1287
Use of ATP-MgCl2 in the Evaluation and
Treatment of Children With Pulmonary
Hypertension Secondary to
Congenital Heart Defects
Michael M. Brook, MD; Jeffrey R. Fineman, MD; Ann M. Bolinger, PharmD;
Alvin F. Wong, PharmD; Michael A. Heymann, MD; Scott J. Soifer, MD
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Background Pulmonary hypertension results in increased
morbidity and mortality in children after surgical repair of
congenital heart defects. Various vasodilators have been unsuccessful in providing preferential pulmonary vasodilation in
these patients. Identification of a more preferential pulmonary
vasodilator would improve the assessment, management, and
outcome of these children. To determine whether ATP-MgCl2
is a preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects,
ATP-MgCl2 was administered during routine cardiac catheterization, and the effects were compared with tolazoline. In
addition, ATP-MgCl2 was infused intravenously during episodes of postoperative pulmonary hypertension.
Methods and Results During cardiac catheterization in 28
children, the effect of ATP-MgCl2 on the pulmonary artery
pressure (PAP) and pulmonary vascular resistance index (Rp)
was compared with tolazoline. ATP-MgCl2 (0.1 mg of ATP per
kilogram per minute) decreased mean PAP by 24% (P<.05)
and Rp by 47% (P<.05) without changing mean systemic
arterial pressure or systemic vascular resistance. These effects
were comparable to those of tolazoline (1 mg/kg). ATP-MgCl2
produced no significant side effects; tolazoline caused tachycardia, nausea, and vomiting. After cardiac surgery in 7
patients, ATP-MgCl2 decreased PAP by 14% (P<.05) and
systemic arterial pressure by 6% (P<.05) and eliminated
pulmonary hypertensive crises in 3 of 3 patients.
Conclusions ATP-MgCl2 is a safe, effective, and preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects. It is useful for
evaluating pulmonary vasoreactivity during cardiac catheterization and for treating pulmonary hypertension after cardiac
surgery. (Circulation. 1994;90:1287-1293.)
Key Words * pediatrics * hypertension * defects,
congenital * vasodilation * endothelium
P ulmonary hypertension is a serious problem in
children with congenital heart defects associated with increased pulmonary blood flow (particularly when associated with hypoxemia) or left ventricular inflow obstruction. Increased pulmonary
arterial smooth muscle increases pulmonary vascular
resistance and the risk for postoperative pulmonary
Many vasodilators, including oxygen, prostacyclin,4
prostaglandin E1,5 and tolazoline,67 have been used in
children with pulmonary hypertension secondary to
congenital heart defects for both evaluation of pulmonary vasoreactivity and treatment of postoperative pulmonary hypertension. However, all of these may produce side effects. ATP is an endothelium-dependent
vasodilator8 whose rapid metabolism and short duration
of action make it a preferential dilator for the pulmonary circulation when infused intravenously or directly
into the pulmonary artery.9 Therefore, to determine
whether ATP-MgCl2 is a safe, effective, and preferential
pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects, two
studies were performed. In one study, ATP-MgCl2 was
administered to 28 children during routine diagnostic
cardiac catheterization to assess pulmonary vasoreactivity, and the effects were compared with those of tolazoline. In the second study, ATP-MgCl2 was administered to 7 children with pulmonary hypertension
immediately after surgical repair of congenital heart
defects to determine whether ATP-MgCl2 lowers pulmonary arterial pressure and prevents pulmonary hypertensive crises.
hypertensive crises. Long-term elevation of pulmonary
arterial pressure causes intimal hyperplasia and microvascular obstruction,' leading to irreversible pulmonary
vascular disease and Eisenmenger's syndrome.2 During
cardiac catheterization, the measurement of pulmonary
vascular resistance and the assessment of pulmonary
vasoreactivity to vasodilators compare favorably with
lung biopsy findings3 and therefore are used to determine which patients may have developed permanent
vascular changes. Whether response to pulmonary vasodilators can predict which patients will have immediate postoperative hypertension or hypertensive crises is
unclear.
Received February 8, 1994; revision accepted May 18, 1994.
From the Department of Pediatrics (M.M.B., J.R.F., M.A.H.,
S.J.S.), the Cardiovascular Research Institute (M.A.H., S.J.S.),
and the Division of Clinical Pharmacy (A.M.B., A.F.W.), University of California San Francisco.
Correspondence to Michael M. Brook, MD, University of
California San Francisco, 505 Parnassus Ave, Box 0214, San
Francisco, CA 94143-0214.
X 1994 American Heart Association, Inc.
Methods
The protocols were approved by the Committee on Human
Research, University of California San Francisco. Informed
1288
Circulation Vol 90, No 3 September 1994
consent was obtained from the parents of all patients before
cardiac catheterization or cardiac surgery.
