Paracetamol y Ductus arterioso

Diciembre 2017


Paracetamol y Ductus arterioso


Colaboración      Dra Patricia Alvarez  Cantwell                             Pediatra Neonatóloga   Puerto Montt       Chile                                      



1.- Intravenous paracetamol was associated with closure of the ductus arteriosus in extremely premature infants


S Juujärvi, 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 infants


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 analysis.


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 reported.


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;;; World Health Organization International Clinical Trials Registry Platform at 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 new trials.


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 Review Group.


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 Härkin 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 the drug.


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: 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, 17: 182


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 adverse effects.


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: NCT02422966 . Eudract no. 2013-003883-30.



6.- Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants


Kadir Şerafettin Tekgündüz 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 the cases



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 patients.


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 weight infants


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 also considered.


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



Daniëlla 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 infants.


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).