MANUSCRIPT CITATION 

El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017; 176:233-240. PMID 28004188.

REVIEWED BY

Jane E Stremming, MD
Neonatal-Perinatal Medicine Fellow
University of Colorado, Aurora, CO

Clyde J Wright, MD
Associate Professor of Pediatrics
University of Colorado, Aurora, CO

Laura D Brown, MD
Associate Professor of Pediatrics
University of Colorado, Aurora, CO

TYPE OF INVESTIGATION 

Treatment

QUESTION 

(P) In infants born at less than 28 weeks or with birth weight less than 1500 grams who have been diagnosed with a hemodynamically significant patent ductus arteriosus (PDA) in the first two weeks of life, (I) is paracetamol as effective as (C) indomethacin or ibuprofen in (O) closing the PDA, and does paracetamol have fewer side effects? (T) Echocardiograms to assess PDA closure and all laboratory studies were performed before and three days after initiation of medications.

METHODS

• Design: Prospective, randomized, single center. Of note, the manuscript does not state whether the trial was registered.
• Allocation: Allocation concealed.
• Blinding: Partially blinded due to difference in drug doses (outcome assessors were blinded)
• Follow-up period: Not stated
• Setting: 1 NICU
• Patients:
  • Included:
    • Infants with gestational age less than 28 weeks or birth weight less than 1500 grams
    • Less than 2 weeks old
    • Hemodynamically significant PDA (hs-PDA) based on clinical examination and echocardiography
      • All preterm neonates in the neonatal unit at which this study was done were assessed by echocardiographic examination to detect hs-PDA by 48 hours of life
      • However, no CONSORT flow chart was provided by the authors to allow readers to know what the baseline incidence of hs-PDA was in this patient population
    • Echocardiographic criteria of a hs-PDA: left atrial dilation (left atrial: aortic root>1,6), diastolic turbulence in the pulmonary artery, internal diameter of duct>1.5 mm, and reverse end diastolic flow in the descending aorta/mesenteric artery
    • Clinical criteria of a hs-PDA: tachycardia, bounding pulse with wide pulse pressure, hyperdynamic precordium with continuous murmur, hepatomegaly, edema, unexplained metabolic acidosis, failure of respiratory distress syndrome to improve at 2-7 days, and unexplained CO2 retention in mechanically ventilated babies.
  • Excluded:
    • Preterm infants with congenital anomalies, life threatening sepsis, NEC, IVH, UOP<1 ml/kg/hr in the previous 24 hours, serum creatinine>1.5 mg/dL, platelet count<100,00/mL, complex congenital heart disease or ductal dependent lesions
• Intervention:
  • Group 1: paracetamol 15 mg/kg IV over 30 minutes followed by 15 mg/kg IV every 6 hours for 3 days
  • Group 2: ibuprofen 10 mg/kg IV followed by 5 mg/kg/day for 2 days
  • Group 3: indomethacin 0.2 mg/kg IV over 30 minutes every 12 hours for 3 doses
• Outcomes:
  • Primary outcome: Efficacy of the drug in closing a hs-PDA in a preterm neonate 3 days after initiation of medication
  • Secondary outcomes: Compare side effects and complications of each drug in preterm neonates (these were not precisely defined in the methods)
• Analysis and Sample Size: Estimating a difference in closure rate of 21% among the three treatment groups and using a type 1 error of 0.05 and a power of 90%, the sample size was calculated to be 97 participants per group. 100 infants were enrolled into each group.
• Patient follow-up: Of the 300 patients enrolled (100 in each group), 100% were analyzed for the primary outcome.

MAIN RESULTS

Demographic and echocardiographic characteristics of the included infants (including gestational age, sex, weight, age at start of mediation, diameter of PDA, pressure across PDA, and left atrial/aortic root ratio) were not significantly different among the groups.

For the primary outcome, the PDA closed after one course of treatment in 80% of neonates who received paracetamol, 77% of those who received ibuprofen, and 81% of those who received indomethacin

PRIMARY OUTCOME

SECONDARY OUTCOMES 

Neonates who received paracetamol had significantly decreased GI bleeding compared to those who received ibuprofen or indomethacin, although GI bleeding was not defined. There were no significant differences in ROP, NEC, pulmonary hemorrhage, IVH, or sepsis among the groups. Infants who received ibuprofen or indomethacin had a statistically significant increase in creatinine and BUN and decrease in urine output and platelet count following treatment. There were no significant differences in SGPT and SGOT levels among the groups.

