MANUSCRIPT CITATION:

Dani C, Lista G, Bianchi S, Mosca F, Schena F, Ramenghi L et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr 2021; 180: 807–816. PMID: 32888085.

REVIEWED BY: 

Asad Abbas
Neonatal Grid Trainee
Birmingham Women’s Hospital, Birmingham, UK

Matthew Cawsey
Neonatal Consultant
Birmingham Women’s Hospital, Birmingham, UK

TYPE OF INVESTIGATION: 

Treatment

QUESTION: 

(P) In infants born between 25⁺⁰ – 31⁺⁶ weeks gestation who have been diagnosed with hemodynamically significant patent ductus arteriosus (hsPDA) between 24 to 72 hours of life, (I) is intravenous paracetamol more effective than (C) intravenous Ibuprofen in (O) closing the hsPDA (T) after the first course of treatment lasting 3 days.

METHODS: 

• Design: Prospective, randomized, multi-centre.
• Allocation: Stratified block randomization in 1:1 ratio to one of the two treatment groups.
  • The allocation sequence was computer-generated, stratified by gestational age 25⁺⁰ – 27⁺⁶ or 28⁺⁰ – 31⁺⁶.
• Blinding: Carers and people administering the medications were not blinded due to the different dosing schedules of the two medications. The cardiologists/neonatologists performing the echocardiograms were blinded.
• Follow-up period: Neonates were followed up until 30 days after the enrollment.
• Setting: Five Neonatal Intensive Care Units in Italy
• Patients:
  • Included:
    • Infants with gestational age of 25⁺⁰ – 31⁺⁶
    • Echocardiographic evidence of hsPDA between 24 and 72 hours of life, defined as ductal left-to-right shunt, with a left atrium-to-aortic root ratio > 1.3 or a ductal size > 1.5 mm.
  • Excluded:
    • Flow pattern suggesting a restrictive PDA.
    • Infants with major congenital malformations, fetal hydrops, life-threatening infection defined as positive blood culture taken at birth, echocardiographic evidence of pulmonary hypertension and grade ≥ 3 intraventricular haemorrhage, serum creatinine >1.5 mg/dL (132.6 µmol/L), urine output <1 mL/Kg/h during a 24-hour collection period or urine output <0.5 mL/Kg/h during the first 24 hours of life, platelet count <50,000/mm³, major bleeding, defined as hematuria, or blood in the tracheal aspirate, gastric aspirate, or stools or consistent blood oozing from puncture sites; and severe liver failure, defined as elevated liver enzymes (ALT, AST) > 2 times the upper boundary of the normal range (ALT 6–50 U/L; AST 35–140 U/L).
• Intervention:
  • Group I: Intravenous Paracetamol 15mg/kg, 6 hourly for 3 days
  • Group II: Intravenous Ibuprofen, 10 mg/kg, followed by 5 mg/kg after 24 and 48 hours.
• Outcomes:
  • Primary outcome: Closure of hsPDA after the first course of treatment lasting 3 days.
  • Secondary outcomes:
    • Constriction (defined as either a closed PDA or no longer hsPDA) of hsPDA after the first course of treatment.
    • hsPDA closure or constriction after the second course of treatment with ibuprofen.
    • Reopening rate and the incidence of surgical closure 30 days after the enrolment.
• Analysis and sample size:
  • Estimating an absolute improvement of 20% in closing hsPDA with paracetamol compared to ibuprofen, a two-sided alpha level of 5%, power of 80%, and assuming a dropout rate of 10%, a sample size of 110 infants was calculated. 58 infants were allocated to the paracetamol group and 52 infants were allocated to the Ibuprofen group.
  • A modified intention-to-treat analysis (mITT) was conducted on all randomized patients completing the first treatment course and having baseline and day 3 echocardiographs.
  • A per-protocol (PP) analysis was planned on patients from the mITT population with no major protocol violations. The mITT and PP populations were the same, as there were no major protocol violations.
  • Safety analysis was done on safety population (SP), defined as all patients who took at least one dose of medication.
• Patient follow-up: Of the 110 patients enrolled, 101 were analysed for the primary outcome (52 in the paracetamol group, 49 in the Ibuprofen group).

MAIN RESULTS:

The demographic and clinical characteristics of the infants included in the study did not differ significantly between the groups. This included weight, gestational age, sex, maternal risk factors, RDS and need for respiratory support, sepsis, IVH, and NEC. Also, there was no significant difference in the age at enrolment, heart rate, blood pressure, platelet and, haemoglobin counts at the time of enrolment. Of note, the results do not mention the baseline echocardiographic findings in each group.

For the primary outcome, PDA closed after the first course of treatment in 52 % of the infants who received paracetamol, compared to 78% of the neonates who received Ibuprofen. The difference was statistically significant. (Table 1)

For secondary outcomes, there was no significant difference in the rate of ductal constriction between the two groups. The rates of ductal closure or constriction with a second course of Ibuprofen, reopening rates within 30 days of life, and rates of need for surgical closure were also similar between the two groups.

