Single-center Experience with Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy in Infants with <36 Weeks' Gestation.

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..

Changes in Cerebral Regional Oxygen Saturation Variability in Neonates Undergoing Cardiac Surgery: A Prospective Cohort Study.

Near-infrared spectroscopy is routinely used in the monitoring of cerebral regional oxygen saturation (crSO2) in neonates following congenital heart surgery. Decreased postoperative crSO2 variability in these patients is associated with worse clinical outcomes, including neurodevelopmental outcomes. We sought to explore changes in crSO2 variability between the preoperative and postoperative periods and associations with short-term clinical outcomes in neonates undergoing cardiac surgery. We performed a prospective cohort study of neonates undergoing cardiac surgery with cardiopulmonary bypass between November 2019 and May 2021. We calculated crSO2 variability using averaged 1 min of crSO2 values for a minimum of 12 h before, and the first 48 h following surgery. 37 neonates (median age at start of monitoring 4 days (interquartile range 2-5 days)) were included in our study. We observed a 30% decrease in crSO2 variability between the preoperative and postoperative monitoring periods (p < 0.001). Preoperative crSO2 variability increased by 9% (p = 0.009) for each additional postnatal day. There were no associations between the degree of decrease in crSO2 variability postoperatively and class of cardiac lesion (e.g., aortic arch obstruction, single ventricle physiology) or short-term postoperative clinical outcomes. There was a significant decrease in postoperative crSO2 variability following neonatal cardiac surgery as compared to the preoperative period, likely influenced by several factors. The impact of interventions on crSO2 variability and resultant influence on long-term outcomes, such as neurodevelopmental outcomes, requires further exploration.

Early Vital Sign Differences in Very Low Birth Weight Infants with Severe Intraventricular Hemorrhage.

OBJECTIVE: Severe intraventricular hemorrhage (sIVH, grades 3 and 4) is a serious complication for very low birth weight (VLBW) infants and is often clinically silent requiring screening cranial ultrasound (cUS) for detection. Abnormal vital sign (VS) patterns might serve as biomarkers to identify risk or occurrence of sIVH. STUDY DESIGN: This retrospective study was conducted in VLBW infants admitted to two level-IV neonatal intensive care units (NICUs) between January 2009 and December 2018. Inclusion criteria were: birth weight <1.5 kg and gestational age (GA) <32 weeks, at least 12 hours of systemic oxygen saturation from pulse oximetry (SpO2) data over the first 24 hours and cUS imaging. Infants were categorized as early sIVH (sIVH identified in the first 48 hours), late sIVH (sIVH identified after 48 hours and normal imaging in the first 48 hours), and no IVH. Infants with grades 1 and 2 or unknown timing IVH were excluded. Mean heart rate (HR), SpO2, mean arterial blood pressure (MABP), number of episodes of bradycardia (HR < 100 bpm), and desaturation (SpO2 < 80%) were compared. RESULTS: A total of 639 infants (mean: 27 weeks' gestation) were included (567 no IVH, 34 early sIVH, and 37 late sIVH). In the first 48 hours, those with sIVH had significantly higher HR compared with those with no IVH. Infants with sIVH also had lower mean SpO2 and MABP and more desaturations <80%. No significant differences in VS patterns were identified in early versus late sIVH. Logistic regression identified higher HR and greater number of desaturations <80% as independently associated with sIVH. CONCLUSION: VLBW infants who develop sIVH demonstrate VS differences with significantly lower SpO2 and higher mean HR over the first 48 hours after birth compared with VLBW infants with no IVH. Abnormalities in early VS patterns may be a useful biomarker for sIVH. Whether VS abnormalities predict or simply reflect sIVH remains to be determined. KEY POINTS: · A higher HR in the first 48 hours is seen in infants with severe IVH.. · Infants with sIVH have lower blood pressure in the first 48 hours.. · Infants with sIVH have more oxygen desaturations in the first 48 hours..

High Prevalence of Abnormal General Movements in Hospitalized Very Low Birth Weight Infants.

OBJECTIVE: Abnormal general movements (GMs) are predictive of later risk of motor impairments in preterm infants. The goals of this study are to (1) describe the implementation of the GM assessment (GMA) in a neonatal intensive care unit (NICU) and (2) investigate the prevalence and evolution of abnormal GMs in very low birth weight (VLBW) infants. STUDY DESIGN: Observational study of GMs in VLBW infants (gestational age [GA] <32 weeks and/or birth weight [BW] <1,500 g) following GMA implementation in a level-IV NICU. All VLBW infants admitted between November 2017 and April 2019 were eligible for the GMA. Infants were excluded if they required high-frequency ventilation or if they could not be unbundled for video acquisition. GMAs were scored weekly by at least 2 GMA-certified providers. RESULTS: The GMA was performed in 121 VLBW infants with a mean (standard deviation [SD]) GA of 28.3 (2.6) and BW of 1,113 (400 g). Only 28% of infants had normal GMs on initial assessment (32.9 ± 2.7 weeks' GA), while 61 and 11% had poor repertoire and cramped-synchronized GMs, respectively. At NICU discharge (37.6 ± 3.4 weeks corrected GA), 45 and 21% of infants were classified as having poor repertoire and cramped-synchronized GMs, respectively. Most infants with cramped-synchronized GMs on initial assessment had persistent abnormal GMs at discharge. In contrast, only one infant with normal GMs on first assessment developed cramped-synchronized GMs. CONCLUSION: Abnormal GMs are common in VLBW infants, including a high prevalence of the more concerning cramped-synchronized movement pattern. The GMA can be successfully performed in VLBW infants. The GMA may be helpful in identifying infants at increased risk of later motor impairments, as well as assisting clinicians, in the stratification of infants who may benefit from additional brain imaging and/or an intensive hospital-based interventions. KEY POINTS: · Abnormal GMs are common in VLBW infants.. · Poor repertoire in the most prevalent pattern observed.. · Infants at risk for abnormal motor outcomes can be identified in the NICU..

Congenital Cutaneous Candidiasis: Prompt Systemic Treatment Is Associated With Improved Outcomes in Neonates.

BACKGROUND: Congenital cutaneous candidiasis (CCC) is a challenging diagnosis due to various rash presentations. Inadequate early treatment is associated with high rates of dissemination and death. The effects of early diagnosis, dermatologic presentation, and antifungal treatment on outcomes are lacking. METHODS: CCC cases were reviewed from 2 academic neonatal intensive care units (NICUs) from 2004 to 2015. We defined CCC as a diffuse rash involving the body, extremities, face or scalp, and/or funisitis, presenting in the first week (≤7 days), with identification of Candida species from skin or mucous membrane cultures, and/or by culture or staining of the placenta or umbilical cord. RESULTS: CCC occurred in 0.1% of all NICU admissions (21 of 19 303) and 0.6% of infants <1000 grams birth weight. Median gestational age of CCC infants was 26 3/7 (range, 23 0/7-40 4/7) weeks. Skin findings were commonly present on the day of birth [median (range): 0 (0-6) days], appearing most frequently as a desquamating, maculopapular, papulopustular, and/or erythematous diffuse rash. When systemic antifungal therapy was started empirically at the time of rash presentation and continued for a median (interquartile range) of 14 (14-15) days, all patients survived and none developed dissemination. Delaying systemic treatment, exclusive use of nystatin, and treating for <10 days was associated with Candida bloodstream dissemination. CONCLUSIONS: CCC is an invasive infection that presents as a diffuse rash in preterm and term infants. Prompt systemic antifungal treatment at the time of skin presentation for ≥14 days prevents dissemination and Candida-related mortality.

Neonatal therapeutic hypothermia outside of standard guidelines: a survey of U.S. neonatologists.

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.

Depressed heart rate variability is associated with abnormal EEG, MRI, and death in neonates with hypoxic ischemic encephalopathy.

OBJECTIVE: Asphyxia can lead to autonomic nervous system dysfunction, including depressed heart rate variability (HRV). We tested the hypothesis that low HRV is associated with adverse short-term outcomes of abnormalities on electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) and death in neonates with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Neonates undergoing hypothermia therapy for HIE underwent monitoring of HRV. HRV in the first day after birth and after hypothermia and rewarming (days 4-7) were analyzed in relation to death and severity of abnormal findings on EEG and MRI. RESULTS: A total of 37 neonates had data available in the first 24 hour after birth and 67 had data days 2 to 7. Depressed HRV was significantly associated with adverse outcomes of death or moderate-to-severe abnormalities on EEG or MRI. In the first 24 hours, the odds ratio (OR) of one or more adverse outcomes for every 10-millisecond decrease in HRV was 3.19 (95% CI, 1.3-7.8; p = 0.01). HRV improved over time but low HRV remained significantly associated with adverse outcomes days 4 to 7 (OR, 2.72; CI, 1.32-5.61; p < 0.01). CONCLUSIONS: Monitoring HRV, which is reflected in the heart rate characteristic index, may provide useful adjunct information on the severity of brain injury in infants with HIE.

Short children born small for gestational age outcomes in the era of growth hormone therapy.

Small-for-gestational age (SGA) infants are at risk for short and long term medical and metabolic complications. Most SGA infants (85-90%) demonstrate spontaneous catch-up growth, typically in the first year after birth. Although catch-up growth (CUG) is a desired goal, it is important to note if CUG is too rapid the infants are at increased risk for insulin resistance and type 2 diabetes mellitus as they become adults. On the flip side, infants who do not exhibit CUG are also at increased risk of adverse adult outcomes including those for cardiovascular disease, insulin resistance and type 2 diabetes mellitus, neurodevelopmental and cognitive impairments, in addition to adult short stature. Treatment with growth hormone is safe and effective not only in increasing adult height, but also in improving body composition and decreasing metabolic complications. The aims of this review are to summarize the current knowledge on what constitutes "healthy" catch-up growth in children born SGA as well as provide an update on the role of growth hormone treatment for short children born SGA.

The Role of Kainate Receptors in the Pathophysiology of Hypoxia-Induced Seizures in the Neonatal Mouse.

Kainate receptors (KARs) are glutamate receptors with peak expression during late embryonic and early postnatal periods. Altered KAR-mediated neurotransmission and subunit expression are observed in several brain disorders, including epilepsy. Here, we examined the role of KARs in regulating seizures in neonatal C57BL/6 mice exposed to a hypoxic insult. We found that knockout of the GluK2 subunit, or blockade of KARs by UBP310 reduced seizure susceptibility during the period of reoxygenation. Following the hypoxic insult, we observed an increase in excitatory neurotransmission in hippocampal CA3 pyramidal cells, which was blocked by treatment with UBP310 prior to hypoxia. Similarly, we observed increased excitatory neurotransmission in CA3 pyramidal cells in an in vitro hippocampal slice model of hypoxic-ischemia. This increase was absent in slices from GluK2-/- mice and in slices treated with UBP310, suggesting that KARs regulate, at least in part, excitatory synaptic neurotransmission following in vivo hypoxia in neonatal mice. Data from these hypoxia models demonstrate that KARs, specifically those containing the GluK2 subunit, contribute to alterations in excitatory neurotransmission and seizure susceptibility, particularly during the reoxygenation period, in neonatal mice. Therapies targeting KARs may prove successful in treatment of neonates affected by hypoxic seizures.

Mechanisms of ischemic neuroprotection by acetyl-L-carnitine.

Acetyl-L-carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl-L-carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl-L-carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl-L-carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl-L-carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.

Modification of glutamate binding sites in newborn brain during hypoglycemia.

We have shown that acute insulin-induced hypoglycemia leads to specific changes in the cerebral NMDA receptor-associated ion channel in the newborn piglet. The present study tests the hypothesis that exposure to acute hypoglycemia in the newborn will alter the glutamate binding site of both NMDA and kainate receptors. Studies were performed in 3-6 days-old piglets randomized to control (n=6) or hypoglycemic (n=6) groups. Hypoglycemia was maintained for 120 min using insulin infusion. Saturation binding assays were performed in cerebral cell membranes using (3)H-glutamate or (3)H-kainate to determine the characteristics of the glutamate binding sites of the NMDA and kainate receptors, respectively. The concentration of glucose in cerebral cortex was 10-fold less in hypoglycemic piglets than in controls (P<0.05). Brain ATP was not significantly decreased during hypoglycemia, but phosphocreatine decreased from control of 6.6 +/- 1.3 micromoles/g brain to 3.2 +/- 1.9 micromoles/g brain in hypoglycemic piglets. The B(max) for NMDA-displaceable (3)H-glutamate binding was 992 +/- 64 fmol/mg protein in hypoglycemic animals, significantly higher than the control value of 746 +/- 42 fmol/mg protein. However, the dissociation constant for glutamate was unchanged during hypoglycemia. The (3)H-kainate binding studies demonstrated no change in B(max) of high-affinity kainate receptors during hypoglycemia. In contrast, the affinity of the kainate receptor glutamate binding site significantly increased compared to control. Thus, acute hypoglycemia in the newborn piglet had specific effects on the glutamate binding sites of the NMDA and kainate receptors that could be due to alterations in cell membrane lipids or modification of receptor proteins.

Time outside targeted oxygen saturation range and retinopathy of prematurity.

OBJECTIVE: To better understand the impact of hypoxia and hyperoxia on neonatal morbidity and mortality, we examined the number of hypoxia and hyperoxia events as well as percentage of time spent outside oxygen saturation targets in relationship to threshold retinopathy of prematurity (tROP) and mortality in preterm infants. STUDY DESIGN: Saturation data in 2-second sampling from pulse oximeters was prospectively collected in a single NICU. Average SaO2, low and high saturation events, duration of events, and percentage of time infants spent outside of oxygen saturation range were collected and analyzed continuously during the hospitalization. RESULTS: 102 infants <1500g or <32 weeks gestation were enrolled. There were 125, 112, and 43 hypoxia events/day and 106, 80, and 34 hyperoxia events/day for tROP (N=8), non-survivor (N=16) and non-tROP patients (N=78), respectively. Infants were outside saturation targets for 2:35, 1:38, and 1:03 (hypoxia) and 2:02, 1:25, and 0:38 hours/day (hyperoxia) for tROP, non-survivor and non-tROP, respectively. Time spent outside saturation range (hypoxia, hyperoxia and total time) for the hospital course was higher in tROP (P≤0.006) and non-survivor (P≤0.005) compared with non-tROP patients. The three groups defined themselves in the first 10 days after birth, with regard to duration of hypoxia (P=0.0003), hyperoxia (P=0.0004) and total time outside the targeted saturation range (P=0.0006). CONCLUSIONS: Information such as the duration and number of hypoxia and hyperoxia events, as well as total time outside the targeted saturation range, could be factored into assessing clinical interventions and research studies in the prevention, treatment and evaluation of neonatal outcomes.

Lessons from the laboratory: the pathophysiology, and consequences of status epilepticus.

Status epilepticus (SE) is the most common neurologic emergency of childhood. Experimental models parallel several clinical features of SE including (1) treatment is complicated by an increasing probability that benzodiazepines will fail with increasing seizure duration and (2) outcome varies with age and etiology. Studies using these models showed that the activity-dependent trafficking of GABA(A) receptors contributes in part to the progressive decline in GABA-mediated inhibition and the failure of the benzodiazepines. Furthermore, laboratory studies have provided evidence that age and inciting stimulus interact to determine the neuronal circuits activated during SE (ie, functional anatomy) and that differences in functional anatomy can partially account for variations in SE outcome. Future laboratory studies are likely to provide an additional understanding of the cellular and molecular mechanisms that underlie SE and its consequences. Such studies are necessary in the development of rational emergent therapy for SE and its long-term outcomes.

Nitric oxide impairs mitochondrial movement in cortical neurons during hypoxia.

Cortical nitric oxide (NO) production increases during hypoxia/ischemia in the immature brain and is associated with both neurotoxicity and mitochondrial dysfunction. Mitochondrial redistribution within the cell is critical to normal neuronal function, however, the effects of hypoxia on mitochondrial dynamics are not known. This study tested the hypothesis that hypoxia impairs mitochondrial movement via NO-mediated pathways. Fluorescently labeled mitochondria were studied using time-lapse digital video microscopy in cultured cortical neurons exposed either to hypoxia/re-oxygenation or to diethyleneamine/nitric oxide adduct, DETA-NO (100-500 microm). Two NO synthase inhibitors, were used to determine NO specificity. Mitochondrial mean velocity, the percentage of movement (i.e. the time spent moving) and mitochondrial morphology were analyzed. Exposure to hypoxia reduced mitochondrial movement to 10.4 +/- 1.3% at 0 h and 7.4 +/- 1.7% at 1 h of re-oxygenation, versus 25.6 +/- 1.4% in controls (p < 0.05). Mean mitochondrial velocity (microm s(-1)) decreased from 0.374 +/- 0.01 in controls to 0.146 +/- 0.01 at 0 h and 0.177 +/- 0.02 at 1 h of re-oxygenation (p < 0.001). Exposure to DETA-NO resulted in a significant decrease in mean mitochondrial velocity at all tested time points. Treatment with NG-nitro-L-arginine methyl ester (L-NAME) prevented the hypoxia-induced decrease in mitochondrial movement at 0 h (30.1 +/- 1.6%) and at 1 h (26.1 +/- 9%) of re-oxygenation. Exposure to either hypoxia/re-oxygenation or NO also resulted in the rapid decrease in mitochondrial size. Both hypoxia and NO exposure result in impaired mitochondrial movement and morphology in cultured cortical neurons. As the effect of hypoxia on mitochondrial movement and morphology can be partially prevented by a nitric oxide synthase (NOS) inhibitor, these data suggest that an NO-mediated pathway is at least partially involved.