Radiographic
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DAVID
and Echocardiographic Evaluation with Indomethacin for Patent Ductus K.
EDWARDS,1
CHARLES
B. HIGGINS,1
AND
WILLIAM
T. ALLEN MERRITT,2 F. FRIEDMAN2
A series of 33 consecutIve preterm newborns who were treated with Indomethacin, a drug which acts to close the patent ductus arteriosus, were studied retrospectively to cxamine the efficacy of chest radiography and echocardiography in diagnosing the presence of a significant patent ductus arteriosus. Radiographic changes In pulmonary vascular engorgement, pulmonary edema, and cardiac size on the anteroposterior film tended to precede the clinical changes of shunt appearance and resolution. The echocardlographic left atrial to aortic ratio (LA/Ao) supplemented the radiographic findings. The time of disappearance of the ductus arterlosus shunt, as judged by clinical findings, was identified accurately by radiographic and echocardlographlc findings in the majority of cases; errors of under- and overestimation occurred in a minority of patients. In assessing both the presence and the resolution of the shunt, greater reliability was possible by using both radiographic and echocardlographic findings than by using either method alone.
Pulmonary the
overcirculation
ductus
from
is
arteriosus
threatening
problem
changes
radiographic
and
and
newborn
of a patent involving
radiographic
patency
[4],
often
follow
The
arteriosus
ligation
little
information
is
point. No arteriosus
have
been
available
such distinct endpoint closes spontaneously
maneuvers Accurate become
are used diagnosis
with
because agents
Prostaglandin
E
of that
has
the
recent
affect been
the shown
and
is
the
ductus Received
with
arteriosus May
C. B. Higgins Lung Institute. ‘ Department K. Edwards. 2 Department Am J Ro.ntgenol © 1978 American
considerable in effecting
[9-11] nonsurgical
in clinical
12, 1978;
accepted
is the recipient
trials. after
but
When revision
C. H.)
its
left
atnial
acm
a specific
accuracy
of
to determine closure.
chest
the
time
Methods
evaluated
in 33 preterm ductus
without were
and
infants
arteniosus
and
in
knowledge
of the
noted
from
clinical
the
dates
of
course;
patients’
records.
when
it began
to decrease.
data
to aortic
in this
Hospital
described
of normal records
an agent
to
30.3
as small
size. were
were
Of the
examined
determine
the
Career Development
Award,
treated
when
ages
at
these which
age; were
the
in
by
and
average
Three
patients
remainder
male.
The
available
significant
24 at
Hospital
determined
26-35)
18 were
was
hospitals:
at Sunrise
640-2,700).
gestational
33 patients,
of indometh[14].
at two
(range,
The
maximum,
dimension
age at birth
(range,
echo-
[4].
at its
the course
and nine
weeks for
noted
elsewhere
gestational
was 1 .336 grams
23 patients;
described
diastolic
as described series
for
was end
in San Diego
was
birthweight
(LA/Ao)
ventricular
Average
examination
available
as previously
and following
left
17 patients
patients
Las Vegas.
were
ratio
preceding, on
were
measured root
The
Similar
and reduction in edema. Weighcourse, a subjecthe final dose of was also made of
closure.
were
therapy.
The
(23 clinical
were clinical
patients) findings
7. 1978.
Hospital,
225 West Dickinson
of Pediatrics,
University
of California
Hospital,
San Diego. California
1978
to document-
or of the patients
data
of shunt
University
the
of California
December
were
of a signifi-
findings,
of patent
together
maximum,
success
measured
of U.S. Public Health Service Research
Ray Society
working these
University
131:1009-1013,
and
signs
subsequently
of Radiology,
Roentgen
clinical
cardiograms
not invariable closure of the
Seotember
In addition the
clinical
who
signs
diagnostic
were
administration
arterio-
such
clinical
independently success of ductus
Echocardiographic
ductus arteriosus [6-8], while inhibitors of prostaglandin synthesis act to close the ductus [6, 9, 10]. Indomethacin is a potent inhibitor of prostaglandin synthetase that has used success
retrospec-
and
,
newborns
determine
indomethacin
the
has
dilate
compare
times were noted for the onset, maximum, pulmonary vascular enlargement and pulmonary ing these factors and the overall radiographic tive estimate was made of the time when indomethacin was administered. An estimate
development to
of the to
which
Initial chest nadiographs were examined to identify each patient’s initial radiographic diagnosis. Cardiothonacic ratios (C/T) were measured on all films as described elsewhere [4]. Times were noted at which the C/T began to increase, when it
the ductus nonsurgical
ductus
by
whom pharmacologic closure of the ductus was attempted with indomethacin. The use of this drug was as described elsewhere [9, 11 , 13]. The nadiographs were examined by two of us (D. E.
described
patency
after
radiognaphs
exhibited
to
preterm
Subjects who
was
arteriosus.
made
immediately arteriosus
study of 33
ductus
used
markers
echocardiographic
chronology was
G. DiSESSA,2
identify
indomethacin
patent
Treated
be judged.
our
a series
Sequential
that
regarding
exists when or when
to close it. of ductus
imperative
pharmacologic
been [12]
treated the
to
may of
radiography and therapeutic
changes that occur when there is nonsurgical resolution. Surgical closure of the ductus arteriosus has the advantage that the surgery itself provides a therapeutic end-
sus.
in
effort
[1-3].
changes
desirable
radiographic,
findings
ing
is
purpose the
cant
echocardiography
echocardiographic
ductus but
of
it
THOMAS
of therapy
tively
life-
infants
used,
success
of
ductus arteriosus clinical markers,
and
is
reached
The [4],
a frequent
in premature
Preoperative diagnosis usually nonangiographic, chest [4,5].
prolonged
of Newborns Arteriosus
1009
grant no. KO4 HLOO2O1 from
Street, San Diego. California
92103. Address
the National
reprint
Heart
requests
92103. 0361
-803X/78/1
200-1009
$00.00
and
to D.
1010
EDWARDS
ET
TABLE Correlation
of Clinical
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Mean Age (Days)
1
and Radiographic .
.
.
. .
Observations Radiographic and Echocardiographic
clinical
Enlargement
5.1
(1-17)
5.3 5.9 6.6
(2-12) (1-15) (2-17)
7.5
(3-14)
Bounding
9.4 9.4 9.7 10.2 10.2 10.3
(4-33) (3-34) (1-35) (5-35) (5-33) (4-31)
Peak of clinical symptoms First indomethacin dose
1 1 .7
(336)
13.0 13.3 13.8 14.3
(3-43) (6-43) (6-43) (6-47)
Significant
murmur . . .
Enlargement
Onset of pulmonary
. .
pulses
Final
. .
.
. .
indomethacin
... ...
Maximum Maximum Maximum Maximum dose
Radiographic
. . .
Clinicalsymptom
cardiac size vessel enlargement LA/Ao ratio pulmonary edema estimate
of final
dose
Cardiac size decrease Pulmonary vessel decrease Pulmonary edema decrease
. . .
are ranges.
size
edema
...
. . .
in parentheses
of cardiac
noted
. .
.
vessels
...
. . .
(4-39)t
of pulmonary
noted
.
.
Note-Numbers
.
AL.
resolution
...
clinical.
t Radiographic
suggesting
and echocardiographic.
a patent
ductus
arteniosus were
reached
a maximum,
initially
noted,
and resolved. Results
Radiographic
Observations
The primary radiographic diagnosis for 26 patients was respiratory distress syndrome. Four patients demonstrated what has been termed “immature lung” [15], with minimal granularity and no significant airbronchograms. Two patients exhibited no discernable pulmonary parenchymal disease, but had congestive heart failure that was initially mild. One patient had an initially normal chest radiograph, but within a few days developed findings characteristic of Wilson-Mikity syndrome [16]. The time course of the findings of pulmonary vascular enlargement, pulmonary edema, and enlarged cardiac silhouette is summarized in table 1 . All patients during their clinical courses exhibited enlargement of pulmonary vessels, manifested by appearance of numerous hilar and perihilar en face vessels (“shunt vessels”). Initial pulmonary plethora appeared at 1-17 days of age (average, 5.1 days); these enlarged vessels tended to be the first manifestation of patent ductus arteriosus. Vessel enlargement was maximal at 10.2 days of age, and discernable decrease was observed at an average of 13.3 days. Pulmonary edema was observed in all but one patient. The average age at onset was 6.6 days. Edema was maximal at 10.3 days, and began to decrease at 13.8 days. Cardiothoracic ratio (C/T) averaged 52.5% on the initial chest film. Onset of discernable enlargement over the initial value was noted at an average of 5.9 days, and maximal C/T occurred at 9.7 days. Decrease in cardiac size occurred at 13.0 days. Maximum C/T never exceeded 60% in 21 patients. Of these 21 patients, five demonstrated an increase in C/T of 5% or more, while the remainder showed lesser increases. A total of 17 patients had maximum C/T increases of less than 5%. Of
these patients, 16 demonstrated over the sequence of films an increase and subsequent decrease in CIT that paralleled clinical symptomatology, even though the change was less than 5%. One patient demonstrated no discernable increase in cardiac size during his hospital course, and two patients never exhibited a decrease after enlargement of their cardiac silhouettes. The latter two patients did not have subsequent chest radiographs. All patients but one required assisted ventilation during their hospital courses. A wide variety of pulmonary abnormalities,
many
probably
related
to
assisted
venti-
lation, were observed. These included varying degrees of atelectasis (14 patients), pleural effusion (two), aspiration (three), pneumothorax (six), pneumomediastinum (one), pneumopericardium (one), and interstitial emphysema (eight patients). Hyperaeration was not a frequent finding. Echocardiographic
Observations
The echocardiograms obtained in 23 infants showed a peak left atrial to aortic root (LA/Ao) ratio of 0.8-0.9 in four infants, suggesting a moderate left to right shunt, and a peak ratio of 1 .0 or greater in 12 infants, suggesting a large-volume shunt [17]. The average peak LA/Ao ratio was 1 .0 (range, 0.5-1 .4). The average age at the peak LA/Ao ratio was 10.2 days. The average LA/Ao ratio prior to initiation of indomethacin was 0.9 (range, 0.41 .4),
and
after
the
course
of
the
drug
was
0.6
(range,
0.4-1 .0). The LA/Ao ratio decreased after indomethacin therapy in all but one patient. All patients who exhibited elevated LA/Ao ratios also demonstrated enlarged left ventricular end diastolic dimension, in the 17 patients for whom this was measured. Of
the
seven
patients
with
LA/Ao
of
less
than
0.8,
absolute cardiomegaly (C/T more than 60%) was seen in two patients, and four patients exhibited significant increase in CIT (more than 5%). Only one patient with normal LA/Ao ratio demonstrated neither cardiomegaly nor significant increase in C/T. However, this patient did
INDOMETHACIN
IN
PATENT
DUCTUS
ARTERIOSUS
1011
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..
r Fig. 1.-Patient after indomethacin
Fig.
=i
who exhibited gradual clearing after drug therapy. A, Anteropostenion therapy showing partial resolution of pulmonary plethora and edema.
2.-Patient
who responded therapy showing
after indomethacin
immediately to drug therapy. A, Anteroposterior marked clearing of cardiomegaly, and pulmonary
exhibit pulmonary plethora and edema. Thus in all patients either radiographic or echocardiographic signs of a large volume shunt were identified prior to indomethacm therapy.
view
Evaluation
Radiographic When
the
time
of
the
Four
patients
were
arteriosus after ductal ligation. appeared
to
to
have
felt
to have
indomethacin Radiographically improved
recurrent
patent
therapy and three of in
terms
of
ductus
underwent these four
shunt-related
abnormalities but had not entirely resolved; in the fourth infant the radiographic abnormalities appeared to have resolved completely. At surgery the patent ductus arteriosus was very small (2 mm) in the latter patient, and persisting moderate-sized in the other three.
In
dose
have
closed
seven
successful
average
time
of
these
over slow trasted clearing
cases the
the
time
cases
final
exhibited
dose
than
time
the
in 17 cases
the
resolution
to
of
by up
nine
average cases
therapy
dose that
was
6 days.
The
of indomethacin
as the
of successful
indomethacin
dose estimate
up
dose
same
felt
estimate
the final
by
final
was
radiographic
radiographic dose
the actual
that
the
actual
of
estimate
actual
the
of success-
with
ductus),
of the was
date
radiographic
the
final
examination
radiographic
than
the
earlier
which
Subsequent the
of the
is,
was
estimated
was 1 1 .7 days, time.
(that
the
Therapy
compared
24 hr of the
in nine
the
was
cases,
therapy
5 days;
past
final
lay within
(52%).
B, Film 1 day
administration.
estimate
therapy
B, Film
administration.
of Indomethacin
radiographic
ful indomethacin
to
to indomethacin
Estimation
estimate
A chronologic summary of the major clinical events is presented in table 1 . The first time a significant murmur was noted was at an average age of 5.3 days; the average peak of clinical symptoms was 9.4 days, the same average time as the first dose of indomethacin. The average time of clinical resolution was 14.3 days.
prior
view of chest prior to indomethacin plethora and edema.
clinically Clinical
of chest
actual in which was
later
revealed
occurred
that slowly
several days. An example of a patient who exhibited clearing is shown in figure 1, which may be conwith after
a patient indomethacin
who
exhibited therapy
marked (fig.
2).
immediate
EDWARDS
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1012
Examination of the seven cases in which the radiographic signs of significant improvement preceded the actual completion of indomethacin therapy revealed that, in four cases, the volume of the left-to-right shunt was probably small prior to indomethacin treatment because the C/T was below 60% and the peak LA/Ao ratio (in the two cases measured) was only 0.6. In three of these cases, two doses of indomethacin were administered after radiographic clearing of what appeared to be small shunts. In one of these patients, persisting respiratory dependency led eventually to ductal ligation; as predicted radiographically, this patient had a very small patent ductus arteriosus. In the other four cases, radiographic findings suggested significant improvement after the first dose of indomethacin, but clinical findings
prompted
additional
doses.
Of the 16 patients in whom radiographic assessment of successful therapy was erroneous, 1 1 were among the 23 patients on whom echocardiography was done. Of these 1 1 five patients demonstrated decreases in LA/Ao ratio from 1 .0 or above to below 0.8 with indomethacin therapy. Had this LA/Ao ratio drop been used in conjunction with the radiographic findings, the number correct would thus have been 17 of 23, or 74%. In the remaining five patients, neither the LA/Ao ratio nor the radiographs reflected the exact time of shunt closure as defined by clinical evidence of closure. ,
ET AL. indomethacin dose, but there were errors of up to 5 and 6 days in either direction. Accuracy within 24 hr was attained with only 52% of patients. Of the factors that may contribute to this inaccuracy, possibly the most important is that the standard for radiographic evaluation in this study was clinical assessment of the shunt. The accuracy of clinical evaluation is always open to question in the absence of direct evidence. This factor, together with partial or incomplete ductus closure, may have contributed to the error made in seven cases in which the radiographs would have suggested cessation of therapy
In evaluating the onset of a significant shunt across a patent ductus arteriosus in a newborn infant, the current study supports a previous report [4] that indicative changes on the chest radiograph are contemporary with and often in advance of clinical detection of a significant heart murmur. The sequence of clinical and radiographic changes is more striking than the average times of these observations would suggest (table 1), because in many cases radiographic evaluation was not requested until after there was clinical suspicion of a shunt. In examining the radiographic indices of significant shunt, the most sensitive were engorged pulmonary vessels, which were observed with all patients except one. The size of the cardiac silhouette was a relatively insensitive
index
of shunt
severity.
Absolute
indomethacin
which probably represents left-to-right shunt [17]. In diagnosing
of the average tration
radiographs estimation coincided
ductus
the arteriosus
lower
limit shunt
for closure,
a moderate the
It may
actually
discontinued.
in infancy
be concluded
from
are a fairly
of
a significant
of
pulmonary
[9].
in considering
the
ductus
study
weighed
that
indicator
arteriosus
vascular
are
this
reliable
shunt,
appearance
if the
enlargement more
radiographic
of the and
heavily
changes
pulmonary
than
measurable
changes in the cardiothoracic (C/T) ratio. If the C/T is considered together with the echocardiographic LA/Ao ratio, greater accuracy is possible than with using either measurement alone. The exact time of ductus closure is not reliably estimated by any of the variables examined in this study , although again greater accuracy is attained by using echocardiographic data together with the radiographs than by using either alone. More reliable indices of
shunt
closure
developed logic
agents
than
those
examined
in order
to monitor
the
such
as indomethacin.
here
effects
need
to
be
of pharmaco-
REFERENCES 1 . Kitterman Tooley
JA, WH,
mature
Edmunds Rudolph
LH AM:
infants.
Incidence,
and management.
N EnglJ
2. Neal WA, Bessingen
Jn,
Gregory
Patent
relation Med
GA,
ductus
FB Jn, Hunt
4. Higgins
CB,
Rausch
12:57-65, J, Friedman
MA, in
to pulmonary
287:473-477,
CE, Lucas
arteniosus complicating respiratory drome. J Pediatr 86: 127-131 , 1975 3. Rudolph AM, Heymann MA: Medical treatment
arteniosus.HospPrac
Heymann
arteniosus
ductus
pre-
disease
1972
RV Jr: Patent distress ofthe
synductus
1977 WF,
Hirschklau
MJ, Kirk-
patrick SE, Goergen TG, Reinke AT: Patent ductus sus in preterm infants with idiopathic respiratory
arteniodistress
syndrome. Radiographic and echocardiographic evaluation . Radiology 1 24 : 189-1 95, 1977 5. Laird WP, Fixler DE: Echocardiography of premature infants with pulmonary disease: a noninvasive method for detecting large ductal left-to-right shunts. Radiology
use
was only modestly successful. The of the date of indomethacin ad miniswith the average date of the final
therapy
changes
cardiomeg-
aly (C/T more than 60%) was seen in only 36% of patients, and significant increase in C/T (more than 5%) was seen in only 48%. A large number of patients (48%) demonstrated neither absolute cardiomegaly nor significant increase in C/T. The other numerical variable examined in this study was the echocardiographic LA/Ao ratio. Like the C/T findings, this ratio was not always indicative of clinical status. In 48% of 23 cases, the peak LA/Ao ratio was below 1.0, and in 30% the peak was below 0.8, the value
it was
accuracy of radiographic evaluation of patent ductus arteriosus shunt, it is worth noting that with the four cases who underwent surgical ligation, the final radiographs predicted the operative findings correctly.
edema Discussion
before
In nine cases the radiographs alone would have suggested a need for additional doses of indomethacin. In the majority of these patients clearance of pulmonary plethora and/or edema was relatively slow. It is speculated that this type of error may relate to slow clearance of fluid; transient oliguria is a known side-effect of
122:455-457,
1977
6. Elliott RB, Starling MB, Neutz JM: Medical manipulation the ductus arteniosus. Lancet 1:140-142, 1975
of
7.
by
Heymann
MA,
Rudolph
AM:
Ductus
arteniosus
dilatation
INDOMETHACIN
IN
PATENT
DUCTUS
prostaglandin
E1 in infants with pulmonary atresia. Pediat1977 8. Lang P, Freed MD, Rosenthal A, Castaneda AR, Nadas AS: The use of prostaglandin E1 in an infant with interruption of the aortic arch. J Pediatr 91 : 805-807, 1977 9. Friedman WF, Hirschklau MJ, Pnintz MP, Pitlick PT, Kirkpatrick SE: Pharmacologic closure of patent ductus arteriosus in the premature infant. N EngI J Med 295:526-529, 1976 10. Heymann MA, Rudolph AM, Silverman NH: Closure of the ductus arteniosus in premature infants by inhibition of prostaglandin synthesis. N EngI J Med 295: 530-533, 1976
13.
11.
16.
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rics
59:325-329,
Friedman WF, Heymann MA, Rudolph AM: Commentary: new thoughts on an old problem-patent ductus arteniosus in the premature infant. J Pediatr 90:338-340,1977
12. Neal WA, Kyle JM, Mullett MD: Failure of indomethacin therapy to induce closure of patent ductus arteniosus in premature infants Pediatr 91:621-623,
with
1977
respiratory
distress
syndrome.
J
14.
Friedman taglandin
1013
ARTERIOSUS
WF, Pnintz synthesis-a
MP, Kirkpatrick novel therapy
SE: Blockers of prosin the management of the premature infant with patent ductus arteniosus, in Advances in Prostaglandin and Thromboxane Research , ed-
ited by Coceani 373-381
F, Olley
PM, New York,
Hirschklau MJ, Echocardiographic
DiSessa TG, diagnosis:
fant with a large patent ductus 477, 1978 15.
Parker
Immature
BR,
Pinckney
LE,
lung syndrome
Hodgman
JE,
respiratory syndrome.
distress Pediatrics
Mikity
and
JD,
Northway
WH
Jr:
Clin Res 24: 194A, 1976 D,
Cleland
AS:
Chronic
in the
premature infant: Wilson-Mikity 44: 179-195, 1969 Y, Williams DE, Allen HD, Goldberg SJ,
17. Sahn DJ, Vauchen Friedman WF: Echocardiographic night shunts Am J Cardiol
CB, Friedman WF: in the premature inarteniosus. J Pediatr 92 : 474-
Johnson Tatter
1978, pp
Higgins pitfalls
(abstr).
VG,
Raven,
cardiomyopathies
38:73-79,
1976
detection in infants
of large left to and
children.
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DAVID
and Echocardiographic Evaluation with Indomethacin for Patent Ductus K.
EDWARDS,1
CHARLES
B. HIGGINS,1
AND
WILLIAM
T. ALLEN MERRITT,2 F. FRIEDMAN2
A series of 33 consecutIve preterm newborns who were treated with Indomethacin, a drug which acts to close the patent ductus arteriosus, were studied retrospectively to cxamine the efficacy of chest radiography and echocardiography in diagnosing the presence of a significant patent ductus arteriosus. Radiographic changes In pulmonary vascular engorgement, pulmonary edema, and cardiac size on the anteroposterior film tended to precede the clinical changes of shunt appearance and resolution. The echocardlographic left atrial to aortic ratio (LA/Ao) supplemented the radiographic findings. The time of disappearance of the ductus arterlosus shunt, as judged by clinical findings, was identified accurately by radiographic and echocardlographlc findings in the majority of cases; errors of under- and overestimation occurred in a minority of patients. In assessing both the presence and the resolution of the shunt, greater reliability was possible by using both radiographic and echocardlographic findings than by using either method alone.
Pulmonary the
overcirculation
ductus
from
is
arteriosus
threatening
problem
changes
radiographic
and
and
newborn
of a patent involving
radiographic
patency
[4],
often
follow
The
arteriosus
ligation
little
information
is
point. No arteriosus
have
been
available
such distinct endpoint closes spontaneously
maneuvers Accurate become
are used diagnosis
with
because agents
Prostaglandin
E
of that
has
the
recent
affect been
the shown
and
is
the
ductus Received
with
arteriosus May
C. B. Higgins Lung Institute. ‘ Department K. Edwards. 2 Department Am J Ro.ntgenol © 1978 American
considerable in effecting
[9-11] nonsurgical
in clinical
12, 1978;
accepted
is the recipient
trials. after
but
When revision
C. H.)
its
left
atnial
acm
a specific
accuracy
of
to determine closure.
chest
the
time
Methods
evaluated
in 33 preterm ductus
without were
and
infants
arteniosus
and
in
knowledge
of the
noted
from
clinical
the
dates
of
course;
patients’
records.
when
it began
to decrease.
data
to aortic
in this
Hospital
described
of normal records
an agent
to
30.3
as small
size. were
were
Of the
examined
determine
the
Career Development
Award,
treated
when
ages
at
these which
age; were
the
in
by
and
average
Three
patients
remainder
male.
The
available
significant
24 at
Hospital
determined
26-35)
18 were
was
hospitals:
at Sunrise
640-2,700).
gestational
33 patients,
of indometh[14].
at two
(range,
The
maximum,
dimension
age at birth
(range,
echo-
[4].
at its
the course
and nine
weeks for
noted
elsewhere
gestational
was 1 .336 grams
23 patients;
described
diastolic
as described series
for
was end
in San Diego
was
birthweight
(LA/Ao)
ventricular
Average
examination
available
as previously
and following
left
17 patients
patients
Las Vegas.
were
ratio
preceding, on
were
measured root
The
Similar
and reduction in edema. Weighcourse, a subjecthe final dose of was also made of
closure.
were
therapy.
The
(23 clinical
were clinical
patients) findings
7. 1978.
Hospital,
225 West Dickinson
of Pediatrics,
University
of California
Hospital,
San Diego. California
1978
to document-
or of the patients
data
of shunt
University
the
of California
December
were
of a signifi-
findings,
of patent
together
maximum,
success
measured
of U.S. Public Health Service Research
Ray Society
working these
University
131:1009-1013,
and
signs
subsequently
of Radiology,
Roentgen
clinical
cardiograms
not invariable closure of the
Seotember
In addition the
clinical
who
signs
diagnostic
were
administration
arterio-
such
clinical
independently success of ductus
Echocardiographic
ductus arteriosus [6-8], while inhibitors of prostaglandin synthesis act to close the ductus [6, 9, 10]. Indomethacin is a potent inhibitor of prostaglandin synthetase that has used success
retrospec-
and
,
newborns
determine
indomethacin
the
has
dilate
compare
times were noted for the onset, maximum, pulmonary vascular enlargement and pulmonary ing these factors and the overall radiographic tive estimate was made of the time when indomethacin was administered. An estimate
development to
of the to
which
Initial chest nadiographs were examined to identify each patient’s initial radiographic diagnosis. Cardiothonacic ratios (C/T) were measured on all films as described elsewhere [4]. Times were noted at which the C/T began to increase, when it
the ductus nonsurgical
ductus
by
whom pharmacologic closure of the ductus was attempted with indomethacin. The use of this drug was as described elsewhere [9, 11 , 13]. The nadiographs were examined by two of us (D. E.
described
patency
after
radiognaphs
exhibited
to
preterm
Subjects who
was
arteriosus.
made
immediately arteriosus
study of 33
ductus
used
markers
echocardiographic
chronology was
G. DiSESSA,2
identify
indomethacin
patent
Treated
be judged.
our
a series
Sequential
that
regarding
exists when or when
to close it. of ductus
imperative
pharmacologic
been [12]
treated the
to
may of
radiography and therapeutic
changes that occur when there is nonsurgical resolution. Surgical closure of the ductus arteriosus has the advantage that the surgery itself provides a therapeutic end-
sus.
in
effort
[1-3].
changes
desirable
radiographic,
findings
ing
is
purpose the
cant
echocardiography
echocardiographic
ductus but
of
it
THOMAS
of therapy
tively
life-
infants
used,
success
of
ductus arteriosus clinical markers,
and
is
reached
The [4],
a frequent
in premature
Preoperative diagnosis usually nonangiographic, chest [4,5].
prolonged
of Newborns Arteriosus
1009
grant no. KO4 HLOO2O1 from
Street, San Diego. California
92103. Address
the National
reprint
Heart
requests
92103. 0361
-803X/78/1
200-1009
$00.00
and
to D.
1010
EDWARDS
ET
TABLE Correlation
of Clinical
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Mean Age (Days)
1
and Radiographic .
.
.
. .
Observations Radiographic and Echocardiographic
clinical
Enlargement
5.1
(1-17)
5.3 5.9 6.6
(2-12) (1-15) (2-17)
7.5
(3-14)
Bounding
9.4 9.4 9.7 10.2 10.2 10.3
(4-33) (3-34) (1-35) (5-35) (5-33) (4-31)
Peak of clinical symptoms First indomethacin dose
1 1 .7
(336)
13.0 13.3 13.8 14.3
(3-43) (6-43) (6-43) (6-47)
Significant
murmur . . .
Enlargement
Onset of pulmonary
. .
pulses
Final
. .
.
. .
indomethacin
... ...
Maximum Maximum Maximum Maximum dose
Radiographic
. . .
Clinicalsymptom
cardiac size vessel enlargement LA/Ao ratio pulmonary edema estimate
of final
dose
Cardiac size decrease Pulmonary vessel decrease Pulmonary edema decrease
. . .
are ranges.
size
edema
...
. . .
in parentheses
of cardiac
noted
. .
.
vessels
...
. . .
(4-39)t
of pulmonary
noted
.
.
Note-Numbers
.
AL.
resolution
...
clinical.
t Radiographic
suggesting
and echocardiographic.
a patent
ductus
arteniosus were
reached
a maximum,
initially
noted,
and resolved. Results
Radiographic
Observations
The primary radiographic diagnosis for 26 patients was respiratory distress syndrome. Four patients demonstrated what has been termed “immature lung” [15], with minimal granularity and no significant airbronchograms. Two patients exhibited no discernable pulmonary parenchymal disease, but had congestive heart failure that was initially mild. One patient had an initially normal chest radiograph, but within a few days developed findings characteristic of Wilson-Mikity syndrome [16]. The time course of the findings of pulmonary vascular enlargement, pulmonary edema, and enlarged cardiac silhouette is summarized in table 1 . All patients during their clinical courses exhibited enlargement of pulmonary vessels, manifested by appearance of numerous hilar and perihilar en face vessels (“shunt vessels”). Initial pulmonary plethora appeared at 1-17 days of age (average, 5.1 days); these enlarged vessels tended to be the first manifestation of patent ductus arteriosus. Vessel enlargement was maximal at 10.2 days of age, and discernable decrease was observed at an average of 13.3 days. Pulmonary edema was observed in all but one patient. The average age at onset was 6.6 days. Edema was maximal at 10.3 days, and began to decrease at 13.8 days. Cardiothoracic ratio (C/T) averaged 52.5% on the initial chest film. Onset of discernable enlargement over the initial value was noted at an average of 5.9 days, and maximal C/T occurred at 9.7 days. Decrease in cardiac size occurred at 13.0 days. Maximum C/T never exceeded 60% in 21 patients. Of these 21 patients, five demonstrated an increase in C/T of 5% or more, while the remainder showed lesser increases. A total of 17 patients had maximum C/T increases of less than 5%. Of
these patients, 16 demonstrated over the sequence of films an increase and subsequent decrease in CIT that paralleled clinical symptomatology, even though the change was less than 5%. One patient demonstrated no discernable increase in cardiac size during his hospital course, and two patients never exhibited a decrease after enlargement of their cardiac silhouettes. The latter two patients did not have subsequent chest radiographs. All patients but one required assisted ventilation during their hospital courses. A wide variety of pulmonary abnormalities,
many
probably
related
to
assisted
venti-
lation, were observed. These included varying degrees of atelectasis (14 patients), pleural effusion (two), aspiration (three), pneumothorax (six), pneumomediastinum (one), pneumopericardium (one), and interstitial emphysema (eight patients). Hyperaeration was not a frequent finding. Echocardiographic
Observations
The echocardiograms obtained in 23 infants showed a peak left atrial to aortic root (LA/Ao) ratio of 0.8-0.9 in four infants, suggesting a moderate left to right shunt, and a peak ratio of 1 .0 or greater in 12 infants, suggesting a large-volume shunt [17]. The average peak LA/Ao ratio was 1 .0 (range, 0.5-1 .4). The average age at the peak LA/Ao ratio was 10.2 days. The average LA/Ao ratio prior to initiation of indomethacin was 0.9 (range, 0.41 .4),
and
after
the
course
of
the
drug
was
0.6
(range,
0.4-1 .0). The LA/Ao ratio decreased after indomethacin therapy in all but one patient. All patients who exhibited elevated LA/Ao ratios also demonstrated enlarged left ventricular end diastolic dimension, in the 17 patients for whom this was measured. Of
the
seven
patients
with
LA/Ao
of
less
than
0.8,
absolute cardiomegaly (C/T more than 60%) was seen in two patients, and four patients exhibited significant increase in CIT (more than 5%). Only one patient with normal LA/Ao ratio demonstrated neither cardiomegaly nor significant increase in C/T. However, this patient did
INDOMETHACIN
IN
PATENT
DUCTUS
ARTERIOSUS
1011
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..
r Fig. 1.-Patient after indomethacin
Fig.
