Cardiogenic Shock

Cardiogenic Shock Recent advances in pharmacologic management (I)

Recent advances in pharmacologic management {II)

RICHARD J. KONES, M.D. Pound R1dge, New York

Reprinted from NEW YORK STATE JOURNAL OF MEDICINE, Vol. Ia, Nos. 14, 15, July 15 and August 1, 1973

Reprinted from NEW YORK ~TATEJotJR;>ALOf'Mr:J?lC!NE, \lul73, Nos. 14, 15, July I and August I, 1973 Copynght 1973 by the MedH~ai!Soctety of the Stat-e of ~ew 'ork and repr:mted by pe-rroi$$iM of the oopyrlght owner~

Cardiogenic Shock Recant advances in pharmacologic management (I)

RICHARD J. KONES, M.D. Po~md

Aidge, New York

ASS$tant Profe$$0f of Cl:tmc.al Medlt:!O.e {CatdiO!ogyL New York Med1cal College-. New Vorl!: Cttv

Recent advatWeli in the understanding of the pathogenesis of cardiogenie shock has had a pro· found effect on the management of such patients.' A critical re·examination of the present treatment program of patients with cardiogenic shock there· fore appears appropriate. General care 1 • Although there is little doubt that enviromnen· tal and risk factors contribute to the incidence and course of acute myocardial infarction and car· diogenic shock, a discussion of the preventive as· pects is beyond the scope of this review. '·• The beneficial effect of resting the heart, via bed rest, in part probably due to diminution in myocardial oxygen oonsumption, has been appreciated for some time.•- 11 Attention should be given to both environmental temperature and humidity, for ex· cesses have been shown to increase heart work and, hence, myocardial oxygen consumption."'" Early relief of pain is important and may partially reverse hypotension in itself. Morphine sui· fate: in li·mg. increments, or dihydromorphinone hydrochloride (Dilaudid), 2 to 4 mg., injected in· travenously over a two-minute period, is usually efficacious. Among other actions, morphine sui· fate blocks sympathetically medicated venous constriction in the "capacitance bed" to reduce preload, and all act to reverse pulmonary edema. Blood pressure is not unduly affected by morphine," and myocardial contractility is unaltered.,. Naw.ea and emesis may be minimi~ed with the use of dimenhydrinate, 25 to 50 mg., or hydroxyzine, 25 to 50 mg. Diazepam, 2 to 5 mg., intravenously may be the tranquilizer of choice, since recent work suggests a positive inotropic property of this agent. Tachy- or bradyarrhythmias should "''"'ive 1886

prompt attention.!?-~> Arrhythmias may have a profound deleterious effect on cardiac output and coronary blood tlow. "'·" Although not completely settled, lidocaine administration intravenously, 1 to 3 mg. per mmute after an initial bolus of 50 to 100 mg., has gained wide acceptance. 22-24 This agent, which may also be administered intramuscularly!'·'• does not excessively depress myocar· dial contractility, alter afterload, or elevate myo. cardia! oxygen consumption slgnit"wantly when used in low doses."'"' Procalnamide, quinidine, and diphenylhydantoin, now used less frequently in the acute tachyarrhythmi...,, may also depress contractility to a greater extent than does lido· caine, although simultaneously decreased after· load may lessen the net effect of these agents on cardiac index. 119 ' " All of these substances appear to act by reducing the maximum rate of depolar· ization of cardiac muscle. ao Bretylium tosylate is a unique antiarrhythmic agent because of its positive inotropic proper· ty. 33' 34 lt decreases aiterload, an action due solely to the release of norepinephrine from sympathetic nerve endings. Although presently experimental," bretylium tosylate is most useful in treating refractory ventricular arrhythmias. 36-3• Arterial catheterization The relative inaccuracy of blood·pressure mea· surement with the cuff technique in patients with cardiogenic shock is now aceepted. Peripheral vasoconstriction renders cuff blood pressure lower than true arterial pressure. When vasopresaor drugs are used, this difference is ncL"E!ntuated. When vasodilator drugs are employed, peripheral blood flow may improve, and cuff pressure becomes measurable, even though true arterial pressure may fall. Therefore, insertion of a small catheter into either the femoral or brachial artery, connected to a suitable transducer for direct recording of pressures, is becoming routine in many centers. Arterial samples for oxygen tension determinations may be easily obtained; the catheter may also be used for measurement of cizculation time and cardiac output.'""' Acid-base and electrolyte balance Abnormalities in serum electrolyte activities and their ratios may alter both the membrane potentials of myocytes, their cable properties, and contractility. An adverse effect on contractility may be considered a true metabolic cardiomyopathy. Alkalosis increaaes myocardial contractiii· ty," while acidosis markedly diminishes contrac· tility ." Possible mechanisms of these actions will be discussed further. Changes in pH may also alter the responses to cardio-active drugs and, therefore, should be corrected forthwith. Survival of patients with cardiogenic shock is inversely proportional to the extent of lactic