Study 1 -ATP-MgCI2 During Cardiac
Catheterization
Patient Selection
Forty newborns, infants, and children with clinical, ECG, or
echocardiographic evidence of pulmonary hypertension secondary to congenital heart defects were enrolled in the study.
During routine diagnostic cardiac catheterization, ATP-MgCl2
was administered if the patient's mean pulmonary artery
pressure was >50% of mean systemic arterial pressure or if the
pulmonary vascular resistance was >3 Wood Units. Twentyeight patients (16 girls and 12 boys) met these inclusion
criteria; 3 patients were studied twice during separate cardiac
catheterizations. The median age of the patients was 6 months
(range, 3 to 145 months) (Table 1).
Protocol
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Baseline (preinfusion) measurements of right atrial, pulmonary and systemic arterial, and pulmonary capillary wedge
pressures and heart rate (hemodynamic variables) were made.
Pulmonary and systemic arterial and venous blood samples were
obtained for measurement of hemoglobin and hemoglobin oxygen saturation. Oxygen consumption was measured.10 ATPMgGl2 (0.05, 0.1, and 0.2 mg of ATP per kilogram per minute)
was infused into the main pulmonary artery through an end-hole
catheter using a Y-connector, which allowed for the simultaneous
measurement of pulmonary arterial pressure. The infusion of
ATP-MgCI2 was started at the lowest dose. After 1 to 3 minutes
of the infusion, when a new steady state was achieved, the
hemodynamic variables were again measured, and blood samples
for hemoglobin and hemoglobin oxygen saturation were obtained. The dose of ATP-MgGl2 was increased, and all measurements were repeated as described above. This was repeated until
all three doses were infused. The infusion of ATP-MgCl2 was
then stopped. After recovery and return of the hemodynamic
variables to preinfusion values, the hemodynamic variables were
measured, and blood samples for hemoglobin and hemoglobin
oxygen saturation were obtained. Tolazoline (1 mg/kg) was then
injected into the main pulmonary artery over 1 minute. Hemodynamic measurements were repeated after 2 minutes to allow
for stabilization. In the first S patients, oxygen consumption was
measured during each condition. There was no significant difference in oxygen consumption during each condition5; therefore in
subsequent patients, oxygen consumption was measured only
during the preinfusion state. Six of 28 patients did not receive
tolazoline because the patient's cardiologist refused administration. When the hemodynamic variables returned to preinfusion
values, the cardiac catheterization continued.
Study 2 -ATP-MgC12 During Postoperative
Pulmonary Hypertension
Patient Selection
Thirty-five newborns, infants, and children with clinical, ECG,
echocardiographic, or cardiac catheterization evidence of pulmonary hypertension secondary to congenital heart defects were
enrolled in the study. Each patient underwent surgical repair of
the congenital heart defect(s). After surgery, ATP-MgCG2 was
administered if the patient's mean pulmonary arterial pressure
was >50% of mean systemic arterial pressure despite mechanical
hyperventilation with 100% oxygen (Paco2 <30 mm Hg, pH
>7.50). Seven patients (4 girls and 3 boys) met these inclusion
criteria. The median age of the patients was 6 months (range, 3
to 18 months) (Table 2). One patient participated in both study
1 (patient 4) and study 2 (patient E).
All patients were receiving fentanyl sodium analgesia alone
or with midazolam sedation. No patients were receiving inhaled anesthetics or muscle relaxants.
Protocol
Baseline (preinfusion) measurements of right atrial and
pulmonary and systemic arterial pressures (hemodynamic variables) were made. Systemic arterial blood gases and pH were
also measured. ATP-MgGl2 (0.01 mg of ATP per kilogram per
minute) was infused into the main pulmonary artery. The
hemodynamic variables and systemic arterial blood gases and
pH were measured after 15 minutes. If there was no decrease
in mean systemic arterial pressure or worsening of the systemic
arterial blood gases, the dose of ATP-MgGl2 was sequentially
increased (0.025, 0.05, 0.10, and 0.2 mg of ATP per kilogram
per minute). An improvement in the patient's condition was
assessed by a decrease in mean pulmonary arterial pressure
without a proportional decrease in mean systemic arterial
pressure, by a decrease in the number of pulmonary hypertensive crises per hour (defined as an acute increase in pulmonary
arterial pressure associated with a decrease in systemic arterial
pressure and/or a decrease in oxygenation), or by an improvement in systemic arterial blood gases at constant ventilation.
The dose of ATP-MgGl2 was adjusted to produce maximal
pulmonary vasodilation and minimal systemic vasodilation
(optimal dose). If improvement occurred, the optimal dose
was maintained for 12 to 24 hours and then gradually reduced
and discontinued. If there was a 20% decrease in systemic
arterial pressure, the infusion was reduced; if there was no
improvement at the maximum dose, the infusion was stopped.
