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The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Paracetamol versus ibuprofen for the treatment


of patent ductus arteriosus in preterm neonates: a
meta-analysis of randomized controlled trials

Xintao Huang, Fang Wang & Kai Wang

To cite this article: Xintao Huang, Fang Wang & Kai Wang (2017): Paracetamol versus
ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: a meta-analysis
of randomized controlled trials, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2017.1338263

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1338263

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Published online: 18 Jul 2017.

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Download by: [University of Florida] Date: 20 July 2017, At: 07:55


THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017
https://doi.org/10.1080/14767058.2017.1338263

REVIEW ARTICLE

Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus


in preterm neonates: a meta-analysis of randomized controlled trials
Xintao Huanga, Fang Wangb and Kai Wangb
a
Department of Cardiology, Zhumadian Central Hospital, Zhumadian, China; bDepartment of Pediatrics, Zhengzhou Central Hospital,
Zhengzhou, China

ABSTRACT ARTICLE HISTORY


Background: Paracetamol has been suggested as an effective treatment for patent ductus arte- Received 11 May 2017
riosus (PDA). However, the comparative efficacy and safety between paracetamol and ibuprofen Revised 29 May 2017
were not determined. Accepted 31 May 2017
Methods: A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant studies
were identified via database searching. A fixed or random effect model was applied depending KEYWORDS
on the extent of heterogeneity. Ibuprofen; meta-analysis;
Results: Five RCTs with 677 neonates were included. The efficacies for the primary (risk ratio paracetamol; patent ductus
[RR]: 1.03, p ¼ .56) and overall PDA closure were comparable between the two medications (RR: arteriosus; randomized
1.02, p ¼ .62). Neonates of the two groups were comparable for the incidence of PDA complica- controlled trials
tions, including necrotizing enterocolitis (RR: 0.86, p ¼ .70), intraventricular hemorrhage (RR: 0.84,
p ¼ .55), bronchopulmonary dysplasia (RR: 0.69, p ¼ .16), and retinopathy of prematurity (RR: 0.58,
p ¼ .15), and the risks of sepsis (RR ¼ 0.88, p ¼ .48) and death (RR: 1.45, p ¼ .45) within hospitaliza-
tion. However, treatment with paracetamol was associated with a trend of reduced risk of renal
failure (RR: 0.20, p ¼ .07), and a significantly reduced risk of gastrointestinal bleeding (RR: 0.28,
p ¼ .009).
Conclusions: Paracetamol may confer comparable treatment efficacy for the closure of PDA as
ibuprofen, although paracetamol is associated with lower risk of adverse events.

Introduction
without the risk of potential morbidities related to the
Patent ductus arteriosus (PDA) is a common congenital surgical procedures, including vocal cord palsy, pul-
cardiac defect, which mainly affects the preterm neo- monary dysplasia, and neurosensory dysfunction [4].
nates of gestational age (GA) < 28 weeks [1]. The inci- Pathophysiologically, prostaglandins (Pg) have been
dence of PDA is reported to be between 30 and 70%, recognized to be a key mediator for the patency of
depending on the GA of the preterm neonates investi- the ductus arteriosus [5]. Accordingly, nonsteroidal
gated [2]. Neonates with PDA often suffer from the anti-inflammatory drugs (NSAIDs), particularly of ibu-
left-to-right shunt, which causes the increment of the profen, are conventionally used as the pharmacologic-
pulmonary blood flow [3]. Moreover, patients with ally treatment for neonates with PDA [6]. By
hemodynamically significant PDA are associated with competitively inhibition of cyclooxygenase (COX), ibu-
increased risk for long-term complications, including profen reduces the endogenous level of Pg, resulting
chronic lung disorders, retinopathy, cardiac failure, or in the successful closure of PDA in about 70% of the
even death [2]. Therefore, closure of PDA is indicated cases [7]. However, ibuprofen is contradicted in
in neonates with significant hemodynamic disorders patients with renal dysfunction or those at higher risk
for the prevention of the above complications and for bleeding, because administration of ibuprofen is
improvement of prognosis. associated with the increased incidence of renal failure
Currently, closure of PDA could be achieved via and gastrointestinal bleeding (GIB), probably related to
medications or surgical interventions [2]. its effect of peripheral vasoconstriction [8]. Therefore,
Pharmacologically closure of PDA is considered to be development of alternative medications for the closure
the first-line treatment, because it is noninvasive and of PDA is of important significance in clinical practice.

