAD In patients with low cardiac outputs secondary to myocardial ischemia or infarction, the suggestion has been offered that a decrease in afterload may improve flow because cardiac work is reduced. Current data might support a clinical trial of the vasodilators trimethaphon or nitroprusside in hypertensive patients suffering low flow statesY Thus, head injuries may unleash an overwhelming sympathoadrenal discharge leading to extreme systemic hypertension and left ventricular failure. Therapy may benefit this class of patients, but data are conflicting regarding benefit to normotensive or hypotensive patients whose stroke volume may be normal. Indeed, in sepsis further lowering of the diastolic pressure may induce or potentiate myocardial ischemia because of reduced coronary blood flow. P 1I0~
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100
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c.o. Figure 3. As positive end expiratory pressure (PEEP) is increased arterial oxygen tension rises. Cardiac output initially rises and then falls. The best end expiratory pressure is that which provides the highest oxygen availability. In this particular patient 5 cm PEEP was chosen. Note that pulse rate and arterial pressure do not correlate with cardiac output.
Pa02
50
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50
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600 C.O.XC a 02
500
400
20
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Acute increases in right ventricular afterload are not uncommon clinical problems, particularly in patients suffering acute respiratory failure. Thus, mechanical ventilation and positive end inspiratory pressure, particularly above 10 cm H 2 0 may cause significant pulmonary hypertension and right ventricular failure. 12 The reduction in the force of right ventricular contraction induced by the high afterload may not be counteracted by the concomitant increase in preload. There is often a resultant decline in stroke volume. Therapy should be directed at unloading the right ventricle. Thus, positive end expiratory pressure should be reduced to a level which optimizes oxygen availability. Often the benefits of PEEP, that is, an increased P a02 are far outweighed by the dangerous fall in blood flow (Fig. 3).
CONTRACTILITY The contractile state of the heart may be impaired, independent of low preloads or high afterloads. Figure 4 compares a group of patients suffering sepsis and those suffering coronary artery disease. The latter group demonstrate Starling curves which are shifted downward and to the right, a decrease in the contractile state. At any filling pressure, stroke work is lower in the patient suffering coronary artery disease than in the septic patient. The ischemic heart is known to manifest decreased contractility.23 The use of beta-adrenergic agents such as
VENTRICULAR PERFORMANCE CURVES
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Figure 4. Patients with coronary artery disease have Starling curves which are shifted downward and to the right. This negative inotropic effect is thought to be due to myocardial ischemia. Septic patients have upslopes and stroke works which are relatively normal. However, at an average filling pressure of 10 mm Hg, stroke work decreases with further increases in preload. This limitation in myocardial reserve may relate to the development of subendocardial ischemia as filling pressures increase above 10 mm Hg. The precise pathophysiology remains to be defined. The values shown are means and one standard deviation.
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50 Figure 5. The rapid infusion of a mixture of glucose, insulin, and potassium usually results in an inotropic effect, shifting the Starling curve upward and to the left. The ordinate is left ventricular stroke work index (LVSWI) and the abscissa left atrial pressure (LAP). The control curve was constructed using an equiosmolar solution of mannitoL Note that this curve shows a downslope. Other inotropic agents such as isoproterenol, dopamine, or epinephrine may exert similar effects. The action of these drugs, however, is not always predictable. In critically ill patients the close monitoring of flow and filling pressure may be required.
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epinephrine, norepinephrine, or isoproterenol may not be advantageous under such circumstances. 15. 28 Increases in contractility are known to be associated with greater increases in myocardial oxygen requirements. In addition, changes in wall stress or abnormal distributions of blood flow induced by these inotropic agents may result in further impairment of myocardial oxygenation. Despite these arguments a salutary inotropic effect is often achieved as demonstrated in Figure 5. The infusion of glucose insulin and potassium shifts the Starling curve in a patient with coronary artery disease upward and to the left. The presence of myocardial depression in patients suffering critical illness is now well documented. The Starling curve may be shifted downward and to the right such that the left ventricular stroke work is lower than predicted at any filling pressure. In addition to this decrease in overall contractility the Starling mechanism may itself be abnormal. This is illustrated by the descending limbs of the curves in Figures 4 and 5. The descending portion of the curve can be considered subclinical cardiac failure, which becomes clinically manifest as a low perfusion state, when preload is further increased. It is surprising to observe that in severely septic patients the Starling curve will peak at relatively normal filling pressures, which average 10 mm Hg (see Fig. 4). At higher preloads these septic patients show a rapid decline in work. There is no virtue in the use of fluid infusions which increase preload much above 10 mm Hg in most severely ill septic patients. Indeed, since these patients are very vulnerable to pulmonary interstitial and intraalveolar edema (that is, acute pulmonary insufficiency), the lowest left ventricular preload should be used which provides a satisfactory cardiac output. It is reasonable to suppose that the loss of pulmonary capillary integrity in these septic patients will nullify the protective effects of plasma colloid osmotic pressure and allow an increase in edema formation at all levels of pulmonary venous pressure.
