Primary Pulmonary Hypertension in a Child: Response to Pharmacologic Agents
B. N. SATYANARAYANA RAO, JAMES H. MOLLER and JESSE E. EDWARDS
Circulation. 1969;40:583-588
doi: 10.1161/01.CIR.40.4.583
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Primary Pulmonary Hypertension in
Response
to
a
Child
Pharmacologic Agents
By B. N. SATYANARAYANA RAO, M.B., B.S., JAMES H. MOLLER, M.D.,
AND JESSE E. EDWARDS, M.D.
SUMMARY
Clinical, pharmacologic, and pathologic findings presented are those in a 12-year-old
boy with primary pulmonary hypertension associated with medial hypertrophy of the
pulmonary muscular arteries and arterioles.
Intrapulmonary arterial administration of acetylcholine, tolazoline (Priscoline), or
isoproterenol resulted in a fall in pulmonary vascular resistance and pressure.
Perforation of the right ventricle by an indwelling catheter terminated studies on the
results of long-term intrapulmonary arterial administration of drugs shown to be effective.
Additional Indexing Words:
Acetylcholine
Tolazoline
Isoproterenol
the principal structural abnormality of the
pulmonary arterial vessels to be medial hypertrophy, a process which suggests the potential
of vasodilatation.
CINCE Romberg's description in 18911 of a
a case of primary pulmonary hypertension,
numerous examples of this condition have
been reported. From this background, the concept has evolved that primary pulmonary hypertension is a progressive, fatal condition,
unresponsive to therapeutic attempts, and related to fixed pulmonary vascular changes. In
a few patients, however, administration of certain drugs has been followed by a decrease
in pulmonary vascular resistance and pressure
(table 1).
The primary purpose of this report is to
describe the case of a 12-year-old boy with
primary pulmonary hypertension in whom
isoproterenol, tolazoline (Priscoline), and
acetylcholine each resulted in a three to fourfold decrease in total pulmonary vascular resistance. After the patient died from an
unfortunate complication, necropsy showed
Report of Case
Clinical Features
A 12-year-old boy, on admission to the University of Minnesota Hospitals, presented a history of well-being until 2 years earlier when dizzy
spells, syncope, headaches, and chest pain began.
Initially, these symptoms were considered to have
resulted from an automobile accident in which
the boy had been rendered temporarily unconscious. Neurologic examination following the accident failed to reveal any abnormality. Because
of the symptoms named and the development of
dyspnea on exertion, the patient was referred for
evaluation. The family history was negative for
collagen disease and pulmonary hypertension.
Physical examination revealed a slender, acyanotic, white boy in no apparent distress. The
body weight was 74 pounds and the height was
58 inches. The brachial blood pressure was 92 mm
Hg, systolic, and 55, diastolic, and the pulse rate
was 70 beats/min. Slight cardiomegaly was associated with a diffuse left parasternal heave. While
the first cardiac sound was normal, the pulmonic
component of the second sound was markedly
accentuated and no murmur was present. The
liver was enlarged, its lower edge lying 2 cm
below the right costal margin. There was no
From the Department of Pathology, the Charles T.
Miller Hospital, St. Paul, Minnesota, and the Departments of Pediatrics and Pathology, University of
Minnesota, Minneapolis, Minnesota.
This study was supported by U. S. Public Health
Service Research Grant 5 ROI HE05694 and Research
Training Grant 2 TI HE05570, from the National
Heart Institute, and the Dwan Family Fund.
Circulation, Volume XL, October 1969
Intrapulmonary arterial drug therapy
583
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RAO ET AL.
584
Table 1
Summary of Reported Response to Short-Term
Intravenous or Intrapulmonary Arterial Administration of Various Drugs in Primary Pulmonary
Hypertension*
Drug
Tolazolinet
Acetylcholine
Hexamethonium
Isoproterenol
Response (cases)
Positive Equivocal Negative
Total
5(3-6)
1(2)
1(7)
7
3(8-10)
2(8,11)
2(8,11)
1(5)
3(12)
0
1(2)
0
0
7
2
3
* Except one patient of Wade and Ball2 who was 11
years old, each subject was an adult, the oldest being 48
years of age.
t Hemodynamic response unknown in two cases.'
clinical evidence of systemic disease, chronic
pulmonary disease, or chronic obstruction of the
airways.
An electrocardiogram revealed right axis deviation (+ 1300), evidence of right atrial enlargement, right ventricular hypertrophy, and inverted
T waves in leads V1 to V4. The vectorcardiogram
showed signs of severe right ventricular hypertrophy. Thoracic roentgenograms revealed normal
cardiac size and dilatation of the pulmonary trunk
and of both the pulmonary arteries. There was
attenuation of the peripheral pulmonary vascular
markings.
