Survival and Long-Term Outcomes of Children Who Survived after End-of-Life Decisions in a Neonatal Intensive Care Unit.

OBJECTIVE: To investigate long-term outcomes of infants who survive despite life-and-death discussions with families and a decision to withdraw or withhold life-sustaining interventions (WWLST) in one neonatal intensive care unit. STUDY DESIGN: Medical records for neonatal intensive care unit admissions from 2012 to 2017 were reviewed for presence of WWLST discussions or decisions, as well as the 2-year outcome of all children who survived. WWLST discussions were prospectively recorded in a specific book; follow-up to age 2 years was determined by retrospective chart review. RESULTS: WWLST discussions occurred for 266 of 5251 infants (5%): 151 (57%) were born at term and 115 (43%) were born preterm. Among these discussions, 164 led to a WWLST decision (62%) and 130 were followed by the infant's death (79%). Of the 34 children (21%) surviving to discharge after WWLST decisions, 10 (29%) died before 2 years of age and 11 (32%) required frequent medical follow-up. Major functional limitations were common among survivors, but 8 were classified as functionally normal or with mild-to-moderate functional limitations. CONCLUSIONS: When a WWLST decision was made in our cohort, 21% of the infants survived to discharge. By 2 years of age, the majority of these infants had died or had major functional limitations. This highlights the uncertainty of WWLST decisions during neonatal intensive care and the importance of ensuring that parents are informed of all possibilities. Additional studies including longer-term follow-up and ascertaining the family's views will be important.

Guilt and Regret Experienced by Parents of Children Born Extremely Preterm.

OBJECTIVES: To explore decisional regret of parents of babies born extremely preterm and analyze neonatal, pediatric, and parental factors associated with regret. STUDY DESIGN: Parents of infants born <29 weeks of gestational age, aged between 18 months and 7 years, attending neonatal follow-up were enrolled. Hospital records were reviewed to examine morbidities and conversations with parents about levels of care. Parents were asked the following question: "Knowing what you know now, is there anything you would have done differently?" Mixed methods were used to analyze responses. RESULTS: In total, 248 parents (98% participation) answered, and 54% reported they did not have regret. Of those who reported regret (n = 113), 3 themes were most frequently invoked: 35% experienced guilt, thinking they were responsible for the preterm birth; 28% experienced regret about self-care decisions; and 20% regretted decisions related to their parental role, generally wishing they knew sooner how to get involved. None reported regret about life-and-death decisions made at birth or in the neonatal intensive care unit. Impairment at follow-up, gestational age, and decisions about levels/reorientation of care were not associated with regret. More mothers reported feeling guilt about the preterm birth (compared with fathers); parents of children with severe lesions on ultrasonography of the head were less likely to report regret. CONCLUSIONS: Approximately one-half of the parents of infants born extremely preterm had regrets regarding their neonatal intensive care unit stay. Causes of regret and guilt should be addressed and minimized.

Pulmonary important outcomes after extremely preterm birth: Parental perspectives.

AIM: To describe pulmonary important outcomes (PIO) reported by parents of children born extremely preterm. METHODS: Over 1-year, all parents of children aged 18 months-7-years born <29 weeks' GA were asked regarding their perspectives. The proportion of parents who described PIO and the themes they invoked were examined. Results were analysed using mixed methods. RESULTS: Among parental responses (n = 285, 98% participation rate), 44% spoke about PIO, invoking 24 themes pertaining to NICU hospitalisation and/or long-term respiratory health. Some themes had an impact primarily on the child (e.g. exercise limitation), while the majority had an impact on the whole family (e.g. hospital readmissions). None mentioned oxygen at 36 weeks nor bronchopulmonary dysplasia (BPD). The proportion of responses invoking PIO were statistically similar between parents of children with and without BPD, born before or after 25 weeks or with birthweight < or ≥750 g. PIO were more likely to be mentioned in males and among those readmitted for respiratory problems. CONCLUSION: Parents describe many PIO, most related to the functional impact of lung disease on their child (and family), rather than the diagnosis of BPD itself. Most of these PIO are not primary outcomes in large neonatal trials nor collected in neonatal databases.

Gratitude, fragility and strength: Perspectives of adults born preterm about prematurity.

