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Physiologic abnormalities and clinical diagnosis
798
Am. Heart J. November, 1959
ANNOTATIONS
It appears that less toxic agents should be employed initially for the relief of pain in angina pectoris and that the MAO inhibitors may be used when simpler and safer methods are ineffective. Travis Winsor Los Angeles, Calif. REFERENCE
1. Gertner, Sheldon B.: Ganglionic 183:750, March 14, 1959.
Block and Monoamine
Oxidase
Inhibitors,
Nature,
The pendulum in research sometimes swings slowly and often internationally. This is particularly true with reference to digitalis. It is surprising how much difference of opinion still is found among clinicians on the use of this drug, despite the enormous literature available, and also how much prejudice exists even among investigators. Withering originally used digitalis fordropsy, being unaware of the existence of auricular fibrillation which was described later, chiefly by Mackenzie. It was Mackenzie and Lewis who emphasized the use of the drug for auricular fibrillation with congestive heart failure, using ventricular rate as an index of its effectiveness. Later, in the United States and in Austria, the drug was advocated for all cases of congestive failure, regardless of associated arrhythmias, the chief protagonists of this point of view being Christian and Wenckebach. The latter point of view received support from physiologists such as Cournand working with the cardiac catheter, although it remained difficult in the intact animal to be sure whether the effect of the drug was direct on the heart or at least in part indirect via peripheral blood vessels. There was some conflict of opinion, for example, as to whether the drug was effective in the isoiated heart. From a more practical standpoint, however, considering the effectiveness and availability of modern diuretics, does digitalis add anything to the management of congestive heart failure with sinus rhythm? Some workers insist that it does and others that it adds nothing, or at most very little. They also point to the ease with which digitalis toxicity is produced in such cases. The whole question is complicated by the fact that congestive failure is not a steady state but is exacerbated by such events as pulmonary embolism, infection, dietary indiscretion, etc. The question of whether or when to use digitalis in the presence of arrhythmias, with or without congestive failure, is even more complex. All this confusion, however, has one salutary effect. It becomes clear that digitalis must not be given as a “routine” drug for heart disease regardless of whether there is an arrhythmia, congestive heart failure, or both. When the drug is given or withheld, the decision must always be preceded by a careful evaluation of all factors and objectives in each individual case. Milton Mendlowitz New York, N. Y.
Physiologic
Abnorm&tks
end Cheat
Dkgaosis
When measurements of physiologic parameters are applied to clinical diagnosis, utility combines with scientific reason. When such application promises aid in diagnosis of a common clinical problem, the method deserves detailed consideration. Such a situation is encountered in the recent report by Robin, Julian, Travis, and Crumpr on the diagnosis of acute pulmonary embolism from measurements of end-tidal and arterial PCOr. The method is based on the observation that ordinarily there is close agreement between arterial and alveolar PC02 (no a-A gradient) but that following acute pulmonary embolism the alveolar gas will be diluted by contributions from ventilated but poorly perfused segments’ of the
ANNOTATIONS
700
lung and this will cause a significant a-A PC02 gradient. In other words, the demonstration of an arterial-alveolar PC02 gradient in a given nonemphysematous subject suggests the diagnosis of acute pulmonary embolism. It seems to us that this statement must rest on two assumptions and implies a third, as follows: (1) There is no PC02 gradient unless some form of cardiopulmonary disease is present. (2) Clinical entities which might become confused with pulmonary vascular obstruction (pneumonia, bronchial obstruction) will not cause physiologic alterations similar to those observed in (3) The physiologic mechanism claimed as the cause for the abpulmonary artery embolism. not nal measurement is exclusively or predominantly responsible for the observed phenomenon. Yet, Martin? In general, the first assumption is valid in normal subjects in a supine position. has shown recently that erect posture causes alterations in the ventilation-perfusion relationships due to relative hyperventilation and underperfusion of the upper lobes resulting in a-A PCOz gradients in excess of 9 mm. Hg. Rapid ventilatory rates also may be the &use for such a gradient. If, for some reason (anxiety, dyspnea), the measurements were mdde in the semierect position or if tachypnea was present or both, a significant PC02 gradient might have occurred on this basis alone. In consequence, present evidence does not support the assumption that a significant a-A PCO, gradient may not be found in the absence of disease. The second assumption is based on the observation that any disturbance in ventilationperfusion ratios in the lung will result in a PC02 gradient, but that ventilation without perfusion will exert a greater effect than that of an equivalent fraction of lung which is perfused but not ventilated.3 This conclusion depends upon the presence of a small mixed venous to pulmonary capillary PC02 difference (about 10 mm. Hg) under normal circumstances. It is reasonable to expect that with low rates of blood flow and hyperventilation of normal alveoli this venocapillary In conditions which allow a high PC02 in the mixed PCOt gradient might be greatly elevated. venous blood and a low PC02 in the capillary blood which is ventilated, the effects of venous admixture will approach the effects of an equivalent degree of ventilation without perfusion (vascular obstruction) and the data would not by themselves allow differentiation. Recently, for example, subjects suffering from postinfluenzal pneumonia were shown to exhibit high a-A gradients either on the basis of uneven ventilation or caused by venous admixture from nonventilated but perfused alveoli4 The statement, then, that cardiorespiratory diseases other than pulmonary emboli are not associated with a significant a-A PC02 gradient is open to debate. The third assumption is required if the gradient is to be used for calculating the fraction of the alveolar dead space and thereby estimating the fraction of the obstructed pulmonary arterial bed. There may well be more than one cause for the gradient observed in pulmonary embolism. That this may be sigThe potential effect of venous admixture has already been mentioned. nificant is suggested by the common finding of moderate to severe arterial desaturation in patients with acute pulmonary embolism, which is not completely corrected by 100 per cent oxygen breathing. This cannot be explained on the basis of increased alveolar dead space3 and is characteristic of a large venous admixture component. It has been produced in dogs by experimental embolization.6 Since acute or repeated pulmonary emboli frequently occur in subjects with a low cardiac output and hyperventilation at rest, a larger than normal pulmonary artery-pulmonary capillary PC02 gradient can be expected. The effects of a large venous admixture could be manifest We know that venous admixture of severe degree can result by a significant a-A PC02 gradient. from obstruction of a relatively small fraction of the arterial bed, thus gross misinterpretation At present only the simulof a gradient might occur in the presence of arterial desaturation. taneous measurements of venous and arterial blood gases and the a-A gradient for both oxygen and carbon dioxide tension allow the effects of nonventilation (or venous admixture) to be separated from nonperfusion (vascular obstruction). This work is reviewed primarily to suggest possible application of physiologic data directly to clinical problems. At present the existence of a single, hopeful concept, so desirable in clinical medicine, seems threatened by the presence of multiple physiopathologic factors encountered in cardiorespiratory measurements. In the case under discussion, several assumptions are made. Failure of the first would allow a “false positive” Existing evidence casts doubt on their validity. diagnosis. Failure of the second would confuse pulmonary embolism with other cIinical entitles. Failure of the third would prevent the possibility of estimating the fraction of the pulmonary
800
Am. Heart J. November, 1959
ANNOTATIONS
vascular bed obstructed. investigation into the thought to be reserved
Reports such as these, however, are needed to stimulate mysteries of abnormalities of ventilation and perfusion-too for the physiology laboratory. Salt
further
Lake
bedside commonly
R. L. Lange City, titah
REFERENCES
1. 2. 3. 4. 5.
Robin,
E., Julian, D., Travis, D., and Crump, 0.: A Physiologic Approach to the Diagnosis of Acute Pulmonary Embolism, New England J. Med. 8601586, 1959. Martin, C., and Young, A.: Ventilation-Perfusion Variations Within the Lung, J. Appl. Physiol. 11:371, 1957. Severinghaus, J., and Stupfel, M.: Alveolar Dead Space as an Index of Distribution of Blood Flow in Pulmonary Capillaries, J. Appl. Physiol. 101335, 1957. Herzog, H., Staub, H., and Richterich, R.: Gas-analytical Studies in Severe Pneumonia, Lancet 1:593, 1959. Dick, M.: Respiratory and Circulatory Responses to Intravenous Oxygen and their Relation to Anoxemia, Am. J. Physiol. 127:228, 1939.
Angina
Pectoris
and Congestive
Failure
The immediate hemodynamic consequences in man of deficient oxygenation of the myocardium that results from coronary artery obstruction have not been widely investigated. Fries and his associates’ studied patients soon after acute myocardial infarction and confirmed the basic observations made by Wigger@ in his classical study of coronary artery occlusion in animals. This study indicated that just after myocardial infarction in man the circulation may be normal or there may be hemodynamic evidences of shock, congestive failure, or both. Precise measurements of the cardiac output and of pulmonary vascular pressuresduring attacks of angina pectoris are now available for consideration. Muller and Rorvik’ performed right heart catheterization upon patients with angina pectoris whose systemic blood pressures and heart sizes were normal and who at rest were free of congestive failure. Although some of their subjects had previously sustained myocardial infarction, others had not, but they were Catheterization studies of their all alike in that they were subject to attacks of angina pectoris. patients at rest and in the absence of angina1 pain yielded normal or near normal hemodynamics, but during angina1 pain induced by exercise there was found a surprising elevation of pulmonary capillary pressure, often to a degree where pulmonary edema is imminent4 The cardiac outputs were for the most part normal at rest and rose physiologically in response to exercise. This abnormal elevation of pulmonary capillary pressure induced by exercise and interpreted as indicating acute left ventricular failure usually preceded the development of angina1 pain and it promptly Left ventricular failure accompanied not subsided as exercise was terminated and pain ceased. only the angina1 pain induced by exercise but also that which developed spontaneously in 2 patients during the catheterization procedure. Muller and Rorvik then expanded their study to include observations both before and after the administration of nitroglycerine. They found that amounts of exercise that had produced both angina1 pain and abnormal elevation of pulmonary capillary pressure before the administration of nitroglycerine failed to produce either after it. Their data did not indicate significant reduction of cardiac output, stroke volume, or left ventricular work load during the second exercise period preceded by the administration of nitroglycerine as compared to the first without it. Therefore, the authors concluded that their subjects tolerated the postnitroglycerine exercise period better hemodynamically as well as symptomatically because the drug either dilated coronary vessels of normal caliber or relaxed constricted ones. Experience with patients naturally comes to ,mind and raises the question whether there are clinical observations which these hemodynamic studies clarify. Angina decubitus is first thought of. Attacks of angina pectoris that awaken patients from a sound sleep are often not only misinterpreted but they also stubbornly resist the efforts of physicians to control them. It has been recorded,6*’ however, that attacks of angina decubitus are usually though not always,
Am. Heart J. November, 1959
ANNOTATIONS
It appears that less toxic agents should be employed initially for the relief of pain in angina pectoris and that the MAO inhibitors may be used when simpler and safer methods are ineffective. Travis Winsor Los Angeles, Calif. REFERENCE
1. Gertner, Sheldon B.: Ganglionic 183:750, March 14, 1959.
Block and Monoamine
Oxidase
Inhibitors,
Nature,
The pendulum in research sometimes swings slowly and often internationally. This is particularly true with reference to digitalis. It is surprising how much difference of opinion still is found among clinicians on the use of this drug, despite the enormous literature available, and also how much prejudice exists even among investigators. Withering originally used digitalis fordropsy, being unaware of the existence of auricular fibrillation which was described later, chiefly by Mackenzie. It was Mackenzie and Lewis who emphasized the use of the drug for auricular fibrillation with congestive heart failure, using ventricular rate as an index of its effectiveness. Later, in the United States and in Austria, the drug was advocated for all cases of congestive failure, regardless of associated arrhythmias, the chief protagonists of this point of view being Christian and Wenckebach. The latter point of view received support from physiologists such as Cournand working with the cardiac catheter, although it remained difficult in the intact animal to be sure whether the effect of the drug was direct on the heart or at least in part indirect via peripheral blood vessels. There was some conflict of opinion, for example, as to whether the drug was effective in the isoiated heart. From a more practical standpoint, however, considering the effectiveness and availability of modern diuretics, does digitalis add anything to the management of congestive heart failure with sinus rhythm? Some workers insist that it does and others that it adds nothing, or at most very little. They also point to the ease with which digitalis toxicity is produced in such cases. The whole question is complicated by the fact that congestive failure is not a steady state but is exacerbated by such events as pulmonary embolism, infection, dietary indiscretion, etc. The question of whether or when to use digitalis in the presence of arrhythmias, with or without congestive failure, is even more complex. All this confusion, however, has one salutary effect. It becomes clear that digitalis must not be given as a “routine” drug for heart disease regardless of whether there is an arrhythmia, congestive heart failure, or both. When the drug is given or withheld, the decision must always be preceded by a careful evaluation of all factors and objectives in each individual case. Milton Mendlowitz New York, N. Y.
Physiologic
Abnorm&tks
end Cheat
Dkgaosis
When measurements of physiologic parameters are applied to clinical diagnosis, utility combines with scientific reason. When such application promises aid in diagnosis of a common clinical problem, the method deserves detailed consideration. Such a situation is encountered in the recent report by Robin, Julian, Travis, and Crumpr on the diagnosis of acute pulmonary embolism from measurements of end-tidal and arterial PCOr. The method is based on the observation that ordinarily there is close agreement between arterial and alveolar PC02 (no a-A gradient) but that following acute pulmonary embolism the alveolar gas will be diluted by contributions from ventilated but poorly perfused segments’ of the
ANNOTATIONS
700
lung and this will cause a significant a-A PC02 gradient. In other words, the demonstration of an arterial-alveolar PC02 gradient in a given nonemphysematous subject suggests the diagnosis of acute pulmonary embolism. It seems to us that this statement must rest on two assumptions and implies a third, as follows: (1) There is no PC02 gradient unless some form of cardiopulmonary disease is present. (2) Clinical entities which might become confused with pulmonary vascular obstruction (pneumonia, bronchial obstruction) will not cause physiologic alterations similar to those observed in (3) The physiologic mechanism claimed as the cause for the abpulmonary artery embolism. not nal measurement is exclusively or predominantly responsible for the observed phenomenon. Yet, Martin? In general, the first assumption is valid in normal subjects in a supine position. has shown recently that erect posture causes alterations in the ventilation-perfusion relationships due to relative hyperventilation and underperfusion of the upper lobes resulting in a-A PCOz gradients in excess of 9 mm. Hg. Rapid ventilatory rates also may be the &use for such a gradient. If, for some reason (anxiety, dyspnea), the measurements were mdde in the semierect position or if tachypnea was present or both, a significant PC02 gradient might have occurred on this basis alone. In consequence, present evidence does not support the assumption that a significant a-A PCO, gradient may not be found in the absence of disease. The second assumption is based on the observation that any disturbance in ventilationperfusion ratios in the lung will result in a PC02 gradient, but that ventilation without perfusion will exert a greater effect than that of an equivalent fraction of lung which is perfused but not ventilated.3 This conclusion depends upon the presence of a small mixed venous to pulmonary capillary PC02 difference (about 10 mm. Hg) under normal circumstances. It is reasonable to expect that with low rates of blood flow and hyperventilation of normal alveoli this venocapillary In conditions which allow a high PC02 in the mixed PCOt gradient might be greatly elevated. venous blood and a low PC02 in the capillary blood which is ventilated, the effects of venous admixture will approach the effects of an equivalent degree of ventilation without perfusion (vascular obstruction) and the data would not by themselves allow differentiation. Recently, for example, subjects suffering from postinfluenzal pneumonia were shown to exhibit high a-A gradients either on the basis of uneven ventilation or caused by venous admixture from nonventilated but perfused alveoli4 The statement, then, that cardiorespiratory diseases other than pulmonary emboli are not associated with a significant a-A PC02 gradient is open to debate. The third assumption is required if the gradient is to be used for calculating the fraction of the alveolar dead space and thereby estimating the fraction of the obstructed pulmonary arterial bed. There may well be more than one cause for the gradient observed in pulmonary embolism. That this may be sigThe potential effect of venous admixture has already been mentioned. nificant is suggested by the common finding of moderate to severe arterial desaturation in patients with acute pulmonary embolism, which is not completely corrected by 100 per cent oxygen breathing. This cannot be explained on the basis of increased alveolar dead space3 and is characteristic of a large venous admixture component. It has been produced in dogs by experimental embolization.6 Since acute or repeated pulmonary emboli frequently occur in subjects with a low cardiac output and hyperventilation at rest, a larger than normal pulmonary artery-pulmonary capillary PC02 gradient can be expected. The effects of a large venous admixture could be manifest We know that venous admixture of severe degree can result by a significant a-A PC02 gradient. from obstruction of a relatively small fraction of the arterial bed, thus gross misinterpretation At present only the simulof a gradient might occur in the presence of arterial desaturation. taneous measurements of venous and arterial blood gases and the a-A gradient for both oxygen and carbon dioxide tension allow the effects of nonventilation (or venous admixture) to be separated from nonperfusion (vascular obstruction). This work is reviewed primarily to suggest possible application of physiologic data directly to clinical problems. At present the existence of a single, hopeful concept, so desirable in clinical medicine, seems threatened by the presence of multiple physiopathologic factors encountered in cardiorespiratory measurements. In the case under discussion, several assumptions are made. Failure of the first would allow a “false positive” Existing evidence casts doubt on their validity. diagnosis. Failure of the second would confuse pulmonary embolism with other cIinical entitles. Failure of the third would prevent the possibility of estimating the fraction of the pulmonary
800
Am. Heart J. November, 1959
ANNOTATIONS
vascular bed obstructed. investigation into the thought to be reserved
Reports such as these, however, are needed to stimulate mysteries of abnormalities of ventilation and perfusion-too for the physiology laboratory. Salt
further
Lake
bedside commonly
R. L. Lange City, titah
REFERENCES
1. 2. 3. 4. 5.
