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Use of Vasoactive Drugs in the Treatment of Shock
Symposium on a Physiologic Approach to Critical Care
Use of Vasoactive Drugs in the Treatment of Shock James L. Berk, M.D.*
\
The effective use of vasoactive drugs in shock requires an understanding of the hemodynamic and metabolic changes occurring in different types and stages of shock; how these changes are affected by the patient's response to critical illness which in turn is influenced by the nutritional status and organ system disease; the role of the catecholamines in shock; and the specific pharmacologic actions of each drug in the abnormal state. For example, a young previously healthy patient with a good myocardium in early septic shock very likely will have a hyperdynamic circulation with an increased cardiac output, increased blood volume, decreased total systemic resistance, significant pulmonary shunting, and a normal or slightly increased CVP. Later, if treatment has been inadequate, because of vascular pooling and actual loss from the circulation, the effective blood volume falls, the cardiac output decreases, the total systemic resistance tends to increase and the CVP will tend to decrease. If the myocardium fails from the excessive work demanded by the increased metabolic and hyperdynamic state, and this is more likely if there is preexisting disease, the cardiac output will decrease further, the total systemic resistance will tend to increase more, and the CVP or pulmonary wedge pressure will tend to increase. As the circulation becomes hypodynamic, the measured shunt may actually decrease for a time but the P a02 may not reflect it, depending on the oxygen extraction and mixed venous oxygen content. (As the cardiac output falls and the flow to the tissues decreases, if the oxygen consumption remains constant, more oxygen will be extracted per unit of blood and the mixed venous oxygen will fall. If the pulmonary shunt is the same, the P a02 will fall.) As the pathologic changes of shock lung develop, i.e., interstitial and alveolar edema, alveolar collapse, focal pneumonia, etc., the shunt will increase. The blood sugar usually is elevated, particularly if glucose has been given intravenously. However, if the patient is depleted or the anaerobic metabolism is excessive, the blood glucose may fall to very low levels and make the shock worse. l The initial cause of shock is the *Professor of Surgery, Case Western Reserve University School of Medicine, and Director of Surgery, The Mt. Sinai Hospital of Cleveland, Ohio
Surgical Clinics of North America- Vol. 55, No.3, June 1975
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Figure 1.
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Summary of the role of catecholamine stimulation in shock.
same in each instance, but the results of treatment with the same drug and with other vasoactive drugs will be entirely different depending on the hemodynamic and metabolic stage. In the hyperdynamic state, cardiac stimulation would not be helpful and could even be harmful. A vasopressor which is an alpha adrenergic stimulant would increase the afterload and decrease the cardiac output, but because of the hyperdynamic circulation, this deleterious effect probably would not be immediately evident. A vasopressor which is both an alpha and beta stimulant could on rare occasions be temporarily helpful depending on the net effect on the cardiac output of the increased afterload and the increased contractility. However, if myocardial failure is present, an inotropic agent would be beneficial; and a vasopressor, particularly a pure alpha stimulant, would very likely be harmful. In the late or decompensated stage when the catecholamines become less effective, sodium bicarbonate followed by a vasopressor which stimulates both alpha and beta receptors would very likely be beneficial. Quantification of the hemodynamic and metabolic patterns in a given patient at a given time must be obtained for optimum selection of drugs. The role of catecholamine stimulation in shock is summarized in Figure 1. Because these hormones are the prototype for many drugs used in shock, an understanding of their actions will simplify the use of vasoactive drugs. In shock of various causations, there is increased and prolonged catecholamine stimulation both from the adrenal medulla and the sympathetic nervous system. Plasma epinephrine and norepinephrine levels are significantly elevated. In general, epinephrine is a potent alpha and beta adrenergic stimulant and norepinephrine is a potent
VASOACTIVE DRUGS IN THE TREATMENT OF SHOCK
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alpha and a weak beta adrenergic stimulant. In addition to the cardiovascular effects shown in Figure 1, beta stimulation results in bronchodilatation, glycogenolysis, and lipolysis. Early in shock, all of the effects of adrenergic stimulation are compensatory and beneficial except the vasodilatation and shunting of the beta stimulation in the pulmonary and splanchnic areas. The increased heart rate and contractility tend to compensate for the increased circulatory and metabolic demands in septic and traumatic shock, the decreased blood volume in hypovolemic shock, and impaired cardiac function in cardiogenic shock. The arteriolar vasoconstriction in the renal and cutaneous areas balances the loss of resistance in the dilated areas. Constriction of the large capacitant veins tends to give an autotransfusion as does contraction of the spleen in some species. As shock continues, plasma begins to pool and blood is actually lost in the splanchnic and pulmonary beds, decreasing the effective blood volume and leading to decreased tissue perfusion. The pulmonary shunting results in progressive arterial hypoxia. The increased metabolic demands of shock coupled with the decreased oxygen supply leads to more anaerobic metabolism and a progression of lactic acidosis and a tendency for the catecholamines to become less effective. The heart begins to fail from decreased coronary artery perfusion and hypoxia. Following an acute myocardial infarction, the low coronary flow can result in progression of the infarct. As the decompensated stage of shock is reached, there is loss of compensatory vasoconstriction, further pooling, progressive organ system failure, and death. In all types of shock, there is increased catecholamine stimulation but the response depends on the cause of shock and the organ system response. In untreated hemorrhagic shock, the cardiac output is decreased despite increased catecholamine stimulation of the heart, and the systemic vascular resistance is significantly increased. However, when blood has been replaced late after secondary compensatory changes have taken place, the patient may remain in shock but in a hyperdynamic stage unless the low coronary flow has adversely affected the heart. As described above, septic shock will be hyperdynamic if the effective blood volume is adequate and the myocardium is functioning well.