AIM: The aim of the study was to explore how young adults thought that being born preterm had affected their lives. METHODS: Adult participants of a research cohort were questioned about their perspectives. Answers were analysed using mixed methods. RESULTS: Forty-five participants evaluated their health at median score of 8/10. When asked about the meaning of being born preterm, 65% had positive self-centred answers, invoking two main themes: being stronger/'a fighter'/more resilient and being a survivor/chosen; 42% also reported negative themes, such as having health problems and a difficult start. All heard about their prematurity from their parents, 55% with positive child-centred or healthcare system-centred themes, 19% with neutral themes; 35% also heard negative parent-centred themes (tragic experience, guilt, mother's health). When asked which words were associated with prematurity, participants mainly chose positive words for themselves and their family, but more negative words for how the media and society depicted prematurity. Answers were not correlated with adverse objective health measures. CONCLUSION: Participants evaluated their health in a balanced fashion. Preterm-born adults often feel that they have experienced positive transformations as a result of their traumatic start. They often have feelings of gratitude and strength, independent of health problems.

Next generation sequencing in neonatology: what does it mean for the next generation?

Rapid whole genome sequencing (WGS) and whole exome sequencing (WES), sometimes referred to as "next generation sequencing" (NGS) are now recommended by some experts as a first-line diagnostic test to diagnose infants with suspected monogenic conditions. Estimates of how often NGS leads to diagnoses or changes in management vary widely depending on the population being studied and the indications for testing. Finding a genetic variant that is classified as pathogenic may not necessarily equate with being able to predict the resultant phenotype or to give a reliable prognosis. Molecular diagnoses do not usually lead to changes in clinical management but they often end a family's diagnostic Odyssey and allow informed decisions about future reproductive choices. The likelihood that NGS will be beneficial for patients and families in the NICU remains uncertain. The goal of this paper is to highlight the implications of these ambiguities in interpreting the results of NGS. To do that, we will first review the types of cases that are admitted to NICUs and show why, at least in theory, NGS is unlikely to be useful for most NICU patients and families and may even be harmful for some, although it can help families in some cases. We then present a number of real cases in which NGS results were obtained and show that they often lead to unforeseen and unpredictable consequences. Finally, we will suggest ways to communicate with families about NGS testing and results in order to help them understand the meaning of NGS results and the uncertainty that surrounds them.

Avoidance of routine endotracheal intubation and general anesthesia for primary closure of gastroschisis: a systematic review and meta-analysis.

PURPOSE: Over the last few decades, several articles have examined the feasibility of attempting primary reduction and closure of gastroschisis without general anesthesia (GA). We aimed to systematically evaluate the impact of forgoing routine intubation and GA during primary bedside reduction and closure of gastroschisis. METHODS: The primary outcome was closure success. Secondary outcomes were mortality, time to enteral feeding, and length of hospital stay. RESULTS: 12 studies were included: 5 comparative studies totalling 192 patients and 7 descriptive case studies totalling 56 patients. Primary closure success was statistically equivalent between the two groups, but trended toward improved success with GA/intubation (RR = 0.86, CI 0.70-1.03, p = 0.08). Mortality was equivalent between groups (RR = 1.26, CI 0.26-6.08, p = 0.65). With respect to time to enteral feeds and length of hospital stay, outcomes were either equivalent between the two groups or favored the group that underwent primary closure without intubation and GA. CONCLUSION: There are few comparative studies examining the impact of performing primary bedside closure of gastroschisis without GA. A meta-analysis of the available data found no statistically significant difference when forgoing intubation and GA. Foregoing GA also did not negatively impact time to enteral feeds, length of hospital stay, or mortality.

Impact of Deferred Cord Clamping on Mortality and Severe Neurologic Injury in Twins Born at <30 Weeks of Gestation.

