Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.
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ABSTRACT:
SUBMITTER: Ohlsson A
PROVIDER: S-EPMC7012639 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.
Ohlsson Arne A Walia Rajneesh R Shah Sachin S SS
The Cochrane database of systematic reviews 20200211
<h4>Background</h4>Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects.<h4>Objectives</h4>To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-w ...[more]
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| S-EPMC6494526 | biostudies-literature
Project description:BackgroundSymptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored.ObjectivesTo determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA.Search methodsWe used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.Selection criteriaWe included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants.Data collection and analysisWe used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding.Main resultsWe included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision.Authors' conclusionsHigh-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.
| S-EPMC8095061 | biostudies-literature
Project description:AimsRacemic 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.MethodsWe 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.ResultsWe 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.ConclusionS-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.
| S-EPMC7495289 | biostudies-literature
Project description:ImportancePersistent patent ductus arteriosus (PDA) in preterm infants is associated with increased mortality and respiratory morbidities, including bronchopulmonary dysplasia (BPD). Despite recent increasing use of noninterventional approaches, no study to our knowledge has yet directly compared the nonintervention vs pharmacologic treatment for mediating PDA closure for decreasing mortality and preventing BPD.ObjectiveTo determine the noninferiority of nonintervention vs oral ibuprofen treatment for PDA in decreasing BPD incidence or death in very preterm infants.Design, setting, and participantsA randomized, double-blind, placebo-controlled, noninferiority clinical trial was conducted on preterm infants (gestational age [GA] 23-30 weeks) with hemodynamically significant PDA (ductal size >1.5 mm plus respiratory support) diagnosed between postnatal days 6 and 14. Participants included 383 infants screened between July 24, 2014, and March 15, 2019.InterventionsInfants were stratified by GA and randomly assigned (1:1) to receive either oral ibuprofen (initial dose of 10 mg/kg followed by a 5-mg/kg dose after 24 hours and a second 5-mg/kg dose after 48 hours) or placebo.Main outcomes and measuresThe primary outcome was BPD or death; the secondary outcomes included major morbidities and ductal closure rates. Per-protocol analysis was used.ResultsAmong 383 infants screened for participation, 146 infants were randomly assigned, with 72 in the nonintervention and 70 in the ibuprofen treatment group in the final analyses. The PDA closure rate at 1 week after randomization was significantly higher with ibuprofen (11 [34%]) than nonintervention (2 [7%]) in infants at GA 27 to 30 weeks (P = .007); however, the findings were not significant at GA 23 to 26 weeks (ibuprofen, 3 [8%] vs nonintervention, 1 [2%], P = .34). In addition, the ductal closure rates before hospital discharge (ibuprofen, 62 [89%] vs nonintervention, 59 [82%], P = .27) and device closure (ibuprofen, 2 [3%] vs nonintervention, 4 [6%], P = .40) were not significantly different between the 2 groups. The nonintervention approach was noninferior to ibuprofen treatment in terms of BPD incidence or death (nonintervention, 44%; ibuprofen, 50%; 95% CI, -0.11 to 0.22; noninferiority margin -0.2; P = .51). One infant in the ibuprofen arm received oral ibuprofen backup rescue treatment owing to cardiopulmonary compromise refractory to conservative management, and another infant in the ibuprofen group received surgical ligation; none of the infants in the placebo group received backup treatment.Conclusions and relevanceNonintervention showed noninferiority compared with ibuprofen treatment in closing of hemodynamically significant PDA and reduction of BPD or death. The noninferiority of nonintervention over ibuprofen might be attributable to the low efficacy of oral ibuprofen for closing PDA, especially in infants born at 23 to 26 weeks' gestation.Trial registrationClinicalTrials.gov Identifier: NCT02128191.
| S-EPMC7296457 | biostudies-literature
Project description:Indomethacin prophylaxis (IP) reduces the risk of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA) in preterm infants. However, the optimal time to administer IP has not been determined. We hypothesised that IP at ?6?h is associated with a lower incidence of IVH or death than if administered at >6-24?h of age.We performed a retrospective cohort study of extremely low birth weight infants (?1000?g birth weight) treated in the neonatal intensive care units in the Neonatal Research Network from 2003 to 2010 and who received IP in the first 24?h of age. Infants were dichotomised based upon receipt of IP at ?6 or >6-24?h of age. The primary outcomes were IVH alone and IVH or death. Secondary outcomes were PDA alone and PDA or death. We used multivariable analyses to determine associations between the age of IP and the study outcomes expressed as an OR and 95% CI.IP was given at ?6?h to 2340 infants and at >6-24?h to 1915 infants. Infants given IP at ?6?h had more antenatal steroid exposure, more inborn and less cardiopulmonary resuscitation (p<0.01). After multivariable analyses, age of IP receipt was not associated with IVH, and IVH or death but PDA receiving treatment/ligation or death was lower among IP at ?6?h compared with IP at >6-24?h (OR 0.83, 95% CI 0.71 to 0.98).IP at ?6?h of age is not associated with less IVH or death, but is associated with less PDA receiving treatment/ligation or death.
