Dra Patricia Alvarez Cantwell
Pediatra Neonatóloga Puerto Montt
1.- Intravenous paracetamol was associated
with closure of the ductus arteriosus in extremely premature infants
S Juujurvi, T Saarela, M Hallman, O Aikio
Acta Paediatrica 2017 November 4
AIM: Symptomatic patent ductus arteriosus may lead to
serious complications in extremely preterm and extremely low birth weight
infants and is often resistant to medication. We evaluated early intravenous
paracetamol for pain prevention during respiratory therapy, in an attempt to
understand the ductal treatment of such infants.
METHODS: Our cohort were 295 extremely preterm or
extremely low birth weight infants, born at less than 28 weeks or 1,000g,
respectively, who were treated in the neonatal intensive care unit of Oulu
University Hospital from 2002-2015, before and after intravenous paracetamol was
introduced in June 2009. Ductal closure dates, paracetamol medication details,
morbidities and mortality data were evaluated.
RESULTS: Intravenous paracetamol was given to 128
infants, starting at a median of 4.4 hours age (range 0-169 hours), with a mean
total dosage of 212 mg/kg (range 7.5 - 1175 mg/kg). We also included 167
controls who were mainly treated before we used intravenous paracetamol.
Ibuprofen (p<0.001) and ligation (p = 0.002) were lower in the paracetamol group
than controls. No adverse effects were detected. Paracetamol was not associated
with other morbidities.
CONCLUSION: We found that early use of intravenous
paracetamol decreased the incidence of ductal therapies in extremely premature
or extremely low birth weight infants.
2.- Early paracetamol treatment
associated with lowered risk of persistent ductus arteriosus in very preterm
Outi Aikio y cols
Journal of Maternal-fetal & Neonatal Medicine 2014, 27 (12): 1252-6
OBJECTIVES: Persistent ductus arteriosus (PDA) delays
the recovery of very preterm infants (VLGA, gestation <32 weeks). Indomethacin/ibuprofen
treatment and ligation of PDA have complications. As a prostaglandin synthase
inhibitor paracetamol may also promote the closure of ductus arteriosus. We
studied retrospectively whether early paracetamol therapy was associated with
decreased incidence of PDA without adverse events.
METHODS: On June 2009, we introduced intravenous
paracetamol during early respiratory therapy. We included 105 VLGA infants who
received paracetamol before the age of 72 h. The loading dose was 20 mg/kg
followed by 7.5 mg/kg every 6 hours. The 96 VLGA infants admitted from January
2008 to May 2009 without lethal congenital disease were controls. Infants dying
very early were excluded, leaving 102 paracetamol-exposed and 88 controls for
RESULTS: After the introduction of paracetamol, the
incidence of PDA decreased from 30.7% to 14.7% (p = 0.008). Ibuprofen treatment
was given to 15 paracetamol-treated and to 26 control infants (p = 0.013). Three
paracetamol-exposed and seven control infants required surgery. There was no
detectable increase in adverse events.
CONCLUSIONS: Annual incidence of PDA decreased after
introduction of paracetamol. Efficacy and safety in promoting the early closure
of ductus arteriosus remains to be established.
3.- Paracetamol (acetaminophen) for patent ductus
arteriosus in preterm or low-birth-weight infants
Arne Ohlsson y cols
Cochrane Database of Systematic Reviews 2015 March 11, (3): CD010061
BACKGROUND: In preterm newborns, the ductus arteriosus
frequently fails to close and the infants require medical or surgical closure of
the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically
with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case
reports suggest that paracetamol may be an alternative for the closure of a PDA.
Concerns have been raised that in neonatal mice paracetamol may cause adverse
effects on the developing brain, and an association between prenatal exposure to
paracetamol and later development of autism or autism spectrum disorder has been
OBJECTIVES: To determine the efficacy and safety of
intravenous or oral paracetamol compared with placebo or no intervention,
intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase
inhibitors for closure of a PDA in preterm or low-birth-weight infants.
SEARCH METHODS: We used the standard search strategy of
the Cochrane Neonatal Review Group. This included electronic searches of the
Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library),
MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the
Pediatric Academic Societies and the Perinatal Society of Australia and New
Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au;
World Health Organization International Clinical Trials Registry Platform at
who.int/ictrp for ongoing trials and the Web of Science for articles quoting
identified randomised controlled trials. We searched the first 200 hits on
Google Scholar(TM) to identify grey literature. All searches were conducted in
December 2013. A repeat search of MEDLINE in August 2014 did not identify any
SELECTION CRITERIA: We identified two randomised
controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for
the treatment of an echocardiographically diagnosed PDA in infants born preterm
(≤ 34 weeks postmenstrual age (PMA)).
