lnotropic Agents and Infarct Size Theoretical and Practical Considerations
MICHAEL
LESCH,
MD,
Recent data demonstrating the ability of interventions that alter the balance between myocardial oxygen demand and supply to affect infarct size are reviewed. The effects of inotropic agents on the determinants of myocardial oxygen consumption and coronary blood flow are discussed relative to the potential of these drugs to decrease or increase infarct size in the experimental animal and in man. The applicability of the animal data to the clinical situation is discussed and, on the basis of these considerations, guidelines are presented for the use of inotropic agents in patients with acute myocardial infarction.
FACC’
Boston, Massachusetts
pathologic studies of human autopsy material have related pump failure in acute myocardial infarction to the extent of muscle necrosis, pump failure occurring when greater than 40 percent of the left ventricle is infarcted. 1~2Advances in circulatory assist devices and emergency surgery for the treatment of pump failure in acute myocardial infarction notwithstanding,“T4 inotropic agents remain the primary therapy for the pump failure syndromes that complicate acute ischemic heart disease.” However, recent laboratory data indicate that the extent of necrosis that results from an experimental coronary occlusion may be increased by inotropic agents.6r7 These considerations define a potential therapeutic dilemma for the clinical cardiologist; that is, the therapy for a complication of acute infarction may simultaneously create or worsen the complication. Since inotropic agents are widely used to treat various complications of acute myocardial infarction and it is possible that such treatment may extend infarct size, this presentation reviews pertinent laboratory and clinical data relative to these factors. On the basis of this review, guidelines are suggested for the appropriate use of inotropic agents in acute myocardial infarction. Quantitative
Historical
From the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Mass. This study was supported in part by U. S. Public Health Service Grant HL 11306. Established Investigator of the American Heart Association, Dallas, Texas. Address for reprints: Michael Lesch, MD, Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Mass. 02115. l
508
March
31, 1978
The American
Journal
Considerations
Pathologic analyses of coronary artery disease have emphasized the roles of coronary atherosclerosis and arterial occlusion in the genesis of ischemic heart disease.s It has long been recognized that acute myocardial infarction can occur in the presence of only partial coronary occlusion; recently the predilection for subendocardial, as opposed to transmural, infarction in the absence of total vascular occlusion has been reemphasized.g The less adequate coronary circulation of the subendocardium, as compared with the subepicardium, is thought to be responsible for the phenomenon of subendocardial infarction without occlusion.‘s These considerations have generated the concept that augmentation of myocardial oxygen demand, over and above fixed degrees of supply, could result in infarction. Infarction is now thought of not only as a manifestation of decreased arterial flow, but also as a consequence of the imbalance between myocardial oxy-
01 CARDIOLOGY
Volume
37
INOTROPIC AGENTS AND INFARCT SIZE-LESCH
gen supply and demand with alterations in either variable of this equation capable of causing necrosis.6,7 These observations, coupled with the concept that a border zone of ischemic but potentially viable tissue surrounds the central core area of a myocardial infarct,* led to the hypothesis that infarct size could be reduced or augmented by appropriate manipulations of oxygen supply and demand.6,7 Knowledge of the factors regulating myocardial oxygen supply and demand and the effect that inotropic agents may have on these variables is thus prerequisite to a discussion of the effect of inotropic agents on infarct size. Determinants
of Myocardial
Oxygen Balance