doois.

New Yori< State Journal of Medieine I July 15.1973

ad~

During therapy, it is important to recog·

nil:e that arterial pH may paradoxically fall due to mobilizatkln of lactic acid from pooled blood in peripheral areas. •• Anemia and blood viscosity

A higher mean hematocrit in patient< with acute myocardial infarction than in control subjects w1111 (l.l'St noted by Burch and DePasquale.·•• In male patient< with "stress erythrocytosis," chronically contracted plasma volume may cause the measured hematocrit to he higher than expected. Such patients probably have a higher incidence of myocardial infarction. The prognosis of patients with higher or lower admission hematoerits and cardiogenic shock remains unknown. Diagnostic phlebotomy may account fot" a substantial fall in hematocrit levels during the course of illness. •• Blood viscosity increases with hematocrit, especially in the range 4S to 65."" Perhaps equally as important, the pressure head required to begin blood flow after it bu stopped, known 1111 the yield shear stress, increases 115 the third power of the hematocrit and square of the fi. bri.nogen concentration. A reductkln in viscosity incre1111es coronary blood flow. Conversely, byperviscosity, fur example, 115 in mac:roglobulinemia, may considerably reduce coronary blood flow. To decNase blood viscosity, infusions at 37•c. of either albumin, 3.0 to 3.5 Gm. per 100 ml. in saline, or of low molecular weight dextran may be employed. Dextrans with molecular weights in exc- of 60,000 AMU increase yield shear stress, whereas dextrans with molecular weights much less than 60,000 AMU are rapidly cleared by the kidneys. Reported mortality rates in acure myocardial infarction are said to be reduced in patients treated with low molecular weight dextran. However, whether the beneficial effect claimed is due to decressed viscosity or incressed preload remains unproved.." Anemia directly reduces the oxygen-carrying capacity of the blood, and correction of a red-cell mass def.~eieney may improve myocardial oxygen supply. Excessive infusion of erythrocytes, bowever, may raise blood viscosity and, hence, reduce coronary blood flow. Mild anemia may influence the determinants of myocardial performance; heart rare, preload, and contractility all inc.rease, while afterload decreases. Net myocardial Ol(ygen consumption is probably diminished, but this question is debated." Further, the effects of anemia on the performance of diseased myocardium are even more unclear. For instance, when hemoglobin is severely reduced below a critical level, compensatory mechanisms may fail, and symptoms of congestive heart failure may appear. The variation in such a critical level in patient.• with scure myocardial infarction and cardiogenic shock is unknown.

VarioU$ modes of treatment f()l' cr:trdwgelli.c shock ond myocardial infarction tm: discus•ed in. this report, which appeiJrs in two parts. Pllrt I d!!.U. with general ctm: of patients su/{erl."'J from co.rdi
July 15. 1973 I New Vorl< Stat., Journal of Medicine

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fective blood volume. When used as an index of left ventricular function, central venous pressure ~orrelates poorly with left ventricular end-diastol· 1c pressure and/or left ventricular end-dilllltoH TO £FFECT CONTRACTION

•

CUli!CAL CONSEQUENCES OF IIIPA!R£0 COIITIIACTlliTY FiGURE 2. Acute reduction !n contractility from dt· mir»shed cOtQnary blood flow probably due to mtraceih.dar acidosis. In turn, excess hydronium ion results m competitiOn wlth calc•um for blnttin:g s•tes on tro,:x:mi-n. Affinity of sarcoplasmic rettcu!um for caJclum may also be reduced in actdie environment. Oimirushed activator calcu.;~m ton reduces actomyosin siidi:ng and hence contractility IS 1mpair-ed.

mance. If left ventricular end-diastolic pressure, as measured directly or with the Swan-Ganz catheter, exceede 20 mm. Hg, diuresis or phlebotomy is indicated to reduce pulmonary venous pressure. Overzealous use of potent diuretics may adversely alter potassium balance acroes myocellular membranes and contractility, and, hence, phlebotomy may be preferable, especially if the patient is simultaneously receiving a short-acting digitalis glycoside.» Myocardial and systemic hypoxia

Advances in the understanding of pulmonary physiology-'- In addition, oxygen must also be regarded as a pharmacologic agent, since oxygen iteelf produces direct effects on several organ systems."' For example, oxygen may cause arterial constriction to raise blood pressure..,·" As previously mentioned, myocellular hypoxia, secondary to diminished coronary blood flow, is the event from which all sequelae of cardiogenic shock arise (Fig. 2}. 100 _,.,. Biochemically, intracellular accumulation of hydronium ion may increase the affinity of sarcoplasmic reticulum for calcium ion and may compete for calcium-binding sites on troponin, the calcium receptor protein of actomyosin, Since myocardial contractility directly depends on local

calcium ion activity surrounding actomyosin,'"" deprivation of calcium from the contractile filaments, caused by intracellular acidosis, ultimately reduces contractile strength. In addit:ion to myocardial hypoxia, distal to cor· onary occlusion, systemic hypoxia, (whether resulting from pulmonary complications of cardiogenic shock or another etiologic cause) adversely influences all organ systems including the myocardium.''"' Thus, a "vicious cycle" may be encountered (Fig. 3), Further, myocardial hypoll:ia may cause intracellular potassium loss, with attendant changes in membrane potential and excitability,'"" Finally, the response to such commonly used positive inotropic agents as the digitalis glycosides and pressors may he significantly depressed in the hypoxic heart. 1011 Clinical hypoxia is a common finding in patients with acute myocardial infarction and is even more striking in cardiogenic shock.9s..ur.-ns The decrease in arterial oxygen tension is in· versely proportional to the elevation in left ven· tricular filling pressure.'"-"· 11 • In addition, the extent of arterial oxygen tension deficiency is proportional to infarct size, since the alveolar-arterial O$ygen tension difference is directly related to ere· atine phoaphokinase levels. H 6

Three mechanisms have been proposed to ex-

Jutv 15, 1973

I New York State Journal of Medicine

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ttv-:;,t, lfiiJJ\'X'.vl!!YI ! and fails to increase intramyocardial oxygen ten· sion measured directly.'"' Based on the latter observation, it has been suggested that oxygen may reduce myocardial capillarity, which, if confirmed, is of far-reaching significance. l Westchester Avenue Pound Ridge, New Y()rk 10576

References L J{.:),tWs, R J,: Pathogenesis of cardiogenic shock, New York State J. Med" 73; 1662 3). U. Dub. M.: Bed rest in aeuw myocardial in!aroti,;m: a study i physician prll
27. Nayler, W. G.• et at.: Effect of lignocaine on myocar~ dial functkm, high energy pho&phate stores, and ()Xygen consumption: compariSOn with propranolol, Am. Heart J. 78: 338 (1969). 28. Rahimtoola, S. H .• et al.: Lidocaine infusion in acute myocardial inf~xeti9). 42. Lorkovi~. H,: tnfluence of changes in pH on the me· chankal act:vity of cardiac muscle, Circulation Res. lt: 71 1 {[966). 4:'\.

S;e-geL .J. H .. o>l al. · A rnthod of quantifym~ ~he n~ed for surgical therapy in chnical myvc:a:rdial lnfarctltm shoek.