DATA COLLECTION AND ANALYSIS: We performed data
collection and analyses in accordance with the methods of the Cochrane Neonatal
MAIN RESULTS: Two unmasked studies of treatment of PDA
that enrolled 250 infants were included. The sequence of randomisation and the
allocation to treatment groups were concealed in both studies. In one study the
cardiologist assessing PDA closure was blinded to group allocation of the infant.
In the other study it was not stated if that was the case or not. The quality of
the trials, using GRADE, was low for the primary outcome of PDA closure and
moderate for all other important outcomes. There was no significant difference
between treatment with oral paracetamol versus oral ibuprofen for failure of
ductal closure after the first course of drug administration (typical relative
risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk
difference (RD) -0.04, 95% CI -0.16 to 0.08; I(2) = 0 % for RR and 23% for RD).There
were no significant differences between the paracetamol and the ibuprofen groups
in the secondary outcomes except for 'duration for need of supplemental oxygen'
(mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for
hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to
-0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of
paracetamol; 1 study, n = 160).
AUTHORS' CONCLUSIONS: Although a limited number of
infants with a PDA have been studied in randomised trials of low to moderate
quality according to GRADE, oral paracetamol appears to be as effective in
closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse
effects on the developing brain from paracetamol, and another report of an
association between prenatal paracetamol and the development of autism or autism
spectrum disorder in childhood, 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. Such trials are required before any recommendations for the use of
paracetamol in the newborn population can be made.
4.- Paracetamol Accelerates Closure of the Ductus
Arteriosus after Premature Birth: A Randomized Trial
Pia Harkin y cols
Journal of Pediatrics 2016, 177: 72-77.e2
OBJECTIVE: To study the biologic effect of
paracetamol, an inhibitor of prostaglandin synthase, on early closure of
ductus arteriosus, and to evaluate possible adverse effects associated with
STUDY DESIGN: In a controlled, double-blind, phase
I-II trial, very low gestational age (<32 weeks) infants requiring intensive
care were randomly assigned to intravenous paracetamol or placebo (0.45%
NaCl). A loading dose of 20 mg/kg was given within 24 hours of birth,
followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound
examinations of ductal calibers were performed before the first dose, and
until 1 day after the last dose. The main outcome was a decrease in the
ductal caliber without side effects.
RESULTS: Of 63 screened infants, 48 were randomized:
23 were assigned to paracetamol and 25 to placebo. Before the intervention,
their ductal calibers were similar. During the intervention, the ductus
closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97,
P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours
(31.1-324) for the paracetamol-treated vs 338 hours (118-557) for controls
(P = .045). Paracetamol serum levels were within the therapeutic range, and
no adverse effects were evident.
CONCLUSIONS: Prophylactic paracetamol induced early
closure of the ductus arteriosus without detectable side effects. Further
trials are required to determine whether intravenous paracetamol may safely
prevent symptomatic patent ductus arteriosus.
TRIAL REGISTRATION: ClinicalTrials.gov:
NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.
5.- Efficacy and safety of intravenous
paracetamol in comparison to ibuprofen for the treatment of patent ductus
arteriosus in preterm infants :
study protocol for a
randomized control trial
Carlo Dany y cols Trials 2016 April 2,
BACKGROUND: Patent ductus arteriosus (PDA) is one
of most common complications in preterm infants. Although ibuprofen
represents the first choice for the closure of PDA, this treatment can cause
severe gastrointestinal and adverse renal effects and worsen platelet
function. The successful closure of the PDA with paracetamol has been
recently reported in several preterm infants, and the safety of paracetamol
for this use has been suggested by the available data.
METHODS/DESIGN: We present the design of a
randomized, multicenter, controlled study, whose aim is to assess the
effectiveness and safety of intravenous paracetamol in comparison to
intravenous ibuprofen for the treatment of PDA in preterm infants. A total
of 110 infants born at 25(+0) to 31(+6) weeks of gestational age will be
enrolled and randomized to receive paracetamol or ibuprofen (55 patients per
group) starting at 24-72 h of life. The primary endpoint of the study is the
comparison of the PDA closing rate observed after a 3-day course with
paracetamol or ibuprofen. The secondary endpoints include the closure rate
of PDA after the second course of treatment with ibuprofen, the re-opening
rate of the PDA, the incidence of surgical ligation, and the occurrence of
DISCUSSION: The results of this study will provide
new information about the possible use of paracetamol in the treatment of
PDA. Paracetamol could offer several important therapeutic advantages over
current treatment options, and it could become the treatment of choice for
the management of PDA, mainly due to its more favorable side effect profile.
TRIAL REGISTRATION: Clinicaltrials.gov NCT02422966
. Eudract no. 2013-003883-30.
paracetamol with a lower dose is also effective for the treatment of patent
ductus arteriosus in pre-term infants
Kadir Şerafettin Tekgendoz y cols
Cardiology in the Young 2015, 25 (6): 1060-4
INTRODUCTION: Haemodynamically significant patent
ductus arteriosus is a significant cause of morbidity and mortality in pre-term
infants. This retrospective study was conducted to investigate the
usefulness of lower-dose paracetamol for the treatment of patent ductus
arteriosus in pre-term infants.
MATERIALS AND METHODS: A total of 13 pre-term
infants who received intravenous paracetamol because of contrindications or
side effects to oral ibuprofen were retrospectively enrolled. In the first
patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient
developed significant elevation in transaminase levels, the dose was
decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients.
Echocardiographic examination was conducted daily. In case of closure, it
was repeated after 2 days and when needed thereafter in terms of reopening.
RESULTS: A total of 13 patients received
intravenous paracetamol. Median gestational age was 29 weeks ranging from 24
to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The
median postnatal age at the first intravenous paracetamol dose was 3 days
ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus
arteriosus was closed at the median 2nd day of intravenous paracetamol
ranging from 1 to 4 days. When the patient who developed hepatotoxicity was
eliminated, the closure rate was found to be 83.3% (10/12).
CONCLUSION: Intravenous paracetamol may be a useful
treatment option for the treatment of patent ductus arteriosus in pre-term
infants with contrindication to ibuprofen. In our experience, lower-dose
paracetamol is effective in closing the patent ductus arteriosus in 83.3% of
7.- Intravenous paracetamol treatment in the
management of patent ductus arteriosus in extremely low birth weight infants
Mehmet Yekta Oncel y cols
Neonatology 2013, 103 (3): 166-9
BACKGROUND: Treatment options for the closure of a
hemodynamically significant patent ductus arteriosus (hsPDA) include medical
therapy such as ibuprofen and indomethacin and surgical ligation.
OBJECTIVE: To evaluate the efficacy of intravenous
paracetamol in preterm infants with hsPDA whose feeding was contraindicated
or had feeding intolerance.
METHODS: Preterm infants with hsPDA were started on
intravenous paracetamol treatment with parental consent. Paracetamol was
administered at a dose of 60 mg/kg/day, in four divided doses, for a period
of 3 days. In the absence of closure of hsPDA, treatment was extended up to
6 days, after which echocardiographic examination was performed.
RESULTS: A total of 10 preterm infants were
included in the study with a median gestational age of 27(4/7) weeks (minimum-maximum:
24-29) and a median birth weight of 775 g (590-990). The first dose of
intravenous paracetamol was given after a median of 6 days (2-15). On
echocardiographic examination, median internal ductal diameter was 2 mm
(1.5-3), with a median left atrium-to-aortic root ratio of 1.95 (1.6-2.2).
Intravenous paracetamol resulted in successful closure of hsPDA in all
CONCLUSIONS: This study is the first case series in
the literature which used intravenous paracetamol treatment for hsPDA. We
believe that intravenous paracetamol could be used as an alternative drug
for infants. Further prospective randomized-controlled trials are needed to
evaluate the efficacy of intravenous paracetamol for the closure of hsPDA.
8.- Prophylactic surgical ligation of patent ductus
arteriosus for prevention of mortality and morbidity in extremely low birth
R Mosalli, K Alfaleh
Cochrane Database of Systematic Reviews 2008, (1): CD006181
BACKGROUND: Patent ductus arteriosus (PDA) is
associated with increased mortality and morbidity in preterm infants.
Prophylactic indomethacin results in favorable intermediate outcomes such as
reduction of significant PDA, need for surgical ligation, severe
intraventricular hemorrhage and serious pulmonary hemorrhage without
modifying long-term neurosensory outcomes. Little is known about the
effectiveness and safety of prophylactic surgical closure of the PDA in
extremely low birth weight (ELBW) infants.