Oxygen Consumption The many factors that influence myocardial oxygen consumption (MVOz) have been extensively studied and clearly identified in recent years.i1J2 These variables may be subclassified into the categories of major and minor determinants. The oxygen cost related to the development of intramyocardial wall tension, the inotropic state of the left ventricle and the heart rate represent three major determinants of MVOz. The oxygen cost of basal maintenance, depolarization, activation, maintenance of active state and shortening against an external load are minor determinants. Wall tension and ventricular volume: Intramyocardial wall tension, as defined by the Laplace relation, varies directly with ventricular pressure and radius and inversely with wall thickness. Since wall thickness is relatively fixed at a given time, shortterm alterations in wall tension are related to variations in developed tension and ventricular radius (volume). The development of pressure is a systolic event and the prime determinant of systolic wall tension is developed pressure. In contrast, variations of ventricular radius (volume) are related primarily to diastolic events such as compliance, venous return and duration of diastole. Since the inotropic agents are capable of simultaneously augmenting developed pressure and reducing cardiac volume, the influence on MVOz varies depending upon which effect predominates. Contractile state: Despite recent controversy about the precise techniques suitable for defining contractile state in the intact human heart,i3 available experimental data define a direct correlation between contractile state and MVOs. When all other variables are held constant, augmentation of the inotropic state enhances MVOz whereas interventions that depress contractile state decrease oxygen consumption. Since the inotropic agents, by definition, augment contractile state, they must perforce augment MVOz. Heart rate: The number of times per minute t,hat the heart is activated determines the cumulative systolic tension generated per unit of time, and thus
March
MVOz is directly proportional to heart rate. The chronotropic activity of the various inotropic agents varies widely, although most of the agents tend to accelerate heart rate.i4 Oxygen Supply Oxygen supply to an organ may be increased either by augmenting blood flow or by increasing oxygen extraction from arterial blood. Since the heart maximally extracts oxygen presented to it in coronary arterial blood under basal conditions,1° enhanced myocardial oxygen demands can be accommodated only by augmenting coronary flow. The manner in which the inotropic agents affect the variables that regulate coronary flow must therefore be considered. Coronary perfusion pressure: Blood flow through the coronary circulation, as in other vascular beds, is related directly to perfusion pressure and inversely to vascular resistance. Because of the unique mechanical features of the coronary circulation wherein the intramyocardial portion of the left ventricular circulation is collapsed during systole by intramyocardial pressure, coronary perfusion pressure cannot be equated with mean aortic pressure. To a significant degree, coronary flow in the left ventricle is a diastolic phenomenon (roughly 70 percent of left ventricular flow occurs during diastole), and thus mean aortic diastolic pressure more closely approximates coronary perfusion pressure. However, this formulation may also be inaccurate since the wall tension generated by the subendocardium exceeds that of the mid- and subepicardium and the large coronary conduit vessels run on, rather than through, the ventricular myocardium. Further complicating a simple definition of perfusion pressure is the fact that diastolic left ventricular wall tension is transmitted to the coronary vessels that traverse the left ventricular myocardium and, with increased diastolic pressures, this effect must be taken into account. Under circumstances of increased diastolic ventricular pressures, net perfusion pressure may best be equated with the expression aortic diastolic pressure minus mean left ventricular diastolic pressure. When the diseased coronary circulation is considered, the effects of obstructive lesions and collateral vessels on coronary perfusion pressure must be accounted for on a regional basis and the inability of a single mathematical expression to define coronary perfusion pressure becomes apparent. The former creates pressure gradients of all degrees of severity across the obstruction, whereas the latter range in caliber from vessels that are sufficiently large to transmit pressures from a nonobstructed artery to a site distal to an obstruction to vessels so small that pressure gradients occur across the collateral pathway. Alternatively stated, because coronary perfusion pressure in coronary disease must be considered on a regional and not a global basis, no single mathematical model or formulation can adequately describe the pertinent variables in this condition.
31, IQ76
The American
Journal
of CARDIOLOGY
Volume
37
509
INOTROPIC AGENTS AND INFARCT SIZE-LESCH
Coronary resistance: A similar degree of complexity is manifest when considering the factors known to regulate coronary resistance. Although the metabolic, neurohumoral and reflex mechanisms regulating coronary resistance have been extensively studied and partially defined,l’ a direct extrapolation of this knowledge from the laboratory animal to the diseased human coronary circulation may not be warranted for several reasons: (1) The regional nature of ischemic heart disease creates a degree of heterogeneity in arteriolar resistance levels within the coronary arterial tree; (2) the possible occurrence of as yet undefined factors that regulate coronary resistance in collateral vessels cannot be discounted; and (3) the possibility that mechanisms known to regulate resistance in a nondiseased coronary artery may not be functional in an atherosclerotic vessel must be considered (that is, it is not known whether and to what extent the factors known to regulate coronary resistance in normal vessels are operative in atherosclerotic vessels). Effect of lnotropic Agents
Although the many factors capable of affecting both myocardial oxygen supply and demand have been characterized, it is impossible to state the degree to which each variable is operative under the various conditions present in the patient with coronary artery disease in general or with acute myocardial infarction in particular. Moreover, since the inotropic agents are capable of altering all factors known to contribute to the regulation of MVOz (heart rate, wall tension and contractility) and coronary blood flow (perfusion pressure and resistance), it is similarly difficult to predict the net effect that an inotropic drug will have on the balance between oxygen supply and demand in a specific location in the heart of a given patient with acute myocardial infarction. An inotropic agent that favorably affects the net oxygen balance under one set of circumstances may adversely affect this balance given an alternative situation. Since the pertinent variables may not be defined (or, if defined, not measurable) in the patient with acute infarction, any generalization about the effects of inotropic agents on infarct size is untenable. Observations made under one set of conditions cannot be used as a data base to predict the effect of an inotrope on infarct size in other circumstances, and available data on inotropic agents and infarct size must be reviewed with this constraint. Laboratory
Studies
The feasibility of measuring infarct size in an animal model and the potential of specific interventions for altering the extent of ischemic injury after experimental vascular occlusion has recently been studied with the combined techniques of epicardial S-T segment mapping and creatine phosphokinase (CPK) analysis in myocardial biopsy specimens.s,7,15 Recent criticisms of these techniques notwithstanding,rs these investigations represent the first attempt to
510
March
31, 1976
The American
Journal
of CARDIOLOGY
evaluate the ability of specific interventions to alter the extent of ischemic injury resulting from a single, controlled vascular occlusion. When inotropic agents (digitalis, norepinephrine, isoproterenol) were administered within 3 to 6 hours after creation of a coronary occlusion in normotensive animals (with sinus rhythm and without congestive heart failure) the extent and degree of tissue injury increased. At first glance, these data appear to demonstrate a generalized capability of inotropic agents to increase the severity and extent of a myocardial infarction but, as the authors point out, such an interpretation would be erroneous. Rather, the data demonstrate that when experimental conditions are s.0 manipulated that the inotropic agents augment MVOz, then these agents uniformly increase tissue damage as defined by the S-T segment map and CPK biopsy technique. Alternatively stated, these studies tend to prove the hypothesis that augmenting myocardial oxygen consumption will increase the extent of ischemic damage induced by a fixed vascular occlusion if other variables are held constant. Conversely, in situations such as cardiac failure, wherein the inotropic agents may be expected to decrease MVOz by virtue of a decrease in wall stress that is proportionately greater than augmentation of contractility, no increase in ischemic injury and possibly a decrease would be predicted. Such data have been obtained in the canine heart pharmacologically depressed with procainamide, propranolol or barbiturate.r7 The latter experiments indicate the variable effects that the inotropic agents may have on infarct size and reinforce the dictum that no single statement can adequately define the effects of the inotropes on infarct size. Clinical Clinical Application
Considerations
of Animal Data
Since techniques for the antemortem measurement of infarct size in patients have only recently been developedr8Jg and are incompletely validated,20 data on the effects of inotropic agents on infarct size in human subjects are unavailable. Consequently, one is forced to draw clinical conclusions from the animal data. The extrapolation of animal laboratory data to the bedside is difficult when a valid animal model of the disease under study is available. When one is considering acute myocardial infarction, the relevance of such extrapolations may be questioned. There are dissimilarities between the short-term observations made after placement of an experimental ligature on a coronary vessel in an animal with an otherwise normal coronary circulation and myocardium and the findings after a spontaneous infarct in a patient with diffuse coronary atherosclerosis and impaired ventricular function who presents to the hospital some hours after the onset of symptoms. Moreover, although the term “inotropic agent” may be sufficiently precise for the pharmacologist or physiologist, it is not for the clinician. Although the clinician recognizes an agent as potentially inotropic,
