Comparison of intravenous Paracetamol with oral Ibuprofen for medical closure of PDA (patent ductus arteriosus) in preterm newborns – can it be an eective, safe and preferable choice?

Introduction: close and than half of have Patent Ductus Arteriosus (PDA) after the first 24hours. About 70% of infants born before 28 weeks may require medical or surgical closure of PDA. Objectives: To compare the effect of i/v PCM and oral Ibuprofen on PDA closure rate in preterm neonates with a gestational age of < 37 weeks and evaluate the side effect profile of both drugs. Material and Methods: This time-bound prospective observational study for comparison of the efficacy of the two drugs on the closure of PDA in preterms admitted during 1.5 years of the study period in a neonatal ICU caring for inborn as well as outborn neonates in central India. After approval of the institutional ethics committee, initial clinical screening included all preterms but only those with PDA (open ductus arteriosus) confirmed by 2D-echocardiography were allocated to receive either of two treatment regimens (3-day courses of each oral Ibuprofen and i/v PCM) which already exist as evidence-based therapeutic practice options. Result: Out of a total of 43 cases clinically suspected on initial screening, 30 preterm babies confirmed by 2D-Echo to have PDA were finally enrolled and analysed. Twenty-one patients received i/v PCM with a resultant PDA closure rate of 85.7 % (n = 18/21), while nine cases could be allocated oral Ibuprofen arm and ductus closure was obtained in seven patients (77.78%). Conclusion: Paracetamol, preferably by the intravenous route, seems to be an effective, cheap, easily available and safe first-line alternative to oral Ibuprofen for the closure of PDA, especially in newborns with extreme prematurity, who are initially intolerant to oral feeds or drugs. in

Since the late nineties only, the role of Paracetamol against prostacyclin-synthesis was known [10,11], but it was suggested as an acceptable alternative drug for PDA closure in the current decade only after certain observations verified its dose dependent effectiveness [2,12]. Paracetamol seems to act at the peroxidase segment of PG-H2 synthetase while Ibuprofen acts on the cyclooxygenase enzyme.
Peroxidase is activated at 10 fold lower peroxide concentration than is cyclooxygenase, therefore paracetamol mediated inhibition is mediated at reduced local peroxide level concentrations (as the condition with hypoxia). Many studies mainly including small randomized trials or case series used Paracetamol usually in cases that failed to respond to, or had contraindications for, Ibuprofen, and most of them used an oral paracetamol regimen of 15 mg/kg per dose every 6 hours [13][14][15][16][17][18].
Non-availability of IV Ibuprofen in India is a major concern along with similar high cost and side effects of intravenous Indomethacin, whereas easy availability, less side effects, and less cost of both intravenous and oral paracetamol make this acceptable alternative. Therefore, the present study was conducted to compare the role of IV paracetamol with oral Ibuprofen for PDA closure in preterm infants.   week and only 10% were 34-36 weeks late

Material and methods
preterms. Table 2 also shows that 56.67% of cases were ELBW (extremely low birth weight, < 1000 g), 33.33% cases were Very Low BW (between birth weight 1000 -1499 g), remaining 10% cases also had low birth weight between 1500-2500 g. Mean gestational age and birth weight of these preterm subjects was 30.54 week and 1137g respectively.
Thus, the incidence of PDA is much higher in lower gestational age and ELBW groups.        Table 7 shows that in the i/v paracetamol group there was only 2 death (2/21, 9.52%) and amongst 9 PDA cases those got treated with oral Ibuprofen, only 1 patient (11.11%) died. This result suggested no statistical or significant difference (p= 0.291) in overall mortality in the two treatment groups.   [20] and it might persist in as low as 57 per 100 000 live births after the second week of life due to functional followed by structural closure [21]. Schneider DJ M et al. reported that the incidence of PDA in term neonates is only 1 in 2,000 births, and accounting for 5%-10% of all congenital heart disease [22].  In this index study finally including 30 preterm patients, on comparison of the primary outcome as closure rate between two primary intervention groups, in the intravenous Paracetamol group, the PDA closure was confirmed by 2D-Echo in 18/21 subjects (85.7%); whereas in oral Ibuprofen group, PDA closure was achieved in 7 out of 9 patients (77.78%). Although the PDA closure rate with Paracetamol was marginally high, there was no statistically significant difference in efficacy between intravenous Paracetamol and oral Ibuprofen (p=0.593).
In a recent study by Al-Lawama M et al (2017), who had used oral route of paracetamol like other initial studies on the efficacy of PCM, the primary closure rate was 69% in the Paracetamol group and 78% in the Ibuprofen group and they also had not found a significant difference in the short-term neonatal outcomes [13]. Table 9 also reveals that many studies conducted in recent years have proved the acceptable efficacy or non-inferiority of Paracetamol when compared to Ibuprofen along with comparable mortality profile in two study groups.  Paracetamol and the ibuprofen groups in terms of a failure of PDA closure (the quality of evidence was moderate grade). [13,24,31,32,33] In our index study, the all-cause mortality rate even Only one additional serious side effect with the use of Ibuprofen was significant gastrointestinal bleed, but such bleeding manifestations including pulmonary hemorrhage in critical preterm patients (observed also in the recipient of i/v paracetamol) could be attributed also to co-existing factors like sepsis, fluid overload, or failure of PDA closure, CCF/shock and DIC.
No other serious immediate complications like renal injury or IVH was documented in either of the study groups. Table 10 shows the comparison of the sideeffect profile of both the intervention drugs as observed in different studies. The incidence of gastrointestinal bleeding and hyperbilirubinemia was significantly higher in the Ibuprofen group compared to the paracetamol group (P < 0.05). No significant differences found for other adverse events.
Once MY et al. [24] Bilirubin and liver enzyme levels before and after each treatment course were not significantly different between groups. No patient showed oliguria or AKI.

Al-Lawama
M et al. [13] Favourable data showed the safety of paracetamol, although little evidence of side effects was found. None showed signs of hepatic toxicity.
Ibuprofen had mild vasoconstrictive side effects.

El Mashad
AER et al. [32] There was a significant difference between the paracetamol and the ibuprofen groups in serum bilirubin (mmol/ L) following treatment, with lower serum bilirubin levels in the paracetamol group.

Conclusion
For early medical closure of PDA in preterm newborns, intravenous Paracetamol is a cheap, easily available and equally effective alternate to oral Ibuprofen, with a relatively better safety profile.
The intravenous route seems to be more feasible and preferable especially amongst extremely premature and clinically sick babies, who usually can't tolerate oral feeds as well as any drugs.

What this study adds to existing knowledge
This study supports and strengthens the favourable role of intravenous paracetamol as a first-line drug for medical closure of PDA as a potentially effective, cheap and safe alternative to oral Ibuprofen, which itself is most widely used due to easy availability and less toxicity than Indomethacin.

Contributions by authors
Rathia SK conceptualized and helped in protocol writing, analyzed data, prepared and finalized the manuscript. Kurrey VK helped in conceptualization (as a guide), protocol writing, data analysis and manuscript writing, and will be the principal corresponding author.
Shrivastava S helped during protocol writing, concept build-up, and patient enrolment by screening & confirmatory echocardiography. Gupta AK wrote the protocol, recruited patients and helped in data analysis and manuscript writing.
Phuljhele S supervised the study and helped in protocol writing and finalizing the manuscript. The   [Crossref] 02. Hamrick SEG, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics.