Ibuprofen
Oral Suspension for the Treatment of Patent Ductus
Arteriosus at the Neonatal Intensive Care Unit,
Prince Rashid Hospital
.........................................................................................................................
Issa Khashashneh MD, Wajdi
Amayreh, MB BS, MRCPCH
From the department of pediatrics, Prince Rashid
Hospital
Correspondence:
Dr Wajdi Amayreh
P O Box 1479,
Irbid, Jordan.
E mail wajdidr@yahoo.com
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ABSTRACT
Objective This
study was carried out to determine whether
Oral Ibuprofen treatment is efficacious
and safe in closure of Patent Ductus Arteriosus
(PDA) in premature infants with or without
respiratory distress syndrome.
Setting
Neonatal intensive care unit, Prince Rashid
Hospital, Irbid, Jordan, during the period
from June 2008 to March 2009.
Patients and
methods All premature newborns less
than 37 weeks gestation admitted to the
neonatal Intensive Care Unit (NICU) with
clinical suspicion of Patent Ductus Arteriosus
(PDA) underwent echocardiography; twenty
eight newborns with proved hemodynamically
significant PDA were enrolled in the study.
These newborns were given oral Ibuprofen
suspension 10 mg/kg for the first 24 hours
followed by two doses of 5 mg/kg each,
after 24 and 48 hours and the course was
repeated once more if needed. Treatment
was started on the third day of life.
A follow up echocardiography was done
for these patients daily until closure
of the PDA or completion of the treatment
doses.
Results A
total of 107 premature newborns were admitted
to the NICU during the study period, of
whom 47 had PDA proved by echocardiography;
19 newborns were excluded and twenty-eight
newborns were enrolled. 18 were males
and 10 were females. Ductal closure was
achieved in 27 (96.5%) newborns, as all
except one patient (3.5 %) had successful
closure of their PDA. No re-opening of
the ductus took place after treatment.
No significant complications were recorded
during the study period.
Conclusion Oral
ibuprofen is an effective and safe method
of treating hemodynamically significant
PDA in premature infants.
Key words Patent
ductus arteriosus, Ibuprofen, premature.
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Patent ductus arteriosus
(PDA), a common finding among premature infants,
can result in serious hemodynamic changes causing
respiratory, gastrointestinal and renal morbidities
if not treated within the first week of life(1).
Its incidence varies from 20% in premature infants
older than 32 weeks' gestational age up to 60%
in those less than 28 weeks' gestational age(2,3).
Treatment options available for its management
are a conservative approach, pharmacological
treatment with cyclo-oxygenase (COX) inhibitors
and surgical ligation(1,4). Pharmacological
closure of the ductus arteriosus in premature
infants with symptomatic left-to-right shunting
has been shown to decrease morbidity(5,6).
Indomethacin has been used widely in the prophylaxis
and treatment of hemodynamically significant
PDA, however, ibuprofen has been proposed as
a preferential alternative to indomethacin in
treating patent ductus arteriosus (PDA), because
it is thought to have less renal, mesenteric,
and cerebral vaso-constrictive effects(7,8,9).
The intravenous forms of ibuprofen and indomethacin
are unavailable at our hospital, and the waiting
list for surgical ligation is long, therefore
we carried out this prospective study at our
NICU to evaluate the effectiveness of oral ibuprofen
to close a hemodynamically significant PDA in
premature newborns, which, to our knowledge,
was the first trial of its kind in the country.
All premature newborns less
than 37 weeks gestation admitted to the neonatal
Intensive Care Unit (NICU) during the study
period from July 2008 to March 2009 were candidates
in this study. Those with the clinical suspicion
of Patent Ductus Arteriosus (PDA) underwent
echocardiography.
Exclusion criteria included babies with multiple
congenital anomalies, necrotizing enterocolitis,
disseminated intravascular coagulation or bleeding
tendency, platelet count <50000, renal impairment,
grade III or more IVH.
Twenty-eight newborns were found to have a hemodynamically
significant PDA meeting the selection criteria
and were prospectively enrolled.