Volume
37
INOTROPIC
he is also cognizant of its antiarrhythmic versus arrhythmogenic properties, its negative and positive chronotropic properties, and its peripheral vasodilator versus vasoconstrictor properties in addition to a variety of noncardiovascular side effects. Thus, a clinically oriented discussion of the effects of inotropit drugs on infarct size cannot be generalized, but rather must specify particular drugs. Despite the availability of many drugs with positive inotropic actions, and the recent introduction of yet newer inotropic agents,21g22 only digitalis, isoproterenol and norepinephrine have been extensively studied or widely used in patients with acute myocardial infarction, and discussion will be limited to these agents. Although the animal laboratory data cannot be directly extrapolated to the bedside, the potential clinical implications of the observation that inotropic agents may under certain circumstances aggravate ischemic injury cannot be discounted. Thus, the clinician must review previously accepted indications for administering these drugs to patients with acute myocardial infarction. As is so often true in evaluating alternative therapeutic modalities, there are no absolute answers, and potential risks must be balanced against potential benefits. Digitalis
Effects on cardiac function in pump failure: Although digitalis glycosides have traditionally been used to treat three specific complications of acute myocardial infarction-atria1 arrhythmias, congestive heart failure and cardiogenic shock-a consensus concerning indications or contraindications for such therapy exists only for treatment of atria1 arrhythmias.2s,24 Even in this situation, personal clinical experiences rather than definitive clinical trials are quoted as justification of glycoside therapy.*” Extensive investigations on the effects of glycosides on cardiac function in the presence of pump failure in patients in the acute and convalescent phases of infarction and in various animal models of infarction have yielded conflicting and inconsistent data.2a,‘4 When all the data on pump function from various studies are considered as a whole, no evidence for a beneficial hemodynamic or mechanical effect can be defined in the first 24 hours after infarct, whereas a possible salutary effect may be discerned when glycosides are administered after the init,ial 24 hours. The failure of a considerable research effort to define specifically the effects of glycoside therapy on pump function in acute infarction is exemplified by the summary statements in two recent reviews dealing directly with glycoside therapy in acute myocardial infarction.2a,“4 In one, the authors2” state: “Digitalis is commonly utilized early in the treatment of congestive heart failure and cardiomegaly complicating acute myocardial infarction, despite the paucity of experimental and clinical evidence in support of such therapy. Whether the digitalis glycosides should continue to be used routinely in such patients is an important subject for
March
AGENTS
AND
INFARCT
SIZE-LESCH
clinical investigation.” The second article,“4 written by investigators who have interpreted their own data as indicating digitalis is of benefit in acute myocardial infarction, concludes with the ambiguous statement that “digitalis may (italics mine) be recommended following acute myocardial infarction if the usual indications, supraventricular tachyarrhythmias or cardiac failure, are present.” Guidelines for therapy in acute myocardial infarction: Since the animal data discussed indicate potential extension of infarct size with glycoside therapy in the hyperacute phases of experimental infarction and the clinical data indicate that digitalis is effective in the treatment of pump failure only after the first 24 hours, the following guidelines for digitalis therapy in acute myocardial infarction seem prudent: (1) Avoid administering glycosides in the first 6 hours after acute infarction. This is not a major problem since the mean delay between onset of pain and admission to a coronary care facility is 6 hours”” and the signs of pump failure frequently do not manifest in the first 12 hours.27 (2) Avoid administering glycosides in the first 24 hours after pain if other equally effective therapeutic measures are available. Thus, in this time period one would attempt to treat pulmonary congestion with diuretic agents, as suggested by Swan et a1.,28 rather than with glycosides, and one would use propranolol, quinidine, procainamide and cardioversion to treat atria1 arrhythmias. (3) When using glycosides to treat pump failure in acute myocardial infarction, one must prove unequivocally the presence of pump failure and should have available methods for defining quantitative improvement. Because the clinical and radiologic signs of congestive heart failure in acute myocardial infarction are fallible,2s demonstration of elevated left ventricular filling pressures throughout diastole (and not merely at end-diastole since the latter finding may be related to compliance changes) should be requisite for the treatment of heart failure in the first 24 hours after infarction.sO The use of digitalis after the initial 24 hour period after infarction remains conjectural. However, the lack of evidence suggesting increased sensitivity to digitalis intoxication in acute myocardial infarction,:
MICHAEL
LESCH,
MD,
Recent data demonstrating the ability of interventions that alter the balance between myocardial oxygen demand and supply to affect infarct size are reviewed. The effects of inotropic agents on the determinants of myocardial oxygen consumption and coronary blood flow are discussed relative to the potential of these drugs to decrease or increase infarct size in the experimental animal and in man. The applicability of the animal data to the clinical situation is discussed and, on the basis of these considerations, guidelines are presented for the use of inotropic agents in patients with acute myocardial infarction.
