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22.
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24.
25.
VOL 56, No 4, OCTOBER 1977
CIRCULATION
pathetic nervous system in the reflex control of heart rate. Circ Res 16:
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Scher AM, Ohm WW, Bumgarner K, Boynton R, Young AC: Sympathetic and parasympathetic control of heart rate in the dog, baboon and
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Mancia G, Donald DE: Demonstration that the atria, ventricles, and
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in the dog. Circ Res 36: 310, 1975
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Johnson JM, Rowell LB, Niederberger M, Eisman MM: Human
splanchnic and forearm vasoconstrictor responses to reductions of right
atrial and aortic pressures. Circ Res 34: 515, 1974
26. Zoller RP, Mark AL, Abboud FM, Schmid PG, Heistad DD: Role of
low pressure baroreceptors in reflex vasoconstrictor responses in man. J
Clin Invest 51: 2967, 1972
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denervation. Ann Surg 111: 102, 1940
29. Cowley AW, Liard JF, Guyton AC: Role of the baroreceptor reflex in
daily control of arterial blood pressure and other variables in the dog.
Circ Res 32: 564, 1973
30. Guyton AC, Coleman TG, Cowley AW, Scheel KW, Manning RD Jr,
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the kidneys in long-term regulation and in hypertension. Am J Med 52:
584, 1972
Comparative Hemodynamic Effects of Inotropic
and Vasodilator Drugs in Severe Heart Failure
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ESTEBAN MIKULIC, M.D., JAY N. COHN, M.D.,
AND
JOSEPH A. FRANCIOSA, M.D.
SUMMARY In 12 patients with severe congestive heart failure
(CHF) due to ischemic heart disease or nonischemic cardiomyopathy the hemodynamic response to intravenous infusion of
sodium nitroprusside (N) was compared to that of dobutamine (D)
10 jg/kg/min. D and N produced comparable increases in cardiac
output (CO) (2.8 to 5.8 L/min and 2.9 to 5.0 L/min, respectively),
but, compared to N, D caused a higher arterial pressure (99.3 vs 86.2
mm Hg, P < 0.01) and heart rate (102.5 vs 95.3, P < 0.05) and less
reduction in pulmonary wedge pressure (PWP) (28.9 to 20.2 mm Hg
vs 29.1 to 16.6 mm Hg, P < 0.05). In five additional patients N and
D were studied separately and then were infused together. The com-
bination resulted in a higher CO, lower PWP and greater reduction
in systemic and pulmonary vascular resistances than either drug
alone. Brachial arterial infusion of nitroprusside produced prominent forearm vasodilation in a dose less than 10% of the systemic
dose, whereas vasodilation with dobutamine was only modest even
when 50% of the systemic dose was infused. Therefore, potent inotropic and vasodilator drugs produce similar and additive augmentation of left ventricular performance in heart failure. Reduction in
vascular resistance with dobutamine probably is largely of reflex
origin, but the vasodilation itself may be an important determinant
of the rise in cardiac output.
RECENT STUDIES from this and other laboratories have
revealed that infusion of a vasodilator drug can result in
significant improvement in left ventricular pump function in
patients with heart failure.' This functional improvement,
which is characterized by a reduction in left ventricular filling pressure, an increase in stroke volume and no change in
heart rate or in indices of left ventricular contractility, has
been attributed to a reduction in impedance to left ventricular outflow.8 9 The traditional means of improving left ventricular performance in the failing heart has been by administration of an inotropic drug. Since previously available
inotropic agents exerted considerable effect on the peripheral
circulation or heart rate, it has not been possible to evaluate
in the intact circulation the effects of a pure inotropic intervention. Furthermore, a direct comparison of the relative
effectiveness of vasodilator and inotropic therapy on the failing heart has not been reported previously.
The purpose of the present study was to compare in a
group of patients with severe congestive heart failure the
functional response of the left ventricle to infusion of sodium
nitroprusside, a potent vasodilator with no direct cardiac
effect,10'" and dobutamine, an inotropic agent that is
relatively devoid of peripheral vascular and chronotropic
From the Cardiovascular Division, University of Minnesota Medical
School and the Veterans Administration Hospital, Minneapolis, Minnesota.
Supported in part by USPHS Grant HL 18043 from the National Heart
and Lung Institute.
Dr. Mikulic's present address is Lamadrid 658, Villa Lynch, Buenos
Aires, Argentina.
Address for reprints: Jay N. Cohn, M.D., University of Minnesota
Hospital, Box 488, Minneapolis, Minnesota 55455.
Received February 11, 1977; revision accepted May 16, 1977.
effects.'2 '5
Materials and Methods
Studies were performed in 21 hospitalized patients with
class III or class IV congestive heart failure as defined by
the New York Heart Association. In eleven patients the
heart failure was thought to be on the basis of nonischemic
myocardial disease due in some cases to excessive alcohol ingestion and in others to unknown cause. The absence of
significant coronary artery disease was documented by
angiography in nine of these patients. The other ten patients
had severe ischemic heart disease with previous myocardial
infarctions or documented multiple vessel coronary artery
disease. All patients had had symptomatic heart failure for
at least six months and had been treated with digitalis and
diuretics without complete relief of symptoms. Digitalis
therapy was continued on a daily basis throughout the study
period, but diuretics were withheld on the day of study.
Patients gave informed, written consent for performance of
the studies.
INOTROPISM VS VASODILATION IN CHF/Mikulic, Cohn, Franciosa
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All studies were carried out without premedication and
with the patient supine or as nearly supine as was compatible
with comfortable breathing. In 17 patients a Swan-Ganz
balloon tipped catheter was inserted via the basilic or
femoral vein and advanced into the pulmonary artery so that
balloon inflation occluded the pulmonary artery and allowed
recording of pulmonary wedge pressure. In two patients the
catheter could not be advanced into the pulmonary artery
and in three other patients balloon occlusion of the
pulmonary artery could not be accomplished throughout the
entire study. The brachial artery or femoral artery was cannulated for pressure recording and blood sampling. All
pressures were recorded using Statham P23Db transducers
and a multiple channel Hewlett-Packard recorder. Cardiac
output was determined by the indicator dilution technique
with indocyanine green dye injected into the pulmonary
artery and sampled from the aorta or brachial artery.
After control measurements of pressures and cardiac output 12 patients received an intravenous infusion of sodium
nitroprusside (100 ,vg/ml) at a rate of 15 ,ug/min which was
increased at 3 min intervals until pulmonary arterial wedge
pressure was reduced by 40% or until systolic arterial
pressure fell to 95 mm Hg. The average infusion rate at the
time of stabilization was 83.9 ,ug/min. Pressures and flows
were remeasured at this time and the infusion of nitroprusside was discontinued. After a minimum of 30 minutes
during which pressures and outputs were allowed to return to
control levels, repeat control measurements were obtained
and an infusion of dobutamine was begun in gradually increasing doses until an infusion rate of 10 ,g/kg/min was
achieved. After this stable infusion rate had been maintained
for at least 15 minutes and the pressures were stable cardiac
outputs were again measured. This dose of dobutamine was
selected because in previous studies the response to
dobutamine was demonstrated to be dose-dependent and 10
Aig/kg/min produced a striking effect in all subjects.'8
In five additional patients nitroprusside and dobutamine
were studied as above but without measuring cardiac output
again during the recontrol period. Immediately after studies
were completed during dobutamine infusion the nitroprusside infusion was restarted at the previously established
dose and pressures and output were measured again when
hemodynamics had stabilized during infusion of both drugs.
In four other patients with heart failure forearm blood
flow was measured by venous occlusion plethysmography
utilizing a Whitney mercury-in-rubber resistance gauge
529
applied to the upper forearm and a matching Wheatstone
bridge."6 Changes in arm girth were recorded durlng 15
seconds of venous occlusion produced by an arm cuff filled
acutely from a reservoir whose pressure was maintained at
50 mm Hg. Sodium nitroprusside or dobutamine was then
infused directly into the brachial artery on that side using a
motor-driven Harvard infusion pump. The dose of the drugs
was progressively increased until forearm flow had increased
by at least 3-4 fold. Concentration of the infusate was adjusted so that at no time did infusion rate exceed 1.4 ml per
minute. The order of drug infusions was varied, and 30-60
minutes was allowed after completion of one drug infusion
before the other was instituted.
Cardiac output (CO) was calculated by semilog replot of
the indicator dilution curves. Systemic vascular resistance
(SVR) and pulmonary arteriolar vascular resistance (PVR)
were calculated by the standard formulae. Systolic ejection
time (ET) in milliseconds was measured from the beginning
of the upstroke to the dicrotic notch of the brachial arterial
pressure recorded at a paper speed of 100 mm/sec. Mean
systolic pressure was calculated by planimetry. Mean
systolic outflow resistance (MSOR) was calculated by the
formula (MSP X ET)/SV." Mean systolic ejection rate in
ml/sec was calculated as the stroke volume divided by ET in
seconds. Tension-time index was calculated from the formula: MSP X SV X ET. Forearm blood flow was
calculated from the slope of the change in forearm girth corrected for calibration of the gauge and for the initial forearm
girth."5
Results
Hemodynamic data in the 12 patients receiving nitroprusside and dobutamine sequentially are shown in table
and figure 1. During infusion of nitroprusside most patients
reported an improvement in their dyspnea and cessation of
their sweating if this had been present prior to infusion.
Some who were somnolent or confused appeared to become
more alert during the infusion. During infusion of dobutamine a similar clinical response was noted although several
patients complained of the sensation of palpitations, even
when little change in heart rate was noted.
Heart rate was unchanged during nitroprusside infusion,
but cardiac output rose significantly and there were significant reductions in arterial pressure, pulmonary arterial and
wedge pressure and systemic and pulmonary arteriolar
TABLE 1. Hemodynamic Effects of Nitropru.sside and Dobutamine in 12 Patients with Congestive Heart Failure
HR
Mean
SEM
Nitroprusside Mean
Control
97.3
*4.7
Mean
Dobutamine Mean
P
Diastolic
AP
126.1
81.8
*2.8
*5.1
95.3
*4.8
116.0
-3.9
*2.1
98.1
<0.001
126.0
<0.001
81.5
P
Recontrol
Systolic
AP
*4.6
*5.2
73.0
*2.7
_
AP
PA
95.1
39.9
*3.2
PCW
CO
29.1
2.9
*1.9
*2.6
86.2
*2.4
27.1
*1.3
*1.6
16.6
-0.3
5.0
<0.001
95.0
<0.001
39.2
<0.001
28.0
<0.001
2.8
*3.3
*2.5
*1.8
*0.4
*0.2
CI
1.6
*0.1
2.8
*0.3
<0.001
1.5
*0.1
SVR
PVR
2339
*173
1254
330
*62
189
A 99
<0.001
2388
<0.001
341
*179
*32
1350
*57
193
*32
<0.05
<0.02
<0.01 <0.001 <0.001
<0.001
=
=
=
heart rate (beats/min); AP arterial pressure (mm Hg); AP rmean arterial pressure (mm Hg); PA mean pulmonary artery
=
=
=
vascular
SVR =
102.5
*4.4
141.2
*6.1
82.2
*3.2
99.3
*3.9
34.1
*2.0
20.2
*2.0
Abbreviations: HR =
pressure (mm Hg); PCW pulmonary wedge pressure (mm Hg); CO cardiac output (L/min); CI
resistance (dynes-sec-cm-5); PVR = pulmonary vascular resistance (dynes-sec-cm-6).
5.8
*0.5
3.1
* 0.3
cardiac index (L/min/m2);
*125
<0.001
systemic
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VOL 56, No 4, OCTOBER 1977
CIRCULATION
Arterial Pressure
(mm Hg)
150
70
Cardiac Output
(L/min)
Heart Rate
(beats/min)
Sv
(ml)
100
50
SW
(g-m)
PWP
(mm Hg)
30
-
20
-
SVR
PVR
(dynes-sec-cm5) (dynes-sec-cm5)
2500 400
-
1500
-
500
10
250
-
100
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FIGURE 1. Relationship between pulmonary wedge pressure
(PWP) and stroke volume (SV) or stroke work (SW) during infusion of nitroprusside (N) and dobutamine (D). Both agents shifted
the left ventricular function curve similarly upward and to the left.
FIGURE 2. Comparison between hemodynamic effects of nitroprusside (N) and dobutamine (D). *indicates significant differences
(P < 0.05). Arterial pressure, heart rate and pulmonary wedge
pressure (PWP) were higher during dobutamine infusion, but
systemic vascular resistance (SVR ) and pulmonary vascular
resistance (PVR) were similarly reduced.
resistances. Pressure and output returned to pre-infusion
levels after nitroprusside was discontinued. During dobutamine infusion systolic arterial pressure and cardiac output
rose significantly while pulmonary arterial and wedge
pressures and systemic and pulmonary vascular resistances
fell. Heart rate increased insignificantly.
Since the recontrol measurements before the dobutamine
infusion were practically identical to the control observations
prior to nitroprusside infusion, it was possible to compare
directly the data during dobutamine infusion to that during
nitroprusside infusion (fig. 2). The hemodynamic pattern was
quite similar, with cardiac output and systemic and
pulmonary arteriolar resistances at similar levels. The main
differences were that heart rate was slightly higher during
dobutamine infusion whereas arterial, pulmonary arterial
and pulmonary wedge pressures were lower during nitroprusside infusion.
Left ventricular ejection dynamics differed during administration of the two drugs (fig. 3). Ejection time was
significantly prolonged during nitroprusside infusion
whereas it was not significantly altered from control values
during dobutamine infusion. Since stroke volume was
slightly higher during dobutamine infusion, the mean systolic
ejection rate was greater during dobutamine than during
nitroprusside, although both drugs significantly increased the
rate over control values. Although mean systolic pressure
was increased by dobutamine and reduced by nitroprusside,
both drug infusions resulted in similar decrements in mean
systolic outflow resistance.
Since systolic pressure and heart rate were higher during
dobutamine infusion than during nitroprusside, the heart
rate-blood pressure product was significantly higher, as was
the tension-time index.
When nitroprusside and dobutamine were infused in com-
PWP (mmHg)
Mean Systolic Outflow
Ejection Time
(m sec)
Resistance
Mean Systolic Pressure
(mm Hg)
150 r
120 F
(mm Hg sec/ml
-
1.0
T
,
Mean Systolic Ejection Rate
(ml/sec)
r
0.8 F
90F
0.6 F
60k
0.4 k
30 F
0.2
T*
,
-0
///,
I.::::: //"/
0
0
.....V,A
FIGURE 3. Left ventricular ejection dynamics in the control period (C) and during infusion of nitroprusside (N) and
dobutamine (D). *indicates significant difference (P < 0.05) from control and tindicates difference (P < 0.05) from
nitroprusside response.
INOTROPISM VS VASODILATION IN CHF/Mikulic, Cohn, Franciosa
531
TABLE 2. Hemodynamic Effects of Nitroprusside and Dobutamine Singly and Together in Five Patients with Heart Failure
HR
Control (C)
Mean
SEM
Nitroprusside (N) Mean
P (N vs C)
Dobutamine (D) Mean
P (D vs C)
P (D vs N)
Nitroprusside + Mean
Dobutamine (ND)
P (ND vs C)
(ND vs N)
(ND Vs D)
97.2
4.2
89.6
i6.0
<0.2
89.6
7.6
<0.4
>0.4
94.0
k4.0
<0.4
<0.4
>0.4
Systolic
AP
Diastolic
AP
AP
PA
PCW
116.2
13.8
105.2
10.6
<0.2
126.4
71.2
7.3
60.6
4.2
<0.2
65.0
83.8
9.1
73.4
5.6
<0.2
81.8
42.3
3.7
27.3
4.7
<0.01
13.6
<0.2
<0.01
3.1
<0.4
<0.05
111.2
8.2
>0.4
<0.2
<0.2
58.0
3.7
<0.2
<0.4
<0.05
6.7
>0.4
<0.05
72.2
4.3
32.8
5.5
<0.05
<0.2
25.0
3.3
12.5
2.6
<0.01
16.5
2.2
<0.05
<0.2
25.5
5.5
<0.01
<0.4
<0.05
10.5
2.8
<0.01
<0.01
<0.05
<0.2
>0.4
<0.05
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bination in five subjects, the hemodynamic effects were
greater than when the drugs were given in the same dose independently (table 2, fig. 4). The cardiac output was higher
during combination therapy, the mean arterial pressure was
lower than during dobutamine alone and the systemic
vascular resistance was consequently lower than during
either drug infusion given alone. The cardiac output rose less
in these five subjects during infusion of nitroprusside alone
and dobutamine alone than the average response to these
drugs in the other 12 patients. The apparently diminished
response to these drugs in this small subgroup of patients
appears to be a chance occurrence, since the drugs were administered identically.
Nitroprusside infused into the brachial artery produced
dose-dependent forearm vasodilation. The threshold for
vasodilation ranged from 0.6 to 4 ,ug/min, which represented
in these patients an average of 2.5% of the systemic dose
effective in improving left ventricular performance in these
individuals. The dose-response curve was sharp, flow increasing to more than three times resting flow with local infusion of 10% of the systemic dose. Intra-arterial
dobutamine also exerted a mild vasodilator effect but the
threshold was noted at a dose ranging from 15 to 100
AMg/min, which represented an average of 8.1% of the
systemic dose (10 ,g/kg/min) (fig. 5). The dose-response
curve to dobutamine was flat, flow increasing to only twice
C0
2.7
0.6
3.4
0.5
<0.05
4.1
0.5
<0.05
<0.4
5.5
0.5
<0.01
<0.01
<0.01
CI
1.5
0.4
1.9
0.3
<0.05
2.3
0.3
<0.05
<0.4
3.1
0.3
<0.01
<0.01
<0.05
SVR
PVR
2294.8
255.1
1565.0
103.3
<0.05
1509.8
243.2
516.5
200.6
379.5
<0.2
>0.4
958.4
74.3
<0.01
<0.05
<0.05
182.5
<0.01
274.7
81.6
<0.2
>0.4
199.5
76.8
<0.2
<0.4
<0.01
resting flow with local infusion of half the systemic dose (5
Atg/kg/min), a dose that has a prominent systemic effect.18
Discussion
Ventricular pump function usually is defined by the FrankStarling curve, which relates end-diastolic fiber length to
stroke volume, stroke work or cardiac output. In practice,
the filling pressure of the left ventricle is substituted for the
fiber length,18 even though compliance changes of the
chamber may alter the relationship between fiber length and
pressure. In the presence of left ventricular failure depressed
pump function may be improved by the administration of an
inotropic drug that increases the force of myocardial contraction and shifts the Frank-Starling relationship upward
and to the left resulting in a higher stroke volume or stroke
work for any given end-diastolic pressure or fiber length.1,
Such an improvement in pump function has been
demonstrated in the past during administration of digitalis,
norepinephrine, and other sympathomimetic amines.2 In
recent studies it has also been demonstrated that a
vasodilator drug, by reducing outflow resistance or impedance, also results in an improvement in pump function
N (4)
60r
D+N
50F
sv
40F
& FBF
NQ
D
(ml)
30 F
N
D(4)
20k
0.6
0
10
20
30
PWP (mmHg)
FIGURE 4. Mean changes in five patients of pulmonary wedge
pressure (PWP) and stroke volume (SV) during infusion of
nitroprusside (N) followed by dobutamine (D) and then the combination (D + N).
lntroorteriol/Systemic Dose
FIGURE 5. Effect of brachial arterial infusion of nitroprusside
(N) and dobutamine (D) on forearm blood flow in four patients
with heart failure. The percent change in forearm blood flow is
plotted in relationship to the intraarterial infusion rate of the drugs
expressed as a fraction of the intravenous dose needed to produce
systemic hemodynamic effects.
532
CIRCULATION
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characterized by a reduction in left ventricular filling
pressure and chamber size accompanied by an increase in
stroke volume and stroke work.'-8, 28 This response has been
achieved during administration of nitroprusside, phentolamine, nitroglycerin, trimethaphan and hydralazine.
The present study confirms that both an inotropic agent
and a vasodilator drug may significantly improve left ventricular pump function in patients with severe heart failure.
Indeed, the magnitude of the augmentation in left ventricular performance was similar with these two agents, which
probably are the most potent and selective vasodilator and
inotropic drugs available for clinical use. Extensive studies
have revealed that nitroprusside's action is limited to relaxation of smooth muscle and therefore its hemodynamic effect
must be attributed to dilation of arteries, arterioles or the
venous capacitance vessels.24 25 In contrast, dobutamine is
an agent that has quite selective actions on myocardial contractility.'1216 Although the drug has both alpha and beta
adrenergic stimulating properties, and therefore exerts an
effect on peripheral vessels, the balance of alpha and beta
stimulating properties in the periphery results in relatively
little direct peripheral vascular action; the effects of infusion
of the drug are then predominantly related to its action on
the myocardium. It is also interesting that dobutamine exerts
little effect on heart rate despite its prominent effect on myocardial contractility.'2 13
Despite the markedly divergent sites of action of these two
agents, the circulatory effects of these drugs in the patients
with congestive heart failure in the present series were
remarkably similar. Cardiac output increased to a similar
extent with both drugs, and pulmonary capillary wedge
pressure was reduced. Although infusion of dobutamine was
associated with a slight but significant rise in systolic
pressure whereas infusion of nitroprusside was associated
with a significant reduction in both systolic and diastolic
arterial pressure, the total systemic vascular resistance and
pulmonary vascular resistance were reduced similarly with
the two drugs. Neither nitroprusside nor dobutamine
significantly altered heart rate from control levels, but the
heart rate during dobutamine infusion was significantly
faster than during nitroprusside infusion, reflecting a slight
increase during dobutamine and a slight reduction during
nitroprusside. In addition wedge pressure, which was
reduced with both drugs, remained significantly higher during dobutamine infusion than during nitroprusside infusion.
Further evidence that these two agents are working
through independent mechanisms was obtained when the two
drugs were infused together. In all instances the combination
of nitroprusside with dobutamine resulted in a higher cardiac
output and usually a lower pulmonary wedge pressure than
when either drug was infused alone.
Whereas the mechanism of the reduction in vascular
resistance during infusion of nitroprusside can be attributed
simply to its direct vasodilator properties, the mechanism of
the vasodilator effect of dobutamine is less clear. One
possibility would be that in the setting of high vascular
resistance in patients with congestive heart failure the direct
action of dobutamine on beta adrenergic receptors would
predominate over its effect on alpha adrenergic receptors and
result in a reduction in vascular tone.
In an attempt to study this possibility, the drugs were in-
VOL 56, No 4, OCTOBER 1977
fused in progressively increasing doses into the brachial
artery of patients with heart failure while forearm blood flow
was measured. Nitroprusside infusion at doses averaging
2.5% of the systemic dose produced prominent vasodilation,
whereas dobutamine had only a modest dilator effect with a
threshold more than three times that of nitroprusside when
the intra-arterial dosage was related to the systemic dose. If
the forearm bed can be assumed to be representative of
peripheral vascular effects,"' these data make it unlikely that
the fall in systemic vascular resistance during dobutamine intravenous infusion is primarily related to a direct vasodilator
effect of the drug.
An alternate explanation for the vasodilator effect of
dobutamine is that its direct cardiac effect results in relaxation of heightened vascular tone, possibly in part by virtue of
baroreceptor stimulation of an increased rate of left ventricular ejection. Furthermore, since vasodilation alone
produces such a prominent increase in cardiac output in
patients with heart failure, it is attractive to postulate that
the increase in output observed with such inotropic drugs as
dobutamine, dopamine and isoproterenol may be due largely
to vasodilation rather than directly to inotropism.
Since the drugs produce similar improvement in left ventricular pump performance and their combined effects seem
to be additive, the selection of the appropriate therapy for a
given patient with severe heart failure should be based on
other differences between the agents. The rise in systolic
arterial pressure produced by dobutamine may be helpful in
clinical situations in which pretreatment pressure is critically
reduced. On the other hand, the higher arterial pressure and
slightly faster heart rate during dobutamine treatment as
compared to nitroprusside treatment is indicative of a higher
myocardial oxygen consumption that could be deleterious in
the presence of ischemic heart disease. When arterial
pressure falls to dangerously low levels during nitroprusside
therapy, the addition of dobutamine usually is effective in
supporting pressure and further augmenting the cardiac output. Since dobutamine has not yet been approved for
marketing, dopamine could be substituted clinically with the
likelihood that the systemic hemodynamic response would be
somewhat similar.
The regional distribution of the increased cardiac output
in response to nitroprusside and dobutamine has not been
studied. Data on their relative effects on renal and visceral
perfusion would probably provide further distinguishing
features that could be used in selecting the proper drug for
particular clinical situations.
Although our studies explored only the intravenous effects
of these agents, the results suggest that oral administration
of a combination of an inotropic and vasodilator drug might
be effective in managing patients who remain symptomatic
despite treatment with digitalis and diuretics. Orally effective
vasodilator regimens are already available,28-28 and new
orally effective inotropic drugs are being developed.29
References
I. Franciosa JA, Guiha NH, Limas CJ, Rodriguera E, Cohn JN: Improved left ventricular function during nitroprusside infusion in acute
myocardial infarction. Lancet 1: 650, 1972
2. Guiha NH, Cohn JN, Mikulic E, Franciosa JA, Limas CJ: Treatment
of refractory heart failure with infusion of nitroprusside. N EngI J Med
291: 587, 1974
HR AND PULMONARY DIASTOLIC PRESSURE GRADIENT/Enson et al.
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3. Cohn JN, Mathew KJ, Franciosa JA, Snow JA: Chronic vasodilator
therapy in the management of cardiogenic shock and intractable left
ventricular failure. Ann Intern Med 81: 777, 1974
4. Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2: 719, 1971
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The Influence of Heart Rate
on Pulmonary Arterial-Left Ventricular
Pressure Relationships at End-diastole
YALE ENSON, M.D., JOHN A. WOOD, M.D., NORDAL B. MANTARAS, B.S.,
AND RtJANE M. HARVEY, M.D.
SUMMARY Increased resistance to blood flow stemming from
structural and functional abnormalities of the lungs may cause pressure in the pulmonary artery to exceed that in the left ventricle at the
end of ventricular diastole. This study explores the possible contribution of heart rate to the diastolic pressure gradient observed in the
presence of acutely induced hypoxia. Pulmonary hemodynamics were
examined in mongrel dogs with chronic atrioventricular dissociation
with and without hypoxia at two different heart rates and during sequential increments in heart rate while the animals breathed room
air. Studies during sequential pacing indicate that heart rate was of
greater importance than blood flow in determining the magnitude of
the gradient. Heart rate has to be considered when the causes of
pulmonary hypertension and the effects of drugs or other agents on
the pulmonary circulation are being investigated.
AS A CONSEQUENCE of increased resistance to pulmonary blood flow, pulmonary arterial pressure exceeds
that in the left ventricle at the end of diastole in certain cardiopulmonary disorders. In some patients this diastolic pres-
sure gradient may be ascribed to external encroachment on
the bed by diffuse parenchymal disease or to obstruction of
the bed from within by thromboemboli or other pulmonary
vascular lesions. In other patients the vasoconstrictor effects
of alveolar hypoxia and acidemia contribute to the gradient.
In a previous consideration of factors regulating the gradient
in patients with chronic obstructive lung disease, 61% of the
observed variation in the gradient could be ascribed to abnormal gas exchange.' While heart rate also appeared to be
related to the level of the gradient, addition of this factor to
multiple regression analysis of the determinants of the
From the Department of Medicine, Columbia University College of
Physicians and Surgeons, New York, New York.
Supported in part by Grants HL 17813, HL 07018 and 5 K06 HL 16603
from the National Heart, Lung and Blood Institute.
Address for reprints: Yale Enson, M.D., Department of Medicine, College
of Physicians and Surgeons, Columbia University, 630 W. 168th Street, New
York, New York 10032.
Received March 31, 1977; revision accepted May 18, 1977.
Comparative hemodynamic effects of inotropic and vasodilator drugs in severe heart
failure.
E Mikulic, J N Cohn and J A Franciosa
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Circulation. 1977;56:528-533
doi: 10.1161/01.CIR.56.4.528
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