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16 Proc. roy. Soc. Med. Volume 70 1977 Supplement 2
Dopamine in the Treatment ofHeart Failureby Dr Albert J Miller(Department ofClinical Medicine,.Northwestern Memorial Hospital,Chicago, Illinois, USA)
The rationale for the use of catecholamines inclinical practice has often been related to theirpressor effects. In the early 1950s, when norepine-phrine was first used in the treatment of cardio-genic shock, the focus of attention was thearterial blood pressure (Miller & Baker 1952,Miller et al. 1953). Indeed, at that time we hadlittle understanding of the complex systemic andcardiac effects of the catecholamines, but we didconsider that they might improve blood flow tothe intact myocardium.
In the 1960s it was shown that dopamine, thenaturally occurring precursor of norepinephrine,had a significant positive inotropic effect onheart muscle, and that its pharmacologicalproperties were different from those of norepine-phrine (Holmes & Fowler 1962, Black & Rolett1966, McDonald & Goldberg 1963, MacCannell1969). And, almost predictably, its clinical usewas directed primarily to the treatment ofcardiogenic shock. This really remains true uptill the present time.
Various studies have shown that dopamineincreases cardiac output in man by increasingmyocardial contractility (Loeb et al. 1971,Horwitz et al. 1962, Rosenblum et al. 1972,McDonald et al. 1964), and that when thearterial blood pressure rises, this is a function ofthe positive inotropic effect and the resultantincrease in cardiac output (Loeb et al. 1971,Holzer et al. 1973). It has been held that dopaminedoes not generally cause troublesome arrhythmias(Rosenblum et al. 1972, Holzer et al. 1973,MacCannell et al. 1966), and that it gives rise tolittle or no increase in heart rate (Rosenblumet al. 1972). Evidence has been presented that itincreases mesenteric blood flow (Eble 1964) andrenal blood flow (McDonald et al. 1964, McNayet al. 1965). It has been reported to dilate coronaryarteries (Brooks et al. 1967), and at least one
paper suggests that the increased stroke output itproduces is achieved at a relatively small meta-bolic cost (Crexells et al. 1973).One could anticipate that these various
pharmacological properties of dopamine wouldmake it effective in the treatment of shock, andindeed, its value here has been confirmed (Loebet al. 1971, Holzer et al. 1973, MacCannell et al.1966). There is some recent evidence indicatingthat dopamine does not increase mesenteric bloodflow (Pawlik et al. 1976, Hirsch, personal com-
munication), and this controversy will have to beresolved by further data.The problem is complicated by the fact that
cardiogenic shock, at least that true state ofshock following acute myocardial infarctionwhich mobilizes the therapeutic ardour of somany of us, has a terrible prognosis no matterwhat the treatment. Certainly dopamine is animportant addition to the pharmacologicalagents available to treat this condition, but itsresults are predictably poor. The destroyedmyocardium is not restored by any catechola-mine. As one would expect, dopamine has beenextremely effective in patients who are hypo-tensive after cardiac surgery, and in helpingpatients who are coming off cardiopulmonarybypass. I question the practice of some workersof lumping these patients together with those inshock after myocardial infarction. In the post-operative subjects the heart is usually in bettercondition, and has more potential for effectivefunction, than in patients who have just had aninfarct. In our experience with certain high riskpatients, the combination of dopamine withintra-aortic balloon pumping is often highlyeffective, and even life-saving, after cardiacsurgery.The first important data showing that dopa-
mine produced a sodium diuresis in patients withcongestive heart failure appeared in 1963 (Gold-berg et al. 1963). It was thought possible that thesodium diuresis was due to renal vasculardilatation (McNay et al. 1965). This dopamine-induced renal vasodilatation was considered tobe nonadrenergic, because the effect was notblocked by alpha or beta adrenergic blockingagents (Goldberg 1968). The increase in renalblood flow and the overall decrease in systemicvascular resistance made the use of dopamine anattractive proposition for the treatment of con-gestive heart failure (Goldberg 1968), particularlyas it was reported that it hardly ever producedtroublesome arrhythmias or tachycardias. Table 1summarizes the theoretical assets of dopamine inthe treatment of congestive heart failure. In spiteof this impressive list of qualities, there have beenfew reports on its actual use in heart failure(McDonald et al. 1964, Goldberg 1968, Mac-Cannell 1969).