TREATMENT OF SHOCK Regardless of the initial cause, shock is a dynamic process that is continually changing. An understanding of these changes is necessary for effective treatment. For survival, correction of the primary problem is essential: in hypovolemic shock, this would entail replacement of appropriate fluids; in septic shock, antibiotics and surgical treatment of the infection; and in cardiogenic shock, improvement in the cardiac output by drugs or, if necessary, aortic counterpulsation. In addition, any of the secondary abnormalities that have developed must be corrected such as hypovolemia, acid-base and metabolic abnormalities, hypoxia, hypoventilation, and
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cardiac decompensation. After all of the primary and secondary factors have been treated, then appropriate vasoactive drugs may be used. Vasoconstrictors, Vasopressors These terms are often used interchangeably. In general a drug that primarily causes arteriolar vasoconstriction is considered a vasoconstrictor and one that raises the arterial pressure, a vasopressor. The arterial pressure is dependent on both the resistance which is effected by arteriolar vasoconstriction and the cardiac output. There are several types of drugs, each with different actions, that are grouped as vasoconstrictors and vasopressors. However, it makes more sense to understand the specific pharmacologic actions of a drug rather than to group it as a vasopressor or vasoconstrictor. Methoxamine (Vasoxyl) and phenylephrine (Neo-Synephrine) are virtually pure alpha stimulators with little or no beta effects. These drugs raise the total systemic resistance and the blood pressure, increase the afterload, and tend to decrease the cardiac output. In addition, the vasoconstriction results in more pooling in the dilated areas. Other socalled "vasoconstrictors," such as norepinephrine and metaraminol (Aramine), are potent alpha stimulants in the periphery and beta stimulants of the heart and may increase the cardiac output in addition to the arterial pressure. Epinephrine in very low doses, 0.1 (.Lg per kg per min, is primarily a beta stimulant, causing an increased cardiac output and a fall in the systemic resistance and the mean arterial pressure and is not a vasopressor at these concentrations. Higher doses result in alpha stimulation with increased resistance and arterial pressure and epinephrine is then considered a vasopressor. Dopamine, the third endogenous catecholamine, is a potent beta stimulant on the heart and alpha stimulant on the peripheral circulation but differs from the other endogenous catecholamines and from synthetic sympathomimetic amines in exerting unusual vasodilatation in the renal, mesenteric, coronary, and intracerebral arterial vascular beds. 7 This effect is not antagonized by propranolol or atropine but is selectively attenuated by haloperidol and apomorphine, supporting the concept of a specific dopamine receptor. Just as with epinephrine, the hemodynamic effects are dose dependent. With the intravenous infusion of small doses (1 to 10 (.Lg per kg per min), dopamine increases the cardiac output and renal blood flow in most subjects. The heart rate does not usually change and the mean arterial blood pressure is unchanged or decreased and at these levels, it is not a vasopressor. When higher doses are given, arterial pressure increases due to alpha stimulation and the heart rate decreases, and it is a vasopressor. In small doses, epinephrine increases cardiac output and decreases peripheral resistance but unlike dopamine, epinephrine reduces the renal blood flow and increases the heart rate. Norepinephrine increases the peripheral resistance, decreases the renal blood flow, and in normal subjects does not increase the cardiac output. Several studies have suggested that dopamine increases the cardiac output, blood pressure and urine flow in patients in shock unresponsive to other agents/I. 13 but because of the great variation in clinical states, a
VASOACTIVE DRUGS IN THE TREATMENT OF SHOCK
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great deal more experience is necessary to be certain that it is more effective than epinephrine. Dopamine has been released for the treatment of shock. Infusion rates of 2 to 5 f..tg per kg per min should be adequate for most patients, but if necessary it may be increased to rates as high as 50 f..tg per kg per min. Like other catecholamines, arrhythmias can occur. By and large, the drugs that primarily cause alpha stimulation are not beneficial in shock and usually are harmful. The elevated blood pressure gives a false sense of security because most often the cardiac output and coronary flow progressively fall, resulting in refractory shock and death. In the presence of hypovolemia, these effects are accentuated. Occasionally, drugs that are both alpha and beta agonists are helpful in shock depending on the overall effect of the increased afterload and contractility on the cardiac output. Alpha stimulants may be beneficial in hypotension caused by arteriolar vasodilatation but drugs that also causebeta