CONTACT Kai Wang kaiwang2017@sina.com Department of Pediatrics, Zhengzhou Central Hospital, Zhengzhou, China
These authors contributed equally to the work
Supplemental data for this article can be accessed here.
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 X. HUANG ET AL.

Paracetamol is recently proposed as an alternative of the medications); (d) reported at least one of the
medication for the closure of PDA since it functions as following efficacy or safety outcomes: incidence of
an inhibitor to the prostaglandin synthetase, and primary PDA closure (defined as echocardiography
causes reduced endogenous Pg [9,10]. Besides, para- confirmed closure of PDA after the first course of the
cetamol may be superior to other NSAIDs regarding treatment); incidence of overall PDA closure (defined
the safety because it is proved to have no effect of as echocardiography confirmed closure of PDA after
peripheral vasoconstriction [11]. Indeed, accumulating one or more courses of the treatment); incidences of
evidence from case series and cohort studies con- complications, including necrotizing enterocolitis (NEC,
firmed the efficacy of paracetamol as an effective defined in accordance with the modified Bell’s classifi-
treatment for neonates with PDA [12]. However, the cation [19]), intraventricular hemorrhage (IVH, defined
efficacy and safety of paracetamol as compared with in accordance with the Volpe’s classification [20]),
ibuprofen for the treatment of PDA in preterm neo- bronchopulmonary dysplasia (BPD, defined in accord-
nates have not been fully determined. Although some ance with the National Institutes of Health consensus
related randomized controlled trials (RCTs) have been definition [21]), and retinopathy of prematurity (ROP,
published to compare the therapeutic effects of para- defined in accordance with the international classifica-
cetamol and ibuprofen for PDA [13–17], most of these tion [22]); incidences of adverse events, including renal
studies retrieved insignificant results, possibly due to failure, GIB, and sepsis, which were defined in consist-
the limited sample sizes of the studies. Therefore, in ence with the definitions from the original studies;
this study, we aimed to combine the results of the and all-cause mortality within hospitalization. Reviews,
RCTs via a meta-analysis to systematically compare the nonhuman studies, observational studies without lon-
efficacy of safety between paracetamol and ibuprofen gitudinal follow-up, cross-sectional studies, duplicate
in neonates with PDA. publications, and studies in which the outcomes of
interest were not reported or unavailable were
excluded from the current study.
Materials and methods
This systematic review and meta-analysis was con-
Data extraction and quality assessment
ducted in accordance with the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta- Two authors independently performed the literature
Analyses) statement and the Cochrane Handbook searching, data extraction, and quality assessment
guidelines [18]. according to inclusion criteria. Discrepancies were
resolved by consensus. Extracted data included the
country where the study was performed, study design
Search strategy
characteristics (blind or open-label), characteristics of
PubMed, Embase, and the Cochrane Library (Cochrane the neonates (number of participants, gender, mean
Center Register of Controlled Trials) were systematic- GA, mean birth weight [BW], and the postnatal ages),
ally searched for relevant studies, using the term mean diameters of the PDA, administrative routes and
“patent ductus arteriosus” or “PDA”, paired with dosages of the medications, and treatment durations.
“paracetamol” or “acetaminophen”, “ibuprofen”, and We used the seven domains of the Cochrane risk of
“randomly”, “randomized” or “random”. The search was bias tool to evaluate the quality of the included stud-
limited to studies in humans. We also analyzed refer- ies [18], which include criteria concerning sequence
ence lists of the original and review articles using a generation, allocation concealment, blinding of partici-
manual approach. The final searching was performed pants and personnel, blinding of outcome assessors,
on 25 February 2017. incomplete outcome data, selective outcome report-
ing, and other potential threats to validity.
Study selection
Statistical analysis
Studies were included if they met the following crite-
ria: (a) published as full-length articles in English; (b) Dichotomous data were analyzed using risk ratios
reported as RCTs with a parallel design; (c) included (RRs) with 95% confidence intervals (CIs). Cochrane’s Q
preterm neonates with echocardiography confirmed test was applied to evaluate the heterogeneity among
PDA who were assigned to either a paracetamol treat- the included studies, and significant heterogeneity was
ment group or an ibuprofen treatment group (regard- considered for p < .10 [23]. Also, determined was the I2
less of the administrative routes or the dosages statistic, which describes the percentage of total
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