*Comparison of three groups after treatment

CONCLUSION 

The authors conclude that paracetamol is equally effective in closing a hemodynamically significant PDA as indomethacin and ibuprofen with fewer cases of GI bleeding and less of a reduction in renal function and platelet count.

COMMENTARY

This study was a prospective, randomized trial comparing paracetamol to indomethacin and ibuprofen for closing a hemodynamically significant patent ductus arteriosus (hs-PDA) in premature neonates (<28 weeks GA or <1500 grams). Currently available treatments to close the PDA include indomethacin and ibuprofen, but these treatments have been associated with transient reduction in kidney function (1,2), and they are contraidicated in patients with active bleeding or renal dysfunction. Surgical ligation of the PDA has been associated with worse neurodevelopmental outcomes and BPD (3), although there may be no difference in outcomes after correcting for perinatal cofounders (4). The search for safe pharmacologic treatments to close the hs-PDA continues.

In this study, echocardiogram was performed in all infants by 48 hours of age. The severity of PDA-related symptomatology that led to treatment is not well-defined. It is not clear how many echocardiographic and/or clinical criteria were necessary to qualify a hs-PDA. The authors state that PDA closure occurs in 70% of cases following a course of either indomethacin or ibuprofen. However, the spontaneous ductal closure rate in this population is 73% (5). This trial found slightly higher closure rates of 80%, 77%, and 81% in the paracetamol, ibuprofen, and indomethacin groups respectively. Thus, paracetamol may be as effective as indomethacin or ibuprofen for ductal closure, but the benefit of medical versus spontaneous ductal closure remains unknown. Ongoing studies, such as the Baby-OSCAR trial (ISRCTN84264977) (6), which is investigating ibuprofen versus placebo are attempting to evaluate outcomes after early medical closure of the PDA.

In this study, infants receiving paracetamol had less gastrointestinal bleeding, lower BUN/creatinine, higher platelet counts, and higher urine output when compared to the indomethacin and ibuprofen groups. The definition of gastrointestinal bleeding was not specified. The clinical significance of these statistically significant changes remains uncertain.

The overall complication was low; a larger sample size is necessary to truly estimate the risk of adverse events. Further, the duration of follow up was not specified, so whether these results are inclusive or important in hospital and post-discharge morbidities is unknown. Larger studies are necessary to evaluate whether paracetamol – when used to close the PDA – will be associated with a lower rate of adverse events compared to currently available pharmacologic treatment and morbidities including BPD and neurodevelopmental outcomes.

In general, the ability to interprt the trial is limited. CONSORT guidelines have been developed for transparent report of clinical trials (http://www.consort-statement.org/checklists/view/32–consort-2010/66-title). In this study, a CONSORT flow diagram was not provided, thus it is difficult to determine how many studied infants were ultimately included in the trial. Furthermore, it is not clear whether this trial was registered in ClinicalTrials.gov. Following CONSORT guidelines in the reporting of clinical trials allows providers the opportunity to critically appraise and interpret trial results. We advocate that trials adhere to these guidelines, and that Journals request that they be reported. Uniformly adopting this practice will facilitate data interpretation and implementation of practice change at the bedside.

REFERENCES

1. Clyman RI, Chorne N. Patent Ductus Arteriosus: Evidence For and Against Treatment. J Pediatr 2007; 150:216-219.
2. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2015; CD003481.
3. Medan JC, Kendrick D, Hagadorn JI, Frantz III ID. Patent Ductus Arteriosus Therapy: Impact on Neonatal and 18-Month Outcome. Pediatrics 2009; 123: 674-681.
4. Weisz DE, Mirea L, Resende MHF, Ly L, Church PT, Kelly E. Outcomes of Surgical Ligation after Unsuccessful Pharmacotherapy for Patent Ductus Arteriosus in Neonates Born Extremely Preterm. J Pediatr 2018 195: 292-6.
5. Rolland A, Shankar-Aguilera S, Diomande D, V Zupan-Simunek, Boileau P. Natural evolution of patent ductus arteriosus in the extremely preterm infant. Arch Dis Child Fetal Neonatal Ed 2015; 100: F55-58.
6. ISRCTN Registry [Internet]. London: Biomed Central. ISRCTN84264977, Does selective early treatment of patent ductus arteriosus in extreme preterm infants reduce complications and improve long-term outcome; 2010 Aug 13. Available from https://www.isrctn.com/ISRCTN84264977?q=paracetamol AND PDA&filters=&sort=&offset=2&totalResults=2&page=1&pageSize=10&searchType=basic-search (Cited May 16, 2018)