Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan's Project Baby Deer.

The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan's Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project's impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95-214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.

Effect of Catheter Dwell Time on Risk of Central Line-Associated Bloodstream Infection in Infants.

BACKGROUND AND OBJECTIVE: Central venous catheters in the NICU are associated with significant morbidity and mortality because of the risk of central line-associated bloodstream infections (CLABSIs). The purpose of this study was to determine the effect of catheter dwell time on risk of CLABSI. METHODS: Retrospective cohort study of 13,327 infants with 15,567 catheters (93% peripherally inserted central catheters [PICCs], 7% tunneled catheters) and 256,088 catheter days cared for in 141 NICUs. CLABSI was defined using National Health Surveillance Network criteria. We defined dwell time as the number of days from line insertion until either line removal or day of CLABSI. We generated survival curves for each week of dwell time and estimated hazard ratios for CLABSI at each week by using a Cox proportional hazards frailty model. We controlled for postmenstrual age and year, included facility as a random effect, and generated separate models by line type. RESULTS: Median postmenstrual age was 29 weeks (interquartile range 26-33). The overall incidence of CLABSI was 0.93 per 1000 catheter days. Increased dwell time was not associated with increased risk of CLABSI for PICCs. For tunneled catheters, infection incidence was significantly higher in weeks 7 and 9 compared with week 1. CONCLUSIONS: Clinicians should not routinely replace uninfected PICCs for fear of infection but should consider removing tunneled catheters before week 7 if no longer needed. Additional studies are needed to determine what daily maintenance practices may be associated with decreased risk of infection, especially for tunneled catheters.

Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation?

OBJECTIVE: To evaluate the relationships among cerebral palsy (CP) phenotypes and bronchopulmonary dysplasia (BPD) severity and, in the process, to generate hypotheses regarding causal pathways linking BPD to CP. STUDY DESIGN: We studied 1047 infants born before the 28th week of gestation. Receipt of supplemental oxygen at 36 weeks postmenstrual age (PMA), with or without the need for mechanical ventilation (MV) at 36 weeks PMA, defined two levels of BPD. At 24 months, the children underwent neurologic examinations and CP diagnoses were made using an algorithm based on topographic localisation. RESULTS: The 536 infants with BPD were at increased risk of all three CP phenotypes. In time-oriented multivariable analyses that adjusted for potential confounders, receipt of supplemental oxygen without MV at 36 weeks PMA (BPD) was not associated with increased risk of any CP phenotype. In contrast, BPD accompanied by MV at 36 weeks PMA (BPD/MV) was associated with a nearly sixfold increased risk of quadriparesis and a fourfold increased risk of diparesis. CONCLUSIONS: Combined treatment with both MV and supplemental oxygen at 36 weeks PMA strongly predicts the more common bilateral CP phenotypes. BPD without MV at 36 weeks PMA was not significantly associated with any form of CP.

Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation.

OBJECTIVE: Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number of infants with chronic lung disease (CLD). Historical neonatal exposures associated with CLD now less frequently precede the disease. There is now increasing interest in exposures and events before delivery that predict CLD. The objective of this study was to identify current prenatal predictors of CLD. METHODS: We collected data about prenatal, placental, and neonatal characteristics of 1241 newborns who were delivered before completion of the 28th week of gestation. Associations between prenatal factors, microbiologic and histologic characteristics of the placenta, and selected neonatal characteristics and CLD risk were first evaluated in univariate analyses. Subsequent multivariate analyses investigated the contribution of prenatal factors, particularly fetal growth restriction (FGR), to CLD risk. RESULTS: Among the prenatal factors, birth weight z scores, used as a marker of FGR, provided the most information about CLD risk. Indicators of placental inflammation and infection were not associated with increased risk of CLD. Within nearly all strata of prenatal, placental, and neonatal variables, growth-restricted infants were at increased CLD risk, compared with infants who were not growth-restricted. FGR was the only maternal or prenatal characteristic that was highly predictive of CLD after adjustment for other risk factors. CONCLUSIONS: FGR is independently associated with the risk of CLD. Thus, factors that control fetal somatic growth may have a significant impact on vulnerability to lung injury and in this way increase CLD risk.

Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children born at extremely low gestational age.

Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.

Evaluation and development of potentially better practices to reduce bronchopulmonary dysplasia in very low birth weight infants.

OBJECTIVE: The objective of this study was to describe development and implementation of potentially better practices to reduce bronchopulmonary dysplasia in very low birth weight infants (birth weight: 501-1500 g). METHODS: Results of Breathsavers Group meetings, conference calls and critically appraised topic summaries were used to construct potentially better practices. Implementation plans and experiences were reported by participants and collated. RESULTS: The Breathsavers Group developed 13 potentially better practices, based on published evidence and expert opinion. Participants determined which potentially better practices to implement and implementation methods. Participating NICUs implemented an average of 5 potentially better practices (range: 3-9). The Breathsavers Group also developed a resource kit, identified common obstacles to implementation, and initiated research to define bronchopulmonary dysplasia better. CONCLUSIONS: Multiinstitutional collaboration facilitated development and implementation of potentially better practices to reduce bronchopulmonary dysplasia.

Reduction of bronchopulmonary dysplasia after participation in the Breathsavers Group of the Vermont Oxford Network Neonatal Intensive Care Quality Improvement Collaborative.

OBJECTIVE: The objective of this study was to compare the primary and secondary outcomes of very low birth weight infants before and after participation in the Breathsavers Group of the Vermont Oxford Network-sponsored Neonatal Intensive Care Quality Collaborative. METHODS: Hospitals that participated in the Breathsavers Group contributed clinical data on the outcomes of their very low birth weight infants to the Vermont Oxford Network using standardized clinical definitions, data forms, and inclusion criteria. Outcomes from the last year of the collaborative, 2003, were compared with those from the baseline year, 2001. Models for treatment practices and outcomes measures were adjusted for within-hospital correlation (clustering) and standard risk factors that were present at birth. RESULTS: Bronchopulmonary dysplasia dropped significantly in 2003 compared with the baseline year. Survival improved but not significantly. In addition, severe retinopathy of prematurity, severe intraventricular hemorrhage, and supplemental oxygen at discharge dropped significantly. The use of conventional ventilation at any time during the initial hospitalization, postnatal steroids, and time to first dose of surfactant all decreased significantly. The use of nasal continuous positive airway pressure at any time during hospitalization increased. The use of high-frequency ventilation, delivery room intubation, and surfactant at any time during hospitalization did not change. CONCLUSIONS: The Breathsavers Group improved both clinical care processes and clinical outcomes during the Neonatal Intensive Care Quality Collaborative.

Retinopathy of prematurity and risk factors: a prospective cohort study.

BACKGROUND: Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 - International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants. METHODS: Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993-2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP. RESULTS: Of the neonates with

Anthropometric measurements for neonates, 23 to 29 weeks gestation, in the 1990s.

Reference data describing weight, length, and head circumference (anthropometric measurements) at birth were published by Lubchenco and Usher before 1970. Few attempts have been made to investigate whether these data are appropriate for today's cohort of preterm neonates. We analysed anthropometric data for neonates born between 23 and 29 weeks' gestation. Reference charts were developed from the measurements obtained from neonatal records, and gestational age, obtained from maternal charts, on 975 neonates delivered at four neonatal centres in Michigan during 1992 and 1997. The analysis was confined to children with gestational age that was consistent or within 7 days by last menstrual period, obstetric examination, ultrasound and neonatal determinations. At 23 to 29 weeks' gestation, ethnicity and multiple births did not have any significant impact on birthweight but girls were lighter. We compared our anthropometric charts with those presently being used at many neonatal centres. In our study, physical measurements at birth of preterm neonates born between 1992 and 1997 were significantly different from those currently used to assess growth status. Furthermore data derived from published studies that utilised birth certificates with gestational age based on last menstrual period seem to overestimate birthweight. For preterm infants, our findings are concordant with recently published values from 18 states of the US. Because of improved survival, gestational age assessment and perinatal care of preterm neonates, development of new reference anthropometric measurements for neonates is overdue. Our Michigan data of 23-29 weeks preterm provides new national reference values, which we recommend for use in US neonatal centres for extremely preterm neonates.

Specific compliance and gas exchange during high-frequency oscillatory ventilation.

OBJECTIVES: To evaluate the use of specific compliance (static compliance/functional residual capacity) to adjust mean airway pressure, resulting in optimal gas exchange during high-frequency oscillatory ventilation in a surfactant-deficient newborn piglet. DESIGN: Prospective controlled animal study. SETTING: Laboratory. SUBJECTS: Eight newborn piglets at 5 days of age. BACKGROUND: High-frequency oscillatory ventilation enables the use of relatively high mean airway pressures without the lung damage associated with conventional positive pressure ventilation. Mean airway pressures can be increased, resulting in static lung expansion that approaches total lung capacity with its negative impact on venous return. Therefore, knowledge of lung volume is important for safe patient management. A simple, noninvasive technique to enable the clinician to determine the optimal mean airway pressure likely would improve patient management. INTERVENTIONS: The lungs were lavaged after placement of central catheters and tracheostomy to lower respiratory system compliance and worsen ventilation perfusion matching. The animals were ventilated with high-frequency oscillatory ventilation at the same mean airway pressure as before lung lavage. Mean airway pressures then were increased in a step-wise fashion up to 30 cm H2O or until clinical deterioration occurred. All other ventilator variables, Fio2, frequency, and pressure amplitude were constant throughout the experiment. MEASUREMENTS AND MAIN RESULTS: Before lavage and at each level of mean airway pressure after lung lavage, respiratory system compliance and functional residual capacity were measured. Additionally, central arterial pressure, central venous pressure, heart rate, arterial blood gas, and pulse oximetric saturation were recorded. Lung lavage significantly lowered respiratory system compliance (static as well as specific compliance) and worsened ventilation perfusion matching as evidenced by an increase in Paco2 and a decreased arterial to alveolar oxygen ratio. With increasing mean airway pressures, static/specific compliance improved and then peaked before declining, functional residual capacity increased, and blood gas improved until reaching the flat portion of the pressure-volume relationship of the lung. Optimal gas exchange as reflected by the highest arterial to alveolar oxygen ratio and lowest Paco2 at constant ventilation was found at a mean airway pressure that maintained the functional residual capacity and static respiratory system compliance at the same level as the preinjury levels ("normalized" functional residual capacity and respiratory system compliance). CONCLUSIONS: These results suggest that specific compliance measurement that incorporates static respiratory system compliance and functional residual capacity during high-frequency oscillatory ventilation can be used to adjust mean airway pressure and achieve "normalized" functional residual capacity, static compliance, and gas exchange. These measurements may provide a simple method to optimize lung volume in a surfactant-deficient patient during high-frequency oscillatory ventilation.