variation across studies that is due to heterogeneity Iran [15], and Egypt [16], respectively. The number of
rather than chance [24]. I2 > 50% indicated significant the neonates included in each study varied from 80 to
heterogeneity among the trials. Pooled analyses were 200, with the proportions of males ranging from 51.9
calculated using fixed-effect models if no significant to 70.0%. The mean GA of the included neonates var-
heterogeneity was detected by Cochrane’s Q test, ied between 25.5 and 33.5 weeks, and the mean BW
whereas random-effect models were applied in cases varied between 952 and 2155 grams. All of the
of significant heterogeneity across studies [18]. included neonates were at a postnatal age of
Predefined subgroup analyses were used to evaluate 14 days. The mean diameters of PDA varied from 2.0
whether the treatment efficacy for PDA closure were to 2.8 mm. As for the characteristics of the interven-
different between studies in which the medications tions, oral paracetamol of 60 mg daily for 3 days or
were administered orally and those in which the medi- oral ibuprofen of 10, 5, and 5 mg for day 1 to day 3
cations were applied intravenously. Sensitivity analyses were applied in three RCTs [13,14,17]; oral paracetamol
by omitting one study at a time were used to evaluate of 60 mg daily for 3 days or oral ibuprofen of 20, 10,
the robustness of the results [18]. Potential publication and 10 mg for day 1 to day 3 were applied in one
bias was assessed with Egger’s regression asymmetry RCTs [15]; while intravenous paracetamol of 60 mg
test [25] and visual inspection of funnel plots; p values daily for 3 days or intravenous ibuprofen of 10, 5, and
were two-tailed and statistical significance was set at 5 mg for day 1 to day 3 were applied in the other one
0.05. We used RevMan software for the meta-analysis study [16]. The course of the medication was main-
and statistical study (Version 5.1; Cochrane, Oxford, tained for 3 days in each of the included studies and
UK) and Stata software (Version 12.0; Stata, College all the medications were treated as the first-line ther-
Station, TX). apy for the PDA of the included neonates.

Results Data quality

Search results The details of risks of biases of the included studies


according to the Cochrane assessment tool are listed
A total of 126 articles were identified through the in Supplemental Table 1. Briefly, one of the included
database searching, and 112 were excluded based on RCTs were double-blinded studies [16], two were sin-
titles and abstracts screening, mainly because they gle-blinded [14,15], while the other two [13,17] were
were not relevant studies. Of the 14 potentially rele- open label. Details of random sequence generation
vant articles, five studies met the inclusion criteria for were reported in two studies [16,17], and the strat-
the current meta-analysis [13–17] (Supplemental egies of allocation concealment were reported in three
Figure 1). Nine articles were excluded because two of studies [13,14,16]. Details of withdrawals and dropouts
them were not relevant studies, five were not RCTs, were reported in all studies.
one was duplicated publications, and the other one
did not report data interested outcomes.
Efficacy of paracetamol versus ibuprofen for PDA
closure in preterm neonates
Study characteristics
Pooled results of the five RCTs with a fixed-effect
Overall, five RCTs [13–17] with a total of 677 neonates model showed that the efficacies for the primary
were included in the current meta-analysis, all of (RR: 1.03, 95%CI: 0.93–1.13, p ¼ .56; Figure 1(A)) and
which were published after year 2013. The characteris- overall PDA closure were comparable between
tics of the included RCTs were summarized in Table 1. paracetamol and Ibuprofen (RR: 1.02, 95%CI:
Two [13,17] of the included studies were performed in 0.95–1.09, p ¼ .62; Figure 1(B)) with no significant het-
China, and the other three were performed in Turkey [14], erogeneity among included studies (both I2 ¼ 0%).

Table 1. Characteristics of included studies.