OBJECTIVES: To identify and summarize evidence from
randomized controlled trials investigating the effectiveness and safety of
prophylactic surgical ligation of the PDA on mortality and morbidities of
preterm infants less than 1000 g at birth as compared to no prophylaxis or
prophylactic cyclooxygenase inhibitors.
SEARCH STRATEGY: The standard search strategy for
the Cochrane Neonatal Review Group was performed by two review authors.
Searches were made of MEDLINE (1966 to December 2006), EMBASE (1980 to
December 2006), the Cochrane Central Register of Controlled Trials (The
Cochrane Library, Issue 4, 2006), and abstracts of annual meetings of the
Society for Pediatric Research (1995 - 2006). Contacts were made with the
authors of published articles.
SELECTION CRITERIA: Randomized or quazi-randomized
controlled trials that enrolled infants less than 28 weeks gestation or less
than 1000 g at birth who are on assisted ventilation and/or supplemental
oxygen without clinical signs of hemodynamic significance of the ductus
arteriosus were considered. Trials addressing prophylactic surgical ligation
of the patent ducts arteriosus (i.e. procedure done during the first 72
hours of life) versus no intervention or cyclooxygenase inhibitor
prophylaxis were included. The primary outcome was bronchopulmonary
dysplasia (BPD). Other important short and long-term neonatal outcomes were
DATA COLLECTION AND ANALYSIS: Standard methods of
the Cochrane Collaboration and its Neonatal Review Group were used to assess
the methodologic quality of the trials. Retrieved articles were assessed for
eligibility and data was abstracted independently by two reviewer authors.
Where data were incomplete, the primary investigators were contacted for
further information and clarifications. For dichotomous outcomes, relative
risk (RR) and its associated confidence interval were calculated. For
continuous outcomes, treatment effect was expressed as mean difference and
its calculated standard deviation. When appropriate, meta-analysis of pooled
data was performed assuming a fixed effect model
MAIN RESULTS: Only one eligible study that enrolled
84 ELBW infants was identified. The prophylactic group had ductal ligation
performed within 24 hours of life following a pre-specified protocol, while
the control group received standard care without indomethacin. Prophylactic
surgical ligation of the PDA resulted in a statistically significant
reduction of severe stage II or III necrotizing enterocolitis (NEC), [RR
0.25, 95% CI (0.08,0.83), p value 0.02, NNT 5]. The study found no
statistically significant difference in mortality, severe grade III and IV
intraventricular hemorrhage (IVH), BPD, and retinopathy of prematurity
(ROP). Of note, the study was unblinded and underpowered to detect
clinically important differences in the above mentioned outcomes.
AUTHORS' CONCLUSIONS: Prophylactic surgical
ligation of the PDA did not decrease mortality or BPD in ELBW infants. A
significant reduction of stage II or III NEC was noted. Based on the current
evidence, the high rate of spontaneous closure, availability of effective
safe medical therapies, and the potential short and long-term complications
of surgical ligation, the use such prophylactic surgical therapy is not
indicated in the management of the preterm infants.
9.- Limited effects of intravenous paracetamol on
patent ductus arteriosus in very low birth weight infants with
contraindications for ibuprofen or after ibuprofen
Daniella W E Roofthooft y cols
European Journal of Pediatrics 2015, 174 (11): 1433-40
UNLABELLED: Finding the optimal pharmacological
treatment of a patent ductus arteriosus (PDA) in preterm neonates remains
challenging. There is a growing interest in paracetamol as a new drug for
PDA closure. In this prospective observational cohort study, we evaluated
the effectiveness of intravenous paracetamol in closing a PDA in very low
birth weight infants with a hemodynamically significant PDA who either did
not respond to ibuprofen or had a contraindication for ibuprofen. They
received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3-7
days. Cardiac ultrasounds were performed before and 3 and 7 days after
treatment. Thirty-three patients were included with a median gestational age
of 25(1/7) weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a
median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in
27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this
was even 100 %.
CONCLUSION: In this study, paracetamol after
ibuprofen treatment failure was not effective for PDA closure in VLBW
infants. From the findings of this study, paracetamol treatment for PDA
closure cannot be recommended for infants with a postnatal age >2 weeks.
Earlier treatment with paracetamol for PDA might be more effective.
10.- Comparative study of the efficacy and safety
of paracetamol, ibuprofen, and indomethacin in closure of patent ductus
arteriosus in preterm neonates
Abd El-Rahman El-Mashad, Heba El-Mahdy, Doaa El
Amrousy, Marwa Elgendy European Journal of Pediatrics
2017, 176 (2): 233-240
In this prospective study, we compared the efficacy
and side effects of indomethacin, ibuprofen, and paracetamol in patent
ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm
neonates with hemodynamically significant PDA (hs-PDA) admitted at our
neonatal intensive care unit were enrolled in the study. They were
randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h
IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg
IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin
group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses.
