Indomethacin For Patent Ductus Arteriosus Research Articles

Predictors of a non-response to prophylactic indomethacin for patent ductus arteriosus in preterm infants.

Preterm infants are recommended for prophylactic indomethacin (PIND) to promote closure of patent ductus arteriosus (PDA) and reduce morbidity and mortality. This study investigated the predictive factors of a non-response to PIND for PDA in preterm-birth infants. Consecutive preterm-birth infants (gestational age: < 28 weeks) who received PIND between 2009 and 2019 were retrospectively enrolled. Seventy-six eligible participants were classified as PIND responders (N=42) or non-responders (N=34). Information on potential confounders in maternal obstetric and perinatal data were collected from medical records. Multiple logistic regression analysis was carried out to identify the prognostic factors of a PIND response in preterm-birth infants. The prevalence of intrauterine infection and multiple births was significantly different between responders and non-responders to PIND (intrauterine infection: 2 [4.8%] vs. 8 [23.5%], P=0.036; twins: 3 [7.1%] vs. 9 [ 26.5%], P=0.029, respectively). In multivariate logistic regression analysis after adjustment for multiple births, intrauterine infection was a significant and independent predictive factor of a non-response to PIND (odds ratio [OR] 5.54, 95% confidence interval [CI] 1.05-29.2, P=0.044). A remarkable association was also noted for multiple births with a non-response to PIND (OR 4.22, 95% CI 0.99-17.8, P=0.050). Intrauterine infection and multiple births were identified as potential risk factors of a non-response to PIND for PDA in preterm infants.

Is ibuprofen superior to indomethacin for patent ductus arteriosus in Japanese preterm infants?

Many clinical trials have indicated that ibuprofen (IBU) has similar effects to indomethacin (IND) on the closure of patent ductus arteriosus (PDA) with fewer adverse effects. Owing to the scarce evidence on IBU use in Japan because of its recent approval we performed this observational study to compare the efficacy and safety of IBU with the efficiency and safety of IND. We included infants (gestational age < 30weeks) with hemodynamically significant PDA under a prophylactic IND protocol for intraventricular hemorrhage who were treated with either IND (n = 30) or IBU (n = 30). We compared a PDA closing effect, changes in ultrasonography findings, and adverse effects between the groups. There was no significant difference in the rates of PDA closure in the first treatment course (IND vs IBU: 46.7% vs 50.0%, P = 0.796) and surgical closure (IND vs IBU: 20.0% vs 20.0%, P = 1.000) between the groups. Both groups showed significant oliguria (IND vs IBU: 30.0% vs 23.3%, P = 0.559) and increased serum creatinine levels after treatment. However, an increase in serum creatinine level by >0.3mg/dL, a criterion for acute kidney injury, was less frequent in the IBU group (35.7%) compared with that in the IND group (84.2%, P=0.004). There were no significant differences in echocardiographic changes and jaundice and hypoglycemia incidence rates between the groups. Except for an increase in serum creatinine levels by >0.3mg/dL, which was less frequent with IBU, IBU had similar efficacy and safety as IND for preterm PDA. Ibuprofen and IND should be cautiously administered.

Urinary acute kidney injury biomarkers in very low-birth-weight infants on indomethacin for patent ductus arteriosus.

Serum creatinine (SCr)- or urine output-based definitions of acute kidney injury (AKI) have important limitations in neonates. This study evaluates the diagnostic value of urinary biomarkers in very low-birth-weight (VLBW) infants receiving indomethacin for closure of a patent ductus arteriosus (PDA). Prospective cohort study in 14 indomethacin-treated VLBW infants and 18 VLBW infants without indomethacin as controls. Urinary biomarkers were measured before, during, and after indomethacin administration. Indomethacin therapy was associated with significantly higher SCr concentrations at 36, 84, and 120 h compared to controls. At 36 h, three indomethacin-treated patients met the criteria for neonatalmodified Kidney Disease: Improving Global Outcomes (KDIGO) AKI. The product of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) was significantly elevated in the AKI subgroup at 12 h (P < 0.05), hence 24 h earlier than the increase in SCr. Urinary neutrophilgelatinase-associated lipocalin (NGAL) and calprotectin were significantly increased in the indomethacin group at 12 h (P < 0.05), irrespective of fulfillment of the AKI criteria. Urinary kidney injury molecule-1 (KIM-1) was not significantly altered. While urinary [TIMP-2]•[IGFBP7] proves valuable for the early diagnosis of neonatal modified KDIGO-defined AKI, elevated urinary NGAL and calprotectin concentrations in indomethacin-treated VLBW infants not fulfilling the AKI criteria may indicate subclinical kidney injury.