Study No. of GA BW PA Ductal Route Dose (P/I) Durations Timing
Author, year Location design infants Male % weeks grams days diameter mm (P/I) mg/kg/d (P/I) (P/I)
Dang, 2013 China R, OL 160 51.9 31.1 1562  14 2.4 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Oncel, 2014 Turkey R, SB 80 52.5 27.3 952 24 2.3 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Yang, 2016 China R, OL 87 59.8 33.5 2155  10 2 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Bagheri, 2016 Iran R, SB 150 53.5 31.6 1644  14 NR Oral/Oral 60-60-60/20-10-10 3 days First-line therapy
El-Mashad, 2017 Egypt R, DB 200 70 25.5 1050  14 2.8 IV/IV 60-60-60/10-5-5 3 days First-line therapy
R: Random; OL: open label; SB: single blinded; DB: double blinded; GA: gestational age; BW: birth weight; PA: postnatal age; P: paracetamol; I: ibuprofen.
4 X. HUANG ET AL.

Figure 1. Forest plots comparing the efficacies of paracetamol and ibuprofen on PDA closure in preterm neonates. (A) The out-
come of primary PDA closure with one course of medication; (B) The outcome of overall PDA closure with multiple courses of
medications.

Subsequent subgroup analyses showed that these change the results, suggesting that these results were
results were consistent for studies in which the medi- not driven by a single study.
cations were administered orally, and for those in
which the medications were administered intraven-
Complication risks of paracetamol versus
ously (p for the subgroup interaction ¼ .86 and .38,
ibuprofen for preterm neonates with PDA
respectively, for the outcomes of primary and overall
PDA closure; Figure 1(A,B)). Subgroup analyses by The comparative risks for the incidences of the compli-
omitting one study at a time did not significantly cations of PDA in neonates assigned to a paracetamol
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

or an ibuprofen treatment group were shown in the risk of renal failure, or the mortality risk within
Supplemental Figure 2. Pooled results showed that the hospitalization. However, treatment with paracetamol
preterm neonates with PDA allocated to the two was associated with reduced risk of adverse events,
groups were comparable as for the risk of NEC (RR: 0. including renal failure and GIB, as compared with ibu-
86, 95%CI: 0.41–1.81, p ¼ .70; Supplemental Figure profen. Taken together, these results suggested that
2(A)), IVH (RR: 0.84, 95%CI: 0.49–1.46, p ¼ .55; paracetamol may confer comparable treatment efficacy
Supplemental Figure 2(B)), BPD (RR: 0.69, 95%CI: 0. as ibuprofen for the closure of PDA. Moreover, para-
41–1.16, p ¼ .16; Supplemental Figure 2(C)), and ROP cetamol may be optimal in this clinical condition since
(RR: 0.58, 95%CI: 0.28–1.21, p ¼ .15; Supplemental it was associated with lower risk of adverse events of
Figure 2(D)), with no evidence of significant renal failure and GIB as compared with ibuprofen.
heterogeneities. A previous meta-analysis [26] including only two
RCTs [13,14] investigated the safety and efficacy of
paracetamol as compared with ibuprofen for the treat-
Risks of adverse events in neonates receiving
ment of PDA. However, it included only 240 neonates
paracetamol versus ibuprofen
in total, and suggested that no confirmed conclusion
Pooled results showed that PDA neonates that could be drawn regarding the relative efficacy of para-
received paracetamol were associated with a trend of cetamol as compared with ibuprofen for the closure of
reduced risk of renal failure (RR: 0.20, 95%CI: 0.04–1.15, PDA since limited evidence was available. Our study
p ¼ .07; Figure 2(A)), and a significantly reduced risk of updated the previous meta-analysis by including 5
GIB (RR: 0.28, 95%CI: 0.11–0.73, p ¼ .009; Figure 2(B)) as available RCTs with a total of 677 neonates, found that
compared with those received ibuprofen. However, treatment of paracetamol and ibuprofen have no sig-
the two groups were not significantly different for the nificant differences regarding the closure rate of PDA.
incidences of sepsis (RR: 0.88, 95%CI: 0.62–1.25, The insignificant result was not likely to be caused by
p ¼ .48; Figure 2(C)). No significant heterogeneities the inadequate of the statistical power due to limited
were detected for the above analyses (all I2 ¼ 0%). In participants included, because over 300 neonates were
addition, meta-analyses with a random-effect model included in each group. Although these results need
showed that the two groups were not significantly dif- to be confirmed in further studies, our study did not
ferent for the incidence of death within hospitalization support that there is significant difference regarding
(RR: 1.45, 95%CI: 0.55–3.81, p ¼ .45; Figure 2(D)), the efficacy between paracetamol and ibuprofen for
although considerable heterogeneity was detected the closure of PDA in preterm neonates. These results
among the included studies (I2 ¼ 42%). were further reflected by the findings that no signifi-
cant differences were detected between the two treat-
ment groups for the incidences of PDA related
Publication bias
complications, including NEC, IVH, BPD, and ROP.
The publication bias for the current meta-analysis was Interestingly, as for the incidence of adverse events,
difficult to estimate because only five studies were we found that neonates receiving paracetamol were
included. The funnel plots seemed to be symmetrical associated with lower incidences of renal failure and
on visual inspection for both the meta-analyses com- GIB as compared with ibuprofen. Both of these events
paring the primary and overall closure of the PDA after were considered to be related to the potential periph-
paracetamol or ibuprofen treatment (Supplemental eral vasoconstrictive effect of ibuprofen [27], and para-
Figure 3(A,B)). These were consistent with the results cetamol did not have this effect [28]. Besides, the
of the Egger’s regression tests which suggested no sig- potential antiplatelet aggregative effect of ibuprofen
nificant publication bias for the above meta-analyses may also contribute to the pathogenesis of GIB related
(p ¼ .81 and .28, respectively). to the use of ibuprofen [29]. These results suggested
that although conferring comparative efficacy towards
the closure of PDA, administration of paracetamol may
Discussion
be safer as compared with ibuprofen, particularly in
In this meta-analysis, by pooling the results of five those at risk for the development of renal dysfunction
available RCTs, we found that there was no significant or GIB.
difference between paracetamol and ibuprofen for the Our study has limitations which should be consid-
closure of PDA in preterm neonates. Moreover, treat- ered when interpreting the results. First, since limited
ment with paracetamol or ibuprofen did not signifi- RCTs were available and individual patient-based data
cantly affect the risk of PDA associated complications, was unavailable, we could not determine whether
6 X. HUANG ET AL.

