To the Editor,
We wish to thank Dr. Sarici SU et al for their letter (1).
The primary objective of this pilot study was to determine whether orally
administered ibuprofen is effective in closure of patent ductus arteriosus
(PDA) in premature infants with respiratory distress syndrome (RDS). It
was not a comparative study between two medications or two different mode
of administration of the same drug (2).
The definition of hemodinamically significant PDA in our study was
based on clinical signs (tachycardia of more than 160 beats per minute,
presence of a murmur, bounding pulses) and echocardiographic finding of a
ductal size> 1.5 mm or left atrial to aortic root ratio > 1.4, as
published elsewhere (3).
The cardiologist who performed the echocardiography was blind to the
child’s clinical condition and the treatment administered to the child.
There was no bias in patients recruitment. Each premature newborn who met
the above mentioned criteria was included in the study.
Twenty three percent of our patients had severe ductal shunting,
while 77% had moderate ductal shunting. This proportion of severe/moderate
ductal shunting is the usual proportion published in the literature (4).
The age at start treatment was 2.5± 0.6 days. Fourteen premature
infants received one dose, six received two doses and two infants received
3 doses. No reopening of the ductus after closure nor surgical ligation
were needed.
The administration of surfactant is an indication for the severity of lung
disease and does not necessarily indicate the severity of PDA.
We use prostaglandin inhibitors orally to close PDA for more than 20
years. We never used indomethacin intravenously (IV). We used indomethacin
orally 0.5 mg/kg/day once daily, which is more than double then the IV
recommended dose, usually no more than 3 doses (with no surgical ligation
for the last 20 years).
In our medical center, there are 6000 deliveries each year with about
80-100 premature babies weighing less than 1500 gr per year. By 20 years
we had hundreds of babies treated orally and no one needed surgical
ligation of the PDA.
Indomethacin administration to the premature newborn might be
associated with vasoconstriction of cerebral, renal and mesenteric
vascular beds, in addition to its effects on the ductus. Ibuprofen appears
to be as effective as indomethacin in mediating ductal closure but
possibly causing less vascular compromise (3). After the publication by
Van Overmeire et al. (3), we have started to use ibuprofen orally.
Since the publication of our pilot study, 25 more premature babies in
our NICU, with moderate to severe PDA received oral ibuprofen, still with
no need for surgical ligation.
Closure of the PDA occurs in two phases. Smooth muscle constriction
produces a functional closure, followed by anatomic occlusion of the
lumen. The functional constriction produces a zone of ischemic hypoxia
which is associated with local production of hypoxic-induced growth factor
which play role in ductal remodelling (5).
Preterm infants require more ductal constriction (phase 1) to produce
the same level of ductal wall hypoxia as is found in term babies.
Therefore, it is possible that the slower rate of oral ibuprofen
absorption, together with the longer time to peak plasma levels, as
compared with the intravenous route, and prolonged time of contact and
exposure of the drug with the ductus enables the ibuprofen to induce the
level of hypoxia needed for the anatomic changes.
We define bronchopulmonary dysplasia (BPD) as oxygen dependency
beyond 36 weeks (6). This definition rather than oxygen dependency at the
age of 28 days correlates more closely with continuing respiratory
morbidity after discharge (positive predictive value of 65%). Pulmonary
edema and PDA increases the incidence of BPD. There is an association
between the duration of PDA and the increased risk of BPD (7,8).
We, like other investigators (9), believe that the extremely high
morbidity and mortality seen in infants who had RDS and PDA provided
abundant justification to pursue nonsurgical methods to alter the course
of this common complication of preterm infants.
However, despite our results and our experience with oral ibuprofen,
larger comparative studies are needed.
Sincerely,
Eli Heyman, MD
Iris Morag, MD
David Batash, MD
Rimona Keidar, MD
The Neonatal Intensive Care Unit
Shaul Baram, MD
Pediatric Cardiology Unit
Matitiahu Berkovitch, MD
Clinical Pharmacology & Toxicology Unit
References:
1) Serdar Sarici et al. "Is oral ibuprofen so efficacious in closure of
PDA?" article ID: 112/5/e354
2) Heyman E, Morag I, Batash D et al. Closure of Patent Ductus
Arteriosus with oral Ibuprofen suspension in premature newborns: A pilot
study. Pediatrics 2003; 112(5): e354e358.
3) Van Overmeire B, Smets K, Lecoutere D et al. A comparison of
ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl
J Med 2000; 343: 674-681.
4) Nich Evans, Parvathi Iyer. Longitudinal changes in the diameter of
the ductus arteriosus in ventilated preterm infants: correlation with
respiratory outcomes. Archives of disease in childhood 1995; 72: F156-
F161.
5) Narayanan-Sankar M, Clyman RI. Pharmacologic Closure of Ptent
ductus Arteriosus in the Neonate. NeoReview 2003; 4(8): e215-e220.
6) Shenan AT, Dunn MS, Ohlsson A et al. Abnormal pulmonary outcomes
in premature infants: prediction from oxygen requirment in the neonatal
period. Pediatrics 1988; 82: 527-532.
7) Merritt TA et al. Early closure of patent ductus arteriosus in
very low birth weight infants: A controlled trial. J Pediatr 1981; 99:218.
8) Rojas M et al. Changing trends in the epidemiology and
pathogenesis of neonatal chronic lung disease. J Pediatr 1998; 126: 605.
9) William F. Friedman. A look back: the clinical initiation of
pharmacologic Closure of Ptent ductus arteriosus in the preterm infant.
NeoReview 2003; 4(10): e259-e262.
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