stimulation, such as epinephrine or norepinephrine, are better. Also, alpha stimulants may be beneficial by causing constriction of the large capacitant veins, which results in an autotransfusion and temporary benefit. In the decompensated stages of shock when contractility is lessening and the compensatory vasoconstriction is diminishing, vasopressors that are both alpha and beta agonists may be helpful. Vasodilators Just as in the case of vasoconstrictors, several drugs are grouped together, each with different pharmacologic actions, and called vasodilators. One of the best known vasodilators is phenoxybenzamine (Dibenzyline), an alpha blocker. There have been very few, if any, patients in shock successfully treated with phenoxybenzamine alone. Usually large amounts of fluid are given and experimental studies suggest that animals do better with the fluids alone. One reason is that phenoxybenzamine causes an increase in the pulmonary shunt in patients and animals in shock. 4 • 5 In addition, the loss of compensatory resistance results in marked hypotension and a worsening of shock. This is accentuated when the effective blood volume is inadequate. In addition to the decreased coronary flow, the pressure in the microcirculation may fall below the critical closing pressure and result in small vessel collapse and further impairment of the circulation. Alpha blockers have been useful in the pretreatment of certain forms of shock in animals in which hepatic venoconstriction with an outflow block occurs, but this form of block does not occur in man. Phenoxybenzamine is a cardiac stimulant and may act as an afterload reducing agent. In shock it must be given by intravenous infusion, the dose being 1 mg per kg. It has not . been released for use in shock. Another so-called vasodilator, entirely different from phenoxybenzamine, is isoproterenol (Isuprel). This drug is a powerful beta adrenergic stimulant affecting the heart and the microcirculation, causing an increase in the cardiac output and a fall in the systemic resistance. However, it is not frequently useful because it usually increases the already rapid heart rate present in shock and may cause serious arrhythmias. Also, it increases the pulmonary shunting. In addition, because of
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the increased myocardial oxygen requirements and the fall in the diastolic pressure caused by isoproterenol, the coronary blood flow may not increase sufficiently and result in myocardial ischemia despite the increased cardiac output. This may explain the increased left ventricular-end-diastolic pressure in patients and myocardial necrosis demonstrated in animals following prolonged use. Isoproterenol does not abolish the compensatory vasoconstriction as does phenoxybenzamine, and by increasing the cardiac output may tide the patient over until the primary problem is corrected. The usual dose of isoproterenol is 1 to 8 f.Lg per min in an intravenous infusion. Other vasodilators such as phentolamine (Regitine), an alpha blocker, and sodium nitroprusside, with direct action on the blood vessel, are useful in low cardiac output states if the arterial pressure is only moderately decreased. (This is discussed in detail by Dr. Forrester in this symposium.)
Other Vasoactive Drugs The following drugs are not usually classified as vasoconstrictors or vasodilators, but are vasoactive and useful in shock. DOBUTAMINE. A new synthetic catecholamine, dobutamine is a beta stimulant. It is said to increase the cardiac output with little of the chronotropic and peripheral vascular effects of isoproterenol. Experimental work suggests that the incidence of cardiac arrhythmias may also be less with dobutamine. More work is needed to determine its effectiveness in shock. It has not been released for use. 6 , 9 PROPRANOLOL. By blocking the vasodilatation and shunting caused by excessive beta adrenergic stimulation, improved oxygenation and a favorable redistribution of the blood flow can be expected. Studies in animals and man have supported this thesis. 2 , 3 Because of the cardiodepressant and hypoglycemic effects of beta blockade, propranolol must be used with caution. Propranolol has not been released for the treatment of shock except for investigational purposes. GLUCAGON. This drug has a positive chronotropic and inotropic effect similar to that of beta adrenergic stimulation except that the action persists despite the presence of adequate beta blockade. tO In addition, glucagon can increase the cardiac performance even with full digitalization. Glucagon has been shown to cause a fall in the systemic resistance thought to be due to a splanchnic vasodilatory effect but the beneficial effects from this have yet to be demonstrated clinically. Glucagon is short acting, the effect being complete within 10 minutes so that a continuous infusion is usually necessary. In our experience, it is a much weaker cardiac drug than isoproterenol. Glucagon combined with isoproterenol seems to be a useful combination, achieving the desired cardiac output with less of the undesirable effects of isoproterenol. Glucagon is a specific antagonist of the cardiodepression of beta block~de with propranolol and we have found it useful in this respect. The dose of glucagon is 3 to 5 mg per hr in a constant infusion. Unfortunately, glucagon is not approved by the Food and Drug Administration for cardiovascular disorders. CORTICOSTEROIDS. In patients in shock with pharmacologic doses,