In this modern era, the treatment of congestiveheart failure generally is quite effective. Thepotent diuretics available, the better under-standing of how to use digitalis products, ourability to control heart rates, and our improvedability to treat ectopic impulse formation have allcontributed to this efficacy. It would be ludicrousto suggest dopamine as a 'first line' interventionin the uncomplicated patient with chronic con-gestive heart failure. However, I believe that
Dopamine Hydrochloride
Table 1Reported effects of dopamine pertinent to its use in thetreatment of congestive heart failure
(1) Increased cardiac output(a) Increased stroke output(b) Increased heart rate(2) Increased urine formation(a) Increased renal blood flow(b) Increased glomerular filtration rate(3) Increased urine sodium excretion(4) Decrease in prerenal azotemia (fall in BUN)(5) Rise in systolic arterial pressure with a fall in diastolicpressure(6) Acts promptly, with clinical evidence ofeffectiveness atlow dosage(7) No significant increase in myocardial irritability(8) Compatible with, and possibly synergistic to, action ofdiuretics(9) Possible dilatation ofcoronary arteries. Possible thatincreased cardiac output is at relatively small energy cost
dopamine does significantly extend our ability totreat chronic heart failure which has notrespondedto the usual therapeutic measures, and that itmay have a role in patients with acute pulmonarycedema who do not recover rapidly on the usualtreatments.At our hospital we have had a relatively
modest amount of experience with the use ofdopamine in congestive heart failure, but thepatients treated have been carefully selected andhave all been under close supervision. All were
seriously ill and all had received the usual treat-ment with unsatisfactory responses.
Let me present one patient in some detail and afew others briefly to illustrate some of ourexperiences with the use of dopamine. The othermedications which each patient was receivingwere continued.
Case 1 PR, a 65-year-old retired car worker, had beenhospitalized repeatedly for congestive heart failuredue to a cardiomyopathy. He had high degree atrio-ventricular block requiring a permanent transvenouspacemaker. In the past he had suffered both cerebraland pulmonary emboli. His clinical picture hadbecome that of deteriorating cardiac cachexia. On 12November 1975, he was admitted to the NortlhwesternMemorial Hospital with increasing congestive heartfailure.He had marked cedema of the lower extremities,
rales at the lung bases bilaterally, shortness of breathon minimal exertion and an apical diastolic gallop.He was intermittently confused, and showed theclinical signs ofa 'low cardiac output syndrome'.By 28 November 1975, he had shown little im-
provement. His blood urea nitrogen (BUN) variedbetween 102 and 110 mg/100 ml, with a creatinine of2.90 mg/100 ml. Serum potassium was 5.3 mEq,chloride 79 mEq, sodium 134 mEq and CO2 27. Hehad lost no significant amount of oedema fluid aftertreatment with frusemide, digoxin, isosorbide, nitro-paste, allopurinol and potassium supplementation.On 4 December 1975, a Swan-Ganz catheter was
passed. Right ventricular pressure was 50/4 mmHg;
pulmonary artery pressure was 50/20 mmHg, andcardiac output by the thermodilution method was3.8 litres per minute. A pulmonary capillary wedgepressure was 20 mumHg.The patient's weight at this stage was 122 lb. An
infusion of dopamine, 100 jug per minute, was started.One hour later the cardiac output was 4.35 litres perminute. Occasional ventricular premature beats wereseen. Urine output significantly increased. The bloodpressure was 100/40 mmHg shortly after dopaminewas begun. By 6 December 1975, this had risen to130/60 and his BUN had fallen to 84 mg/100 ml. Acardiac output determination (thermodilution) withdopamine running at 100 ug per minute was 4.7 litresper minute. Lidocaine was used intermittently totreat ventricular premature beats, which becamefrequent at times.On 10 December 1975, dopamine treatment was
stopped. The patient's weight had dropped to 116pounds, and he showed significant loss of cedema. Hisappetite and affect were both improved. The BUNwas down to 68 mg/100 ml. His blood pressure was1 6/68 mmHg.The patient was discharged from hospital on 19
December 1975, having shown significant improve-ment.
Case 2 FS, a 54-year-old sanitary district worker withdiabetes was admitted to the Northwestern MemorialHospital on 7 January 1976. This was his secondhospital admission, now with the clinical picture ofsevere congestive heart failure. Cardiac catheteriza-tion studies supported the clinical diagnosis ofcongestive cardiomyopathy. His coronary arterieswere quite normal, and no etiology was found for hismarked cardiomegaly.At the time of hospital admission his weight was
252 pounds. His blood pressure was 130/90 mmHg.There was marked foot, ankle and leg cedema. He wasorthopnceic, with some shortness of breath at rest inthe sitting position, and rales were heard at both lungbases posteriorly. The liver was palpable 5 cm belowthe right costal margin. An S3 was heard at thecardiac apex.
Treatment was instituted with digoxin, a sodium-restricted diet, triamterene and furosemide. Hisdiabetes mellitus was treated with lente insulin.Increasing dosages of furosemide resulted only inslow diuresis, with no improvement in his symptoms.Blood pressures varied between 110/80 and 90/70mmHg. The BUN was 25 mg/100 ml, sodium 138mEq, potassium 316 mEq, chloride 96 mEq. Ahiemoglobin was 14.7 gm; the hvmatocrit was 47%.Frequent ventricular premature beats were treatedwith procainamide. A repeat BUN was 27 mg/100 ml.On 18 January he was started on dopamine at a
rate of 100 ztg per minute, which was soon increasedto 150 ,tg per minute. His heart rate increased to 110beats per minute when the dopamine was increasedto the maximum dosage he received, 250 Hg perminute, and he had some sensation of his heartpounding. The ventricular premature beats weregenerally less frequent than before he started thedopamine therapy. On 20 January his BUN was18 mg/100 mil.
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18 Proc. roy. Soc. Med. Volume 701977 Supplement 2
His weight fell steadily on continuous dopaminetherapy for four days. During this time his othermedications were continued unchanged, as they wereafter dopamine was stopped. At the time of hospitaldischarge his weight was 200 pounds, he was cedema-free, without shortness of breath, and he again had agood appetite.Three weeks after hospital discharge he had gained
five pounds and was feeling well. Physical examinationrevealed no evidence of fluid retention. Four monthslater he had gained a total of eight pounds from thetime of hospital dischalge, he was feeling well, andwas working regulaily at his undemanding desk job.
Case 3 JS, a 69-year-old man with a history of aprevious massive myocardial infarction, was seenwith progressive congestive heart failure and poorresponse to treatment with the usual medications.He showed Cheyne-Stokes respiration, bluntedintellectual reactions, with recurrent stupor, andrecurrent pulmonary cedema. His blood pressure was110/70 mmHG; and heart rate was 100 beats/min.He was started on dopamine 225 ug per minute on
19 May 1975. Prior to that time his BUN variedbetween 31 and 34 mg/100 ml, and creatinine between1.79 and 2.04 mg/100 ml; his serum sodium was133 mEq. Central venous pressure was stable at18 mmHg.On 20 May he had an increased urine output and
the central venous pressure was down to 12 mmHg.He had a sinus tachycardia of 105 beats per minute.At 5.00 a.m. on 20 May the dopamine was suddenly
stopped at a time when the patient's general conditionwas improved. He quickly became short of breath andtachypnceic, and his skin felt clammy. The dopaminewas restarted at 8.30 a.m., after which his clinicalstate improved and the urine output increased. Hisblood pressure was 94/70 mmHg at that time.At 2.30 p.m. on 20 May the dopamine was again
stopped, and again his general condition appeared todeteriorate. A Swan-Ganz catheter was passed at4.00 p.m., and the dopamine was restarted at 150 ,zgper minute. He became more alert, the central venouspressure varied between 8 and 12 mmHg, and hisurine output increased. The Cheyne-Stokes respira-tion ceased. He was continued on dopamine until24 May, at which time his blood pressure was 120/70 mmHg. He was clinically improved, and his weighthad fallen from 169 to 160 pounds. His BUN was31 mg/100 ml, and his serum sodium was 135 mEq.
Case 4 BH, a 72-year-old woman, was admitted tothe Northwestern Memorial Hospital with thepicture of cardiac cachexia on 29 March 1976. Heradmission weight of 71 pounds did not change until16 April, when it was 75 pounds and she showedevidence of fluid retention with cedema of the feet andankles and more rales in the chest. On the next dayshe was gravely ill with increasing shortness of breath,hypotension, with blood pressures varying between60/50 and 70/50 mmHg, increasing peripheral cedema,vomiting and pallor. Her BUN was 82, creatinine1.56, uric acid 11.2 mg/100 ml. Serum sodium was131, potassium 5.3, chloride 96 mEq; bicarbonate 21.The hlimatocrit was 29 %.
The patient was known to have longstandingvalvular heart disease, with aortic stenosis andinsufficiency and mitral insufficiency. The picture wasfurther complicated by a recent myocardial infarction,with a rise in CPK isoenzymes to 36%.On the morning of 17 April she was transferred to
the coronary care unit, a Swan-Ganz catheter waspassed, and she was started on dopamine at a rate of50 ,ug per minute. The pulmonary artery pressure was75/28 mmHg, with a mean pressure of46. A pulmonarycapillary wedge pressure was read as 36 mmHg, withtall V waves present. A repeat pulmonary arterypressure shortly after the dopamine was begun was75/24 mmHg. A repeat BUN was 83 mg/100 ml. Themean arterial pressure rose to 75 mmHg, the heartrate increased to 100 beats per minute, and the patientshowed clinical improvement.The rate of dopamine infusion was increased to
75 ug per minute. Her mean arterial pressure variedaround 68 mmHg, and her heart rate varied between100 and 110 beats per minute. The pulmonary diastolicpressure remained at a mean of 25 mmHg. Shebecame less short of breath, but ventricular prematurebeats occurred at 8 to 10 per minute. The dopaminewas decreased to 62.5 /tg per minute. Her conditionremained fairly stable on 18 April. On 19 April hermean arterial pressure was 64 mmHg, and centralvenous pressure varied between 6 and 12 mmHg. Anadequate urine output seemed to depend on the rateof dopamine infusion. Her weight came down to 72pounds and the BUN fell to 74 mg/100 ml. Her heartrate varied between 100 and 120 beats per minute,with some further increase in ventricular prematurebeats. She was started on oral procainamide, and thedopamine infusion was maintained at 62.5 ,g perminute.On 20 April the dopamine infusion rate was
decreased to 50 ug per minute. She showed only rareventricular premature beats. The BUN was 68 mg/100 ml, her urine output increased to as high as 70 mlper hour, and the mean arterial pressure was around80 mmHg. The dopamine infusion rate was decreasedto 37.5 Hg per minute.On 21 April her urine output varied between 30 and
50 ml per hour, with dopamine at a rate of 37.5 ugper minute. Her heart rate varied around 100 beatsper minute. On 22 April the dopamine infusion ratewas decreased to 25 ,ug per minute, and her conditioncontinued to improve. Her BUN fell to 55 mg/100 mland her creatinine was 0.90 mg/100 ml. Dopaminewas discontinued, after which her heart rate slowed tobetween 90 and 96 beats per minute. No ventricularpremature beats were seen after dopamine wasdiscontinued.
Other therapy which was continued during theperiod of time that she received dopamine includednitropaste, digoxin, diazepam, sublingual nitro-glycerine, and procainamide.Two days after dopamine was discontinued her
BUN was 70, creatinine 1.56 mg/100 ml.
Case 5 SL, a 69-year-old male retired factory worker,was admitted to the Northwestern Memorial Hospitalon 22 May, with the clinical picture of severe congestiveheart failure. Previous cardiac catheterization studies
Dopamine Hydrochloride
had revealed severe coronary atherosclerosis and a
ventricular aneurysm, which were not considered tobe operable In 1973 recurrent pulmonary emboliwere successfully treated by the placement of an
inferior vena cava 'umbrella' prosthesis.At the time of hospital admission his weight was
142 pounds. Blood pressure was 100/90 mmHg, BUNwas 51, creatinine 2.10 mg/100 ml. A chest X-rayrevealed congestion and pleural effusion.On 25 May his BUN was 66 and the creatinine was
1.98 mg/100 ml. On 2 May his weight had fallen to140 pounds with diuretics, but he still had severe
cedema of the feet and ankles.On 30 May his blood pressure was 120/96 mmHg,
and his pulse rate 112 beats per minute. Markedaedema of the feet and ankles persisted. The patientwas started on dopamine at a rate of 350 Ftg per
minute; this was soon decreased to 250 jug perminute. His urine output dramatically increased to350 ml of urine in the first four hours of treatment.His blood pressure was 116/82 mmHg and his heartrate was 114 beats per minute. On the next day hisweight was down to 135 pounds, his heart rate was118 beats per minute, and the nurses described thepatient as 'more comfortable'.On 1 June the rate of dopamine infusion was
decreased from 200 to 150 zg per minute. His hearfrate wa6 130 beats per minute and his blood pressurewas 110/70 mmHg. It was noted that his previouslypersistent Cheyne-Stokes respiration now disappearedfor short periods of time. On 2 June he was describedas 'alert'. Dopamine was stopped on June 3, after itsrate of administration had been reduced to 100 jg perminute. The patient's weight had fallen to 134 pounds.
The clinical progress of these 5 patients issummarized in Table 2.We have also treated 2 patients with pulmonary
cedema. One was a 62-year-old woman withcardiac cachexia on the basis of severe rheumaticmitral valve disease. She developed acute pul-monary aedema after blood transfusion, and didnot respond well to intravenous digoxin andfrusemide. Dopamine produced a prompt clinicalimprovement, with clearing of lung rales anda diuresis. However, lidocaine had to be usedto control ectopic beats. The other, a 69-year-oldwoman, sustained an acute myocardial infarct,and went into pulmonary cedema. The responseto intravenous frusemide was unsatisfactory,but dopamine led to rapid improvement, withclearing of lung rales and a moderate diuresis.The improvement was transient, and the patientdied four hours later in cardiac asystole.
In 1963, Goldberg, McDonald & Zimmermanreported careful studies of dopamine treatmentin four patients in congestive heart failure, andfound a significant sodium diuresis together withclinical improvement. Subsequently, Goldberg(1968) summarized their group's experience inthe treatment of 11 patients in congestive heartfailure with dopamine, and emphasized thatsodium excretion increased in all of them. Theygave dopamine infusions for up to six hours.More recently Beregovich and his co-workershave studied the effects of dopamine admini-
Table 2Dopamine treatment in congestive heart failure
Patient Age DiagnosisPR 65 Cardiomyopathy;
high degree AVblock; permanenttransvenouspacemaker
FS 54 Cardiomyopathy;diabetes mellitus
Dose
range
75-250
d7
4
JS 69 Coronary heart 5disease
BH 72 Cardiac cachexia; 5rheumatic heartdisease withmitral insufficiencyand aortic stenosisand insufficiency;acute myocardialinfarction
SL 69 Coronary heart 5disease; ventricularaneurysm
Heart rate(beats/min)aD pD
100- 80 110250 90
150- 10025037.5- 9075 96
105
100120
Arterialbloodpressure(mm Hg)aD pD
100/85 100/40130/60116/68
130/9090/70110/80110/7094/7070/50
Weight(in lbs)aD pD122 116
140/70 235 212
120/70 169 160
110/80 75 72
Blood ureanitrogen(mgm %)aD pD130 68
25 1827
Serumcreatinine(mgm %)aD pD2.90 2.75
Ventricularectopic beatsaD pD0 2+
- - 2+ 1+
31 31 1.70 1.80 034 2.0482 55 1.56 0.90 0
75- 116 114 100/90 116/82 142 134 51 61350 130 120/96 110/70 66
1.60 1.90 02.10
0
2+
1+
d, days on dopamine infusionaD, before dopaminepD, after dopamineDose range is given in ,tg per minute
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20 Proc. roy. Soc. Med. Volume 70 1977 Supplement 2
stered for one and a half hours in nine patientswith congestive heart failure. The clinical resultsof this short-term therapy were good, and theyconcluded that there may be an important rolefor dopamine in the management of heart failure.Rosenblum, Tai & Lawson (1972) studied 12patients in chronic heart failure during cardiaccatheterization. They found an increase incardiac output, an increased sodium excretion,and little change in heart rate. The maximumperiod for which they administered dopaminewas 89 minutes.How well has the promise of dopamine held
up in the treatment of congestive heart failure?If we look at Table 1 again, it would appear thatit does for the most part measure up quite well.It produces improvement in the clinical picture,there is an added diuresis, prerenal azotemia islessened, and there is direct and indirect evidenceof improvement in cardiac output. At times theheart rate does increase quite a lot. But in thetreatment of heart failure this is not necessarilya disadvantage. After all, increasing the heartrate is often an effective means of increasing thecardiac output. More important, however, is thefact that dopamine not infrequently causesventricular premature beats, which at timesrequire treatment. Thus, at least under idealcircumstances, it appears desirable to monitorheart rhythm in patients receiving dopamine. Inspite of this problem we have found that con-tinuous dopamine infusions can be given safelyfor up to seven days.Dopamine proved to be relatively easy to use.
When it caused ventricular ectopic beats theseresponded promptly to treatment with lidocaineor procainamide. The dosages of dopamine whichproved clinically effective were at times sur-prisingly small.
It was of particular interest that two of thepatients we treated had long-term remissions intheir state of chronic congestive heart failure.Both were patients with cardiomyopathy, inwhom clinical improvement persisted for threeand four months respectively. Perhaps we should
not be surprised at such an observation; after all,we know that patients in congestive heart failurewill improve for significant periods of time aftertreatment with a sufficient period of bedrest.We can conclude, I believe, that dopamine has
an important role in the treatment of severechronic congestive heart failure, and that treat-ment with low doses is often efficacious. It maywell prove to be of value in the treatment of acutepulmonary oedema. Because these patients withheart failure seem to be susceptible to ventricularectopic beats with dopamine treatment, heartrhythms should be monitored and arrhythmiasappropriately treated.
REFERENCESBeregovich J. Bianchi C, Rubler S, Lomnitz E, Cagin N& Levitt B (1974) American Heart Journal 87, 550BlackW L & Rolett E L(1966) Circulation Research 19, 71-79BrooksH L, Stein P D, Matson J L & Hyland JW(1967) Circulation 36, Suppl. II, p. 78Crexells C, BourossaM B & Biron P(1973) Cardiovascular Research 7, 438Eble J N (1964) Journal ofPharmacology and ExperimentalTherapeutics 145, 64Goldberg L I (1968) American Journal ofCardiology 22, 177Goldberg L I, McDonald RW & Zimmerman AM(1963) New EnglandJournal ofMedicine 269, 1060-1064Holmes J C & Fowler NO(1962) Circulation Research 10, 68-72Holzer J, Karliner J S, O'Rourke R A, PittW & Ross J(1973) American Journal ofCardiology 32, 79Horwitz D, Fox S & Goldberg L(1962) Circulation Research 10, 237Loeb H S, WinslowH B J, Rahimitoola S H, Rosen KM &Gunmar RM(1971) Circulation 44, 163-173MacCannell K L (1969) Canadian Journal ofPhysiology andPharmacology 47, 25MacCannell K L, McNay J L, MeyerM B & Goldberg L I(1966) New EnglandJournalofMedicine 275, 1389McDonald R H jr & Goldberg L I (1963) Journal ofPharmacology and Experimental Therapeutics 140, 60-66McDonald R H, Goldberg L I, McNay J L & Tuttle E P(1964) Journal ofClinical Investigation 43, 1116McNay J L, McDonald R H jr & Goldberg L I(1965) Circulation Research 16, 510Miller A J & Baker L A(1952) Archives ofInternal Medicine 89, 591Miller A J, Shifrin A, Kaplan B M, Gold H, Billings A &Katz L N (1953) Journal ofthe American Medical Association152,1198Pawlik W, Mailman D. Shanbour L L & Jacobson E D(1976) American Heart Journal 91, 325Rosenblum R, Tai A R & Lawson D (1972) Journal ofPharmacology and Experimental Therapeutics 183, 256
Dopamine Hydrochloride
DISCUSSIONProfessor Dollery (Chairman): Dr Miller, youbegan by saying that if there was no myocardiumleft after myocardial infarction then dopaminecould not do very much. I wondered if the samewas not really true in some of these people withvery severe congestive heart failure, in whom themyocardium, or the mechanical state of the heart,is severely damaged. Because in fact in only oneor two of the patients that you presented wasthere a really impressive change; in the others,although there was a small fall in the BUN, theserum creatinine did not change - that could havebeen a dietary effect, I suppose - and the weightlosses were only of the order of 4 or 5 lbs, whichwas not very dramatic. I think the patients res-
ponses were much greater than that, but thegeneral impression was not very dramatic.
Dr Miller: I think, first of all, that we have tostart off with the fact that there is a differencebetween the patient who has had an acutemyocardial infarction and is in cardiogenic shockdue to myocardial infarction, and the patientwho presents in intractable congestive heartfailure. Most of the patients that we see in so-called intractable congestive heart failure are,indeed, treatable. The intractability is often afunction of inadequate therapy.
In these 5 patients treatment had been vigorousby acceptable clinical yardsticks, and they hadnot adequately responded. It is true that thefigures for some of these patients are not dramatic.Weight loss of 5 pounds in a patient with in-tractable congestive heart failure is in itself per-haps not a dramatic finding. Actually in these 5
patients the clinical improvement was reallyquite striking.The two patients with cardiomyopathies had
much more edema. I think these were the ones
who showed the more dramatic results, becausethey lost so much more weight.
I am by no means suggesting that dopamine isthe end-all for the treatment of congestive heartfailure; but if you recall, in the early days ofnorepinephrine there were some people whothought that norepinephrine might be of valuein the treatment of congestive heart failure. Therewere reports at that time that it increased renalblood flow under certain circumstances and thaturine output increased. What I am suggesting isthat there are a certain number of patients whopresent with intractable failure, who have a
decreased cardiac output, with or without sig-nificant cedema, and who will improve with long-term dopamine therapy. In one of these cases Ithink it allowed us to get the patient over a humpand, finally, to transfer him to the surgeon whocould replace the valves that needed replacing.
Professor Goldberg: That is essentially the kindof patient that we have seen respond. It isinteresting to me that, once these refractorypatients have a diuresis, they seem to go for aconsiderable period of time before they getcedema again.The question I have is this: the vogue in
America is for using after-load reduction or pre-load reduction with sodium nitroprusside, andwe are trying to work out which of these re-fractory patients should receive dopamine. I justwonder whether you have any comments, andthen perhaps I can tell you what conclusions wehave come to.
Dr Miller: Well, that is a good question and, asyou know, everybody is confused about this.At least one group in the United States whichstrongly supports the concept of nitroprussideunloading of the left ventricle in intractable heartfailure is now adding dopamine to the treatmentin some of their patients. So they are using nitro-prusside combined with dopamine.Our own experience with nitroprusside at
Northwestern is vast. This is mainly because ouranesthesiologists use nitroprusside hypotensiveanmsthesia, and they find this very suitable inpatients who have essentially normal coronaryarteries. I think that we are far from the answerson how to proceed in patients with failure and Ishould be interested to know your views.
I was going to ask the clinical pharmacologistsa question, so let me take advantage of being uphere to do that. One pharmacologist mentioned tome, when I was talking to him about the fact thata couple of heart failure patients we treated withdopamine seemed to persist in their improvement(apparently this is your experience, too), thatintermittent treatment of such patients perhapsfor a couple of days once a month might be ofvalue. The question is whether there may be some-thing here that really is different from just bedrest. It may be that something is changing.
Professor Goldberg: I do not know whether thereis something unusual about dopamine or not. Ithink it is simply starting the diuresis; that is myguess. Once the heart gets smaller it does well,however you achieve this. Some patients respondto furosemide and then do well for a long periodof time. But what we are trying to find out iswhen to use nitroprusside and when to usedopamine. If you use nitroprusside and perfusionpressure drops, and there is a chance of coronaryischmmia, then I think you had better stop. Thenwe try dopamine. Ifdoparnine increases peripheralresistance, that is bad. You are working on a veryfine knife edge. So what we generally do, if apatient's pressure is high, is to start with nitro-
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22 Proc. roy. Soc. Med. Volume 701977 Supplement 2
prusside and see what happens. Frequently thecardiac output goes up dramatically and theyrespond, but if the pressure drops too much,then we may switch to dopamine. We also use thetwo together. I think they may be pretty goodtogether because the nitroprusside blocks some
of the vasoconstriction of dopamine and alsodilates the venous bed like an internal tourniquet.I think most of us have found that once a patientlike this has a diuresis, however he achieves it, hedoes well for a certain period of time until theheart gets big again. I think it is simply puttingthe heart on a better Starling curve.
I might mention a few words of caution. Wealways start with a very small dose of dopamine,because if you increase peripheral resistance andincrease after-load then it may be detrimental.So we start with about 0.55,g/kg per min, graduallygo up to 1.0, then very gradually go up furtheruntil we get a diuresis; at that point we cut back,continuing careful observation. Of course, we
are very careful to avoid ventricular ectopicactivity.The other thing that we noticed in a couple of
patients was angina pectoris. This is anotherreason for being very cautious about the after-load. One has to proceed very cautiously, but wehave given dopamine for three weeks at a veryslow rate in one case. This particular patient leftthe hospital, and he is still doing well.
Dr Miller: Our experience also is that patientswho are hypertensive - for example, the patientwho has had an acute myocardial infarction andcomes in to the hospital with a raised bloodpressure will do very well with nitroprusside.
Professor Dollery: Did Dr Goldberg make anycontrolled observations? Did he have a controlseries? Because, when we were considering some
studies with dobutamine and wanted to do workin patients of this kind, we looked at the Hammer-smith to find how many patients there were, andwe found there really were very few who wouldfulfil the necessary criteria - in whom one mightwant to use the drug and who were suitable to gointo a clinical trial. In fact, we abandoned it forthat reason. It is very difficult to get manypatients to study. The thing that persuaded usthat we would have to have a control group was
that these patients with severe congestive failureoften did improve rather dramatically just withbed rest. That is why I personally would besceptical of observations which are not con-
trolled. Was there any control group?
Professor Goldberg: This is not very difficult to doin our studies. We had a long control periodbefore treatment, and dopamine acts quickly. In
that patient I showed, you will remember therewere 7 days during which he was excreting0.3 mEq of sodium per 24 hours. He was in thehospital for three weeks and then there was oneweek when he had a metabolic balance study.Then we gave dopamine and, within 10 minutes,he was having a diuresis. It is a rapid pheno-menon. So one does not have to have a longcontrol period to see a hxemodynamic effectdevelop. That patient was in the hospital forthree weeks.
Professor Dollery: You must make a distinction,presumably, between a number of objectives. Ifthe objective is primarily to produce this sodiumdiuresis acutely, then I accept of course that whatyou say is correct. If your primary aim is toimprove cardiac output, tissue perfusion and thepatient's wellbeing, perhaps it is a more difficultmatter to assess.
Professor Goldberg: If one gets a diuiresis withfurosemide, then the patient's heart becomessmaller and it becomes more efficient. We knowthat, in a large heart, by La Place's law, theradius of the heart is large, it uses more oxygenand it is less efficient. So a simple diuresis hasbeen shown many times to improve cardiacfunction, and cardiac output will increase simplyby decreasing the pre-load. So that a diuresisitself is very useful.
I see dopamine in acute pulmonary adema asacting like aminophylline, which a lot of us use.I might say that we had some interesting ex-periences with acute pulmonary cedema. Iremember the first time we tried dopamine wasin a patient who was a compulsive salt eater. Hewould come into the hospital repeatedly withpulmonary cedema. I was listening to his chestand my colleague was starting the intravenousdrip. I said, 'He's better, he's better, he's better',and he said, 'I haven't started the dopamine yet'.So, you know, with acute pulmonary cedema it isjust reassurance sometimes.
Professor Dollery: I think you have underlinedmy point about the control group.
Dr Miller: I should like to comment on thatthough. I think that this particular kind of patientis not common in our institution either. Obviouslywe do not have a series of 20 patients. But I alsoagree that it is extremely difficult to get what youwould call a control group. I think that if wetried to figure out a control group based upontreatment versus non-treatment there would begreat flaws in trying to define an adequate controlgroup. The question here is whether the patient'sstatus prior to the time of treatment represents an
Dopamine Hydrochloride
adequate control period. I think that that is thecritical question. I believe that the answer is 'Yes',but it is certainly debatable.
In the area of acute pulmonary cedema, Ishould like to speak as a clinical cardiologist fora moment. Certainly, treating two patients is nobasis from which to make broad generalizations.However, anybody who cares for patients hasseen that type of acute pulmonary cedema whichjust does not respond to the usual treatments,that is oxygen, intravenous furosemide, intra-venous digitalization, and so on. We then have apatient who is desperately sick. That was the kindof situation where we gave the dopamine, andthose two patients showed a dramatic and promptresponse. I am not saying that they might nothave responded just as well to unloading the leftventricle with intravenous nitroprusside, but thepoint is that we have to think about dopamine asa relatively heroic measure.
Dr Zaroslinski: I wonder whether Dr Millermight comment on his experience with otherpatients with reference to the effects on heart rate.This goes back to the point made by ProfessorDollery about the extent of myocardial damage.We found, in analysing the data on the multi-clinic trials, that the patients who survivedappeared to have cardiac slowing, which we feltwas a compensatory mechanism resulting from animproved cardiac output. I wonder whether youmay have observed a similar type of response inother categories of patients, because in yourcongestive failure group you seemed to haveeither a constant heart rate or an increase.
