Cardiopulmonary Function Abnormalities in Cohort of Adults following Bronchopulmonary Dysplasia as Preterm Infants.

OBJECTIVE: This study was aimed to describe the cardiopulmonary profiles of adult patients with bronchopulmonary dysplasia (BPD), comparing them to normative adult values. STUDY DESIGN: This study presents a retrospective chart review of all BPD patients followed in the adult BPD clinic, identified from institutional and archive databases, born preterm at ≤33 weeks of estimated gestational age (EGA) between January 1980 and December 2000. RESULTS: Forty-four patients with BPD (26.4 ± 2.7 weeks of EGA) were included. Average age at follow-up was 19 years. Majority (61.4%) of the patients had a diagnosis of asthma. Mean spirometry values were: first second of forced expiration (FEV1) 74.1%, forced vital capacity (FVC) 80.7%, and FEV1/FVC 82.5%. Echocardiography (ECHO) images were reviewed, left ventricular (LV) structure and performance did not differ between obstructive and nonobstructive pulmonary function test (PFT) groups, but values of LV longitudinal strain were 4.8% lower than expected normal for adults. Patients with obstructive PFT had additional decreased right ventricular (RV) function by ECHO. CONCLUSION: BPD patients in this study were found to have a burden of cardiorespiratory alterations that persisted into adulthood, with RV performance abnormalities found among patients with obstructive PFT. KEY POINTS: · BPD patients born at extremes of prematurity have cardiorespiratory alterations in adulthood.. · Among patients with obstructive lung function, subtle cardiac performance abnormalities were found.. · Future directions should include systematic follow-up of premature newborns with BPD..

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.

Serratia marcescens Outbreak in a Neonatal Intensive Care Unit: New Insights from Next-Generation Sequencing Applications.

Serratia marcescens is an environmental bacterium that is commonly associated with outbreaks in neonatal intensive care units (NICUs). Investigations of S. marcescens outbreaks require efficient recovery and typing of clinical and environmental isolates. In this study, we investigated how the use of next-generation sequencing applications, such as bacterial whole-genome sequencing (WGS) and bacterial community profiling, could improve S. marcescens outbreak investigations. Phylogenomic links and potential antibiotic resistance genes and plasmids in S. marcescens isolates were investigated using WGS, while bacterial communities and relative abundances of Serratia in environmental samples were assessed using sequencing of bacterial phylogenetic marker genes (16S rRNA and gyrB genes). Typing results obtained using WGS for the 10 S. marcescens isolates recovered during a NICU outbreak investigation were highly consistent with those obtained using pulsed-field gel electrophoresis (PFGE), the current standard typing method for this bacterium. WGS also allowed the identification of genes associated with antibiotic resistance in all isolates, while no plasmids were detected. Sequencing of the 16S rRNA and gyrB genes both showed greater relative abundances of Serratia at environmental sampling sites that were in close contact with infected babies. Much lower relative abundances of Serratia were observed following disinfection of a room, indicating that the protocol used was efficient. Variations in the bacterial community composition and structure following room disinfection and among sampling sites were also identified through 16S rRNA gene sequencing. Together, results from this study highlight the potential for next-generation sequencing tools to improve and to facilitate outbreak investigations.

Pathophysiology, screening and diagnosis of pulmonary hypertension in infants with bronchopulmonary dysplasia - A review of the literature.

Bronchopulmonary dysplasia (BPD) is a common complication of extreme prematurity, which has increased over the last 20 years. BPD is associated with increased morbidities and mortality. It has been increasingly recognized that BPD affects overall lung development including the pulmonary vasculature. More recent studies have demonstrated an increased awareness of pulmonary arterial hypertension (PH) in BPD patients and recent international guidelines have advocated for better screening. This review will describe the current understanding of the pathophysiology of PH in infants with BPD, the in-depth assessment of the available literature linking PH and BPD, and propose an approach of screening and diagnosis of PH in infants with BPD.

Do transport factors increase the risk of severe brain injury in outborn infants <33 weeks gestational age?

OBJECTIVE: We evaluated transport factors and postnatal practices to identify modifiable risk factors for SBI. STUDY DESIGN: Retrospective review of Canadian Neonatal Transport Network data linked to Canadian Neonatal Network data for outborns <33 weeks gestational age (GA), during January 2014 to December 2015. SBI was defined as grade 3 or 4 intraventricular hemorrhage or parenchymal echogenicity, including hemorrhagic and/or ischemic lesions. RESULT: Among 781 infants, 115 (14.7%) had SBI with range 5.6-40% among transport teams. In multivariable analysis, SBI was associated with GA [0.77 (0.71, 0.85)] per week, receipt of chest compressions and/or epinephrine at delivery [1.81 (1.08, 3.05)] and receipt of fluid boluses [1.61 (1.00, 2.58)]. CONCLUSIONS: Risk factors for SBI were related to the condition at birth and immediate postnatal management and not related to transport factors. These results highlight the importance of maternal transfer to perinatal centers to allow optimization of perinatal management.

Bacillus cereus infection in neonates and the absence of evidence for the role of banked human milk: Case reports and literature review.

BACKGROUND: Banked human milk (BHM) has inherent infectious risks, even when pasteurized. Because of the ubiquity of Bacillus cereus in the environment and its ability to resist the Holder pasteurization process, there is a concern that BHM might lead to severe B. cereus infections. OBJECTIVE: We reviewed observed and published cases to determine the potential causal role of BHM as the source of these infections. METHODS: Two infants in the province of Québec (Canada) developed a B. cereus neonatal infection, and both had received BHM. We conducted bacteriological studies to compare clinical isolates and those found in these cases. RESULTS: After extended culture of BHM retention lots, B. cereus was found to have been involved in batches related to the first case. However, molecular typing showed that the strain was different from the clinical isolate, therefore excluding BHM as the source of contamination. In the second case, a Brevibacillus spp was isolated, a species distinct from the clinical isolate. CONCLUSION: Based on these cases and others reported in the literature, a causal link between B. cereus contaminated BHM and preterm neonatal infection has never been documented. Therefore, the risk that BHM can cause this infection remains theoretical. Given the widespread presence of B. cereus in the hospital environment and its capacity to resist standard cleaning procedures, it seems likely that airborne or direct or indirect contact are the main sources of most, if not all, cases of severe B. cereus neonatal infections, even in babies exposed to BHM.

Evaluation of pentavalent rotavirus vaccination in neonatal intensive care units.

BACKGROUND & OBJECTIVES: Preterm infants are at highest risk for severe rotavirus gastroenteritis. While rotavirus vaccination is recommended for age-eligible, clinically stable preterm infants, controversy exists regarding vaccination of these infants during hospitalization. The objectives of this study were to examine tolerance of pentavalent rotavirus vaccination (RV5) among hospitalized infants and nosocomial rotavirus transmission in the neonatal intensive care units (NICU) at two urban hospitals. METHODS: A retrospective, medical chart review of patients receiving RV5 vaccine was conducted to examine clinical histories of vaccine recipients. Average risk differences of gastrointestinal complications were estimated between the three days prior and up to four weeks following RV5 vaccination. A generalized linear regression model was used to examine the association between days since RV5 administration and daily feeding totals, using fixed effects to account for individual-level clustering. Rates of nosocomial rotavirus from active surveillance were compared between pre- and post-NICU-based vaccination periods. RESULTS: From July 1, 2011 to March 30, 2013, RV5 vaccination was initiated for 102 NICU patients. No changes in the average risk of gastrointestinal complications or daily feeding among participants overall were detected following RV5 administration. Rates of nosocomial rotavirus were similar during the periods before and after NICU-based vaccination. CONCLUSIONS: On average, RV5 appeared to be well tolerated among vaccine recipients, with no increase in nosocomial rotavirus transmission observed following NICU-based rotavirus vaccination. While the benefits of a RV5 NICU-based vaccination program for otherwise eligible preterm infants seem to outweigh the possible risk of vaccine virus transmission, further studies are needed.

Chlorhexidine bathing in a tertiary care neonatal intensive care unit: impact on central line-associated bloodstream infections.

BACKGROUND: Despite implementation of recommended best practices, our central line-associated bloodstream infection (CLABSI) rates remained high. Our objective was to describe the impact of chlorhexidine gluconate (CHG) bathing on CLABSI rates in neonates. METHODS: Infants with a central venous catheter (CVC) admitted to the neonatal intensive care unit from April 2009 to March 2013 were included. Neonates with a birth weight of 1,000 g or less, aged less than 28 days, and those with a birth weight greater than 1,000 g were bathed with mild soap until March 31, 2012 (baseline), and with a 2% CHG-impregnated cloth starting on April 1, 2012 (intervention). Infants with a birth weight of 1,000 g or less, aged 28 days or more, were bathed with mild soap during the entire period. Neonatal intensive care unit nurses reported adverse events. Adjusted incidence rate ratios (aIRRs), using Poisson regression, were calculated to compare CLABSIs/1,000 CVC-days during the baseline and intervention periods. RESULTS: Overall, 790 neonates with CVCs were included in the study. CLABSI rates decreased during the intervention period for CHG-bathed neonates (6.00 vs 1.92/1,000 CVC-days; aIRR, 0.33 [95% confidence interval (CI), 0.15-0.73]) but remained unchanged for neonates with a birth rate of 1,000 g or less and aged less than 28 days who were not eligible for CHG bathing (8.57 vs 8.62/1,000 CVC-days; aIRR, 0.86 [95% CI, 0.17-4.44]). Overall, 195 infants with a birth weight greater than 1,000 g and 24 infants with a birth weight of 1,000 g or less, aged 28 days or more, were bathed with CHG. There was no reported adverse event. CONCLUSIONS: We observed a decrease in CLABSI rates in CHG-bathed neonates in the absence of observed adverse events. CHG bathing should be considered if CLABSI rates remain high, despite the implementation of other recommended measures.

Transitioning from stiff chest tubes to soft pleural catheters: prospective assessment of a practice change.

BACKGROUND: Tube thoracostomies in children are required for multiple indications and can be associated with significant discomfort. In 2010, a multidisciplinary team at our institution developed a protocol to replace stiff chest tubes with 8.5-French soft pleural catheters in children requiring pleural drainage. METHODS: Before initiating the protocol, an audit sheet was developed to prospectively capture data regarding insertion, removal, complications, and success. After 8 months of new protocol utilization, these data were reviewed, along with a retrospective review of the patients' charts. RESULTS: Twenty-three patients had 33 pleural catheters inserted over an 8-month period. Mean age was 6.7 years (1 day to 17 years). Indications for insertion were pneumothorax (24%), simple effusion (24%), chylothorax (27%), parapneumonic effusion/empyema (21%), and malignant effusion (3%). Complications included premature dislodgment (33%), blockage (15%), pneumothorax (3%), and bleeding (3%). Mean duration of pleural drainage was 7.27 days (0 to 37 days). Pleural drainage was successful in 91% of patients. CONCLUSION: Soft pleural catheters are an acceptable alternative to traditional stiff chest tubes in the pediatric population. Premature dislodgment was the most common problem. Prospective audits are extremely valuable in assessing new procedural protocols and practice changes.

Neurologic outcome at school entry for newborns treated with extracorporeal membrane oxygenation for noncardiac indications.

The neurologic outcomes at school age in children who underwent neonatal extracorporeal membrane oxygenation for noncardiac indications in a single institution surviving till the age of 5 years was determined by standardized neurologic assessment. Of 42 newborns undergoing extracorporeal membrane oxygenation, 24 underwent neurologic assessment by a single neurologist at 5 years of age. In all, 12 (50%) had a normal neurologic outcome. Lower gestational age and birth weight was found to be associated with an abnormal outcome as was septic shock as an indication for extracorporeal membrane oxygenation initiation. The number of peri-extracorporeal membrane oxygenation complications experienced by a child was associated with later epilepsy. Although invasive and implemented in critically ill infants, half of newborns undergoing extracorporeal membrane oxygenation will have a normal neurologic outcome at school age. Preexisting factors, rather than factors related to the extracorporeal membrane oxygenation itself, appear to be greater determinants of later neurologic outcomes.

Changes in expression of vascular endothelial growth factor and its receptors in neonatal hypoxia-induced pulmonary hypertension.

Vascular endothelial growth factor (VEGF) is a potent mitogen with angiogenic and vasoactive properties. VEGF can bind to two types of receptors. VEGF receptor 2 (VEGFR2) is mainly responsible for the dilator response to VEGF through nitric oxide (NO) release, whereas VEGFR1 may sequestrate the ligand. We hypothesized that in neonatal hypoxia-induced pulmonary hypertension, VEGF vasodilation is reduced. The dilator response to VEGF was assessed in isolated perfused lung of 1-d-old piglets that were exposed to either normoxia or hypoxia (fraction of inspired oxygen 0.10) for 14 d. The plasma and pulmonary artery concentration of VEGF was measured by quantitative sandwich enzyme immunoassay in piglets that were exposed to either normoxia or hypoxia for 1, 3, 7, or 14 d. The expression of VEGFR1, VEGFR2, and endothelial NO synthase in pulmonary artery was measured in the same study groups using Western blot analysis. VEGF (10(-12)-10(-9) M) induces a dose-dependent relaxation in 14-d normoxic piglets, whereas vasodilation is abolished after 14 d of hypoxia. VEGF tissue concentration is increased by hypoxia. VEGFR1 expression is dramatically increased after 1, 3, and 7 d of hypoxia compared with normoxia and returns to normal afterward. VEGFR2 expression is reduced by hypoxia at 14 d. However, endothelial NO synthase expression is not affected by hypoxia compared with normoxia. In neonatal hypoxia-induced pulmonary hypertension, VEGF is increased, whereas vasodilation to VEGF is abolished. This reduced vasodilation may be due to decreased VEGFR2 expression. We speculate that sequestration by VEGFR1 may also limit, to some extent, the vascular protecting effect of VEGF, thus contributing to the pathophysiologic changes seen in neonatal hypoxia-induced pulmonary hypertension.

Role of vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 in the vasodilator response to vascular endothelial growth factor in the neonatal piglet lung.

OBJECTIVE: Vascular endothelial growth factor (VEGF) regulates vascular proliferation and causes vasodilation. In the pulmonary circulation, the vasorelaxing effect of VEGF has been attributed to nitric oxide, whereas in other vascular beds, prostacyclin and other mechanisms are also involved. This vascular effect follows binding to two receptors, VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2), the latter of which is thought to be the main receptor responsible for the vasorelaxing effect of VEGF. The role of VEGFR1 in the neonatal pulmonary vasculature remains to be determined. DESIGN: Prospective randomized laboratory investigation. SETTING: Animal laboratory. SUBJECTS: Newborn Yorkshire-Landrace piglets. INTERVENTIONS: To determine the mechanisms of action of VEGF in the neonatal pulmonary vasculature, the effect of VEGF (10-10 M) was tested in isolated perfused piglet lungs, alone and in the presence of a VEGFR2 kinase inhibitor, N-nitro-l-arginine (L-NNA), indomethacin (Indo), L-NNA + Indo, and GF109203X, a protein kinase C inhibitor. The effect of a VEGFR1 agonist, placenta growth factor (PlGF), was also studied with or without L-NNA. Perfusate was collected, and cyclic guanosine monophosphate (cGMP), as well as 6-keto prostaglandin F1alpha and thromboxane B2, the stable metabolites of prostacyclin and thromboxane, respectively, was measured. MEASUREMENTS AND MAIN RESULTS: VEGF caused vasorelaxation with a concomitant increase in cGMP. PlGF also decreased vascular tone and increased cGMP. VEGFR2 kinase inhibitor did not prevent the reduction in perfusion pressure seen with VEGF but blocked the increase in cGMP. Pretreatment with L-NNA completely inhibited VEGF and PlGF vasodilation and prevented the increase in cGMP seen with both agonists. Pretreatment with Indo or GF109203X did not reduce the dilator response to VEGF. CONCLUSIONS: VEGF vasodilation may follow nitric oxide release in the piglet pulmonary circulation. VEGF vasorelaxation may not only occur through binding to VEGFR2, since PlGF, the specific VEGFR1 agonist, also causes vasodilation. Therefore, vasodilator response to VEGF may involve both types of receptor in the neonatal piglet pulmonary vasculature.

Endothelin in the perinatal circulation.

During the fetal period, blood is oxygenated through the placenta, and most of the cardiac output bypasses the lung through the ductus arteriosus. At birth, pulmonary vascular resistance falls with the initiation of ventilation. Coincidentally, the ductus arteriosus constricts. Endothelin-1 (ET-1) appears to play an important role during that transition period and postnatally. ET-1 can dramatically increase resistance in the placental microcirculation and may be involved in blood flow redistribution with hypoxia. At birth, the increase in oxygen tension is important in triggering ductus vasoconstriction. It is proposed that oxygen triggers closure of the ductus arteriosus by activating a specific, cytochrome P450-linked reaction, which in turn stimulates the synthesis of ET-1. On the neonatal heart, ET-1 has a positive chronotropic but negative inotropic effect. In the newborn piglet and the fetal lamb, both term and preterm, ET-1 causes a potent, long-lasting pulmonary vasoconstriction. Furthermore, a transient dilator response has been identified, and it is ascribed to nitric oxide formation. ET receptors are abundant in the piglet pulmonary vasculature. They are predominantly of the ETA constrictor subtype, though ETB2 constrictor receptors may also be present in certain species. The dilator response is linked to the ETB1 receptor, and the number of ETB1 receptors is reduced in hypoxia-induced pulmonary hypertension. ET-1 appears to be a causative agent in the pathogenesis of hypoxia- and hyperoxia-induced pulmonary hypertension as demonstrated by reversal of hemodynamic and morphological changes with treatment with an ETA receptor antagonist. Findings are amenable to practical applications in the management of infants with pulmonary hypertension or requiring persistent patency of the ductus arteriosus.