Table 1: Primary and secondary outcome measures

There rate of adverse events was low and there was no significant difference in the number of adverse events between two groups. The rates of liver failure, renal failure, NEC, gastrointestinal perforations/bleeds, thrombocytopenia, hyperbilirubinemia and coagulopathy were similar between the two groups.

CONCLUSION:

The authors conclude that intravenous paracetamol is less effective than intravenous ibuprofen in closing hsPDA, however, paracetamol has a similar constrictive effect and hsPDA treated with it has the same outcome as those treated with Ibuprofen in terms of need for second course of treatment, reopening rates and need for surgical closure.

COMMENTARY: 

The study was a prospective randomised controlled trial comparing a 3-day cause of intravenous (IV) paracetamol to IV ibuprofen in closing a hemodynamic significant PDA (hsPDA) in infants born at 25+0 – 31+6 weeks gestation. Paracetamol is thought to produce ductal closure by blocking the peroxidase segment of prostaglandin synthetase, resulting in inhibition of prostaglandin production. (1)

In the studies conducted so far comparing paracetamol to Ibuprofen, paracetamol has proven to be equally efficacious in closing hsPDA, however, most of these trials included more mature neonates where the rates of spontaneous ductal closure are already high. (2, 3) In the PDA- TOLERATE trial, when compared with the rate of spontaneous PDA closure, the odds ratio of paracetamol-induced ductal closure was lower at 1.33 (95% CI, 0.55-3.24) compared to 2.03 for ibuprofen (95% CI, 1.05-3.91). (4)

This study confirmed previous findings that neonates treated with paracetamol compared to ibuprofen had lower incidence of thrombocytopenia and fewer renal and gastrointestinal side effects. Two systematic reviews comparing paracetamol to ibuprofen (oral or intravenous) showed there was a significant difference favouring paracetamol in creatinine levels, urine output, platelet count, serum bilirubin, and incidence of gastrointestinal bleeding. (2, 3) This study did not replicate these findings. This again highlights the fact that safety data for paracetamol use is still emerging. Other potential adverse effects, including neurodevelopmental impairment with paracetamol use in pregnancy and early infancy, were not reported. (2, 5)

The population was stratified by gestational age but not by the centre of study. As the rates of the spontaneous ductal closure between centres can vary from 8% to 77% in infants born at 27 weeks or less this makes head-to-head comparison between the two drugs difficult when a placebo group is not included and the rate of spontaneous closure is unknown. (4) Furthermore, this study included infants born between 25-31 weeks gestational age, with a mean gestational age of 28 weeks. It is not clear why infants born below 25 weeks were excluded.

This is only the third randomised trial that used intravenous paracetamol for PDA closure, and only the second that used it in direct comparison with Ibuprofen. (6,7) El- Mashad et al included 300 infants with a mean gestational age of 25 weeks and found no difference in the rates of PDA closure with IV paracetamol and Ibuprofen.(7) In this study by Dani et al, the rate of PDA closure after the first treatment course was significantly lower compared to IV ibuprofen, they found no significant difference between rates of PDA constriction (defined as either a closed PDA or no longer hsPDA) between the two groups, however, the study was not powered for that outcome. It is possible that these inconsistent findings are related to the lack of pharmacokinetic and pharmacodynamic data on the best dose, duration and route of administration of paracetamol for PDA closure. Two small studies compared intravenous paracetamol versus oral paracetamol for ductal closure showed opposing results leaving uncertainty as to the best route of administration. (1, 8)

In summary, more studies are needed to detect the effectiveness and systemic safety of paracetamol in closing hsPDA in more immature neonates below 28 weeks’ gestation that are powered to detect long-term neurodevelopmental outcomes. Similarly, pharmacokinetics and pharmacodynamics studies to find the best route, dosages, and duration of use of paracetamol are also needed.

REFERENCES:

1. El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res 2014; 76: 238-44.
2. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev 2020; 1: CD010061.
3. Xiao Y, Liu H, Hu R, You Q, Zeng M, Jiang X. Efficacy and Safety of Paracetamol for Patent Ductus Arteriosus Closure in Preterm Infants: An Updated Systematic Review and Meta-Analysis. Front Pediatr 2020; 7: 1–14.
4. Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J et al. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol 2019; 39: 599-607.
5. Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm Behav 2018; 101: 125-147.
6. Härkin P, Härmä A, Aikio O, Valkama M, Leskinen M, Saarela T, et al. Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. Journal of Pediatrics 2016; 177: 72-7.
7. El-Mashad AE, El-Mahdy H, El Amrousy DE, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European Journal of Pediatrics 2017; 176: 233-40.
8. Sancak S, Gokmen Yildirim T, Topcuoglu S, Yavuz T, Karatekin G, Ovali F. Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants? J Matern Fetal Neonatal Med 2016; 29: 135-9.