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MONITORING Patients who continue to manifest evidence of poor perfusion, e.g., peripheral vasoconstriction, low urine output, or cerebral symptoms, after initial attempts at resuscitation, should be considered candidates for more intensive monitoring. A thermistor-tipped, flow-directed, pulmonary arterial catheter is positioned, usually through a cutdown site in a medial antecubital vein. 26 Systemic arterial catheterization is also of value. The following information now becomes available: preload of right and left ventricles, that is, central venous and pulmonary arterial wedge pressures, and afterload of right ventricle, i.e., pulmonary arterial pressure. The afterload of the left ventricle is the systemic arterial pressure. Cardiac output is measured by thermodilution. 25 All these measurements may conveniently be done by the intensive care unit nursing staff. Derived hemodynamic variables include pulmonary and systemic vascular resistance as well as right and left ventricular stroke work. The measurement of venous admixture, oxygen availability, and consumption requires pulmonary and sytemic arterial blood sampling. Starling curves are constructed with a rapid volume infusion of-25 to 50 gm of albumin, blood, and/or saline in patients whose pulmonary arterial wedge pressures are below 10 mm Hg. Sequential pressure and flow measurements are made which are then used to draw a myocardial performance curve (see Fig. 5).
CORONARY BLOOD FLOW The heart may not only be the determinant of systemic abnormalities resulting from reduced flow and oxygen availabilty, but may also be the recipient of many of these effects. Myocardial oxygen levels, like those in other tissues, depend on supply and demand. Supply of oxygen to the heart or other tissues relates to blood flow, arterial oxygen content, oxygen-hemoglobin affinity, and the diffusion distance to cell mitochondria. The major determinants of myocardial oxygen demand, in addition to basal metabolic requirement, are (1) peak systolic wall force or peak intraventricular pressure, (2) heart rate, and (3) contractile state. 2 Thus, the use of the cardiac reserve mechanisms of increased preload, heart rate, and contractile or inotropic state are associated with increased oxygen requirements which necessitate increased coronary flow. The depressed myocardial performance which may accompany hemorrhage and sepsis is most likely related to reduced oxygen supply. It is probable that coronary blood flow during hemorrhagic hypotension is reduced to a greater extent than myocardial nutritional requirements.14 Coronary flow is the principal determinant of myocardial oxygen availability since normally oxygen extraction is large, about 55 to 65 per cent, and coronary sinus P0 2 is low. Further oxygen delivery to
CIRCULATION
939
myocardial tissue is not possible since the driving force which determines oxygen movement from blood to tissue, oxygen partial pressure, is already severely reduced. Increases in myocardial oxygen delivery are only made possible by increases in coronary flow. In addition to coronary blood flow and oxygen availability, other factors may reduce myocardial performance by acting directly on cardiac contractility mechanisms. The data, however, are inconclusive. It has been difficult to separate the effects of toxins from those of reduced oxygen availability.10 For example, myocardial depressant factors originating in the pancreas are thought to damage both normal as well as ischemic hearts.2o Conflicting evidence, however, discredits these pancreatic factors and denies their role in myocardial depression. 7 Other toxic factors are of undefined clinical importance, such as pH electrolytes, calcium, or vasoactive materials such as prostaglandins, angiotensin, the kinins, and various sympathetic amines. Coronary blood flow remains a recognized critical determinant of oxygen availability. Normally as aortic or coronary perfusion pressure falls, peripheral resistance in the myocardial vascular bed is autoregulated to maintain flow. An average change in coronary flow of only ±7 per cent occurs over a pressure range of 70 to 150 mm HgY Under normal conditions it is only when coronary perfusion pressures fall below 70 to 80 mm Hg that coronary flow is reduced and myocardial depression occurs.21 Autoregulation is not only significant in maintaining flow during periods of hypotension but is the critical mechanism which provides increased flow during periods of heightened myocardial oxygen demand. Under resting conditions only one half of the available capillary bed is perfused. 9 As the heart is made hypoxic or infused with a coronary vasodilator such as nitroglycerine, there is capillary recruitment. The reverse effect is seen with angiotensin. Despite these powerful autoregulatory reserve mechanisms, mechanical factors may significantly liInit or alter the distribution of coronary flow and render portions of the heart ischeInic. The beating heart inhibits its own blood supply. The subendocardial region of the left ventricle is particularly vulnerable and normally receives most of its flow during diastole. If preload falls because of hemorrhage or sepsis, the systolic-intramyocardial pressure is high across most of the left ventricular wall.'~ This high systolic intramyocardial pressure will inhibit coronary flow throughout the myocardium during the period of systole. In this case coronary diastolic flow becomes even more critical. s The volume of diastolic flow will be determined by the diastolic time interval and diastolic pressure. Thus the tachycardia which usually accompanies trauma and sepsis reduces the diastolic time interval and therefore coronary flow. The diastolic pressure in many seriously ill patients will frequently be lower than the criticallevel of 70 to 80 mm Hg, again jeopardizing myocardial flow. These considerations suggest that myocardial ischemia may be frequent in patients suffering trauma and sepsis. *Based on the Laplace relationship.
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Following the infusion of fluid and/or blood, preload increases as do arterial pressure, stroke work, and oxygen consumption. Coronary flow may now occur during both diastole and systole. The uniformity of the distribution of this flow however has been questioned. Certain portions of the heart, particularly the subendocardium, may be deprived of adequate flow both because of mechanical factors as well as myocardial edema. In such cases myocardial work and oxygen consumption may increase beyond the limits set by coronary flow and oxygen availability. . It is possible that this accounts for the descending limb of the Starling curve (see Fig. 4). It is at this level of preload when oxygen demand exceeds supply. Another important contributor to myocardial work is afterload. Increased aortic pressure may' well increase coronary perfusion; however, the advantage is lost in the hypertensive patient because of the extraordinary increase in myocardial oxygen requirements. There are other critical determinants of coronary flow. Thus, preexistent coronary arteriosclerosis can be a substantial cause of flow limitations.
TISSUE OXYGENATION The importance of coronary perfusion relates to the oxygenation of the myocardium. Three other aspects of oxygenation will now be considered: (1) hemoglobin levels, (2) interstitial edema, and (3) the oxygenhemoglobin affinity state. The oxygen content of blood is primarily determined by hemoglobin concentration. Unfortunately, high hematocrits do not necessarily mean increased oxygen availability since the high hematocrit blood is more viscous and flow may be impeded in the microcirculation. The optimum hemoglobin in critically ill patients is unknown. We have usually attempted to maintain hemoglobin levels between 12 and 14 grams per 100 milliliters of blood as have others.Is Severe sepsis is thought to lead to endothelial cell damage which in turn results in generalized extravascular fluid accumulations. This fluid is clinically most evident in the lungs of septic patients suffering respiratory failure. Extravascular fluid and endothelial cell damage are also found in other tissues including the heart. s Delivery of oxygen from blood to mitochondria is inhibited under these circumstances by the added diffusion barrier. There is speculation that prevention or reduction of extravascular myocardial edema will improve myocardial performance. Indeed, the experimental use of the osmotically active agent mannitol has resulted in improved cardiac contractility.27 Clinical use of such agents remains unproven. The diffusion process which determines oxygen transport from capillary blood to tissues depends not only on the thickness of the diffusion barrier but also on the difference in partial pressure of oxygen on both sides of the barrier, i.e., capillary blood and mitochondria. It is this difference in partial pressure which serves as the driving force for diffusion.
941
CIRCULATION PRESERVED REO CELLS WITH.'
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Adequate Circulatory Responses or Cardiovascular Failure Herbert B. Hechtman, M.D. *
The function of the cardiovascular system is to supply oxygenated blood and substrates to the tissues and organs of the body in accord with their metabolic requirements. The circulation is ordinarily subjected to an enormous variety of stresses. An understanding of the manner in which this system responds is of importance to clinicans since the clinical manifestations of most cardiovascular disorders arise from an impairment of these responses. Under usual physiologic conditions each tissue and organ receives almost exactly the blood flow required for adequate nutrition. Metabolic needs vary greatly from moment to moment. During heavy exercise, a twenty-fold increase in total oxygen consumption may take place in the course of several seconds. The reserves of the cardiovascular system are large and adapt rapidly to such changing needs. Normally cardiac output increases in proportion to the increase in oxygen consumption. An integrated response of the heart and peripheral vascular bed must occur to provide these increments of oxygen and to distribute them to the appropriate tissues. Oxygen consumption is the key physiologic determinant of the cardiovascular system. Normal, abnormal, and inadequate responses of this system to changing tissue -demands for oxygen form the substance of this article.
OXYGEN AVAILABILITY The amount of oxygen presented to tissues is, in the first instance, a function of blood flow and oxygen content. Oxygen in capillary blood then diffuses into tissues and becomes available to mitochondria. The diffusion process is dependent upon the difference between blood and tissue oxygen tensions. A certain amount of oxygen is extracted by each *Associate Professor of Surgery, Boston University Medical Center, Boston, Massachusetts Supported in part by National Institute of General Medical Sciences Grant, #5P01-GM17366-05 and the U.S. Army Research and Development Command Contract, #DADA17-67-C-7149.
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tissue or organ such that a predictable end capillary or venous oxygen tension is reached. Normally mixed venous oxygen tension is 35 mm Hg but this composite figure averages a wide range of venous tensions from different organs. Thus, coronary sinus tensions are about 23 mm Hg. In order to meet increased oxygen requirements the body will normally respond by increasing blood flow. The reserve option of increasing oxygen extraction is available to many tissues but not the heart where end capillary or venous PO z is so low that the driving force for diffusion has virtually been exhausted. Chronic adaptations to low flow states, such as chronic heart failure, probably involve multiple intracellular adjustments to allow survival with normal total body oxygen consumption, despite low capillary and tissue oxygen levels. These chronic adjustments are poorly defined and are not necessarily available to patients suffering acute trauma and sepsis.
REGULATION OF CARDIAC OUTPUT Providing cardiac pumping ability is normal, peripheral tissues themselves regulate their own blood flow. It is this regulation of local flow that ordinarily is the dominant factor in determining total cardiac output. The arteriolar network, usually in a state of partial contraction, functions as the primary regulator of blood flow to tissues. Opposing vasodilator influences, as a general rule, arise from the surrounding tissue. As a result of these chemical, neural, and physical stimuli, resting arteriolar tone is modified in accordance with local tissue needs. If metabolic requirements are constant, most organs have an intrinsic tendency to maintain constant blood flow despite changes in arterial perfusion pressure. This autoregulation is accomplished by changing vascular resistance and has been observed in kidney, skeletal muscle, brain, intestine, myocardium, and liver. A general reduction in tissue and organ metabolic requirements will lead to a decrease in cardiac output by virtue of a relaxation in venous smooth muscle and increase in capacitance. Peripheral venous pressure decreases and blood pools in these capacitance vessels. The volume of blood returned to the right atrium will fall as a consequence of the decrease in venous pressure returning blood to the heart. When tissue requirements are high, the reverse occurs. As long as the pumping ability of the heart is normal, the actual adjustment of cardiac output to the metabolic level required by tissues is executed by the peripheral vasculature. Normally the heart plays a permissive role in the regulation of cardiac output. Multiple factors may limit this normal tissue regulation of venous return and cardiac output. Vasoactive agents, anesthetics and drugs, may dilate or constrict portions of the peripheral vasculature independent of tissue metabolic requirements. Other stresses may induce varied flow patterns. The reduction in vascular volume and venous return following hemorrhage leads to low tissue perfusion. Autonomic controls
931
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CARDIAC RESPONSE TO PEEP 6
Figure 1. As positive end expiratory pressure (PEEP) rises, there frequently is a decrease in thoracic venous return unless extrathoracic venous pressure rises. This animal study demonstrates a fall in cardiac output related to the level of applied PEEP. The transmural CVP (central venous minus intrapleural pressure) must be used to measure right ventricular preload under conditions where pleural pressure varies. Oleic acid was used to induce pulmonary edema. The hemodynamic consequences of PEEP were similar under these circumstances. PEEP may also reduce cardiac output by inducing right ventricular failure. This phenomenon is discussed in the text.
TRANSMURAL 4 PRESSURE (mmHg) 2
o ·2
CARDIAC OUTPUT (L/min)
3
2
v
PEEP 10 (em H2 0)
o
redistribute this lowered flow away from skin, muscle, and the splanchnic region to the brain and heart. This homeostatic redistribution of flow is appropriate for limited periods of time. In addition to these smooth muscle effects, mechanical factors may playa determinant role in the regulation of venous return. The use of mechanical ventilation with high tidal volumes and positive end expiratory pressure may increase intrathoracic pressure and reduce venous return. The reduction in venous return is a consequence of the narrowing of the pressure differential between the intra- and extrathoracic veins (Fig. 1). Similar reductions in venous return may attend elevations in intraabdominal pressure. Finally, despite appropriate tissue and vascular regulation of venous return, the pumping activity of the heart may be insufficient. It has only been in recent years that the separate contributions and functional limitations of peripheral and cardiac hemodynamics have been appreciated and defined.
SHOCK The imprecise term shock is defined clinically as a syndrome of acute onset, associated with arterial hypotension and oliguria with various and inconstant manifestations of sympathetic overactivity including restlessness, cool moist skin, and pallor. The syndrome is most apt to be observed during hemorrhagic hypotension, but may accompany other forms of trauma or sepsis. Resuscitative measures frequently reverse this clinical state but may not prevent the subsequent development of multiple systems failure and death. Thus, the average time from the occurrence of septic hypotension to death has been observed to range from 9 to 21 days.24 There is a general consensus that complex transport and intracellular biochemical changes occur during the relatively brief shock period. The severity of the basic injury in-
932
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curred may in part be judged by the duration and degree of shock as well as by the subsequent abnormalities noted in the days following resuscitation. Trauma and severe sepsis are often accompanied by a characteristic pattern of tissue and organ failure. This fact is well documented although pathophysiologic mechanisms remain poorly understood. Functional abnormalities include impaired phagocytosis and bacterial lysis, defects in delayed hypersensitivity, reduction in clotting factors, and thrombocytopenia. Organ failure is exemplified by superficial gastric ulcerations as well as abnormalities in lung, liver, and kidney function. With such multisystem derangements, it is not surprising that the adequacy of cardiac function has been called into question. The observation that following severe stress such as hemorrhage or sepsis, the cardiac output and oxygen consumption tend to be normal or increased has been interpreted to mean that the cardiovascular system is not impaired. However, within the past 10 to 15 years a number of authors have drawn attention to the fact that "normal" flows and oxygen consumption in severely ill patients are inadequate, and are associated with a poor prognosis. 4 A growing body of evidence argues that cardiac reserves are frequently insufficient to provide the requirements of supernormal perfusion and oxygenation in these seriously ill patients. I. 13
PROGNOSTIC INDICATORS Physiologic variables developed by Shoemaker18 which predict survival of critically ill patients relate directly and indirectly to tissue oxygenation. Thus, early in the patient's course, oxygen consumption below 80 ml per min per m 2 and oxygen availability':' below 400 ml per min per m 2 are associated with death. On the other hand, oxygen consumption above 200 ml per min per m 2 and availability above 450 ml per min per m 2 are uniformly favorable indicators. Factors which relate to venous return and tissue perfusion are also predictive. A blood volume deficit greater than 1500 mlleads to death presumably because venous return, cardiac output, and oxygen availability are reduced to very low levels. Similarly, death is associated with a systemic vascular resistance above 3500 dyn ·sec per cm5 ·m2 because of the severe inhibition of tissue perfusion. Cardiac output, whether limited by venous return or by cardiac failure, leads to death when its value is below 1.8 liters per min per m 2 while a uniformly favorable prognosis is noted with outputs above 4.5 liters per min per m 2 • Diminution in cardiac reserves is not well tolerated in these ill patients who require abundant flows and oxygen availability. Thus, relative cardiac failure and the associated flow limitations might be expected to predict death. The following measures of cardiac performance are illustrative. Death is predictable if: the systolic ejection rate is less than 80 ml per min per m2, the tension time index is less than 700, the central venous pressure is above 13 mm Hg, or the right ventricular stroke work is less than 4 gm·m per m 2 • "'The product of cardiac index and arterial oxygen content.
933
CIRCULATION
Pulmonary vascular resistance above 500 dyn·sec per cm5 ·m2 predicts death while a value below 250 dyn·sec per cm5 ·m2 predicts survival. The presence of a high pulmonary vascular resistance may limit flow and therefore survival because of right ventricular failure. A clinical setting where this phenomenon is observed is in patients with pulmonary difficulties who require mechanical ventilation and end-expiratory pressure. These patients suffer reductions in cardiac output not only because venous return may be lower, but more often because of increases in pulmonary vascular resistance 12 (see Fig. 1). The elevated resistance is secondary to high alveolar pressures and obstruction of the pulmonary capillary bed. Other causes of increased pulmonary vascular resistance relate to neurohumoral factors. Most other investigators agree with the importance of the variables which Shoemaker has selected, although the quantitative values which he gives must be viewed as tentative. 19 In addition, the optimal levels of these cardiovascular variables remain unknown. Other variables of predictive value relate to the arterial oxygen content, an important determinant of oxygen availability. Thus, if arterial oxygen tension is below 60 mm Hg or hemoglobin concentration is below 9.0 gm per 100 mI, death is predictable. 1s Factors which either affect or reflect oxygen transport from capillaries to tissues, such as the 02-oxygen-hemoglobin affinity state and mixed venous oxygen tensions will be discussed later. It should be emphasized that these empiric correlations with survival do not necessarily define underlying etiologic factors and only in part explain the pathophysiologic alterations of the cardiovascular system.
CARDIAC RESERVES A number of the prognostic indicators relate to intrinsic cardiac function. Frequently it is difficult to separate intrinsic function from extrinsic factors which may reduce flow. Thus, a low cardiac output may relate to a decrease in venous return or to cardiac failure. The normal heart responds to an increase in venous return by increasing cardiac output, which is the product of heart rate and stroke volume. The response to exercise in conditioned athletes is an increase in both rate and stroke volume. Both share equally as mechanisms for flow increase. Heart rate is regulated by neurohumoral mechanisms and normally represents a major reserve mechanism. Most seriously ill patients have a sinus tachycardia. In such patients increases in cardiac output subsequent to fluid loading are characteristically the result of increases in stroke volume. Heart rate usually does not playa major role. On occasion a bradycardic patient with low flow may be significantly improved with chronotropic agents or pacing. The determinants of stroke volume are: (1) preload, which in general terms may be described by the end-diastolic ventricular filling pressures, central venous and left atrial, for the right and left hearts respectively. The force of contraction is directly related to preload and is
934
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described by Starling's law of the heart. (2) Afterload is the force-resisting fiber shortening and is equivalent to pulmonary or systemic arterial pressure for right and left ventricles respectively. The force of contracture is inversely related to afterload. (3) The contractile state of the heart relates to factors such as beta-adrenergic agonists and antagonists which can change the force of contraction independent of preload and afterload. 3
CARDIAC WORK When pulse and afterload are constant, the Starling mechanism is the major determinant of stroke volume and cardiac output. Thus, in severe sepsis, vasodilatation and sequestration of volume in capacitance vessels lead to a reduction in venous return. There is a resultant lowering of right and then left ventricular filling pressures or preloads. This leads to a fall in cardiac output. Therapy involves the infusion of fluids to increase venous return, preload, and flow. However, when afterload also changes, the reserve function of the heart is more difficult to describe. Figure 2 demonstrates that fluid loading increases cardiac output in mild sepsis and that for equivalent preloads the septic subject has a higher flow. In this case the Starling mechanism is operating normally while contractility appears to be increased. This "hyperdynamic" state is common. The cardiac work performed in the septic group, however, remains unchanged (right panel, Fig. 2). The decrease in arteriolar resis-
THREE HOURS AFTER E. COLI FLUID CHALLENGE _ _ SEPTIC
o---{) CONTROL ( I NUMBER OF DOGS CARDIAC INDEX
LEFT VENTRICULAR
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8
11
14
17
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2
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14
17
MPAWP mm Hg
Figure 2. Following a moderate but not lethal E. coli bacteremia, septic animals become hyperdynamic. The left panel shows that when the animals were volume loaded, the cardiac index was increased in the septic group at all levels of mean pulmonary arterial wedge pressure (MPAWP). Flow was significantly higher than controls at a MPAWP between 14 and 17 mm Hg. This increased flow is an advantage to peripheral tissues because of increased oxygen availability. However, the function of the heart itself is best described by left ventricular stroke work, which is the product of stroke volume and the difference between afterload and preload. The right panel shows that intrinsic cardiac function is unchanged by nonlethal sepsis.
