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SMOFlipid Protects Preterm Neonates against Perinatal Nutrition–Associated Cholestasis


DOI: 10.1055/s-0038-1676977
Background Intravenous lipid infusions improve both short- and long-term outcomes of premature neonates. However, prolonged infusion of lipids has been implicated in the development of parenteral nutrition-associated cholestasis (PNAC). We speculated that the multicomponent SMOFlipid would be hepatoprotective against PNAC.

Study Design This is a retrospective review comparing the incidence and severity of direct hyperbilirubinemia in preterm infants <1,500 g who were hospitalized for a minimum of 2 weeks during a 20-month period in which all preterm infants on total parenteral nutrition (TPN) received fat as Lipofundin with the following 20-month period in which all preterm infants on TPN received SMOFlipid.

Results Infants in the SMOFlipid period had a lower incidence of PNAC (6 vs. 13%; p = 0.022), lower peak direct bilirubin levels (3.2 vs. 7.1 mg/dL; p = 0.018), and a shorter length of stay (51 vs. 60 days; p = 0.019). The relative risk of developing direct hyperbilirubinemia during the Lipofundin period was 2.22 (1.1–4.3) as compared with period 1; p = 0.018; NNT-14.

Conclusion SMOFlipid was hepatoprotective in our population of preterm neonates <1,500 g receiving long-term TPN as compared with those receiving Lipofundin, despite similar levels of exposure to both intravenous lipid load and duration in the two groups.


Preventing Continuous Positive Airway Pressure Failure: Evidence-Based and Physiologically Sound Practices from Delivery Room to the Neonatal Intensive Care Unit


DOI: 10.1016/j.clp.2018.01.011
The incidence of bronchopulmonary dysplasia, and the competing outcomes death or bronchopulmonary dysplasia, is decreased with early initiation of nCPAP.  The best available evidence supports the premise that efforts to minimize CPAP failure start in the delivery room.  Various modes and interfaces to deliver CPAP exist; although there may be considerable differences in the ability of these various CPAP devices to prevent failure, little data from RCT exist to support this.


Optimizing Caffeine Use and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review, Meta-analysis, and Application of Grading of Recommendations Assessment, Development, and Evaluation Methodology


DOI: 10.1016/j.clp.2018.01.012
Earlier initiation of caffeine, compared to later initiation, is associated with a decreased risk of bronchopulmonary dysplasia.  High-dose caffeine, compared to standard-dose caffeine, may reduce the risk of bronchopulmonary dysplasia.  The overall quality of evidence of studies on the dose and timing of caffeine and risk of bronchopulmonary dysplasia is low.  Higher-quality evidence is needed to understand the risks and benefits of early initiation and high-dose caffeine to decrease the risk of bronchopulmonary dysplasia.


Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review


DOI: 10.1136/archdischild-2017-313418
Objective Binasal prongs are the most commonly used interface for the delivery of nasal positive airway pressure (CPAP) to preterm infants. However, they are associated with pressure-related nasal injury, which causes pain and discomfort. Nasal injury may necessitate a change in interface and occasionally damage is severe enough to require surgical repair. We aim to determine the incidence and risk factors for nasal injury in preterm infants, and to provide clinicians with strategies to effectively prevent and treat it.
Design We conducted a systematic search of databases including MEDLINE (PubMed including the Cochrane Library), EMBASE, CINAHL and Scopus. Included studies enrolled human preterm infants and were published prior to 20 February 2017.
Results Forty-five studies were identified, including 14 ra ndomised controlled trials, 10 observational studies, two cohort studies, eight case reports and 11 reviews. The incidence of nasal injury in preterm infants ranged from 20–100%.
Conclusions and relevance Nasal injury is common in preterm infants born <30 weeks’ gestational age receiving CPAP via binasal prongs. Larger randomised trials are required to fully evaluate strategies to reduce nasal injury.


Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis


DOI: 10.1136/archdischild-2015-310299
Context In spontaneously breathing preterm infants with respiratory distress syndrome (RDS) receiving nasal continuous positive airway pressure, a method of less invasive surfactant administration (LISA) using a thin catheter has been described as an alternative to endotracheal intubation for surfactant delivery to reduce lung injury.
Objective A systematic review of randomised controlled trials (RCTs) comparing LISA with the standard method of surfactant delivery for clinical outcomes. Methods Medline, CENTRAL and Embase databases were searched (until 29 October 2015). Additional citations were identified from trial registries, conference proceedings and the bibliographies of selected articles. The included studies were RCTs enrolling preterm infants with RDS and compared LISA technique with intubation for surfactant delivery for any of the prespecified clinical outcomes.
Results Six RCTs were identified, enrolling a total of 895 infants. The use of LISA technique reduced the composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks (risk ratio (RR)=0.75 (95% CI 0.59 to 0.94), p=0.01), BPD36 among survivors (RR=0.72 (0.53 to 0.97), p=0.03), need for mechanical ventilation within 72 hours of birth (RR=0.71 (0.53 to 0.96), p=0.02) or need for mechanical ventilation anytime during the neonatal intensive care unit stay (RR=0.66 (0.47 to 0.93), p=0.02). There were no differences noted for the outcome of death and other neonatal morbidities. Procedure failure rate on the first attempt and the need for additional doses of surfactant were not different between the intervention groups.
Conclusions LISA technique for surfactant delivery results in a lesser need for mechanical ventilation in infants with RDS, reduction in the composite outcome of death or BPD at 36 weeks, and BPD36 among survivors.


Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis


DOI: 10.1136/archdischild-2017-313759
Objective To determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.
Study design We systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers independently selected randomised controlled trials (RCTs) of postnatal corticosteroids in preterm infants. A Bayesian network meta-analysis and subgroup analyses were performed.
Results We included 47 RCTs with 6747 participants. The use of dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.29, 95% credible interval (CrI) 0.14 to 0.52; OR 0.58, 95% CrI 0.39 to 0.76, respectively). High-dose dexamethasone was more effective than hydrocortisone, beclomethasone and low-dose dexamethasone. Early and long-term dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.11, 95% CrI 0.02 to 0.4; OR 0.37, 95% CrI 0.16 to 0.67, respectively). There were no statistically significant differences in the risk of cerebral palsy (CP) between different corticosteroids. However, high-dose and long-term dexamethasone ranked lower than placebo and other regimens in terms of CP. Subgroup analyses indicated budesonide was associated with a decreased risk of BPD in extremely preterm and extremely low birthweight infants (OR 0.60, 95% CrI 0.36 to 0.93).
Conclusions Dexamethasone can reduce the risk of BPD in preterm infants. Of the different dexamethasone regimens, aggressive initiation seems beneficial, while a combination of high-dose and long-term use should be avoided because of the possible adverse neurodevelopmental outcome. Dexamethasone and inhaled corticosteroids need to be further evaluated in large-scale RCTs with long-term follow-ups.

Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and metaanalysis


DOI: 10.1136/archdischild-2017-314046
Background Systemic corticosteroids as the frontline treatment of respiratory distress syndrome (RDS) in preterm infants are associated with adverse effects on growth and neurodevelopmental outcome, but the pulmonary administration of steroids may help prevent the development of bronchopulmonary dysplasia (BPD) without these side effects.

Objectives To evaluate the efficacy and safety of pulmonary application of corticosteroids in preterm infants with RDS.

Conclusions Pulmonary administration of corticosteroids reduces the incidence of BPD or death, pneumonia, PDA without causing any major side effects in preterm infants with RDS.


Prevention of bronchopulmonary dysplasia in extremely low gestational age neonates: current evidence


DOI: 10.1136/archdischild-2017-314264
Bronchopulmonary dysplasia (BPD) is one of the most frequent complications in extremely low gestational age neonates, but has remained largely unchanged in rate. We reviewed data on BPD prevention focusing on recent meta-analyses. Interventions with proven effectiveness in reducing BPD include the primary use of non-invasive respiratory support, the application of surfactant without endotracheal ventilation and the use of volume-targeted ventilation in infants requiring endotracheal intubation. Following extubation, synchronised nasal ventilation is more effective than continuous positive airway pressure in reducing BPD. Pharmacologically, commencing caffeine citrate on postnatal day 1 or 2 seems more effective than a later start. Applying intramuscular vitamin A for the first 4 weeks reduces BPD, but is expensive and painful and thus not widely used. Low-dose hydrocortisone for the first 10 days prevents BPD, but was associated with almost twice as many cases of late-onset sepsis in infants born at 24–25 weeks’ gestation. Inhaled corticosteroids, despite reducing BPD, were associated with a higher mortality rate. Administering dexamethasone to infants still requiring mechanical ventilation around postnatal weeks 2–3 may represent the best trade-off between restricting steroids to infants at risk of BPD while still affording high efficacy. Finally, identifying infants colonised with ureaplasma and treating those requiring intubation and mechanical ventilation with azithromycin is another promising approach to BPD prevention. Further interventions yet only backed by cohort studies include exclusive breastmilk feeding and a better prevention of nosocomial infections.


Ending the Culture of Culture-Negative Sepsis in the Neonatal ICU


DOI: 10.1542/peds.2017-0044
Sepsis is a major cause of morbidity and mortality among infants in the NICU. Because septic infants present with nonspecific clinical findings, providers are justifiably concerned about missing sepsis. Blood cultures are the gold standard for diagnosis of sepsis, and when adequate volumes are obtained, cultures have excellent sensitivity even when the infant has very low levels of bacteremia.1 However, many providers view sterile culture results with skepticism, especially when the infant appears ill or received antibiotics before cultures were obtained. Therefore, we have developed a culture (no pun intended) of acceptance in treating “culture-negative” sepsis. Recent reports suggest that up to 10 times as much antibiotic is used for culture-negative sepsis as for culture-proven sepsis.2,3 This practice must stop. The evidence for unintended harm caused by prolonged or unnecessary antibiotic exposure continues to mount and includes increased risk for obesity, atopy, and, for preterm infants, necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia, and death.4 Why then do providers view sterile cultures with such skepticism?
The first reason is that providers have all-too-frequent experiences with cultures that are obtained incorrectly. Blood cultures collected inappropriately cannot be trusted, but such cultures, unfortunately, are a common problem. The recommendation is that a minimum of 1 mL of blood, either in 1 culture or divided into 2 0.5 mL cultures, be obtained from infants …



DOI: 10.1016/S0140-6736(17)31444-7

Background Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment.
Methods We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with, number NCT00854932.
Findings Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI −4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (−5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group).
Interpretation Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death.
Funding The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.