=i
who exhibited gradual clearing after drug therapy. A, Anteropostenion therapy showing partial resolution of pulmonary plethora and edema.
2.-Patient
who responded therapy showing
after indomethacin
immediately to drug therapy. A, Anteroposterior marked clearing of cardiomegaly, and pulmonary
exhibit pulmonary plethora and edema. Thus in all patients either radiographic or echocardiographic signs of a large volume shunt were identified prior to indomethacm therapy.
view
Evaluation
Radiographic When
the
time
of
the
Four
patients
were
arteriosus after ductal ligation. appeared
to
to
have
felt
to have
indomethacin Radiographically improved
recurrent
patent
therapy and three of in
terms
of
ductus
underwent these four
shunt-related
abnormalities but had not entirely resolved; in the fourth infant the radiographic abnormalities appeared to have resolved completely. At surgery the patent ductus arteriosus was very small (2 mm) in the latter patient, and persisting moderate-sized in the other three.
In
dose
have
closed
seven
successful
average
time
of
these
over slow trasted clearing
cases the
the
time
cases
final
exhibited
dose
than
time
the
in 17 cases
the
resolution
to
of
by up
nine
average cases
therapy
dose that
was
6 days.
The
of indomethacin
as the
of successful
indomethacin
dose estimate
up
dose
same
felt
estimate
the final
by
final
was
radiographic
radiographic dose
the actual
that
the
actual
of
estimate
actual
the
of success-
with
ductus),
of the was
date
radiographic
the
final
examination
radiographic
than
the
earlier
which
Subsequent the
of the
is,
was
estimated
was 1 1 .7 days, time.
(that
the
Therapy
compared
24 hr of the
in nine
the
was
cases,
therapy
5 days;
past
final
lay within
(52%).
B, Film 1 day
administration.
estimate
therapy
B, Film
administration.
of Indomethacin
radiographic
ful indomethacin
to
to indomethacin
Estimation
estimate
A chronologic summary of the major clinical events is presented in table 1 . The first time a significant murmur was noted was at an average age of 5.3 days; the average peak of clinical symptoms was 9.4 days, the same average time as the first dose of indomethacin. The average time of clinical resolution was 14.3 days.
prior
view of chest prior to indomethacin plethora and edema.
clinically Clinical
of chest
actual in which was
later
revealed
occurred
that slowly
several days. An example of a patient who exhibited clearing is shown in figure 1, which may be conwith after
a patient indomethacin
who
exhibited therapy
marked (fig.
2).
immediate
EDWARDS
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1012
Examination of the seven cases in which the radiographic signs of significant improvement preceded the actual completion of indomethacin therapy revealed that, in four cases, the volume of the left-to-right shunt was probably small prior to indomethacin treatment because the C/T was below 60% and the peak LA/Ao ratio (in the two cases measured) was only 0.6. In three of these cases, two doses of indomethacin were administered after radiographic clearing of what appeared to be small shunts. In one of these patients, persisting respiratory dependency led eventually to ductal ligation; as predicted radiographically, this patient had a very small patent ductus arteriosus. In the other four cases, radiographic findings suggested significant improvement after the first dose of indomethacin, but clinical findings
prompted
additional
doses.
Of the 16 patients in whom radiographic assessment of successful therapy was erroneous, 1 1 were among the 23 patients on whom echocardiography was done. Of these 1 1 five patients demonstrated decreases in LA/Ao ratio from 1 .0 or above to below 0.8 with indomethacin therapy. Had this LA/Ao ratio drop been used in conjunction with the radiographic findings, the number correct would thus have been 17 of 23, or 74%. In the remaining five patients, neither the LA/Ao ratio nor the radiographs reflected the exact time of shunt closure as defined by clinical evidence of closure. ,
ET AL. indomethacin dose, but there were errors of up to 5 and 6 days in either direction. Accuracy within 24 hr was attained with only 52% of patients. Of the factors that may contribute to this inaccuracy, possibly the most important is that the standard for radiographic evaluation in this study was clinical assessment of the shunt. The accuracy of clinical evaluation is always open to question in the absence of direct evidence. This factor, together with partial or incomplete ductus closure, may have contributed to the error made in seven cases in which the radiographs would have suggested cessation of therapy
In evaluating the onset of a significant shunt across a patent ductus arteriosus in a newborn infant, the current study supports a previous report [4] that indicative changes on the chest radiograph are contemporary with and often in advance of clinical detection of a significant heart murmur. The sequence of clinical and radiographic changes is more striking than the average times of these observations would suggest (table 1), because in many cases radiographic evaluation was not requested until after there was clinical suspicion of a shunt. In examining the radiographic indices of significant shunt, the most sensitive were engorged pulmonary vessels, which were observed with all patients except one. The size of the cardiac silhouette was a relatively insensitive
index
of shunt
severity.
Absolute
indomethacin
which probably represents left-to-right shunt [17]. In diagnosing
of the average tration
radiographs estimation coincided
ductus
the arteriosus
lower
limit shunt
for closure,
a moderate the
It may
actually
discontinued.
in infancy
be concluded
from
are a fairly
of
a significant
of
pulmonary
[9].
in considering
the
ductus
study
weighed
that
indicator
arteriosus
vascular
are
this
reliable
shunt,
appearance
if the
enlargement more
radiographic
of the and
heavily
changes
pulmonary
than
measurable
changes in the cardiothoracic (C/T) ratio. If the C/T is considered together with the echocardiographic LA/Ao ratio, greater accuracy is possible than with using either measurement alone. The exact time of ductus closure is not reliably estimated by any of the variables examined in this study , although again greater accuracy is attained by using echocardiographic data together with the radiographs than by using either alone. More reliable indices of
shunt
closure
developed logic
agents
than
those
examined
in order
to monitor
the
such
as indomethacin.
here
effects
need
to
be
of pharmaco-
REFERENCES 1 . Kitterman Tooley
JA, WH,
mature
Edmunds Rudolph
LH AM:
infants.
Incidence,
and management.
N EnglJ
2. Neal WA, Bessingen
Jn,
Gregory
Patent
relation Med
GA,
ductus
FB Jn, Hunt
4. Higgins
CB,
Rausch
12:57-65, J, Friedman
MA, in
to pulmonary
287:473-477,
CE, Lucas
arteniosus complicating respiratory drome. J Pediatr 86: 127-131 , 1975 3. Rudolph AM, Heymann MA: Medical treatment
arteniosus.HospPrac
Heymann
arteniosus
ductus
pre-
disease
1972
RV Jr: Patent distress ofthe
synductus
1977 WF,
Hirschklau
MJ, Kirk-
patrick SE, Goergen TG, Reinke AT: Patent ductus sus in preterm infants with idiopathic respiratory
arteniodistress
syndrome. Radiographic and echocardiographic evaluation . Radiology 1 24 : 189-1 95, 1977 5. Laird WP, Fixler DE: Echocardiography of premature infants with pulmonary disease: a noninvasive method for detecting large ductal left-to-right shunts. Radiology
use
was only modestly successful. The of the date of indomethacin ad miniswith the average date of the final
therapy
changes
cardiomeg-
aly (C/T more than 60%) was seen in only 36% of patients, and significant increase in C/T (more than 5%) was seen in only 48%. A large number of patients (48%) demonstrated neither absolute cardiomegaly nor significant increase in C/T. The other numerical variable examined in this study was the echocardiographic LA/Ao ratio. Like the C/T findings, this ratio was not always indicative of clinical status. In 48% of 23 cases, the peak LA/Ao ratio was below 1.0, and in 30% the peak was below 0.8, the value
it was
accuracy of radiographic evaluation of patent ductus arteriosus shunt, it is worth noting that with the four cases who underwent surgical ligation, the final radiographs predicted the operative findings correctly.
edema Discussion
before
In nine cases the radiographs alone would have suggested a need for additional doses of indomethacin. In the majority of these patients clearance of pulmonary plethora and/or edema was relatively slow. It is speculated that this type of error may relate to slow clearance of fluid; transient oliguria is a known side-effect of
122:455-457,
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6. Elliott RB, Starling MB, Neutz JM: Medical manipulation the ductus arteniosus. Lancet 1:140-142, 1975
of
7.
by
Heymann
MA,
Rudolph
AM:
Ductus
arteniosus
dilatation
INDOMETHACIN
IN
PATENT
DUCTUS
prostaglandin
E1 in infants with pulmonary atresia. Pediat1977 8. Lang P, Freed MD, Rosenthal A, Castaneda AR, Nadas AS: The use of prostaglandin E1 in an infant with interruption of the aortic arch. J Pediatr 91 : 805-807, 1977 9. Friedman WF, Hirschklau MJ, Pnintz MP, Pitlick PT, Kirkpatrick SE: Pharmacologic closure of patent ductus arteriosus in the premature infant. N EngI J Med 295:526-529, 1976 10. Heymann MA, Rudolph AM, Silverman NH: Closure of the ductus arteniosus in premature infants by inhibition of prostaglandin synthesis. N EngI J Med 295: 530-533, 1976
13.
11.
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59:325-329,
Friedman WF, Heymann MA, Rudolph AM: Commentary: new thoughts on an old problem-patent ductus arteniosus in the premature infant. J Pediatr 90:338-340,1977
12. Neal WA, Kyle JM, Mullett MD: Failure of indomethacin therapy to induce closure of patent ductus arteniosus in premature infants Pediatr 91:621-623,
with
1977
respiratory
distress
syndrome.
J
14.
Friedman taglandin
1013
ARTERIOSUS
WF, Pnintz synthesis-a
MP, Kirkpatrick novel therapy
SE: Blockers of prosin the management of the premature infant with patent ductus arteniosus, in Advances in Prostaglandin and Thromboxane Research , ed-
ited by Coceani 373-381
F, Olley
PM, New York,
Hirschklau MJ, Echocardiographic
DiSessa TG, diagnosis:
fant with a large patent ductus 477, 1978 15.
Parker
Immature
BR,
Pinckney
LE,
lung syndrome
Hodgman
JE,
respiratory syndrome.
distress Pediatrics
Mikity
and
JD,
Northway
WH
Jr:
Clin Res 24: 194A, 1976 D,
Cleland
AS:
Chronic
in the
premature infant: Wilson-Mikity 44: 179-195, 1969 Y, Williams DE, Allen HD, Goldberg SJ,
17. Sahn DJ, Vauchen Friedman WF: Echocardiographic night shunts Am J Cardiol
CB, Friedman WF: in the premature inarteniosus. J Pediatr 92 : 474-
Johnson Tatter
1978, pp
Higgins pitfalls
(abstr).
VG,
Raven,
cardiomyopathies
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detection in infants
of large left to and
children.
