European Journal of Cardiovascular Medicine

PDA (patent ductus arteriosus) incidence is quite high in preterm infants with the reported range of 20% to 60% in the literature. An increase in the incidence of PDA is attributed to the lack of a normal closure mechanism owing to immaturity. Also, birth weight and gestational age are closely associated with the closure of PDA. PDA is seen in 80% of infants with a birth weight of <1200 grams at birth. In infants with a birth weight of <2000 grams, the rate is 40%. Other literature data shows that PDA symptoms are seen in 48% of infants having a birthweight of <1000 grams. Also, 80% of infants with RDS (respiratory distress syndrome) have PDA. In subjects that depict significant mortality and morbidity, it can be attributed to hemodynamically significant patent ductus arteriosus. It includes BPD (bronchopulmonary dysplasia), ROP (retinopathy of prematurity), NEC (necrotizing enterocolitis), and IVH (intra-ventricular hemorrhage).^1,2

DA or ductus arteriosus comprises smooth muscle fibers that are longitudinally arranged in spiral layers and are surrounded by concrete elastic tissue layers. Following birth, contraction occurs in the medial smooth muscle fiber owing to exposure to oxygen-rich air which further leads to shortening of DA length and lumen constriction which starts at the pulmonary end till there is functional closure in 24-48 hours. The second closure starts with intimal and medial connective tissue proliferation and atrophy of smooth muscle. Hence, it further leads to lamentation and a non-contractile structure over the next 3 weeks.³

The exact mechanism of ductus arteriosus closure is still unclear, however, the involvement of prostaglandins synthesized by Cox 2 (ptgs2) and Cox 1 (ptgs1) are vital mediators of DA patency as well as closure. It is noted that with the advanced gestation and after birth, Cox-2 expression is increased depicting that COX-2 expression in the DA of premature offspring prevented its post-natal constriction. Prostaglandins act via a family of G protein receptors. The EP family is vital whereas the EP4 subtype has the most vital role. Like closely related NSAIDs, paracetamol interferes with the peroxidase activity of COX isoenzymes, particularly COX2 when the cellular environment is low with peroxides and arachidonic acid. This can explain the apparent central effects of PCM as COX2 is expressed in neural tissues and the reason for its ineffective appearance in inflamed tissues.⁴   

For PDA management in preterm infants, extensive research has been done with extensive data since 1976 with first indomethacin use. FDA has approved the use of ibuprofen and indomethacin in pharmacological management for the closure of patent DA. Owing to associated adverse effects, the use of indomethacin has greatly reduced over the years and has largely been replaced with ibuprofen. However, it has continued as a discussion and controversy topic. Recently PCM has been used for PDA closure. Owing to scarce literature data, further studies are needed for the comparison of paracetamol to Ibuprofen in the management of hemodynamically significant patent ductus arteriosus concerning long-term outcomes, drug safety, and closure percentage.⁵ Hence, the present study aimed to assess the efficacy of ibuprofen and paracetamol in treating hemodynamically significant patent ductus arteries in preterm infants. The study also focused on different postnatal and prenatal factors that might affect pharmacological closure and different comorbidities associated with PDA.

The present observational clinical study aimed to assess the efficacy of ibuprofen and paracetamol in treating hemodynamically significant patent ductus arteries in preterm infants. The study also focused on different postnatal and prenatal factors that might affect pharmacological closure and different comorbidities associated with PDA. The study subjects were from the Department of Pediatrics of the Institute. Verbal and written informed consent were taken from all the subjects before study participation.

The present study assessed 200 infant subjects with patent ductus arteriosus admitted to the neonatal ICU of the Institute within the defined study period. The inclusion criteria for the study were subjects aged ≤34 weeks, with confirmed echocardiographic diagnosis of hemodynamically significant patent ductus arteriosus, and postnatal age ≤14 days. The exclusion criteria for the study were infants with major congenital malformations, infants older than 34 weeks, and subjects with congenital heart diseases requiring PDA for maintenance of blood flow.