Figure 2. Forest plots comparing the influences of paracetamol and ibuprofen on the incidences of adverse events in preterm
neonates with PDA within hospitalization. (A) The incidence of renal failure; (B) The incidence of gastrointestinal bleeding; (C) The
incidence of sepsis; (D) The incidence of death.

characteristics of the treatment (such as the dosages, Further studies are needed to evaluate whether the
administrative routes, and the timing) may affect the therapeutic efficacies of paracetamol or ibuprofen for
therapeutic efficacy of paracetamol or ibuprofen on PDA remained after these neonates were discharged.
PDA closure by performing a metaregression analysis. Moreover, long-term safety of these medications in
Future RCTs with adequate sample sized are warranted preterm neonates with PDA also deserves investiga-
to evaluate the potential influence of above factors on tion. Third, some of the included RCTs were open-label
the therapeutic efficacies of the medications. Second, and of low quality, which may introduce potential
the follow-up durations of the included studies were bias. Our results need to be confirmed in high-quality
relatively short and limited to the hospitalization. RCTs in the future. Finally, since PDA is prevalent in
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7

extreme preterm neonates, whether paracetamol and [13] Dang D, Wang D, Zhang C, et al. Comparison of oral
ibuprofen confer comparable therapeutic efficacy in paracetamol versus ibuprofen in premature infants
these subgroups of the patients deserve further with patent ductus arteriosus: a randomized con-
trolled trial. PLoS One. 2013;8:e77888.
investigation.
[14] Oncel MY, Yurttutan S, Erdeve O, et al. Oral paraceta-
In conclusion, paracetamol may confer comparable mol versus oral ibuprofen in the management of
treatment efficacy for the closure of PDA as ibuprofen, patent ductus arteriosus in preterm infants: a random-
although paracetamol is associated with lower risk of ized controlled trial. J Pediatr. 2014;164:510–514.e1.
adverse events including renal failure and GIB. [15] Bagheri MM, Niknafs P, Sabsevari F, et al. Comparison
of oral acetaminophen versus ibuprofen in premature
infants with patent ductus arteriosus. Iran J Pediatr.
Disclosure statement 2016;26:e3975.
[16] El-Mashad AE, El-Mahdy H, El Amrousy D, et al.
The authors report no declarations of interest.
Comparative study of the efficacy and safety of para-
cetamol, ibuprofen, and indomethacin in closure of
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