DOBUTAMINE VS DOPAMINE IN HEART FAILURE/Loeb, Bredakis, Gunnar

Acknowledgment

The authors thank Mr. Rodney A. Kjersten for technical assistance, MissSanta L. Ferraro for secretarial help and Dr. Milenko Medakovic of ScheringCorporation, Bloomfield, New Jersey for kindly supplying the drug.

References1. Prichard BNC: Propranolol as an antihypertensive agent. Am Heart J

79: 128, 19702. Holland DB, Kaplan NM: Propranolol in the treatment of hypertension.N Engl J Med 294: 930, 1976

3. Alderman EL, Davies RO, Crowley JJ, Lopes MG, Brooks JF, FriedmanJP, Graham AF, Matlof HG, Harrison DC: Dose response effectivenessof propranolol for the treatment of angina pectoris. Circulation 51: 964,1975

4. Beilin LF, Juel-Jensen BE: Alpha and beta adrenergic blockade in hyper-tension. Lancet 1: 979, 1972

5. Boakes AJ, Knight EJ, Pritchard BNC: Preliminary studies of the phar-macological effects of (5-1 (1-hydroxy-2-[(-1 methyl-3-phenyl prophyl2amino) ethyl] salicylamide) (AH 5158) in man. Clin Sci 40: 18, 1971

6. Collier JG, Dawnay NAH, Nachev CH, Robinson BP: Clinical investiga-tion of an antagonist at alpha and beta adreno receptors - AH 5158A.Br J Pharmacol 44: 286, 1972

7. Farmer JB, Kennedy I, Levy JP, Marshall RJ: Pharmacology of AH5158: A drug which blocks both alpha and beta adreno-receptors. Br. JPharmacol 45: 660, 1972

8. Skinner C, Gaddie J, Palmer KNV: Comparison of intravenous AH 5158(Ibidomide) and propranolol in asthma. Br Med J 2: 59, 1975

9. Prichard BNC, Thompson FO, Boakes AJ, Joekes AM: Somehemodynamic effects of compound AH 5158 compared with propranoldt,propranolol plus hydralazine and diazoxide: The use of AH 5158 in thetreatment of hypertension. Chemother Mol Med 48: 97, 1975

10. Bruce RA, Hornsten TR: Exercise stress testing in evaluation of patients

with ischemic heart disease. Prog Cardiovasc Dis 11: 371, 196911. Gifford RW: Drug combinations as rational antihypertensive therapy.

Arch Intern Med 133: 1053, 197412. Zacest R, Gilmore E, Koch-Weser J: Treatment of essential hypertension

with combined vasodilation and B-adrenergic blockade. N Engl J Med286: 617, 1972

13. Sannerstedt R, Stenberg J, Vedin A, Wilhelmsson C, Werko L: Chronicbeta adrenergic blockade in arterial hypertension: hemodynamic in-fluences of dihydralazine and dynamic exercise and clinical effects ofcombined treatment. Am J Cardiol 29: 718, 1972

14. Hollifield JW, Sherman K, Zwagg RV, Shand DG: Proposed mechanismof propranolol's antihypertensive effect in essential hypertension. N EnglJ Med 295: 68, 1976

15. Vlachakis ND, Mendlowitz M: Combined alpha and beta adrenergicreceptor blocking agents in the treatment of essential hypertension. ClinRes 23: 212A, 1975

16. Shinebourne E, Fleming J, Hamer J: Effects of beta adrenergic blockadeduring exercise in hypertensive and ischemic heart disease. Lancet 2:1217, 1967

17. Prichard BNC, Shinebourne E, Fleming J, Hamer J: Hemodynamicstudies in hypertensive patients treated by oral propranolol. Br Heart J32: 236, 1970

18. Cohn JN: Vasodilator therapy for heart failure: The influence of im-pedance on left ventricular performance. Circulation 48: 5, 1973

19. Fitzgerald JG, Wale JL, Austin M: The hemodynamic effects ofpropranolol, dexpropranol, oxprenolol, practolol and sotalol inanesthetized dogs. Eur J Pharmacol 17: 123, 1972

20. Nies AS, Shand DG: Clinical pharmacology of propranolol. Circulation52: 6, 1975

21. Winer N, Choski DS, Yoon MS, Friedman AD: Adrenergic receptormediation of renin secretion. J Clin Endocrinol 29: 1168, 1969

22. Assaykeen TA, Clayton PL, Goldfein A, Ganong WF: Effect of alpha-and beta-adrenergic blocking agents on the renin response to hypo-glycemia and epinephrine in dogs. Endocrinology 87: 1318, 1970

Superiority of Dobutamine over Dopaminefor Augmentation of Cardiac Output

in Patients with Chronic Low Output Cardiac Failure

HENRY S. LOEB, M.D., JOHN BREDAKIS, M.D., AND ROLF M. GUNNAR, M.D.

