Download Significance of systemic vascular resistance in determining the

THERAPY AND PREVENTION
CONGENITAL HEART DISEASE
Significance of systemic vascular resistance in
determining the hemodynamic effects of hydralazine
on large ventricular septal defects
MAKOTO NAKAZAWA, M.D., ATSUYOSHI TAKAO, M.D., YONG CHON, M.D.,
TAKASHI SHIMIZU, M.D., MAYUMI KANAYA, M.D., AND KAzuo MOMMA, M.D.
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ABSTRACT The hemodynamic effects of hydralazine were studied in 17 infants and young children
with ventricular septal defects to clarify the significance of systemic vascular resistance (SVR) in
determining these effects. Patients with peak pulmonary arterial pressures greater than 75% of systemic
pressure were placed in group 1, which was further divided into group Ia (n = 6), consisting of those
with a control SVR of 20 U m2 or higher, and group lb (n = 8), consisting of those with a lower SVR.
Group II consisted of three patients with lower pulmonary arterial pressures. Intravenous injection of
hydralazine (0.3 mg/kg) reduced SVR in all but two patients. The magnitude of reduction correlated
with prehydralazine (control) SVR (r = .66, p < .01). Systemic blood flow (Qs) increased from 3.7
0.7 to 5.0 + 0.8 1/min/m2 (p < .005). The mean systemic arterial pressure for all patients decreased
from 69 + 2 to 65 2 mm Hg (p < .01) and the mean pulmonary arterial pressure decreased from the
control value by 9 4% (p < .01) in group I and by 17 + 1% in group II. Pulmonary blood flow (Qp)
did not change significantly in either group. The Qp/Qs ratio was reduced from 3.6 0.4 to 2.4 0.2
(p < .02) in group Ia. In sharp contrast, however, it increased from 2.6 + 0.3 to 3.3 0.5 (p = .06) in
group lb. The posthydralazine Qp/Qs ratio, expressed as percent of the control value, inversely
correlated with the control SVR (r = - .61, p = .02) in group I. The response was not different in the
group II patients. Thus, we conclude that control SVR is important for prediction of the hemodynamic
effects of afterload reduction by hydralazine in infants and young children with large ventricular septal
defects, and that this drug may be beneficial in patients with high control SVRs since a high SVR brings
about a decrease in the Qp/Qs ratio.
Circulation 68, No. 2, 420-424, 1983.
THE HEMODYNAMIC EFFECTS of vasodilating
drugs on ventricular septal defects (VSDs) have been
reported by several investigators," although the results are not conclusive. In previous studies a wide
variety of drugs with different sites of action were
used, which resulted in inconsistent results. In addition, there was a great variation in hemodynamic characteristics of study subjects at control, i.e., in the size
of their VSDs, in their systemic or pulmonary vascular
resistances (SVRs or PVRs), and in the responsiveness
of the vessels on which the drugs acted in the subjects.
The amount of shunt flow through a VSD is determined by the ratio of PVR to SVR in a large and
nonrestrictive VSD, or by the interrelationship between the size of the VSD and SVR in a restrictive
VSD.7 In either condition, the amount of shunt flow is
From the Department of Pediatric Cardiology, The Heart Institute of
Japan, Tokyo Women's Medical College, Tokyo.
Address for correspondence: Makoto Nakazawa, M.D., Department
of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's
Medical College, 10 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan.
Received Dec. 2, 1982; revision accepted April 25, 1983.
420
greatly affected by SVR.8 Since SVR is a major factor
determining afterload to the left ventricle, it can be
hypothesized that the effect of afterload reduction on
the amount of interventricular shunting is dependent
on the control SVR and on responsiveness of the systemic vascular beds. To test this hypothesis, we studied 17 infants and young children with VSDs and obtained hemodynamic data before and after the
intravenous administration of hydralazine, an afterload-reducing drug.
Subjects and methods
The subjects of this study were 14 patients with isolated
VSDs, two patients with VSDs and a patent ductus arteriosus,
and one patient with a VSD type of double-outlet right ventricle.
Patients' ages ranged from 2 to 36 months (mean, 12 +- 10 [SD]
months) and 11 were less than 1 year old. The major clinical
findings and treatments for each patient are summarized in table
1. Informed consent was obtained for each patient before the
study began. Right and left heart catheterization was done in
each patient before and 10 min after an intravenous injection of
hydralazine at a dose of 0.3 mg/kg and while oxygen consumption was being measured by the flow-through method. Systemic
CIRCULATION
THERAPY AND PREVENTION-CONGENITAL HEART DISEASE
TABLE 1
Clinical findings and treatments
Patient
No.
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Group la
1
2
3
4
5
6
Group lb
7
8
9
10
11
12
13
14
Group II
15
16
17
Age
(months)
Weight
(kg)
RR
7
11
20
4
13
6
6.0
8.0
9.5
5.5
7.6
7.1
5
6
7
11
5
2
26
26
6
32
15
Paco2
Liver
(cm)
CTR
(%)
Digoxin
(mg)
50
48
36
45
50
46
48
47
37
50
40
42
4
2
1
3
2
3
61
59
59
61
65
63
0.06
0.08
0.06
0.10
0.08
4.0
5.4
5.6
7.7
6.0
4.2
9.0
11.0
58
53
50
55
54
56
40
40
43
43
36
40
32
47
44
40
2
3
3
2
2
2
3
1
61
62
58
65
55
60
61
58
0.04
0.06
0.05
0.08
5.8
14.0
48
30
40
36
35
33
4
1
2
58
57
54
8.1
SpironoFurosemide lactone
(mg)
(mg)
10
12
5
4
-
4
-
-
15
15
0.04
-
10
10
12
5
-
0.05
15
0.08
-
15
RR = respiratory rate (times/min); CTR = cardiothoracic ratio.
and pulmonary blood flows (Qs and Qp) were obtained by the
Fick method and then SVR and PVR were calculated and expressed in units per square meter (mm Hg/l/minim2).
The patients were assigned to one of three groups according
to their hemodynamic characteristics at control. The patients
who had a peak pulmonary arterial pressure (PAP) of more than
75% of the peak systemic arterial pressure (SAP) were assigned
to group I, which was further divided into a group of patients
with SVRs of 20 U_m2 or higher (group Ia, n = 6) and a group
of those with lower SVRs (group Ib, n = 8). The patients with
lower peak PAPs were placed in group II (n = 3). The data were
analyzed by the Student t test. All values were expressed as
mean + SEM.
Results
The effects of an elevation in SVR on hemodynamics in
patients with large VSDs. There was no statistical difference between group la and group lb for each of following parameters: mean SAP, mean PAP, mean right
atrial pressure (RAP), Qp, PVR, and peak PAP/peak
SAP ratio. However, in group Ia mean left atrial pressure (LAP) was higher (p < .01), Qs was less (p <
.005), and the Qp/Qs ratio was larger (p < .05) than in
group lb (table 2).
The effect of hydralazine on cardiovascular pressure.
Mean SAP for the total patient group decreased from
69 + 2 to 65 + 2 mm Hg (by 7 + 2%; p < .01) after
hydralazine. The largest reduction observed among the
patients was from 77 to 57 mm Hg (26% reduction).
LAP was reduced in 12 patients and remained unchanged in five, the mean reduction being from 12 ± 1
Vol. 68, No. 2, August 1983
to 10 + 1 mm Hg (- 2 + 1 mm Hg; p < .02) after
hydralazine. For these changes there was no difference
between the groups. Mean PAP in group I, which was
56 + 3 mm Hg before hydralazine, was reduced to 50
+ 3 mm Hg (p < .01). PAP was also reduced in group
II (by 17 ± 1% from control). The mean RAP decreased in 13 patients and increased in two others and it
was unchanged in the remaining two patients. The total
group mean reduction was from 6 + 1 before to 5 ± 1
mm Hg after hydralazine, but this reduction was not
statistically significant.
The effects of hydralazine on SVR and PVR. Mean SVR
in all patients was significantly (p < .005) reduced
(from 19.0 + 1.6 to 15.1 ± 0.9 U m2) by hydralazine.
Posthydralazine SVR, expressed as percent of the control value, inversely correlated with prehydralazine
SVR (r = - .66, p < .01; figure 1). In group Ia, in
which the control SVR was high by definition, the
reduction in SVR was greater (29 ± 6%) than in group
Ib (6 + 5%; figure 2).
The change in PVR in group Ia was not significant
and was only barely significant in group lb (4.8 ± 0.7
to 3.6 ± 0.6 U-m2; p < .05). The magnitude of
changes in PVR did not correlate with prehydralazine
PVR.
The effects of hydralazine on Qs, Qp, and the Qp/Qs
ratio. Qs increased after hydralazine in all but one
421
NAKAZAWA et al.
TABLE 2
Hemodynamic effects of hydralazine in infants and children with VSDs
Patient
SAP
Age
No. (months) C
Group la
1
7
11
2
3
20
4
5
6
Mean
± SD
4
13
6
(SEM)
Group lb
7
5
8
6
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9
10
11
12
13
14
Mean
7
11
5
2
26
26
±SD
(SEM)
Group II
15
6
16
17
36
15
PAP
LAP
RAP
H
C
H
C
H
72
70
83
64
75
67
72
7
(3)
74
70
85
56
68
56
68
11
(5)
41
67
57
47
65
35
52
13
(5)
52
55
39
47
57
31
47
10
(4)
13.5
18.5
17
9.5
12
13.5
13.5
16
17
8
12
7
12
4
4
15
4
4
7
5
7
4
(2)
61
77
70
68
53
60
67
75
66
8
(3)
53
57
65
68
60
60
63
60
61
5
(2)
72
77
61
60
38
50
56
60
59
12
(4)
62
67
59
53
40
35
53
51
53B
11
(4)
11.5 11.5
11.5 9
10.5 9.5
9
8
8
7
9
8.5
10
9
10
9.5
98
10
1.2 1.3
(0.4) (0.4)
63
80
75
57
73
72
25
31
18
21
26
15
15
15
8
14A
3
(1)
7
15
4.5
PVR
H
C
H
C
2.3
4.0
3.1
6.2
5.4
2.4
3.9
1.6
(0.7)
4.3
5.8
2.0
5.9
4.6
21.8
22.0
30.5
23.6
34.1
23.1
(2)
7
10.5
7
3
5.5
3.5
6
3
(1)
6
9
9.5
6
3
2
5
5
6
3
5
8
6.5
5
2.5
2
5
3
5 B
2
6.8
7.6
4.2
5.3
2.8
2.9
2.8
5.6
4.8
1.9
(1)
(0.7) (0.7) (0.6)
11
7.5
3.5
3.5
6
3
C
2.7
1.5
2.6
Qp
SVR
2.4
4.2
1.7
(0.7)
6.8
5.6
3.5
2.4
2.9
1.0
3.0
3.2
3.6B
1.8
2.3
0.9
1.9
H
C
H
20.0
18.0
16.1
16.8
24.3
12.4
25.9A 17.9B
5.2 4.0
(2.1) (1.6)
11.9
10.5
12.8
6.1
9.8
9.0
10.0
2.4
(1.0)
8.9
3.3
6.9
3.0
11.2 2.7
6.6
2.5
9.8
2.2
10.2
2.9
8.9
2.8A
1.8 0.4
(0.8) (0.2)
14.5
13.9
9.4
15.9
15.1
18.8
12.0
17.5
14.6
3.0
8.9
8.6
11.8
9.7
10.8
13.8
16.7
9.1
11.2
2.8
(1.0)
7.4
10.2
14.2
18.8
11.5
27.7
14.7
13.0
14.7
6.2
12.6
11.6
10.5
15.0
17.1
14.1
10.9
16.3
13.5
2.5
(I1.1) (0.9)
20.0
15.4
23.4
12.0
11.0
18.0
C = control data;H = 10 min after hydralazine.
kp < .05 for difference between group Ia and group Ib; 8p < .05 for difference between C and H; cp
patient (No. 9) who already had a Qs of 6.4 I/min/m2
and a SVR of 9.4 U.m2. After hydralazine in this
patient Qs was 5.6 1/min/m2 and SVR was 10 U.m2.