OBJECTIVE: To determine whether deferred cord clamping (DCC) compared with early cord clamping (ECC) was associated with reduction in death and/or severe neurologic injury among twins born at <30 weeks of gestation. STUDY DESIGN: We performed a retrospective cohort study including all liveborn twins of <30 weeks admitted to a tertiary-level neonatal intensive care unit (NICU) in Canada between 2015 and 2018 using the Canadian Neonatal/Preterm Birth Network database. We compared DCC ≥30 seconds vs ECC <30 seconds. Our primary outcome was a composite of death and/or severe neurologic injury (severe intraventricular hemorrhage grade III/IV and/or periventricular leukomalacia). Secondary outcomes included neonatal morbidity and health care utilization outcomes. We calculated aORs and ß coefficients for categorical and continuous variables, along with 95% CI. Models were fitted with generalized estimated equations accounting for twin correlation. RESULTS: We included 1597 twins (DCC, 624 [39.1%]; ECC, 973 [60.9%]). Death/severe neurologic injury occurred in 17.8% (n = 111) of twins who received DCC and in 21.7% (n = 211) of those who received ECC. The rate of death/severe neurologic injury did not differ significantly between the DCC and ECC groups (aOR 1.07; 95% CI, 0.78-1.47). DCC was associated with reduced blood transfusions (adjusted ß coefficient, -0.49; 95% CI, -0.86 to -0.12) and NICU length of stay (adjusted ß coefficient, -4.17; 95% CI, -8.15 to -0.19). CONCLUSIONS: The primary composite outcome of death and/or severe neurologic injury did not differ between twins born at <30 weeks of gestation who received DCC and those who received ECC, but DCC was associated with some benefits.

Cerebral oxygen saturation and autoregulation during hypotension in extremely preterm infants.

BACKGROUND: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO2) and autoregulatory capacity (CAR) remains unknown. METHODS: Prospective cohort study of blinded rScO2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO2, mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. RESULTS: In 89 potentially eligible HIP trial patients with rScO2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO2 was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. CONCLUSIONS: Dopamine had no effect on rScO2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. IMPACT: Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

Bovine Lactoferrin Supplementation Does Not Disrupt Microbiota Development in Preterm Infants Receiving Probiotics.

OBJECTIVE: The aim of the study was to assess whether bovine lactoferrin (bLf) supplementation disrupts intestinal microbiota development in preterm infants less than 31 weeks gestational age receiving prophylactic probiotic administration. METHODS: Subjects were recruited from the LACUNA trial (ISRCTN66482337), designed to assess bLf safety. These subjects were randomized to daily receive either probiotic supplements or probiotics supplemented with 100 mg bLf mixed with their feeds (human milk or formula). Stools were collected weekly from enrolled infants for 1 month and the microbiota characterized using V6-16S rRNA gene amplicon profiling. RESULTS: Infants' microbiomes did not increase in alpha diversity over time in both feeding interventions. Infants receiving bLf supplementation had overall higher species richness as compared with those not receiving these supplements and lactoferrin supplementation had differing effects on infant microbiota species richness depending on the infant's gestational age. Principal co-ordinate analysis revealed that the infant microbiotas did not separate by intervention group, gestational age bracket at birth or sampling time and the main factor dictating sample clustering was infant identity. There were very few detectable differences in taxa relative abundance or functional gene content between the microbiotas in the 2 study groups. CONCLUSIONS: Bovine lactoferrin supplementation has minimal impact on microbiota composition/function in preterm infants receiving probiotics, and therefore, is unlikely to disrupt microbiota development.

Building trust and improving communication with parents of children with Trisomy 13 and 18: A mixed-methods study.

BACKGROUND: Trisomy 13 and trisomy 18 are common life-limiting conditions associated with major disabilities. Many parents have described conflictual relationships with clinicians, but positive and adverse experiences of families with healthcare providers have not been well described. AIM: (1) To investigate parental experiences with clinicians and (2) to provide practical recommendations and behaviors clinicians could emulate to avoid conflict. DESIGN: Participants were asked to describe their best and worse experiences, as well as supportive clinicians they met. The results were analyzed using mixed methods. SETTING/PARTICIPANTS: Parents of children with trisomy 13 and 18 who were part of online social support networks. A total of 503 invitations were sent, and 332 parents completed the questionnaire about 272 children. RESULTS: The majority of parents (72%) had met a supportive clinician. When describing clinicians who changed their lives, the overarching theme, present in 88% of answers, was trust. Parents trusted clinicians when they felt he or she cared and valued their child, their family, and made them feel like good parents (69%), had appropriate knowledge (66%), and supported them and gave them realistic hope (42%). Many (42%) parents did not want to make-or be part of-life-and-death decisions. Parents gave specific examples of supportive behaviors that can be adopted by clinicians. Parents also described adverse experiences, generally leading to conflicts and lack of trust. CONCLUSION: Realistic and compassionate support of parents living with children with trisomy 13 and 18 is possible. Adversarial interactions that lead to distrust and conflicts can be avoided. Many supportive behaviors that inspire trust can be emulated.