After the final inclusion of the study subjects when the decision was made on pharmacological closure, subjects were screened strictly for compliance with inclusion and exclusion criteria and were assigned to either intravenous or oral paracetamol or oral ibuprofen. Consecutive 200 subjects were allotted to either of the two groups. Operation hsPDA definitions were made depending on 2D echocardiographic findings or clinical history. The outcomes assessed were also defined.

Infants that received either IV or oral paracetamol at a dose of 15mg/kg every 6 hours for 3 days or oral ibuprofen as an initial dose of 10mg/kg followed by 5mg/kg after 24 and 48 hours. Option as to whether to manage with ibuprofen or paracetamol was made on individual infant characteristics including present comorbidities, platelets, creatinine, and serum bilirubin level. If the subject needed or not needed second treatment course was assessed with echocardiography following the first course, when only minor ductal shunting was seen following two courses without respiratory support needed, and no further treatment was given.

In cases with treatment failure, subjects were assessed and if they were fit for rescue treatment, an alternate drug was given as a third course. Subjects were again evaluated and when clinical management was not feasible, subjects were referred for catheter or surgical ligation. Drug safety factors were daily assessed during management including bilirubin levels, serum creatinine levels, IVH grade, the tendency to bleed, and 24-hour urine output.

The stopping of treatment was prompted in cases with any of the following conditions gastrointestinal bleeding, IVH grade 3-4. NEC, and/or renal failure. The main outcome assessed in the study was ductal closure rates following treatment and whether subjects showed hemodynamic improvement as LFT, RFT, and CBC in the normal range depicting decreased oxygen need from these investigations. Each infant was echocardiographically monitored daily during the management. Secondary outcomes assessed were safety for both the drug including early adverse events including death, hyperbilirubinemia, NEC, tendency to bleed, emerging IVH, and oliguria. Late adverse events assessed included death, sepsis, ROP, NEC, periventricular leukomalacia (PVL), and/or BPD. Early adverse events were considered for those effects seen during and up to 1 week after treatment administration.

The data gathered were analyzed statistically using SPSS (Statistical Package for the Social Sciences) software version 24.0 (IBM Corp., Armonk. NY, USA) for assessment of descriptive measures, Student t-test, ANOVA (analysis of variance), and Chi-square test. The results were expressed as mean and standard deviation and frequency and percentages. The p-value of <0.05 was considered statistically significant.

The present observational clinical study aimed to assess the efficacy of ibuprofen and paracetamol in treating hemodynamically significant patent ductus arteries in preterm infants. The study also focused on different postnatal and prenatal factors that might affect pharmacological closure and different comorbidities associated with PDA. The study assessed subjects for hsPDA (hemodynamically significant patent ductus arteriosus) using 2D echo and clinical findings. After the final inclusion of the study subjects, 200 subjects were assigned to PCM (paracetamol) and IBU (ibuprofen) groups in a 3-day course. For treatment outcomes in two groups of study subjects, PDA was closed in 76.25% (n=122) subjects, referred in 1.25% (n=2) subjects, and death in 22.5% (n=36) subjects respectively. With ibuprofen, PDA was closed in 75% (n=30) of study subjects, 6.67% (n=2) cases were referred, and 26.67% (n=8) subjects died. In total, PDA was closed in 76% (n=152) subjects, 2% (n=4) cases were referred, and 22% (n=44) subjects died. A total of 160 subjects were managed with paracetamol and 40 subjects were managed with ibuprofen (Table 1).

Table 1: Treatment outcomes in two groups of study subjects

It was seen that for closure rates with paracetamol and ibuprofen after the first and second courses, with paracetamol, 16.25% of cases with paracetamol reported closure in the first course, and in 71.6% of subjects PDA was closed in the second course. With ibuprofen, PDA was closed in the first course in 45% of subjects and the second course in 54.5% of subjects (Table 2).

Table 2: Closure rates with paracetamol and ibuprofen after the first and second course

The study results showed that for PDA closure with ibuprofen and paracetamol based on the birth weight, for birth weight of <1, 1-1.5, 1.5-2, 2-2.5, and >2.5 kg, PDA closure was seen in 62.50%, 77.78%, 72%, 82.35%, 83.33% subjects respectively with paracetamol and in 0, 50%, 80%, 80%, and 100% subjects respectively with ibuprofen (Table 3).   