935
CIRCULATION
tance in sepsis leads to systemic hypotension (lowered afterload), such that work which is the product of flow and systemic minus left atrial pressure remains constant. High flow states are characteristic of septic patients who survive. It appears that the septic patient may exchange flow for pressure work, thus increasing oxygen availability. The experiment shown in Figure 2 illustrates the importance of evaluating cardiac work, not simply stroke volume, when attempting to describe intrinsic myocardial function.
AFTERLOAD In patients with low cardiac outputs secondary to myocardial ischemia or infarction, the suggestion has been offered that a decrease in afterload may improve flow because cardiac work is reduced. Current data might support a clinical trial of the vasodilators trimethaphon or nitroprusside in hypertensive patients suffering low flow statesY Thus, head injuries may unleash an overwhelming sympathoadrenal discharge leading to extreme systemic hypertension and left ventricular failure. Therapy may benefit this class of patients, but data are conflicting regarding benefit to normotensive or hypotensive patients whose stroke volume may be normal. Indeed, in sepsis further lowering of the diastolic pressure may induce or potentiate myocardial ischemia because of reduced coronary blood flow. P 1I0~
PULSE
100
MART. PRESS.7Oi
-
MAP
-
50~ 8/
80
7
70
c.o. Figure 3. As positive end expiratory pressure (PEEP) is increased arterial oxygen tension rises. Cardiac output initially rises and then falls. The best end expiratory pressure is that which provides the highest oxygen availability. In this particular patient 5 cm PEEP was chosen. Note that pulse rate and arterial pressure do not correlate with cardiac output.
Pa02
50
5
50
700
600 C.O.XC a 02
500
400
20
o
936
HERBERT
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Acute increases in right ventricular afterload are not uncommon clinical problems, particularly in patients suffering acute respiratory failure. Thus, mechanical ventilation and positive end inspiratory pressure, particularly above 10 cm H 2 0 may cause significant pulmonary hypertension and right ventricular failure. 12 The reduction in the force of right ventricular contraction induced by the high afterload may not be counteracted by the concomitant increase in preload. There is often a resultant decline in stroke volume. Therapy should be directed at unloading the right ventricle. Thus, positive end expiratory pressure should be reduced to a level which optimizes oxygen availability. Often the benefits of PEEP, that is, an increased P a02 are far outweighed by the dangerous fall in blood flow (Fig. 3).
CONTRACTILITY The contractile state of the heart may be impaired, independent of low preloads or high afterloads. Figure 4 compares a group of patients suffering sepsis and those suffering coronary artery disease. The latter group demonstrate Starling curves which are shifted downward and to the right, a decrease in the contractile state. At any filling pressure, stroke work is lower in the patient suffering coronary artery disease than in the septic patient. The ischemic heart is known to manifest decreased contractility.23 The use of beta-adrenergic agents such as
VENTRICULAR PERFORMANCE CURVES
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60
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8
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28
LEFT VENTRICULAR FILLING PRESSURE, mmHg
Figure 4. Patients with coronary artery disease have Starling curves which are shifted downward and to the right. This negative inotropic effect is thought to be due to myocardial ischemia. Septic patients have upslopes and stroke works which are relatively normal. However, at an average filling pressure of 10 mm Hg, stroke work decreases with further increases in preload. This limitation in myocardial reserve may relate to the development of subendocardial ischemia as filling pressures increase above 10 mm Hg. The precise pathophysiology remains to be defined. The values shown are means and one standard deviation.
937
CIRCULATION
50 Figure 5. The rapid infusion of a mixture of glucose, insulin, and potassium usually results in an inotropic effect, shifting the Starling curve upward and to the left. The ordinate is left ventricular stroke work index (LVSWI) and the abscissa left atrial pressure (LAP). The control curve was constructed using an equiosmolar solution of mannitoL Note that this curve shows a downslope. Other inotropic agents such as isoproterenol, dopamine, or epinephrine may exert similar effects. The action of these drugs, however, is not always predictable. In critically ill patients the close monitoring of flow and filling pressure may be required.
J.D.
~
CI)
> -'
15
20
25
l.A.P. - mm Hg
epinephrine, norepinephrine, or isoproterenol may not be advantageous under such circumstances. 15. 28 Increases in contractility are known to be associated with greater increases in myocardial oxygen requirements. In addition, changes in wall stress or abnormal distributions of blood flow induced by these inotropic agents may result in further impairment of myocardial oxygenation. Despite these arguments a salutary inotropic effect is often achieved as demonstrated in Figure 5. The infusion of glucose insulin and potassium shifts the Starling curve in a patient with coronary artery disease upward and to the left. The presence of myocardial depression in patients suffering critical illness is now well documented. The Starling curve may be shifted downward and to the right such that the left ventricular stroke work is lower than predicted at any filling pressure. In addition to this decrease in overall contractility the Starling mechanism may itself be abnormal. This is illustrated by the descending limbs of the curves in Figures 4 and 5. The descending portion of the curve can be considered subclinical cardiac failure, which becomes clinically manifest as a low perfusion state, when preload is further increased. It is surprising to observe that in severely septic patients the Starling curve will peak at relatively normal filling pressures, which average 10 mm Hg (see Fig. 4). At higher preloads these septic patients show a rapid decline in work. There is no virtue in the use of fluid infusions which increase preload much above 10 mm Hg in most severely ill septic patients. Indeed, since these patients are very vulnerable to pulmonary interstitial and intraalveolar edema (that is, acute pulmonary insufficiency), the lowest left ventricular preload should be used which provides a satisfactory cardiac output. It is reasonable to suppose that the loss of pulmonary capillary integrity in these septic patients will nullify the protective effects of plasma colloid osmotic pressure and allow an increase in edema formation at all levels of pulmonary venous pressure.
938
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HECHTMAN
MONITORING Patients who continue to manifest evidence of poor perfusion, e.g., peripheral vasoconstriction, low urine output, or cerebral symptoms, after initial attempts at resuscitation, should be considered candidates for more intensive monitoring. A thermistor-tipped, flow-directed, pulmonary arterial catheter is positioned, usually through a cutdown site in a medial antecubital vein. 26 Systemic arterial catheterization is also of value. The following information now becomes available: preload of right and left ventricles, that is, central venous and pulmonary arterial wedge pressures, and afterload of right ventricle, i.e., pulmonary arterial pressure. The afterload of the left ventricle is the systemic arterial pressure. Cardiac output is measured by thermodilution. 25 All these measurements may conveniently be done by the intensive care unit nursing staff. Derived hemodynamic variables include pulmonary and systemic vascular resistance as well as right and left ventricular stroke work. The measurement of venous admixture, oxygen availability, and consumption requires pulmonary and sytemic arterial blood sampling. Starling curves are constructed with a rapid volume infusion of-25 to 50 gm of albumin, blood, and/or saline in patients whose pulmonary arterial wedge pressures are below 10 mm Hg. Sequential pressure and flow measurements are made which are then used to draw a myocardial performance curve (see Fig. 5).
CORONARY BLOOD FLOW The heart may not only be the determinant of systemic abnormalities resulting from reduced flow and oxygen availabilty, but may also be the recipient of many of these effects. Myocardial oxygen levels, like those in other tissues, depend on supply and demand. Supply of oxygen to the heart or other tissues relates to blood flow, arterial oxygen content, oxygen-hemoglobin affinity, and the diffusion distance to cell mitochondria. The major determinants of myocardial oxygen demand, in addition to basal metabolic requirement, are (1) peak systolic wall force or peak intraventricular pressure, (2) heart rate, and (3) contractile state. 2 Thus, the use of the cardiac reserve mechanisms of increased preload, heart rate, and contractile or inotropic state are associated with increased oxygen requirements which necessitate increased coronary flow. The depressed myocardial performance which may accompany hemorrhage and sepsis is most likely related to reduced oxygen supply. It is probable that coronary blood flow during hemorrhagic hypotension is reduced to a greater extent than myocardial nutritional requirements.14 Coronary flow is the principal determinant of myocardial oxygen availability since normally oxygen extraction is large, about 55 to 65 per cent, and coronary sinus P0 2 is low. Further oxygen delivery to
CIRCULATION
939
myocardial tissue is not possible since the driving force which determines oxygen movement from blood to tissue, oxygen partial pressure, is already severely reduced. Increases in myocardial oxygen delivery are only made possible by increases in coronary flow. In addition to coronary blood flow and oxygen availability, other factors may reduce myocardial performance by acting directly on cardiac contractility mechanisms. The data, however, are inconclusive. It has been difficult to separate the effects of toxins from those of reduced oxygen availability.10 For example, myocardial depressant factors originating in the pancreas are thought to damage both normal as well as ischemic hearts.2o Conflicting evidence, however, discredits these pancreatic factors and denies their role in myocardial depression. 