Download with Cardiomyopathic Heart Failure

Comparative Systemic and Regional Hemodynamic
Effects of Dopamine and Dobutamine in Patients
with Cardiomyopathic Heart Failure
CARL V. LEIER, M.D., PAUL T. HEBAN, M.D., PATRICIA Huss, R.N.,
CHARLES A. BUSH, M.D., AND RICHARD P. LEWIS, M.D.
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SUMMARY Thirteen patients with severe cardiac failure underwent a single crossover study of dopamine and dobutamine
in order to compare the systemic and regional hemodynamic effects of the two drugs. The dose-response data demonstrated
that dobutamine (2.5-10 ,ug/kg/min) progressively and predictably increases cardiac output by increasing stroke volume,
while simultaneously decreasing systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure. There
was no change in heart rate or premature ventricular contractions (PVCs)/min at this dose range. Dopamine (2-8
,ug/kg/min) increased the stroke volume and cardiac output at 4 ,g/kg/min. Dopamine at >4 ,Ag/kg/min provided little additional increase in cardiac output and increased the pulmonary wedge pressure and the number of PVCs/min. At >6
Ag/kg/min, dopamine increased heart rate. During the 24-hour maintenance-dose infusion of each drug (dopamine 3.7-4,
dobutamine 7.3-7.7 ,ug/kg/min), only dobutamine maintained a significant increase of stroke volume, cardiac output, urine
flow, urine sodium concentration, creatinine clearance and peripheral blood flow. Renal and hepatic blood flow were not
significantly altered by the maintenance dose of either drug. Systemic and regional hemodynamic data suggest that
dobutamine has many advantages over dopamine when infused in patients with cardiac failure.
dose-hemodynamic response curves, the maintenance
dose-systemic and regional responses (during a 24hour infusion) and the withdrawal responses of
dopamine and dobutamine in 13 patients with low output cardiac failure.
DOPAMINE HAS REPLACED most other
catecholamine preparations (e.g., isoproterenol,
norepinephrine) in clinical situations where inotropic
and circulatory support is required. The popularity of
dopamine has, as its basis, several studies1-5 showing
that dopamine is less chronotropic and has less
dramatic peripheral vascular effects than the other
catecholamines. In addition, dopamine appears to
have a unique property of stimulating renovascular
receptors (dopaminergic receptors) directly.3 6-10 Tuttle and Mills" have systematically formulated and
synthesized a new catecholamine, dobutamine,
designed to selectively increase cardiac contractility
without altering heart rate and blood pressure.
Animal and human data'2-18 indicate that dobutamine
increases stroke volume, cardiac output and overall
cardiocirculatory performance in a dose range that
does not elicit significant chronotropic and peripheral
vascular responses. Dobutamine has also improved
some parameters of renal function in patients with
severe cardiac failure."8 Acute hemodynamic studies
(catheterization laboratory data) comparing
dopamine and dobutamine19 20 suggest that the ventricular function of patients with heart failure improves with both agents; however, dobutamine
appears to be less chronotropic and, in contrast to
dopamine, tends to lower left ventricular filling
pressure. This study was designed to compare the
Methods and Materials
Patients
Thirteen patients with moderately severe-to-severe
left ventricular failure were studied. The mean age was
58 years (range 30-70 years), and all subjects were
male. All patients had a form of congestive cardiomyopathy (10 idiopathic, two alcohol, one postviral). The congestive cardiomyopathy diagnosis was
confirmed in each patient with cardiac catheterization. Twelve patients were categorized as Functional Class IV (New York Heart Association), and
one patient as Functional Class III. All patients were
on a digitalis preparation (daily oral digoxin dose of
0.25 mg in eight patients, 0.125 mg in two patients and
digitoxin 0.1 mg in three patients) and furosemide
(daily oral dose range 40-240 mg). Five patients were
receiving oral quinidine sulfate (daily dose range of
800-2000 mg). The digitalis, furosemide and quinidine
were continued throughout the study. Written informed consent was obtained from the patients before
each study.
Protocol
From the Division of Cardiology, Ohio State University College
of Medicine, and the Department of Medicine, Mount Carmel
Medical Center, Columbus, Ohio.
Supported by grants from the Central Ohio Heart Chapter of the
American Heart Association and the S. J. Roessler Foundation.
Dr. Leier is an Investigator for the Central Ohio Heart Chapter
of the American Heart Association.
Address for reprints: Carl V. Leier, M.D., 643 Means Hall, Division of Cardiology, Ohio State University Hospitals, Columbus,
Ohio 43210.
Received February 22, 1978; revision accepted May 5, 1978.
A single crossover design was utilized. The sequence
of study for each patient consisted of a 24-hour
baseline period (control data for drug I), a 24-hour
drug I infusion period (dose-response and
maintenance dose infusion parts), a four-hour drug I
discontinuation phase, a 24-hour re-equilibration
period (control data for drug II), a 24-hour drug II infusion period (dose-response and maintenance dose in466
DOPAMINE AND DOBUTAMINE/Leier et al.
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fusion parts) and a four-hour drug II discontinuation
phase. Odd-numbered patients received dobutamine
as drug I and dopamine as drug II, and evennumbered patients received dopamine as drug I and
dobutamine as drug II. The infusions were administered into a peripheral vein by a calibrated Harvard pump. The volume of infusion admixture (drug in
5% dextrose in water) was less than 275 ml/24 hours.
The dose range of the dose-response phase of the infusions was selected on the basis of the infusion doses
generally used clinically. Dopamine was started at 2
Ag/kg/min and was increased every 30 minutes in 2
,ug/kg/min dose increments until the maximal dose of
8 ug/kg/min was achieved. Dobutamine was started
at 2.5 ug/kg/min and was increased every 30 minutes
in 2.5 ,ug/kg/min dose increments up to a maximal
dose of 10 ,ug/kg/min. After the dose-response phase
of the infusion period, a maintenance dose was administered for the remainder of the 24-hour infusion
period. The maintenance dose for each patient was
determined on the basis of data derived from the doseresponse phase and had to meet the following criteria:
heart rate increase of <120% x control, systolic
blood pressure <120% X control, pulmonary
capillary wedge pressure <140% X control, and
premature ventricular contractions of < 12/min. The
dose was also lowered if intolerable symptoms
(vomiting, severe headache, etc.) developed. After 12
hours of the maintenance dose infusion, the dose was
re-evaluated for each patient, and was adjusted based
on the above criteria. The maintenance dose range for
dopamine was 2-6 gg/kg/min and for dobutamine
was 5-10 Ag/kg/min.
Before the study period, a triple-lumen thermodilution Swan-Ganz catheter was introduced percutaneously into the subclavian vein and placed in the
pulmonary artery for the measurement of pulmonary
artery pressure, pulmonary capillary wedge pressure
(PCWP, pulmonary arterial occlusive pressure) and
cardiac output (thermodilution technique21). The
pulmonary artery and capillary wedge pressures were
measured by Electronics for Medicine M2101
pressure amplifier units. Pulmonary capillary wedge
positioning was verified by the development of a
pulmonary capillary pressure wave form and a mean
pressure lower than the mean pulmonary artery
pressure upon inflation of the balloon. The cardiac
outputs were computed with an Instrumentation
Laboratory computer unit 601 and recorder unit 602.
Each cardiac output value represents the mean of at
least three measurements. Noninvasive assessment of
left ventricular (LV) function was made by performing
systolic time intervals and echocardiography. Systolic
time intervals were obtained with an Electronics for
Medicine VR6 unit using the specifications previously
outlined.22 The pre-ejection period/left ventricular
ejection time (PEP/LVET) was used as a measure of
LV performance. Echocardiograms were performed
with a Unirad series C echoscope and an Electronics
for Medicine VR6 recorder. The %AD and Vcf were
used as the echocardiographic determinants of LV
467
function and were derived from the formulae,
%AD
Vcf
=
EDD-ESD X
EDD
100
and
EDD-ESD 23, 24
EDD x LVET '
where EDD and ESD are end-diastolic and endsystolic diameters, respectively. The ECG was continuously monitored during the study. The mean heart
rate and frequency of premature ventricular contractions per minute (PVCs/min) were determined from
1-minute monitor recordings taken every 5 minutes
during the dose-response phase of each drug, and
every 30 minutes during the baseline and maintenance
dose periods of each drug. The systemic blood
pressure was measured indirectly with a calibrated
sphygmomanometer. The hemodynamic, noninvasive
and ECG data (i.e. pulmonary artery and capillary
wedge pressures, systemic blood pressure, cardiac output, PEP/LVET, %AD, Vcf, heart rate and
PVCs/min) were obtained 1 hour before drug infusion
(control data), after each dose increment of the doseresponse phase, every 12 hours of the maintenance
dose period and 30 minutes, 1, 2 and 4 hours after discontinuation of the study drug. The same data were
then obtained on drug II following the same schedule.
Regional hemodynamic studies were performed
during the baseline and maintenance dose periods of
each drug. Forearm and hand blood flow was
measured in six patients by the venous occlusive
method using a water-containing plethysmograph
(Szanati Engineering, Columbus, Ohio). The limb
blood flow is expressed as cc blood/100 cc tissue/min,
and each value for each patient represents a mean of
three determinations. Hepatic blood flow was determined in six patients by the indocyanin green
clearance method,25 26 and renal blood flow was
measured in seven patients by the PAH clearance
method.27 Twenty-four hour urine collections were obtained during the baseline and re-equilibration periods
and the two infusion (drug I and II) periods for the
determinations of urine flow (cc/min) and creatinine
clearance. Urine sodium concentration (meq/l) was
measured every 8 hours throughout the study.
The hemodynamic, noninvasive and ECG data were
compared to control values for each drug, with
analysis of variance of repeated measures. Analysis of
inter-drug and regional blood flow data and of
changes in urine flow, urine sodium concentration and
creatinine clearance was performed by using the t test
for paired and unpaired data. Data points with P
values <0.05 were considered significant.
Results
Hemodynamic and Noninvasive Data
The effects of dopamine and dobutamine on cardiac
index, stroke volume index and PCWP are presented
468
VOL 58, No 3, SEPTEMBER 1978
CI RCULATION
A. BASELINE 1
DOCE-ESPONSE
4.00 1
j MAINTENANCE I *t
SOONTINUATION
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FIGURE 1. Graphs showing the effects of dopamine and dobutamine on cardiac index (A), stroke volume
index (B), and the pulmonary capillary wedge pressure (C). dob = dobutamine; dop = dopamine.
in figure 1. The control cardiac index (2.45 1/min/m2)
was the same for both drugs. Dobutamine
progressively increased the cardiac index at all dose
increments. Dopamine required an infusion of 4
,ug/kg/min before the cardiac index rose significantly
above baseline. Increasing the dopamine infusion to
6-8 ,g/kg/min resulted in an insignificant further increase in the cardiac index. The cardiac index curve of
dopamine remained below the dobutamine curve
throughout the dose-response portion of the study,
and was significantly different at dopamine doses of 2,
6 and 8 ,ug/kg/min. The maintenance dose cardiac index values for dobutamine remained significantly
above baseline and significantly greater than
dopamine values. Only the 12-hour maintenance dose
(4 ug/kg/min) of dopamine was significantly increased above baseline. The values for each drug
returned toward baseline upon discontinuation with
DOPAMINE AND DOBUTAMINE/Leier et al.
A SASELINE-I -1401
SE -RESPONSE
MAINTENANCE
kx
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FIGURE 2. Blood pressure (A), total systemic resistance (B), and total pulmonary resistance (C) changes
elicited by dopamine and dobutamine. dob = dobutamine; dop = dopamine.
the 2 and 4-hour post-dopamine values dropping
significantly below control. The mean heart rate during the entire dobutamine infusion did not change
from control, so that the increase in cardiac output for
this drug was secondary to an increase in stroke
volume (fig. 1 B). Dopamine significantly increased
stroke volume only at the 4 ,ug/kg/min infusion of the
dose-response phase, indicating that the significant in-
of cardiac output at dopamine doses of 6 and 8
1ug/kg/min were in part secondary to increases in
heart rate. The mean PCWP (fig. I C) rose
dramatically with dopamine at doses .4,tg/kg/min,
while dobutamine significantly lowered the PCWP at
infusion rates .5 ,ug/kg/min. The PCWP returned
toward control for each drug during the maintenance
dose and discontinuation periods. Figure 2 illustrates
creases
470
470
58, No 3, SEPTEMBER 1978
~~~~~~~~~~~VOL
CIRCULATION
CIRCULATION
A. BASELmNE
~IMAINTENAWCE
WM---o-RESPONSE
ICVSCONTW4UATION4it SEM
*P-c 0.05 (bmuibn.)
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12
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TIME (houar)
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0
26
0
0
26
FIGURE 3. Aliterations of the heart rate (A) and the frequency of premature ventricular contractions/mmn
(B) noted with the dopamine and dobutamine infusions. dob =dobutamine; dop =dopamine.
the changes in systemic blood pressure and total
systemic and pulmonary resistances during the infusions. Dopamine significantly increased the systolic
blood pressure at .4 jtg/kg/min and the diastolic
pressure at 8 aig/kg/min. Dobutamine did not alter
dilastolic pressure, but significantly increased systolic
pressure at 10 Atg/kg/min and during the maintenance
period. Post-dobutamine and dopamine pressures
returned toward baseline values with 1- and 2-hour
post-dopamine diastolic pressures falling below control. Total systemic resistance dropped significantly at
all dose increments of dobutamine, and remained at
this level during the maintenance dose period. The
total systemic resistance during the dopamine infusion
did not differ from control, but was significantly
higher than dobutamine values at 8 jtg/kg/min and
during the maintenance period. Total pulmonary
resistance decreased at dobutamine infusion rates
>7.5 gg/kg/min. WVhile dopamine did not increase
total pulmonary resistance above control, the 8
1ug/kg/min, maintenance dose, and the 1- and 4-hour
discontinuation values were significantly higher than
corresponding dobutamine values.
Dopamine at 8 Atg/kg/min significantly increased
the mean heart rate above control and above the 10
Aig/kg/min dobutamine values (fig. 3A). No heart rate
changes were noted with dobutamine. Dopamine at
>4 ~ug/kg/min significantly increased the number of
PVCs/min above control and above the number noted
during the dobutamine infusion (fig. 3B). During the
respective maintenance dopamine and dobutamine
doses of 3.7 and 7.7 A~g/kg/min, the mean number of
PVCs/min were the same. However, because of the
wider range of PVCs/min for dobutamine at this
point, the mean value was significantly increased for
dopamine only.
The noninvasive LV function data is presented in
figure 4. The PEP/LVET decreased significantly at all
dose levels of dobutamine, and was significantly lower
than most of the corresponding dopamine points during the entire infusion period. The ratio decreased at
>4 Atg/kg/min of dopamine and rose above baseline 1
and 2 hours after the drug was discontinued. The %AD
and Vcf rose significantly at all infusion rates of
dobutamine and remained above baseline after the
drug was discontinued. Dopamine at .4 vtg/kg/min
increased the %zAD and Vcf, but the values- remained
significantly lower than the corresponding dobutamine
values during most of the infusion period.
Renal Function and Regional Blood Flow Data
Urine flow, urine sodium concentration and
creatinine clearance increased significantly during the
maintenance dose infusion of dobutamine (fig. 5).
While the mean values also increased with
maintenance dose dopamine, the wide range of individual responses kept the data at P > 0.05. Mean
renal blood flow did not increase significantly during
maintenance dose infusions of either drug in the seven
DOPAMINE AND DOBUTAMINE/Leier et al.
A
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FIGURE 4. Systolic time intervals and echocardiographic data showing the effects of dopamine and
dobutamine on the left ventricular function parameters of PEP/L VET (A), %AD (B), and Vcf (C). See text
for discussion and abbreviations.
patients tested. Of the renal function parameters
studied, only the mean change in creatinine clearance
for dobutamine was significantly greater than that for
dopamine. Mean hepatic blood flow did not change
significantly from control (fig. 6A) for either drug, and
the mean values of the two drugs were not significantly
different from each other. Mean upper extremity
blood flow (fig. 6B) increased with dobutamine and
did not change significantly with dopamine. The
change in upper extremity blood flow elicited by
dobutamine was significantly greater than that of
dopamine.
Clinical Information
Five of seven patients with severe dyspnea at rest
noted a reduction of this symptom with the
maintenance dose of either dobutamine or dopamine.
Orthopnea improved in one of eight patients during
maintenance dopamine and four of eight patients with
dobutamine. Significant somnolence developed in four
patients during the dopamine infusion and in one
patient with dobutamine. One patient experienced
mild nausea with dobutamine. Another patient noted
mild nausea and two other patients developed severe
VOL 58, No 3, SEPTEMBER 1978
CIRCULATION
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FIGURE 5. Graphs showing the changes in urine flow (A), urine sodium concentration (B), creatinine
clearance (C), and renal bloodflow (D) elicited by the maintenance doses ofdobutamine and dopamine. The
values are mean ± SD and statistical analysis (t test for paired data) was applied to changes from baseline.
n = number of patients studied, NS = not significant.
nausea and vomiting with dopamine. Dobutamine
caused a headache in one patient; dopamine produced
the same reaction in another.
Discussion
While Loeb and colleagues'9 and Stoner et al.20
found that the hemodynamic effects of dobutamine
were superior to dopamine at one matched cardiac
output or at one dose, this study demonstrates the advantages of dobutamine over dopamine over the entire
dose-response curve, during the continuous
maintenance dose infusion period, and upon discontinuation of the drugs. Data derived from the doseresponse phase of each drug of this study are shown in
figure 7. The graphs in this figure illustrate for each
agent the relationship between cardiac index (as a
standard of improved cardiac function) and the other
cardiovascular parameters known to be affected by inotropic agents, namely, heart rate, ventricular
irritability (PVCs/min), systemic and pulmonary
resistances, PCWP and myocardial oxygen consumption (estimated by the heart rate-systolic blood
pressure product). Dobutamine in doses up to 10
,g/kg/min progressively increases cardiac output
while decreasing systemic and pulmonary resistances
FIGURE 6. Panel A shows that maintenance dose
dobutamine and dopamine did not significantly alter hepatic
blood flow, while panel B shows improvement oflimb blood
flow with maintenance dose dobutamine and no significant
change with dopamine. n = number of patients studied,
NS = not significant.
and PCWP, and without affecting heart rate or ventricular irritability. Dopamine at doses .4 ,ug/kg/min
increases the PCWP and the number of PVCs/min,
and at doses >6 ,ug/kg/min increases heart rate and
systemic and pulmonary resistances. Undesirable
effects occur with dopamine at doses as low as 4
,ug/kg/min and, infusion rates <4 ,tg/kg/min do not
appear to improve cardiac output or ventricular performance (PEP/LVET, %AD or Vcf) above baseline.
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FIGURE 7. Graphs generated from the dose-response data of dopamine and dobutamine showing the relationship between
cardiac index and other cardiovascular parameters for each drug. The doses in ,g/kg/min are indicated next to the data points.
Dopamine values are designated by closed dots (.) and dobutamine by open triangles (A).
474
ClIRCULATION
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Dopamine doses of >4 ,g/kg/min increase the undesirable effects with very little further improvement
of cardiac output. While the heart rate-systolic blood
pressure product (HR X SBP) increases with both
agents, the increase with dopamine is more dramatic
than with dobutamine. The HR X SBP product for
dopamine at 4 ug/kg/min was the same as that for
dobutamine at 10 ,ug/kg/min, while their respective
cardiac outputs increased by 0.60 and 1.13 1/min/m2.
Thus, compared with dopamine, the increase in cardiac output with dobutamine is nearly twice as great
with the same energy expenditure, with no increase in
PVCs/min and with a decrease in LV filling pressure
and systemic and pulmonary resistances.
Although this study was performed in patients
without coronary artery disease, it appears that
dobutamine should be the catecholamine of choice in
patients with the combination of low output failure
and atherosclerotic heart disease. Gillespie and
colleagues28 administered dobutamine to patients with
acute myocardial infarction and found that the drug
improved hemodynamic parameters without provoking undesirable effects, and without increasing the extent of myocardial injury. However, because Meyer et
al.29 noted that dobutamine elicited inhomogeneous
myocardial perfusion in two of three patients with
triple-vessel coronary artery disease, this drug should
be administered with caution in the setting of severe
coronary artery disease.
The inability of dopamine to further improve stroke
volume (and cardiac output) at doses >4 ,tg/kg/min
in these patients was probably related to the increase
in systolic pressure (t afterload) and the increase in
cumulative heart rate (sinus beats plus PVCs/min) in
a failing ventricle. While Beregovich and colleagues30
reported that the mean cardiac output increased (five
patients) as the dopamine dose was increased from
5-10 ,Ag/kg/min, the mean stroke volume did not increase, indicating that the improvement in cardiac
output was secondary to an increase in the mean heart
rate. They noted that the cardiac output decreased in
two of the patients. The elevation of the PCWP with
dopamine in our patients was also probably related to
an increase in afterload and cumulative heart rate in a
severely impaired ventricle, although one cannot exclude the possibility that dopamine may increase LV
filling pressure independently of the above factors by
diminishing ventricular compliance.
In accordance with the clinical guidelines for inotropic dose selection (e.g., heart rate and blood
pressure), the maximal mean maintenance infusion
doses for dopamine were 4 and 3.7 ,ug/kg/min, and
for dobutamine 7.3 and 7.7 Atg/kg/min. Dopamine
maintained an improved cardiac output and
PEP/LVET only with the 4 ,Ag/kg/min infusion at 12
hours. The number of PVCs/min was still higher than
baseline for both the 4 and 3.7 ,g/kg/min
maintenance dose dopamine infusions. At these doses,
dopamine did not improve renal, hepatic or peripheral
blood flow, creatinine clearance, urine flow or renal
sodium excretion. At maintenance doses, dobutamine
maintained an improved cardiac index, stroke volume,
VOL 58, No 3, SEPTEMBER 1978
PEP/LVET, %AD, and Vcf, while decreasing
pulmonary and systemic resistances and without increasing the number of PVCs/min. Maintenance
doses of dobutamine significantly increased peripheral
blood flow, urine flow, renal sodium excretion and
creatinine clearance. At maintenance doses,
dobutamine also did not significantly alter renal or
hepatic blood flow. The HR X SBP product of
maintenance dose dopamine and dobutamine were not
significantly different.
Beregovich and colleagues30 noted an increase in
urine flow and renal sodium excretion in patients
with heart failure only at dopamine doses of >5
,ug/kg/min. This suggests that in the low cardiac output heart failure population the beneficial renal
properties of dopamine are dose-related (i.e. >5
,ug/kg/min). Using the criteria generally used to
determine the maintenance dose of an inotropic agent,
the maximal safe and tolerable maintenance dose of
dopamine in our patients was 4 ,ug/kg/min. Increasing the infusion rate elicited undesirable side
effects and, in fact, the mean maintenance dose of
dopamine had to be reduced to 3.7 ,ug/kg/min when
PVCs, vomiting and somnolence occurred in some of
the patients. The beneficial renal effects of dopamine
at >5 ,Ag/kg/min30 thus appear to be of little use in
these patients if this dose range cannot be safely
achieved or is not tolerated.
Because a previous study from this laboratory'8
showed that cardiac performance remained improved
after a 72-hour dobutamine infusion (10-15
pug/kg/min) and because studies31 32 have suggested
that dopamine may, in part, act through the release of
endogenous norepinephrine, measurements were performed over a 4-hour period after discontinuing each
drug. While none of the parameters deteriorated
below control when dobutamine was discontinued,
only Vcf and %AD remnained significantly above control, suggesting that a 24-hour infusion at 7.3 and 7.7
,g/kg/min will not result in improved hemodynamic
function in this patient population upon discontinuation of the drug. After discontinuation of dopamine,
the cardiac index fell (P < 0.05 at 2 and 4
hours), the stroke volume decreased (P < 0.05 at 30
minutes), the systemic diastolic pressure fell below
baseline at 1 and 2 hours and the PEP/LVET increased significantly at 1 and 2 hours. The mechanism of the transient cardio-circulatory deterioration
after dopamine is discontinued is not clear; however,
myocardial and peripheral vascular norepinephrine
depletion could be a factor.
The superiority of dobutamine over dopamine in
low output congestive cardiomyopathy is apparent in
the dose-response phase, the maintenance dose period
and the discontinuation phase of administration. If an
inotrope is to improve cardiac performance without
provoking deleterious or intolerable side effects, then
dobutamine appears to be the best inotrope available.
The next step in the advancement of pharmacology for
heart failure should be the development of a safe,
effective inotropic agent which can be administered
orally.
DOPAMINE AND DOBUTAMINE/Leier et al.
Acknowledgments
The authors wish to thank Ms. Barbara Metzner and Mr. Fred
Davis for their technical assistance.
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C V Leier, P T Heban, P Huss, C A Bush and R P Lewis
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Circulation. 1978;58:466-475
doi: 10.1161/01.CIR.58.3.466
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