SUMMARY Dobutamine is a newly developed catecholaminereported to have minimal direct vascular effects relative to its in-otropic activity and to have less chronotropic and arrhythmogenicproperties than other catecholamines used in the treatment of lowoutput states. In this study, the acute hemodynamic effects ofdobutamine were compared to those of dopamine in 13 patients withchronic low output cardiac failure. At dosages adjusted to achievesimilar increments in cardiac output, dobutamine reduced left yen-

OF THE MANY AGENTS capable of improving cardiacoutput in patients with low output cardiac failure, thecatecholamines are among the most widely used. As a

group, these drugs exert similar direct cardiac effectsmediated by stimulation of beta adrenergic receptors. Im-portant differences in their peripheral vascular actions are

found among them. At times, these vascular effects are un-

From the Section of Cardiology, Department of Medicine, Loyola Univer-sity Stritch School of Medicine, Maywood, Illinois; and the Veterans Ad-ministration Hospital, Hines, Illinois.

Supported in part by National Institutes of Health grant HE15040.Address for reprints: Henry S. Loeb, M.D., Program Director in Car-

diology, Veterans Administration Hospital, Hines, Illinois 60141.Received June 7, 1976; revision accepted September 27, 1976.

tricular filling pressure (LVFP) from 25 ± 2 mm Hg (SEM) to 17 ± 2mm Hg, while dopamine increased LVFP to 30 ± 3 mm Hg and insix patients caused arterial 02 saturation to fall below 90%. Thispoor response to dopamine was probably the result of itsvasoconstrictive effects and illustrates the potential advantages ofusing a cardioselective agent such as dobutamine when the desiredgoal of therapy is to improve ventricular function by direct inotropicstimulation.

desirable and can offset benefits gained from the inotropicactions. In addition, the catecholamines currently used fortreatment of heart failure frequently cause tachycardiaand/or arrhythmias. Newer agents have been developed andtested under laboratory conditions with the purpose of find-ing one that would retain the inotropic activity of the earliercatecholamines without direct vascular, chronotropic andarrhythmogenic actions. Of many such compounds tested,dobutamine appears to come close to fulfilling these criteria.We' and others2 3 have previously described the acute hemo-dynamic effects of dobutamine in patients with severe leftventricular dysfunction. In the present study, we comparedthe effects of dobutamine to those of dopamine in 13 suchpatients. Our studies suggest that dobutamine has important

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advantages over dopamine for augmentation of cardiac out-put in patients with chronic low output cardiac failure whenhypotension is not present.

Methods and Materials

The patients studied were all males, hospitalized forsymptoms of chronic cardiac failure due to cardiomyopathy(8), arteriosclerotic heart disease (4), or persisting afterprosthetic aortic valve replacement (1). Their ages rangedbetween 48 and 68 years, averaging 58 years. All patientshad received digitalis and diuretic therapy prior to the studyand none were in acute pulmonary edema or cardiogenicshock at the time of study. Two patients were in chronicatrial fibrillation and the remainder were in sinus rhythm.Prior to the study, informed consent was obtained from eachpatient.On the morning of the study, the patient was brought to a

specially equipped hemodynamic study unit in the fastingstate without specific pre-medication. A #7F thermal dilu-tion Swan-Ganz catheter was inserted from a surgically-ex-posed basilic vein and advanced under fluoroscopic controluntil the catheter tip was situated in the right or leftpulmonary artery. It was positioned to yield a reliable wedgepressure (WP) waveform when the balloon was inflated andpulmonary artery systolic (PASP) and diastolic (PADP)pressure waveform when the balloon was deflated. Rightatrial pressure (RAP) was measured from the proximallumen. Cardiac output (CO) was determined by averagingtwo or more thermal dilution curves obtained by injecting 10cc of 00 C saline into the right atrium. A Model 9500Edwards laboratory cardiac output computer was used togive on-line readout of CO. Arterial systolic (ASP) anddiastolic (ADP) pressure was measured from an indwellingcannula inserted into the radial, brachial, or femoral artery.All pressures were obtained fromr Statham 23 Db trans-ducers leveled at the midchest position. Mean pulmonary(MPAP) and systemic arterial (MAP) pressures were de-termined by electrical dampening. Heart rate (HR) was

determined from a standard ECG lead which was monitoredcontinuously. Pressures and ECGs were recorded on a mul-tichannel photographic recorder run at various paper speeds.Arterial (AO2) and pulmonary artery (PAO2) oxygensaturations were determined by oximetry using an AmericanOptical oximeter.The following calculations were made:

Cardiac Index (CI) = CO/body surface area (DuBois)

Stroke Index (SI) = CI/HR

*Left Ventricular Stroke Work Index (LVSWI) =

(MAP-WP) X SI X 13.61000

Right Ventricular Stroke Work Index (RVSWI) =

(MPAP-RAP) X SI X 13.61000

Systemic Arteriolar Resistance (SAR) =(MAP - RAP)/COPulmonary Arteriolar Resistance (PAR) =(MPAP-WP)/COProtocol

After control measurements had been obtained and hemo-dynamic stability established, either dobutamine ordopamine was infused at a constant rate using an IVAC con-stant infusion pump. Repeat measurements were made anddosages adjusted at 15 to 30 min intervals once a new stablestate was achieved. When measurements had been obtainedat one or more dosages, the first drug was stopped and thepatient allowed to return to control status. After 30 min, thesecond drug was infused and measurements obtained in asimilar manner.The following considerations were important in determin-

ing the dosages used for comparing the two drugs. Since im-proved cardiac output is a major objective when inotropicagents are given to patients with low output cardiac failure,we thought it necessary that the two drugs be compared ifpossible, at dosages yielding significant and similar increasesin cardiac output. In previous studies of patients with poorleft ventricular function,1 we found that infusions ofdobutamine in amounts of 10.7 ± 1.1 ,ug/kg/min (mean ±SEM) were well tolerated and raised cardiac index by anaverage of 82% (from 1.9 ± 0.2 L/min/m2 to 3.3 ± 0.2L/min/m2). Accordingly, in the present study, we chose tostudy dobutamine at an infusion rate of 10 ,ug/kg/min.Since it was also important that dobutamine not always bethe first agent studied, when dopamine was studied first, wegave it at more than one infusion rate (table 1) and thenchose for analysis, data obtained at the dopamine infusionrate which yielded a cardiac output closest to that which waspresent during the 10 jig/kg/min dobutamine infusion. Ascan be seen, a CI obtained during infusion of dopamineagreed within 0.4 L/min/m2 of the CI present duringdobutamine infusion in all but three patients.

Results

In table 2 are listed the various parameters measured dur-ing the control and drug infusion periods for each of the 13

TABLE 1. Cardiac Index at Varying Dopamine Infusion RatesCompared to Dobutamine at 10 Ag/kg/min

Infusion Rate (jtg/kg/min)Dopamine Dobutamine

Pt 1.25 2.5 5.0 7.5 10.0 10.0

CT (3.1) 3.1HP (3.5) 4.0 3.6LP (2.4) 2.3 3.1VB 1.6 (1.9) 2.3AW 1.5 (1.5) 2.4HH 2.3 (2.6) 3.7JB (2.5) 1.8 2.3LB (1.9) 2.0 1.8HG (3.0) 3.9 4.7 3.31)W (2.9) 2.5IIJ (1.8s) 1.8LF (3.6) 3.5 3.6CP 3.5 (4.1) 4.3Cardiac in(lex in L/min/m. Parenthesis refer to the dopamine dosage

chosen for comparing to 10 jg/kg,,min dolbutamine infusion.

*In five patients, a satisfactory WP could not be obtained and in these pa-tients, the LVSWI was calculated using the PADP as a reflection of the leftventricular filling pressure (LVFP).

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patients studied. Dobutamine was the first drug evaluated ineight patients and dopamine the first in five patients.Dosages were 10.3 ± 0.3 ,g/kg/min for dobutamine and5.4 ± 0.8 ug/kg/min for dopamine.Arterial Pressures. Mean arterial systolic pressure was109 ± 5 mm Hg during control (12 patients), increasedminimally to 112 ± 5 mm Hg with dobutamine and to124 ± 7 mm Hg during dopamine infusion. Mean arterialpressure was 83 ± 3 mm Hg before the drug infusion, fell to76 ± 3 mm Hg during infusion of dobutamine, and in-creased slightly to 86 ± 5 mm Hg with dopamine. ADP (12pts) was 70 ± 3 mm Hg during control, fell to 56 ± 5 mmHg during dobutamine infusion, and increased slightly withdopamine to 72 ± 4 mm Hg. Each of the above pressureswere significantly higher (P < 0.05) during dopamine infu-sion than during dobutamine infusion.Pulmonary Artery and Right A trial Pressures. PASP,

