Aims Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight‐based dosing guidelines are based on total ibuprofen, while only the S‐enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer‐specific population pharmacokinetic model. Methods We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S‐ and R‐ibuprofen. Results We found that S‐ibuprofen clearance (CLS, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11‐fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R‐ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R‐ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S‐ibuprofen and R‐ibuprofen. Conclusion S‐ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3‐fold increase in CLS during a 3‐day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.

Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3–7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 251/7 weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %.Conclusion: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective. What is known: • The ductus arteriosus fails to close after birth in 30 to 60 % of prematurely born neonates and is a significant cause of morbidity and mortality in these infants. • Paracetamol gained importance as an alternative drug in PDA closure. What is new: • Paracetamol for PDA closure after ibuprofen treatment failure was not effective in VLBW infants. • Effect of paracetamol on PDA closure was observed when given as primary treatment.

The optimal management strategy for patent ductus arteriosus in preterm infants remains a topic of debate. Available evidence for a treatment strategy might be biased by the delayed spontaneous closure of the ductus arteriosus in preterm infants, which appears to depend on patient characteristics. We performed a systematic review of all literature on PDA studies to collect patient characteristics and reported numbers of patients with a ductus arteriosus and spontaneous closure. Spontaneous closure rates showed a high variability but were lowest in studies that only included preterm infants with gestational ages below 28 weeks or birth weights below 1,000 g (34% on day 4; 41% on day 7) compared to studies that also included infants with higher gestational ages or higher birth weights (up to 55% on day 3 and 78% on day 7). The probability of spontaneous closure of the ductus arteriosus keeps increasing until at least 1 week after birth which favors delayed treatment of only those infants that do not show spontaneous closure. Better prediction of the spontaneous closure of the ductus arteriosus in the individual newborn is a key factor to find the optimal management strategy for PDA in preterm infants.

PurposeIbuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge.MethodsWe performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure.ResultsThe most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg−1 followed by 10 mg kg−1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L−1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg−1, followed by 4 mg kg−1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg−1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower.ConclusionsWe propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.Electronic supplementary materialThe online version of this article (10.1007/s00228-018-2529-y) contains supplementary material, which is available to authorized users.

Introduction:Inotropes are frequently being used in children undergoing heart surgery to prevent or treat low cardiac output syndrome (LCOS). There is only limited evidence that inotropes actually positively influence postoperative outcome. Our aim was to describe the current international practice variation in the use of inotropes following congenital heart surgery.Methods:We developed an online survey regarding the postoperative use of inotropes. We sent an invitation to all 197 registered members of the Pediatric Cardiac Intensive Care Society (PCICS) to participate in the survey. We also performed a systematic review of the literature.Results:Ninety-eight people (50%) responded, representing 62 international centers. Milrinone is routinely used perioperatively by 90 respondents (97%). Adrenaline/epinephrine is routinely used by 43%, dopamine by 36%, dobutamine by 11%, and levosimendan by 6%. Steroids are used routinely by 54% before initiating cardiopulmonary bypass. Vasopressin is used by 44% of respondents. The development of LCOS is monitored with lactate in 99% of respondents, physical examination (98%), intermittent mixed venous saturation (76%), continuous mixed venous saturation (13%), echocardiography (53%), core–peripheral temperature gap (29%), near-infrared spectrometry (25%), and 4% use cardiac output monitors (PiCCO, USCOM). To improve cardiac output, 42% add/increase milrinone, 37% add adrenaline, and 15% add dopamine. Rescue therapy is titrated individually, based on the patients’ pathophysiology. A systematic review of the literature failed to show compelling evidence with regard to the benefit of inotropes.Conclusions:Despite the lack of sufficient evidence, milrinone is used by the vast majority of caregivers following congenital heart surgery.

Aim: Patent ductus arteriosus (PDA) is treated with ibuprofen and it is known that the clearance of ibuprofen increases with postnatal age. We aimed to study whether postnatal age-adjusted ibuprofen dosages improve the effectiveness of treatment compared to standard ibuprofen dosages after the first days of life. Methods: A historical cohort of 207 preterm neonates treated with standard ibuprofen dosages (Group A; 2011-2015) was compared to a prospective cohort of 66 preterm neonates treated with postnatal age-adjusted ibuprofen dosages (Group B; 2015-2016). Results: Both groups had comparable background characteristics. Treatment was started after median 6 (25-75th percentile: 4-11) and 5 (25-75th percentile: 4-11) days and effectiveness was 33.2 and 44.7% (p ¼ .17) in groups A and B, respectively. No hemodynamically significant PDA was found in 23/49 (46.9%) of the patients born before 28 weeks after adjusted ibuprofen dosages compared to 48/162 (29.6%) after standard ibuprofen dosages (p ¼ .04). There were significantly more reversible side effects with the postnatal age-adjusted ibuprofen dosages (p ¼ .04). Conclusions: There seems to be a trend to higher effectiveness with the adjusted ibuprofen dosages in preterm neonates before 28 weeks, but it is associated with more reversible side effects.