solufenum and Ductus-Arteriosus--Patent

Persistent patent ductus arteriosus (PDA) in preterm infants can result in serious hemodynamic changes causing respiratory, gastrointestinal and renal morbidities if not treated within the first week of life. The treatment options available are a conservative approach, pharmacological treatment with cyclo-oxygenase (COX) inhibitors and surgical ligation. The COX inhibitors approved for use in the United States are indomethacin and ibuprofen lysine. Both of these drugs are equally effective in closing the PDA. Subtle differences exist between these two preparations. Indomethacin has a protective effect on the incidence of intraventricular hemorrhage (IVH) but reduces the blood flow to the kidneys and the brain. Ibuprofen is less toxic but has no effect on IVH. Efficacy of pharmacological treatment is influenced by timing of initiation of therapy. Surgical treatment is the only option when pharmacological treatment fails to close the PDA in symptomatic infants. Long-term neurological and respiratory morbidities are associated with surgical ligation. This paper reviews these medical considerations in the treatment options for PDA in premature infants.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Lysine

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.

Topics: Double-Blind Method; Ductus Arteriosus, Patent; Female; Humans; Ibuprofen; Infant, Extremely Low Birth Weight; Infant, Newborn; Injections, Intravenous; Lysine; Male; Time Factors; Treatment Outcome; Ultrasonography

Presence of symptomatic patent ductus arteriosus is common in small preterm infants and ibuprofen is commonly used for its medical closure. While efficacy is comparable to indomethacin, there are few case reports of severe hypoxemia and pulmonary hypertension following prophylactic ibuprofen administration. Cumulative dose effects and chemical composition may be important considerations. Possible mechanisms of occurrence of this complication in a preterm infant are discussed.

Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Hypertension, Pulmonary; Ibuprofen; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lysine

This retrospective, study compared the efficacy and safety of Ibuprofen-Lysinate (Arfen, intramuscular formulation, Group I, n=156) used during 2000-2005 and Sodium-ibuprofen (Pedea, intravenous solution, Group II, n=60) used during 2006-2008, for the prophylaxis of Patent Ductus Arteriosus in inborn neonates with gestational age ≤ 28 weeks. Ductus closure rate after prophylaxis was significantly higher (73.1% vs 50%; P=0.002) and surgical ligation significantly lower (8.2% vs 23.3%; P=0.005) in Group I. A smaller number of neonates of Group I vs Group II showed oliguria and hemorrhagic disease.

Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Ibuprofen; Infant, Newborn; Infant, Premature, Diseases; Lysine; Retrospective Studies; Treatment Outcome

Persistently patent ductus arteriosus (PDA), affecting approximately one-third of all very low birth weight infants, can lead to significant morbidity and mortality. Recently, ibuprofen has been recommended over indomethacin to close PDAs because of a reduction in risk of necrotizing enterocolitis. Pulmonary hypertension is a rare but potentially fatal complication of ibuprofen administration in preterm infants. We report 2 infants who developed this complication after receiving therapeutic L-lysine ibuprofen preparation for the PDA closure. The first infant, 1 of twins weighing 640 g, was born at 24 weeks' gestation. The second infant, born at 26 weeks' gestation, was small for gestational age, weighing 439 g. In both cases, ibuprofen was initiated after echocardiographic confirmation of a moderate-sized to large PDA and an otherwise normal intracardiac anatomy. Both infants had echocardiographic evidence of increased pulmonary vascular resistance but shunting across the PDA was left to right. The infants deteriorated within 48 to 72 hours, and repeat echocardiograms revealed evidence of severe pulmonary hypertension. Both infants died of refractory hypotension and hypoxemia. When considering the use of ibuprofen therapy for PDA closure, clinicians should keep in mind the potential serious complication of pulmonary hypertension, even if a shunt across the PDA is left to right.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diseases in Twins; Ductus Arteriosus, Patent; Echocardiography; Fatal Outcome; Humans; Hypertension, Pulmonary; Ibuprofen; Infant, Newborn; Infant, Premature, Diseases; Infant, Small for Gestational Age; Lysine; Male

To evaluate the effect of ibuprofen on bilirubin-albumin binding affinity and unbound bilirubin in premature infants.. A prospective study with subjects serving as their own controls was performed on <30 weeks' gestational age infants with unconjugated hyperbilirubinemia and who received ibuprofen for patent ductus arteriosus. Infants with congenital malformation, TORCH infections, and conjugated hyperbilirubinemia were excluded. Total serum bilirubin (TSB) and unbound bilirubin (modified peroxidase test) were measured prior to (baseline) and after (follow-up) initiation of ibuprofen. The bilirubin/albumin equilibrium association binding constant was calculated using albumin, TSB, and unbound bilirubin.. Ten infants were studied. The mean TSB between baseline (5.9±1.7 mg/dL) was higher than that at follow-up [4.9±1.7 mg/dL]. Mean unbound bilirubin at baseline (0.75±0.65 μg/dL) was similar to that at follow-up (0.63±0.46 μg/dL). No difference existed between mean baseline binding constant (49±50 L/μmol) and that at follow-up (44±36 L/μmol). The ratio of unbound bilirubin with and without ibuprofen, index of displacing effect, was 0.88 (95% CI 0.63-1.14).. Ibuprofen may not be associated with bilirubin displacing effect in relatively stable premature infants with mild to moderate unconjugated hyperbilirubinemia.

Topics: Albumins; Bilirubin; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Female; Humans; Hyperbilirubinemia; Ibuprofen; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lysine; Male; Prospective Studies

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.. 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.. 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.. 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.. 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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Ductus Arteriosus, Patent; Humans; Ibuprofen; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Infusions, Intravenous; Logistic Models; Lysine; Respiratory Distress Syndrome, Newborn