Robin,
E., Julian, D., Travis, D., and Crump, 0.: A Physiologic Approach to the Diagnosis of Acute Pulmonary Embolism, New England J. Med. 8601586, 1959. Martin, C., and Young, A.: Ventilation-Perfusion Variations Within the Lung, J. Appl. Physiol. 11:371, 1957. Severinghaus, J., and Stupfel, M.: Alveolar Dead Space as an Index of Distribution of Blood Flow in Pulmonary Capillaries, J. Appl. Physiol. 101335, 1957. Herzog, H., Staub, H., and Richterich, R.: Gas-analytical Studies in Severe Pneumonia, Lancet 1:593, 1959. Dick, M.: Respiratory and Circulatory Responses to Intravenous Oxygen and their Relation to Anoxemia, Am. J. Physiol. 127:228, 1939.
Angina
Pectoris
and Congestive
Failure
The immediate hemodynamic consequences in man of deficient oxygenation of the myocardium that results from coronary artery obstruction have not been widely investigated. Fries and his associates’ studied patients soon after acute myocardial infarction and confirmed the basic observations made by Wigger@ in his classical study of coronary artery occlusion in animals. This study indicated that just after myocardial infarction in man the circulation may be normal or there may be hemodynamic evidences of shock, congestive failure, or both. Precise measurements of the cardiac output and of pulmonary vascular pressuresduring attacks of angina pectoris are now available for consideration. Muller and Rorvik’ performed right heart catheterization upon patients with angina pectoris whose systemic blood pressures and heart sizes were normal and who at rest were free of congestive failure. Although some of their subjects had previously sustained myocardial infarction, others had not, but they were Catheterization studies of their all alike in that they were subject to attacks of angina pectoris. patients at rest and in the absence of angina1 pain yielded normal or near normal hemodynamics, but during angina1 pain induced by exercise there was found a surprising elevation of pulmonary capillary pressure, often to a degree where pulmonary edema is imminent4 The cardiac outputs were for the most part normal at rest and rose physiologically in response to exercise. This abnormal elevation of pulmonary capillary pressure induced by exercise and interpreted as indicating acute left ventricular failure usually preceded the development of angina1 pain and it promptly Left ventricular failure accompanied not subsided as exercise was terminated and pain ceased. only the angina1 pain induced by exercise but also that which developed spontaneously in 2 patients during the catheterization procedure. Muller and Rorvik then expanded their study to include observations both before and after the administration of nitroglycerine. They found that amounts of exercise that had produced both angina1 pain and abnormal elevation of pulmonary capillary pressure before the administration of nitroglycerine failed to produce either after it. Their data did not indicate significant reduction of cardiac output, stroke volume, or left ventricular work load during the second exercise period preceded by the administration of nitroglycerine as compared to the first without it. Therefore, the authors concluded that their subjects tolerated the postnitroglycerine exercise period better hemodynamically as well as symptomatically because the drug either dilated coronary vessels of normal caliber or relaxed constricted ones. Experience with patients naturally comes to ,mind and raises the question whether there are clinical observations which these hemodynamic studies clarify. Angina decubitus is first thought of. Attacks of angina pectoris that awaken patients from a sound sleep are often not only misinterpreted but they also stubbornly resist the efforts of physicians to control them. It has been recorded,6*’ however, that attacks of angina decubitus are usually though not always,