Enteral feeding during indomethacin treatment for patent ductus arteriosus: association with gastrointestinal outcomes.

Enteral feeds are often discontinued or reduced during indomethacin treatment for patent ductus arteriosus (PDA) in preterm neonates, but the clinical impact of this practice is unknown. The objective of this study was to study the associations between enteral feed volume at the time of indomethacin therapy in preterm neonates with PDA and subsequent gastrointestinal outcomes. Retrospective cohort study. Single-center level III Neonatal Intensive Care Unit. All consecutive preterm neonates who had received treatment with indomethacin for PDA over a 5-year period were included and categorized based on enteral feed volume exposure during treatment (Group A: nil per oral (NPO, N=229); Group B: ⩽60 ml kg(-1) day(-1) (N=142); Group C:>60 ml kg(-1) day(-1) (N=44)). Baseline characteristics and clinical outcomes were compared between the three groups. The primary outcome was necrotizing enterocolitis (NEC) ⩾stage IIa, while secondary outcomes included other gastrointestinal complications and common prematurity-related morbidities. Group C had a higher gestational age (mean±s.d.; A: 26.3±1.8; B: 26.1±1.8; C: 27.0±2.0 weeks), birth weight (A: 864±239; B: 847±202; C: 932±234 g) and postnatal age at the time of indomethacin treatment (A: 5.3±2.9; B: 7.2±4.9; C: 15.4±6.6 days). All groups had similar rates of the primary outcome NEC (A: 6.1%, B: 7.8% and C: 4.6%, respectively). They also had similar rates of the secondary outcomes with the exception of days to reach enteral feeds of 120 ml kg(-1) day(-1) (A: 22.8±8.5; B: 20.5±8.6; C: 16.8±7.7; P<0.05 for all inter-group comparisons). Secondary analysis including only those neonates who were not already NPO before indomethacin treatment (N=261) and categorized based on preemptive management (made NPO; enteral feed volume reduced; enteral feed volume unchanged/increased) also showed similar results. This large retrospective study did not identify any association between enteral feed volumes during indomethacin treatment or preemptive reduction in enteral feeds and subsequent incidence of adverse gastrointestinal outcomes in preterm neonates. Preemptive reduction in enteral feed volume was associated with longer time to reach full enteral feeds.

Early versus Conventional Treatment for Patent Ductus Arteriosus in Preterm Infants

After the introduction of a new protocol based on the early treatment with indomethacin for patent ductus arteriosus, the objective of this study was to assess the safety and efficacy of this new practice in comparison with the safety and efficacy of the conventional treatment in a high-risk population. We conducted a retrospective cohort study including 154 newborns with an average gestational age of 26.4 weeks (1.37 standard deviation) and an average birth weight of 855 g (201.5 standard deviation). A statistically descriptive analysis was performed with SPSS Statistics Pack version 17.0. We did not find any statistically significant differences in the clinical features of the two treatment groups, nor in the main efficacy, morbidity, and mortality results.

Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus

To evaluate the effect of furosemide on renal function and water balance in preterm infants treated with indomethacin (3 x 0.2 mg/kg at 12-h intervals) for symptomatic patent ductus arteriosus. We performed a retrospective multi-centre double cohort study in preterm infants <32 weeks of gestational age. Thirty-two infants treated with furosemide (1 mg/kg i.v.) before each indomethacin dose (furosemide group) were matched with 32 infants with indomethacin treatment alone (control-group). Renal effects (urine output, weight gain, serum creatinine, sodium concentration) were registered. The study groups were comparable for gestational age, birth weight and day of therapy. Pretreatment differences were observed for urine output, weight and serum sodium. However, no differences were noticed in day-to-day urine output change or weight gain between the groups. A significant increase in serum creatinine concentration (50% vs. control, 18%; p < 0.05) and a concomitant significant decrease in serum sodium (-9 vs. control, -3 mmoL/L; p < 0.05) in the furosemide group was observed 72-96 h after starting therapy. Furosemide before each indomethacin dose resulted in a significant increase in serum creatinine and hyponatremia, without increasing urine output.

Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus

Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus

Drug Pricing in Pediatrics: The Egregious Example of Indomethacin

Indomethacin for closure of a patent ductus arteriosus (PDA) in preterm infants has been the standard of care since the 1970s. Indomethacin was the first drug specifically approved for use in infants by the US Food and Drug Administration as the result of collaborations between academic pediatricians and the pharmaceutical company Merck. Indomethacin was not a new chemical entity when evaluated for PDA, and it remains today one of the most frequently used over-the-counter nonsteroidal antiinflammatory drugs. The unique aspect of indomethacin for PDA is that the drug is formulated for intravenous use. There are no other approved uses for intravenous indomethacin in the United States. Ovation Pharmaceuticals acquired the distribution rights for … Address correspondence to Alan H. Jobe, MD, PhD, Cincinnati Children's Hospital, Division of Pulmonary Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail: alan.jobe{at}cchmc.org

Usefulness of Indomethacin for Patent Ductus Arteriosus in Full-Term Infants

The aim of this retrospective study was to evaluate the effectiveness of indomethacin therapy for patent ductus arteriosus (PDA) in full-term infants. The patients were 41 full-term infants with a PDA birth weight (BW) > or =2500 g and a gestational age (GA) > or =37 weeks. The echocardiographic evaluation and medical management of PDA in these infants was similar to that for PDA in low-birth-weight infants. Indomethacin (0.2-0.25 mg/kg/dose) was given intravenously at 12-24-hour intervals within 23 days of birth. Of the 41 infants, 12 showed complete closure, and 13 showed improvement of clinical symptoms. These 25 infants were classified as the responder group (61%). The other 16 infants, who did not show improvement in clinical symptoms, were classified as the nonresponder group. Statistical analysis revealed no difference between the two groups regarding GA, BW, Apgar score at 1 minute, minimum diameter of the DA before treatment, the average age at the initiation of treatment, and DA flow pattern. No severe adverse reactions were observed in any infant. Indomethacin therapy appears to be an effective medical treatment option for PDA in full-term symptomatic infants prior to considering surgical treatment.

Lenticulostriate vasculopathy in twin-to-twin transfusion syndrome

Intracranial pathology is a common and important complication in extremely low birth weight babies. Lenticulostriate vasculopathy (LSV) is an abnormal finding on cranial ultrasounds of sick babies and has been associated with congenital infection, chromosomal aberration and twin-to-twin transfusion. We describe a previously unreported situation of LSV being detected in both donor and recipient twin. This pair of monochorionic, diamniotic twins was admitted to the Neonatal Intensive Care Unit at 28 weeks of gestation. The mother underwent an emergency caesarean section because ultrasound and Doppler studies showed stage III twin-to-twin transfusion syndrome. The first twin weighed 998 g and second twin weighed 600 g. The first twin had an uneventful stay, whereas the second twin needed prolonged continuous positive airway pressure and indomethacin for patent ductus arteriosus. Both of them developed LSV. The clinical significance of this condition on the neuro-developmental outcome of a neonate has not yet been fully determined.

Renal impairment associated with indomethacin treatment for patent ductus arteriosus in extremely preterm neonates—is postnatal age at start of treatment important?

Objective. To study serum creatinine (SCr) levels following indomethacin for patent ductus arteriosus (PDA) closure in extremely preterm neonates in relation to postnatal age at the start of treatment.Methods. This was a retrospective (January 2000–December 2002) analysis of data on preterm neonates (gestation <29 weeks) who received indomethacin for PDA. Pre-existing renal malformation and/or impairment and high serum levels of nephrotoxic drugs were criteria for exclusion.Results. Indomethacin was commenced at postnatal age <7 days and ≥7 days in 60 (group 1) and 30 (group 2) neonates, respectively. The median (Q1, Q3) gestational age and birth weight for group 1 and group 2 neonates were 25 (23, 27) vs. 25 (24, 26) weeks and 740 (620, 909) vs. 780 (663, 966) grams, respectively. Postnatal age <7 days at start of indomethacin was associated with higher baseline (0.083 (0.074, 0.090) vs. 0.073 (0.054, 0.083) mmol/L, p = 0.001) and peak SCr levels (0.099 (0.089,0.109) vs. 0.090 (0.064, 0.104) mmol/L, p = 0.015). Logistic regression analysis controlling for gestational age and baseline SCr level indicated that postnatal age ≥7 days was a risk factor for elevated SCr after indomethacin (OR = 13.4, 95% CI: 3.8–46.6, p < 0.001).Conclusion. Postnatal age ≥7 days at the start of indomethacin is a predictor of a significant rise in SCr in extremely preterm neonates.

Effectiveness and complications of indomethacin for patent ductus arteriosus in preterm infants

Effectiveness and complications of indomethacin for patent ductus arteriosus in preterm infants

Continuous Versus Multiple Rapid Infusions of Indomethacin: Effects on Cerebral Blood Flow Velocity

Therapeutic administration of indomethacin for patent ductus arteriosus (PDA) closure has been documented to decrease cerebral blood flow velocity which may be harmful to the vulnerable premature neonate. We have therefore compared the effects of administering indomethacin by rapid injection versus slow, continuous indomethacin infusion at the same total therapeutic dose on middle cerebral artery (MCA) systolic and diastolic flow velocity, resistance index, and cerebral blood flow (as reflected by the integrated area under the curve). Premature neonates (< 1750 g) documented echocardiographically to have a PDA were randomized to receive indomethacin either by three rapid injection doses or by continuous intravenous infusion over the ensuing 36 hours, providing an equivalent total dose. Echocardiograms and transcranial color flow mapping of the MCA flow velocity were measured at baseline and serially following initiation of therapy in both groups. Effects on cerebral blood flow velocity are presented. Eighteen infants [rapid injection-1.2 +/- 0.3 kg (n = 9) and continuous-1.1 +/- 0.2 kg (n = 9)] were studied. In the rapid injection treated infants decreased flow velocity in the MCA as manifested by abrupt, significant decreases in systolic (to 70 +/- 8% baseline) and diastolic (to 65 +/- 13% baseline) flow velocity and area under the curve (to 60 +/- 10% of baseline) were evident by 4 minutes and progressed to 30 minutes after treatment initiation. These changes were not observed in the group treated with continuous indomethacin. Both therapeutic modalities were equally successful in closing the ductus, although the numbers are too small to definitively determine therapeutic efficacy. Slow, continuous infusion eliminated the decrease in cerebral flow velocity and appears to be effective in closing the PDA.

Isolated small bowel perforation following intrauterine treatment with indomethacin.

Indomethacin, a prostaglandin synthetase inhibitor, is an effective tocolytic agent that may have adverse fetal side effects such as constriction of the ductus arteriosus, pulmonary hypertension, and reduced urine production. We describe an unusual neonatal complication following 6 days of tocolysis with indomethacin. A 22-year-old gravida 5, para 3104 was admitted at 25 weeks of gestation in labor. Attempts to stop labor using magnesium sulfate and terbutaline failed. The contractions stopped following the administration of indomethacin, which was continued for 6 days. On day 7, due to contractions and vaginal bleeding, she underwent a classic cesarean section. The female newborn, weighting 1044 g, did well for 2 days, when she developed pneumoperitoneum. On laparotomy, an isolated midileal perforation was found, with otherwise normal-appearing bowel. Isolated intestinal perforation has been described in premature neonates who were treated with indomethacin for patent ductus arteriosus. This complication is caused by splanchnic ischemia secondary to the loss of the vasodilatory effect of prostaglandins. This case indicates that this rare but serious complication may also follow intrauterine exposure to indomethacin.

Prolonged bleeding time in preterm infants receiving indomethacin for patent ductus arteriosus

Sequential bleeding times were performed on 25 preterm infants receiving intravenous indomethacin for closure of the patent ductus arteriosus. Prolongation of bleeding time was observed after the initial dose of indomethacin, with an increase from a pretreatment mean of 3.6 minutes to 8.7 minutes. The bleeding time was not further prolonged at the end of the three-dose course of indomethacin, but was still elevated 48 hours after the completion of therapy. Clinical bleeding developed in six of the patients, but was generally limited to occult hematuria. Serial echoencephalography during indomethacin therapy showed progression from mild periventricular-intraventricular hemorrhage to moderate or severe grades in five of 21 infants at risk for this complication. However, no clear temporal relationship between indomethacin administration and intraventricular hemorrhage extension was observed, and no difference in the degree of bleeding time prolongation was noted between infants with and without hemorrhage extension. Other factors, including surfactant deficiency, amount of volume expansion used, and lowest PO2 in the first day of life, did distinguish those with hemorrhage extension. The results suggest that indomethacin-induced platelet dysfunction is not associated with major hemorrhagic complications in the majority of preterm infants with patent ductus arteriosus.