Bart Van Overmeire

Treatment of patent ductus arteriosus with ibuprofen

AIM To evaluate the efficiency and side effects of ibuprofen for the early treatment of patent ductus arteriosus (PDA)and compare it with indomethacin. METHODS Forty preterm infants with gestational ages of less than 33 weeks, with respiratory distress syndrome (RDS) and echocardiographically confirmed PDA, were randomly assigned at days 2 to 3 of life to receive either intravenous indomethacin 3 × 0.2 mg/kg at 12 hour intervals or intravenous ibuprofen 1 × 10 mg/kg, followed by 5 mg/kg 24 and 48 hours later. RESULTS PDA closed in 15 of 20 patients from the indomethacin group (75%) and in 16 of 20 (80%) from the ibuprofen group. Seven patients (three indomethacin, four ibuprofen) required a second treatment with indomethacin and in five (three in the indomethacin group and two in the ibuprofen group) the duct was ultimately ligated. Ibuprofen patients had a better urinary output and showed no increase in serum creatinine concentrations compared with the indomethacin group. Ibuprofen was not associated with any other side effect. CONCLUSIONS Ibuprofen treatment seems to be as efficient as indomethacin in closing PDA on the third day of life in preterm infants with respiratory distress syndrome and seems to have fewer renal side effects.

Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus

Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth.

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus.

Ibuprofen (IBU) has previously been shown to be as effective as indomethacin (INDO) in closing the patent ductus arteriosus (PDA) of preterm infants, without severely affecting renal hemodynamics or basal cerebral blood flow. We conducted a meta-analysis of randomized trials to compare the efficacy and safety of IBU and INDO for treatment of PDA. Data from the nine relevant trials ( n =566), showed no significant difference in the efficacy of IBU and INDO in PDA closure ( P =0.70). However, five trials ( n =443) provided serum creatinine concentration data that revealed a significantly lower increase favoring IBU ( P < 0.001), and urine output data that showed a significantly lower decrease favoring IBU ( P < 0.001). In two trials ( n =188) the proportion of infants who required postnatal oxygen therapy at 28 days (defined as chronic lung disease) was significantly higher with IBU (52/94; 55.3%) than with INDO (38/94; 40.4%, P < 0.05). No statistically significant differences were found in mortality, intraventricular hemorrhage, necrotizing enterocolitis, surgical ligation, sepsis, retinopathy of prematurity, periventricular leukomalacia, length of hospital stay, gastrointestinal bleeding, re-opening of PDA, back-up treatment, surfactant therapy, or days on a ventilator. Conclusion:ibuprofen and indomethacin have similar efficacy in patent ductus arteriosus closure, but preterm infants treated with ibuprofen experience lower serum creatinine values, higher urine output, and less undesirable decreased organ blood flow and vasoconstrictive adverse effects.

Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Ibuprofen is used for treatment and prevention of patent ductus arteriosus in low-birthweight infants. Its effects on regional circulations differ from those of indometacin. Because prophylactic indometacin reduces the frequency of severe intraventricular haemorrhage and patent ductus arteriosus, we aimed to study the efficacy of early ibuprofen in reducing these outcomes in a double-blind, multicentre trial. METHODS Within 6 h after birth, 415 low-birthweight infants (gestational age <31 weeks) were randomly allocated ibuprofen-lysine (10 mg/kg then two doses of 5 mg/kg after 24 h and 48 h) or placebo intravenously. The primary outcome was occurrence of severe intraventricular haemorrhage; secondary outcomes were occurrence of patent ductus arteriosus and possible adverse effects of ibuprofen. Analysis was by intention to treat. FINDINGS 17 (8%) of 205 infants assigned ibuprofen and 18 (9%) of 210 assigned placebo developed severe intraventricular haemorrhage (relative risk 0.97 [95% CI 0.51-1.82]). In 172 (84%) infants of the ibuprofen group, the ductus was closed on day 3 compared with 126 (60%) of the placebo group (relative risk 1.40 [1.23-1.59]). No important differences in other outcomes or side-effects were noted; however, urine production was significantly lower on day 1 and concentration of creatinine in serum was significantly higher on day 3 after ibuprofen. INTERPRETATION Ibuprofen prophylaxis in preterm infants does not reduce the frequency of intraventricular haemorrhage, but does decrease occurrence of patent ductus arteriosus.

