Keywords
indomethacin - paracetamol - patent ductus arteriosus - premature infant - surgical
closure
Maintaining the patency of ductus arteriosus (DA) is essential for fetal circulation
and normal development of the fetus. In almost-term infants, the DA constricts and
causes intraluminal ischemic hypoxia, which eventually leads to the closure and remodeling
of the DA a few days after birth. The occurrence of patent DA (PDA) is inversely related
to gestational age and weight, with a higher incidence in preterm infants.[1] PDA is a significant cause of morbidity and mortality in preterm infants, including
bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis,
and acute renal failure due to increased pulmonary blood flow and focal organ ischemia.[2]
[3]
[4] In Japan, the standard pharmacological treatment for hemodynamically significant
PDA (hsPDA) closure involves the intravenous administration of a nonselective cyclooxygenase
inhibitor indomethacin (IND). However, IND can be associated with potentially significant
adverse effects, such as acute renal failure, necrotizing enterocolitis, and hypoglycemia.[4]
It is widely believed that the effect of paracetamol is a manifestation of inhibition
of prostaglandin synthetase activity. Although its precise mechanism of action remains
controversial, evidence suggests that paracetamol seems to act at the peroxidase segment
of the enzyme,[5] which indicates that paracetamol-mediated inhibition is facilitated by a reduction
in the concentration of local peroxide. Paracetamol is widely used as an antipyretic
analgesic for children. The efficacy of paracetamol in ductal constriction has been
demonstrated in pregnant animal models.[6] Furthermore, a case of in utero closure of the DA as a result of maternally used
nimesulide and paracetamol has been reported.[7] Oncel et al first reported on intravenous paracetamol treatment in the management
of PDA in extremely low birth weight infants,[8] and conducted a randomized controlled trial which compared oral paracetamol with
ibuprofen in preterm infants and demonstrated that paracetamol may be a medical alternative
in the management of PDA.[9] Recently, some reports have also demonstrated the safety and efficacy of paracetamol
treatment as a substitute for IND or ibuprofen in managing hsPDA.[10]
[11]
[12]
[13] However, the safety and efficacy of paracetamol have not been reported in Japan.
We present the first cases of hsPDA treated with intravenous paracetamol (Acelio,
Terumo, Tokyo, Japan) in Japan. The protocol for the use of paracetamol was covered
by the clinical trial insurance and was approved by the institutional review board
(IRB) of Saitama Medical Center, Saitama Medical University. Parental consents were
obtained before paracetamol administration.
Cases
[Table 1] summarizes the three cases. Infant A was a male at 252/7 weeks of gestational age (GA), with birth weight of 880 g [appropriate for date (AFD)]
and an Apgar score of 5 at 1 minute and 7 at 5 minute. He had no malformation and
received acute cardiopulmonary management. On days 0, 2, and 3, IND was intravenously
administered to treat hsPDA, which induced acute renal failure on day 5, including
a decreased urine output and elevated serum creatinine levels (2.82 mg/dL), without
PDA closure. The diagnosis of hsPDA was made by echocardiographic findings in terms
of ductal diameter ˃1.5 mm, atrial: aortic root ratio ˃1.5 mm, peak velocity in the
diastole of the left pulmonary artery, and the evaluation of end-diastolic retrograde
flow in the descending aorta and poor cardiac function in addition to clinical signs.[14] From days 5 to 7, a 7.5 mg/kg of paracetamol was intravenously administered every
6 hour for 3 days and PDA closure was confirmed using echocardiography on day 7. On
day 16, PDA reopened and paracetamol was re-administered for 3 days because of consistent
high serum creatinine levels (1.35 mg/dL). During the second course of intravenous
paracetamol treatment, the DA diameter remained unchanged, which enlarged to 2.0 mm
after the therapy. A surgical DA closure was performed on day 27. In our institution,
surgical ligation of PDA is only undertaken in patients when medical treatment has
failed and if the patient requires extensive respiratory support or is unable to be
weaned off a ventilator. During the two courses of intravenous paracetamol treatment,
no adverse events, such as elevated hepatic enzyme and hypothermia, were observed.
Table 1
Summary of the three cases
|
Case
|
GA (wk)
|
BW (g)
|
Contraindication to indomethacin
|
Age when treatment was started (d)
|
Duration of treatment (d)
|
Pretreatment DA diameter (mm)
|
Pretreatment LA/Ao
|
Posttreatment PDA status
|
Adverse events
|
Surgical ligation
|
|
A
|
252/7
|
880
|
Acute renal failure
|
05
|
6
|
1.3
|
1.23
|
Temporary closure
|
–
|
+
|
|
B
|
253/7
|
715
|
Ineffective
|
20
|
3
|
1.3
|
1.71
|
Ineffective
|
–
|
+
|
|
C
|
263/7
|
890
|
Acute renal failure
|
12
|
6
|
1.5
|
1.05
|
Temporary closure
|
–
|
+
|
Abbreviations: BW, birth weight; DA, ductus arteriosus; GA, gestational age; LA/Ao,
left atrial/aortic root ratio; PDA, patent ductus arteriosus.
Infant B was a female at 253/7 weeks of GA, with a birth weight of 715 g (AFD) and an Apgar score of 4 at 1 minute
and 7 at 5 minute. She had no malformation and received acute cardiopulmonary management
and antibiotic treatment for intrauterine infection. On days 0 and 2, IND was administered
for hsPDA, and PDA closure was confirmed using echocardiography on day 3. The PDA
reopened on day 7. Because four courses of IND administration were ineffective, a
7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days starting
from day 20. The DA diameter remained unchanged and required a surgical closure on
day 24. During this one course of intravenous paracetamol treatment, no adverse events
were observed.