Lactoferrin infant feeding trial_Canada (LIFT_Canada): protocol for a randomized trial of adding lactoferrin to feeds of very-low-birth-weight preterm infants.

BACKGROUND: In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants. METHOD: Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months. DISCUSSION: Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation. TRIAL REGISTRATION: Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

Prostanoids and their analogues for the treatment of pulmonary hypertension in neonates.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a disease entity that describes a physiology in which there is persistence of increased pulmonary arterial pressure. PPHN is characterised by failure to adapt to a functional postnatal circulation with a fall in pulmonary vascular resistance. PPHN is responsible for impairment in oxygenation and significant neonatal mortality and morbidity. Prostanoids and their analogues may be useful therapeutic interventions due to their pulmonary vasodilatory and immunomodulatory effects. OBJECTIVES: Primary objective• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and the need for extracorporeal membrane oxygenation (ECMO) among neonates with PHSecondary objective• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PHComparisons• Prostanoids and their analogues at any dosage or duration used to treat PPHN versus 'standard treatment without these agents', placebo, or inhaled nitric oxide (iNO) therapy• Prostanoids and their analogues at any dosage or duration used to treat refractory PPHN as an 'add-on' therapy to iNO versus iNO alone SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE via PubMed (1966 to 16 September 2018), Embase (1980 to 16 September 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 16 September 2018). We also searched clinical trials databases, conference proceedings of the Pediatric Academic Societies (1990 to 16 September 2018), and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. We contacted authors who have published in this field as discerned from the reference lists of identified clinical trials and review authors' personal files. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials evaluating prostanoids or their analogues (at any dose, route of administration, or duration) used in neonates at any gestational age less than 28 days' postnatal age for confirmed or suspected PPHN. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal to conduct a systematic review and to assess the methodological quality of included studies (neonatal.cochrane.org/en/index.html). Three review authors independently assessed the titles and abstracts of studies identified by the search strategy and obtained full-text versions for assessment if necessary. We designed forms for trial inclusion or exclusion and for data extraction. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: We did not identify any eligible neonatal trials evaluating prostanoids or their analogues as sole agents in the treatment of PPHN. AUTHORS' CONCLUSIONS: Implications for practiceCurrently, no evidence shows the use of prostanoids or their analogues as pulmonary vasodilators and sole therapeutic agents for the treatment of PPHN in neonates (age 28 days or less).Implications for researchThe safety and efficacy of different preparations and doses and routes of administration of prostacyclins and their analogues in neonates must be established. Well-designed, adequately powered, randomized, multi-center trials are needed to address the efficacy and safety of prostanoids and their analogues in the treatment of PPHN. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes, in addition to short-term outcomes.

Correlations between near-infrared spectroscopy, perfusion index, and cardiac outputs in extremely preterm infants in the first 72 h of life.

Haemodynamic assessment during the transitional period in preterm infants is challenging. We aimed to describe the relationships between cerebral regional tissue oxygen saturation (CrSO2), perfusion index (PI), echocardiographic, and clinical parameters in extremely preterm infants in their first 72 h of life. Twenty newborns born at < 28 weeks of gestation were continuously monitored with CrSO2 and preductal PI. Cardiac output was measured at H6, H24, H48, and H72. The median gestational age and birth weight were 25.0 weeks (24-26) and 750 g (655-920), respectively. CrSO2 and preductal PI had r values < 0.35 with blood gases, lactates, haemoglobin, and mean blood pressure. Cardiac output significantly increased over the 72 h of the study period. Fifteen patients had at least one episode of low left and/or right ventricular output (RVO), during which there was a strong correlation between CrSO2 and superior vena cava (SVC) flow (at H6 (r = 0.74) and H24 (r = 0.86)) and between PI and RVO (at H6 (r = 0.68) and H24 (r = 0.92)). Five patients had low SVC flow (≤ 40 mL/kg/min) at H6, during which PI was strongly correlated with RVO (r = 0.98). CONCLUSION: CrSO2 and preductal PI are strongly correlated with cardiac output during low cardiac output states. What is Known: • Perfusion index and near-infrared spectroscopy are non-invasive tools to evaluate haemodynamics in preterm infants. • Pre- and postductal perfusion indexes strongly correlate with left ventricular output in term infants, and near-infrared spectroscopy has been validated to assess cerebral oxygenation in term and preterm infants. What is New: • Cerebral regional tissue oxygen saturation and preductal perfusion index were strongly correlated with cardiac output during low cardiac output states. • The strength of the correlation between cerebral regional tissue oxygen saturation, preductal perfusion index, and cardiac output varied in the first 72 h of life, reflecting the complexity of the transitional physiology.

Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death?

OBJECTIVE: The aim was to compare survival of patients with septic shock receiving or not hydrocortisone (HC) and to analyze the hemodynamic response to HC. STUDY DESIGN: It is a retrospective study of 62 premature neonates with septic shock (confirmed bacteremia) and/or necrotizing enterocolitis (NEC) stage 2 and above receiving inotropes with or without HC. We analyzed survival and hemodynamic response to HC. RESULTS: Thirty-nine (63%) premature neonates received HC and were compared with 23 (37%) who only received inotropes. Vasoactive index score (VAI) decreased and blood pressure, urine output, and oxygen requirements improved significantly following HC. Despite receiving more inotropes (VAI of 33 [20-53] vs 10 [8-20], p < 0.001), being more premature (26 ± 2 vs 27 ± 2 weeks, p = 0.02) and more frequently having NEC (64 vs 26%, p = 0.004), patients who received HC had similar survival from septic episode (death: 22% vs 41%, p = 0.12). However, patients receiving HC during their sepsis were less likely to survive at their 1-year postmenstrual age follow-up when accounted for gestational age (GA) at birth and duration of inotropes (hazard ratio 6.08 p = 0.01). CONCLUSION: HC was used in infants with increased inotropic support. HC during septic shock was associated with similar survival from episode, but with decreased survival at 1-year postmenstrual age.

Inhaled nitric oxide for respiratory failure in preterm infants.

BACKGROUND: Inhaled nitric oxide (iNO) is effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure and the potential risks of iNO differ substantially in preterm infants, necessitating specific study in this population. OBJECTIVES: To determine effects of treatment with inhaled nitric oxide (iNO) on death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH) or other serious brain injury and on adverse long-term neurodevelopmental outcomes in preterm newborn infants with hypoxic respiratory failure.Owing to substantial variation in study eligibility criteria, which decreases the utility of an overall analysis, we divided participants post hoc into three groups: (1) infants treated over the first three days of life because of defects in oxygenation, (2) preterm infants with evidence of pulmonary disease treated routinely with iNO and (3) infants treated later (after three days of age) because of elevated risk of BPD. SEARCH METHODS: We used standard methods of the Cochrane Neonatal Review Group. We searched MEDLINE, Embase, Healthstar and the Cochrane Central Register of Controlled Trials in the Cochrane Library through January 2016. We also searched the abstracts of the Pediatric Academic Societies. SELECTION CRITERIA: Eligible for inclusion were randomised and quasi-randomised studies in preterm infants with respiratory disease that compared effects of iNO gas versus control, with or without placebo. DATA COLLECTION AND ANALYSIS: We used standard methods of the Cochrane Neonatal Review Group and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: We found 17 randomised controlled trials of iNO therapy in preterm infants. We grouped these trials post hoc into three categories on the basis of entry criteria: treatment during the first three days of life for impaired oxygenation, routine use in preterm babies along with respiratory support and later treatment for infants at increased risk for bronchopulmonary dysplasia (BPD). We performed no overall analyses.Eight trials providing early rescue treatment for infants on the basis of oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD (typical risk ratio (RR) 0.94, 95% confidence interval (CI) 0.87 to 1.01; 958 infants). Four studies examining routine use of iNO in infants with pulmonary disease reported no significant reduction in death or BPD (typical RR 0.94, 95% CI 0.87 to 1.02; 1924 infants), although this small effect approached significance. Later treatment with iNO based on risk of BPD (three trials) revealed no significant benefit for this outcome in analyses of summary data (typical RR 0.92, 95% CI 0.85 to 1.01; 1075 infants).Investigators found no clear effect of iNO on the frequency of all grades of IVH nor severe IVH. Early rescue treatment was associated with a non-significant 20% increase in severe IVH.We found no effect on the incidence of neurodevelopmental impairment. AUTHORS' CONCLUSIONS: iNO does not appear to be effective as rescue therapy for the very ill preterm infant. Early routine use of iNO in preterm infants with respiratory disease does not prevent serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD could be effective, but current 95% confidence intervals include no effect; the effect size is likely small (RR 0.92) and requires further study.