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. METHODS Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. RESULTS Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated. CONCLUSIONS To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.

A randomized, double-blind, placebo- controlled trial on intravenous ibuprofen L-lysine for the early closure of nonsymptomatic patent ductus arteriosus within 72 hours of birth in extremely low-birth-weight infants

A multicenter, double-blind, randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of intravenous (IV) ibuprofen (L-lysine) for the early closure of nonsymptomatic patent ductus arteriosus (PDA) within 72 hours of birth in extremely low-birth-weight (ELBW) infants with evidence of ductal shunting by echocardiogram. Eleven sites enrolled 136 infants with nonsymptomatic early PDA (gestational age < 30 weeks; body weight 500 to 1000 g) to receive a 3-day course (10 mg/kg, 5 mg/kg, and 5 mg/kg) of IV ibuprofen ( N = 68) or placebo ( N = 68). Cardiac echocardiogram was performed on study days 1 and 14, and with rescue. Infants were followed to 36 weeks postconceptional age. Patient demographics, mean (standard deviation), were similar between ibuprofen and placebo: birth weight: 798.5 g (128.7) versus 797.3 g (132.8); gestational age: 26.1 weeks (1.3) versus 26.2 weeks (1.4); and age at first dose: 1.5 days (0.7). The intent-to-treat analysis of the primary endpoint, subjects rescued, died, or dropped through study day 14, was 21/68 (30.9%) with ibuprofen and 36/68 (52.9%) for placebo ( P = 0.005). Death, intraventricular hemorrhage, necrotizing enterocolitis, daily fluid intake/output, liver function, bronchopulmonary dysplasia, and retinopathy of prematurity did not differ. A trend toward decreased periventricular leukomalacia by ibuprofen was noted. IV ibuprofen was effective and safe in the early closure of PDA in preterm neonates.

Safe oxygen saturation targeting and monitoring in preterm infants: can we avoid hypoxia and hyperoxia?

Oxygen is a neonatal health hazard that should be avoided in clinical practice. In this review, an international team of neonatologists and nurses assessed oxygen saturation (SpO2) targeting in preterm infants and evaluated the potential weaknesses of randomised clinical trials.

Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study

BACKGROUND Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries. METHODS EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745. FINDINGS From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001). INTERPRETATION Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia. FUNDING European Communitys Seventh Framework Programme.

Paracetamol to induce ductus arteriosus closure: is it valid?

There remains a need for alternative medical treatments for patent ductus arteriosus (PDA) closure in extreme preterm neonates because of therapeutic failure and adverse effects associated with non-selective cyclo-oxygenase inhibitors. Reports of an association between paracetamol exposure and PDA closure in a limited number of extreme preterm neonates have been published. However, causality cannot be taken for granted because a link between the current knowledge of the clinical pharmacology of paracetamol and (patho)physiology of ductal closure is not known. In contrast to non-selective cyclo-oxygenase inhibitors, paracetamol has limited effects at peripheral sites, is a poor antithrombotic and anti-inflammatory drug and exerts its effects primarily within the central nervous system. Although paracetamol appears an effective and safe analgesic in term and near term neonates, its effectiveness and safety for PDA closure are uncertain because the drug is administered in high doses and there remain a limited number of observations in this specific subpopulation so far. Prospective comparative trials are reasonable and are urgently needed to establish both the effectiveness and safety data of paracetamol when used for this indication.

Cardiac tamponade and pericardial effusion due to venous umbilical catheterization.

AIM We present three cases of neonatal cardiac tamponade due to umbilical venous catheterization, a rare, but potentially fatal complication. METHODS Timely diagnosis was made by echocardiography, and an urgent pericardiocentesis revealed TPN fluid. Perforation of the cardial wall was proven by contrast X-ray showing contrast diffusing into the pericardial space. DISCUSSION Most frequently, perforation has a delayed course and results from endothelial injury, caused by the hyperosmolar fluids, leading to transmural necrosis and thrombosis. Subsequently, the fluid diffuses transmurally across the myocardium into the pericardium. As migration of the catheter tip can occur, we suggest that its position should be checked immediately after insertion and twice a week thereafter. CONCLUSION Pericardial effusion and cardiac tamponade should be considered in any infant with a central venous line who develops a rapid, unexplained clinical deterioration. Timely diagnosis and drainage has been proven to be life-saving.