Dr Miller: Our experience in patients with con-gestive heart failure is not enough for me toanswer that question. I do not know. I think itprobably makes a certain amount of sense, butif a patient who is in congestive heart failure ismobilizing tachycardia as a means of maintainingcardiac output, and if with treatment he tends toslow that heart rate, they may represent a goodprognostic sign.My own experience in the treatment of cardio-
genic shock, where we have pretty much followedthe kind of protocol suggested by Dr Goldberg,and tailor-make the catecholamine administrationto the circumstances, is that our results are usuallypoor irrespective of the drug used. As a purelysubjective response, I feel more comfortable usingdopamine in congestive heart failure, which youwill recall was the original suggestion of DrGoldberg and his group, than I do in trying totreat cardiogenic shock.
Mr D Longmore (London): I was very interestedin Dr Miller's presentation, particularly in his
slide which showed changes in the efficiency ofthe heart - I forget how it was worded. It seemsto me, having the advantage of not having useddopamine so far and, therefore, being an instantexpert on it, that the thing that we really want toknow is whether the increase in cardiac output ispaid for by an enormous price in myocardialoxygen consumption, or whether it is an economicmethod of increasing cardiac output.We are trying to check this by measuring
myocardial oxygen consumption in patients in theintensive care unit, and it is extremely difficult todo. However, it is quite easy to increase a patient'scardiac output by 10% and increase myocardialoxygen consumption by 200 %. Where doesdopamine come in this league of catecholamine-like drugs ?
Dr Miller: That is a fine question and I shouldlike to defer to my clinical pharmacologistfriends. I think that Dr Goldberg can probablyanswer that better than I can.
Professor Goldberg: You know, you do not getanything for nothing. It used to be thought thatdigitalis did not waste oxygen, but this is, ofcourse, wrong. The reason why we had thecourage to use dopamine at all was simplyLa Place's law: if one increases cardiac outputwithout changing heart rate very much, and withno increase in peripheral resistance, and if theheart becomes smaller, then it is not wastingoxygen. If the heart becomes larger or does notchange in size, then oxygen is wasted. If you givedigitalis to a patient with a big heart, the cardiacoutput goes up and the rate is slowed, and theoxygen consumption decreases. A group inMontreal (Crexells et al. 1973, CardiovascularResearch 7, 438) did in fact measure oxygenconsumption in patients with coronary heartdisease who were given dopamine and it did notincrease.The only way I can possibly explain this is that
the heart became smaller. I do not know anyother way to explain it, because a positiveinotropic effect has got to use oxygen. If onestudies things which increase oxygen consump-tion, they are ranked in this order. The greatestwaster of oxygen is increased peripheral re-sistance or increased after-load, which makes theheart bigger. For example, if you give methoxa-mine or angiotensin, which have no positiveinotropic effect, oxygen is wasted because theheart gets bigger. If you just increase the rate,more oxygen is wasted than with a positiveinotropic effect. Lastly, there is the positiveinotropic effect itself, which certainly wastesoxygen. So I do not know how one could tell in anindividual patient. I do not think that there is
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24 Proc. roy. Soc. Med. Volume 70 1977 Supplement 2
going to be a magic positive inotropic drug.This, of course, underlies the controversy aboutnitioprusside versus positive inotropic drugs. Ithink that it has swung a little bit too far the otherway. That is, everybody is using after-loadreduction, but if one decreases after-load anddecreases perfusion pressure one can be in trouble.
I consider it a very fine knife-edge, and I do notknow anything one can do except observe a
patient very carefully clinically. Dopamine, ofcourse, can produce arrhythmias; any inotropicdrug can, particularly in the hypoxic myocardium.So I think that it has to be done very carefullyand, hopefully, if digitalis works then a drug likethis should do the same. That at least has beenmy thinking.
Professor Dollery: What happens to the wholebody metabolic rate when you infuse dopamine?
Professor Goldberg: It does not increase. Dopa-mine has much less metabolic stimulating actionthan, say, epinephrine. Epinephrine is numberone in that area and dopamine is number three,say, after norepinephrine. I am very concerned
about infusing dopamine very slowly and beingvery careful not to let after-load increase verymuch. This, I think, would be the biggest dangerin treating congestive heart failure with dopa-mine.
Dr A Bennett (London): This question of controlsis very important, and should not be skipped overtoo lightly. I think it is probably easier to achievethan has been suggested. For example, you canfirst infuse the vehicle alone and see whathappens to the patient, and then you can ad-minister dopamine. When the response comesback to base line again give the vehiclealone.
Professor Goldberg: We always did that (seeFig 2 on page 8).
Dr Bennett: In other words, you undervaluedyour data when you said there were no controls.
Dr Miller: I think we have to emphasize that weneed much more study of the use of dopamine inthe treatment of congestive heart failure.