MPAP, and PADP were 53 + 4 mm Hg, 39 + 3 mm Hgand 30 + 2 mm Hg, respectively, during the control period.During dobutamine infusion, these pressures fell to 46 ± 5mm Hg, 32 ± 3 mm Hg, and 23 ± 3 mm Hg; and duringdopamine infusion they increased to 58 ± 4 mm Hg, 42 ± 4mm Hg, and 32 ± 3 mm Hg. Each was significantly lower(P < 0.01) during dobutamine infusion than duringdopamine infusion. Wedge pressure was measured in eightpatients and averaged 24 + 2 mm Hg during the controlperiod, falling to 16 ± 3 mm Hg during infusion ofdobutamine. Wedge pressure increased to 28 ± 5 mm Hgduring dopamine infusion, a value significantly higher(P < 0.01) than during dobutamine infusion. Right atrialpressure (12 pts) fell from 11 ± 2 mm Hg to 6 ± 2 mm Hg

during dobutamine infusion and was significantly higherduring dopamine infusion, averaging 12 ± 3 mm Hg.

Cardiac Index. Cardiac index prior to drug infusion was1.9 ± 0.1 L/min/m2. During dobutamine infusion, CI in-creased to 2.9 ± 0.2 L/min/m2 and as expected, was notsignificantly different than the average of 2.7 ± 0.2L/min/m2 achieved during dopamine infusion.Heart Rate. Heart rate averaged 85 ± 2 beats/min dur-

ing the control period and increased to a similar extent dur-ing both dobutamine and dopamine infusions averaging100 ± 4 and 99 ± 6 beats/min respectively.Stroke Index. Stroke index was 25 ± 2 cc/beat during the

control period and increased by a similar extent during infu-sion of dobutamine and dopamine averaging 31 ± 2 and30 ± 3 cc/beat respectively.

Left Ventricular Stroke Work Index (fig. 1). During thecontrol period LVSWI averaged 19 ± 2 g-m/m2. Duringdobutamine infusion, LVSWI increased to 25 ± 2 g-m/m2and during dopamine infusion decreased to 23 ± 3 g-m/m2.Differences in LVSWI between dobutamine and dopaminewere not significant.Systemic Arteriolar Resistance. This parameter

(measured in 12 pts) fell during infusion of both agents froma control value of 21 i 2 mm Hg/L/min to 13 ± 1 mmHg/L/min with dobutamine and to 16 + 2 mm Hg/L/minduring infusion of dopamine. The difference in SARbetween dobutamine and dopamine was not significant.

Right Ventricular Stroke Work Index (fig. 2). RVSWI in-creased from 10 + 1 g-m/m2 to 11 + 1 g-m/m2 during

STROKE WORK

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STROKE WORK LEFT VENTRICULAR FUNCTIONg-m/m230r

25

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FIGURE 1. Left ventricular stroke work index on the vertical axisis plotted against left ventricular filling pressure (wedge orpulmonary artery diastolic pressure) on the horizontal axis. Duringdobutamine infusion, (unfilled circle) the plot moves upward and tothe left suggesting significant improvement in left ventricular func-tion. During dopamine infusion, the plot moves upward and to theright suggesting minimal, ifany, change in left ventricularfunction.

4 6 8 10 I 1 14FILLING PRESSURE m m Hg

FIGURE 2. Right ventricular stroke work index is plotted againstright atrial pressure. As infigure I for left ventricularfunction, rightventricular function seems to have improved significantly more dur-ing infusion of dobutamine than during infusion of dopamine.

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dobutamine infusion and to 12 ± 1 g-m/m2 during infusionof dopamine. The difference in RVSWI betweendobutamine and dopamine was not significant.Pulmonary Arteriolar Resistance. This measurement (8

pts) fell from 5.1 ± 1.0 mm Hg/L/min to 3.9 ± 0.8 mmHg/L/min during dobutamine infusion, which was notsignificantly different from the mean of 2.9 + 0.4 mmHg/L/min present during dopamine infusion.Oxygen Saturation. Arterial and pulmonary oxygen

saturation was measured in 12 patients. During control, AO2was 90% or above in every patient averaging 96 ± 0.4%.During dobutamine, AO2 remained above 90% in 11 patientsaveraging 93 ± 0.8%. During dopamine infusion, AO2 wassignificantly lower (P < 0.01) averaging 87 ± 2% and wasbelow 90% in six patients. As can be seen in figure 3, in eachof these six patients, the fall in AO2 which occurred duringdopamine infusion was associated with LVFP above 35 mmHg which, in four of the six patients, was due to a large in-crease in LVFP, ranging from 15 to 21 mm Hg. In contrast,four of the six patients whose AO2 remained above 90% dur-ing dopamine infusion, had a fall in LVFP and in none wasLVFP above 28 mm Hg.PAO2 averaged 45 ± 5% during the control period and in-

creased during both dobutamine and dopamine infusions,averaging 64 ± 2% and 57 ± 4%, respectively. AlthoughPAO2 was higher with dobutamine than with dopamine, theAO2 - PAO2 difference, which averaged 51 ± 5% prior toinfusion of either drug, was narrowed similarly with bothdobutamine and dopamine, averaging 30 ± 2% and30 ± 3%, respectively.Adverse Effects. No serious adverse effects resulted from

the study. In a few patients, shortness of breath developedduring dopamine infusion, and in one patient, chest pain oc-curred during infusion of dopamine at a dosage of 5,vg/kg/min but he responded promptly to nitroglycerin anddiscontinuation of the infusion. Although arrhythmias wereuncommon, some patients had more ventricular ectopic

0lor

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0 ** 0

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FIGURE 3. Arterial oxygen saturation is plotted against left ven-

tricular filling pressure in each of 12 patients. Solid circles are con-

trol values, unfilled circles are values obtained during dobutamineinfusion and unfilled squares are values obtained during infusion ofdopamine. In six of the 12 patients, dopamine infusion was

associated with an arterial oxygen saturation under 90% and in each

of these six patients, the low arterial oxygen saturation was

associated with a left ventricular filling pressure above 35 mm Hg.

beats noted during administration of the drugs. Since ec-topic beats were not counted during the study, a comparisonof the two agents with regard to arrhythmogenic effects wasnot possible.

Discussion

In 1963, Goldberg, McDonald, and Zimmerman4reported improved sodium diuresis in patients with con-gestive heart failure during dopamine infusion. Subse-quently, dopamine has become popular for the treatment ofpatients with various types of shock5 and low output states.6The popularity of dopamine is largely due to its potent in-otropic activity coupled with its unique ability to selectivelyvasodilate vessels in splanchnic and renal vascular beds by amechanism other than adrenergic stimulation.7 In addition,when used in moderate dosages, dopamine, although exert-ing both alpha- and beta-adrenergic peripheral vasculareffects, seems less likely to cause either excessive vaso-dilatation and hypotension than isoproterenol or excessivevasoconstriction and increased cardiac work, as norepi-nephrine does. In spite of these theoretical advantages,the direct peripheral vascular effects of dopamine whichare largely dose dependent8 may, as in the case of isopro-terenol and norepinephrine, limit its usefulness under certainconditions.

In order to eliminate some of these problems, Tuttle andMills9 modified the chemical structure of isoproterenol in anattempt to develop a substance having potent inotropic ac-tivity with minimal chronotropic, arrhythmogenic, or directperipheral vascular effects. Among several substancesevaluated, dobutamine, a derivative of dopamine, appearedto best fit these requirements. Experimental studies haveshown dobutamine to be a direct-acting compound with itsaction being independent of stored catecholamines. Whencompared to other catecholamines at dosages producingequivalent inotropic effects, dobutamine also appears tohave less arrhythmogenic activity and to exert less effect onperipheral vascular resistance. Although both alpha- andbeta-adrenergic actions on peripheral vasculature can beelicited by dobutamine during selective adrenergic blockade,these effects seem to be slight in comparison to its direct car-diac effects.10"

Clinical studies have shown dobutamine to increase car-diac output in patients with and without heart failure'`without substantially raising heart rate. Isoproterenolcaused greater rate increases with comparable increases incardiac output.'2-14

In the present study, we compared the acute hemo-dynamic effects of dobutamine to those of dopamine in pa-tients with chronic low output cardiac failure. It is importantto note that none of these patients were in clinical shock andperfusion pressure was considered to be adequate in all pa-tients prior to infusion of either drug. Augmentation of car-diac output and not arterial pressure was therefore a desiredtherapeutic endpoint in addition to reduction in the elevatedleft ventricular filling pressure.

Experimentally, dobutamine and dopamine exert similarinotropic responses when given at low dosages and at a re-spective ratio of one to four.9 With increasing dosages ofdopamine, however, its pressor effects become important. Inthe present study, it was not possible to measure inotropicactivity per se and we therefore elected to compare the two

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agents at dosages yielding similar, and in most instances,physiologically significant increases in cardiac output.Under these conditions, it becomes apparent thatdobutamine would be preferred to dopamine if the desiredgoal in such patients is to temporarily improve ventricularfunction. As can be seen in figures 1 and 2, dobutamineshifted the plot of stroke work to filling pressure upward andto the left for both left and right ventricles, whereasdopamine shifted this relationship upward and to the right.This difference suggests that considerably more improve-ment in ventricular function occurred with dobutamine thanwith dopamine. Furthermore, LVFP fell in 12 of the 13 pa-tients during dobutamine infusion (increasing by 1 mm Hgin one patient) but increased in eight of the 13 patients dur-ing dopamine infusion. In several instances, the elevatedLVFP was associated with arterial hypoxemia, dyspnea, andauscultatory evidence of early pulmonary edema. These un-desirable effects of dopamine occurred primarily in patientsreceiving infusion rates above 5 ,ug/kg/min.When given to patients with shock, dopamine has been

well tolerated at dosages above 10 ug/kg/min. From ourearly experience with dopamine in 62 patients with shock ofvarious etiologies"5 we reported a mean increase in cardiacoutput of 37% during dopamine given at an average infusionrate of 10,ug/kg/min (assuming the average patient weighs78 kg). In 38 of these patients, left ventricular end-diastolicpressure (LVEDP) was measured directly and althoughLVEDP increased slightly from 13 to 16 mm Hg duringdopamine infusion, the drug was generally well tolerated andclinical evidence of worsening ventricular function withpulmonary edema was not seen. We think it important toemphasize this difference in response to dopamine betweenhypotensive patients with clinical shock and normotensivepatients with chronic low output cardiac failure. In theshock patient, especially when sepsis or miscellaneous fac-tors are responsible, vascular resistance may not beelevated'6' 17 and cardiac function may be only moderatelydepressed. Under such circumstances, large dosages ofdopamine are consistent with satisfactory ventricular perfor-mance since the adverse effect of increased afterload on ven-tricular function can be counterbalanced by the inotropicresponse to the drug coupled with restoration of arterialpressure favoring improved coronary and systemic per-fusion.On the other hand, patients with advanced heart failure

not complicated by a reduction in coronary perfusion pres-sure frequently respond well to vasodilator therapy and aremade worse by interventions causing vasoconstriction.Unlike dobutamine, the inotropic effects of dopamine are inpart mediated by release of stored myocardial cate-cholamines,9 which may be depleted in patients with chronicheart failure.'" Therefore, although vasoconstriction may beavoided in such patients by using dopamine in low dosages,the dosage may be insufficient for achieving the desired in-otropic effect and increase in cardiac output.

In contrast to dopamine, dobutamine is said to haveminimal direct vascular activity even when used at higherdosages. In our patients, systemic arteriolar resistance fell in11 (average from 21 to 13 mm Hg/L/min) during its infu-sion, while mean arterial pressure fell slightly (from 83 to 76mm Hg). This reduction in SAR during dobutamine infu-

sion may have been due to recruitment of latent vesselsand/or withdrawal of compensatory vasoconstriction as hasbeen observed following administration of digitalis to pa-tients with heart failure.'9 It is also possible that, in spite ofexperimental evidence to the contrary, dobutamine acteddirectly to vasodilate vascular smooth muscle. If present,this effect would, in light of our current concepts, be con-sidered desirable with regard to improving ventricular func-tion. Although for the group, SAR also fell during infusionof dopamine, it remained above 18 mm Hg/L/min in theeight patients who also had an increase in LVFP.Dopamine can improve renal and mesenteric perfusion by

selective nonadrenergic vasodilatation7 and this uniqueproperty of dopamine is not shared by dobutamine." Sincewe did not measure urine flow or sodium excretion, it ispossible that dopamine may have exerted beneficial renaleffects not apparent from hemodynamic measurementsalone. It should be noted, however, that these beneficialeffects on regional perfusion can be reversed, whendopamine is given in amounts large enough to cause alpha-adrenergic mediated vasoconstriction. Thus, if in addition toimproved ventricular function, selective vasodilatation inmesenteric and renal vascular beds is desired, one mightconsider using dopamine in low dosages of 1.2 to 2.5gg/kg/min, combined, if necessary, with an agent such asdobutamine, or with a vasodilator to achieve optimalhemodynamic improvement.

Although the effects of dobutamine and dopamine onmyocardial oxygen consumption and coronary blood flowwere not assessed in the present study, production of myo-cardial ischemia with either drug is a potential hazard whenthe drugs are given to patients with coronary artery disease.Tuttle et al.20 have reported a favorable effect withdobutamine on the relationship between myocardial oxygendelivery and demand following experimental coronary liga-tion and Gillespie et al.2" found no evidence of increasingmyocardial ischemia in 12 patients with acute myocardialinfarction infused with dobutamine in dosages of 1 to 40Ag/kg/min. On the other hand, Willerson et al.22 haveshown increased epicardial ST-segment elevation during in-fusion of dobutamine in anesthetized dogs following cor-onary ligation, in spite of concurrent increase of blood flowto all areas of the heart. Experimental studies duringdopamine infusion23' 24 have not found consistent changes inthe net effect on the relationship between myocardial oxygendelivery and demand.

In summary, our study has shown that, when given insufficient amounts, both dobutamine and dopamine can im-prove cardiac output in patients with chronic low output car-diac failure. Dopamine is more likely to cause persistentelevation of vascular resistance, increased left ventricularfilling pressure, and clinical evidence of pulmonary conges-tion and edema. For these reasons, dobutamine should befavored over dopamine for increasing of cardiac output insuch patients.

References

1. Loeb HS, Khan M, Klodnycky ML, Sinno MZ, Towne WD, GunnarRM: Hemodynamic effects of dobutamine in man. Circulatory Shock 2:29, 1975

2. Akhtar N, Chaudhry M, Cohn JN: Dobutamine: Selective inotropic ac-tion in patients with heart failure. Circulation 47 (suppl IV): IV-136, 1973

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ISOSORBIDE DINITRATE IN ANGINA/Danahy et al.

3. Beregovich J, Bianchi C, D'Angelo R, Diaz R, Rubler S: Hemodynamicstudies with dobutamine, a new inotropic agent. Circulation 47 (supplIV): IV-144, 1973

4. Goldberg LI, McDonald RH Jr, Zimmerman AM: Sodium diuresisproduced by dopamine in patients with congestive heart failure. N EngI JMed 269: 1060, 1963

5. Talley RC, Goldberg LI, Johnson CE, McNay JL: A hemodynamic com-parison of dopamine and isoproterenol in patients in shock. Circulation39: 361, 1969

6. Holzer J, Karliner JS, O'Rourke RA, Pitt W, Ross J Jr: Effectiveness ofdopamine in patients with cardiogenic shock. Am J Cardiol 31: 139, 1973

7. McNay JL, McDonald RH Jr, Goldberg LI: Direct renal vasodilatationproduced by dopamine in the dog. Circ Res 16: 510, 1965

8. Mark AL, lizuka T, Wending MG, Eckstein JW: Response of saphenousand mesenteric veins to administration of dopamine. J Clin Invest 49:259, 1970

9. Tuttle RR, Mills J: Dobutamine: Development of a new catecholamine toselectively increase cardiac contractility. Circ Res 36: 185, 1975

10. Robie NW, Nutter DO, Moody C, McNay JL: In vivo analysis ofadrenergic receptor activity of dobutamine. Circ Res 34: 663, 1974

11. Vatner SF, McRitchie RJ, Braunwald E: Effects of dobutamine on leftventricular performance, coronary dynamics, and distribution of cardiacoutput in conscious dogs. J Clin Invest 53: 1265, 1974

12. Loeb HS, Khan M, Saudye A, Gunnar RM: Acute hemodynamic effectsof dobutamine and isoproterenol in patients with low output cardiacfailure. Circulatory Shock 3: 55, 1976

13. Loeb HS, Sinno MZ, Saudye A, Towne WD, Gunnar RM: Elec-trophysiologic properties of dobutamine. Circulatory Shock 1: 217, 1974

14. Hinds JE, Hawthorne EW: Comparative cardiac dynamic effects ofdobutamine and isoproterenol in conscious instrumented dogs. Am JCardiol 36: 894, 1975

15. Loeb HS, Winslow EBJ, Rahimtoola SH, Rosen KM, Gunnar RM:Acute hemodynamic effects of dopamine in patients with shock. Circula-tion 44: 163, 1971

16. Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM:Hemodynamic studies and results of therapy in 50 patients withbacteremic shock. Am J Med 54: 421, 1973

17. Robinson JA, Klodnycky ML, Loeb HS, Racic MR, Gunnar RM: En-dotoxin, prekallikrein, complement and systemic vascular resistance. AmJ Med 59: 61, 1975

18. Chidsey CA, Braunwald E, Morrow AG, Mason DT: Myocardialnorepinephrine concentration in man: Effects of reserpine and of con-gestive heart failure. N Engl J Med 269: 653, 1963