Eligible newborns were given oral Ibuprofen
suspension 10 mg/kg for the first 24 hours followed
by two doses of 5 mg/kg each, after 24 and 48
hours and the course was repeated once more
if needed, treatment was started on the third
day of life. A follow up echocardiography and
kidney function tests were done for these patients
daily until closure of the PDA or completion
of the treatment doses.
A total of 107 premature
newborns were admitted at the NICU, Prince Rashid
Hospital during the study period. 47 were eligible
for entry in the study, 19 of them were excluded
because of tiny PDA, spontaneous closure or
the other mentioned exclusion criteria. The
remaining twenty-eight newborns had a hemodynamically
significant PDA and were started on the treatment
protocol. 18 newborns were males and 10 were
females. The characteristics of the study group
are shown in Table 1.
Ductal closure was achieved in 27 newborns (96.5%)
as there was only one newborn (3.5%), in whom
ductal shunting persisted. There was no reopening
after closure occurred. Eighteen newborns were
treated with 3 doses of ibuprofen; eight were
treated with 4 doses, and the remaining two
needed a second course of treatment with a total
of 6 doses. Two infants of the treated group
died (7%); one died as a result of bronchopulmonary
dysplasia, and the second died as a result of
sepsis. There were no significant differences
in the levels of serum creatinine before and
after treatment.
| Table
1 The
characteristics of the study group
|
|
Mean birth weight (g)
1237 (600-2500) |
|
Mean gestational age (weeks)
31.21 (26-37) |
|
Gestational age categories
(no) |
|
26 - 28 wk
2 |
|
28 – 30 wk
6 |
|
30 – 32 wk
7 |
|
32 – 34 wk
7 |
|
34 – 36 wk
4 |
|
36 – 37 wk
2 |
Surfactant therapy (no)
20
Ibuprofen doses
(no)
3 doses 18
4 doses 8
6 doses 2 |
|
Respiratory distress syndrome
(no) |
|
Mild
6 |
|
Moderate
10 |
|
Sever
7 |
Conventional Mechanical Ventilation (no)
17
High frequency oscillatory ventilation (no) 2 |
Indomethacin is the
conventional pharmacological treatment for promoting
closure of PDA in premature infants(4). As
there has been some concerns about indomethacin
side effects, Ibuprofen (another cyclo-oxygenase
inhibitor) has become increasingly used for
the treatment of PDA in premature infants in
either its intravenous or oral formulation with
possibly less side effects(10-14).
Oral ibuprofen would have a number of advantages
if it was equally effective like easy availability,
less cost, and simpler administration. So our
primary objective was to evaluate the efficacy
of oral ibuprofen in the closure of PDA.
The overall success rate in closing a hemodynamically
significant PDA in this trial was (96.5%) as
27 newborns had successful PDA closure, which
is comparable to other studies using the same
formulation(11, 14-17). This figure is significantly
higher than studies which used the intravenous
form of the drug(18-23).
Regarding side effects and complications of
treatment, our study showed no decrease in renal
function (increase in serum creatinine level),
which is similar to the results of most studies
(9-11,15), and there was no significant difference
in serum creatinine levels before and after
treatment.
Although in a trial by Antonucci et al(24)
decrease in renal function and acute renal failure
occurred in 15 % of patients, none of our patients
had renal failure, this particular complication
seems to be more obvious with indomethacin treated
patients(7-9).
Ibuprofen was administered to our patients
by a small feeding tube, and although there
could be theoretical risks of gastrointestinal
irritation, none of our patients had any significant
gastrointestinal problems.
No cases of necrotizing enterocolitis (NEC)
occurred in our patients in spite of the fact
that the use of ibuprofen increased the risk
of developing NEC in a number of studies(16-21).
No cases of thrombocytopenia, bleeding tendencies,
or reopening of the duct occurred in any of
the treated patients.
Two of our patients in the trial died (7%),
one of them a 28 week- gestational age had bronchopulmonary
dysphasia after 10 weeks of treatment and he
was the one whose duct failed to close, the
other one was of 30 week gestational age and
died of klebsiella septicemia.
Oral ibuprofen is an effective medical treatment
in promoting PDA closure and decreasing its
complications with very minimal side effects.
More studies on a larger scale are recommended
to clarify any possible untoward effects of
treatment.
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