Am. J. Cardia!. 29: 292 (Feb.} 1972. {Comments. Am. Coll~i!:~ CardioL, ~1st Annual Se:ss-lon, Chicag1ol. :.!12! 9t7 ~ 1967L 46. Sriussadaporn. S .. and Cohn, J. ~,: Lactate m:etabo·

bsm m dimcal and experim~ntal s.hock, C!.io. Res. IS: 519 09681 47. Burch. G E , and DePMqua!e. :-..;: P The hemato-· crit in pac.(mts wlth myocarrlnl mfarcuon, J A M A 180! 63

{1962).

48. OePa:squah~:, St. P., and Burch. G. E.: Hematocn1 in women w1tb m-..·ocardial infarction, 1btd. 183-: 142 {i96Jl.

4'9. Hershherg, P. L Wells, R E., and McGanrly, K B.: Hematocrit and PrognO:Si$. in patients with acute myocardi-al infarction, tbid. 2lt: 8$ (Feb. i4J l972:. 50. Rubinow, S. L, and KeUer, J. B.: J:o1ow of a vi.soous fluid through an elasti1· nephrine, and intraaortic oounte:rpulsation on hemodynanncs and myocardial ~etaboli.sm in shock !oikrwing acute myocar~ diallofarrac. Cardlovasc. Surg. 41! 68'/ (1964). 128. Kline, H. J .• et 4.&.: Hemodynamic and tnet&bolh: ef· Cects of hyperbaric oxygenation in myoc.fll'dial i~tiun, J. Appl. Physiol. 2$: 256 {1970). 129. Kulm, L. A. et at.: Htmodymunic effects of hypel'baric OJ;)'Ietl in e:rperiment-al acute myocardial infarn of adttnosme 3', 5' ·monophosphate t:J Thus.. the anticipated augmentation in stroke volume secondary to enhanced contractility may he masked by simultaneous elevation in afterload and reduction in preload, both of which tend to decrease stro.ke volume. 1 Although patients with "clinical" evidence of congestive heart failure following acute myocardial infarction (ra!es, sa gallop, and tachycardia) have been reported w benefit hemodynamically from acute digltaUzation."i;·l other investigators have found a variable response to digitaHs.l6J, suggesting a limited role for digitalis in early myo-

August 1, 1973

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New York State Journal of Medicine

1973

cardia! infarction. Current data do not, however, permit a conclmion regarding the efficacy of digi· talis following acute myocardial infarction wheth· er "clinical'' congestive heart failure is present or not~266

Despite the traditional reluctance to use digital. is after acute myocardial infarction, digitalis is finding greater use in this setting.''" Digitalis appears to he indicated after acute myocardial infarction in the presence of atrial fibrillation with rapid ventricular rates and/ or cardiomegaly with or without an sa gallop, tachycardia, and rales. The use of digitalis in uncomplicated myocardial infan:tion is not recommended. Viewing cardiogenic shock as a variant of acute left ventricular failure, digitalis may have a restricted role in the management of this syndrome. Augmented contractility resulting from digitalis treatment increases myocardial oxygen consump· tion in the normal heart (Fig. 141. However, in the failing heart, digitalis either reduces myocardial oxygen consumption or leaves it nearly un· changed. ""'"• Simultaneus reduction in left· ventricular end-diastolic pressure and volume and heart size, thus decreasing myocardial wall tension. accounts for the net effect of digitalis on myocardial oxygen consumption. In the ischemic zone surrounding an area of necrotic myocardium, such a beneficial effect on net oxygen balance may contribute to the survival of tissue marginally supplied with blood. Since the hemodynamic alterations after acute myocardial infaretion are a function of reduced left ventricular contractile mass and depressed compliance, the pssible regional effects of digital· is must also be considered. '- 270 The contractility and compliance of infareted myocardium is unlikely to be affected by digitalis preparations. Surviving myocardial mw;de may already be hypercontractile due to increased endogenous catecholamine release and, therefore, less responsive to digitalis-induced inotropism. Moreover, in· creasing the contractility of functioning myocar· dium may he futile to the extent that this energy is dissipated by areas of dyssynergy. The hazards of digitalis excess are legion and are well documented."".,,. Following myocardial infarction~ patients have increased sensitivity to the electrical manifestations of digitalis toxici· ty_,,...,.._,,. Quantitative assay of serum-digitalis levels has afforded an important diagnostic tool in prevention and detection of digitalis overdosage."''"' As mentioned, due to digitalis-induced mvocardial potassium loss,'" toxicity is more likely· to develop in the presence of hypokalemia. m Interestingly, the myocardium is also more seosi · tive to the psitive inotropic property. of digitalis when serum potassium is low."" Recently, obht· oration of digitalis-induced arrhythmias with in· travenous arginine was reported . .!t~l White the mechanism for this action is unproved, glucagon,

1974

with antiarrhythmic properties of its own, is secreted in response to arginine infusion in man and may contribute to the genesis of these observa~ tions. "82 Glucagon Since the initial demonstration of the direct psitive inotropic property of glucagon, great interest in the cardiovascular effects of this agent has been shown. 282• 283 In the papillary muscle preparation, glucagon shifted the force-velocity curve upward and to the right, which was unaf. fected by pretreatment with beta-blocking agents. ' 8' Glucagon-enhanced contractility was additive with that of ouabain hut did not precipitate digitalis toxicity. Electrophysiologic actions of glucagon have also received considerable attention. Glucagon facili· tated atrioventricular conduction at fast pacing rates2M and reversed depressed atrioventricular conduction produced by propranolol hydrochloride.""' Not only does glucagon fail to cause ectopic ventricular activity,28 7 ~ 28 • but also it abolishes ouabain-induced arrhythmias, wbich may he related to a decreased rate of rise of action potential and conduction velocity. 2""·z•• In man, hemodynamic effects of glucagon include augmented left ventricular dpfdt, cardiac index, and mean arterial pressure, all of which are independent of beta blockage or administration of digitalis. Glucagon increased the contractility of the noninfarcted portion of the ventriclem and restored arterial pressure and cardiac output after experimentally produced myocardial infan:tion in the dog.'"'"''" Glucagon administration to patients with myocardial infarction has yielded inconclusive data. On the one hand, three studies thus far do not confinn the beneficial hemodynamic actions of glucagon in cardiogenic shock when injected as a single bolus {3 to 5 mg.).'""-"' Other investiga· tors, using a continuo\111. intravenous drip of glucagon, have noted both hemodynamic improvement and favorable clinical results in patients with pstmyocardial infarction with and without cardiThe ogenic shock (Figs. 15 and 16), 237•2 heterogeneity of the syndromes themselves con· tribute to the difficulties in resolving this issue. In contrast with digitalis, which is of greater clinical usefulness in patients with cardiomegaly both pre· and pstinfarction, glucagon appears less likely to be of benefit in patients with heart disease of long duration. 28'-'89 The reasons for this remain unclear, but chronic myocardial dL•ease may he accompanied by a change in the glucagon receptor or in its coupling to adenyl cyclase. Glucagon increases coronary blood flow, but myocardial oxygen consumption rises proportionately, thus classifying this agent as a secondary coronary vasodilator. :.:sz,v.H In ischemic heart dis¥

New Yotk State Joumal of Medicme ; Augusl1, 1973

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FIGURE 15, Beneficia~ effecrs of gfucagon mfus1on m patients wuh tow cardiac output syndromes mclude s1g> nrficant natnufesis

ease, when coronary blood flow is fixed and cannot accommooate great myocardial oxygen demands, use of a positive inotropic agent may

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tentially precipitate angina or extend an infarction. Such adverse effects of glucagon have been reported in man.'"·"' In comparison with norepinephrine, however, glucagon proouced the same increase in cardiac output without any significant change in the time-tension index. This was chiefly attributed to the mooerate decrease in aftcrload effected by glucagon, in conjunction with una!-

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Corticosteroids Attention has recently focused on the visceral microcirculatory abnormalities manifest in shock which include initial arteriolar and venular constriction followed by relative diminution of arteriolar tone, increased capillary permeability and loss of anatomic integrity of capillaries and venules, and, finally, intravascular thrombosis and coagulation defects. In isolated canine forepaw and in intact forelimb preparations, massive doses of corticosteroids stabilized capillary membranes, thus preventing pathologically increased permeability.·"''· ""' In addition, transmission of sympathetic nervous impulses may he slowed by corticosteroids. Both of these effects would tend to

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In addition to the lowered penpheral vascular resistance, it appears that glucagon augments renal blood flow to a greater extent than norepinephrine, isoproterenol, and dopamine.:«Jti In conclusion, glucagon's additive inotropic effect with that of digitalis, antiarrhythmic properties, failure of propranolol hydrochloride to block inotropy, absence of tachyphylaxis, longer biologic half-life than isoproterenol, secondary coronary vasodilatation, and relatively favorable hemooynam•c effects are among the desired clinical properties of glucagon. However, the use of high doses of this agent may produce small pulmonary emboli of chemicophysical nature similar to in vitro glucagon gels. More investigation is necessary to fully characterize this phenomenon.

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Summary of data dunng contmuous in!ravenous mfus10n of glucagon 1r1 patients w1!h card1ogemc acut-e tubular rHaCIOSJS. VT ventncular tacnvcardm

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A11gust 1, 1973 I New York State Journal of Medicine

1975

lower peripheral vascular resistance and be reflected by an augmented stroke volume. Large doses of corticosteroids "stabilize'' lysosomal membranes and thus prevent tL•sue damage/10 although myocardial and skeletal muscle lyS(lSOmal enzyme activity is unaltered by gluoocorticoid pretreatment."' There is substantial evidence that myocardial hypoxia reduces intracellular pH. Lysosomal enzymes become more active in this lower pH environment and are cur· rentlythought to initiate myocellular death. In the heart-lung preparation, large doses of corticosteroids increased stroke work while mini~ mizing stroke oxygen consumption so that corow nary sinus oxygen tension rose.att As with two other reports concerning the positive inotropic action of high-dose corticosteroids, complete and conclusive data have not been presented,'"u" The experimental circumstances under which these data are collected are varied, and the positive inotropic effect is short-lived."'"' Such a property, however, if verified, may he related to the similarity in chemical structure of the cortico· steroids to digitalis, After experimental myocardial infarction in the dog, massive doses of corticosteroids reduced total peripheral resistance and improved animal surviv· al.:ns Since intra-arterial infusions of corticoids were not vasodilating,"' the question of whether lowered afterload was secondary to improved car· diac output or the result of a primary change in peripheral blood vessels remained unanswered. Earlier reports that in cortisone-treated dogs the size of myocardial infarction was smaller, there was a decrease in fibroblastic proliferation and an increase in vascular anlllltomoses, and the mortality rate was diminished had not been confirmed for some time.sl8-S22 Recently, however, the re· duction in tbe extent of experimental myocardial infarction by corticosteroids administration has been established using a s;msitive epicardial mapping technique.'"" Some experimental evidence suggests that crti· costeroid administration may be harmful after myocardial infarction. Enlargement of infarct size and delayed healing attends steroid pretreat· ment and sensitizes to catecholamine,induced myocardial necroois, ''-' Changes in serum and tissue electrolytes, such as the loss of potassium, magnesium, and hydronium ions, may adver:sely affect the coronary vascular bed, thus impairing myocardial oxygen balance, perhaps in the face of increased stroke work.""""'" lt is important to recognize, however, that such prolonged administration of corticoids is unlikely during the treatment of cardiogenic shock, In man~ acute myocardial infarction is accom~ penied by metabolic markers, including elevated cortisol levels, the e•tent of which reflects the se· verity of the infarction."2 ' ·J.H In cardlogenk shock, catecholamine levels are the highest of all 1976

subgroups of patients with acute myocardial infarction (Fig. 9). To achieve the desired effects previously discussed, proponents of corticosteroid therapy for cardiogenic shock have repeatedly stressed the importance of massive "pharmacologic" doses, given intermittently by vein.w7~~ai6.332~3Jlil. For this reason, objection could be raised to the con-. elusion of independent investigators and the cooperative study of the Scottish Society of Physicians thnt glucocorticoid therapy did not benefit patients with severe myocardial infarctions."'-l:>