19. Mason DT, Braunwald E: Studies on digitalis. X. Effects of ouabain onforearm vascular resistance and venous tone in normal subjects and in pa-tients in heart failure. J Clin Invest 43: 532, 1964

20. Tuttle RR, Pollock GD, Todd G, Tust R: Dobutamine: Containment ofmyocardial infarction size by a new inotropic agent. Circulation 47 (supplIV): IV-521, 1973

21. Gillespie TA, Roberts R, Ambos HD, Sobel BE: Salutary effects ofdobutamine on hemodynamics without exacerbation of arrhythmia ormyocardial injury. Circulation 51 (suppl II) 11-294, 1975

22. Willerson JT, Hutton I, Watson JT, Platt MR, Templeton GH: Influenceof dobutamine on regional myocardial blood flow and ventricular perfor-mance during acute and chronic myocardial ischemia in dogs. Circulation53: 828, 1976

23. Luz P, Forrester JS, Wyatt HL, Waters D, Swan HJC: Divergent effectof dopamine upon ischemic myocardium with partial and total coronaryocclusion. Am J Cardiol 37: 130, 1976

24. Wilkes SB, Murthy VS, Laffan RJ: Effect of intravenous infusion ofdopamine on coronary circulation and oxygen transport to myocardiumin anesthetized dogs. (abstr) Clin Res 24: 514A, 1976

Sustained Hemodynamic and Antianginal Effectof High Dose Oral Isosorbide Dinitrate

DANIEL T. DANAHY, M.D., DOUGLAS T. BURWELL, M.D.,

WILBERT S. ARONOW, M.D., AND RAVI PRAKASH, M.D.

SUMMARY Twenty-one patients with documented coronary

atherosclerotic heart disease were studied to determine the effect ofhigh dose oral isosorbide dinitrate (ISDN) on heart rate, bloodpressure, and exercise time until angina pectoris. Patients were testedin two phases, initially with 0.4 mg of sublingual nitroglycerin andwith sublingual placebo, and then with oral ISDN, mean dose 29 mg,and oral placebo. Both phases of the study were conducted in a ran-

domized, double-blind, crossover manner. After ISDN was comparedto oral placebo, heart rate increased at 30 to 300 min (P < 0.01)

SUBLINGUAL NITROGLYCERIN has enjoyed long-standing and almost universal acceptance as an antianginalagent. The remarkable efficacy of this drug has led to its usenot only as a therapeutic agent but also as a standard forevaluating other antianginal agents' and even as a diagnostictool.2 Many attempts have been made to prolong the briefaction of sublingual nitroglycerin by altering both molecularstructure and method of administration. These attempts

From the Cardiology Section, Long Beach Veterans AdministrationHospital, and the University of California College of Medicine, Irvine,California.

Supported by VA Project Number 0366-02.Address for reprints: Daniel T. Danahy, M.D., Cardiology Section,

Veterans Administration Hospital, Long Beach, California 90822.Received June 17, 1976; revision accepted September 2, 1976.

(peak increase 18 beats/min at 60 min), and systolic blood pressuredecreased from 45 to 300 min (P < 0.005) (peak decrease 18 mm Hgat 60 min). Exercise time at 2 min after sublingual nitroglycerin in-creased 51% as compared to sublingual placebo (P < 0.001). AfterISDN was compared to oral placebo, exercise time increased 54% at1 hr (P < 0.005), 37% at 3 hr (P < 0.01), and 12% at 5 hr (NS).Twelve of 21 patients (57%) improved their exercise time until angina2 25% at I hr after oral ISDN. The exercise response to sublingualnitroglycerin was a good predictor of this response to oral ISDN.

have generated a long history of controversy, still un-resolved.3 16 Orally administered nitrates in particular havebeen subject to attack.'7- ' Needleman and associates,20working with rats, reported rapid and nearly completedegradation by the liver of orally administered nitrates.Thus it has been argued that there is no rational basis for theuse of orally administered nitrates.More recent hemodynamic studies, however, have caused

us to reexamine this issue. Decreases in arterial bloodpressure and left ventricular filling pressure following oralisosorbide dinitrate (ISDN) have been demonstrated inseveral carefully conducted studies in cardiac patients.20-24These hemodynamic effects suggested that an antianginaleffect might also be present. Careful review of previousstudies on the antianginal effect of oral isosorbide dinitrate

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H S Loeb, J Bredakis and R M Gunnerwith chronic low output cardiac failure.

Superiority of dobutamine over dopamine for augmentation of cardiac output in patients

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1977 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.55.2.375

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