FACC’
Boston, Massachusetts
pathologic studies of human autopsy material have related pump failure in acute myocardial infarction to the extent of muscle necrosis, pump failure occurring when greater than 40 percent of the left ventricle is infarcted. 1~2Advances in circulatory assist devices and emergency surgery for the treatment of pump failure in acute myocardial infarction notwithstanding,“T4 inotropic agents remain the primary therapy for the pump failure syndromes that complicate acute ischemic heart disease.” However, recent laboratory data indicate that the extent of necrosis that results from an experimental coronary occlusion may be increased by inotropic agents.6r7 These considerations define a potential therapeutic dilemma for the clinical cardiologist; that is, the therapy for a complication of acute infarction may simultaneously create or worsen the complication. Since inotropic agents are widely used to treat various complications of acute myocardial infarction and it is possible that such treatment may extend infarct size, this presentation reviews pertinent laboratory and clinical data relative to these factors. On the basis of this review, guidelines are suggested for the appropriate use of inotropic agents in acute myocardial infarction. Quantitative
Historical
From the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Mass. This study was supported in part by U. S. Public Health Service Grant HL 11306. Established Investigator of the American Heart Association, Dallas, Texas. Address for reprints: Michael Lesch, MD, Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Mass. 02115. l
508
March
31, 1978
The American
Journal
Considerations
Pathologic analyses of coronary artery disease have emphasized the roles of coronary atherosclerosis and arterial occlusion in the genesis of ischemic heart disease.s It has long been recognized that acute myocardial infarction can occur in the presence of only partial coronary occlusion; recently the predilection for subendocardial, as opposed to transmural, infarction in the absence of total vascular occlusion has been reemphasized.g The less adequate coronary circulation of the subendocardium, as compared with the subepicardium, is thought to be responsible for the phenomenon of subendocardial infarction without occlusion.‘s These considerations have generated the concept that augmentation of myocardial oxygen demand, over and above fixed degrees of supply, could result in infarction. Infarction is now thought of not only as a manifestation of decreased arterial flow, but also as a consequence of the imbalance between myocardial oxy-
01 CARDIOLOGY
Volume
37
INOTROPIC AGENTS AND INFARCT SIZE-LESCH
gen supply and demand with alterations in either variable of this equation capable of causing necrosis.6,7 These observations, coupled with the concept that a border zone of ischemic but potentially viable tissue surrounds the central core area of a myocardial infarct,* led to the hypothesis that infarct size could be reduced or augmented by appropriate manipulations of oxygen supply and demand.6,7 Knowledge of the factors regulating myocardial oxygen supply and demand and the effect that inotropic agents may have on these variables is thus prerequisite to a discussion of the effect of inotropic agents on infarct size. Determinants
of Myocardial
Oxygen Balance
Oxygen Consumption The many factors that influence myocardial oxygen consumption (MVOz) have been extensively studied and clearly identified in recent years.i1J2 These variables may be subclassified into the categories of major and minor determinants. The oxygen cost related to the development of intramyocardial wall tension, the inotropic state of the left ventricle and the heart rate represent three major determinants of MVOz. The oxygen cost of basal maintenance, depolarization, activation, maintenance of active state and shortening against an external load are minor determinants. Wall tension and ventricular volume: Intramyocardial wall tension, as defined by the Laplace relation, varies directly with ventricular pressure and radius and inversely with wall thickness. Since wall thickness is relatively fixed at a given