Fluid restriction for treatment of preterm infants with chronic lung disease.

BACKGROUND: Fluid restriction is often recommended as part of the management of infants with early or established bronchopulmonary dysplasia (BPD). OBJECTIVES: To determine whether fluid restriction as part of the therapeutic intervention for early or established BPD improves clinical outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1) in the Cochrane Library (searched 16 February 2016), MEDLINE via PubMed (1966 to 16 February 2016), Embase (1980 to 16 February 2016), and CINAHL (1982 to 16 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Prospective randomised clinical trials comparing two distinct fluid administration volumes in preterm infants with early or established BPD. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. For the included trial, we extracted data and assessed the risk of bias, and used GRADE methods to assess the quality of the evidence. The outcomes considered in this review are effects on mortality or requirement for oxygen at 36 weeks' postmenstrual age (primary outcome measure), the duration of supplemental oxygen therapy, proportion of infants discharged from hospital on oxygen, duration of assisted ventilation, duration of hospitalisation, weight gain, feeding tolerance, apnoea, necrotizing enterocolitis, renal dysfunction or nephrocalcinosis, lung mechanics, and use of diuretic therapy (secondary outcome measures). MAIN RESULTS: One trial was found, including 60 preterm infants at 28 days of age with persistent oxygen requirements. Infants were randomised to either 180 mL/kg/day of standard formula or 145 mL/kg/day of concentrated formula. This single study did not provide data regarding our primary outcome. No effects of the intervention were found on any of our secondary outcomes. The quality of the evidence from this study was graded low. AUTHORS' CONCLUSIONS: There is no evidence to support the practice of fluid restriction in infants with early or established BPD.

Nitric oxide for respiratory failure in infants born at or near term.

BACKGROUND: Nitric oxide (NO) is a major endogenous regulator of vascular tone. Inhaled nitric oxide (iNO) gas has been investigated as treatment for persistent pulmonary hypertension of the newborn. OBJECTIVES: To determine whether treatment of hypoxaemic term and near-term newborn infants with iNO improves oxygenation and reduces rate of death and use of extracorporeal membrane oxygenation (ECMO), or affects long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE via PubMed (1966 to January 2016), Embase (1980 to January 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 2016). We searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We contacted the principal investigators of studies published as abstracts to ascertain the necessary information. SELECTION CRITERIA: Randomised studies of iNO in term and near-term infants with hypoxic respiratory failure, with clinically relevant outcomes, including death, use of ECMO and oxygenation. DATA COLLECTION AND ANALYSIS: We analysed trial reports to assess methodological quality using the criteria of the Cochrane Neonatal Review Group. We tabulated mortality, oxygenation, short-term clinical outcomes (particularly use of ECMO) and long-term developmental outcomes. STATISTICS: For categorical outcomes, we calculated typical estimates for risk ratios and risk differences. For continuous variables, we calculated typical estimates for weighted mean differences. We used 95% confidence intervals and assumed a fixed-effect model for meta-analysis. MAIN RESULTS: We found 17 eligible randomised controlled studies that included term and near-term infants with hypoxia.Ten trials compared iNO versus control (placebo or standard care without iNO) in infants with moderate or severe severity of illness scores (Ninos 1996; Roberts 1996; Wessel 1996; Davidson 1997; Ninos 1997; Mercier 1998; Christou 2000; Clark 2000; INNOVO 2007; Liu 2008). Mercier 1998 compared iNO versus control but allowed back-up treatment with iNO for infants who continued to satisfy the same criteria for severity of illness after two hours. This trial enrolled both preterm and term infants but reported most results separately for the two groups. Ninos 1997 studied only infants with congenital diaphragmatic hernia.One trial compared iNO versus high-frequency ventilation (Kinsella 1997).Six trials enrolled infants with moderate severity of illness scores (oxygenation index (OI) or alveolar-arterial oxygen difference (A-aDO2)) and randomised them to immediate iNO treatment or iNO treatment only after deterioration to more severe criteria (Barefield 1996; Day 1996; Sadiq 1998; Cornfield 1999; Konduri 2004; Gonzalez 2010).Inhaled nitric oxide appears to have improved outcomes in hypoxaemic term and near-term infants by reducing the incidence of the combined endpoint of death or use of ECMO (high-quality evidence). This reduction was due to a reduction in use of ECMO (with number needed to treat for an additional beneficial outcome (NNTB) of 5.3); mortality was not affected. Oxygenation was improved in approximately 50% of infants receiving iNO. The OI was decreased by a (weighted) mean of 15.1 within 30 to 60 minutes after the start of therapy, and partial pressure of arterial oxygen (PaO2) was increased by a mean of 53 mmHg. Whether infants had clear echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) did not appear to affect response to iNO. Outcomes of infants with diaphragmatic hernia were not improved; outcomes were slightly, but not significantly, worse with iNO (moderate-quality evidence).Infants who received iNO at less severe criteria did not have better clinical outcomes than those who were enrolled but received treatment only if their condition deteriorated. Fewer of the babies who received iNO early satisfied late treatment criteria, showing that earlier iNO reduced progression of the disease but did not further decrease mortality nor the need for ECMO (moderate-quality evidence). Incidence of disability, incidence of deafness and infant development scores were all similar between tested survivors who received iNO and those who did not. AUTHORS' CONCLUSIONS: Inhaled nitric oxide is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia.

