In preterm infants more than 30 weeks of
gestational age, the ductus arteriosus usually closes by 5 days. In
contrast, in two-thirds of the infants less than 30 weeks of gestational
age, who often have significant lung disease, it does not close by 5
days of age [1,2].
A large left-to-right shunt has the potential to
contribute to severe complications such as congestive cardiac failure,
chronic lung disease, necrotizing enterocolitis and intraventricular
hemorrhage (IVH) in low birth weight infants [3,4]. However,
meta-analyses of randomized controlled trials of the use of indomethacin
for prevention and treatment of PDA have not documented a decrease in
the incidence of these morbidities, despite success in closure of the
PDA [5,6].
Although indomethacin has been widely accepted to be
effective in closing PDA in LBW infants, it may not be effective in up
to 40% of cases [2, 9]. Reopening of the ductus after initial closure
also occurs in 20% to 100% of treated infants [9, 10]. Indomethacin is
also known to be associated with adverse effects such as renal
dysfunction, electrolyte abnormalities, thrombocytopenia, intestinal
perforation and gastrointestinal bleeding [11]. Furthermore, there is no
consensus on the timing, dosage and the duration of indomethacin
treatment for PDA. Risk factors for subsequent reopening of the PDA also
remain poorly defined. We studied the PDA closure rates for extremely
preterm infants at our center and the factors determining a poor
clinical response to indomethacin treatment. The incidence of the
adverse effects in the study population was also investigated.
Methods
All infants of gestational age 28 weeks or less, born
between 1st January, 2003
and 30th June, 2006 at a
Level 3 Neonatal Intensive Care unit (NICU) in New South Wales were
included in this retrospective, case-control study. Infants who were
out-born and admitted were also included. Infants who died within the
first 72 hours of life and those with congenital heart disease were
excluded, as it was considered too short a time for closure of PDA to be
achieved with any treatment, medical or surgical. The study design was
approved by the Human Research Ethics Committee of the Local Area Health
Service.
After collecting baseline and clinical data, infants
were classified into three groups for further analysis. Group I included
infants with closed PDA or non- significant PDA, Group II included
infants who had a significant PDA which closed with medical treatment,
and Group III included infants where the PDA failed to close after
multiple courses of indomethacin.
Clinical examination and echocardiogram findings were
used to evaluate the PDA before commencing treatment. All
echocardiograms were performed and reported by a consultant pediatric
cardiologist. A significant PDA was defined as one that had one or more
of the following clinical signs - (i) unexplained worsening of
respiratory support, (ii) widening of the blood pressure
amplitude or low blood pressure, or (iii) systolic or continuous
murmur; and met one or more of the following echocardiographic
criteria: (i) LA/Ao ratio of >1.4, (ii) ductal diameter
more than 1.5 mm, and (iii) moderate to large left to right
shunt. If PDA was considered significant enough to cause clinical signs
in the absence of all the echocardiographic criteria, the decision to
treat was at the discretion of the on-call neonatologist.
Response to indomethacin was defined as closed or
non-significant PDA confirmed on echocardiogram after treatment with
indomethacin. Dosage regimens used for a course of indomethacin were
0.2mg/kg × 3 doses, 12 hrs apart or 0.1mg/kg × 5 to 6 doses, 24 hr
apart. If anything other then above was used it was specifically
elaborated. A tail course (0.1mg/kg every 24 hr × 3 doses) was used
immediately following the initial indomethacin course, if considered to
be indicated by the on-call neonatologist, and counted as part of one
indomethacin course. Prophylactic indomethacin was not used during the
study. The decision regarding the dosage to be used and number of
courses to be given were at the discretion of the on-call neonatologist.
Indomethacin was administered via the intravenous route for all the
study patients.
Some of the outcomes assessed included closure of
PDA, mortality, surgical ligation, chronic lung disease (CLD) (oxygen
requirement or pressure support at 36 weeks corrected gestation age),
intraventricular hemorrhage (grade 3-4), proven necrotizing
enterocolitis (NEC), duration of hospital stay, duration of assisted
ventilation, pulmonary hemorrhage and, retinopathy in the study
population. The definitions used for each of the outcome were as
mentioned in the Report of the Neonatal Intensive Care Units (NICUS)
data collection [14].
Statistical analysis: Data were analyzed using
Intercooled STATA version 10.0 for Windows. Categorical data were
summarized using frequency distributions with 95% confidence intervals
and continuous data were described using mean (standard deviation) when
normally distributed or using medians and interquartile ranges
otherwise. Categorical variables were analyzed using the Fisher exact
test while ANOVA and Kruskal-Wallis tests were used for continuous
variables as appropriate. Regression analysis was used to adjust for
variations in study groups with respect to gestational age and CRIB
score.
Results
A total of 166 infants born at <29 weeks gestation
were admitted to the neonatal intensive care unit during the study
period. Fifteen infants were excluded from the analysis (4 had
congenital heart disease, 10 died within 72 hrs, and 1 infant was
extremely premature with extensive IVH, where a decision on withdrawal
of support was made within 72 hours without any treatment offered for
PDA). The data on the remaining 151 infants were analysed. 104 infants
(69%) were diagnosed as having a significant PDA and were treated with
indomethacin. 9 of these infants had significant clinical symptoms to
warrant treatment inspite of not fulfilling the echocardiographic
criteria (7 in group II and 2 in group III). 91 (87.5%) of those infants
responded to multiple courses of indomethacin and were classified as
Group II. Of the 13 infants (Group III) who did not respond to
indomethacin, 7 underwent surgical ligation and 6 were observed
expectantly with closure of PDA on follow up. The infants with PDA that
did not respond to indomethacin (group III) were born at lower gestation
(P=0.0014) and were more likely to be female (P= 0.019) (Table
I). Infants with gestation less than 26 weeks were 5.6 times (95% CI
1.6-19.9) and female infants were 5.8 (95% CI 1.5-22.8) times more
likely to not respond to indomethacin as compared to those who responded
to indomethacin. There were 9 infants in group III and 25 infants in
group II, which were less than 26 week gestation. Chorioamnionitis,
ethnicity, intrauterine growth retardation, need for resuscitation,
maximum oxygen required, fluid management, and need for inotropes were
analyzed and not significantly different between the groups.
TABLE I Demographics of the Study Population
|
All
(n=151) |
Group 1(n=47) |
Group 2(n=91) |
Group 3 (n=13) |
P
value |
Gestation* |
27 (25, 28) |
27 (26, 28) |
27 (25, 28) |
25 (24, 27) |
0.001
|
Birthweight$ |
950
(244) |
941 ± 223 |
967 (257) |
860
(218) |
0.42 |
Male gender# |
91 (60.3) |
30 (63.8) |
58 (63.7) |
3 (23) |
0.019 |
Antenatal
steroids (complete course) # |
90 (59.6) |
30 (63.8) |
53 (58.2) |
7 (53.8) |
0.71 |
CRIB score* |
4 (2, 7) |
4 (2, 6) |
4 (2, 7) |
8 (2, 9) |
0.16 |
Surfactant# |
101 (66.9) |
24 (51) |
68 (74.7) |
9 (69.2) |
0.088 |
Sepsis
(culture proven) # |
66 (44.3) |
17 (36.2) |
41 (46) |
8 (61.5) |
0.24 |
*Median (iqr1, iqr3); # Number (%);
(SD); $Mean (SD). |
An echocardiogram was performed in all infants (n
= 141), except 10 who were clinically well and asymptomatic for PDA. Of
the 104 infants treated with indomethacin, only 12 infants received
three or more courses of indomethacin while 70 infants responded to one
course of indomethacin. If the duct did not close by the third course,
then it was unlikely to close with further courses of indomethacin. The
median age beyond which duct failed to close was 29 days (iqr1 = 12,
iqr3 = 39). No significant differences between group 2 and group 3 were
observed with regards to the age at the time of first indomethacin dose,
PDA size, LA/Ao ratio, and PDA shunt (Table II).
Indomethacin was well tolerated in the study population with 26.9%
infants experiencing adverse effects; all of these were transient and
non life threatening. The specific adverse effects were thrombocytopenia
(infants), and low urine output <0.5 mL/kg/hr, high creatinine >150 mmol/L
in 1 infant. Hyponatremia (Na <130 mmol/L) occurred in 18 infants in
group II and 6 in group III.
TABLE II Patent Ductus Arteriosus Status and Indomethacin Use
|
Group II (n=91) |
Group III (n=13) |
LA/Ao Ratio* |
1.4 (1.2,1.6) |
1.45 (1.2, 1.6) |
PDA Size* |
2 (1.5,2.3) |
2 (1.6, 2) |
Moderate to Large# |
59 (82) |
10 (91) |
Postnatal age* (d)
|
3 (2,4) |
4 (3,4) |
>1 course, No (%)# |
21 (23) |
12 (92.3) |
>2 courses, No (%)## |
6 (6.6) |
6 (46) |
Adverse effects, No (%) $ |
21 (23%) |
7 (53.8%) |
*Median (iqr1, iqr3); #
P=0.0001; ##P=0.001; $P=0.039. |
Table III shows the outcome of all the study
infants. The duration of CPAP, duration of ventilation, and length of
stay remained significantly different even after correcting for
gestation age and CRIB score, with infants in group III remaining on
CPAP for a longer duration (43.5 days), requiring prolonged ventilation
(4.3 days), and requiring hospitalisation for a longer time (102.8
days).
TABLE III Outcome of Study Infants (N=151)
|
All |
Group I |
Group II |
Group III |
P
value* |
NEC# |
15 (9.9%) |
8 (17%) |
7 (7.7%) |
0 |
0.40 |
IVH (Grade
3/4) or PVL# |
16 (10.6%) |
5 (10.6%) |
10 (11%) |
1 (7.7%) |
0.66 |
ROP (any)# |
67 (50.8%) |
20 (51.3%) |
38 (47.5%) |
9 (69.2%) |
0.56 |
Pulmonary
hemorrhage# |
8 (5.3%) |
1 (2.1%) |
7 (7.7%) |
0 |
0.77 |
Duration of
CPAP (hrs)^ |
720 (240,
991) |
336 (58,
934) |
729 (326,
994) |
1045 (890,
1387) |
0.001 |
Duration of
ventilation (hrs)^ |
49 (0, 177) |
0 (0, 63) |
83 (0, 91) |
104 (34,
556) |
0.027 |
CLD (Oxygen
at 28 d)# |
93 (66%) |
19 (46.3%) |
61 (70.1%) |
13 (100%) |
0.44 |
Oxygen at 36
wks# |
49 (35.8%) |
9 (22%) |
30 (36.1%) |
10 (77%) |
0.45 |
Home oxygen# |
30 (24.8%) |
4 (12.1%) |
20 (26.7%) |
6 (46.1%) |
0.47 |
Postnatal
dexamethasone# |
5 (4.5%) |
1 (3.4%) |
1 (1.4%) |
3 (23%) |
0.50 |
Length of
stay (d)@ |
65.9 (34) |
55.6 (35.8) |
65.9 (28.8) |
102.8 (38.4) |
0.004 |
Mortality# |
15 (9.9%) |
6 (12.8%) |
9 (9.9%) |
0 |
0.42 |
^Median (iqr1, iqr3); #Number (%);
Mean (SD); ROP: Retinopathy of prematurity; CLD: Chronic lung
disease; IVH: Intra-ventricular hemorrhage; NEC: Necrotizing
enterocolitis. * P value adjusted for gestation and CRIB score. |
Discussion
A significant PDA was diagnosed in 69% of the infants
born at less then 29 week gestation, which is similar to the incidence
reported in literature [2,3]. We found a high response rate (87.5%) with
multiple courses of standard dosage of indomethacin, with or without a
tail course. There are very few studies which have reported the closure
rate after multiple courses of indomethacin. The response rate of 60 to
80% to standard dosage of indomethacin reported by other authors [2,9]
is less than the response rate seen in our study population. Prolonged
course of indomethacin compared to the short course has not been
reported to be more effective either [16]. Several population-based,
observational studies have used higher doses of indomethacin to treat
infants where PDA failed to close with conventional dosing. These
studies report PDA closure rates of more than 90% with a stepwise,
escalating approach to indomethacin dosing [17-19]. A recent multi-center
randomized controlled trial reported contrasting findings with little
effect on the rate of PDA closure with indomethacin concentrations above
the levels achieved with a conventional dosing regimen but reported
higher rates of moderate/severe ROP and renal compromise [20].
The number of infants who underwent surgical ligation
during the study period was 7 (7%), which in effect leaves 93% of the
infants managed non-surgically. This is comparable with ANZNN statistics
of 9% of the newborns between 23 and 27 weeks who underwent surgical
ligation [14].
Several authors have reported low gestation to be a
risk factor for poor responsiveness [21-23], while gender has not been
reported by any. However, it has been shown that neonatal mortality,
short-term morbidity and adverse neurodevelopmental outcomes are higher
among male than female infants [24]. Poor response to indomethacin is
also reported to be more common in extremely LBW infants and in infants
with infection or advanced postnatal age [25-27]; however, we did not
note those differences. The reasons for non-responsiveness of PDA to
indomethacin in preterm infants remains ill defined.
Our findings conform to those of other studies in
that treatment was not found to alter the incidence of neonatal
morbidities associated with PDA [28]. Based on the available evidence,
it is difficult to infer if the reported association between a
persistent PDA and other neonatal morbidities is a result of left to
right shunt itself, the pharmacotherapies used, or the immaturity of the
infant who is likely to develop a PDA. However, unlike the meta-analysis
by Cooke, et al. [6], we did find that significant PDA was
associated with need for prolonged respiratory support (CPAP and
ventilatory requirement), and increased length of stay which does lead
to significant utilization of resources. There were no deaths in infants
in group III who did not respond to indomethacin, which needs to be
interpreted with caution in the light of few infants in that group.
None of these adverse effects were related to the
duration and total dosage of indomethacin (Group II and III), which is
similar to that reported by other authors [29,30].
The limitation of our study is that it is a
retrospective analysis. There was no long-term data available for the
study population. The infants were treated after they developed symptoms
so the results may not be applicable to prophylactic treatment or
presymptomatic treatment based on echocardiography. The advantage of
this strategy is that it allows spontaneous ductal closure thereby
avoiding overtreatment with indomethacin. Some of the babies were
treated with indomethacin just based on clinical symptoms, which may
represent liberal use; however, the numbers of such babies were very
small. Such a pragmatic approach allows for clinical acumen to guide
treatment rather than just relying on echocardiographic cut-offs. The
study base is well defined with controls drawn from the same population
as the cases. It is also one of the few studies to report on the closure
rate of PDA in the preterm population after multiple courses of standard
dose of intravenous indomethacin therapy.
In summary, multiple indomethacin courses (up to a
maximum of 3) using the standard dosing approach resulted in high
closure rates (87.5%) for infants less then 29 weeks of gestation in our
NICU. Decreasing gestation and female gender were the only indicators
for predicting response to indomethacin. If PDA remained open despite
three courses of indomethacin or until 4 weeks of age, it was unlikely
to close by medical treatment. Indomethacin in the dosage used was well
tolerated in the study population.
Contributors: JT conceived and designed the
study, analyzed data and revised the manuscript. JT will act as the
guarantor of the study. HP collected data, helped in data analysis and
drafted the manuscript. VK helped with data collection and revised the
manuscript. The final manuscript was approved by all the authors.
Funding: None; Competing interests:
None stated.
What is Already Known?
• There is no consensus on the dosage and the
duration of indomethacin treatment for PDA, and it may not be
effective in 10-40% cases.
What This Study Adds?
• Multiple indomethacin courses (up to a
maximum of 3) using the standard dosing approach resulted in
high closure rates for infants less then 29 weeks of gestation.
• If PDA remained open despite three courses
of indomethacin or till 4 weeks of age, it was unlikely to close
by medical treatment.
|
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