time, shortterm alterations in wall tension are related to variations in developed tension and ventricular radius (volume). The development of pressure is a systolic event and the prime determinant of systolic wall tension is developed pressure. In contrast, variations of ventricular radius (volume) are related primarily to diastolic events such as compliance, venous return and duration of diastole. Since the inotropic agents are capable of simultaneously augmenting developed pressure and reducing cardiac volume, the influence on MVOz varies depending upon which effect predominates. Contractile state: Despite recent controversy about the precise techniques suitable for defining contractile state in the intact human heart,i3 available experimental data define a direct correlation between contractile state and MVOs. When all other variables are held constant, augmentation of the inotropic state enhances MVOz whereas interventions that depress contractile state decrease oxygen consumption. Since the inotropic agents, by definition, augment contractile state, they must perforce augment MVOz. Heart rate: The number of times per minute t,hat the heart is activated determines the cumulative systolic tension generated per unit of time, and thus
March
MVOz is directly proportional to heart rate. The chronotropic activity of the various inotropic agents varies widely, although most of the agents tend to accelerate heart rate.i4 Oxygen Supply Oxygen supply to an organ may be increased either by augmenting blood flow or by increasing oxygen extraction from arterial blood. Since the heart maximally extracts oxygen presented to it in coronary arterial blood under basal conditions,1° enhanced myocardial oxygen demands can be accommodated only by augmenting coronary flow. The manner in which the inotropic agents affect the variables that regulate coronary flow must therefore be considered. Coronary perfusion pressure: Blood flow through the coronary circulation, as in other vascular beds, is related directly to perfusion pressure and inversely to vascular resistance. Because of the unique mechanical features of the coronary circulation wherein the intramyocardial portion of the left ventricular circulation is collapsed during systole by intramyocardial pressure, coronary perfusion pressure cannot be equated with mean aortic pressure. To a significant degree, coronary flow in the left ventricle is a diastolic phenomenon (roughly 70 percent of left ventricular flow occurs during diastole), and thus mean aortic diastolic pressure more closely approximates coronary perfusion pressure. However, this formulation may also be inaccurate since the wall tension generated by the subendocardium exceeds that of the mid- and subepicardium and the large coronary conduit vessels run on, rather than through, the ventricular myocardium. Further complicating a simple definition of perfusion pressure is the fact that diastolic left ventricular wall tension is transmitted to the coronary vessels that traverse the left ventricular myocardium and, with increased diastolic pressures, this effect must be taken into account. Under circumstances of increased diastolic ventricular pressures, net perfusion pressure may best be equated with the expression aortic diastolic pressure minus mean left ventricular diastolic pressure. When the diseased coronary circulation is considered, the effects of obstructive lesions and collateral vessels on coronary perfusion pressure must be accounted for on a regional basis and the inability of a single mathematical expression to define coronary perfusion pressure becomes apparent. The former creates pressure gradients of all degrees of severity across the obstruction, whereas the latter range in caliber from vessels that are sufficiently large to transmit pressures from a nonobstructed artery to a site distal to an obstruction to vessels so small that pressure gradients occur across the collateral pathway. Alternatively stated, because coronary perfusion pressure in coronary disease must be considered on a regional and not a global basis, no single mathematical model or formulation can adequately describe the pertinent variables in this condition.
