[Risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus]. / æœ‰è¡€æµåŠ¨åŠ›å­¦æ„ä¹‰çš„åŠ¨è„‰å¯¼ç®¡æœªé—­æ—©äº§å„¿å¸ƒæ´›èŠ¬æ²»ç–—å¤±è´¥çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA). METHODS: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis. RESULTS: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% (P<0.05). CONCLUSIONS: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

The impact of the route of administration on the efficacy and safety of the drug therapy for patent ductus arteriosus in premature infants: a systematic review and meta-analysis.

Background: This systematic review and meta-analysis aims to explore the potential impact of the route of administration on the efficacy of therapies and occurrence of adverse events when administering medications to premature infants with patent ductus arteriosus (PDA). Method: The protocol for this review has been registered with PROSPERO (CRD 42022324598). We searched relevant studies in PubMed, Embase, Cochrane, and the Web of Science databases from March 26, 1996, to January 31, 2022. Results: A total of six randomized controlled trials (RCTs) and five observational studies were included for analysis, involving 630 premature neonates in total. Among these infants, 480 were in the ibuprofen group (oral vs. intravenous routes), 78 in the paracetamol group (oral vs. intravenous routes), and 72 in the ibuprofen group (rectal vs. oral routes). Our meta-analysis revealed a significant difference in the rate of PDA closure between the the initial course of oral ibuprofen and intravenous ibuprofen groups (relative risk (RR) = 1.27, 95% confidence interval (CI) [1.13-1.44]; P < 0.0001, I2 = 0%). In contrast, the meta-analysis of paracetamol administration via oral versus intravenous routes showed no significant difference in PDA closure rates (RR = 0.86, 95% CI [0.38-1.91]; P = 0.71, I2 = 76%). However, there was no statistically significant difference in the risk of adverse events or the need for surgical intervention among various drug administration methods after the complete course of drug therapy. Conclusion: This meta-analysis evaluated the safety and effectiveness of different medication routes for treating PDA in premature infants. Our analysis results revealed that compared with intravenous administration, oral ibuprofen may offer certain advantages in closing PDA without increasing the risk of adverse events. Conversely, the use of paracetamol demonstrated no significant difference in PDA closure and the risk of adverse events between oral and intravenous administration.

A Case of Enterococcal Patent Ductus Arteriosus-associated Endarteritis in a Preterm Neonate.

INTRODUCTION: The persistent patency of the ductus arteriosus frequently occurs in premature neonates and can cause infective endocarditis (IE) or ductal endarteritis (DE) during sepsis. Even though neonatal IE and DE are believed to be a rare eventuality, their incidence has been increasing in the last decades due to the improved survival of even more preterm babies, favored by highly invasive procedures and therapies. In parallel, antimicrobial resistance is another rising problem in neonatal intensive care units, which frequently compels to treat infections with broad-spectrum or last generation antibiotics. CASE PRESENTATION: We report the case of a preterm neonate affected by patent ductus arteriosus-associated DE that followed an episode of sepsis caused by a high-level aminoglycoside-resistant enterococcus. The neonate was successfully treated with the synergistic combination of ampicillin and cefotaxime. DISCUSSION: IE and patent ductus arteriosus-associated DE are rising inside neonatal intensive care units and neonatologists should be aware of these conditions. Enterococcal IE and patent ductus arteriosus-associated DE sustained by high-level aminoglycoside-resistant strains can be successfully treated with the synergistic combination of ampicillin and cefotaxime even in preterm neonates.

Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment.

A circular shunt is a poor prognostic factor associated with Ebstein's anomaly. Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes. Prenatal non-steroidal anti-inflammatory drugs (NSAIDs) have been known to constrict the DA. Recently, prenatal NSAIDs have been used for that purpose in the treatment of circular shunt. Limited research shows that it may be an effective treatment leading to improved fetal outcomes. In this article, we did an extensive review of literature to describe this therapy's effectiveness and outcomes. 82% of fetuses were able to achieve ductal constriction with prenatal NSAID therapy. For fetuses who achieved ductal constriction, fetal demise was less likely (6%) when compared to those who were unable to achieve the same (50%). Of all the fetuses with hydrops, 50% had resoluation of hydrops with prenatal NSAID treatment.

Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.

BACKGROUND: The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days' and 28 weeks 6 days' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age. RESULTS: A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. CONCLUSIONS: The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).

Clinical and echocardiography predictors of response to first-line acetaminophen treatment in preterm infants with hemodynamically significant patent ductus arteriosus.

OBJECTIVE: To assess clinical and echocardiography predictors of acetaminophen response for the treatment of patent ductus arteriosus (PDA) in preterm neonates. STUDY DESIGN: Retrospective cohort study of preterm infants born <30 weeks, with a diagnosis of hemodynamically significant PDA, who received 1st line treatment with intravenous acetaminophen during the first 2 postnatal weeks. Response was defined by PDA closure or improvement in PDA score of >50%. RESULTS: A total of 100 infants were included whose median weight and gestational age at birth were 663 grams and 24.6 weeks respectively. In total, 66 infants were classified as responders and were more likely to have intrauterine growth restriction, exposure to maternal hypertension and chorioamnionitis. Non-response was more common among infants with thrombocytopenia and anemia. CONCLUSION: Responders were more likely to be IUGR with echocardiography indices of lower preload. Response to 1st line intravenous acetaminophen therapy is comparable to non-steroidal drugs in preterm infants. Relationship of response to acetaminophen to perinatal characteristics requires further characterization.

Intravenous prostaglandin E1 (alprostadil) bolus in ductus arteriosus-dependent CHD: valid or absolutely contraindicated?

The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The intravenous infusion is well established in loading infusion and maintenance with an onset of action of 30 minutes until 2 hours or even more. Our aim is to report three patients with pulmonary atresia that presented hypercyanotic spell due to a ductal spasm during cardiac catheterisation in whom the administration of a bolus of alprostadil reversed the spasm and increased pulmonary flow, immediately stabilising the condition of the patients allowing subsequent successful stent placement with no serious complications or sequelae after the administration of the bolus. More studies are needed to make a recommendation regarding the use of alprostadil in bolus in cases where the ductal spasm might jeopardise the life of the patient.

The impact of cyclooxygenase inhibitor use on urinary prostaglandin metabolites in preterm infants.

BACKGROUND: There is limited evidence on the association between the clinical course of patent ductus arteriosus (PDA) and prostaglandin (PG) metabolites. This study aimed to determine the influence of PDA treatment on urinary PG metabolite excretion in very-low-birth-weight (VLBW) infants. METHODS: Urine samples were collected from 25 VLBW infants at 1, 3, and 7 days of age. Infants were separated into two groups: a PDA-treated group that received a cyclooxygenase-2 (COX) inhibitor (n = 12) and a control group that did not receive a COX inhibitor during the first 7 days after birth (n = 13). Urinary PG metabolite tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM) levels were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Urinary t-PGEM excretion levels were not significantly different between the groups at 1, 3, and 7 days of age. Urinary t-PGDM excretion levels at 1 day of age were higher in PDA-treated infants than in control infants (median [interquartile range]: 5.5 [2.6, 12.2] versus 2.1 [1.0, 3.9] ng/mg creatinine; p = 0.017); however, among PDA-treated infants, the levels were significantly lower at 3 and 7 days than at 1 day of age (5.5 [2.6, 12.2] versus 3.4 [1.7, 4.5] and 4.0 [1.7, 5.3] ng/mg creatinine, respectively; p < 0.05). The urinary t-PGDM excretion level in the control group did not significantly differ among the time points. CONCLUSION: PDA and COX inhibitor administration affected PG metabolism in VLBW infants. Our results indicated that urinary t-PGDM excretion was significantly associated with PDA-treatment in preterm infants.

Pharmacokinetic and Pharmacodynamic Analysis of Acetaminophen and Ibuprofen Dual Therapy for Patent Ductus Arteriosus Closure in Preterm Neonates at Less Than 29 Weeks of Gestation.

Patent ductus arteriosus (PDA) is a blood vessel that critically supports fetal circulation. The ductus naturally closes within a few days after birth. However, it can stay open in premature neonates for an extended period of time, which is associated with increased mortality and various co-morbidities. Ibuprofen and indomethacin are currently the only 2 drugs approved for inducing PDA closure, but both have been associated with adverse renal and bleeding events. Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The objective of this study was to establish a disease-drug-trial model to characterize and predict PDA closure following single and combination drug therapy with ibuprofen and/or APAP in children at less than 29 weeks of gestation. The model was informed by a comprehensive literature review. The results of our analysis suggest that ibuprofen and APAP achieve therapeutic synergy. They further suggest that the younger the preterm neonates, the higher the treatment benefit. A 5-day oral dosing regimen consisting of ibuprofen (20 mg/kg Q24h on day 1, followed by 10 mg/kg Q24h on days 2-5) plus APAP (15 mg/kg Q6h) was deemed appropriate to achieve at least 90% PDA in all preterm neonates evaluated within 1 month of life. The model can now be used to design prospective pediatric trials to evaluate optimal drug combinations for PDA closure in preterm neonates and to refine optimal dosing regimens in cohorts of differing gestational age.

