Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

High-frequency nasal ventilation for 21 d maintains gas exchange with lower respiratory pressures and promotes alveolarization in preterm lambs.

BACKGROUND: Short-term high-frequency nasal ventilation (HFNV) of preterm neonates provides acceptable gas exchange compared to endotracheal intubation and intermittent mandatory ventilation (IMV). Whether long-term HFNV will provide acceptable gas exchange is unknown. We hypothesized that HFNV for up to 21 d would lead to acceptable gas exchange at lower inspired oxygen (O2) levels and airway pressures compared to intubation and IMV. METHODS: Preterm lambs were exposed to antenatal steroids and treated with perinatal surfactant and postnatal caffeine. Lambs were intubated and resuscitated by IMV. At ~3 h of age, half of the lambs were switched to noninvasive HFNV. Support was for 3 or 21 d. By design, Pao2 and Paco2 were not different between groups. RESULTS: At 3 d (n = 5) and 21 d (n = 4) of HFNV, fractional inspired O2 (FiO2), peak inspiratory pressure (PIP), mean airway, intratracheal, and positive end-expiratory pressures, oxygenation index, and alveolar-arterial gradient were significantly lower than matched periods of intubation and IMV. Pao2/FiO2 ratio was significantly higher at 3 and 21 d of HFNV compared to matched intubation and IMV. HFNV led to better alveolarization at 3 and 21 d. CONCLUSION: Long-term HFNV provides acceptable gas exchange at lower inspired O2 levels and respiratory pressures compared to intubation and IMV.

Mechanical stretch induces lung α-epithelial Na(+) channel expression.

ABSTRACT During fetal development physiological stretching helps drive lung growth and maturation. At birth, the α-subunit of the alveolar epithelial sodium channel (α-ENaC) is a critical factor in helping to facilitate clearance of lung fluid during the perinatal period. The effects of stretch, however, on α-ENaC expression in the fetal lung have yet to be elucidated. In an effort to explore this question, we used both an in vitro cell culture model that exposes cells to repetitive cyclic stretch (CS) as well as an in vivo preterm animal model of mechanical ventilation (MV). We found that murine lung epithelial (MLE-12) cells exposed to repetitive CS showed a significant rise in α-ENaC mRNA expression. Total and cell-surface protein abundance of α-ENaC were also elevated after 24 h of CS. Stretch-induced increases in α-ENaC expression were suppressed in the presence of either actinomycin D or cycloheximide. Pharmacological inhibition of the extracellular signal-regulated protein kinase (ERK1/2) did not attenuate stretch-induced increases in α-ENaC protein, whereas inhibition of p38 MAPK or c-Jun NH2-terminal kinase (JNK) did. In 29-day preterm rabbits, alveolar stretching secondary to postnatal MV markedly elevated fetal lung α-ENaC expression compared to spontaneously breathing counterparts. In summary, our findings indicate that mechanical stretch promotes α-ENaC expression.

Managing established bronchopulmonary dysplasia without using routine blood gas measurements.

OBJECTIVE: Routine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA). STUDY DESIGN: We examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020. RESULTS: 485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1-10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements. CONCLUSIONS: We found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Characteristics of pediatric non-cardiac eCPR programs in United States and Canadian hospitals: A cross-sectional survey.

OBJECTIVE: To characterize practices surrounding pediatric eCPR in the U.S. and Canada. METHODS: Cross-sectional survey of U.S. and Canadian hospitals with non-cardiac eCPR programs. Variables included hospital and surgical group demographics, eCPR inclusion/exclusion criteria, cannulation approaches, and outcomes (survival to decannulation and survival to discharge). RESULTS: Surveys were completed by 40 hospitals in the United States (37) and Canada (3) among an estimated 49 programs (82% response rate). Respondents tended to work in >200 bed free-standing children's hospitals (27, 68%). Pediatric general surgeons respond to activations in 32 (80%) cases, with a median group size of 7 (IQR 5,9.5); 8 (20%) responding institutions take in-house call and 63% have a formal back-up system for eCPR. Dedicated simulation programs were reported by 22 (55%) respondents. Annual eCPR activations average approximately 6/year; approximately 39% of patients survived to decannulation, with 35% surviving to discharge. Cannulations occurred in a variety of settings and were mostly done through the neck at the purview of cannulating surgeon/proceduralist. Exclusion criteria used by hospitals included pre-hospital arrest (21, 53%), COVID+ (5, 13%), prolonged CPR (18, 45%), lethal chromosomal anomalies (15, 38%) and terminal underlying disease (14, 35%). CONCLUSIONS: While there are some similarities regarding inclusion/exclusion criteria, cannulation location and modality and follow-up in pediatric eCPR, these are not standard across multiple institutions. Survival to discharge after eCPR is modest but data on cost and long-term neurologic sequela are lacking. Codification of indications and surgical approaches may help clarify the utility and success of eCPR.

A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.

OBJECTIVE: To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. STUDY DESIGN: Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. RESULTS: Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. CONCLUSIONS: Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.

Noninvasive neurocritical care monitoring for neonates on extracorporeal membrane oxygenation: where do we stand?

OBJECTIVE: To determine practice variation in the utilization of neuromonitoring modalities in neonatal extracorporeal membrane oxygenation (ECMO) patients across Level IV neonatal intensive care units (NICUs). STUDY DESIGN: Cross-sectional survey design using electronic surveys sent to site sponsors of a multicenter collaborative of 34 Level IV NICUs of the Children's Hospitals Neonatal Consortium (CHNC) from June to August 2018. RESULTS: We had 22 survey respondents from CHNC ECMO centers. Twenty-seven percent of respondents routinely monitored for seizures using electroencephalogram. Cerebral near infrared spectroscopy was used by 50%. Head ultrasound was performed by 95% but the frequency, duration, and type of views varied. Post ECMO screening brain MRI prior to hospital discharge was routinely performed by 77% of respondents. A majority of centers (95%) performed neurodevelopmental follow-up after hospital discharge. CONCLUSIONS: There is variation in neuromonitoring practices in Level IV NICUs performing ECMO. Lack of evidence and clear outcome benefits has contributed to practice variation across institutions.

Reducing Unplanned Extubations in the NICU Following Implementation of a Standardized Approach.

BACKGROUND: Unplanned extubations (UEs) have been associated with increased ventilator days, risk of infection, cardiopulmonary resuscitation, and resuscitation medication usage. The UE rate in our level 4 NICU is lower than the national average. Efforts to further reduce UE events at our institution led an interdisciplinary group to define steps to eliminate UEs. Steps included: (1) requiring at least 2 care providers at the bedside for movement of an intubated subject; (2) standardizing head and endotracheal tube (ETT) position; (3) defining a set methodology for ETT securing; (4) introducing a postoperative handoff to improve communication; and (5) implementing a post-UE assessment tool. METHODS: A quality improvement initiative reviewed subjects and compared UE rates before (January 2013 to December 2013) and after (January 2014 to December 2014) implementation of UE prevention guidelines. A de-identified data set was used for analysis. RESULTS: 67 UE events were identified with 46 UE events at baseline in 2013 compared with 21 in 2014 post-implementation. This amounted to a 64% decrease in total UE events (from 46 to 21) (P < .001). Additionally, monthly UE rates decreased 50% (from 3.8 to 1.9), and UE events per 100 ventilator days decreased 53% (from 1.15 to 0.54). CONCLUSIONS: The development of standard guidelines to prevent UE and a quality review process to track UE provided important information for education and practice change. In our NICU, these changes have significantly improved the UE rate through improved teamwork, accountability, and communication.

Ventricular peritoneal shunt infection resulting from group B streptococcus.

OBJECTIVE: To report, to our knowledge, the first case of a ventricular peritoneal shunt infection by group B streptococcus occurring in infancy. DESIGN: Descriptive case report. SETTING: Neonatal intensive care unit in a tertiary referral military hospital. PATIENT: A 3-month-old, former preterm infant with a case of postoperative ventricular peritoneal shunt infection by group B streptococcus occurring in infancy. INTERVENTIONS: The infant's shunt infection was treated with a prolonged course of antibiotics, shunt removal, and eventual shunt replacement. He developed a persistently enlarging third ventricular region cyst, which ultimately required endoscopic surgical fenestration. MEASUREMENTS AND MAIN RESULTS: Currently, at 25 months of age, the patient has some moderate developmental delays but is otherwise healthy and making progress with no evidence of any recurrent infection CONCLUSIONS: Group B streptococcus should be considered as a potential pathogen in ventricular peritoneal shunt infections in infants even outside of the immediate neonatal period. Providers caring for infants should be especially cognizant of the potential risk for nosocomial infections in former premature neonates, especially following high-risk surgical procedures. Prompt recognition of ventricular peritoneal shunt infections and management to include early shunt removal and appropriate antibiotic coverage are recommended in an effort to optimize outcome.

Utility of neuroradiographic imaging in predicting outcomes after neonatal extracorporeal membrane oxygenation.

BACKGROUND: The need for routine neuroimaging after extracorporeal membrane oxygenation (ECMO) and the optimal radiographic study remains unclear. We sought to evaluate the correlation between findings on head ultrasound (HUS) and magnetic resonance imaging (MRI) and determine the association of these findings to neurodevelopmental outcome. METHODS: A retrospective review was performed (2003-2010) to identify neonates who had a MRI after ECMO. Each MRI was reviewed by a single pediatric neuroradiologist. Neurodevelopmental data was collected from the high-risk neonatal follow-up clinic. RESULTS: Fifty neonates had a MRI (venoarterial 37, venovenous 13) after ECMO. HUS was abnormal in 24%, whereas MRI was abnormal in 62%. All infants with an abnormal HUS had an abnormal MRI, but an additional 50% of patients with a normal HUS had an abnormal MRI. Venoarterial ECMO was significantly associated with an abnormal MRI. Follow-up data was available for 26 neonates. The only predictor of abnormal neurodevelopment was the need for supplemental tube feeds at discharge. CONCLUSIONS: MRI identified significantly more abnormalities compared to routine HUS after neonatal ECMO. However, neither MRI nor HUS findings correlated with early neurodevelopmental outcome. Feeding ability at discharge was the overall best predictor of neurologic impairment in survivors.

Comparison of the Sensormedics 3100A and Bronchotron transporter in a neonatal piglet ARDS model.

The Sensormedics 3100A (Cardinal Health, Dublin, OH) (HFOV) and the Bronchotron (Percussionaire, Sandpoint, ID) (HFPV) are high-frequency ventilation devices used to support neonatal respiratory failure; however, a comparison of the devices, with respect to gas exchange at similar ventilator settings, has not been previously studied. Thus, we compared the ability of HFOV to that of HFPV to provide oxygenation and ventilation during acute lung injury in a newborn animal model. Using a saline lung lavage model, 12 neonatal piglets were randomized to initial support with either the HFOV or HFPV with settings adjusted to achieve PaCO2 of 45-60 mmHg. After stabilization, ventilator settings and arterial blood gases were serially recorded for 30 min. Animals were then crossed over to the alternative device set to deliver the same V(t), MAP, and F for an additional 30 min with the same parameters recorded. We found that the DeltaP needed to generate adequate V(t) on HFPV (35 +/- 7 cm H2O) trended higher versus HFOV (31 +/- 7 cm H2O P = 0.09) when the devices were matched for V(t), F, and MAP. No significant differences in ventilation (PaCO(2) = 50 +/- 10.7 mmHg vs. 46 +/- 10 mmHg, P = 0.22) or oxygenation (PaO2 = 150 +/- 76 mmHg vs. 149 +/- 107 mmHg, P = 0.57) between the devices were found. We conclude that HFPV ventilates and oxygenates as well as HFOV at equivalent ventilator settings. HFPV may require larger DeltaP's to generate equivalent V(t).

Remodeling of the tight junction during recovery from exposure to hydrogen peroxide in kidney epithelial cells.

Renal ischemia-reperfusion injury results in oxidative stress-induced alterations in barrier function. Activation of the mitogen-activated protein (MAP) kinase pathway during recovery from oxidative stress may be an effector of oxidant-induced tight junction reorganization. We hypothesized that tight junction composition and barrier function would be perturbed during recovery from oxidative stress. We developed a model of short-term H(2)O(2) exposure followed by recovery using Madin Darby canine kidney (MDCK II) cells. H(2)O(2) perturbs barrier function without a significant cytotoxic effect except in significant doses. ERK-1/2 and p38, both enzymes of the MAP kinase pathway, were activated within minutes of exposure to H(2)O(2). Transient exposure to H(2)O(2) produced a biphasic response in the transepithelial electrical resistance (TER). An initial drop in TER at 6 h was followed by a significant increase at 24 h. Inhibition of ERK-1/2 activation attenuated the increase in TER observed at 24 h. Expression of occludin initially decreased, followed by partial recovery at 24 h. In contrast, claudin-1 levels decreased and failed to recover at 24 h. Claudin-2 levels were markedly decreased at 24 h; however, inhibition of ERK-1/2 activation was protective. Occludin and claudin-1 localization at the apical membrane on immunofluorescence images was fragmented at 6 h after H(2)O(2) exposure with subsequent recovery of appropriate localization by 24 h. MDCK II cell recovery after H(2)O(2) exposure is associated with functional and structural modifications of the tight junction that are mediated in part by activation of the MAP kinase enzymes ERK-1/2 and p38.

Survival after prolonged pediatric extracorporeal membrane oxygenation support for adenoviral pneumonia.

Adenoviral pneumonia can cause significant pulmonary morbidity leading to extracorporeal membrane oxygenation (ECMO) rescue. Reported survival of adenoviral pneumonia requiring ECMO has been poor, and prolonged time on ECMO is associated with increased mortality. We present 2 pediatric cases of adenoviral pneumonia in patients who survived after greater than 30 days on ECMO and review the Extracorporeal Life Support Organization (ELSO) registry to describe the collective experience of children with viral pneumonia requiring prolonged ECMO. Although survival has improved over the past decade for pediatric adenoviral pneumonia, the ELSO database previously has had no surviving children reported with a primary diagnosis of adenovirus after more than 4 weeks on ECMO. Our experience suggests that there may be use for prolonged ECMO support in children despite severe adenoviral pneumonia.

Congenital diaphragmatic hernia: a simplified postnatal predictor of outcome.

BACKGROUND/PURPOSE: The incidence of congenital diaphragmatic hernia (CDH) approximates 1 in 3000 births, with mortality rates up to 50%. The ability to accurately and easily predict the outcomes of these infants could be a valuable management tool. The purpose of this study was to develop and validate a simplified clinical method for predicting survival outcomes in infants born with CDH. METHODS: The Wilford Hall/Santa Rosa clinical prediction formula (WHSR(PF) = highest PaO2 - highest PCO2) was generated from arterial blood gas values obtained during the initial 24 hours of life, but before surgical repair or extracorporeal membrane oxygenation, in a local group of infants with CDH identified by prospective and retrospective review. The WHSR(PF) was validated using a comparative group from the Congenital Diaphragmatic Hernia Study Group (CHDSG). Bivariate, multivariable, and area under the receiver operating curve (AUC) analysis was performed using SigmaStat and SPSS statistical programs (SPSS, Chicago, Ill). RESULTS: As initially developed from the local data, the WHSR(PF) had a positive predictive value (PPV) of 82%, a negative predictive value of 88% and AUC of 0.87. When validated against the CDHSG data, the positive predictive value was 83%, negative predictive value was 66%, and AUC 0.79. Area under the receiver operating curve analysis by the previously published CDHSG predictive equation was 0.76. CONCLUSION: This novel formula is an easy to apply clinical tool with similar or better predictive abilities compared to previous methods of predicting survival in infants born with CDH. Currently, no method appears to have sufficient clinical accuracy for predicting the outcome of an individual infant with CDH. Further studies are indicated.

Mechanical ventilation down-regulates surfactant protein A and keratinocyte growth factor expression in premature rabbits.

Surfactant-associated proteins (SP-A, SP-B, and SP-C) are critical for the endogenous function of surfactant. Keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF) are key regulators of lung development. The objective of this study was to evaluate the effects of early mechanical ventilation on the expression of these important regulatory proteins in a preterm rabbit model. Premature fetuses were delivered at 29 d of gestation and randomized to necropsy at birth, i.e. no ventilation (NV), spontaneous breathing (SB), or mechanical ventilation (MV) for 16 h. MV animals were further randomized to treatment with dexamethasone (dex). Our findings showed that SB rabbits increased their expression of SP-A mRNA and protein after birth compared with NV controls. MV significantly attenuated this response in the absence of dex. Exposure to dex elevated SP-B mRNA expression in both SB and MV rabbits. KGF protein levels were markedly increased in SB animals compared with MV counterparts. VEGF levels were similar in SB and MV animals, but were significantly increased compared with NV controls. These data suggest that MV alters surfactant-associated protein and growth factor expression, which may contribute to injury in the developing lung.

Cyclic stretch attenuates effects of hyperoxia on cell proliferation and viability in human alveolar epithelial cells.

The treatment of severe lung disease often requires the use of high concentrations of oxygen coupled with the need for assisted ventilation, potentially exposing the pulmonary epithelium to both reactive oxygen species and nonphysiological cyclic stretch. Whereas prolonged hyperoxia is known to cause increased cell injury, cyclic stretch may result in either cell proliferation or injury depending on the pattern and degree of exposure to mechanical deformation. How hyperoxia and cyclic stretch interact to affect the pulmonary epithelium in vitro has not been previously investigated. This study was performed using human alveolar epithelial A549 cells to explore the combined effects of cyclic stretch and hyperoxia on cell proliferation and viability. Under room air conditions, cyclic stretch did not alter cell viability at any time point and increased cell number after 48 h compared with unstretched controls. After exposure to prolonged hyperoxia, cell number and [(3)H]thymidine incorporation markedly decreased, whereas evidence of oxidative stress and nonapoptotic cell death increased. The combination of cyclic stretch with hyperoxia significantly mitigated the negative effects of prolonged hyperoxia alone on measures of cell proliferation and viability. In addition, cyclic stretch resulted in decreased levels of oxidative stress over time in hyperoxia-exposed cells. Our results suggest that cyclic stretch, as applied in this study, can minimize the detrimental effects of hyperoxia on alveolar epithelial A549 cells.

Distribution of corticotropin releasing hormone in the fetus, newborn, juvenile, and adult baboon.

Corticotropin releasing hormone (CRH) has previously been identified in extrahypothalamic tissues and may act in a paracrine fashion within these tissues. To date, CRH production and its role in the fetus and newborn have not been investigated. The aim of this study was to explore the distribution and ontogeny of CRH in extrahypothalamic tissues of the fetus, newborn, juvenile, and adult baboon. Pituitary, adrenal, kidney, liver, and lung tissues from baboons at 125 d gestation, 140 d gestation, 185 d gestation (term), juveniles, and adults were obtained at necropsy. The tissues were quantified for protein and immunoreactive CRH was determined by a RIA. CRH levels were normalized to the protein content of each tissue. CRH was present in all tissues and varied over a 100-fold range according to tissue type. The highest concentration of CRH was found in the pituitary, which did not differ with the gestation and/or age of the animal. In the lung tissues of 125- and 140-d gestation animals, CRH was greater than the term, juvenile, and adult lung (p < 0.02). CRH in the adrenal gland of the 125-d samples was greater than the other four ages tested (p < 0.02). Liver CRH levels were higher in the term animals compared with the juvenile baboons. Our study documents the existence of CRH in extrahypothalamic tissues of the baboon from 125 d of gestation to adulthood. Given its presence and distribution, we speculate that CRH may exert ongoing paracrine and/or autocrine actions in these tissues from the time of intrauterine life throughout adulthood.