Keywords ibuprofen - indomethacin - paracetamol - patent ductus arteriosus - premature infant
- surgical closure
Background
Ductus arteriosus (DA) is an essential blood vessel for fetal circulation and development.
In most term infants, DA closes spontaneously within 1 to 2 days after birth due to
the loss of the prostaglandin supply from the placenta and the rise of arterial oxygen
pressure.[1 ] In contrast, DA often does not close spontaneously in preterm infants, including
especially very-low-birth-weight infants (VLBWIs), due to the poor responsiveness
to arterial oxygen pressure and the high responsiveness to prostaglandin inherent
in this population.[2 ]
[3 ] It is well known that hemodynamically significant patent ductus arteriosus (hsPDA)
increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis,
and bronchopulmonary dysplasia.[4 ]
[5 ]
[6 ] In Japan, the cyclooxygenase inhibitor—indomethacin—has been used as standard therapy
for hsPDA. In addition, another cyclooxygenase inhibitor—ibuprofen—has been available
for application in cases of hsPDA since June 2018. However, because of their side
effects such as acute kidney injury and gastrointestinal perforation, the introduction
of other novel treatments for hsPDA with fewer side effects is required.[6 ]
Paracetamol has recently been reported to have the same effects on DA closure with
fewer side effects as those of indomethacin and ibuprofen observed during the treatment
for hsPDA.[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
[12 ] We have previously reported a case series of three patients in Japan treated with
low-dose intravenous paracetamol (7.5 mg/kg, given every 6 hours for 3 days) for preterm
infants with hsPDA, who were indomethacin-resistant or -contraindicated. A temporary
DA closure was observed in two of the three infants without any side effects. However,
all three infants eventually required surgical closure.[13 ] This treatment failure was thought to be due to an inadequate dose of paracetamol,
given that a higher dose (15 mg/kg, given every 6 hours for 3 days) has been used
in most studies, elsewhere in which degree of the efficacy of paracetamol on DA closure
was observed.[7 ]
[8 ]
[9 ]
[10 ]
[11 ] Therefore, in the present research, we increased the dose of paracetamol up to 15 mg/kg/dose
for evaluation in 16 preterm infants who were indomethacin/ibuprofen-resistant or
-contraindicated and examined the safety and feasibility outcomes.
Methods
About 16 VLBWIs (birth weight <1,500 g) with hsPDA born at Saitama Medical Center,
Saitama Medical University from July 1, 2017 to March 31, 2019 were included in this
research. hsPDA was determined by each physician using echocardiography and ultrasonography
of the brain and abdomen. These patients showed resistance or contraindications, such
as acute renal failure, to indomethacin and/or ibuprofen. In each patient, 15 mg/kg/dose
of paracetamol (Acelio Intravenous Injection; TERUMO Co. Ltd., Tokyo, Japan) was administered
every 6 hours for 3 days as one course. Arterial duct diameter, left atrial aortic
root ratio, and end-diastolic flow velocity of the left pulmonary artery were subsequently
evaluated using ultrasonography by the physician. Physical examinations; vital signs;
and blood tests including creatinine (Cr), aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and acetaminophen blood levels were performed to evaluate
the presence of adverse events. Acute renal failure was defined as serum Cr level > 1.5 mg/dL.
Elevated AST and ALT levels were defined as >100 and >280 U/L, respectively. This
study was covered by the clinical trial insurance program, and was approved by the
institutional review board of Saitama Medical Center, Saitama Medical University (approval
no. 1656-III). Parental consent was obtained before paracetamol administration.
Results
About 16 patients were included in this study ([Table 1 ]). The median gestational age was 27.6 weeks (range: 23.0–29.4 weeks) and the median
birth weight was 913 g (range: 475–1,423 g). Paracetamol was administered because
of resistance to indomethacin or ibuprofen in seven cases and the presence of acute
kidney injury in ten cases (one case had both findings). The median starting date
of paracetamol administration was a day 10 after birth (range: days 2–36), and the
median duration of paracetamol administration was 6 days (range: 3–9 days). The initial
median DA diameter was 1.3 mm (range: 0.8–2.2 mm), and the initial median left atrial
aortic root ratio was 1.66 (range: 0.87–2.08). Among the 16 cases, paracetamol treatment
was effective in 14 cases (88%), with DA closure or narrowing observed, while two
cases (13%) were refractory to the therapy. Surgical closure of PDA was required in
seven cases (44%), and the DA remained open at discharge and was followed up on an
outpatient basis in one case (6%).
Table 1
Summary of cases
Case
GA (wk)
BW (g)
Contraindication to indomethacin/ibuprofen
Age when treatment was started (d)
Duration of treatment (d)
Pretreatment DA diameter (mm)
Pretreatment LA/Ao
Posttreatment PDA status
Adverse events
Surgical ligation
PDA status at discharge
1
24
653
Ineffective +
acute renal failure
4
6
1.6
1.77
Temporary
closure
–
+
Closed
2
28
1,053
Acute renal failure
2
3
1.3
1.96
Closed
–
–
Closed
3
28
721
Acute renal failure
3
3
2
1.68
Closed
–
–
Closed
4
25
1,036
Acute renal failure
20
3
1
1.59
Ineffective
–
+
Closed
5
29
1,363
Ineffective
24
3
1.5
1.73
Temporary
closure
–
–
Closed
6
29
1,173
Ineffective
25
6
2.1
2.08
Narrowing
–
–
Open
7
26
920
Ineffective
5
6
1.2
1.48
Narrowing
–
+
Closed
8
23
475
Acute renal failure
9
6
1.0
1.24
Narrowing
–
+
Closed
9
28
905
Acute renal failure
6
6
1.2
1.63
Closed
–
–
Closed
10
23
517
Acute renal failure
8
9
1.1
1.32
Closed
–
–
Closed
11
28
820
Ineffective
14
9
1.1
1.88
Temporary
closure
–
–
Closed
12
24
695
Acute renal failure
36
3
0.8
0.87
Closed
–
–
Closed
13
23
565
Acute renal failure
6
3
1.2
1.52
Temporary
closure
–
–
Closed
14
27
1,015
Ineffective
11
9
2
1.70
Narrowing
–
+
Closed
15
28
1,083
Ineffective
25
3
2.2
1.29
Narrowing
–
+
Closed
16
28
1,423
Acute renal failure
3
9
1.9
2.03
Ineffective
–
+
Closed
Abbreviations: BW, birth weight; DA; ductus arteriosus; GA, gestational age; LA/Ao,
left atrial/aortic root ratio; PDA; patent ductus arteriosus.
In all 16 cases, no adverse events—including elevated AST or ALT levels, hypothermia
(<36°C body temperature), or the need for a higher incubator temperature—were observed
after paracetamol administration. Plasma paracetamol levels were measured in ten cases
([Fig. 1 ]). In two (cases 7 and 13) of the ten cases, the third course of paracetamol administration
was avoided because relatively high plasma paracetamol levels (64.3 and 97.7 μg/mL,
respectively) were observed at 6 hours after the earlier two courses of paracetamol
treatments. In addition, in one case (case 16), plasma paracetamol level of 116.7 μg/mL
was observed 4 hours after the first course of treatment, so the second course was
discontinued.
Fig. 1 Plasma paracetamol levels. The plasma paracetamol levels were measured in ten cases. The x-axis shows hours
after the last dose of paracetamol (hours) and the y-axis shows plasma paracetamol
levels (μg/mL).
In case 1, colostomy was performed on day 5 after the birth for congenital intestinal
atresia, and ascites could not be controlled thereafter, resulting in death on day
64. Cases 2 and 3 were monochorionic diamniotic twins with twin-to-twin transfusion
syndrome, and both patients had periventricular leukomalacia from birth. Case 14 developed
IVH on day 1 after birth with circulatory failure due to intrauterine infection. Case
16 was born with fetal heart failure and fetal hydrops, and had IVH and intracerebral
hemorrhage.
Discussion
In this case series, we confirmed the safety and feasibility of higher-dose intravenous
paracetamol (15 mg/kg given every 6 hours for 3 days) for VLBWIs with hsPDA who were
indomethacin/ibuprofen-resistant or -contraindicated in Japan, similar to that previously
observed in patients with low-dose intravenous paracetamol (7.5 mg/kg, given every
6 hours for 3 days).[13 ]
In our previous study performed using low-dose intravenous paracetamol (7.5 mg/kg
given every 6 hours for 3 days), temporary DA closure was observed in two of three
(67%) cases with hsPDA and no short-term adverse events occurred during the provision
of pharmacological treatment in any cases. However, our protocol of applying low-dose
intravenous paracetamol ultimately could not avoid the need for surgical treatment
(avoidance rate of surgical ligation: 0%). In contrast, the presently discussed pharmacological
treatment approach with higher-dose intravenous paracetamol (15 mg/kg given every
6 hours for 3 days) increased both the success of DA closure or narrowing (14/16;
88%) and avoidance of surgical PDA ligation (9/16; 56%) as compared with the low-dose
paracetamol regimen. In a systematic review, the analysis of uncontrolled studies
suggested that as compared with the use of low-dose paracetamol (30–60 mg/kg/day),
the use of higher doses (60 mg/kg/day) appears unnecessary because of no significant
differences in DA closure rate between two doses.[10 ] However, this result should be interpreted with caution considering the high proportion
of subjects with a gestational age of more than 28 weeks treated with low doses. Therefore,
higher-dose (15 mg/kg/dose) paracetamol should be used in further clinical trials
involving patients with PDA who have resistance or contraindications to indomethacin
and/or ibuprofen.
Of note, paracetamol clearance is lower in neonates than in children and adults. After
metabolic conversion, conjugation with glucuronic acid and sulfate, paracetamol is
subsequently eliminated via the renal route. In the present study, the plasma paracetamol
levels were measured in ten cases. With acute ingestions of paracetamol, the Rumack-Mathews
nomogram is a valuable tool to use to assess the risk of hepatotoxicity. This nomogram
was originally constructed in the 1970s as a method to discriminate those patients
who were more likely to suffer hepatotoxicity and those who were not. A line between
200 mg/mL at 4 hours after ingestion and 25 mg/mL at 16 hours, known as the “200 line”
defined the group at risk.[14 ] Conversely, a parallel line at 150 mg/mL at 4 hours—also known as the treatment
line or “150 line”—is the treatment line most commonly used in the United States.[15 ] Although no paracetamol-related adverse events—including elevated AST or ALT levels—were
observed in any patients in this research, another course of paracetamol administration
was avoided because of high plasma paracetamol levels in three of ten cases in which
plasma paracetamol levels were measured. All three cases had circulatory failure,
oliguria, or elevated serum Cr levels before and during intravenous paracetamol treatment.
Therefore, we stress that plasma paracetamol levels should be monitored in patients
who are at a high risk for circulatory and/or renal failure.
We determine that good feasibility and short-term safety were present during pharmacological
treatment with intravenous paracetamol in our research. However, it has been reported
that the long-term administration of paracetamol to the pregnant mother is implicated
in the development of autism or autism spectrum disorder in children.[16 ] In contrast, however, one study reported that there were no differences in neurodevelopmental
outcomes at 18 to 24 months, including on the Bayley Scales of Infant Development,
second edition; the Mental Developmental Index; and the Psychomotor Developmental
Index, with recommended adaptations suggested for visual and auditory impairments
in preterm or low–birth weight infants exposed to paracetamol as compared with ibuprofen
for PDA.[17 ] Importantly, because the quality of evidence of this study is low, long-term follow-up
to at least 18 to 24 months after birth must be incorporated in any studies of paracetamol
in the newborn population, including our previous and present case series.
In our current case series, several limitations exist. (1) Being a descriptive study
with a small number of patients and with the absence of a control group weakens our
study, especially in the presence of several published randomized controlled pilot
studies suggesting the efficacy and safety of paracetamol for hsPDA.[8 ]
[9 ]
[10 ]
[11 ] However, those studies also included a limited number of cases. Therefore, reporting
a case series still has some degree of enhancement to the quality of evidence as part
of a cumulative data. (2) We confirmed the treatment's safety and feasibility with
the anticipated results and a lack of serious adverse reactions in small populations
whose treatment with paracetamol were determined by physician's discretion. To estimate
the efficacy of this treatment in hsPDA patients, randomized control trials are warranted
in the future.
Conclusion
This is the first report in Japan describing the safety and feasibility of treatment
with higher dose intravenous paracetamol for preterm infants with hsPDA in whom indomethacin
or ibuprofen was contraindicated or ineffective. Plasma paracetamol levels should
be monitored in higher risk patients with circulatory and/or renal failure. Further
follow-up study among these subjects and the conduction of prospective clinical trials
such as randomized control trials are needed to evaluate the long-term prognosis and
efficacy of intravenous paracetamol for hsPDA closure.