Table 3: PDA closure with ibuprofen and paracetamol based on the birth weight

Concerning the comparison of pre-treatment and post-treatment values of different study parameters, with ibuprofen, bilirubin levels were 10.31 and 8.75 respectively before and after treatment, urea was 53.4 and 45.54 respectively before and after treatment, creatinine was 0.982 and 0.892 respectively before and after treatment, and platelet was 220500 and 190500 respectively before and after treatment. All these values were statistically non-significant with p=0.5484, 0.5315, 0.3285, and 0.4002 respectively. With paracetamol, statistically non-significant results were seen for bilirubin, urea, creatinine, and platelet respectively with p=0.08, 0.06, 0.7895, and 0.506 (Table 4). 

Table 4: Comparison of pre-treatment and post-treatment values of different study parameters

The present study assessed subjects for hsPDA (hemodynamically significant patent ductus arteriosus) using 2D echo and clinical findings. After the final inclusion of the study subjects, 200 subjects were assigned to PCM (paracetamol) and IBU (ibuprofen) groups in a 3-day course. For treatment outcomes in two groups of study subjects, PDA was closed in 76.25% (n=122) subjects, referred in 1.25% (n=2) subjects, and death in 22.5% (n=36) subjects respectively. With ibuprofen, PDA was closed in 75% (n=30) of study subjects, 6.67% (n=2) cases were referred, and 26.67% (n=8) subjects died. In total, PDA was closed in 76% (n=152) subjects, 2% (n=4) cases were referred, and 22% (n=44) subjects died. A total of 160 subjects were managed with paracetamol and 40 subjects were managed with ibuprofen. These data were comparable to the studies of Rheinlaender C et al⁶ in 2009 and El-Mashad AE et al⁷ in 2017 where authors assessed subjects with demographic data comparable to the present study.

The study results showed that for closure rates with paracetamol and ibuprofen after the first and second courses, with paracetamol, 16.25% of cases with paracetamol reported closure in the first course, and 71.6% of subjects' PDA was closed in the second course. With ibuprofen, PDA was closed in the first course in 45% of subjects and the second course in 54.5% of subjects. These results were consistent with the studies of Meena V et al⁸ in 2020 and Ahranjani BM et al⁹ in 2020 where closure rates with paracetamol and ibuprofen similar to the present study were reported by the authors in their respective studies.

It was seen that for PDA closure with ibuprofen and paracetamol based on the birth weight, for birth weight of <1, 1-1.5, 1.5-2, 2-2.5, and >2.5 kg, PDA closure was seen in 62.50%, 77.78%, 72%, 82.35%, 83.33% subjects respectively with paracetamol and in 0, 50%, 80%, 80%, and 100% subjects respectively with ibuprofen. These findings were in agreement with the results of Xiao Y et al¹⁰ in 2020 and McCrae JC et al¹¹ in 2018 where PDA closure with ibuprofen and paracetamol based on the birth weight reported by the authors in their studies was comparable to the present study.     

The study results also showed that concerning the comparison of pre-treatment and post-treatment values of different study parameters, with ibuprofen, bilirubin levels were 10.31 and 8.75 respectively before and after treatment, urea was 53.4 and 45.54 respectively before and after treatment, creatinine was 0.982 and 0.892 respectively before and after treatment, and platelet was 220500 and 190500 respectively before and after treatment. All these values were statistically non-significant with p=0.5484, 0.5315, 0.3285, and 0.4002 respectively. With paracetamol, statistically non-significant results were seen for bilirubin, urea, creatinine, and platelet respectively with p=0.08, 0.06, 0.7895, and 0.506. These results were in line with the studies of Ohlsson A et al¹² in 2011 and Swathi R et al¹³ in 2023 where the comparison of pre-treatment and post-treatment values of different study parameters similar to the present study were reported by the authors in their respective studies.  

The present study, considering its limitations, concludes that paracetamol can be given as the first-line treatment in hemodynamically significant patent ductus arteriosus cases in preterm infants and is a superior choice in subjects with low platelet counts and comorbidities. Further longitudinal studies with larger sample sizes and longer assessments with more drugs were needed to attain a conclusion

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