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such as 30 mg per kg of methylprednisolone, there is often a small increase in the cardiac output, a slight decrease in the total systemic resistance, and a small increase in the pulmonary shunt. However, in our experience, very few patients show clinical improvement, except an occasional one with occult adrenal insufficiency. There is evidence that the steroids increase the reflexly stimulated release of epinephrine from the adrenal gland and also enhance the cardiovascular reactivity to the catecholamines, thus exerting a permissive effect on catecholamine activity. Most likely, the corticosteroids do not influence the course of shock by their direct cardiovascular effects; rather, any beneficial actions probably result from other mechanisms such as stabilization of lysosomes and/or protection of the integrity of the cell membrane. DIGITALIS. Although not usually considered as such, digitalis is vasoactive. There is substantial evidence that digitalis exerts a direct action on vascular smooth muscle, causing constriction of arterioles and veins at the level of the process of excitation and contraction, probably by increasing the intracytoplasmic calcium concentration. Catecholamines are not necessary for the action of digitalis, but both catecholamines and potassium may modify the effects of digitalis. CALCIUM. Calcium plays a role in coupling excitation with muscular contraction. Occasionally, intravenous calcium may be useful in late circulatory failure by increasing myocardial contractility and peripheral resistance. THERAPEUTIC COMBINATIONS. A combination of vasoactive drugs to achieve a balance between the cardiac and microcirculatory effects has been suggested. In addition to those discussed, examples are norepinephrine and isoproterenol, dopamine and isoproterenol, and phenoxybenzamine or phentolamine and dopamine or norepinephrine. 7 • 8.12 Dopamine in conjunction with intra-aortic balloon counterpulsation has also been used. As yet, there is insufficient evidence to suggest which of these combinations is the most effective but selective organ system control is possible and in the future this type of therapy should be rewarding.
SUMMARY The effective use of vasoactive drugs in shock requires an understanding of the pathophysiologic mechanisms involved in the various types and stages of shock and knowledge of the specific pharmacologic effects of each drug in the abnormal state. Vasoactive drugs should be used after the primary and secondary causes of shock have been corrected. Specific vasoactive drugs should be selected on the basis of measured hemodynamic abnormalities.
REFERENCES J. L., Hagen, J. F., Beyer, W. H., and Gerber, M. J.: Hypoglycemia in shock. Ann. Surg., 171 :400-408,1970. 2. Berk, J. L., Hagen, J. F., Beyer, W. H., Dochat, G. R. and LaPOinte, R.: The treatment of 1. Berk,
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3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13.
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hemorrhagic shock by beta adrenergic receptor blockade. Surg. Gynec. Obstet., 125:311-318,1967. Berk, J. L., Hagen, J. F., Maly, G., and Koo, R: The treatment of shock with beta adrenergic blockade. Arch. Surg., 104:46-51,1972. Berk, J. L., Hagen, J. F., Koo, R, Beyer, W., Dochat, G. R, Rupright, M., and Nomoto, S.: Pulmonary insufficiency caused by epinephrine. Ann. Surg., 178:423-435, 1973. Eckenhoff, J. E., and Cooperman, L. H.: The clinical application of phenoxybenzamine in shock and vasoconstrictive states. Surg. Gynec. Obstet., 121 :483-490,1965. Holloway, G. A., Jr., and Frederickson, E. L.: Dobutamine, a new beta agonist. Anesth. Analg. (Cleve.), 53:616-623, 1974. Goldberg, L. 1.: Dopamine-Clinical uses of an endogenous catecholamine. N. Eng!. J. Med., 291:707-710,1974. Goldberg, L. I., and Talley, R C.: Current therapy of shock. Adv. Intern. Med., 17:363378, 1971. Jewitt, D., Mitchell, A., Birkhead, J., and DoUery, C.: Clinical cardiovascular pharmacology of dobutamine; a selective inotropic catecholamine. Lancet, 2:363-365, 1974. Lefebvre, P. J. and Unger, R H. (eds.): Glucagon: Molecular Physiology, Clinical and Therapeutic Implications. Oxford, Pergamon Press, 1972. Loeb, H. S., Winslow, E. B. J., Rahimtoola, S. H., Rosen, K. M., and Gunnar, R M.: Acute hemodynamic effects of dopamine in patients with shock. Circulation, 44:163-173, 1971. Tally, R C., Goldberg, L. I., Johnson, C. E., and McNay, J. L.: A hemodynamic comparison of dopamine and isoproterenol in patients in shock. Circulation, 39:361-378, 1969. Winslow, E. J., Loeb, H. S., Rahimtoola, S. H., Kamath, S., and Gunnar, R: Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am. J. Med., 54:421-432, 1973.
