Our study found that the ductal closure rate on day 7 of life was similar in low dose and conventional dose paracetamol group. Though the ductal reopening rate needing second course of medical treatment for PDA was higher in the low dose group compared to the paracetamol group, the difference was not statistically significant. None of the babies had a persistent ductus which needed surgical intervention. There was no significant difference in the incidence of adverse effects between the two groups. We found low dose paracetamol to be equally effective as conventional dosing regimen. Our trial that evaluated the efficacy of very low dose paracetamol in extreme and early preterm infants could add to the limited evidence in this area. Our findings are also important in the current scenario where there is emerging evidences for considering conservative management for haemodynamically significant PDA [17, 18].
The efficacy of conventional dose iv paracetamol in closing hsPDA has been extensively studied previously and has shown a closure rate of about 70–80% [19, 20]. Recently The Preterm Infants’ Paracetamol Study (PreParaS) [21] [high loading dose of 20mg/Kg followed by low dose of 7.5mg/Kg/dose every 6 hourly for four days] and the Early PARacetamol (EPAR) [16] trial [high loading dose of 15mg/kg followed by 7.5mg/Kg every 6 hourly for five days) have studied the effect of early low dose paracetamol and found it to be effective as compared to placebo in ductal closure. The ductal closure was practised within six hours in EPAR while in the PreParaS trial, the ductal closure was performed within 24 hours of life. In both the studies, the decision to close the duct was based on the transductal diameter only. However in our study, we decided to close the duct only when six other significant echocardiographic criteria were also met.
The efficacy of low dose iv paracetamol (10mg/kg/dose 6 hourly) vs conventional dose (15mg/Kg/dose 6 hourly) for a period of 120 hours was recently studied for early targeted closure of PDA in preterm infants < 30 weeks gestation [15]. They found that at completion of the sixth postnatal day, closure of PDA was achieved in 92% of infants in the low dose group as compared with 94% of those in the standard dose group (RD: −1.6%, 95% CI: −11.6–8.5%, p = 0.38). The rates of rescue therapies, adverse effects and other neonatal morbidities were comparable in both groups.
Adverse events which were noted in our study included pulmonary haemorrhage which was similar in both the arms. This could be related to the increased incidence of sepsis and septic shock in the study population. Similarly three deaths in the low dose group and seven in the conventional dose group were also attributed to septic shock. The incidence of severe IVH was higher in the conventional paracetamol group though the difference was not statistically significant. No NEC was reported in both the study groups. We could observe a statistically significant increased incidence of severe IVH in the conventional arm of very preterm infants which could be explained due to perinatal asphyxia and early onset sepsis in these infants.
To our knowledge this is one of the first prospective observational study conducted to study the effectiveness of lower paracetamol dose in closing PDA which fulfilled more than six echocardiographic criteria at the end of 24 hours of life. The study has also analysed the paracetamol levels and the effect on liver function by paracetamol administration. There was no evidence of hepatic impairment in either of the groups. Number of infants with raised paracetamol levels being similar in both the groups were reassuring.
Our study had several limitations. The PDA closure rate in our study was higher than that reported in other studies. This cannot be attributed solely due to paracetamol use as spontaneous closure of hsPDA do happen in a third of extreme and very preterm infants [22, 23]. The study was conducted as a prospective observational study and thus randomisation was not done. A robust randomised controlled trial is needed to prove our hypothesis. Another limitation of the study could be its smaller sample size. Larger sample size would be needed to conclusively evaluate the effect of a lesser dosing regimens of paracetamol. Further, long term neurodevelopmental outcomes also needs to be studied.
To conclude, low dose paracetamol was found to be equally effective compared to conventional dose paracetamol for early targeted closure of hsPDA in very and extreme preterm infants. Larger multicentric adequately powered randomised controlled will be required to confirm the findings. Such a study should also look at long term neurodevelopmental outcomes in these infants.