Interaction of hydrocortisone and illness severity on head growth in cohort of ELBW infants.

BACKGROUND: Extremely low birth weight (ELBW) infants comprise a fragile population at risk for neurodevelopmental disabilities (NDD). Systemic steroids were previously associated with NDD, but more recent studies suggest hydrocortisone (HCT) may improve survival without increasing NDD. However, the effects of HCT on head growth adjusted for illness severity during NICU hospitalization are unknown. Thus, we hypothesize that HCT will protect head growth, accounting for illness severity using a modified neonatal Sequential Organ Failure Assessment (M-nSOFA) score. METHODS: We conducted a retrospective study that included infants born at 23-29 weeks gestational age (GA) and < 1000 g. Our study included 73 infants, 41% of whom received HCT. RESULTS: We found negative correlations between growth parameters and age, similar between HCT and control patients. HCT-exposed infants had lower GA but similar normalized birth weights; HCT-exposed infants also had higher illness severity and longer lengths of hospital stay. We found an interaction between HCT exposure and illness severity on head growth, such that infants exposed to HCT had better head growth compared to those not exposed to HCT when adjusted for illness severity. CONCLUSION: These findings emphasize the importance of considering patient illness severity and suggest that HCT use may offer additional benefits not previously considered. IMPACT: This is the first study to assess the relationship between head growth and illness severity in extremely preterm infants with extremely low birth weights during their initial NICU hospitalization. Infants exposed to hydrocortisone (HCT) were overall more ill than those not exposed, yet HCT exposed infants had better preserved head growth relative to illness severity. Better understanding of the effects of HCT exposure on this vulnerable population will help guide more informed decisions on the relative risks and benefits for HCT use.

Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates.

BACKGROUND: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks' GA. METHODS: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. RESULTS: Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks' GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. CONCLUSIONS: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury. IMPACT: Normative data of six brain injury-related biomarkers is being proposed. When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates. Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

Reducing Staphylococcus aureus infections in the neonatal intensive care unit.

OBJECTIVE: Our neonatal intensive care unit (NICU) saw an increase in Staphylococcus aureus (SA) infections-methicillin-resistant SA (MRSA) infections increased from 2.1/10,000 patient days (PD) to 5.1/10,000 PD, and methicillin-sensitive SA (MSSA) infections from 1.2/10,000 PD to 3.9/10,000 PD. This quality improvement project aimed to decrease the rates of SA infections to less than 2.0/10,000 PD, and to determine the rate of SA decolonization. METHODS: Infection prevention interventions targeted patient factors (SA surveillance, patient cohorting, decolonization protocol), provider factors (provider cohorting, enhanced hand hygiene) and environmental factors (room structure, equipment optimization). RESULTS: The rates of MRSA and MSSA infections decreased to 0.6/10,000 PD and 0.7 infections/10,000 PD respectively. Persistent decolonization of SA was successful in 67% of colonized patients. CONCLUSIONS: Specific interventions targeting patient, provider, and environmental factors, including the implementation of a SA decolonization protocol, were successful in decreasing the incidence of SA infections in neonates.

Hypotonic infant with PURA syndrome-related channelopathy successfully treated with pyridostigmine.

PURA syndrome is a rare, clinically heterogeneous disorder characterized by a wide spectrum of neurodevelopmental problems, and occasionally congenital heart defects, urogenital malformations, skeletal abnormalities and endocrine disorders. We describe the hospital course, diagnostic evaluations as well as neurologic and neuromuscular follow up of an infant diagnosed with PURA syndrome based on a pathogenic deletion at c.697_699 (p.Phe233del) of the PURA gene identified on whole exome sequencing. Upon initial examination, fluctuation of neuromuscular tone and reflexes were noted in conjunction with hypotonia and severe apneic episodes, suggestive of neuromuscular junction involvement. A definitive role of the neuromuscular junction has not been previously reported with PURA syndrome. The infant was started on pyridostigmine, an acetylcholinesterase inhibitor, with significant improvement in neuromuscular tone and motor movements. In addition, pyridostigmine also resulted in resolution of apneas and improved respiratory status which suggests its potential therapeutic role in patients with PURA syndrome.

Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury.

BACKGROUND: Neonates are at risk of gastrointestinal emergencies including necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP). Identifying biomarkers to aid in diagnosis is imperative. We hypothesized that circulating intestinal-specific protein concentrations would distinguish infants with intestinal injury from controls. AIMS: To identify serum concentrations of intestinal-specific protein(s) in infants with intestinal injury and controls. METHODS: We used an in silico approach to identify intestinal-specific proteins. We collected serum from control infants and infants with NEC or SIP and measured protein concentrations using ELISA. If baseline concentrations were near the detection limit in initial control assays, we proceeded to assess concentrations in a larger cohort of controls and infants with injury. Control infants were frequency matched to infants with injury and compared with nonparametric and mixed-effects models analysis. RESULTS: We evaluated four proteins with high intestinal expression: Galectin-4 (Gal-4), S100G, Trefoil Factor-3, and alanyl aminopeptidase. Only Gal-4 demonstrated consistent results near the lower limit of quantification in controls and was studied in the larger cohorts. Gal-4 concentration was low in 111 control infants (median 0.012 ng/ml). By contrast, Gal-4 was significantly increased at diagnosis in infants with surgical NEC and SIP (n = 14, p ≤ 0.001 and n = 8, p = 0.031) compared to matched controls, but not in infants with medical NEC (n = 32, p = 0.10). CONCLUSIONS: Of the intestinal-specific proteins evaluated, circulating Gal-4 concentrations were at the assay detection limit in control infants. Gal-4 concentrations were significantly elevated in infants with surgical NEC or SIP, suggesting that Gal-4 may serve as a biomarker for neonatal intestinal injury.

Therapeutic Hypothermia Modulates the Relationships Between Indicators of Severity of Neonatal Hypoxic Ischemic Encephalopathy and Serum Biomarkers.

Objective: To determine the changes due to therapeutic hypothermia (TH) exposure in the strength of association between traditional clinical and biochemical indicators of severity of neonatal hypoxic-ischemic encephalopathy (HIE) and serum biomarkers. We hypothesized that culmination of TH changes the strength of the relationships between traditional indicators of severity of HIE and serum biomarkers. Methods: This was a single-center observational cohort study of 178 neonates with HIE treated with TH and followed with serum biomarkers: (i) brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) (neurotrophins); (ii) tau and glial fibrillary acidic protein (GFAP) (neural cell injury); and (iii) interleukin 6 (IL-6), IL-8, and IL-10 (cytokines), during their first week of life. Adjusted mixed-effect models tested associations with HIE indicators in relation to TH exposure. Results: At admission, lower Apgar scores and base excess (BE) and higher lactate and nucleated red blood cell (NRBC) count correlated with higher Sarnat scores. These indicators of worse HIE severity, including higher Sarnat score, correlated with lower VEGF and higher tau, GFAP, and IL-10 levels at different time points. Within the first 24 h of life, patients with a Sarnat score >2 had lower VEGF levels, whereas only those with score of 3 also had higher GFAP and IL-10 levels. Tau levels increased during TH in patients with Sarnat score of 3, whereas tau and GFAP increased after TH in those with scores of 2. After adjustments, lower VEGF levels during TH and higher tau, GFAP, and IL-10 levels during and after TH were associated with worse Sarnat scores. Tau and GFAP relationship with Sarnat score became stronger after TH. Conclusion: Therapeutic hypothermia exerts an independent modulatory effect in the relationships between traditional indicators of severity of HIE and serum biomarkers after adjustments. Thus, the timing of biomarker testing in relation to TH exposure must be carefully considered if biomarkers are proposed for patient stratification in novel clinical trials.

Racial disparities in COVID-19 associated pulmonary embolism: A multicenter cohort study.

BACKGROUND: Thromboembolism is a recognized component of severe coronavirus disease 2019 (COVID-19) disease. However, research into racial disparities in COVID-19-related pulmonary embolism is limited. MATERIALS AND METHODS: In this retrospective cohort study, we examined adults diagnosed with COVID-19 between January 20 and September 30, 2020, using a multicenter electronic health record dataset of over 73 million patients (TriNetX), mostly in the USA. The main study outcomes were development of pulmonary embolism or mortality within 30 days of COVID-19 diagnosis. Secondary outcome analysis included hospitalization, mechanical ventilation, and ICU admission within 30 days of diagnosis, as well as lab values within 0-1 days of diagnosis. Sociodemographic and clinical variables were used to create balanced cohorts via propensity matching. RESULTS: 346,953 patients were identified, with 56.0% non-Hispanic white and 14.7% non-Hispanic black; the mean age was 47.6 years. 3879 patients developed PE, with 2036 (1.30% of 157,049) white and 1088 (2.16% of 50,376) black patients. After propensity matching, black race was associated with higher mortality (risk ratio 1.890 [95% CI 1.727-2.067]) and PE (RR 1.537 [1.380-1.711]; p < 0.0001). Both races had higher mortality with COVID-associated PE than COVID or PE alone (RR 1.575-1.627 and 3.000-5.389 respectively; p < 0.0001). Black patients with COVID-19 and PE had a higher rate of mortality compared to white patients (RR 1.397 [1.059-1.844]; p = 0.0174). INTERPRETATION: Black race was associated with higher risk of pulmonary embolism and mortality after COVID-19. Additionally, black patients with COVID-19 and PE had a higher mortality compared to white patients.

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

Factors associated with pediatric drowning admissions and outcomes at a trauma center, 2010-2017.

BACKGROUND: Drowning is a leading cause of preventable mortality and morbidity in children. Its high fatality rate and frequent severe sequelae (e.g. brain damage and permanent loss of functioning) place a premium on preventive efforts. METHODS: A retrospective analysis of patients ≤21 years of age admitted between 2010 and 2017 to a pediatric trauma center was conducted to identify factors associated with drowning admissions, fatal drowning, and severe outcome (ventilator use, ICU admission, or death). Outcomes were modeled and estimated by use of logistic regression and Poisson regression. RESULTS: Drowning accounted for 153/4931 (3.1%) trauma admissions between 2010 and 2017. The risk of death (13.1% vs. 1.5%, p < .01), and severe outcome (24.8% vs. 7.8%, p < .01) was significantly higher for drownings vs. other causes. All 20 drowning deaths occurred among children left unattended. In Poisson regression analysis, weekends, summer breaks, and hotter days were independently associated with a higher probability of drowning admissions. Additionally, in analyses excluding indicators of severity, the odds of severe outcome were higher for children age ≤ 2 years [adjusted odds ratio (AOR) = 3.88 95% CI (1.58, 9.53)], and injury downtime of >5 min or unknown length [AOR = 6.66 95% CI (2.74-16.15)]. Immediate intervention after the discovery was associated with ~70% lower odds of a severe outcome. CONCLUSIONS: Drowning admissions were both more severe and more often fatal compared to other pediatric injury causes of admission. Enhanced and targeted educational messages for parents of young children, focused on prevention behaviors on high-risk days and immediate bystander intervention, may reduce the occurrence and severity of these tragic accidents. TABLE OF CONTENTS SUMMARY: A retrospective multi-year cohort study to identify modifiable factors associated with drowning admissions, severe complications, and death from a large trauma registry database. WHAT'S KNOWN ON THIS SUBJECT: Drowning is a leading cause of unintentional injury that results in severe morbidity and a high rate of mortality. Children are disproportionately affected by drowning and have a higher risk of long term sequelae and death. WHAT THIS STUDY ADDS: This study identified high-risk populations and periods for drowning, the importance of supervision, and the effectiveness of immediate intervention in reducing unfavorable outcomes after drowning. It also highlights a need for heightened local intervention for drowning prevention.

Plasma and Cerebrospinal Fluid Candidate Biomarkers of Neonatal Encephalopathy Severity and Neurodevelopmental Outcomes.

OBJECTIVES: To identify candidate biomarkers in both plasma and cerebrospinal fluid (CSF) that are associated with neonatal encephalopathy severity measured by encephalopathy grade, seizures, brain injury by magnetic resonance imaging (MRI), and neurodevelopmental outcomes at 15-30 months. STUDY DESIGN: A retrospective cohort study of plasma (N = 155, day of life 0-1) and CSF (n = 30, day of life 0-7) from neonates with neonatal encephalopathy and healthy neonates born at term (N = 30, ≥36 weeks of gestation) was conducted. We measured central nervous system necrosis (glial fibrillary acidic protein [GFAP], neurogranin [NRGN], tau), inflammatory (interleukin [IL]-6, IL-8, IL-10), and trophic (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor) proteins. Clinical outcomes were Sarnat scores of encephalopathy, seizures, MRI scores, and Bayley Scales of Infant and Toddler Development III at 15-30 months. RESULTS: Plasma NRGN, tau, IL-6, IL-8, and IL-10 were greater, whereas BDNF and vascular endothelial growth factor were lower in patients with neonatal encephalopathy vs controls. In plasma, tau, GFAP, and NRGN were directly and BDNF inversely associated with encephalopathy grade. IL-6 was inversely related to seizures. Tau was directly related to MRI abnormalities. Tau was inversely associated with Bayley Scales of Infant and Toddler Development III cognitive and motor outcomes. In CSF, NRGN was inversely associated with cognitive, motor, and language measures. GFAP, IL-6, and IL-10 were inversely related to cognitive and motor outcomes. IL-8 was inversely related to motor outcomes. CSF candidate biomarkers showed no significant relationships with encephalopathy grade, seizures, or MRI abnormalities. CONCLUSIONS: Plasma candidate biomarkers predicted encephalopathy severity, seizures, MRI abnormalities, and neurodevelopmental outcomes at 15-30 months.

Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages.

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality. Serum biomarkers to aid diagnosis, such as intestinal fatty acid binding protein (IFABP) and calprotectin, are actively being investigated; however, the normative values of these markers among healthy premature and term infants remains unknown. We sought to identify normative values for the serum concentrations of IFABP and calprotectin across gestational (GA) and post-menstrual age. METHODS: We collected serum from infants (24-40 weeks GA) in the first week of life and at multiple time points in a sub-cohort of premature infants (24-29 weeks GA), excluding sepsis or known intestinal disease. IFABP and calprotectin were measured using ELISA. Groups were compared with descriptive statistics and mixed effects linear regression. RESULTS: One hundred twelve infants had specimens in the first week of life, and 19 premature infants had longitudinal specimens. IFABP concentration in the first week of life was low and did not differ across gestational ages. Longitudinally, IFABP increased 4% per day (P < 0.001). Calprotectin concentration in the first week of life was more variable. An inverse relationship between day of life and calprotectin level was found in the longitudinal cohort (P < 0.001). CONCLUSIONS: Serum IFABP and calprotectin fluctuate over time. Infants had low levels of IFABP during the first week of life, independent of gestational age, and levels increased longitudinally in premature infants. Calprotectin levels generally declined over time. Normative data for infants is necessary to establish meaningful cut-off levels for clinical use.

Temporal trends in patient characteristics, injury mechanisms and outcomes in pediatric trauma admissions between 2010 and 2017.

INTRODUCTION: Injuries are a leading cause of preventable morbidity and mortality in children. Mechanisms of injuries and presentations are diverse in pediatric injuries and require special attention. Dedicated pediatric trauma care centers are ideal for management of children with injuries simultaneously serving as sources of research data. The objective of the current study was to identify changes in injury mechanisms, modifiable risk factors, and outcomes independently associated with admissions at a large pediatric trauma center in Tampa, Florida. METHODS: We conducted retrospective analysis of 8-years (2010-2017) of pediatric trauma admissions to a large trauma center. Demographic factors and injury characteristics were examined for temporal trends over two year increments. Temporal changes in admissions with major trauma, admission to ICU, and length of stay were examined using logistic regression analysis, and factors associated with independent temporal trends were identified using ordinal logistic regression modeling. RESULTS: During the study period, there were 4,934 trauma admissions with a predominance of falls (45.1%) and traffic injuries (20.5%). Trends were observed with less frequent head injuries (2010-2011: 35.7% vs 2016-2017: 28.3%, p < .01) and abdominal injuries (2010-2011:10.3% vs 2016-2017: 8.2%, p = .03), and more frequent chest injuries (2010-2011: 9.0% vs 2016-2017: 11.4%, p < .01). Over the study period, evaluated in 2-year increments, higher use of private insurance (Adjusted Odds Ratio (AOR)=1.44, 95% Confidence Interval (CI) 95% CI: 1.29-1.61) and helicopter transport (AOR=1.91, 95% CI: 1.58 -2.30) was observed. Admissions for drownings (AOR=1.50, 95% CI: 1.10 -2.02) and animal bites (AOR=1.99, 95% CI: 1.46 -2.71) increased during the study period. Improvement in patient outcomes (adjusted for injury severity) were observed with shorter, ≤1 day length of stay (LOS) (AOR=1.19, 95% CI: 1.06 -1.33), reduction in complications (AOR=0.47, 95% CI: 0.33 -0.66), and more admissions without an intensive care unit (ICU) stay (AOR=1.6 95% CI = 1.36 -1.88). CONCLUSIONS: Significant reductions in LOS, ICU stay, and complications were temporally observed despite an increase in admissions with higher use of helicopter transport. These results can most likely be attributed to dedicated pediatric trauma experts and resources available at an integrated pediatric trauma center.

Long-Term Outcomes of Infants with Neonatal Abstinence Syndrome.

Parents of infants with neonatal abstinence syndrome (NAS) in the NICU may have questions about the long-term consequences of prenatal exposure to methadone, both asked and unasked. Although the signs of withdrawal will abate relatively quickly, parents should be aware of potential vision, motor, and behavioral/cognitive problems, as well as sleeping disturbances and ear infections so their infants can be followed closely and monitored by their pediatrician with appropriate referrals made. Furthermore, this knowledge may inspire parents to enroll their infants in an early intervention program to help optimize their outcomes. There are still many unanswered questions about epigenetic consequences, risk for child abuse/neglect, and risk of future substance abuse in this population.