Department of Surgery Mt. Sinai Hospital of Cleveland University Circle Cleveland, Ohio 44106
Use of Vasoactive Drugs in the Treatment of Shock James L. Berk, M.D.*
\
The effective use of vasoactive drugs in shock requires an understanding of the hemodynamic and metabolic changes occurring in different types and stages of shock; how these changes are affected by the patient's response to critical illness which in turn is influenced by the nutritional status and organ system disease; the role of the catecholamines in shock; and the specific pharmacologic actions of each drug in the abnormal state. For example, a young previously healthy patient with a good myocardium in early septic shock very likely will have a hyperdynamic circulation with an increased cardiac output, increased blood volume, decreased total systemic resistance, significant pulmonary shunting, and a normal or slightly increased CVP. Later, if treatment has been inadequate, because of vascular pooling and actual loss from the circulation, the effective blood volume falls, the cardiac output decreases, the total systemic resistance tends to increase and the CVP will tend to decrease. If the myocardium fails from the excessive work demanded by the increased metabolic and hyperdynamic state, and this is more likely if there is preexisting disease, the cardiac output will decrease further, the total systemic resistance will tend to increase more, and the CVP or pulmonary wedge pressure will tend to increase. As the circulation becomes hypodynamic, the measured shunt may actually decrease for a time but the P a02 may not reflect it, depending on the oxygen extraction and mixed venous oxygen content. (As the cardiac output falls and the flow to the tissues decreases, if the oxygen consumption remains constant, more oxygen will be extracted per unit of blood and the mixed venous oxygen will fall. If the pulmonary shunt is the same, the P a02 will fall.) As the pathologic changes of shock lung develop, i.e., interstitial and alveolar edema, alveolar collapse, focal pneumonia, etc., the shunt will increase. The blood sugar usually is elevated, particularly if glucose has been given intravenously. However, if the patient is depleted or the anaerobic metabolism is excessive, the blood glucose may fall to very low levels and make the shock worse. l The initial cause of shock is the *Professor of Surgery, Case Western Reserve University School of Medicine, and Director of Surgery, The Mt. Sinai Hospital of Cleveland, Ohio
Surgical Clinics of North America- Vol. 55, No.3, June 1975
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f---.~~ ~ - - i MYOCARDIAL
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Figure 1.
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L. BERK
I
Summary of the role of catecholamine stimulation in shock.
same in each instance, but the results of treatment with the same drug and with other vasoactive drugs will be entirely different depending on the hemodynamic and metabolic stage. In the hyperdynamic state, cardiac stimulation would not be helpful and could even be harmful. A vasopressor which is an alpha adrenergic stimulant would increase the afterload and decrease the cardiac output, but because of the hyperdynamic circulation, this deleterious effect probably would not be immediately evident. A vasopressor which is both an alpha and beta stimulant could on rare occasions be temporarily helpful depending on the net effect on the cardiac output of the increased afterload and the increased contractility. However, if myocardial failure is present, an inotropic agent would be beneficial; and a vasopressor, particularly a pure alpha stimulant, would very likely be harmful. In the late or decompensated stage when the catecholamines become less effective, sodium bicarbonate followed by a vasopressor which stimulates both alpha and beta receptors would very likely be beneficial. Quantification of the hemodynamic and metabolic patterns in a given patient at a given time must be obtained for optimum selection of drugs. The role of catecholamine stimulation in shock is summarized in Figure 1. Because these hormones are the prototype for many drugs used in shock, an understanding of their actions will simplify the use of vasoactive drugs. In shock of various causations, there is increased and prolonged catecholamine stimulation both from the adrenal medulla and the sympathetic nervous system. Plasma epinephrine and norepinephrine levels are significantly elevated. In general, epinephrine is a potent alpha and beta adrenergic stimulant and norepinephrine is a potent
VASOACTIVE DRUGS IN THE TREATMENT OF SHOCK
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alpha and a weak beta adrenergic stimulant. In addition to the cardiovascular effects shown in Figure 1, beta stimulation results in bronchodilatation, glycogenolysis, and lipolysis. Early in shock, all of the effects of adrenergic stimulation are compensatory and beneficial except the vasodilatation and shunting of the beta stimulation in the pulmonary and splanchnic areas. The increased heart rate and contractility tend to compensate for the increased circulatory and metabolic demands in septic and traumatic shock, the decreased blood volume in hypovolemic shock, and impaired cardiac function in cardiogenic shock. The arteriolar vasoconstriction in the renal and cutaneous areas balances the loss of resistance in the dilated areas. Constriction of the large capacitant veins tends to give an autotransfusion as does contraction of the spleen in some species. As shock continues, plasma begins to pool and blood is actually lost in the splanchnic and pulmonary beds, decreasing the effective blood volume and leading to decreased tissue perfusion. The pulmonary shunting results in progressive arterial hypoxia. The increased metabolic demands of shock coupled with the decreased oxygen supply leads to more anaerobic metabolism and a progression of lactic acidosis and a tendency for the catecholamines to become less effective. The heart begins to fail from decreased coronary artery perfusion and hypoxia. Following an acute myocardial infarction, the low coronary flow can result in progression of the infarct. As the decompensated stage of shock is reached, there is loss of compensatory vasoconstriction, further pooling, progressive organ system failure, and death. In all types of shock, there is increased catecholamine stimulation but the response depends on the cause of shock and the organ system response. In untreated hemorrhagic shock, the cardiac output is decreased despite increased catecholamine stimulation of the heart, and the systemic vascular resistance is significantly increased. However, when blood has been replaced late after secondary compensatory changes have taken place, the patient may remain in shock but in a hyperdynamic stage unless the low coronary flow has adversely affected the heart. As described above, septic shock will be hyperdynamic if the effective blood volume is adequate and the myocardium is functioning well.
TREATMENT OF SHOCK Regardless of the initial cause, shock is a dynamic process that is continually changing. An understanding of these changes is necessary for effective treatment. For survival, correction of the primary problem is essential: in hypovolemic shock, this would entail replacement of appropriate fluids; in septic shock, antibiotics and surgical treatment of the infection; and in cardiogenic shock, improvement in the cardiac output by drugs or, if necessary, aortic counterpulsation. In addition, any of the secondary abnormalities that have developed must be corrected such as hypovolemia, acid-base and metabolic abnormalities, hypoxia, hypoventilation, and
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cardiac decompensation. After all of the primary and secondary factors have been treated, then appropriate vasoactive drugs may be used. Vasoconstrictors, Vasopressors These terms are often used interchangeably. In general a drug that primarily causes arteriolar vasoconstriction is considered a vasoconstrictor and one that raises the arterial pressure, a vasopressor. The arterial pressure is dependent on both the resistance which is effected by arteriolar vasoconstriction and the cardiac output. There are several types of drugs, each with different actions, that are grouped as vasoconstrictors and vasopressors. However, it makes more sense to understand the specific pharmacologic actions of a drug rather than to group it as a vasopressor or vasoconstrictor. Methoxamine (Vasoxyl) and phenylephrine (Neo-Synephrine) are virtually pure alpha stimulators with little or no beta effects. These drugs raise the total systemic resistance and the blood pressure, increase the afterload, and tend to decrease the cardiac output. In addition, the vasoconstriction results in more pooling in the dilated areas. Other socalled "vasoconstrictors," such as norepinephrine and metaraminol (Aramine), are potent alpha stimulants in the periphery and beta stimulants of the heart and may increase the cardiac output in addition to the arterial pressure. Epinephrine in very low doses, 0.1 (.Lg per kg per min, is primarily a beta stimulant, causing an increased cardiac output and a fall in the systemic resistance and the mean arterial pressure and is not a vasopressor at these concentrations. Higher doses result in alpha stimulation with increased resistance and arterial pressure and epinephrine is then considered a vasopressor. Dopamine, the third endogenous catecholamine, is a potent beta stimulant on the heart and alpha stimulant on the peripheral circulation but differs from the other endogenous catecholamines and from synthetic sympathomimetic amines in exerting unusual vasodilatation in the renal, mesenteric, coronary, and intracerebral arterial vascular beds. 7 This effect is not antagonized by propranolol or atropine but is selectively attenuated by haloperidol and apomorphine, supporting the concept of a specific dopamine receptor. Just as with epinephrine, the hemodynamic effects are dose dependent. With the intravenous infusion of small doses (1 to 10 (.Lg per kg per min), dopamine increases the cardiac output and renal blood flow in most subjects. The heart rate does not usually change and the mean arterial blood pressure is unchanged or decreased and at these levels, it is not a vasopressor. When higher doses are given, arterial pressure increases due to alpha stimulation and the heart rate decreases, and it is a vasopressor. In small doses, epinephrine increases cardiac output and decreases peripheral resistance but unlike dopamine, epinephrine reduces the renal blood flow and increases the heart rate. Norepinephrine increases the peripheral resistance, decreases the renal blood flow, and in normal subjects does not increase the cardiac output. Several studies have suggested that dopamine increases the cardiac output, blood pressure and urine flow in patients in shock unresponsive to other agents/I. 13 but because of the great variation in clinical states, a
VASOACTIVE DRUGS IN THE TREATMENT OF SHOCK
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great deal more experience is necessary to be certain that it is more effective than epinephrine. Dopamine has been released for the treatment of shock. Infusion rates of 2 to 5 f..tg per kg per min should be adequate for most patients, but if necessary it may be increased to rates as high as 50 f..tg per kg per min. Like other catecholamines, arrhythmias can occur. By and large, the drugs that primarily cause alpha stimulation are not beneficial in shock and usually are harmful. The elevated blood pressure gives a false sense of security because most often the cardiac output and coronary flow progressively fall, resulting in refractory shock and death. In the presence of hypovolemia, these effects are accentuated. Occasionally, drugs that are both alpha and beta agonists are helpful in shock depending on the overall effect of the increased afterload and contractility on the cardiac output. Alpha stimulants may be beneficial in hypotension caused by arteriolar vasodilatation but drugs that also causebeta stimulation, such as epinephrine