31, IQ76
The American
Journal
of CARDIOLOGY
Volume
37
509
INOTROPIC AGENTS AND INFARCT SIZE-LESCH
Coronary resistance: A similar degree of complexity is manifest when considering the factors known to regulate coronary resistance. Although the metabolic, neurohumoral and reflex mechanisms regulating coronary resistance have been extensively studied and partially defined,l’ a direct extrapolation of this knowledge from the laboratory animal to the diseased human coronary circulation may not be warranted for several reasons: (1) The regional nature of ischemic heart disease creates a degree of heterogeneity in arteriolar resistance levels within the coronary arterial tree; (2) the possible occurrence of as yet undefined factors that regulate coronary resistance in collateral vessels cannot be discounted; and (3) the possibility that mechanisms known to regulate resistance in a nondiseased coronary artery may not be functional in an atherosclerotic vessel must be considered (that is, it is not known whether and to what extent the factors known to regulate coronary resistance in normal vessels are operative in atherosclerotic vessels). Effect of lnotropic Agents
Although the many factors capable of affecting both myocardial oxygen supply and demand have been characterized, it is impossible to state the degree to which each variable is operative under the various conditions present in the patient with coronary artery disease in general or with acute myocardial infarction in particular. Moreover, since the inotropic agents are capable of altering all factors known to contribute to the regulation of MVOz (heart rate, wall tension and contractility) and coronary blood flow (perfusion pressure and resistance), it is similarly difficult to predict the net effect that an inotropic drug will have on the balance between oxygen supply and demand in a specific location in the heart of a given patient with acute myocardial infarction. An inotropic agent that favorably affects the net oxygen balance under one set of circumstances may adversely affect this balance given an alternative situation. Since the pertinent variables may not be defined (or, if defined, not measurable) in the patient with acute infarction, any generalization about the effects of inotropic agents on infarct size is untenable. Observations made under one set of conditions cannot be used as a data base to predict the effect of an inotrope on infarct size in other circumstances, and available data on inotropic agents and infarct size must be reviewed with this constraint. Laboratory
Studies
The feasibility of measuring infarct size in an animal model and the potential of specific interventions for altering the extent of ischemic injury after experimental vascular occlusion has recently been studied with the combined techniques of epicardial S-T segment mapping and creatine phosphokinase (CPK) analysis in myocardial biopsy specimens.s,7,15 Recent criticisms of these techniques notwithstanding,rs these investigations represent the first attempt to
510
March
31, 1976
The American
Journal
of CARDIOLOGY
evaluate the ability of specific interventions to alter the extent of ischemic injury resulting from a single, controlled vascular occlusion. When inotropic agents (digitalis, norepinephrine, isoproterenol) were administered within 3 to 6 hours after creation of a coronary occlusion in normotensive animals (with sinus rhythm and without congestive heart failure) the extent and degree of tissue injury increased. At first glance, these data appear to demonstrate a generalized capability of inotropic agents to increase the severity and extent of a myocardial infarction but, as the authors point out, such an interpretation would be erroneous. Rather, the data demonstrate that when experimental conditions are s.0 manipulated that the inotropic agents augment MVOz, then these agents uniformly increase tissue damage as defined by the S-T segment map and CPK biopsy technique. Alternatively stated, these studies tend to prove the hypothesis that augmenting myocardial oxygen consumption will increase the extent of ischemic damage induced by a fixed vascular occlusion if other variables are held constant. Conversely, in situations such as cardiac failure, wherein the inotropic agents may be expected to decrease MVOz by virtue of a decrease in wall stress that is proportionately greater than augmentation of contractility, no increase in ischemic injury and possibly a decrease would be predicted. Such data have been obtained in the canine heart pharmacologically depressed with procainamide, propranolol or barbiturate.r7 The latter experiments indicate the variable effects that the inotropic agents may have on infarct size and reinforce the dictum that no single statement can adequately define the effects of the inotropes on infarct size. Clinical Clinical Application
Considerations
of Animal Data
Since techniques for the antemortem measurement of infarct size in patients have only recently been developedr8Jg and are incompletely validated,20 data on the effects of inotropic agents on infarct size in human subjects are unavailable. Consequently, one is forced to draw clinical conclusions from the animal data. The extrapolation of animal laboratory data to the bedside is difficult when a valid animal model of the disease under study is available. When one is considering acute myocardial infarction, the relevance of such extrapolations may be questioned. There are dissimilarities between the short-term observations made after placement of an experimental ligature on a coronary vessel in an animal with an otherwise normal coronary circulation and myocardium and the findings after a spontaneous infarct in a patient with diffuse coronary atherosclerosis and impaired ventricular function who presents to the hospital some hours after the onset of symptoms. Moreover, although the term “inotropic agent” may be sufficiently precise for the pharmacologist or physiologist, it is not for the clinician. Although the clinician recognizes an agent as potentially inotropic,