Drug Preparation
ATP and MgGl2 (Sigma Chemical Co) were prepared as
sterile solutions of 100 and 33 mg/mL, respectively, in sterile
water; 1 mol/L NaOH was added to the solutions to obtain pH
7.2 to 7.4. The solutions were sterilized by filtration using a
0.22-,um filter. The sterilized solutions were then placed into
10-mL vials. Each lot was tested for particulate matter,
bacteria, and pyrogens. The vials were frozen and stored at
20°C. The stability of ATP was set at 60 days.11
To infuse ATP-MgGl2, the contents of both vials were
thawed immediately before use and combined to yield a ratio
of 1: 0.33 by weight (ATP: MgGl2). The resulting solution was
mixed with sterile water for injection. The final concentration
of ATP-MgGl2 was determined by the patient's weight, so that
an infusion rate of 2 mL/h corresponded to a concentration of
0.05 mg of ATP per kilogram per minute.
Tolazoline (25 mg/mL) (CIBA-GEIGY) was diluted in 3 mL
of sterile 5% dextrose in 0.2% saline for infusion.
Measurements
During study 1, right atrial, pulmonary arterial, and pulmonary capillary wedge pressures were measured using an endhole balloon catheter (Arrow Intl) connected via a fluid-filled
system to a pressure transducer (Abbott Labs). Mean pressure
was obtained by electrical integration. Systemic arterial pressure was measured either by a catheter placed in the ascending
or descending aorta or by an automated sphygmomanometer
(Critikon Inc). Heart rate was measured with a cardiotachometer. During study 2, pulmonary and systemic arterial and right
atrial pressures were measured using indwelling catheters
placed during surgery.
Systemic arterial blood gases and pH were measured using a
178 pH/Blood Gas Analyzer (Ciba-Corning Diagnostic). Hemoglobin and hemoglobin oxygen saturation were measured in
heparinized whole blood using an OSM2 oximeter (Radiometer America Inc). In some patients, systemic arterial hemoglobin oxygen saturation was measured using pulse oximetry
(Nellcor Inc). During cardiac catheterization, oxygen consumption was measured using a custom-made, flow-by system.10 Pulmonary and systemic blood flows and vascular
resistances were estimated using standard formulas with oxygen consumption in the baseline state.
Brook et al ATP-MgCI2 for Pulmonary Hypertension in CHD
Data Analysis
The mean±SD values were calculated for the hemodynamic
variables, pulmonary and systemic blood flows, and vascular
resistances during baseline and in each experimental condition.
For study 1, comparisons between baseline and each dose of
ATP-MgCl2 and tolazoline for these variables were made by
ANOVA for repeated measures with multiple-comparison testing. For study 2, comparisons between baseline and the maximum response to ATP-MgCl2 for these variables were made by
the paired t test. P<.05 was considered statistically significant.
Results
Study 1 -ATP-MgCl During Cardiac Catheterization
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The baseline mean pulmonary arterial pressure was
54.3±11.9 mm Hg, which was 84% of mean systemic
arterial pressure (Table 1). ATP-MgCl2 (0.05 and 0.1 mg
of ATP per kilogram per minute) decreased pulmonary
arterial pressure by 16% and 24%, respectively (P<.05)
(Fig 1). The highest dose (0.2 mg of ATP per kilogram per
minute) produced no further effect. Mean systemic arterial pressure decreased by 16% only at the highest dose
(P<.05 versus baseline). Similar to ATP-MgCl2, tolazoline
decreased pulmonary arterial pressure by 20% (P<.05
versus baseline). Neither ATP-MgCl2 nor tolazoline
changed pulmonary capillary wedge pressure.
The baseline pulmonary blood flow was 5.6±2.1
L. min-1 * m-2 (Table 1). ATP-MgCl2 (0.05 and 0.1 mg
of ATP per kilogram per minute) increased estimated
pulmonary blood flow by 15% and 33%, respectively [to
6.3 ±2.5 and 7.6±3.4 L * min-' (mol/L)2] (P<.05). The
highest dose produced no further effect. Systemic blood
flow was unchanged. Tolazoline increased estimated
pulmonary blood flow by 36% [to 7.7±3.7
L- min1 m2] (P<.05 versus baseline).
The baseline pulmonary vascular resistance was
9.6±6.6 Wood Units (Table 1). ATP-MgCI2 (0.05 and
0.1 mg of ATP per kilogram per minute) decreased
estimated pulmonary vascular resistance by 34% and
47%, respectively (P<.05) (Fig 2). The highest dose
produced no further effect. Tolazoline, similar to ATPMgCl2, decreased estimated pulmonary vascular resistance by 41% (P<.05 versus baseline).
The baseline heart rate was 120± 20 beats per minute.
ATP-MgCl2 did not change heart rate. Tolazoline increased heart rate by 14% (to 136+25 beats per minute)
(P<.05 versus baseline).
ATP-MgCl2 produced no significant side effects. Two
patients who inadvertently received a large bolus injection of ATP-MgCl2 (-5 mg) developed transient second-degree atrioventricular block that lasted <30 seconds; this did not produce significant bradycardia or
hemodynamic compromnise. Tolazoline produced nausea and vomiting in 6 patients and was severe enough in
1 patient to require intravenous fluid administration.
Twenty-two patients have since undergone surgical
repair of their congenital heart defects. Twenty patients
had no postoperative pulmonary hypertension, 2 patients (patients 4 and 22) had significant postoperative
pulmonary hypertension, 2 patients (patients 6 and 20)
are clinically stable with no plans for surgical repair, and
4 patients (patients 2, 13, 20, and 21) did not have
surgery because they have suspected irreversible pulmonary vascular disease.
1289
Study 2-ATP-MgCl2 During Postoperative
Pulmonary Hypertension
In the 7 patients, preoperative mean pulmonary
artery pressure was 52.1±25.1 mm Hg, pulmonary
m-2 , and pulmonary
blood flow was 5.8±3.3 L * min' m
vascular resistance was 10.5±6.7 Wood Units. ATPMgCl2 (0.01 to 0.05 mg of ATP per kilogram per
minute) decreased pulmonary arterial pressure by 14%
(P<.05) and systemic arterial pressure by only 6%
(P<.05); thus, ATP-MgCl2 tended to be a more preferential vasodilator for the pulmonary circulation than for
the systemic circulation (Table 2). ATP-MgCl2 did not
change heart rate, right atrial pressure, systemic arterial
blood gases, or pH. ATP-MgCl2 infusion eliminated
pulmonary hypertensive crises and restored hemodynamic stability in 3 patients.
ATP-MgCl2 was infused for 30 minutes to 30 hours
(median, 6 hours). There were no serious complications.
Four patients survived surgery and were discharged from
the hospital; 3 patients (patients B, E, and G) died.
Discussion
The present study shows that ATP-MgCl2 is a safe
and effective vasodilator whose short half-life provides
preferential pulmonary vasodilation in children with
pulmonary hypertension secondary to congenital heart
defects. During cardiac catheterization, intrapulmonary
infusions of ATP-MgCl2 decreased pulmonary arterial
pressure and pulmonary vascular resistance and increased pulmonary blood flow. ATP-MgCl2 produced
pulmonary vasodilation comparable to tolazoline without producing tachycardia, nausea, or vomiting. After
cardiac surgery, ATP-MgCl2 decreased pulmonary arterial pressure and the number of postoperative pulmonary hypertensive crises.
The vasodilating effects of ATP and its rapid metabolism have been known for more than 30 years.12 ATP
binds to P2 receptors on vascular endothelial cells,13
increasing the formation of nitric oxide and resulting in
an increased smooth muscle cell concentration of cyclic
GMP, the intracellular messenger involved in smooth
muscle relaxation.812 Metabolism of extracellular ATP
occurs rapidly by endothelial cell ATPases, resulting in a
half-life of <6 seconds.14 In fact, ATP is almost completely cleared after a single passage through the lung.
ATP-MgCl2 also has been studied during pulmonary
hypertension in animals. We have investigated the effects of infusions of ATP-MgCl2 on the circulation in
newborn lambs at rest and during pulmonary hypertension induced by either the infusion of U46619, a thromboxane A2 mimetic, or hypoxia.15 At rest, high doses of
ATP-MgCl2 decreased systemic arterial pressure without changing pulmonary arterial pressure. During pulmonary hypertension, ATP-MgCl2 (0.01 to 1.0 mg of
ATP per kilogram per minute) caused a dose-dependent decrease in pulmonary arterial pressure, whereas
systemic arterial pressure decreased only at the highest
dose. Inferior vena caval and pulmonary arterial infusions of ATP-MgCl2 produced similar hemodynamic
effects. Left atrial infusions decreased systemic arterial
pressure without changing pulmonary arterial pressure.
Nw-nitro-L-arginine16 and methylene blue17 inhibit vasodilation, but indomethacin and theophyllineA8 do not,
indicating that the effects of ATP-MgCl2 are mediated
1290
Circulation Vol 90, No 3 September 1994
TABLE 1. ATP-MgCI2 Preferentially Decreases Pulmonary Arterial Pressure and Vascular Resistance in 28 Patients
With Pulmonary Hypertension Secondary to Congenital Heart Disease
Pulmonary Artery Pressure, mm Hg
Systemic Artery Pressure, mm Hg
ATP-MgC12,
ATP-M9C12,
mg* kg-' * min'1
Patient
1
2
3
4
5
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6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Age
3 mo
10 mo
10 y
4 mo
19 mo
3 mo
8y
6 mo
8 mo
13 mo
4 mo
3 mo
5 mo
16 mo
6 mo
4 mo
6 mo
6 mo
3 mo
Diagnosis
AVS/coarct
s/p repair
VSD
VSD
TOF/shunt
AVS/DS
Mitral stenosis
VSD/DS
VSD/DS
VSD/DS
AVS/DS
AVS/DORV
VSD/DS
s/p PDA closure
VSD/DS
AVS/DS
AVS/DS
VSD
LTGA/DILV
12 y
VSD
12 y
s/p nifedipine
8y
TGA s/p Senning
21 mo AVS s/p PAB
2y
VSD/ASD/PDA/DS
2y
s/p PDA ligation
3 mo AVS
4m
ASD/VSD
5 mo VSD
VSD
10 y
5 mo ASD/VSD/PDA/DS
10 mo IAAIVSD s/p PAB
Baseline 0.05
58
48
24
60
48
46
57
62
60
56
48
45
57
36
58
44
54
46
64
46
80
72
64
66
68
66
55
62
36
38
60
48
54.3
11.9
n
48
34
48
43
46
n
34
34
30
50
n
58
32
49
33
47
46
80
67
66
62
48
52
0.1
42
18
46
26
50
36
44
33
29
28
35
36
20
52
30
46
31
52
46
72
66
65
60
46
50
0.2
42
n
n
n
44
38
48
36
n
mg* kg-1'* min-1
Tolazoline,
1.0 mg/kg Baseline
n
63
3
68
64
66
24
62
4C
3E3
5C
3E
341
32
3C
3E3
27
34
26
n
52
n
52
n
40
22
46
34
68
32
4E
341
6C
40
64
n
n
n
n
59
7C
n
n
72
59
88
62
76
62
60
73
54
68
58
48
42
72
56
88
80
76
74
60
57
60
68
62
76
47
60
65.1
10.9
0.05 0.1
63
64
n
61
50
46
70
53
70
70
50
40
90
86
n
50
62
58
57
55
60
60
68
56
n
43
69
60
55
57
47
42
42
46
82
82
52
52
98
75
71
61
77
62
67
70
50
42
60
55
n
60
70
70
0.2
55
n
n
n
68
40
80
46
Tolazoline,
1.0 mg/kg
n
62
70
55
65
50
n
80
60
76
68
58
55
n
70
65
54
40
76
52
85
n
n
n
n
52
60
50
n
57
n
49
34
63
49
68
50
n
83
n
60
52
70
50
56
51
23
n
44
44
47
52
24
58
40
44
40
54
25
n
n
26
n
n
67
n
n
26
32
n
35
34
72
n
75
72
27
42
40
42
44
44
45
39
52
28
56
40
36
52
53
56
48
48
Mean
47.8 41.4 41.4
433.2
63.5 58.6 53.3
63.1
SD
12.5 13.1
11.0
13 .0
13.9 11.7 10.8
11.7
P vs baseline
...
.05
.05
.05
.05
...
NS NS
.05
NS
P vs tolazoline
.05
NS
NS
NS
NS
NS NS
.05
ASD indicates atrial septal defect; coarct, aortic coarctation; sip, after surgery; VSD, ventricular septal defect; TOF, tetralogy of Fallot;
shunt, postoperative aortopulmonary shunt; DS, Down's syndrome; DORV, double-outlet right ventricle; PDA, patent ductus arteriosus;
AVS, atrioventricular septal defect; LTGA, L-transposition of the great arteries; a, unable to calculate due to differential pulmonary blood
flow; DILV, double-inlet left ventricle; PAB, postoperative pulmonary artery band; and n, dose not given; n=28.
Median patient age was 6 mo.
by endothelial-derived nitric oxide rather than by prostacyclin or adenosine. ATP-MgCl2 is a potent vasodilator whose rapid metabolism allows for preferential
vasodilation of the vascular bed (pulmonary or systemic) first encountered. These properties make ATP-
MgCl2 ideal for use during cardiac catheterization to
assess pulmonary vasoreactivity. The short half-life
decreases the risk of significant side effects when used
either during cardiac catheterization or in the postoperative period.
Brook et al ATP-MgCJ2 for Pulmonary Hypertension in CHD
1291
TABLE 1. Continued
Estimated Pulmonary Blood Flow, L. min' rm-2
Estimated Pulmonary Vascular Resistance, Wood Units
ATP-MgCI2,
ATP-MgCI2,
mg * kg-1 * min~l
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Baseline
3.6
3.1
3.1
6.2
2.5
3.3
3.0
6.4
8.7
8.1
6.4
5.5
8.3
4.0
7.2
7.6
4.6
5.2
7.8
6.8
7.4
a
1.7
3.6
5.1
8.3
4.9
7.3
6.2
8.1
a
5.7
2.1
.
.
.
.05
0.05
4.9
n
4.4
8.5
2.5
4.6
3.0
n
9.6
6.8
5.6
7.1
n
4.0
9.6
10.2
4.0
6.3
7.2
7.5
11.1
a
1.8
4.4
7.4
n
7.0
n
5.8
8.7
a
6.3
2.5
.05
NS
0.1
3.9
3.4
5.0
9.3
2.3
6.2
3.4
8.5
10.8
10.2
4.9
10.2
7.6
4.0
9.6
15.3
5.8
8.6
10.3
9.3
12.7
a
1.8
3.9
7.4
11.6
7.0
9.0
7.4
11.3
a
7.6
3.4
.05
NS
mg kg-' * min-'
0.2
3.8
n
Tolazoline,
1.0 mg/kg
n
2.9
4.7
n
2.1
4.8
3.8
7.9
n
9.0
4.2
14.2
n
3.4
n
13.1
4.9
7.3
11.6
9.3
n
n
1.8
n
7.4
12.9
7.9
n
n
14.1
a
7.6
4.1
.05
NS
13.3
3.2
5.1
3.3
8.5
9.6
8.1
5.9
17.8
n
4.0
14.3
11.5
5.3
6.7
10.3
9.3
n
n
2.4
n
7.4
10.6
7.9
n
7.4
7.1
a
7.8
3.9
.05
.
Recently, inhaled nitric oxide has been found to be a
potent pulmonary vasodilator in patients with congenital heart defects.19'20 It has several advantages in the
treatment of pulmonary hypertension in that it is immediately inactivated on exposure to hemoglobin and
does not require a functioning endothelium.20 However,
as a diagnostic tool in the catheterization laboratory, its
bypass of the endothelium is a disadvantage. Endothelial injury has been shown to be an early and important
Baseline
15.3
5.1
16.7
5.1
11.2
14.4
12.8
8.1
5.3
4.3
6.3
9.7
3.3
12.7
4.5
5.8
7.9
9.9
4.5
10.8
8.4
a
36.3
17.3
11.3
6.1
12.3
3.0
3.9
6.2
a
9.6
6.6
.
.
0.05
0.05
9.0
n
8.7
2.0
9.6
6.1
7.4
n
2.5
2.8
4.1
6.5
n
13.2
1.7
3.7
5.7
4.3
5.0
9.6
5.1
a
31.7
9.7
5.9
n
7.8
n
3.1
3.0
a
7.0
6.0
.05
NS
Tolazoline,
0.1
9.4
2.3
7.1
1.0
11.3
3.4
5.3
2.6
1.6
1.4
5.5
2.9
1.3
11.5
1.5
1.8
3.6
4.2
3.4
6.9
4.3
a
31.7
10.0
5.4
3.4
5.2
1.3
1.8
2.1
a
5.3
5.9
.05
NS
0.2
9.3
n
n
n
12.3
3.7
5.7
3.3
n
1.4
5.7
1.5
n
14.0
n
1.8
2.4
3.9
1.9
6.4
n
n
31.2
n
5.4
3.1
4.7
2.1
a
6.3
7.0
.05
1.0 mg/kg
n
3.7
11.5
0.6
8.1
3.5
6.7
2.8
2.2
2.9
3.7
1.8
n
12.2
1.1
3.1
4.3
6.2
2.7
6.4
n
n
27.1
n
6.4
4.0
5.2
n
8.1
4.0
a
5.5
5.4
.05
NS
aspect of changes associated with irreversible pulmonary vascular disease.12' Many vasodilators (prostacyclin, prostaglandin EB, sodium nitroprusside, and tolazoline) are similar to nitric oxide in that they are not
dependent on a structurally and functionally normal
endothelium. If the loss of endothelial-dependent pulmonary vasodilation occurs before endothelial-independent pulmonary vasodilation,2' loss of ATP responsiveness may identify a group of patients with more
Circulation Vol 90, No 3 September 1994
1292
TABLE 2. Effects of ATP-MgCI2 on Pulmonary and Systemic Arterial Pressures in Seven Patients With Pulmonary
Hypertension After Repair of Congenital Heart Defects
Pulmonary
Systmic
Artery
Artery
Pressure,
Pressure,
mm Hg
mm Hg
Optimal Maximal
Dose,
Dose,
ATPAge,
mg* kg-' mg* kg-1 Base- ATP- Basemin'1
min-1
line MgCI2 line
Patient mo Diagnosis Procedure
Outcome
MgCI2
0.1
62
33
26
65
Weaned
from ATP-MgC12,
0.02
A
6
AVS/DS Complete
survived
repair
0.05
0.12
24
22
47
47
Weaned from ATP-MgCI2,
B
3
Truncus Complete
died
repair
0.15
34
29
59
55
0.05
Weaned from ATP-MgCI2,
C
6
AVS/DS Complete
survived
repair
D
Complete
AVS/DS
5
0.01
0.08
63
51
80
77
repair
E
Complete
repair
0.05
0.2
52
44
67
67
shunt
TOF/s/p
9
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F
18
IAA
Arch repair
0.005
0.01
105
88
87
75
G
13
Mitral
stenosis
MVR
0.01
0.05
54
51
61
51
Weaned from ATP-MgCl2,
survived
ATP-MgCl2 discontinued
at request of physician,
died
ATP-MgCl2 discontinued,
systemic hypotension,
survived
ATP-MgCI2 discontinued,
systemic hypotension,
died
6
Median
52.1 44.4*
66.6
62.0*
Mean
27.1 22.6
13.4
11.6
SD
AVS indicates atrioventricular septal defect; DS, Down's syndrome; truncus, truncus arteriosus; TOF, tetralogy of Fallot; s/p, after
surgery; IAA, interrupted aortic arch with patent ductus arteriosus; and MVR, mitral valve replacement; n=7.
*P<.05 vs baseline.
advanced pulmonary hypertension who would not be
identified by tolazoline. As such it may be a better
predictor of pulmonary vasoreactivity and may identify
those patients most at risk of postoperative pulmonary
hypertensive crises. Further studies will need to be
performed to determine this.
Unlike the study of Gaba et al,22 the patients in this
present study did not have rebound pulmonary hypertension after discontinuation of ATP-MgCl2. The paATP-MgCI2 (mg/kg/min)
tients in that study had pulmonary hypertension secondary to parenchymal lung disease without an intracardiac
shunt. Administration of ATP decreased pulmonary
artery pressure and vascular resistance and simultaneously decreased arterial oxygenation. After discontinuation, pulmonary artery pressure and vascular resistance rose to levels higher than preinfusion levels. In
these patients, vasodilation with ATP may have imATP-MgCI2 (mg/kg/min)
Tolazoline
20 r
10
r
0.05
0.1
0.05
0.1
Tolazoline
1 mg/kg
0.2
1 mg/kg
0.2
?A'
0
0
-0
m
0
-20
c
< > -20
a)
U4-
<,, -30o
-40
1
sir1
1
*t
-L
1
60
-50 L
*
Ptdmonary Artery Pressure
0Systenic Artery Pressure
FIG 1. Bar graph showing ATP-MgCI2 preferentially decreases
pulmonary arterial pressure during cardiac catheterization in 28
patients with pulmonary hypertension secondary to congenital
heart disease. Data are percent change from baseline. *P<.05
vs no change, tP<.05 vs tolazoline.
80
M Pulmonary vasuar resistnc
El Systei
vaslr restance
FIG 2. Bar graph showing ATP-MgCI2 preferentially decreases
pulmonary vascular resistance during cardiac catheterization in
28 patients with pulmonary hypertension secondary to congenital heart disease. Data are percent change from baseline.
*P<.05 vs no change.
Brook et al ATP-MgC12 for Pulmonary Hypertension in CHD
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
paired normal ventilation-perfusion matching, resulting
in perfusion of underventilated lung segments and
lowered systemic arterial oxygenation. This hypoxemia
could induce acute hypoxic pulmonary vasoconstriction
after ATP discontinuation, accounting for the rebound
pulmonary hypertension.
Patients in our study had a higher incidence of
gastrointestinal side effects than in previous studies.6,7
This difference may be due to a variation in supportive
care. The risk of gastrointestinal side effects with tolazoline has been associated with lower gastric pH.23
Patients in the studies by Bush et al67 were studied
while under general anesthesia and neuromuscular
blockade, which may decrease gastric secretions and
result in higher gastric pH and fewer side effects.
ATP-MgCl2 produced preferential pulmonary vasodilation in patients after cardiac surgery, even though
cardiopulmonary bypass causes endothelial dysfunction.20 24 The 2 patients who did not have a preferential
pulmonary vasodilating response to ATP-MgCl2 were
older and may have had more endothelial cell dysfunction. More studies will need to be performed to determine if infusion of ATP-MgCl2 decreases mortality or
shortens postoperative course in these patients.
Conclusions
The present study shows that ATP-MgCl2 is a safe
and effective vasodilator whose short half-life provides
preferential pulmonary vasodilation in children with
pulmonary hypertension secondary to congenital heart
defects, producing maximal pulmonary vasodilation
without systemic effects. In addition, it has no significant
side effects. ATP-MgCl2 also lowers pulmonary arterial
pressure and decreases the number of pulmonary hypertensive crises in the immediate postoperative period.
Therefore, we suggest that ATP-MgCl2 be considered as
an alternative to other vasodilators in the assessment of
children with pulmonary hypertension during cardiac
catheterization. We also suggest that ATP-MgCl2 be
considered in the treatment of postoperative pulmonary
hypertension or life-threatening pulmonary hypertensive crises.
Acknowledgments
This work was supported by US Public Health Service grants
HL-40473 and HL-35518. We would like to acknowledge Dr
Julien Hoffman and Dr James Bristow for their assistance in
the statistical analysis and review of the manuscript, Dr Gary
Haas for his assistance with the study of the postoperative
patients, and the Division of Cardiology at the University of
California San Francisco for providing study patients.
References
1. Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler
GA, Rowe RD, Olley PM, Cutz E. Pulmonary artery endothelial
abnormalities in patients with congenital heart defects and pulmonary hypertension: a correlation of light with scanning electron
microscopy and transmission electron microscopy. Lab Invest.
1986;55:632-653.
2. Hoffman JIE, Rudolph AM, Heymann MA. Pulmonary vascular
disease with congenital heart lesions: pathologic features and
causes. Circulation. 1981;64:873-877.
1293
3. Bush A, Busst CM, Haworth SG, Hislop AA, Knight WB, Corrin
B, Shinebourne EA. Correlations of lung morphology, pulmonary
vascular resistance, and outcome in children with congenital heart
disease. Br Heart J. 1988;59:480-485.
4. Bush A, Busst CM, Shinebourne EA. The use of oxygen and
prostacyclin as pulmonary vasodilators in congenital heart disease.
Int J Cardiol. 1985;9:267-274.
5. Weesner KM. Hemodynamic effects of prostaglandin El in
patients with congenital heart disease and pulmonary hypertension. Cathet Cardiovasc Diagn. 1991;24:10-15.
6. Bush A, Busst CM, Knight WB, Shinebourne EA. Cardiovascular
effects of tolazoline and ranitidine. Arch Dis Child. 1987;62:
241-246.
7. Bush A, Busst CM, Knight WB, Shinebourne EA. Comparison of
the haemodynamic effects of epoprostenol (prostacyclin) and tolazoline. Br Heart J. 1988;60:141-148.
8. Fiscus RR. Molecular mechanisms of endothelium-mediated vasodilation. Semin Thromb Hemost. 1988;14:12-22.
9. Binet L, Burstein M. Poumon et action vasculaire de l'adenosinetriphosphate (ATP). Presse Med. 1950;58:1201-1203.
10. Lister G, Hoffman JI, Rudolph AM. Oxygen uptake in infants and
children: a simple method for measurement. Pediatrics. 1974;53:
656-662.
11. Rankin AC, Oldroyd KG, Chong E, Dow JW, Rae AP, Cobbe SM.
Adenosine or adenosine triphosphate for supraventricular tachycardias? Comparative double-blind randomized study in patients
with spontaneous or inducible arrhythmias. Am Heart J. 1990;2:
316-323.
12. Drury AN, Szent-Gyorgi A. The physiological activity of adenine
compounds with special reference to their action upon the mammalian heart. J Physiol (Lond). 1929;68:213-237.
13. Kennedy C, Delbro D, Burnstock G. P2 purinoceptors mediate
both vasodilation (via the endothelium) and vasoconstriction of the
isolated rat femoral artery. Eur J Pharmacol. 1985;107:161-168.
14. Ryan JW, Smith U. Metabolism of adenosine 5'-monophosphate
during circulation through the lungs. Trans Assoc Am Physicians.
1971;84:297-306.
15. Fineman JR, Crowley MR, Soifer SJ. Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs.
JAppl Physiol. 1990;69:1836-1842.
16. Fineman JR, Heymann MA, Soifer SJ. No-nitro-L-arginine
attenuates endothelium-dependent pulmonary vasodilation in
lambs. Am J Physiol. 1991;260:H1299-H1306.
17. Fineman JR, Crowley MR, Heymann MA, Soifer SJ. In vivo attenuation of endothelium-dependent pulmonary vasodilation by
methylene blue. JAppl Physiol. 1991;71:735-741.
18. Konduri GG, Woodard LL. Selective pulmonary vasodilation by
low-dose infusion of adenosine triphosphate in newborn lambs.
JPediatr. 1991;119(pt 1):94-102.
19. Roberts J Jr. Inhaled nitric oxide for treatment of pulmonary
artery hypertension in the newborn and infant. Crit Care Med.
1993;21(suppl 9):S374-S376.
20. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ. Use of
inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation. 1993;88:2128-2138.
21. Celermajer DS, Cullen S, Deanfield JE. Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics.
Circulation. 1993;87:440-446.
22. Gaba SJ, Bourgouin KD, Dujols P, Michel FB, Prefaut C. Effects
of adenosine triphosphate on pulmonary circulation in chronic
obstructive pulmonary disease. ATP: a pulmonary vasoregulator?
Am Rev Respir Dis. 1986;134:1140-1144.
23. Butt W, Auldist A, McDougall P, Duncan A. Duodenal ulceration:
a complication of tolazoline therapy. Aust Paediatr J. 1986;22:
221-223.
24. Pearson PJ, Lin PJ, Schaff HV. Global myocardial ischemia and
reperfusion impair endothelium-dependent relaxations to aggregating platelets in the canine coronary artery: a possible cause of
vasospasm after cardiopulmonary bypass. J Thorac Cardiovasc
Surg. 1992;103:1147-1154.
Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary
hypertension secondary to congenital heart defects.
M M Brook, J R Fineman, A M Bolinger, A F Wong, M A Heymann and S J Soifer
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Circulation. 1994;90:1287-1293
doi: 10.1161/01.CIR.90.3.1287
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