Laboratory studies gave the following results:
hemoglobin, 14.9 g/100 ml of blood; hematocrit,
43%; sedimentation rate performed twice, 31 and
17 mm per hr.; LE clot test, negative; serum electrolytes, normal; urinalysis, normal; coagulation
profile, normal.
Scintiscan of the brain gave negative results,
and the electroencephalogram was mildly abnormal but without focal abnormalities.
On the basis of the clinical analysis, a presumptive diagnosis of primary pulmonary hypertension
was made, and cardiac catheterization was performed. This study showed severe pulmonary
hypertension with a pulmonary arterial pressure
at rest of 82/45 and an electronically meaned
pressure of 60 mm Hg. Simultaneously determined systemic arterial pressure was 120/80, with
a mean of 94 mm Hg. The pulmonary "arterial
wedge" pressure was normal, the mean being
7 mm Hg. There was no evidence of any shunt.
The right atrial pressure was normal (mean 6 mm
Hg). The levels of systemic arterial blood gases
were: Po2, 81.6 mm Hg; Pco2, 31 mm Hg; and
pH, 7.42. These findings were considered to exclude veno-arterial shunting, obstructive pulmonary disease, and hypoxic pulmonary hypertension
related to hypoventilation. Failure of the pulmon-
ary arterial pressure to change during inhalation
of 100% oxygen further excluded hypoxia as a
basis for the pulmonary hypertension. Simultaneous analysis of alveolar gas (end expiration)
and of arterial blood gasses revealed no alveolararterial gradient of Pco2, thereby excluding any
major ventilation-perfusion defects. Right ventriculography showed a large right ventricular
cavity, massively dilated pulmonary arteries, and
marked attenuation of the peripheral pulmonary
vasculature. There was no evidence for the presence of gross pulmonary emboli.
The findings of the cardiac catheterization,
therefore, strongly favored primary pulmonary
hypertension, although multiple microscopically
sized pulmonary emboli could not be excluded.
To study the reactivity of the pulmonary vascular
bed, hemodynamic measurements were made during exercise and during infusion of pharmacologic
agents. The results are summarized in figure 1.
At rest, the cardiac output was at the lower limits
of normal and the pulmonary arterial pressure
elevated, indicating a high degree of pulmonary
vascular resistance. Inhalation of 100% oxygen
at rest showed no significant change in any of
the measured parameters.
Development of fatigue limited the amount of
exercise possible. With exercise, the systemic
blood pressure and cardiac output increased only
slightly, while the pulmonary arterial pressure
rose to nearly equal the systemic pressure. Infu-
Figure 1
Physiologic parameters in the resting state and under
varying conditions, as obtained during the first study.
Circulation, Volume XL, October 1969
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PRIMARY PULMONARY HYPERTENSION IN A CHILD
sion of acetylcholine (1 mg/min for 10 min) and
isoproterenol (Isuprel) (2 ug/min for 13 min)
separately were each accompanied by a significant
increase in the cardiac output with marked reduction of the pulmonary arterial pressure. The
mean systemic arterial pressure remained unchanged. The results, therefore, indicated a
marked elevation of pulmonary vascular resistance
at rest which was remarkably responsive either
to acetylcholine or to isoproterenol. Following this
study, the patient was discharged without any
medication prescribed. Within a few weeks, he
experienced further dizziness, syncope, and decrease in exercise tolerance. When the patient
was readmitted for further evaluation, the effects
of tolazoline and isoproterenol upon the pulmonary
arterial resistance were tested with a view to
subsequent therapy. The second cardiac catheterization (fig. 2) showed essentially the same fundamental abnormalities as the first. Infusion of 2
,ug/min of isoproterenol for 10 min resulted in
significant decrease in pulmonary arterial pressure and vascular resistance. This change persisted during the period of infusion and for a
few minutes thereafter. Beyond that, there was
a gradual elevation of pulmonary arterial pressure. Twenty minutes after discontinuation of the
infusion, the pulmonary arterial pressure had
risen to the pre-infusion level. Injection of 30
mg of Priscoline into the pulmonary artery over
a period of about 45 sec was followed within a
few minutes by a significant decrease in the pulPHYSIOLOGIC MEASUREMENTS IN PRIMARY PULMONARY HYPERTENSION
(Second Study)
0
Mean
Pulmonary Arterial
(mm HgI
50
2000Pulmonary Resistonce
Dynes Sec cm5
1000
EPul. Vascular Resstance
3 Total Pul. Resistance
Cardiac Output
L /min.
4-
.l
Mean
Brachial Arterial
Pressure (mmHg)
Pulse
Rate
i
l
___
l
5 010
16 _
lL
50
o
20
150-
Minutes
Condition
50: 10
l
o
27
a
-
6
v
_t_
Ro
~~Room
*
Figure
A
Air
2
Hemodynamic parameters in the various conditions,
obtained during the second study.
as
monary arterial pressure to about 40 mm
pressure remained at this level for more
585
Hg. The
than 60
min. While in the hospital, the patient was then
given Priscoline orally and his progress was followed including measurement of systemic blood
pressure. The initial oral dose of Priscoline was
25 mg/day. The dose was gradually increased
to 25 mg four times a day. There were no evident clinical changes, although he exhibited cutaneous flushing. The oral dose of Priscoline was
further increased to 25 mg six times a day.
During this course, the systemic blood pressure
remained unchanged, although the patient continued to have episodes of syncope, some of
which were associated with convulsions. After
2 weeks of this therapy, cardiac catheterization
was performed. The pulmonary arterial pressure
(90/50) and calculated resistance (1400 dynes
sec cm-5) were at the previous hypertensive levels.
The administration of Priscoline by mouth was
discontinued. The oral administration of guanethedine (10 mg/day) and digitalization did not
alter the clinical picture.
It was then decided to place an indwelling
catheter in the pulmonary artery for administration of drugs and measurement of pressure.
For this purpose a no. 5 Teflon catheter was
advanced from an antecubital vein into the main
pulmonary artery and secured. Initially, Priscoline
was used in a constant infusion into the pulmonary artery but in pulmonary arterial pressure was
only slightly reduced (fig. 3). Use of this drug was
discontinued. Isoproterenol infusion was then started (0.1 to 0.4 ,ug/min). With this drug, the mean
pulmonary arterial pressure fell to an even level
between 20 and 35 mm Hg. During this period,
the patient's blood pressure ranged from 90/60 to
120/80 mm Hg. Six days after the catheter had
been secured in the pulmonary artery, the patient
developed severe thoracic pain, respiratory distress, and cyanosis. Roentgenograms of the thorax revealed enlargement of the cardiac shadow.
Withdrawal of a serosanguineous fluid (100 cc)
from the pulmonary arterial catheter was considered evidence of perforation of the pulmonary
artery or right ventricle, with the open end of the
catheter in the pericardial cavity. The cardiac
catheter was withdrawn. Temporary improvement
was followed by recurrent signs and symptoms
of cardiac tamponade. Thoracotomy revealed 500
cc of blood in the pericardial sac and a perforation in the oufflow tract of the right ventricle.
The blood was removed, and the perforation was
sutured. During the operation, the patient had
repeated episodes of bradycardia and cardiac
arrest from which he was resuscitated. In the
immediate postoperative period, the patient developed hypotension and bradycardia from which
he could not be resuscitated and death occurred.
Circulation, Volume XL, October 1969
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586
RAO ET AL.
r-MEAN PU MONARY ARTERIAL----------------K
PRESSURE IN PRIMARY PULMONARY HYPERTENSION WITH DRUG THRRAPY;
5I oW
E -704
t
-
5o
30-
pr iscol.ne
30 -g2
E
.
111
2/23
PrIscolPn 15
/h
2/24
PNscoline
20 nISghr
L------2/ 27
2/28
2126
2/25
Tirne in Days
Figure 3
Mean pulmonary arterial pressure uinder conditions of
,ariations itn adminiistrationt of tolazolitne (Priscoline)
and isoproterenol (Iisprel).
Pathologic Features
Pertinenit findings at n-eciropsy
to the heart and lungs. The heart
lirnited
einlarged
(330 g) on the basis of a markedly dilated and
hypertrophied right ventricle. The latter measured
0.8 cm in thiickiness. The left ventricular thickness
was 1.4 cm. There was a small sutLred perforationl of thlie anteriior wall of the right ventricular
outflow tract just below the pulmonary valve.
The pericardial sac contained a small amount of
residual blood. Except for the right ventricular
hypertroply, there were no intracardiac lesions,
either congenital or acquired. The forameni ovale
shoxved a valvular competent patency. The ventricuilar septum was intact and no sign of a spontaneously closed defect was present. The ductus
arteriosus was represented by a ligament with
no unuisual features.
The pulmoniary trunk, which was markedly
dilated, measured 7.0 cen in diamneter anid vas
were
was
xvider thliai the aorta, whichi wvas 5.5 em in dianeter. The wall of the pulmoniary trunk and of its
two
branches
was
thickened.
Initimal
athero-
sclerotic plaques were present in small numbers.
There was nlo evidence of gross pulmonary emboli
or infarcts.
I-listologically, the pulmonary trunk showed
tlhickeninig of the intima with accumulation of
foam cells. Marked thickening of the media by
elastic tissue and cystic medial necrosis were also
present. The histologic patterm of the media was
similar to that of the aorta. The muiscular pulmonary arteries and arterioles in both lungs
showed medial hypertrophy (fig. 4) as a general
characteristic, and intimal fibrous thickening of
minimal extent was present in isolated small arteries. The pulmonary capillaries, venules, and
parenchyma were normal.
_t.
Figure 4
Photonmicrograph of pulmonary muscular artery of
about 100 microns in diameter. It shows medial hypertrophy anid prominent endothelial cells without fibrous
intimal proliferation. Thtis picture is representative of
the changes seen in this class of vessel as well as in
the musculair segments of the pulmonary arterioles.
Elastic tissue stain;
x
500.
commonly regarded as a progressive, eventuially fatal, condition related to fixed pulmonary
vascular changes.
In those cases folloving such a course, the
process is understandable when the basis for
pulmonary hypertension is organic fibrous obstnietion of the small pullmonary arterial
vessels. It is recognized, however, that, in
addition to cases of primary pulmonary hypertension in which intimal lesions seem primary,
there is a second type of primary pulmonary
hypertension.13 The latter type is characterized
structLrally by medial hypertrophy of the
small arterial vessels of the lung. On hypothetical grounds, such cases would be expected
to respond with a fall in pulmonary arterial
pressure under appropriate vasodilatory stimulus.
Comment
Primary pulimionary hypeitension is conm-
The case reported conforms anatomically to
the latter type.
CircUlation, Volurme XL, October 1969
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PRIMARY PULMONARY HYPERTENSION IN A CHILD
The structure of the media of the pulmonary
trunk resembled that of the aorta. This suggests strongly that the pulmonary hypertension
had been present from birth.14
The significance of the clinical studies are
that administration of certain drugs (acetylcholine, Priscoline, and isoproterenol) resulted
in a fall in pulmonary arterial pressure. It was
of practical importance, however, that high
dosage and intrapulmonary arterial administration were required to achieve the desired
effect. It is, as yet, unknown whether longterm intrapulmonary arterial administration
would have (1) continued to be effective or
(2) been followed by a break in the factor
which led to the pulmonary arterial vasoconstriction responsible for the pulmonary hypertension. In our study, the complication of
perforation of the right ventricle by the indwelling catheter terminated the life of the
patient and therefore precluded the long-term
study desired.
Review of the literature indicates that several drugs have been tested for hemodynamic
response in primary pulmonary hypertension.
The results of these studies are summarized in
table 1. It is evident that, of the four drugs
used, each by short-term intravenous or intrapulmonary arterial administration, tolazoline
or acetylocholine were tried more than the
other two drugs, namely, hexamethonium and
isoproterenol. According to these reports, varying results were obtained with each of the two
major drugs, although more commonly a favorable hemodynamic response was obtained than
an equivocal or negative one.
References
1. ROMBERG, E.: Zur Frage der Herzganglien. Centrabl Physiol 4: 601, 1891.
2. WADE, G., AND BALL, J.: Unexplained pulmonary
hypertension. Quart J Med 26 (NS): 83, 1957.
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3. DRESDALE, D. T., MICHTOM, R. J., AND SCHULTZ,
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M.: Recent studies in primary pulmonary hypertension including pharmacodynamic observations on pulmonary vascular resistance. Bull
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DRESDALE, D. T., SCHULTZ, M., AND MICHTOM.
R. J.: Primary pulmonary hypertension: I.
Clinical and hemodynamic study. Amer J Med
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Yu, P. N.: Primary pulmonary hypertension: Report of six cases and review of literature. Ann
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GORLIN, R., CLARE, F. B., AND ZUSKA, J. J.:
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man. Brit Heart J 20: 346, 1958.
HARRIS, P.: Influence of acetylcholine on the
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MARSHALL, R. J., HELMHOLZ, H. F., JR., AND
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SAMET, P., BERNSTEIN, W. H., AND WIDRICH, J.:
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LEE, T. D.. ROVETI, G. C., AND Ross, R. S.: The
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BERTHRONG, M., AND COCHRAN, T. H.: Pathological findings in nine children with "primary"
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14. HEATH, D., WOOD, E. H., DUSHANE, J. W., AND
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pulmonary hypertension and pulmonary stenosis. J Path Bact 77: 443, 1959.
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