or norepinephrine, are better. Also, alpha stimulants may be beneficial by causing constriction of the large capacitant veins, which results in an autotransfusion and temporary benefit. In the decompensated stages of shock when contractility is lessening and the compensatory vasoconstriction is diminishing, vasopressors that are both alpha and beta agonists may be helpful. Vasodilators Just as in the case of vasoconstrictors, several drugs are grouped together, each with different pharmacologic actions, and called vasodilators. One of the best known vasodilators is phenoxybenzamine (Dibenzyline), an alpha blocker. There have been very few, if any, patients in shock successfully treated with phenoxybenzamine alone. Usually large amounts of fluid are given and experimental studies suggest that animals do better with the fluids alone. One reason is that phenoxybenzamine causes an increase in the pulmonary shunt in patients and animals in shock. 4 • 5 In addition, the loss of compensatory resistance results in marked hypotension and a worsening of shock. This is accentuated when the effective blood volume is inadequate. In addition to the decreased coronary flow, the pressure in the microcirculation may fall below the critical closing pressure and result in small vessel collapse and further impairment of the circulation. Alpha blockers have been useful in the pretreatment of certain forms of shock in animals in which hepatic venoconstriction with an outflow block occurs, but this form of block does not occur in man. Phenoxybenzamine is a cardiac stimulant and may act as an afterload reducing agent. In shock it must be given by intravenous infusion, the dose being 1 mg per kg. It has not . been released for use in shock. Another so-called vasodilator, entirely different from phenoxybenzamine, is isoproterenol (Isuprel). This drug is a powerful beta adrenergic stimulant affecting the heart and the microcirculation, causing an increase in the cardiac output and a fall in the systemic resistance. However, it is not frequently useful because it usually increases the already rapid heart rate present in shock and may cause serious arrhythmias. Also, it increases the pulmonary shunting. In addition, because of
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the increased myocardial oxygen requirements and the fall in the diastolic pressure caused by isoproterenol, the coronary blood flow may not increase sufficiently and result in myocardial ischemia despite the increased cardiac output. This may explain the increased left ventricular-end-diastolic pressure in patients and myocardial necrosis demonstrated in animals following prolonged use. Isoproterenol does not abolish the compensatory vasoconstriction as does phenoxybenzamine, and by increasing the cardiac output may tide the patient over until the primary problem is corrected. The usual dose of isoproterenol is 1 to 8 f.Lg per min in an intravenous infusion. Other vasodilators such as phentolamine (Regitine), an alpha blocker, and sodium nitroprusside, with direct action on the blood vessel, are useful in low cardiac output states if the arterial pressure is only moderately decreased. (This is discussed in detail by Dr. Forrester in this symposium.)
Other Vasoactive Drugs The following drugs are not usually classified as vasoconstrictors or vasodilators, but are vasoactive and useful in shock. DOBUTAMINE. A new synthetic catecholamine, dobutamine is a beta stimulant. It is said to increase the cardiac output with little of the chronotropic and peripheral vascular effects of isoproterenol. Experimental work suggests that the incidence of cardiac arrhythmias may also be less with dobutamine. More work is needed to determine its effectiveness in shock. It has not been released for use. 6 , 9 PROPRANOLOL. By blocking the vasodilatation and shunting caused by excessive beta adrenergic stimulation, improved oxygenation and a favorable redistribution of the blood flow can be expected. Studies in animals and man have supported this thesis. 2 , 3 Because of the cardiodepressant and hypoglycemic effects of beta blockade, propranolol must be used with caution. Propranolol has not been released for the treatment of shock except for investigational purposes. GLUCAGON. This drug has a positive chronotropic and inotropic effect similar to that of beta adrenergic stimulation except that the action persists despite the presence of adequate beta blockade. tO In addition, glucagon can increase the cardiac performance even with full digitalization. Glucagon has been shown to cause a fall in the systemic resistance thought to be due to a splanchnic vasodilatory effect but the beneficial effects from this have yet to be demonstrated clinically. Glucagon is short acting, the effect being complete within 10 minutes so that a continuous infusion is usually necessary. In our experience, it is a much weaker cardiac drug than isoproterenol. Glucagon combined with isoproterenol seems to be a useful combination, achieving the desired cardiac output with less of the undesirable effects of isoproterenol. Glucagon is a specific antagonist of the cardiodepression of beta block~de with propranolol and we have found it useful in this respect. The dose of glucagon is 3 to 5 mg per hr in a constant infusion. Unfortunately, glucagon is not approved by the Food and Drug Administration for cardiovascular disorders. CORTICOSTEROIDS. In patients in shock with pharmacologic doses,
