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.).

Association between immediate oxygenation response and survival in preterm infants receiving rescue inhaled nitric oxide therapy for hypoxemia from pulmonary hypertension: A systematic review and meta-analysis.

PURPOSE: To investigate whether immediate response to inhaled nitric oxide (iNO) therapy is associated with reduced mortality in preterm infants with hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH). METHODS: A systematic review and meta-analysis of observational studies was conducted to examine the association between immediate response (improved oxygenation ≤6 h) compared to non-response, and all-cause mortality among preterm infants <34 weeks gestational age without congenital anomalies or genetic disorders who received iNO treatment. Adjusted and unadjusted odds ratio, were pooled using a random effects meta-analysis Hartung-Knapp-Sidik-Jonkman approach. Subgroup analyses were planned for infants with preterm premature rupture of membranes (PPROM) and those treated within 72 h after birth. RESULTS: The primary analysis included 5 eligible studies, a total of 400 infants (196 responders; 204 non-responders). The studies were rated as low to moderate risk of bias based on the Quality in Prognostic Studies tool. Immediate iNO responsiveness was associated with reduced odds of mortality [odds ratio (OR) 0.22, 95 % confidence interval (95 % CI) (0.10-0.49)]. Although there was insufficient data for a subgroup analysis of infants with PPROM, infants treated with iNO within 72 h demonstrated consistent findings of reduced mortality [OR 0.21 95 % CI (0.13-0.36)]. Based on the GRADE approach, considering the risk of bias of included studies, the overall strength of evidence was rated as moderate. CONCLUSION: There is evidence to suggest that immediate improvement in oxygenation following iNO therapy is associated with reduced odds of mortality before discharge in preterm infants with HRF and clinically suspected or confirmed PH.

Targeted neonatal echocardiography training: a survey of trainees in a region of England.

Targeted neonatal echocardiography (TNE) is an important skill to advise diagnosis and management. Training in TNE is currently optional for neonatal subspecialty (grid) trainees and accessing training is often challenging. We disseminated a survey, asking neonatal grid trainees for their views on TNE training. 48 out of 91 trainees (53%) completed the survey. 96% of trainees (n=48) wanted to learn TNE with similar numbers eager to access a formal training package, using a variety of teaching media. Identified barriers to TNE training included time, access to supervision and the perceived complexity of the skill. These findings will influence the design and delivery of a regional TNE training programme.

Increase in the use of inhaled nitric oxide in neonatal intensive care units in England: a retrospective population study.

Objective: To describe temporal changes in inhaled nitric oxide (iNO) use in English neonatal units between 2010 and 2015. Design: Retrospective analysis using data extracted from the National Neonatal Research Database. Setting: All National Health Service neonatal units in England. Patients: Infants of all gestational ages born 2010-2015 admitted to a neonatal unit and received intensive care. Main outcome measures: Proportion of infants who received iNO; age at initiation and duration of iNO use. Results: 4.9% (6346/129 883) of infants received iNO; 31% (1959/6346) were born <29 weeks, 18% (1152/6346) 29-33 weeks and 51% (3235/6346)>34 weeks of gestation. Between epoch 1 (2010-2011) and epoch 3 (2014-2015), there was (1) an increase in the proportion of infants receiving iNO: <29 weeks (4.9% vs 15.9%); 29-33 weeks (1.1% vs 4.8%); >34 weeks (4.5% vs 5.0%), (2) increase in postnatal age at iNO initiation: <29 weeks 10 days vs 18 days; 29-33 weeks 2 days vs 10 days, (iii) reduction in iNO duration: <29 weeks (3 days vs 2 days); 29-33 weeks (2 days vs 1 day). Conclusions: Between 2010 and 2015, there was an increase in the use of iNO among infants admitted to English neonatal units. This was most notable among the most premature infants with an almost fourfold increase. Given the cost of iNO therapy, limited evidence of efficacy in preterm infants and potential for harm, we suggest that exposure to iNO should be limited, ideally to infants included in research studies (either observational or randomised placebo-controlled trial) or within a protocolised pathway. Development of consensus guidelines may also help standardise practice.

Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial.

BACKGROUND: The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks' gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic. METHODS: This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0-28+ 6 weeks' gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0-28+ 6 weeks' gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. DISCUSSION: Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks' postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age. TRIAL REGISTRATION: ISRCTN84264977 . Date assigned: 15/09/2010.

Cost of nitric oxide therapy in neonates.

A retrospective observational cohort study was performed to review the cost of inhaled nitric oxide (iNO) therapy in a UK neonatal intensive care setting over a 4-year period. 188 neonates with a median (IQR) gestational age and birth weight of 27 (24-37) weeks and 980 (695-2812) g, respectively, were treated with iNO. The median (IQR) duration of iNO therapy was 60 (22-129) hours. The mean cost of iNO therapy was approximately £820 per baby treated equivalent to £8.50 per hour of therapy. Alternative pricing models suggested a calculated cost of iNO therapy of between approximately £950 and £1350 per baby.

Variation in the definition of pulmonary hypertension and clinical indications for the use of nitric oxide in neonatal clinical trials.

AIM: Pulmonary hypertension (PH) frequently complicates neonatal hypoxaemic respiratory failure, but is inconsistently defined. We aimed to describe the variation among randomised controlled trials (RCTs) of inhaled nitric oxide (iNO), in relation to the definition of PH and/or hypoxaemic respiratory failure used to select patients for trial inclusion. METHODS: PubMed, Cochrane Library and ClinicalTrials.gov were systematically searched for RCTs of iNO in neonates. Included studies were assessed for clinical and/or echocardiography criteria used to define PH/hypoxaemic respiratory failure. RESULTS: Thirty-two trials were included in this review, of which 23 enrolled infants ≥34 weeks' gestation. Echocardiographic diagnosis was used in 21 studies, but there was considerable variation in the echocardiographic parameters used to diagnose PH. The most commonly used indices included markers of tricuspid regurgitation and extrapulmonary shunt. CONCLUSION: There is wide variation in the definition of PH used to select infants for inclusion into RCTs of iNO therapy in neonates. We recommend that an international consensus be reached on which parameters should be used and the thresholds defining severity of disease.

Nitric Oxide in Pulmonary Hypoplasia: Results from the European iNO Registry.

OBJECTIVES: The aim of this work was to describe treatment response and outcome data for preterm infants with pulmonary hypoplasia treated with inhaled nitric oxide (iNO). We hypothesised that an acute oxygenation response to iNO would be associated with survival. DESIGN: A retrospective observational study design was used to identify cases of pulmonary hypoplasia in preterm infants <34 weeks' gestation reported to the European iNO Registry. Demographic and clinical data were collected including oxygenation and echocardiographic parameters. The primary outcome was acute oxygenation response defined as a reduction in fractional inspired oxygen of >0.15. Outcome data included chronic lung disease (CLD) and death. RESULTS: Seventy-two infants with pulmonary hypoplasia were treated with iNO during a 10-year period (2007-2016). In total, 30/69 (43%) of the infants showed a significant improvement in oxygenation and were categorised as "responders." Thirty-one treated infants died, and 19 survivors developed CLD. Although there were no differences in demographics and baseline cardiorespiratory parameters between responders and non-responders, an acute response was significantly associated with survival. Neither pulmonary hypertension nor PPHN (persistent pulmonary hypertension of the newborn) physiology predicted the acute response to iNO or survival. CONCLUSION: Although the acute oxygenation response to iNO therapy in pulmonary hypoplasia is comparable to other respiratory disorders in preterm infants, mortality in this group remains very high. An acute response is associated with survival and suggests that a short therapeutic trial of iNO therapy is warranted in this population. This study underscores the value of registries in evaluating therapies for rare neonatal disorders, although their limitations must be recognised.

Prostaglandin E 2 in a preterm infant with coarctation of the aorta.

Prostaglandins are widely used in aortic coarctation to maintain ductal patency and preserve systemic perfusion until surgical intervention can be performed. Although the short-term use of prostaglandins to ameliorate aortic narrowing in neonates with a closed ductus has been reported, it has not been described as a longer term therapy in extremely preterm neonates. A 27-week gestation baby weighing 560 g presented at 40 days of age with coarctation and a closed ductus arteriosus. He was successfully treated with a 7-week course of prostaglandin E2 therapy because surgical intervention was not deemed feasible in view of his size. Treatment resulted in a relaxation of the aortic constriction and improvement in aortic blood flow velocity profile, highlighting the value of long-term prostaglandin therapy in this population and supporting the hypothesis that the presence of ductal tissue contributes to the development of juxtaductal aortic constriction in some extremely preterm infants.

Corticosteroids for treating hypotension in preterm infants.

BACKGROUND: Systemic hypotension is a relatively common complication of preterm birth and is associated with periventricular haemorrhage, periventricular white matter injury and adverse neurodevelopmental outcome. Corticosteroid treatment has been used as an alternative or an adjunct to conventional treatment with volume expansion and vasopressor/inotropic therapy. OBJECTIVES: To determine the effectiveness and safety of corticosteroids used either as primary treatment of hypotension or for the treatment of refractory hypotension in preterm infants. SEARCH METHODS: Randomized or quasi-randomised controlled trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2011), MEDLINE (1996 to Jan 2011), EMBASE (1974 to Jan 2011), CINAHL (1981 to 2011), reference lists of published papers and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1995 to 2011). SELECTION CRITERIA: We included all randomised or quasi-randomised controlled trials investigating the effect of corticosteroid therapy in the treatment of hypotension in preterm infants (< 37 weeks gestation) less than 28 days old. Studies using corticosteroids as primary treatment were included as well as studies using corticosteroids in babies with hypotension resistant to inotropes/pressors and volume therapy. We included studies comparing oral/intravenous corticosteroids with placebo, other drugs used for providing cardiovascular support or no therapy in this review. DATA COLLECTION AND ANALYSIS: Methodological quality of eligible studies was assessed according to the methods used for minimising selection bias, performance bias, attrition bias and detection bias. Studies that evaluated corticosteroids (1) as primary treatment for hypotension or (2) for refractory hypotension unresponsive to prior use of inotropes/pressors and volume therapy, were analysed using separate comparisons. Data were analysed using the standard methods of the Neonatal Review Group using Rev Man 5.1.2. Treatment effect was analysed using relative risk, risk reduction, number needed to treat for categorical outcomes and weighted mean difference for outcomes measured on a continuous scale, with 95% confidence intervals. MAIN RESULTS: Four studies were included in this review enrolling a total of 123 babies. In one study, persistent hypotension was more common in hydrocortisone treated infants as compared to those who received dopamine as primary treatment for hypotension (RR 8.2, 95% CI 0.47 to 142.6; RD 0.19, 95% CI 0.01 to 0.37). In two studies comparing steroid versus placebo, persistent hypotension (defined as a continuing need for inotrope infusion) was less common in steroid treated infants as compared to controls who received placebo for refractory hypotension (RR 0.35, 95% CI 0.19 to 0.65; RD -0.47, 95% CI - 0.68 to - 0.26; NNT = 2.1, 95% CI 1.47, 3.8). There were no statistically significant effects on any other short or long-term outcome. A further two studies that have only been published in abstract form to date, may be eligible for inclusion in a future update of this review. AUTHORS' CONCLUSIONS: Hydrocortisone may be as effective as dopamine when used as a primary treatment for hypotension. But the long term safety data on the use of hydrocortisone in this manner is unknown.Steroids are effective in treatment of refractory hypotension in preterm infants without an increase in short term adverse consequences. However, long term safety or benefit data is lacking. With long term benefit or safety data lacking steroids cannot be recommended routinely for the treatment of hypotension in preterm infants.

Use of inhaled nitric oxide in the new born period: results from the European Inhaled Nitric Oxide Registry.

AIMS: The aim of this study was to present data relating to the use of inhaled nitric oxide (iNO) in newborn infants included in the European Inhaled Nitric Oxide Registry. METHODS: Demographic, clinical and therapeutic data from seven European centres are reported. Univariate analyses were performed to identify factors associated with acute response to iNO and survival without extra corporeal membrane oxygenation (ECMO). RESULTS: A total of 112 newborn infants received iNO, with 40% being less than 34 weeks gestational age. The commonest indication for iNO was secondary pulmonary hypertension. Acute response to iNO was more common in infants with a higher oxygenation index (median OI 32.7 vs 22.6, p = 0.040), although acute response did not predict survival without ECMO. Infants who survived without ECMO had a lower OI prior to therapy (median OI 24 vs 43, p = 0.009), were commenced on a higher starting dose (median dose 20 ppm vs 10 ppm p = 0.013) and received a lower maintenance dose (median dose 10 vs 17 ppm, p = 0.027) than those who died or received ECMO. CONCLUSION: Collating and reporting data about iNO therapy in neonates across a number of European centres using a web-based system is feasible. These data may be used to monitor the clinical use of iNO, identify adverse effects, generate research hypotheses and promote high standards in the clinical use of iNO.

Critical incident reporting in neonatal practice.

Patient safety incidents (PSIs) occur relatively frequently in healthcare. Incident-reporting systems are designed to systematically collect information relating to PSIs in order to identify and rectify problems in the delivery of clinical care. This review provides an overview of the incident reporting process and summarises local and national data of PSIs reported in a neonatal population.

CSF cytokine levels in preterm infants may reflect systemic inflammation and are independent of gestation.

BACKGROUND: Among preterm infants, high concentrations of inflammatory mediators in cerebrospinal fluid (CSF) are associated with poor outcome. Previous studies have not indicated whether CSF concentrations of inflammatory mediators are associated with important confounders such as gestational age. AIMS: To examine associations between CSF concentrations of inflammatory mediators and gestational age, maternal features suggestive of inflammation, characteristics of the CSF sample or the presence of a systemic inflammatory response. STUDY DESIGN AND SUBJECTS: Aliquots of CSF obtained during routine investigation of potential sepsis among infants born before 35 weeks gestation were assayed for 17 mediators of inflammation using a fluorescent multi-bead analyser. Other information was collected from routine clinical records. RESULTS: 39 infants were assessed. CSF levels of mediators of inflammation were not correlated with gestational age. CSF red blood cell counts were correlated with CSF concentrations of IL-6, GM-CSF and IL-17 (each p<0.003). CSF lactate was correlated with CSF concentrations of IL-1beta, IL-6, GM-CSF, G-CSF, IFN-gamma and MIP-1beta. CSF concentrations of IL-1beta, IL-6, G-CSF, TNF-alpha and IFN-gamma were higher in infants with a raised CRP within 24 h of delivery (each p<0.003). CONCLUSIONS: CSF concentrations of inflammatory mediators most probably reflect inflammatory pathologies and are not influenced by gestational age. They may also, however, reflect contamination with blood or systemic inflammation. CSF concentrations of inflammatory mediators may not provide a specific indicator of CNS inflammation.

Telomere length dynamics differ in foetal and early post-natal human leukocytes in a longitudinal study.

Haemopoietic stem cells (HSC) undergo a process of self renewal to constantly maintain blood cell turnover. However, it has become apparent that adult HSC lose their self-renewal ability with age. Telomere shortening in peripheral blood leukocytes has been seen to occur with age and it has been associated with loss of HSC proliferative capacity and cellular ageing. In contrast foetal HSC are known to have greater proliferative capacity than post-natal stem cells. However it is unknown whether they undergo a similar process of telomere shortening. In this study we show a more accentuated rate of telomere loss in leukocytes from pre term infants compared to human foetuses of comparable age followed longitudinally for 8-12 weeks in a longitudinal study. Our results point to a difference in HSC behaviour between foetal and early postnatal life which is independent of age but may be influenced by events at birth itself.

Sequential cardiac troponin T following delivery and its relationship with myocardial performance in neonates with respiratory distress syndrome.

We measured serial cardiac troponin T in babies with respiratory distress syndrome and in "healthy" controls (no cardiorespiratory support required). We investigated relationships between cardiac troponin T and myocardial performance in respiratory distress syndrome. This was a prospective observational study at a large tertiary maternity unit that recruited 104 "healthy" babies from whom individual samples were collected. A further 24 infants with respiratory distress syndrome and 14 "healthy" preterm infants had serial sampling over the first three days. We measured fractional shortening in 14 of the infants with respiratory distress syndrome. Cardiac troponin T rose from a median (interquartile range) of 10 (10-11) pg/mL on day one to 34 (22-46) pg/mL by day three, p=0.005, in "healthy" babies. In respiratory distress syndrome levels were higher, 91 (46-135) pg/mL at 6 (5-7) hours of age, p<0.001, and remained so for all three days. In babies with respiratory distress syndrome on day one cardiac troponin T correlated negatively with fractional shortening, Rho=-0.831, p<0.001, but this correlation did not persist. In "healthy" babies there is a minimal rise of cardiac troponin T by day 3. In respiratory distress syndrome there is an early and sustained elevation of cardiac troponin T, with a negative relationship with fraction shortening, suggesting significant myocardial damage of antenatal/intrapartum origin, giving rise to measurable dysfunction.

Atypical chronic lung disease in preterm infants.

An atypical pattern of chronic lung disease (CLD) has been described in preterm infants and a potential association with intrauterine inflammation has been proposed. We aimed to describe patterns of CLD, to determine the incidence of atypical CLD, and to compare the distribution of various perinatal factors in infants with classic and atypical CLD. Information about demographics, respiratory status and various perinatal variables was collected for all neonatal admissions <1250 g. CLD was defined as oxygen dependency at 28 days of age. Ninety (51%) survivors at 28 days of age developed CLD; of these 37 (41%) were classified as atypical CLD. Factors significantly and independently associated with development of atypical CLD included being inborn, receiving natural surfactant, fewer days of mechanical ventilation within the first 28 days of life and higher birthweight. Chorioamnionitis, postnatal infection and symptomatic PDA were not found to be significantly associated with atypical CLD. Atypical CLD is a common pattern of prolonged oxygen dependency in preterm survivors and is a feature of larger, more mature babies. Our findings do not support the hypothesis that exposure to intrauterine inflammation is an important aetiological factor in the development of atypical CLD.