| S-EPMC4935651 | biostudies-literature
Project description:BackgroundThe treatment of patent ductus arteriosus (PDA) in very low birth weight (VLBW) infants remains a challenge. The ability to predict which infants will respond to indomethacin could spare some from the risks of unnecessary medications. Our objective was to determine if indicators of acid-base homeostasis could predict response to indomethacin treatment for ductal closure, and thus help guide treatment decisions.MethodsWe performed a retrospective analysis of medical records of VLBW (< 1500 g) neonates with hemodynamically significant PDA born at our institution between January 2009 and December 2012; all infants included in the study were treated with indomethacin for ductal closure within the first 2 weeks of life. We extracted data for a number of clinical variables including gestational age, birth weight, blood chemistries, surfactant use, hematocrit, and blood gas parameters. Our primary outcome measure was successful closure of PDA following the first round of indomethacin. Using variables that were significant on initial testing, we created multivariable regression models to determine the independent association of selected variables with indomethacin response.ResultsOf the 91 infants included in the study, 62 (68%) responded to the first course of indomethacin with successful ductal closure. Multivariable regression modeling revealed that both base excess and hematocrit were independently associated with indomethacin response; odds of PDA closure increased with increasing base excess (OR [odds ratio]: 1.81; 95% confidence interval [CI]: 1.36-2.60) and increasing hematocrit (OR: 1.21; 95% CI: 1.01-1.45). The optimal cutoff value for base excess was - 4.56, with a sensitivity of 96.8% (95% CI: 89-100) and specificity of 79.3% (95% CI: 60-92); optimal cutoff value for hematocrit was 40, with 69.4% sensitivity (95% CI: 56-80) and 65.5% specificity (95% CI: 46-82).ConclusionsBase excess and hematocrit may be independent predictors of indomethacin response in VLBW infants with PDA. Low-cost and readily accessible, acid-base indicators such as base excess could help guide treatment decisions.
| S-EPMC6704716 | biostudies-literature
Project description:BACKGROUND:Patent ductus arteriosus (PDA) is a particularly common problem in preterm infants. Although surgical ligation is rarely performed in many contemporary neonatal intensive care units, it remains a necessary treatment option for preterm infants with a large hemodynamically significant PDA under strict clinical criteria, and it can reduce mortality in preterm infants. However, the optimal timing of surgical ligation is still controversial. We conducted this systematic review and meta-analysis to compare the mortality and morbidity of early and late surgical ligation of PDA in preterm or very-low-birth-weight (VLBW) infants. METHODS:This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42019133686). We searched the databases of PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform up to May 2019. RESULTS:This review included 6 retrospective studies involving 397 premature or VLBW infants with PDA. Pooled analysis showed that compared with the late ligation group, the early ligation group had a lower fraction of inspired oxygen (FiO2) at 24 hours postoperatively (mean difference [MD] -6.34, 95% confidence interval [CI] -9.45 to -3.22), fewer intubation days (MD -19.69, 95% CI -29.31 to -10.07), earlier date of full oral feeding (MD -22.98, 95% CI -28.63 to -17.34) and heavier body weight at 36 weeks of conceptional age (MD 232.08, 95% CI 57.28 to 406.88). No significant difference in mortality or other complications was found between the early and late groups. CONCLUSION:Our meta-analysis implies that compared with late surgical ligation, early ligation might have a better respiratory outcome and nutritional status for PDA in preterm or VLBW infants. There was no difference in mortality or postoperative complications between early and late ligation. A randomized prospective clinical trial with a possible large sample size is urgently needed to reinvestigate this conclusion. PROSPERO REGISTRATION NUMBER:CRD42019133686.
| S-EPMC7478603 | biostudies-literature
Project description:Background: Amino acids are increasingly recognized as bioactive molecules in numerous physiological and pathophysiological pathways. The non-essential amino acid glutamate is vasoactive in the rat ductus arteriosus (DA) and a decrease in its levels within the 1st days of life has been associated with the presence of patent DA (PDA) in extremely preterm infants. However, these findings have not been confirmed in other studies. Objective: To investigate the possible association between amino acid concentrations in the 1st day of life and the presence of PDA in a cohort of 121 newborns with gestational age (GA) below 30 weeks and birth weight (BW) below 1,500 g. Methods: Plasma samples were collected 6-12 h after birth and amino acid concentrations were determined by tandem mass spectrometry. Besides PDA, we analyzed the potential association of amino acid concentrations with infant sex, small for GA (SGA, defined as BW < third percentile), antenatal corticosteroids, chorioamnionitis, and preeclampsia. Group differences were analyzed by ANOVA adjusted for GA and BW. A Bonferroni significance threshold of P < 0.0024 was used to correct for multiple testing. Results: PDA was found in 48 of the 121 infants examined. We observed higher mean levels of glutamate in infants with PDA (147.0 μmol/L, SD 84.0) as compared with those without (106.7 μmol/L, SD 49.1, P = 0.0006). None of the other amino acid concentrations in the PDA group reached the level of statistical significance that was pre-set to correct for multiple comparisons. Glutamate levels were not significantly affected by infant sex, being SGA, or by exposure to antenatal corticosteroids, clinical chorioamnionitis, or preeclampsia. Conclusion: Our study not only does not confirm the previous findings of low glutamate levels in preterm infants with PDA, but we have even found elevated glutamate concentrations associated with PDA. Nevertheless, despite the high statistical significance, the difference in glutamate levels may lack clinical significance or may be an epiphenomenon associated with the particular clinical condition of infants with PDA.
| S-EPMC7905031 | biostudies-literature