Volume
37
INOTROPIC
he is also cognizant of its antiarrhythmic versus arrhythmogenic properties, its negative and positive chronotropic properties, and its peripheral vasodilator versus vasoconstrictor properties in addition to a variety of noncardiovascular side effects. Thus, a clinically oriented discussion of the effects of inotropit drugs on infarct size cannot be generalized, but rather must specify particular drugs. Despite the availability of many drugs with positive inotropic actions, and the recent introduction of yet newer inotropic agents,21g22 only digitalis, isoproterenol and norepinephrine have been extensively studied or widely used in patients with acute myocardial infarction, and discussion will be limited to these agents. Although the animal laboratory data cannot be directly extrapolated to the bedside, the potential clinical implications of the observation that inotropic agents may under certain circumstances aggravate ischemic injury cannot be discounted. Thus, the clinician must review previously accepted indications for administering these drugs to patients with acute myocardial infarction. As is so often true in evaluating alternative therapeutic modalities, there are no absolute answers, and potential risks must be balanced against potential benefits. Digitalis
Effects on cardiac function in pump failure: Although digitalis glycosides have traditionally been used to treat three specific complications of acute myocardial infarction-atria1 arrhythmias, congestive heart failure and cardiogenic shock-a consensus concerning indications or contraindications for such therapy exists only for treatment of atria1 arrhythmias.2s,24 Even in this situation, personal clinical experiences rather than definitive clinical trials are quoted as justification of glycoside therapy.*” Extensive investigations on the effects of glycosides on cardiac function in the presence of pump failure in patients in the acute and convalescent phases of infarction and in various animal models of infarction have yielded conflicting and inconsistent data.2a,‘4 When all the data on pump function from various studies are considered as a whole, no evidence for a beneficial hemodynamic or mechanical effect can be defined in the first 24 hours after infarct, whereas a possible salutary effect may be discerned when glycosides are administered after the init,ial 24 hours. The failure of a considerable research effort to define specifically the effects of glycoside therapy on pump function in acute infarction is exemplified by the summary statements in two recent reviews dealing directly with glycoside therapy in acute myocardial infarction.2a,“4 In one, the authors2” state: “Digitalis is commonly utilized early in the treatment of congestive heart failure and cardiomegaly complicating acute myocardial infarction, despite the paucity of experimental and clinical evidence in support of such therapy. Whether the digitalis glycosides should continue to be used routinely in such patients is an important subject for
March
AGENTS
AND
INFARCT
SIZE-LESCH
clinical investigation.” The second article,“4 written by investigators who have interpreted their own data as indicating digitalis is of benefit in acute myocardial infarction, concludes with the ambiguous statement that “digitalis may (italics mine) be recommended following acute myocardial infarction if the usual indications, supraventricular tachyarrhythmias or cardiac failure, are present.” Guidelines for therapy in acute myocardial infarction: Since the animal data discussed indicate potential extension of infarct size with glycoside therapy in the hyperacute phases of experimental infarction and the clinical data indicate that digitalis is effective in the treatment of pump failure only after the first 24 hours, the following guidelines for digitalis therapy in acute myocardial infarction seem prudent: (1) Avoid administering glycosides in the first 6 hours after acute infarction. This is not a major problem since the mean delay between onset of pain and admission to a coronary care facility is 6 hours”” and the signs of pump failure frequently do not manifest in the first 12 hours.27 (2) Avoid administering glycosides in the first 24 hours after pain if other equally effective therapeutic measures are available. Thus, in this time period one would attempt to treat pulmonary congestion with diuretic agents, as suggested by Swan et a1.,28 rather than with glycosides, and one would use propranolol, quinidine, procainamide and cardioversion to treat atria1 arrhythmias. (3) When using glycosides to treat pump failure in acute myocardial infarction, one must prove unequivocally the presence of pump failure and should have available methods for defining quantitative improvement. Because the clinical and radiologic signs of congestive heart failure in acute myocardial infarction are fallible,2s demonstration of elevated left ventricular filling pressures throughout diastole (and not merely at end-diastole since the latter finding may be related to compliance changes) should be requisite for the treatment of heart failure in the first 24 hours after infarction.sO The use of digitalis after the initial 24 hour period after infarction remains conjectural. However, the lack of evidence suggesting increased sensitivity to digitalis intoxication in acute myocardial infarction,:
