Download in Congestive Heart Failure

Combined Dopamine and Nitroprusside Therapy
in Congestive Heart Failure
Greater Augmentation of Cardiac Performance
by Addition of Inotropic Stimulation to Afterload Reduction
RICHARD R. MILLER, M.D., NAJAM A. AWAN, M.D., JAMES A. JOYE, M.D.,
KEVIN S. MAXWELL, B.S., ANTHONY N. DEMARIA, M.D., EZRA A. AMSTERDAM, M.D.,
AND DEAN T. MASON, M.D.
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SUMMARY The hemodynamic benefits of combining administration of dopamine with nitroprusside (NP) were evaluated in nine
patients with chronic congestive heart failure due to ischemic, idiopathic myocardial or valvular cardiac disease. NP alone (68 ,g/min)
produced decline in left ventricular end-diastolic pressure (LVEDP)
from 25.4 to 14.1 mm Hg (P < 0.01) but modest increase in cardiac
index (CI) from 2.41 to 3.02 L/min/m2 (P < 0.05). Dopamine alone
(6 ,g/kg/min) caused an elevation of CI to 3.36 (P < 0.01) but
without decrease of LVEDP. Simultaneous infusion of the two
agents resulted in favorable alterations in both hemodynamic
variables: LVEDP decreased to 15.7 (P < 0.01) and CI increased to
3.52 (P < 0.01).
It is concluded that dopamine substantially enhances the effectiveness of nitroprusside therapy in congestive heart failure by providing
concomitantly the principal beneficial actions of the vasodilator and
dopamine used separately. Thus combined dopamine with NP treatment considerably raises low CI while markedly reducing elevated
LVEDP and provides a potentially efficacious pharmacologic
modality for the treatment of severe congestive heart failure due to
left ventricular dysfunction.
ALTHOUGH IT IS WELL ESTABLISHED that in
patients with congestive heart failure cardiac performance
may be substantially enhanced either by positive inotropic
agents1`7 or by afterload reducing drugs,8'12 it is unknown if
more benefit might be derived from the simultaneous utilization of both of these therapeutic approaches. The afterload
reducing agent nitroprusside has been confined to heart
failure patients without hypotension; the possibility remains,
however, that the vasodilator drug might be employed
beneficially even in cardiac dysfunction with lowered blood
pressure by adding dopamine. In the present study it was
considered that the positive inotropic agent, dopamine, infused concomitantly with nitroprusside, which reduces afterload, could enhance pump function to a degree unattainable
with either agent alone. Accordingly this investigation was
carried out in congestive heart failure patients to determine
the comparative individual and combined actions of
dopamine and nitroprusside on indexes of cardiocirculatory
function.
ischemic heart disease in five patients, idiopathic congestive
cardiomyopathy in three and primary mitral valvular
regurgitation in one. All. patients had elevated resting left
ventricular end-diastolic pressures .18 mm Hg and seven
had reduced cardiac indexes <2.50 L/min/m2. Digitalis administration was discontinued 72 hours prior to catheterization in each case; because digoxin was the glycoside
employed in each instance, it would be expected that most of
the patients had subtherapeutic serum digoxin levels at the
time of the investigation. All patients were studied in the
basal state after an overnight fast and precatheterization
medication consisted of intravenous diazepam, 5 mg. Informed consent was obtained from each patient.
