Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. Objectives: To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection: The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis: Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures: Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. Results: In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance: A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration: PROSPERO Identifier: CRD42015015797.

Factors Associated with Time to Full Feeds in Preterm Very Low Birth Weight Infants.

BACKGROUND: Feeding intolerance prolongs time to full feeds (TFFs) in preterm infants. We studied factors associated with TFF in preterm infants on standardized feeding regimen (SFR) and routine probiotic supplementation (RPS). METHODS: This is a prospective cohort study of preterm infants ≤1500 g. Pearson's correlation, Mann-Whitney test and multivariate analysis were used. RESULTS: In total, 37 of 304 admitted infants died before reaching full feeds. Median (interquartile range) gestation, birth weight and TFF were 31.4 (30-33.05) weeks, 1210 (1066-1400) g and 11 (8-15) days, respectively. Gestation and birthweight were inversely correlated with TFF, whereas low Apgar's, sepsis, patent ductus arteriosus (PDA) and respiratory distress syndrome were directly correlated with TFF. Growth-restricted infants had significantly shorter TFF vs. appropriate for gestational age infants, probably because of higher gestation. On multivariate analysis gestation, sepsis and PDA were significant predictors of TFF. CONCLUSION: In preterm infants managed with SFR and RPS, gestation had inverse correlation with TFF, whereas sepsis and PDA had direct correlation with TFF.

Management of Neonatal Hypotension.

Hypotension is a common problem in neonates with complex underlying pathophysiology. Although treatment of low blood pressure is common, clinicians must use all available information to target neonates with compromised perfusion. Pharmacotherapy should be tailored to the specific physiologic perturbations of the individual neonate. Dopamine is the most commonly utilized agent and may be the most appropriate agent for septic shock with low diastolic blood pressure. However, alternative therapies should be considered for other etiologies of hypotension, including milrinone and vasopressin for persistent pulmonary hypertension of the newborn and dobutamine for patent ductus arteriosus. Additional studies are required to refine the approach to neonatal hypotension and document the long-term outcomes of treated neonates.

Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: Antithrombotic therapy in valvular disease is important to mitigate thromboembolism, but the hemorrhagic risk imposed must be considered. METHODS: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: In rheumatic mitral disease, we recommend vitamin K antagonist (VKA) therapy when the left atrial diameter is > 55 mm (Grade 2C) or when complicated by left atrial thrombus (Grade 1A). In candidates for percutaneous mitral valvotomy with left atrial thrombus, we recommend VKA therapy until thrombus resolution, and we recommend abandoning valvotomy if the thrombus fails to resolve (Grade 1A). In patients with patent foramen ovale (PFO) and stroke or transient ischemic attack, we recommend initial aspirin therapy (Grade 1B) and suggest substitution of VKA if recurrence (Grade 2C). In patients with cryptogenic stroke and DVT and a PFO, we recommend VKA therapy for 3 months (Grade 1B) and consideration of PFO closure (Grade 2C). We recommend against the use of anticoagulant (Grade 1C) and antiplatelet therapy (Grade 1B) for native valve endocarditis. We suggest holding VKA therapy until the patient is stabilized without neurologic complications for infective endocarditis of a prosthetic valve (Grade 2C). In the first 3 months after bioprosthetic valve implantation, we recommend aspirin for aortic valves (Grade 2C), the addition of clopidogrel to aspirin if the aortic valve is transcatheter (Grade 2C), and VKA therapy with a target international normalized ratio (INR) of 2.5 for mitral valves (Grade 2C). After 3 months, we suggest aspirin therapy (Grade 2C). We recommend early bridging of mechanical valve patients to VKA therapy with unfractionated heparin (DVT dosing) or low-molecular-weight heparin (Grade 2C). We recommend long-term VKA therapy for all mechanical valves (Grade 1B): target INR 2.5 for aortic (Grade 1B) and 3.0 for mitral or double valve (Grade 2C). In patients with mechanical valves at low bleeding risk, we suggest the addition of low-dose aspirin (50-100 mg/d) (Grade 1B). In valve repair patients, we suggest aspirin therapy (Grade 2C). In patients with thrombosed prosthetic valve, we recommend fibrinolysis for right-sided valves and left-sided valves with thrombus area < 0.8 cm(2) (Grade 2C). For patients with left-sided prosthetic valve thrombosis and thrombus area ≥ 0.8 cm(2), we recommend early surgery (Grade 2C). CONCLUSIONS: These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk.

Parenteral amino acid and metabolic acidosis in premature infants.

BACKGROUND: Aggressive parenteral nutrition (PN) including amino acids is recommended for low-birth-weight infants to prevent energy and protein deficit. Their impact on acid-base homeostasis has not been examined. METHODS: We investigated the impact of dose and duration of parenteral amino acids, with cysteine, on acid-base parameters in 122 low-birth-weight infants. Premature infants 24 hours), or 3 g/kg/d for a short (5 hour), extended (24 hour), or prolonged (3-5 days) duration were included in the study. Data were obtained at age 0-3 days (n = 43) or, when clinically stable, age 3-5 days (n = 49). Data from 30 infants, matched for birth weight and gestational age, receiving PN during the first 5 days after birth were also obtained. Acidosis was defined as pH <7.25. RESULTS: Acidosis was evident in all infants between 2 and 5 days after birth. Infants with large patent ductus arteriosus (PDA) exhibited significantly (p < .05) lower pH early, had higher blood urea nitrogen levels (26 +/- 9 vs 18 + 8 mg/dL; p < .05), and had greater weight loss ( approximately 17% of birth weight) when compared with infants without PDA. Gestational age, weight loss, and patent ductus arteriosus accounted for 65% of variance in acidosis. CONCLUSIONS: Low-birth-weight infants develop metabolic acidosis between 2 and 5 days after birth, irrespective of dose and duration of parenteral amino acid administration. Careful management of parenteral fluids and comorbidities may lower the incidence of acidosis and promote protein accretion.

Prostaglandin E1 treatment in patent ductus arteriosus dependent congenital heart defects.

Prostaglandin E1 (PGE1) treatment can be life saving in patients suffering from ductus dependent congenital heart defect. We analyzed the indications and side-effects of PGE1 therapy over a five-year period. The purpose of the study was also to examine whether a change in serum electrolyte levels could be detected. Forty-nine patients were treated with PGE1 during this period. PGE1 treatment was indicated by ductus dependent systemic circulation in 16 cases, ductus dependent pulmonary circulation in 17 cases, transposition of the great arteries in 13 cases and pulmonary hypertension (persistent fetal circulation) in three cases. As early side-effects of the treatment, fever occurred in 27/49 cases while apnoea was observed in 15 patients. In a one-week-old neonate with coarctation of the aorta grade III intraventricular hemorrhage developed. A mild decrease of sodium, potassium and chloride levels and a slight shift of pH levels toward metabolic alkalosis could be detected after one day and one week of PGE1 treatment. Because of these side-effects of PGE1 patients should be monitored in an intensive care unit. According to our observations electrolyte levels may exhibit a slight decrease; however, in the case of a short-term therapy extra salt supplementation is not necessary.

Cardiogenic hypertrophic osteopathy in a dog with a right-to-left shunting patent ductus arteriosus.

A 5-year-old castrated male Shetland Sheepdog was examined because of progressive bilateral hind limb thickening. Cyanosis of the preputial mucous membranes was evident, whereas the oral mucous membranes had a normal color. A well-structured, palisade-like periosteal reaction with no underlying bone destruction was evident on radiographs of the hind limbs. The radiographic changes were consistent with hypertrophic osteopathy (HO). Severe right-sided cardiomegaly was seen on thoracic radiographs, and a diagnosis of patent ductus arteriosus with right-to-left shunting was made by means of echocardiography and contrast echoaortography. The cyanotic heart disease was believed to be the cause of the HO. Hypertrophic osteopathy has been associated with a number of diseases in animals and humans. In humans, congenital heart defects that cause cyanosis are among the most common causes of HO.

[Symptomatology and treatment of neonatal hypertension]. / Symptomatologie en behandeling van neonatale hypertensie.

A newborn child of a diabetic mother is described, who developed neonatal hypertension after birth. Clinical signs were not specific and the diagnosis would have been missed if blood pressure had not been measured. The cause of the neonatal hypertension appeared to be a thrombus in the left renal artery, probably originating from the ductus arteriosus Botalli. Control of the neonatal hypertension according to a stepwise treatment regime was very difficult. Based on our experience and on study of the literature it is advised to start treatment in the acute stage with nifedipine orally or with sodium nitroprusside intravenously.

The use of nifedipine in patients with Eisenmenger's syndrome complicating patency of the arterial duct.

Nifedipine has a vasodilatory effect on both the systemic and the pulmonary circulation. Its preferential effect on reducing the pulmonary vascular resistance has been studied in patients with primary pulmonary hypertension. In 4 patients with the Eisenmenger's syndrome complicating patency of the arterial duct (ductus arteriosus), we have studied the possibility of this selective pulmonary vasodilatory effect of nifedipine in reducing the right-to-left shunting. The degree of differential cyanosis was taken to reflect the right-to-left shunting. This was assessed continuously by 2 pulse oximeters applied to the right arm and leg. After sublingual nifedipine, the oxygen saturation of the right leg increased from pretreatment value of 79 +/- 5% (mean +/- SEM) to a maximum of 84 +/- 3% (P less than 0.01). Such a beneficial effect was maximal in the first 2 hours. On maintenance therapy, symptom-limited cycle ergometry showed increased exercise duration with comparable degrees of arterial desaturation and there was symptomatic improvement. This improvement disappeared on changing to placebo. It was concluded that nifedipine reduced right-to-left shunting and improved symptomatology.

[Therapeutic effects of nifedipine in pulmonary hypertension secondary to congenital heart disease].

The hemodynamic effects of nifedipine in 15 patients with pulmonary hypertension (PH) secondary to congenital heart disease (CHD) were evaluated. The basal hemodynamic parameters were obtained before medication. The parameters were also obtained 60 minutes and 2 months after taking nifedipine. After treatment, PAPs were decreased 18% and 15% (P less than 0.01), PAPd 21% and 24% (P less than 0.01), PAPm both 19% (P less than 0.01), respectively. TPR were reduced 33% and 30% (P less than 0.01). SAP decreased slightly after 60 minutes. HR, CO and CI remained unchanged. Of the 10 patients suffering from hyperkinetic PH, 8 patients underwent closure of defects after treatment of nifedipine. The above results suggest that nifedipine is effective for patients with PH secondary to CHD. It acted as an antihypertensive agent in patients with CDH associated with hyperkinetic PH before operation.

[Ligation of the ductus arteriosus in premature infants. Surgical considerations]. / Ligadura del conducto arterioso en prematuros. Consideraciones quirúrgicas.

It is described the surgical interruption of Patent Ductus Arteriosus in ten premature newborn patients with cardiac insufficiency and/or respiratory distress syndrome. The authors mention the technical factors that they consider important to have good results with these fragile infants, as the use of local anesthesia; to perform the procedure in the neonatal intensive care unit, the extrapleural dissection of the ductus, etc. The post-operative care problems are analyzed and this experience is compared with reports from other authors.

Phototherapy and plasma immunoreactive prostaglandin A values. Its effect in premature infants.

Plasma immunoreactive prostaglandin A (iPGA) values were determined for 14 premature infants before and after 48 hours of phototherapy and in a control group of six age-matched premature infants. At 4 to 8 days of life, the infants who had received phototherapy for 48 hours had significantly lower iPGA values compared with controls. At 2 to 3 days of life, four infants with a clinically apparent patent ductus arteriosus were found to have significantly elevated iPGA values compared with controls. After 48 hours of phototherapy, these infants likewise had a significant decrease in iPGA values compared with controls; in all four infants, the ductus closed spontaneously. Phototherapy is an effective method for decreasing plasma iPGA values in premature infants.

Early neonatal hypocalcaemia.

In our hospital early neonatal hypocalcaemia is now the major cause of low serum calcium in the neonatal period. Over a 2-year period, only 2 cases of hypocalcaemic convulsions were seen in a total of 8700 deliveries, though 51 infants had early neonatal hypocalcaemia. All sick low birth-weight infants should have daily serum calcium estimations carried out. Calcium supplements should be considered if symptoms of hypocalcaemia are present.