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.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory.

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.

Later cooling within 6 h and temperatures outside 33-34 °C are not associated with dysfunctional autoregulation during hypothermia for neonatal encephalopathy.

BACKGROUND: Cooling delays, temperature outside 33-34 °C, and blood pressure below the mean arterial blood pressure with optimal cerebral autoregulation (MAPOPT) might diminish neuroprotection from therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized that longer time to reach temperature <34 °C and having temperature outside 33-34 °C would be associated with worse autoregulation and greater brain injury. METHODS: Neonates with HIE had rectal temperature and near-infrared spectroscopy autoregulation monitoring during hypothermia (n = 63) and rewarming (n = 58). All underwent brain MRI, and a subset received diffusion tensor imaging MRI before day 10 (n = 41). RESULTS: Most neonates reached <34 °C at 3-6 h of life. MAPOPT was identified in 54/63 (86%) during hypothermia and in 53/58 (91%) during rewarming. Cooling time was not related to blood pressure deviation from MAPOPT. Later cooling was associated with lower ADC scalar in unilateral posterior centrum semiovale but not in other regions. Temperatures >34 °C were associated with blood pressure above MAPOPT but not with brain injury. CONCLUSIONS: In neonates who were predominantly cooled after 3 h, cooling time was not associated with autoregulation or overall brain injury. Blood pressure deviation above MAPOPT was associated with temperature >34 °C. Additional studies are needed in a more heterogeneous population. IMPACT: Cooling time to reach target hypothermia temperature within 6 h of birth did not affect cerebral autoregulation measured by NIRS in neonates with hypoxic-ischemic encephalopathy (HIE). Temperature fluctuations >33-34 °C were associated with blood pressures that exceeded the range of optimal autoregulatory vasoreactivity. Cooling time within 6 h of birth and temperatures >33-34 °C were not associated with qualitative brain injury on MRI. Regional apparent diffusion coefficient scalars on diffusion tensor imaging MRI were not appreciably affected by cooling time or temperature >33-34 °C. Additional research in a larger and more heterogeneous population is needed to determine how delayed cooling and temperatures beyond the target hypothermia range affect autoregulation and brain injury.

Promoting clinical reasoning with meta-memory techniques to teach broad differential diagnosis generation in a pediatric core clerkship.

OBJECTIVES: Clinical reasoning with generation and prioritization of differential diagnoses (DDx) is a key skill for medical students, but no consensus exists on the best method to teach these skills. Meta-memory techniques (MMTs) may be useful, but the efficacy of individual MMTs is unclear. METHODS: We designed a 3-part curriculum for pediatric clerkship students to teach one of 3 MMTs and provide practice in DDx generation through case-based sessions. Students submitted DDx lists during two sessions and completed pre- and post-curriculum surveys assessing self-reported confidence and perceived helpfulness of the curriculum. Results were analyzed using ANOVA with multiple linear regression. RESULTS: A total of 130 students participated in the curriculum, with 96 % (125/130) completing at least one DDx session, and 44 % (57/130) completing the post-curriculum survey. On average, 66 % of students rated all three sessions as "quite helpful" (4/5 on 5-point Likert scale) or "extremely helpful" (5/5) without difference between MMT groups. Students generated an average of 8.8, 7.1 and 6.4 diagnoses using the VINDICATES, Mental CT, and Constellations methods, respectively. When controlling for case, case order, and number of prior rotations, students using VINDICATES produced 2.8 more diagnoses than those using Constellations (95 % CI [1.1,4.5], p<0.001). There was no significant difference between VINDICATES and Mental CT (Δ=1.6, 95 % CI [-0.2,3.4], p=0.11) or Mental CT and Constellations (Δ=1.2, 95 % CI [-0.7,3.1], p=0.36). CONCLUSIONS: Medical education should include curricula focused on enhancing DDx development. Although VINDICATES helped students produce the most DDx, further research is needed to identify which MMT generates more accurate DDx.

Hepatic and non-hepatic hydrothorax in pediatric ascites.

BACKGROUND: Hydrothorax in the presence of ascites is a serious condition, but it is not well studied, particularly in pediatrics. We aim to identify risk factors for having hydrothorax, compare morbidity and mortality, and report the prevalence of hepatic hydrothorax and non-hepatic hydrothorax in pediatric patients with diagnosis of ascites and hydrothorax. METHODS: This is a retrospective study of pediatric patients under 22 years of age with both ascites and hydrothorax. Hydrothorax was categorized into hepatic and non-hepatic hydrothorax. Demographic data and clinical data including ascites grade, ascites etiology, treatments, length of stay, and death were collected and analyzed using logistic regression. RESULTS: We identified 120 patients with ascites and hydrothorax, 63 (53%) being female. The median age was 13 years (IQR: 4-18). Patients 6 years of age or older (OR=1.90; 95% CI=1.16-3.17; p = 0.012), patients with higher grades of ascites (OR=1.77; 95% CI=1.27-2.47; p < 0.001), those treated with furosemide (OR=2.27; 95% CI=1.37-3.76; p = 0.001), and those with hepatorenal syndrome (OR=4.22; 95% CI=1.19-15.63; p = 0.025) had increased risk of hydrothorax. The underlying etiology of ascites was not associated with mortality, but it was associated with length of stay (p = 0.013), with veno-occlusive disease being the largest contributor. Hepatic versus non-hepatic hydrothorax was also not found to be associated with mortality, but length of stay was significantly greater in former (23 days; IQR=13-38) compared to the latter group (14 days; IQR=8-26) (p = 0.009). CONCLUSIONS: With pediatric ascites, there are  certain risk factors that are associated with having hydrothorax, and ascites etiology may be associated with morbidity.

Development of a composite diffusion tensor imaging score correlating with short-term neurological status in neonatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10-16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10-04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10-13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.

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.