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such as 30 mg per kg of methylprednisolone, there is often a small increase in the cardiac output, a slight decrease in the total systemic resistance, and a small increase in the pulmonary shunt. However, in our experience, very few patients show clinical improvement, except an occasional one with occult adrenal insufficiency. There is evidence that the steroids increase the reflexly stimulated release of epinephrine from the adrenal gland and also enhance the cardiovascular reactivity to the catecholamines, thus exerting a permissive effect on catecholamine activity. Most likely, the corticosteroids do not influence the course of shock by their direct cardiovascular effects; rather, any beneficial actions probably result from other mechanisms such as stabilization of lysosomes and/or protection of the integrity of the cell membrane. DIGITALIS. Although not usually considered as such, digitalis is vasoactive. There is substantial evidence that digitalis exerts a direct action on vascular smooth muscle, causing constriction of arterioles and veins at the level of the process of excitation and contraction, probably by increasing the intracytoplasmic calcium concentration. Catecholamines are not necessary for the action of digitalis, but both catecholamines and potassium may modify the effects of digitalis. CALCIUM. Calcium plays a role in coupling excitation with muscular contraction. Occasionally, intravenous calcium may be useful in late circulatory failure by increasing myocardial contractility and peripheral resistance. THERAPEUTIC COMBINATIONS. A combination of vasoactive drugs to achieve a balance between the cardiac and microcirculatory effects has been suggested. In addition to those discussed, examples are norepinephrine and isoproterenol, dopamine and isoproterenol, and phenoxybenzamine or phentolamine and dopamine or norepinephrine. 7 • 8.12 Dopamine in conjunction with intra-aortic balloon counterpulsation has also been used. As yet, there is insufficient evidence to suggest which of these combinations is the most effective but selective organ system control is possible and in the future this type of therapy should be rewarding.
SUMMARY The effective use of vasoactive drugs in shock requires an understanding of the pathophysiologic mechanisms involved in the various types and stages of shock and knowledge of the specific pharmacologic effects of each drug in the abnormal state. Vasoactive drugs should be used after the primary and secondary causes of shock have been corrected. Specific vasoactive drugs should be selected on the basis of measured hemodynamic abnormalities.
REFERENCES J. L., Hagen, J. F., Beyer, W. H., and Gerber, M. J.: Hypoglycemia in shock. Ann. Surg., 171 :400-408,1970. 2. Berk, J. L., Hagen, J. F., Beyer, W. H., Dochat, G. R. and LaPOinte, R.: The treatment of 1. Berk,
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3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13.
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hemorrhagic shock by beta adrenergic receptor blockade. Surg. Gynec. Obstet., 125:311-318,1967. Berk, J. L., Hagen, J. F., Maly, G., and Koo, R: The treatment of shock with beta adrenergic blockade. Arch. Surg., 104:46-51,1972. Berk, J. L., Hagen, J. F., Koo, R, Beyer, W., Dochat, G. R, Rupright, M., and Nomoto, S.: Pulmonary insufficiency caused by epinephrine. Ann. Surg., 178:423-435, 1973. Eckenhoff, J. E., and Cooperman, L. H.: The clinical application of phenoxybenzamine in shock and vasoconstrictive states. Surg. Gynec. Obstet., 121 :483-490,1965. Holloway, G. A., Jr., and Frederickson, E. L.: Dobutamine, a new beta agonist. Anesth. Analg. (Cleve.), 53:616-623, 1974. Goldberg, L. 1.: Dopamine-Clinical uses of an endogenous catecholamine. N. Eng!. J. Med., 291:707-710,1974. Goldberg, L. I., and Talley, R C.: Current therapy of shock. Adv. Intern. Med., 17:363378, 1971. Jewitt, D., Mitchell, A., Birkhead, J., and DoUery, C.: Clinical cardiovascular pharmacology of dobutamine; a selective inotropic catecholamine. Lancet, 2:363-365, 1974. Lefebvre, P. J. and Unger, R H. (eds.): Glucagon: Molecular Physiology, Clinical and Therapeutic Implications. Oxford, Pergamon Press, 1972. Loeb, H. S., Winslow, E. B. J., Rahimtoola, S. H., Rosen, K. M., and Gunnar, R M.: Acute hemodynamic effects of dopamine in patients with shock. Circulation, 44:163-173, 1971. Tally, R C., Goldberg, L. I., Johnson, C. E., and McNay, J. L.: A hemodynamic comparison of dopamine and isoproterenol in patients in shock. Circulation, 39:361-378, 1969. Winslow, E. J., Loeb, H. S., Rahimtoola, S. H., Kamath, S., and Gunnar, R: Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am. J. Med., 54:421-432, 1973.
Department of Surgery Mt. Sinai Hospital of Cleveland University Circle Cleveland, Ohio 44106