Laboratory investigations such as renal function test, liver function test,
complete blood count, and blood gases were conducted in addition to
echocardiographic examinations. All investigations were done before and 3 days
after treatment. There was no significant difference between all groups
regarding efficacy of PDA closure (P = 0.868). There was a significant
increase in serum creatinine levels and serum blood urea nitrogen (BUN) in
the ibuprofen and indomethacin groups (P < 0.001). There was a significant
reduction in platelet count and urine output (UOP) in both ibuprofen and
indomethacin groups (P < 0.001). There was a significant increase in
bilirubin levels in only the ibuprofen group (P = 0.003). No significant
difference of hemoglobin (HB) level or liver enzymes in all groups
(P > 0.05). Ventilatory settings improved significantly in patients with
successful closure of PDA than those with failed PDA closure (P < 0.001).
CONCLUSION: Paracetamol is as effective as
indomethacin and ibuprofen in closure of PDA in preterm neonates and has
less side effects mainly on renal function, platelet count, and GIT bleeding.
What is Known: � Hemodynamically significant patent ductus arteriosus has
many complications for preterm and low birth weight neonates and better to
be closed. Many drugs were used for medical closure of PDA e.g. indomethacin,
ibuprofen and recently paracetamol. Many studies compare safety and efficacy
of paracetamol with either indomethacin or ibuprofen. What is New: � It is
the first large study that compares the efficacy and side effects of the
three drugs in one study.
11.- Consequences of delayed surgical closure of
patent ductus arteriosus in very premature infants
Sophie Jaillard y cols Annals of Thoracic Surgery
2006, 81 (1): 231-4
BACKGROUND: Surgical closure of ductus arteriosus
is commonly indicated in premature newborns. The aim of this study was to
assess short-term and mid-term effects of delayed surgical closure of the
ductus arteriosus on respiratory and digestive outcome in extremely preterm
METHODS: We retrospectively studied 58 infants less
than 28 weeks gestational age who underwent surgical closure of ductus
arteriosus between January 1997 and December 2002. Nine infants with
intrauterine growth restriction and major congenital malformation were
excluded from the study. Criteria for surgical closure of ductus arteriosus
were: (1) medical treatment failure (ie, indomethacin or ibuprofen) and (2)
hemodynamically patent ductus arteriosus: systemic arterial pressure less
than gestational age in mm Hg, heart failure, left atrial-aortic root ratio
greater than 1.6, mean velocity in the left pulmonary artery greater than
0.6 m/s, and ductus arteriosus diameter greater than 3 mm. Infants were
divided into two groups: (1) the early group who had surgery before 21 days
of life (n = 31), and (2) the late group who had surgery after 21 days of
life (n = 27). Preoperative and postoperative criteria were compared between
the two groups (ie, gestational age, birth weight, hemodynamic, ventilatory,
and echographic [left atrial-aortic root ratio, mean velocity in the left
pulmonary artery] parameters).
RESULTS: Preoperative gestational age and birth
weight did not differ between the two groups. In the early group,
gestational age was 26 weeks (range, 23 to 28 weeks and birth weight was 800
g (range, 630 to 1,240 g). In the late group, gestational age was 26 weeks (range,
24 to 28 weeks) and birth weight was 840 g (530 to 1,130 g). Hemodynamic,
ventilatory, and echographic parameters were similar in both groups. Rate of
bronchopulmonary dysplasia was similar in both groups. However, at 24 hours
post surgery, median FiO2 was higher in the late group (28% [range, 21% to
65%]) than in early group (21% [range, 21% to 60%]) (p < 0.05). Furthermore,
full oral feeding was acquired later in the late group (57 days of life [range,
30 to 136 days]) than in the early group (37 days of life [range, 27 to 84
days]) (p < 0.01), and body weight at 36 weeks of post-conceptional age was
higher in the early group at 1,800 g (range, 1,250 to 2,750 g) than in the
late group at 1,607 g (1,274 to 2,200 g) (p < 0.05).
CONCLUSIONS: Our findings show that early surgical
closure of the ductus arteriosus (< 3 weeks of life) is associated with
shortened delay for full oral feeding and improved body growth when compared
with late surgical closure (> 3 weeks of life).