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Aim: To investigate the blood pressure (BP) and ductal calibre patterns associated with early ductal closure in very low gestational age (<32 weeks) infants. Methods: Blood pressure was continuously measured intra‐arterially among 43 infants participating in a randomised, double‐blind trial of 4 days prophylactic intravenous paracetamol. Early closure of the ductus was verified by daily ultrasound examinations. The BP recordings, before and after the verified ductal closure, were examined and compared to control infants without ductal closure. In the 24‐h preceding the ultrasound‐verified ductal closure, periods of increased BP were searched and identified as suggestive ductal closure time points. In control infants without ductal closure, BP trends were examined during the corresponding age. Results: Mean arterial BP increased significantly before ductal closure (p < 0.001) and stayed higher than in the control group. Mean BP during the 8 h preceding closure significantly predicted the ductal closure [OR 2.094 (95% CI 1.209–3.630), p = 0.008], and multiple potential confounders failed to abolish this association. A linear decrease pattern in ductal calibre was significantly associated with the ductal closure. Conclusion: Blood pressure increased and stabilised before the early ductal closure, offering potential implications on treatment strategies of very premature infants. [ABSTRACT FROM AUTHOR]

Background: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. Objective: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23–26 weeks of gestation. Methods: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23–26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. Results: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9–63.9] and 67.6% (95% PI, 51.5–77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7–82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. Conclusions: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. Trial Registration: ClinicalTrials.gov Identifier: NCT04459117. [ABSTRACT FROM AUTHOR]

Introduction: Paracetamol is a commonly used pain medication for the very-high risk neonates and it is increasingly being used for patent ductus arteriosus treatment in preterm infants. However, randomized trial data on long-term consequences are not yet available, but there is some evidence of serious adverse effects on children exposed to paracetamol during pregnancy. Patients and methods: A five-year follow-up study of a placebo-controlled paracetamol trial on very preterm infants (PreParaS) was conducted (n = 48). Using a web-based parental questionnaire, parents answered questions about their children's cardiac and respiratory symptoms, allergies, neurodevelopment, infections, medications and hospitalizations. Results: Most parents reported that their child had normal development (paracetamol 79% vs. placebo 65%). Physician-diagnosed asthma or allergy (paracetamol 10.5% vs. placebo 25.0%), or hospitalization due to respiratory symptoms (0 vs. 15%) were uncommon and neurological or neuro-psychiatric symptoms were rare. Conclusions: Current follow-up results on paracetamol-exposed very preterm infants may not be alarming suggesting that paracetamol administration shortly after birth is not associated with common adverse consequences. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the long-term adverse reactions of paracetamol in children who required intensive care shortly after birth. Paracetamol is a widely used analgesic in neonates, but the long-term studies are lacking. Previous epidemiological studies have reported associations between early paracetamol intake and diseases in childhood.Design: Five-year follow-up cohort of children who required intensive care shortly after birth.Setting: Single tertiary care hospital; neonatal and paediatric intensive care units.Interventions: Intravenous paracetamol was administered for pain and discomfort to the neonates during their intensive care, while for the control infants, it was not available.Main Outcome Measures: The primary outcome was the incidence of asthma; secondary outcomes were neonatal diseases and long-term morbidities (atopic dermatitis, inflammatory bowel disease, autism, speech disorders, cerebral palsy). Long-term morbidities were adjusted based on antenatal and neonatal risk factors.Results: We screened all neonates admitted to the intensive care units soon after birth in Oulu University Hospital, Oulu, Finland, during 1 October 2007 to 31 December 2013. Altogether, 1552 infants needed intensive care. Of them, 735 (47%) were treated with intravenous paracetamol. We obtained their long-term data from the Finnish National Institute for Health and Welfare, including all physician-made diagnoses from all primary healthcare units and hospitals in Finland. We found no difference in the asthma incidence or in other long-term morbidities between paracetamol-treated and non-exposed infants.Conclusions: Intravenous paracetamol given to neonates did not associate with childhood disorders compared with the non-exposed infants during the 5-year follow-up. The previous hypothesis that early paracetamol use causes childhood morbidities was not confirmed. [ABSTRACT FROM AUTHOR]

Objectives: Persistent ductus arteriosus (PDA) delays the recovery of very preterm infants (VLGA, gestation <32 weeks). In domethacin/ibuprofen treatment and ligation of PDA have complications. As a prostaglandin synthase inhibitor paracetamol may also promote the closure of ductus arteriosus. We studied retrospectively whether early paracetamol therapy was associated with decreased incidence of PDA without adverse events. Methods: On June 2009, we introduced intravenous paracetamol during early respiratory therapy. We included 105 VLGA infants who received paracetamol before the age of 72 h. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 hours. The 96 VLGA infants admitted from January 2008 to May 2009 without lethal congenital disease were controls. Infants dying very early were excluded, leaving 102 paracetamol-exposed and 88 controls for analysis. Results: After the introduction of paracetamol, the incidence of PDA decreased from 30.7% to 14.7% (p = 0.008). Ibuprofen treatment was given to 15 paracetamol-treated and to 26 control infants (p = 0.013). Three paracetamol-exposed and seven control infants required surgery. There was no detectable increase in adverse events. Conclusions: Annual incidence o f PDA decreased after introduction of paracetamol. Efficacy and safety in promoting the early closure of ductus arteriosus remains to be established. [ABSTRACT FROM AUTHOR]