Infant C was a female at 263/7 weeks of GA, with a birth weight of 890 g (AFD) and an Apgar score of 4 at 1 minute
and 6 at 5 minute. She received acute cardiopulmonary management and had a large muscular
ventricular septal defect (2.5 mm). A pharmacological treatment for DA closure was
tried to prevent the exacerbation of congestive heart failure. Despite two courses
of IND administration, the DA diameter remained unchanged and decreased urine output
and elevated serum creatinine levels (2.02 mg/dL) were observed. PDA closure was confirmed
after red blood cell transfusion on day 11. On day 12, DA reopened; therefore, a 7.5
mg/kg of paracetamol was intravenously administered every 6 hour for 3 days, because
of elevated serum creatinine levels (2.04 mg/dL). During paracetamol treatment, the
DA diameter decreased from 1.5 to 0.7 mm, which subsequently increased to 1.0 mm after
the therapy. The second course of paracetamol treatment was started on day 16. PDA
temporarily closed on day 18, which reopened on day 21. No adverse events were observed
during paracetamol treatment. Surgical DA closure was eventually required on day 61
after two courses of paracetamol treatment and three of IND treatment.
Discussion
Nonsteroidal anti-inflammatory drugs (NSAIDs), specifically IND and ibuprofen, have
been the initial medications of choice for PDA closure.[2]
[3]
[4] NSAIDs block prostaglandin E2 (PGE2) production by inhibiting the cyclooxygenase
(COX) enzymes, and thereby facilitate the thickening of the lumen with ductal closure.
Approximately 70 to 85% success rates of NSAIDs in PDA closure have been reported;[4] however, the reopening rate of DA after the pharmacological treatment with these
drugs is 20 to 35%[15]
[16] and they can cause weakened platelet aggregation, hyperbilirubinemia, peripheral
vasoconstriction, and decreased organ blood flow with subsequent renal dysfunction
and gastrointestinal perforations.[2]
[3]
[4]
[17] Paracetamol has recently been considered as an alternative treatment for hsPDA because
of its safety and effectiveness.[18]
[19] El-Mashad et al compared the efficacy and side effects of IND, ibuprofen, and paracetamol
for PDA closure in preterm neonates and concluded that paracetamol is as effective
as IND and ibuprofen and has fewer side effects mainly on renal function, platelet
count, and gastrointestinal bleeding.[12] However, the use of intravenous paracetamol for treating hsPDA has not yet been
reported in Japan. Here, we reported the cases of three extremely low birth weight
infants with hsPDA who were treated with intravenous paracetamol because of contraindication
or resistance to IND. Although all infants eventually needed surgical treatment, temporary
closure and no adverse events were observed during the pharmacological treatment with
low-dose intravenous paracetamol, thereby suggesting that paracetamol treatment might
delay the surgery date for DA closure. The dosage and timing of administration seemed
to be the key factors contributing to the efficacy of paracetamol. In recently conducted
clinical trials, a 60 mg/kg/day of paracetamol was intravenously administered for
3 days.[10]
[11]
[12] However, we selected a lower dosage of 30 mg/kg/day (7.5 mg/kg/dose × 4/day) for
3 days, on the basis of its package insert in Japan, which recommends a dose of 7.5
mg/kg every 6 hours for term neonates up to infants weighing 10 kg. In our three cases,
a dose of 7.5 mg/kg every 6 hours was used according to our treatment protocol, which
was covered by the clinical trial insurance and was approved by the IRB. Therefore,
we could not increase the dose or the duration of paracetamol therapy. With regard
to the timing, a prospective observational cohort study reported that the use of paracetamol
after ibuprofen treatment failure was ineffective for PDA closure in very low birth
weight infants. From these findings, the authors concluded that paracetamol treatment
for PDA closure cannot be recommended for infants with a postnatal age of >2 weeks
and that an early paracetamol treatment might be more effective.[11] In the present cases, the starting days of paracetamol administration were days
5 and 16 in infant A, day 20 in infant B, and days 12 and 16 in infant C. Because
paracetamol treatment was not the first line treatment in our administration protocol,
the timing of dosage was necessarily late because of which our protocol of intravenous
paracetamol eventually could not avoid a surgical treatment.
We showed temporary DA closure and no short-term adverse events during the pharmacological
treatment with intravenous paracetamol. However, in view of a recent report in mice
of adverse effects on the developing brain from paracetamol,[20] and another report of an association between prenatal paracetamol and the development
of autism or autism spectrum disorder in childhood,[21] long-term follow-up to at least 18 to 24 months postnatal age must be incorporated
in any studies of paracetamol in the newborn population. Recently, a follow-up study
conducted by Oncel et al revealed that the neurodevelopmental outcomes did not differ
among the preterm infants who receive either paracetamol or ibuprofen at 18 to 24
months' corrected age.[22] Follow-up will be also necessary for our three cases to investigate long-term adverse
events related to paracetamol.
Conclusion
These are the first case reports of hsPDA in preterm infants treated with low-dose
intravenous paracetamol in Japan. We believe that intravenous paracetamol can be used
for hsPDA closure in premature neonates when IND treatment is unsuccessful and when
the only other therapeutic option is surgery. Further dose-escalation studies and
subsequent prospective, randomized controlled trials are needed to evaluate the efficacy
of intravenous paracetamol for hsPDA closure.