The total group mean Qs increased from 3.7 + 0.7 to
5.0 ± 0.8 I/min/m2 (p < .005). Qp decreased in three
of the six patients in group la and in two of the eight
patients in group Jb, while it increased in two in group
Ia and in six in group lb. The mean changes were not
statistically significant in either group (figure 3).
The Qp/Qs ratio decreased in group Ia from 3.6 +
0.4 to 2.4 ± 0.2 (p < .02). In sharp contrast, the ratio
increased in group lb from 2.6 + 0.3 to 3.3 ± 0.5 (p
= .06); figure 4). There was a significant difference
between the changes in these two groups (p < .005).
The QpIQs ratio did not change substantially in two
group II patients; one of these had a small VSD and
the other had a high Qp/Qs ratio and an SVR of 15.4
U.m2. In another group II patient with a control SVR of
20 U m2, however, the Qp/Qs ratio decreased from 2.0
to 1.3.
To evaluate the effect of control SVR on the change
in Qp/Qs ratio in patients with large VSDs, the posthy422
C
H
C
H
3.7
3.3
5.3
3.2
2.8
4.5
3.8B
0.9
(0.4)
3.4
3.5
4.7
2.4
4.5
3.1
3.6A
0.9
(0.4)
2.4
2.1
2.1
2.1
3.5
2.3
2.4B
0.5
(0.2)
4.3
5.1
5.6
4.2
3.5
4.3
5.8
4.3
4.6
1.1 0.8
(2.2) (0.4) (0.3)
2.1
1.8
1.8
2.5
3.1
4.2
2.8
2.3
2.6
0.8
(0.3)
1.7
2.0
2.5
4.5
3.3
6.0
3.0
3.0
3.3c
1.4
(0.5)
2.0
2.0
1.2
1.3
1.9
1.3
5.6 5.4
10.5 12.4
3.8 5.1
=
Qp/Qs
Qs
4.2
4.9
6.4
3.9
3.5
3.2
5.6
4.0
4.5
2.8
5.2
3.2
4.3
6.6
4.0
.06.
dralazine Qp/Qs ratio, expressed as percent of the control value, was compared with the prehydralazine SVR
in group I patients and a rough but significant correlation was found (r = -.61, p = .02; figure 5). Group
II patients were excluded from this analysis because
their VSDs were smaller, although their SVR responses were not different from those of group I patients (figure 5). The control PVR, however, did not
correlate with the change in the Qp/Qs ratio.
Discussion
In infants with large VSDs, left ventricular performance is depressed by volume overload in association
with a relative lack of left ventricular muscle mass.9
This is hemodynamically manifested by an elevation in
left ventricular filling pressure and a decrease in Qs.
The latter stimulates the renin-angiotensin system, catecholamine release, and the sympathetic nervous system, '° resulting in an increase in SVR. The high resistance impedes left ventricular ejection in a failed heart,
which causes a further decrease in the forward flow
and an increase in the left-to-right shunt, so that a
CIRCULATION
THERAPY AND PREVENTION-CONGENITAL- HEART DISEASE
SVR(0/o) after H
L/min/m'
30 T
0
110 1
*
Y= -1.8 X + 116
r= -0.66
n= 17
*.
90g
I a
-ns
ns
20 -+
II
I -b
.
0
70
.
I
.
10
S
0
50
132±16 %
92*8 %
I
10
0
---I
I
40
prehydralazine SVR; units-m2
20
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FIGURE 1. SVR after hydralazine, expressed as percent of the control
value (SVR [%] after H), correlated significantly (p < .01) with control
SVR.
vicious cycle is formed. It is therefore expected that if
the amount of shunting is reduced by any intervention,
the vicious cycle can be interrupted and clinical improvement can be obtained.
The conditions of patients with VSDs are similar to
those of patients with mitral regurgitation when the left
ventricle is regarded from a purely hemodynamic point
of view. It has been established that afterload reduction
in mitral regurgitation is beneficial because it reduces
the amount of regurgitation, lowers LAP, and increases the forward flow.1'I' This suggests that afterload reduction in patients with VSDs may be effective
in reducing the amount of shunting. However, reaction
of the pulmonary vascular bed to vasodilators can not
be ignored in patients with large VSDs because the
I -b
I .a
units-ml
0o
30
C
C
H
H
c
FIGURE 3. Changes in Qp. There were no statistically significant
changes in either group Ia or group lb patients or when comparing the
two groups.
amount of shunting is determined by the ratio of PVR
to SVR. It is known that in patients with other cardiac
diseases vasodilators dilate the pulmonary vascular
bed as well as the systemic one,"' 'v"7 although Fripp
et al.'8 have reported that hydralazine failed to reduce
the PVR in two patients with pulmonary vascular obstructive disease secondary to congenital heart disease.
In this study and in another by Goldberg et al.'9 the
magnitude of reduction in vascular resistance by vasodilators was shown to be a function of the pretreatment
resistance value. This implies that either a nonconstricted vessel is not dilated to any great extent by the
drugs or that an already dilated vessel no longer responds, as was the case in patient 9. In patients in
whom PVR alone is elevated functionally, vasodilators will act more on the pulmonary than on the sysQp/Qs
11
H
l.a
6-
I-b
11
40T
30\T
30 _
p±
/=
p c 0.02
0.01
ns
+
4-
:0.06
20 --_>
71
+
71*6%
144
2 -
-
10
94t5%
125±11%
71t6 %
p < 0.02
0-
p < 0.005
C
H
C
H
C
H
O
FIGURE 2. Changes in SVR. SVR was significantly (p < .005) reduced in all patients, but the reduction was larger in group Ia than in
group lb. NS = not significant at p > .05; C = control data; H = data
obtained 10 min after hydralazine.
Vol. 68, No. 2, August 1983
~
C
H
C
H
C
H
FIGURE 4. Changes in the Qp/Qs ratio. The ratio decreased in group Ia
and increased in group lb patients. The changes were statistically different in the two groups.
423
NAKAZAWA et al.
QP/Qs after H ( % of the control )
200 ,Y = 165 - 3.3 X
0
r = - 0.61
150 +
n= 14
.
100
*'-
*
0@
+
Group I; 0
Group 11; 0
0
0
.
*s
0.
50
0
References
0
0
10
20
30
40
units-m2
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FIGURE 5. The Qp/Qs ratio after hydralazine, expressed as percent of
the control value, correlated significantly (p = .02) with control SVR in
patients with large VSDs (group I). The data from group II patients are
plotted in this figure, showing that the Qp/Qs response was not different
from that in group I.
temic vascular bed, so that Qp will increase more than
Qs or shunt flow; this was the case in patients in group
lb of this study. The response, however, will be the
opposite in patients with elevated SVRs. This was
shown to be true in group Ia patients. Since in infants
with large VSDs PVR is mildly to moderately elevated
by the medial thickening,7 elevation of SVR is a prerequisite for obtaining reduction in the Qp/Qs ratio
with vasodilators.
The change in PVR varied in this study. Since there
was no correlation between the pretreatment value for
PVR and the magnitude of the change, the apparent
PVR response does not seem to be an active one, but
seems to be affected passively by Qp which, in turn, is
determined by the amount of shunting. It is likely that,
in patients in whom the response of SVR was greater
than that of pulmonary circulation, Qp decreased and
the apparent value for PVR was elevated or unchanged. On the other hand, when PVR was lowered
more than SVR by hydralazine, the decrease in PVR
became apparent.
In a patient with a moderate-sized VSD, the amount
of shunting is determined by the size of the VSD and
augmented by elevation of SVR, as illustrated by the
case of patient 15. This response was also seen in the
experimental studies of Synhorst et al.3 and Boucek et
al.4 The model used in their studies was a restrictive
and moderate-sized VSD and the muscular tone of
systemic resistant vessels would be expected to be high
due to experimental stress. Vasodilators would therefore dilate the constricted systemic vascular bed to
increase Qs and decrease the shunt flow.
424
As shown in our study, reduction of the Qp/Qs ratio
is not necessarily associated with a decrease in Qp
because an increment in venous return secondary to an
increase in Qs offsets the decrease in left-to-right
shunting.2
In summary, the effect of hydralazine on the Qp/Qs
ratio in infants and young children with large VSDs
was largely dependent on pretreatment SVR, which
was shown by the fact that the Qp/Qs ratio was reduced
only in those with a high control SVR.
1. Beekman RH, Rocchini AP, Rosenthal A: Hemodynamic effects of
nitroprusside in infants with a large ventricular septal defect. Circulation 64: 553, 1981
2. Beekman RH, Rocchini AP, Rosenthal A: Hemodynamic effects of
hydralazine in infants with a large ventricular septal defect. Circulation 65: 523, 1982
3. Synhorst DP, Lauer RM, Doty DB, Brody MJ: Hemodynamic
effects of vasodilator agents in dogs with experimental ventricular
septal defect. Circulation 54: 472, 1976
4. Boucek MM, Chang R, Synhorst DP: Effects of prazosin and
hydralazine on the hemodynamics of chronically instrumented
lambs with ventricular septal defect. Circulation 62 (suppl III): III1 15, 1980 (abstr)
5. Linday LA, Levin AR, Klein AA, Reidenberg MM, Engle MA:
Effect of vasodilators on left-to-right shunt in infants and children.
Pediatr Res 14: 447, 1980 (abstr)
6. Macri R, Redaelli S: Vasodilator in VSD's. Circulation 56: 329,
1980 (letter)
7. Rudolph AM: Congenital disease of the heart. Chicago, 1974,
Year Book Publishers
8. Tanenbaum HL, Pfaff WW: Effect of pressor amines on experimental intracardiac shunts and valvular regurgitation. Dis Chest
44: 485, 1963
9. Jarmakani MM, Graham TP Jr, Canent RV Jr, Spach MS, Capp
MP: Effect of site of shunt on the left heart volume characteristics
in children with ventricular septal defect and patent ductus arteriosus. Circulation 40: 411, 1969
10. Talner NS: Heart failure. In Moss AJ, Adams FH, Emmanouilides
GC, editors: Heart disease in infants, children and adolescents, ed
2. Baltimore, 1977, Williams & Wilkins Co., p 660
11. Franciosa JA: Effectiveness of long-term vasodilator administration in the treatment of chronic left ventricular failure. Prog Cardiovasc Dis 24: 319, 1982
12. Greenberg BH, Massie BM, Brundage BH, Botvinick EH, Parmley WW, Chatterjee K: Beneficial effects of hydralazine in severe
mitral regurgitation. Circulation 58: 273, 1978
13. Harshow CW, Grossman W, Munro AB, McLaurin LP: Reduced
systemic resistance as therapy for severe mitral regurgitation of
valvular origin. Ann Intem Med 83: 312, 1975
14. Lupi-Herrera E, Sandoval J, Seoane M, Bialostozky D: The role of
hydralazine therapy for pulmonary arterial hypertension of unknown cause. Circulation 65: 645, 1982
15. Rubin LJ, Peter RH: Oral hydralazine therapy for primary pulmonary hypertenson. N Engl J Med 302: 69, 1980
16. Chatterjee K, Parmley WW: The role of vasodilator therapy in
heart failure. Prog Cardiovasc Dis 19: 301, 1977
17. Mason DT: Symposium on vasodilator and inotropic therapy of
heart failure. Am J Med 65: 101, 1978
18. Fripp RR, Gewitz MH, Werner JC, Whitman V, Rashkind WJ:
Oral hydralazine in patients with pulmonary vascular disease secondary to congenital heart disease. Am J Cardiol 48: 380, 1981
19. Goldberg S, Mann T, Grossmanr W: Nitrate therapy of heart failure
in valvular heart disease. Am J Med 65: 161, 1978
CIRCULATION
Significance of systemic vascular resistance in determining the hemodynamic effects of
hydralazine on large ventricular septal defects.
M Nakazawa, A Takao, Y Chon, T Shimizu, M Kanaya and K Momma
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Circulation. 1983;68:420-424
doi: 10.1161/01.CIR.68.2.420
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