Early versus Late Caffeine Therapy Administration in Preterm Neonates: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Caffeine is commonly used as therapy for apnea of prematurity and has shown potential in preventing other conditions in preterm neonates. However, the optimal timing for caffeine therapy remains uncertain. OBJECTIVE: This study aimed to compare the outcomes of early versus late administration of caffeine in preterm neonates. METHODS: PubMed, Embase, and Cochrane Library were searched for studies comparing 0-2 days to ≥3 days caffeine introduction in preterm neonates. Outcomes included were mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), late-onset sepsis, length of hospital stay, and the composite of BPD or death. RevMan 5.4.1 was used for statistical analysis. RESULTS: A total of 122,579 patients from 11 studies were included, 2 were randomized controlled trials (RCTs), and 63.9% of the neonates received early caffeine administration. The rates of BPD (OR: 0.70; 95% CI: [0.60-0.81]; p < 0.0001), IVH (OR: 0.86; 95% CI: [0.82-0.90]; p < 0.0001), ROP (OR: 0.80; 95% CI: [0.74-0.86]; p < 0.0001), late-onset sepsis (OR: 0.84; 95% CI: [0.79-0.89]; p < 0.00001), and PDA (OR: 0.60; 95% CI: [0.47-0.78]; p < 0.0001) were significantly reduced in the early caffeine group. The composite outcome of BPD or death was also lower in the early caffeine group (OR: 0.76; 95% CI: [0.66-0.88]; p < 0.0003). Mortality rate was higher in the early caffeine group (OR: 1.20; 95% CI: 1.12-1.29; p < 0.001). CONCLUSION: As compared with late caffeine administration, early caffeine is associated with a reduction in BPD, IVH, ROP, late-onset sepsis, and PDA in preterm neonates, albeit increased mortality. Additional RCTs are warranted to confirm these findings and evaluate whether the effect on mortality may be related to survival bias in observational studies favoring the late treatment group.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Ibuprofen Reduces 5-Year Overall Survival of Head and Neck Cancer Patients With Immunotherapy - A Retrospective Case-controlled Real-World Data Analysis of 10,000 Patients.

BACKGROUND/AIM: Resistance to immunotherapy can be explained by an abnormal microbiome of the gut. In Europe in particular, the use of ibuprofen, with or without proton-pump inhibitors to protect the gastric mucosa, is widespread. This study aimed to investigate the impact of ibuprofen use on the effectiveness of immunotherapy in patients with head and neck carcinoma. PATIENTS AND METHODS: Data from patients with head and neck carcinoma (ICD-10-Codes: C00-C14) receiving pembrolizumab, from the TriNetX network, were analyzed. Two groups were formed for the analyses: Cohort I received ibuprofen at least once within 6 months before and after immunotherapy, whereas patients in cohort II received ibuprofen with proton-pump inhibitors or no ibuprofen at all. Cohorts I and II were matched 1:1 with respect to age, sex, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI). The primary outcome was death and a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR), and hazard ratio (HR) were calculated. RESULTS: The analysis showed that 823 patients with ibuprofen and 724 patients without ibuprofen died within 5 years, showing a significant risk difference of 5.3% (p=0.001). The RR was 1.137 [95% confidence interval (CI)=1.053-1.227], OR was 1.245 (95% CI=1.093-1.418), and HR was 1.202 (95%CI=1.088-1.329). CONCLUSION: Ibuprofen significantly decreases the drug effectiveness of immunotherapy and may be related to changes in the human microbiome. However, further prospective, randomized, and double-blind studies are needed to validate our data and to adequately address confounders.

[A Combination Therapy with Antibiotic and Surgical Treatment in a Patient with Patent Ductus Arteriosus with Pulmonary Vegetation:Report of a Case].

We present a case of a 24-year-old female who presented with a history of fever and back pain. She had no particular medical history and was not taking any medication. Transthoracic echocardiology and computed tomography showed a patent ductus arteriosus with vegetation in the pulmonary artery. She was treated with penicillin G;however, the vegetation embolized into the left pulmonary artery. After the antibiotics was changed to clindamycin and ceftriaxone, the resolution of the lung abscess was shown by computed tomography( CT). Two months later, a surgical repair of the patent ductus arteriosus was successfully performed. Patent ductus arteriosus-associated infectious endocarditis is relatively rare in adulthood.

Factors associated with the response to postnatal dexamethasone use in very low birthweight infants: a nationwide cohort study.

BACKGROUND: Dexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology of dexamethasone use to prevent BPD and analyse the factors associated with the response to dexamethasone in very low birthweight infants using a nationwide database. METHODS: We included very low birthweight infants born between January 2013 and December 2020 with a gestational age of 23-31 weeks using data from the Korean Neonatal Network registry. Patients were grouped based on their dexamethasone use into 'Dex' or 'No Dex' groups. Clinical variables and data were collected, and the annual trends of dexamethasone use and the proportion of patients who received dexamethasone according to gestational age were analysed. Respiratory outcomes were compared between the groups. Univariate and multivariate analyses were performed to analyse factors associated with the response to dexamethasone in BPD. RESULTS: Of 11 261 eligible infants, 2313 (20.5%) received dexamethasone, and 1714 (74.1%) of them were diagnosed with moderate-to-severe BPD. The 8-year annual prevalence of dexamethasone use was 17.7-22.3%. The 'Dex' group had more moderate-to-severe BPD, more frequent invasive ventilation use at a postmenstrual age of 36 weeks and longer ventilator duration. Birth weight, 5-minute APGAR score, pulmonary hypertension within the first 28 days, surgical treatment of patent ductus arteriosus, medical treatment of patent ductus arteriosus, pathological chorioamnionitis, hydrocortisone or budesonide use, surgical management of necrotising enterocolitis and fungal sepsis were associated with BPD after dexamethasone use. CONCLUSIONS: Approximately 20.5% of preterm infants received dexamethasone, and the frequency increased as gestational age decreased. Poor response to dexamethasone was associated with antenatal and postnatal inflammation, low birth weight and early pulmonary hypertension.

[Treatment of patent ductus arteriosus in very preterm infants in China].

Objective: To describe the current status and trends in the treatment of patent ductus arteriosus (PDA) among very preterm infants (VPI) admitted to the neonatal intensive care units (NICU) of the Chinese Neonatal Network (CHNN) from 2019 to 2021, and to compare the differences in PDA treatment among these units. Methods: This was a cross-sectional study based on the CHNN VPI cohort, all of 22 525 VPI (gestational age<32 weeks) admitted to 79 tertiary NICU within 3 days of age from 2019 to 2021 were included. The overall PDA treatment rates were calculated, as well as the rates of infants with different gestational ages (≤26, 27-28, 29-31 weeks), and pharmacological and surgical treatments were described. PDA was defined as those diagnosed by echocardiography during hospitalization. The PDA treatment rate was defined as the number of VPI who had received medication treatment and (or) surgical ligation of PDA divided by the number of all VPI. Logistic regression was used to investigate the changes in PDA treatment rates over the 3 years and the differences between gestational age groups. A multivariate Logistic regression model was constructed to compute the standardized ratio (SR) of PDA treatment across different units, to compare the rates after adjusting for population characteristics. Results: A total of 22 525 VPI were included in the study, with a gestational age of 30.0 (28.6, 31.0) weeks and birth weight of 1 310 (1 100, 1 540) g; 56.0% (12 615) of them were male. PDA was diagnosed by echocardiography in 49.7% (11 186/22 525) of all VPI, and the overall PDA treatment rate was 16.8% (3 795/22 525). Of 3 762 VPI who received medication treatment, the main first-line medication used was ibuprofen (93.4% (3 515/3 762)) and the postnatal day of first medication treatment was 6 (4, 10) days of age; 59.3% (2 231/3 762) of the VPI had been weaned from invasive respiratory support during the first medication treatment, and 82.2% (3 092/3 762) of the infants received only one course of medication treatment. A total of 143 VPI underwent surgery, which was conducted on 32 (22, 46) days of age. Over the 3 years from 2019 to 2021, there was no significant change in the PDA treatment rate in these VPI (P=0.650). The PDA treatment rate decreased with increasing gestational age (P<0.001). The PDA treatment rates for VPI with gestational age ≤26, 27-28, and 29-31 weeks were 39.6% (688/1 737), 25.9% (1 319/5 098), and 11.4% (1 788/15 690), respectively. There were 61 units having a total number of VPI≥100 cases, and their rates of PDA treatment were 0 (0/116)-47.4% (376/793). After adjusting for population characteristics, the range of standardized ratios for PDA treatment in the 61 units was 0 (95%CI 0-0.3) to 3.4 (95%CI 3.1-3.8). Conclusions: From 2019 to 2021, compared to the peers in developed countries, VPI in CHNN NICU had a different PDA treatment rate; specifically, the VPI with small birth gestational age had a lower treatment rate, while the VPI with large birth gestational age had a higher rate. There are significant differences in PDA treatment rates among different units.