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BACKGROUND: We aimed to describe our experience with gabapentin use in infants admitted to our neonatal intensive care unit (NICU), including neurodevelopmental follow-up after discharge. METHODS: We performed a retrospective medical record review of infants prescribed gabapentin during admission to the University of Virginia NICU from 01/01/2015 to 04/30/2021. We report clinical characteristics including gabapentin indication, dosing and side-effects while in the NICU, discharge data, and assessments in outpatient developmental follow-up clinic. RESULTS: Gabapentin was prescribed to 104 infants (median gestational age 29 weeks, median postmenstrual age at initiation 41 weeks). Sixty-one percent of infants were male. The primary indication was irritability in 86%, and 67% were receiving at least one other neurosedative medication. Median maximum dose was 25 mg/kg/day (IQR 15–35 mg/kg/day) and 84% were discharged home on gabapentin. The majority required equipment at discharge (64% gastrostomy or nasogastric tube feeds, 54% supplemental oxygen or mechanical ventilation, and 40% both). At the first neurodevelopmental follow-up appointment, at least one area of delay was identified in 93% of infants and by 2 years corrected age 66% had a diagnosis of global developmental delay. CONCLUSIONS: NICU patients treated with gabapentin often require complex post-discharge care and require close neurodevelopmental follow up. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sedation is recommended to optimize neuroprotection in neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Dexmedetomidine is an alternative agent to opioids, which are commonly used but have adverse effects. Both TH and dexmedetomidine can cause bradycardia. In this study, we describe our experience with dexmedetomidine and fentanyl in neonates undergoing TH for HIE, with a focus on heart rate (HR). METHODS: We performed a retrospective chart review from 2011–2019 at a level IV NICU comparing sedation with dexmedetomidine (n = 14), fentanyl (n = 120), or both (n = 32) during TH for HIE. HR trends were compared based on sedation and gestational age. Neonates were included if they underwent TH and received sedation and were excluded if cooling was initiated past 24hours (h) from birth or if they required ECMO. RESULTS: Of the 166 neonates included, 46 received dexmedetomidine, 14 as monotherapy and 32 in combination with fentanyl. Mean hourly HR from 12–36 h after birth was significantly lower for infants on dexmedetomidine versus fentanyl monotherapy (91±9 vs. 103±11 bpm, p < 0.002). Dexmedetomidine was decreased or discontinued in 22 (47.8%) neonates, most commonly due to inadequate sedation with a low HR. Lower gestational age was associated with higher HR but no significant difference in dexmedetomidine-related HR trends. CONCLUSIONS: Despite an association with lower HR, dexmedetomidine may be successfully used in neonates with HIE undergoing TH. Implementation of a standardized protocol may facilitate dexmedetomidine titration in this population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the nutritional impact of a feed-holding guideline during transfusion for infants <32 weeks gestation. STUDY DESIGN: A pre-/post-interventional study was conducted after introduction of a guideline to hold feeds during transfusion. Demographic variables in addition to nutritional outcomes were collected on all infants admitted within 48 hours of birth with gestational age <32 weeks. Data was collected during a 6 month period pre-intervention and the 6 month period post-intervention. RESULTS: There were 145 eligible infants. Mean birth weight and gestational age were similar in both periods. In total, 98 infants received transfusions, and 82 of those had an active feeding order prior to at least one transfusion. Total transfusions per infant and transfusions ordered while an infant had active feeding orders were similar in both periods. Time to full feedings was decreased post-intervention (p < 0.001).Weight at 34 weeks, incidence of second IV placement, additional IV fluid use, and hypoglycemia were similar between groups. Of 593 total transfusions, 207 were ordered while an infant had an active order for enteral nutrition. Pre-intervention, 64% of transfusions had feeds held during transfusion. Post-intervention, 87% of transfusions had feeds held during transfusion. Feeds were held more often (p < 0.001) and for a shorter duration (p = 0.005) in the post-intervention group. CONCLUSION: Implementing a guideline standardizing feeding practices during transfusions in premature infants increases standardization of care and results in decreased variability in practice. Adverse nutritional consequences were not found after the introduction of the routine practice of holding feedings during transfusion in preterm infants. [ABSTRACT FROM AUTHOR]

Background/objectives: Motor deficits following neonatal brain injury, from cerebral palsy to subtle deficits in motor planning, are common yet underreported. Rodent models of motor deficits in neonatal hypoxia-ischemia (HI) allow improved understanding of the underlying mechanisms and neuroprotective strategies. Our goal was to test motor performance and learning in a mouse model of neonatal HI., Methods: We induced HI in postnatal day (p)10 C57/Bl6 mice through unilateral carotid ligation followed by 60 min of 8% oxygen exposure, or a sham procedure. At p30, we assessed complex motor performance and learning using the accelerating rotarod and complex running wheel tasks., Results: In the rotarod task, HI mice performed worse than sham mice, with shorter latencies to fall (n = 6 sham, 9 HI; day 1, p = 0.033; day 2, p = 0.013; day 3, p = 0.023). Sham mice demonstrated improved performance across days ( p = 0.005), and HI mice did not ( p = 0.44). During the simple running wheel task, we observed no difference in wheel rotation and speed between groups (n = 5/group; day 1, p = 0.67; day 4, p = 0.53). However, when navigating a wheel with a random pattern of spokes removed (complex task), HI mice took longer than sham mice to reach a plateau in performance (n = 5/group; day 1, p = 0.02; day 4, p = 0.77)., Conclusions: Our findings demonstrate that young adult mice exposed to HI exhibit significant deficits and delayed learning in complex motor performance compared to sham mice. HI mice do not show deficits in gross motor performance; however, more subtle impairments are present in complex motor performance and learning. This HI model exhibits subtle motor deficits relevant to findings in humans and may be a useful tool in testing further neuroprotective strategies.

Purpose: This study investigated the psychometric properties of a 4-second interval scoring modification of the Assessment of Problem-Solving in Play (ie, Assessment of Problem-Solving in Play 4-second interval scoring [APSP-4])., Methods: A total of 95 children (3-48 months) with or at high risk for neuromotor delay were assessed with the APSP-4 and Bayley Scales of Infant and Toddler Development-III (Bayley). APSP-4 and Bayley cognitive raw scores were compared by age (construct validity) and over time (responsiveness). Twenty percent of videos were scored twice for intra- and interrater reliability., Results: The APSP-4 demonstrated excellent interrater (intraclass correlations [ICCs] ≥ 0.96) and intrarater (ICCs ≥ 0.99) reliability and performed similar to Bayley cognitive raw scores at different ages ( r s > 0.5), and over time ( r  = 0.81). The motor delay had similar effects on APSP-4 and Bayley scores., Conclusions: Results support the validity and reliability evidence of the APSP-4 for use over time in tracking problem-solving skills in young children aged 3 to 48 months. Future research investigating clinical implementation of the APSP-4 is needed., (Copyright © 2024 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Objective:  Hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in neonates. Therapeutic hypothermia (TH) has improved outcomes and mortality in infants with >36 weeks' gestational age (GA) with moderate-to-severe HIE. There are limited data on the safety and efficacy of TH in preterm infants with HIE. This study describes our experience and examines the safety of TH in neonates with <36 weeks' GA., Study Design: A single-center, retrospective study of preterm neonates born at <36 weeks' GA with moderate-to-severe HIE and treated with TH, compared to a cohort of term neonates with HIE (≥37 weeks' GA), was conducted. The term cohort was matched for degree of background abnormality on electroencephalogram, sex, inborn versus outborn status, and birth year. Medical records were reviewed for pregnancy and delivery complications, need for transfusion, sedation and antiseizure medications, electroencephalography and imaging findings, and in-hospital mortality., Results:  Forty-two neonates born at <36 weeks' GA with HIE received TH between 2005 and 2022. Data from 42 term neonates were analyzed for comparison. The average GA of the preterm cohort was 34.6 weeks and 39.3 weeks for the term cohort. Apgar scores, degree of acidosis, and need for blood product transfusions were similar between groups. Preterm infants were more likely to require inotropic support (55 vs. 29%, p  = 0.026) and hydrocortisone (36 vs. 12%, p  = 0.019) for hypotension. The proportion of infants without evidence of injury on magnetic resonance imaging was similar in both groups: 43 versus 50% in preterm and term infants, respectively. No significant difference was found in mortality between groups., Conclusion:  In this single-center cohort, TH in preterm infants appears to be as safe as in term infants, with no significant increase in intracranial bleeds or mortality. Preterm infants more frequently required inotropes and steroids for hypotension. Further research is needed to determine efficacy of TH in preterm infants., Key Points: · TH is used off-protocol in preterm infants.. · Preterm and term infants have similar mortality.. · Preterm cohort required more inotropic support.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To examine acute seizure activity and neuronal damage in a neonatal mouse model of inflammation-sensitized hypoxic-ischemic (IS-HI) brain injury utilizing continuous electroencephalography (cEEG) and neurohistology., Methods: Neonatal mice were exposed to either IS-HI with Escherichia coli lipopolysaccharide (LPS) or HI alone on postnatal (p) day 10 using unilateral carotid artery ligation followed by global hypoxia (n = 10 [5 female, 5 male] for IS-HI, n = 12 [5 female, 7 male] for HI alone). Video cEEG was recorded for the duration of the experiment and analyzed for acute seizure activity and behavior. Brain tissue was stained and scored based on the degree of neuronal injury in the hippocampus, cortex, and thalamus., Results: There was no significant difference in acute seizure activity among mice exposed to IS-HI compared to HI with regards to seizure duration (mean = 63 ± 6 seconds for HI vs mean 62 ± 5 seconds for IS-HI, p = 0.57) nor EEG background activity. Mice exposed to IS-HI had significantly more severe neural tissue damage at p30 as measured by neuropathologic scores (mean = 8 ± 1 vs 23 ± 3, p < 0.0001)., Interpretation: In a neonatal mouse model of IS-HI, there was no significant difference in acute seizure activity among mice exposed to IS-HI compared to HI. Mice exposed to IS-HI did show more severe neuropathologic damage at a later age, which may indicate the presence of chronic inflammatory mechanisms of brain injury distinct from acute seizure activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 June et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding the type and frequency of current neonatal intensive care unit (NICU) therapy services and predictors of referral for therapy services is a crucial first step to supporting positive long-term outcomes in very preterm infants. This study enrolled 83 very preterm infants (<32 weeks, gestational age mean 26.5 ± 2.0 weeks; 38 male) from a longitudinal clinical trial. Race, neonatal medical index, neuroimaging, and frequency of therapy sessions were extracted from medical records. The Test of Infant Motor Performance and the General Movement Assessment were administered. Average weekly sessions of occupational therapy, physical therapy, and speech therapy were significantly different by type, but the magnitude and direction of the difference depended upon the discharge week. Infants at high risk for cerebral palsy based on their baseline General Movements Assessment scores received more therapy sessions than infants at low risk for cerebral palsy. Baseline General Movements Assessment was related to the mean number of occupational therapy sessions but not physical therapy or speech therapy sessions. Neonatal Medical Index scores and Test of Infant Motor Performance scores were not predictive of combined therapy services. Medical and developmental risk factors, as well as outcomes from therapy assessments, should be the basis for referral for therapy services in the neonatal intensive care unit.

Families ( n = 12) with infants born at <29 weeks gestation shared their experiences while in the NICU and transitioning home. Parents were interviewed 6-8 weeks after NICU discharge, including some during the acute phase of the COVID-19 pandemic. Findings regarding the parent experience in the NICU were focused around challenges navigating parent-infant separation, social isolation, communication difficulties, limited knowledge of preterm infants, mental health challenges. Parents also discussed supports that were present and supports they wished were present, as well as the impact of COVID-19 on their experiences. In the transition to home, primary experiences included the sudden nature of the transition, anxiety around discharge preparation, and the loss of the support from nursing staff. During the first few weeks at home, parents expressed joy and anxiety, particularly around feeding. The COVID-19 pandemic limited emotional, informational, and physical support to parents and resulted in limited mutual support from other parents of infants in the NICU. Parents of preterm infants in the NICU present with multiple stressors, rendering attending to parental mental health crucial. NICU staff need to address logistical barriers and familial priorities impacting communication and parent-infant bonding. Providing multiple opportunities for communication, participating in caretaking activities, and meeting other families can be important sources of support and knowledge for parents of very preterm infants.

Postnatal maturation of the motor cortex is vital to developing a variety of functions, including the capacity for motor learning. The first postnatal weeks involve many neuronal and synaptic changes, which differ by region and layer, likely due to different functions and needs during development. Motor cortex layer II/III is critical to receiving and integrating inputs from somatosensory cortex and generating attentional signals that are important in motor learning and planning. Here, we examined the neuronal and synaptic changes occurring in layer II/III pyramidal neurons of the mouse motor cortex from the neonatal (postnatal day 10) to young adult (postnatal day 30) period, using a combination of electrophysiology and biochemical measures of glutamatergic receptor subunits. There are several changes between p10 and p30 in these neurons, including increased dendritic branching, neuronal excitability, glutamatergic synapse number and synaptic transmission. These changes are critical to ongoing plasticity and capacity for motor learning during development. Understanding these changes will help inform future studies examining the impact of early-life injury and experiences on motor learning and development capacity., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The tish (telencephalic internal structural heterotopia) rat is a naturally occurring and unique model of a malformation of cortical development (MCD) arising from a sponeantous mutation in the Eml1 gene. Tish rats are characterized by a macroscopic bilateral heterotopic dysplastic cortex (HDCx) and an overlaying, intact normotopic neocortex (NNCx). These two cortices are functional and have been reported to innervate and establish connections with subcortical regions including the thalamus, resulting in a dual-cortical representation. Additionally, impaired GABAergic neurotransmission and early-onset spike wave discharge bursts have been reported in developing tish rats. Perineuronal nets (PNNs) are specialized extraceullar matrix structures that predominately surround and stabilize parvalbumin-positive (PV + ) GABAergic interneurons and are essential components of the neural landscape. Here, we report a significant reduction in the average number of WFA + -PNNs in the normotopic somatosensory cortex (NSSCx) of the tish rat at two developmental time points, P16 and P35, corresponding to a decrease in the number of PV + interneurons ensheathed by a PNN in the NSSCx. Compared with control animals, PNN expression was partially, but significantly restored following treatment with insulin-like growth factor 1 (IGF-1). These data suggest that the 'dual cortical representation' in the setting of an MCD reduces the cortical activation necessary for proper PNN expression likely contributing to the impairments in GABAergic neurotransmission and network excitability previously identified in the tish rat., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Infants born very preterm (VPT; ≤29 weeks of gestation) are at high risk of developmental disabilities and abnormalities in neural white matter characteristics. Early physical therapy interventions such as Supporting Play Exploration and Early Development Intervention (SPEEDI2) are associated with improvements in developmental outcomes. Six VPT infants were enrolled in a randomised clinical trial of SPEEDI2 during the transition from the neonatal intensive care unit to home over four time points. Magnetic resonance imaging scans and fixel-based analysis were performed, and fibre density (FD), fibre cross-section (FC), and fibre density and cross-section values (FDC) were computed. Changes in white matter microstructure and macrostructure were positively correlated with cognitive, motor, and motor-based problem solving over time on developmental assessments. In all infants, the greatest increase in FD, FC, and FDC occurred between Visit 1 and 2 (mean chronological age: 2.68-6.22 months), suggesting that this is a potential window of time to optimally support adaptive development. Results warrant further studies with larger groups to formally compare the impact of intervention and disparity on neurodevelopmental outcomes in infants born VPT.

Objective: Infants with a history of neonatal hypoxic-ischemic encephalopathy (HIE) are at risk for oral motor dysfunction. Previous studies have associated the need for gastrostomy tube at neonatal intensive care unit discharge with brainstem injury on magnetic resonance imaging (MRI). However, the factors associated with time to full oral feeds in this population have not been previously described. This study aimed to study factors associated with time to full oral feeds in this population., Study Design: This is a single-center, retrospective study that examined these factors using Cox regression., Results: A total of 150 infants who received therapeutic hypothermia from 2011 to 2017 were included in this study. The single clinical factor significantly associated with time to full oral feeds was the severity of background abnormality on electroencephalogram in the first 24 hours of age (severe vs. mild 95% confidence interval [CI]: 0.34-0.74; moderate vs. mild 95% CI: 0.19-0.45). Brainstem injury on MRI was the factor most highly associated with need for gastrostomy tube placement ( p  = 0.028), though the overall incidence of need for gastrostomy tube feeds in this population was low (5%)., Conclusion: These findings may help clinicians counsel families on what to expect in neonates with HIE and make decisions on the need for and timing to pursue gastrostomy tube in this population., Key Points: · The overall incidence of the need for assisted feeding at NICU discharge is low in this population.. · MRI brainstem injury was most highly associated with need for gastrostomy tube placement.. · Worsening severity of background abnormality on EEG was associated with longer time to oral feeds.., Competing Interests: None declared., (Thieme. All rights reserved.)

Whole-brain mapping is an effective approach to investigate which brain areas are activated by the exploration of a novel environment. Previous studies analyzing neuronal activity promoted by novelty focused mostly on one specific area instead of the whole brain and measured activation using cfos immunohistochemistry. In this study, we utilized TRAP2 mice exposed to a novel and familiar environment to examine neuronal activity in exploratory, learning, and memory circuits. We analyzed the behavior of mice during environment exploration. Brain tissue was processed using tissue clarification and neurons active during exploration of an environment were mapped based on the cfos expression. Neuronal activity after each experience were quantified in regions of interest. We observed increased exploratory behavior in mice exposed to a novel environment in comparison to familiar (170.5 s ± 6.47 vs. 112.5 s ± 9.54, p = 0.0001). Neuronal activity was significantly increased in the dentate gyrus (115.56 ± 53.84 vs. 32.24 ± 12.32, p = 0.02) during the exploration of a novel environment. Moreover, examination of the remaining regions of interest showed some increase in the number of active neurons in the novel condition, however, those differences were not statistically significant. Brief exposure to a novel environment results in increased exploratory behavior and significant neuronal activity in the dentate gyrus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cutaneous mucormycosis is a rare, often fatal fungal infection that most commonly affects patients with underlying immunosuppression but also can occur in premature neonates. We report the case of an extremely premature boy (<25 weeks) who developed primary cutaneous mucormycosis shortly after birth. Although surgical debridement has been a mainstay of treatment in combination with antifungal therapy, our patient was successfully treated with amphotericin B alone-the management only reported in three other cases to date. We present this case to highlight that prompt initiation of treatment with amphotericin B alone may be an appropriate alternative to surgical intervention, particularly in patients with non-angioinvasive disease who are poor surgical candidates., (© 2021 Wiley Periodicals LLC.)

Hypoxia ischemia is the most common cause of neonatal seizures. Animal models are crucial for understanding the mechanisms and physiology underlying neonatal seizures and hypoxia ischemia. This manuscript describes a method for continuous video electroencephalogram (EEG) monitoring in neonatal mice to detect seizures and analyze EEG background during hypoxia ischemia. Use of video and EEG in conjunction allows description of seizure semiology and confirmation of seizures. This method also allows analysis of power spectrograms and EEG background pattern trends over the experimental time period. In this hypoxia ischemia model, the method allows EEG recording prior to injury to obtain a normative baseline and during injury and recovery. Total monitoring time is limited by the inability to separate pups from the mother for longer than four hours. Although, we have used a model of hypoxic-ischemic seizures in this manuscript, this method for neonatal video EEG monitoring could be applied to diverse disease and seizure models in rodents.

Objective: To identify circuits active during neonatal hypoxic-ischemic (HI) seizures and seizure propagation using electroencephalography (EEG), behavior, and whole-brain neuronal activity mapping., Methods: Mice were exposed to HI on postnatal day 10 using unilateral carotid ligation and global hypoxia. EEG and video were recorded for the duration of the experiment. Using immediate early gene reporter mice, active cells expressing cfos were permanently tagged with reporter protein tdTomato during a 90-minute window. After 1 week, allowing maximal expression of the reporter protein, whole brains were processed, lipid cleared, and imaged with confocal microscopy. Whole-brain reconstruction and analysis of active neurons (colocalized tdTomato/NeuN) were performed., Results: HI resulted in seizure behaviors that were bilateral or unilateral tonic-clonic and nonconvulsive in this model. Mice exhibited characteristic EEG background patterns such as burst suppression and suppression. Neuronal activity mapping revealed bilateral motor cortex and unilateral, ischemic somatosensory cortex, lateral thalamus, and hippocampal circuit activation. Immunohistochemical analysis revealed regional differences in myelination, which coincide with these activity patterns. Astrocytes and blood vessel endothelial cells also expressed cfos during HI., Interpretation: Using a combination of EEG, seizure semiology analysis, and whole-brain neuronal activity mapping, we suggest that this rodent model of neonatal HI results in EEG patterns similar to those observed in human neonates. Activation patterns revealed in this study help explain complex seizure behaviors and EEG patterns observed in neonatal HI injury. This pattern may be, in part, secondary to regional differences in development in the neonatal brain. ANN NEUROL 2019;86:927-938., (© 2019 American Neurological Association.)

Aim: Therapeutic hypothermia is standard of care in term infants with moderate-to-severe hypoxic-ischaemic encephalopathy (HIE). The goal of this survey was to explore the attitudes of U.S. neonatologists caring for infants with HIE who fall outside of current guidelines., Methods: Case-based survey administered to members of the Section on Neonatal-Perinatal Medicine of the American Academy of Pediatrics., Results: A total of 447 responses were analysed, a response rate of 19%. We found significant variability amongst U.S. neonatologists with regard to the use of therapeutic hypothermia for infants with HIE who fall outside standard inclusion criteria. Scenarios with the most variability included HIE in a late preterm infant and HIE following a postnatal code. Provision of therapeutic hypothermia outside of standard guidelines was not influenced by number of years in practice, neonatal intensive care type (NICU) or NICU size., Conclusion: Significant variability in practice exists when caring for infants with HIE who do not meet standard inclusion criteria, emphasizing the need for continued and rigorous research in this area., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: To investigate if frequency-dependent contrasts using oscillating gradient diffusion MRI (dMRI) can detect hypoxia-ischemia (HI) -induced neurodegeneration in the neonatal mouse hippocampus., Methods: Pulsed- and oscillating-gradient dMR images (at 50, 100, and 150 Hz) were acquired from postmortem fixed brains of mice exposed to neonatal HI using the Rice-Vanucci model. MRI data were acquired at 1, 4, and 8 days following HI, and compared with histological data from the same mice for in situ histological validation of the MRI findings., Results: The rate of change of apparent diffusion coefficient with gradient frequency (Δf ADC) revealed unique layer-specific contrasts in the neonatal mouse hippocampus. Δf ADC measurements were found to show a significant decrease in response to neonatal HI injury, in the pyramidal (Py) and granule (GrDG) cell layers compared with contralateral regions. The areas of reduced intensity in the Δf ADC maps corresponded to regional neurodegeneration seen with H&E and Fluoro-Jade C stainings, indicating that alterations in Δf ADC contrasts are sensitive to early microstructural changes due to HI-induced neurodegeneration in the studied regions., Conclusion: The findings show that the frequency-dependence of ADC measurements with oscillating-gradient dMRI can provide a sensitive contrast to detect HI-induced neurodegeneration in neuronal layers of the neonatal mouse hippocampus., (Copyright © 2013 Wiley Periodicals, Inc.)