All patients underwent complete right and left heart
catheterization, left ventricular angiography in which 40 to
50 ml Hypaque was employed, and selective coronary
arteriography. Left ventriculography was performed prior to
coronary arteriography. Each patient had ventricular
pressures measured serially for five minutes following
angiography and a 10 minute period elapsed subsequent to
coronary arteriography. Thus, the interval between administration of the bolus of contrast material and acquisition of control cardiocirculatory variables for the drug
protocol was at least 25 minutes in each patient. A previous
study indicates that left ventricular function and intravascular volume returned to a steady state within this time
period."3
After obtaining control indexes nitroprusside was infused
at a mean rate of 68 ,ug/min (40 to 100 ,ug/min) to lower
systemic arterial systolic pressure to between 110 and 120
mm Hg and/or left ventricular end-diastolic pressure to
between 10 and 15 mm Hg. When the desired pressures were
attained, the nitroprusside infusion was maintained constant
for 10 minutes and hemodynamic variables were
remeasured. With the nitroprusside infusion continuing at
the same rate, dopamine, 5-7 Ag/kg/min (total dose
300-500 ,ug/min) was begun and the two agents were infused
concomitantly for 10 minutes and all measurements were
Materials and Methods
The study population was comprised of nine patients,
mean age 53 years (41-68 years), with chronic clinical congestive heart failure, New York Heart Association functional class III, requiring the outpatient administration of
digitalis glycosides and diuretics. All nine patients underwent elective diagnostic left and right heart catheterization,
left ventricular cineangiography and selective coronary
arteriography. The etiology of cardiac dysfunction was
From the Section of Cardiovascular Medicine, Departments of Medicine
and Physiology, University of California, School of Medicine, Davis and
Sacramento, California.
Supported in part by Research Program Project Grant HL-14780 from the
NHLI, and California Chapters of the American Heart Association.
Address for reprints: Richard R. Miller, M.D., Section of Cardiovascular
Medicine, University of California, School of Medicine, Davis, California
95616.
Received November 1, 1976; revision accepted January 31, 1977.
881
882
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-
repeated. Nitroprusside was then terminated while the
dopamine infusion was continued at a constant rate for an
additional 20 minutes; the hemodynamic indexes were again
determined during the final 5 minutes of dopamine administration. The sequence of infusion of nitroprusside and
dopamine was reversed in four patients.
Because the period of combined drug administration in
the present study was limited to 10 minutes after attaining a
steady rate, this investigation does not afford evaluation of
the effects of prolonged infusion of dopamine and nitroprusside including the potential deleterious effects of extended inotropic stimulation on ischemic myocardium.
Duplicate measurements of cardiac output (CO) were
made by the dye dilution and thermodilution techniques with
the same method utilized in each patient. Calculations
utilized to quantify cardiocirculatory variables included:
total systemic vascular resistance [TSVR = 80 (P-RIA)/
CO], where 80 is the conversion factor from mm Hg to
dynes sec cm-5, P = mean systemic arterial pressure, RA =
mean right atrial pressure; pressure-time per minute (PTM)
in mm Hg sec per min = P X ET X HR, where ET = left
ventricular ejection time and HR = heart rate; and stroke
work index (SWI) in g-m/m2 = [(P-LVEDP) X SI X
I
95
EL
85
-
75
85
E
Q.
80
.0
cr
3
E
E
a-
75
70
25
20
15
w
3
10
3.50
C 3.00
g-
E 2.50
v>
VOL 55, No 6, JUNE 1977
CI RCULATION
~~~~~~~III
A
(pc.OI)
(p>.05)
(p>.05)
cI
(p.OI)
(p'.OI)
(p<.05)
2.00 -
Results
Mean systemic arterial pressure (fig. IA) was lowered by
NP from 89.9 ± 4.4 to 77.7 ± 1.6 mm Hg (P < 0.01); P was
unchanged from control (C)- by dopamine. With
simultaneous NP and dopamine infusion P was reduced to
83.1 ± 3.6 mm Hg (P < 0.05 vs C; P < 0.05 vs dopamine
alone). The mean heart rate of 74.8 beats/min was not
changed significantly by NP (fig. 1 B), dopamine or by combination of the two agents. Left ventricular end-diastolic
pressure was lowered in each patient by NP; the mean control LVEDP fell from 25.4 ± 4.2 mm Hg to 14.1 ± 2.7
(P < 0.01) (fig. IC). LVEDP was unchanged from C by
dopamine; and significantly reduced from C and dopamine
alone by the combined infusion of NP with dopamine to
15.7 ± 2.8 mm Hg (P < 0.01 vs C; P < 0.01 vs dopamine).
Cardiac index was augmented by both agents administered
individually from C of 2.41 + .10 L/min/m2: NP to
3.02 ± .22 (P < 0.05 vs C); dopamine to 3.36 ± .33
(P < 0.01 vs C; P < 0.05 vs NP). Concomitant infusion of
NP and dopamine effected an even greater increase in cardiac index to 3.52 ± .34 L/min/m2 (P < 0.01 vs C;
P < 0.05 vs NP) (fig. ID).
Each drug individually lowered TSVR from C of
1608 ± 105 dynes sec cm-5' NP to 1154 ± 78 (P < 0.05 vs
C); dopamine to 1294 ± 91 (P < 0.05 vs C); and the combination of both agents lowered TSVR to 1072 ± 115
(P < 0.01 vs C) (fig. 2A). Pressure time per minute declined
during NP infusion from C of 2166 ± 154 to 1875 ± 108
(p'..05)
(p<.OI)
(p>.05)
_
13.6]/1000 where SI = stroke index. Statistical analyses
were carried out by analysis of variance.
(p<.OI)
(p>.05)
(pC.05)
I
I
I
C
NP
Dopamine
to
2000
E
A
0
10
2500
C:
>
00
>
1000
Ln
(p> 05)
(p >.05)
kp(P<.05)
(p<05)
(p<.05)
B
C
.E
(p<.05)
2500
C-)
Tr
2000
E
E
E
4
I-
aC
C;i-
T
45
40
35
3
30
4
NP
FIGURE 1. Effect of NP, dopamine and the combination of NP
with dopamine on A) mean systemic arterial pressure (P), B) heart
rate (HR), C) left ventricular end-diastolic pressure (LVEDP) and
D) cardiac index (CI). C - control. Points are mean ± SEM.
(p >.05)
(p>.05)
(p>.05)
l
Dopomine
C
NP
Dopamine
I
Dopamine
NP
FIGURE 2. Effect of NP, dopamine and the combination of NP
with dopamine on A) total systemic vascular resistance (TSVR), B)
pressure time per minute (PTM). and C) stroke work index (SWI).
COMBINED DOPAMINE AND NITROPRUSSIDE/Miller et al.
mm Hg sec/min (P < 0.05); this variable was unchanged by
dopamine, but lowered by the combined NP and dopamine
infusion to 1906 + 115 (P < 0.05 vs C; P > 0.05 vs NP;
P < 0.05 vs dopamine) (fig. 2B). Neither NP nor dopamine
significantly altered SWI from C of 30.6 ± 4.11 g-m/m'
(fig. 2C). However the combination of the two drugs
augmented this index to 40.6 ± 3.24 (P < 0.05 vs C).
Figure 3 depicts the individual and combined actions of
NP and dopamine on the relationship between cardiac index
and LVEDP: NP alone effected marked leftward but modest
upward shifts in ventricular function, whereas dopamine
greatly augmented cardiac index without significant change
in filling pressure. In contrast, simultaneous infusion of the
two agents achieved the same reduction in left ventricular
end-diastolic pressure as NP alone, while reaching the same
increase in cardiac index as with dopamine alone.
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Discussion
To accomplish the principal objective in the treatment of
cardiac pump dysfunction - facilitation of ventricular emptying - two divergent therapeutic modalities have been
successfully applied in clinical congestive heart failure. The
traditional approach has consisted of increasing the force
and velocity of myocardial contraction with inotropic
stimulating agents.' More recently afterload reducing
drugs have been utilized to enhance cardiac output through
lowering of impedance to left ventricular ejection and thereby improving pump function secondarily.8-12 While each of
these two methods is beneficial in certain clinical circumstances, they also possess disadvantages which limit
their usefulness in other specific settings.11 14-16
Nitroprusside, which is efficacious in congestive heart
failure accompanied by elevated, normal or minimally
reduced systemic arterial pressure, is contraindicated as the
sole drug in the treatment of cardiac dysfunction with hypotension and shock. Dopamine, due to its powerful positive
inotropic properties and differential regional vasodilator and
vasoconstrictor actions17-18 is the preferred agent at present
in most hypotensive conditions of cardiac etiology. However, the usefulness of dopamine is limited in severe
2
N.
-
3.50
I-
883
pulmonary edema due to its failure to uniformly lower left
ventricular filling pressure" (fig. IC). Therefore, pulmonary
venous congestion may not be relieved and left ventricular
end-diastolic volume and wall tension, the most important
determinants of myocardial oxygen consumption, are not
reduced during the concomitant increase in contractile state.
Accordingly substantial augmentation of myocardial oxygen demand may result. The failure of dopamine to predictably lower left ventricular preload simultaneous with increase of ejection fraction and modest decline of systemic
vascular resistance (fig. 2A) appears to result from the
agent's constrictor action on the capacitance bed which
promotes venous return thereby maintaining ventricular filling pressure."
From the present investigation it was shown that the concomitant administration of dopamine with nitroprusside to
patients with congestive heart failure affords maximum
benefit from the principal salutary actions of each agent and
thereby provides hemodynamic improvement unattainable
with either agent alone (fig. 3). Moreover the combined infusion of NP and dopamine obviates the major potential disadvantages of the individually administered drugs and
thereby broadens the spectrum of clinical conditions in
which NP and dopamine may be successfully applied.
The principal advantage afforded by NP added to
dopamine compared to dopamine administered singly is
related to reduction in left ventricular preload. Thus,
although cardiac output is not appreciably augmented by the
addition of NP to the positive inotropic agent, the
dopamine-related increase in stroke output is achieved at a
much lower left ventricular end-diastolic pressure when
nitroprusside is concomitantly infused, so that there are both
marked upward and leftward shifts in this relation (fig. 3).
Additionally, the increase in myocardial oxygen needs
related to dopamine-induced augmented contractile state
may be partially offset by the decline in left ventricular
preload and hence may improve cardiac efficiency compared
to dopamine administered singly.
Dopamine added to nitroprusside provides two major
hemodynamic advantages compared to NP alone. First, cardiac output is augmented to a greater extent by the
N P+ Dopa mine
Dopamine
.E_
.
NP '-
3.00
x
FIGURE 3. Effect of NP, dopamine and the combination of NP with dopamine on left ventricular enddiastolic pressure and cardiac index.
z
Z 2.50
H
:-)
< 2.00
C)
I
ff-
0
I
I
10
20
LVEDP (mm Hg)
30
884
CI RCULATION
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simultaneous administration of the two agents versus NP
separately. Furthermore, it is anticipated that the excessive
preload-dependent decline in cardiac output observed in certain patients given NP alone11 12 would be abolished by
dopamine. Secondly, maintenance of systemic arterial
pressure by dopamine allows the potential extension of
nitruprusside therapy to patients with pump failure complicated by mild or moderate hypotension.
In conclusion, despite continued major efforts to formulate an ideal cardiotonic agent for the therapy of left ventricular failure, at the present time such a drug is lacking.
The combined use of dopamine and nitroprusside, however,
affords the important beneficial actions of each agent while
offsetting its principal disadvantages, thereby allowing extension of the use of the drugs to clinical conditions impractical with either agent alone. Thus simultaneous infusion of
dopamine and nitroprusside appears to provide an
efficacious and rational pharmacologic modality for the
treatment of severe chronic congestive heart failure resulting
from left ventricular dysfunction due to a variety of causes,
and uniquely well suited for application in patients with
ischemic heart disease and reduced systemic blood pressure.
References
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Combined dopamine and nitroprusside therapy in congestive heart failure. Greater
augmentation of cardiac performance by addition of inotropic stimulation to afterload
reduction.
R R Miller, N A Awan, J A Joye, K S Maxwell, A N DeMaria, E A Amsterdam and D T
Mason
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Circulation. 1977;55:881-884
doi: 10.1161/01.CIR.55.6.881
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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