7 Other toxic factors are of undefined clinical importance, such as pH electrolytes, calcium, or vasoactive materials such as prostaglandins, angiotensin, the kinins, and various sympathetic amines. Coronary blood flow remains a recognized critical determinant of oxygen availability. Normally as aortic or coronary perfusion pressure falls, peripheral resistance in the myocardial vascular bed is autoregulated to maintain flow. An average change in coronary flow of only ±7 per cent occurs over a pressure range of 70 to 150 mm HgY Under normal conditions it is only when coronary perfusion pressures fall below 70 to 80 mm Hg that coronary flow is reduced and myocardial depression occurs.21 Autoregulation is not only significant in maintaining flow during periods of hypotension but is the critical mechanism which provides increased flow during periods of heightened myocardial oxygen demand. Under resting conditions only one half of the available capillary bed is perfused. 9 As the heart is made hypoxic or infused with a coronary vasodilator such as nitroglycerine, there is capillary recruitment. The reverse effect is seen with angiotensin. Despite these powerful autoregulatory reserve mechanisms, mechanical factors may significantly liInit or alter the distribution of coronary flow and render portions of the heart ischeInic. The beating heart inhibits its own blood supply. The subendocardial region of the left ventricle is particularly vulnerable and normally receives most of its flow during diastole. If preload falls because of hemorrhage or sepsis, the systolic-intramyocardial pressure is high across most of the left ventricular wall.'~ This high systolic intramyocardial pressure will inhibit coronary flow throughout the myocardium during the period of systole. In this case coronary diastolic flow becomes even more critical. s The volume of diastolic flow will be determined by the diastolic time interval and diastolic pressure. Thus the tachycardia which usually accompanies trauma and sepsis reduces the diastolic time interval and therefore coronary flow. The diastolic pressure in many seriously ill patients will frequently be lower than the criticallevel of 70 to 80 mm Hg, again jeopardizing myocardial flow. These considerations suggest that myocardial ischemia may be frequent in patients suffering trauma and sepsis. *Based on the Laplace relationship.
940
HERBERT
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HECHTMAN
Following the infusion of fluid and/or blood, preload increases as do arterial pressure, stroke work, and oxygen consumption. Coronary flow may now occur during both diastole and systole. The uniformity of the distribution of this flow however has been questioned. Certain portions of the heart, particularly the subendocardium, may be deprived of adequate flow both because of mechanical factors as well as myocardial edema. In such cases myocardial work and oxygen consumption may increase beyond the limits set by coronary flow and oxygen availability. . It is possible that this accounts for the descending limb of the Starling curve (see Fig. 4). It is at this level of preload when oxygen demand exceeds supply. Another important contributor to myocardial work is afterload. Increased aortic pressure may' well increase coronary perfusion; however, the advantage is lost in the hypertensive patient because of the extraordinary increase in myocardial oxygen requirements. There are other critical determinants of coronary flow. Thus, preexistent coronary arteriosclerosis can be a substantial cause of flow limitations.
TISSUE OXYGENATION The importance of coronary perfusion relates to the oxygenation of the myocardium. Three other aspects of oxygenation will now be considered: (1) hemoglobin levels, (2) interstitial edema, and (3) the oxygenhemoglobin affinity state. The oxygen content of blood is primarily determined by hemoglobin concentration. Unfortunately, high hematocrits do not necessarily mean increased oxygen availability since the high hematocrit blood is more viscous and flow may be impeded in the microcirculation. The optimum hemoglobin in critically ill patients is unknown. We have usually attempted to maintain hemoglobin levels between 12 and 14 grams per 100 milliliters of blood as have others.Is Severe sepsis is thought to lead to endothelial cell damage which in turn results in generalized extravascular fluid accumulations. This fluid is clinically most evident in the lungs of septic patients suffering respiratory failure. Extravascular fluid and endothelial cell damage are also found in other tissues including the heart. s Delivery of oxygen from blood to mitochondria is inhibited under these circumstances by the added diffusion barrier. There is speculation that prevention or reduction of extravascular myocardial edema will improve myocardial performance. Indeed, the experimental use of the osmotically active agent mannitol has resulted in improved cardiac contractility.27 Clinical use of such agents remains unproven. The diffusion process which determines oxygen transport from capillary blood to tissues depends not only on the thickness of the diffusion barrier but also on the difference in partial pressure of oxygen on both sides of the barrier, i.e., capillary blood and mitochondria. It is this difference in partial pressure which serves as the driving force for diffusion.
941
CIRCULATION PRESERVED REO CELLS WITH.'
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VOLUME LOADING FUNCTION CURVES
I
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JUST OFF BYPASS
I
Following coron-
ary bypass surgery, patients who
receive low affinity, high 2,3 diphosphoglycerate containing red cells have higher flows at most left ventricular filling pressures (right panel). The stroke work of these hearts is also improved. The effect is thou ght to relate to the increased delivery of oxygen to myocardial tissue, facilitated by the higher available oxygen tensions in capillary blood.
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