tion in Health and Disease. Philadelphia, W. R Saunrlel'l-- Co .. 1968. p. l4L 139. Robison, G. A., Butcher, R W.. and SutherLand, E. W.: The- cho!amines. in Litwak. G . Ed.. Biochemi0. Krasnnw, ;-..;_, t't at; t~lproterenul ttnd r;u-d;nvHH'u!ar p£>rformance,Am.J.Ml'd 37:5H09641 15L Winbnrv, ~t t.L Hm\'tL B. IL anrl Hefner. \1. A Effect of nitrat'es and other coronar\' dllaH.,n- :hm~m ot acr\on of nit; Wexler, R C.: Acute enzyme and m~tabolic changes in artcrin vcntric·

u}ar worK and mym:atdi.ul metabolism in the vostoperati-ve h!!mpar~ti\ffl .ef· fects of dopamine and norepinephrine on m~ocar~tal hmctlott and metabolism during ~~perimental cardl')gemc shock, J. PharmacoL & Et--pe:r, Th¢rap. 173:357 (1970">. 207. Carvalho, M .. e-t .at.: Hemodynamic effect~ ""., Jr., and Zeli~. R.: Nt:'w developments in tM understanding of the actions of the digitalis glycoofdes, Prog-r. Cardiovruoc. Dit:., t l: 443 (196~H. 242. Surawicz, IL Digitali:>. New York, Gnme & Strat· ton, uno. 243. Stern, A.: The molecular medl$nism of ca.rd1a~; giy. cosfdeaction, Am. HeartJ. 83! ?tZ{May) 1972. 24:4, Lee, K S., and Klaus, W.: T'he sulx:eHnhu biD;lJO for the mechanism of inotropi-c actl\'Jn of (ardlae glyc(}Stde::>, Phar· macL Rev. 23: 193 (Sept.) 1971. 245. Langer, G. A.: Effects of digitalis on myocardial ionic exchange, Circulation 46~ ISO (July} Hrn. 246:. Kones, R- J.. The equivalent elec.trkal circuit of the sarcolemma, submitted for puOUcatl\in. 247. Luchi:, R. J., Park, C. D., and Waldbausen, J. A.: Reiationshi.p between rnyocardiaJ ouabain content and inn· tropic acttvlty, Am. J. Pb,ysioL 2~0~ 906 {A{)f ,) !971, 248. Deutscher, R. N., Haruson, D. C., and Goldman, R H.: The relation between myocardial 3 H-rlig:o.xin cun«ntrat-ion and its hemodynamic effects, Am. J, GardioL 29; 47

\Jan.) 1972.

249. Wilson, W. S.: Metabohsrn of dl:gtudis, Progr. Cardiovasc, Dis-. ll; 479 {May) 1971. 250. Doheny, J. E., et .aJ.: ~ew information regard.ing digitalis met$bolism, Chest S9: 433 {Apr. I 197L 25L Bellet. S., Johnston, C. G., and Schecter, A.: fo.Jfect of cardiac infarction on the toierunee of dQ~s to digltahs, Art'h. Int. Me
252. Trave-ll, J"' Gold, H., and MndeU, W_: Effect of ex· peri:mental eardiac infarction on n'l>pon.w t:> canme myot:atdiaf mfarction and shock, CEn. Res, 17: 2!'1:! i t009) :194 Kum.u, tL ct a!.:

Experimmltal myocardial infat:e.·

August 1, 1973 / New Vorl< State Journal o! M&dicine

1979

~ion.

~tcacy of glucag:, R, J.: Systolic time mtervals after acute myocardial infarction; -effect of glucagon administration, in prt;pmatltm. 300. Ghck, G.: Compari.s()ll of the peripheral v~ulat ef~U of gluca~. norepinephrine, isoprourenol and d-opamine, Clin. Res. 18: 307 {1970). 307. Motsay, G. J., e:t at.; EffeC. Bartilai, D., et aL: U$e of hydi'OCOrtisone in the

t.reatmtmt of aet.ite myocardial inl&rction. Summary of a din· ical tnal in 446 patients-, Chest 6.\" 488 !May} 1972.

New York State Journal of Medicine I August 1. 1913