The Impact of Neonatal Simulations on Trainees' Stress and Performance: A Parallel-Group Randomized Trial.

OBJECTIVES: Assess impact of neonatal simulation and simulated death on trainees' stress and performance. DESIGN: A parallel-group randomized trial (November 2011 to April 2012). SETTING: Sainte-Justine University Hospital, Montreal, Canada. SUBJECTS: Sixty-two pediatric trainees eligible, 59 consented, and 42 completed the study. INTERVENTIONS: Trainees performed two simulations where a term neonate was born pulseless. They were randomized to start with either survival (manikin responded to appropriate resuscitation) or death scenario (manikin remained pulseless despite resuscitation). MEASUREMENTS AND MAIN RESULTS: Performance was assessed using the Neonatal Resuscitation Program megacode score sheet by two reviewers. Subjective stress was assessed with a questionnaire. Three salivary cortisol (objective stress) values were compared: at baseline (T0: during lecture), presimulation (T1), and postsimulation (T2: after first scenario). Performance scores were similar in both groups in the first (83% vs 82%; p = 0.85) and second scenarios (82% vs 79 %; p = 0.87). Salivary cortisol levels at T0 (0.10 vs 0.10; p = 0.54), T1 (0.15 vs 0.11; p = 0.35), and T2 (0.23 vs 0.17; p = 0.23) did not differ between groups. Perceived stress level was six out of 10 in survival group versus seven out of 10 in death group (p = 0.19). Salivary cortisol increased significantly from T0 to T1 (p < 0.01). T2 cortisol levels were significantly higher than T1 (p< 0.001), yet this increase was not scenario dependent (p = 0.41) nor associated with performance on either scenario. Subscores for bag mask ventilation were lower than subscores for advanced resuscitation skills. CONCLUSIONS: Neonatal simulations cause significant anticipatory and participatory stress. Despite this, trainees' performance score in simulation was over 80%. Simulated death did not impact performance, magnitude of rise in salivary cortisol level, and perceived stress level. Trainees performed better at advanced resuscitation skills (which are rarely needed) compared with basic skills routinely performed in practice.

Changes in perinatal hospital deaths occurring outside the neonatal intensive care unit over a decade.

AIM: Perinatal deaths occurring outside the neonatal intensive care unit (NICU) are rarely recorded in outcome studies, despite having a direct impact on perinatal statistics. Our aim was to investigate the timing and modes of perinatal deaths that occurred outside the NICU and changes over time. METHOD: We reviewed all perinatal deaths from 22 weeks of gestation onwards, without NICU admissions, during two periods in a Canadian tertiary mother and baby hospital and categorised deaths according to nine specific categories. RESULTS: There were 444 perinatal deaths that satisfied the inclusion criteria. The total number of perinatal deaths increased from 2000 to 2002 (n = 197) and 2007 to 2010 (n = 247). The proportion of foetuses alive at the time of their mother's hospital admission, but then stillborn, decreased. There was a significant increase in terminations for congenital anomalies in the second cohort and a decrease in deaths following induction of labour and comfort care for foetal anomalies. CONCLUSION: Approaches to end-of-life care changed between the two study periods. Paediatricians should be aware of the epidemiology of perinatal mortality in their own practice, as it has a direct impact on the denominator in NICU outcome studies.