Mortality and Timing of Withdrawal of Life-Sustaining Therapies After Out-of-Hospital Cardiac Arrest: Two-Center Retrospective Pediatric Cohort Study.

OBJECTIVES: Pediatric out-of-hospital cardiac arrest (OHCA) is associated with substantial morbidity and mortality. Limited data exist to guide timing and method of neurologic prognostication after pediatric OHCA, making counseling on withdrawal of life-sustaining therapies (WLSTs) challenging. This study investigates the timing and mode of death after pediatric OHCA and factors associated with mortality. Additionally, this study explores delayed recovery after comatose examination on day 3 postarrest. DESIGN: This is a retrospective, observational study based on data collected from hospital databases and chart reviews. SETTING: Data collection occurred in two pediatric academic hospitals between January 1, 2016, and December 31, 2020. PATIENTS: Patients were identified from available databases and electronic medical record queries for the International Classification of Diseases , 10th Edition (ICD-10) code I46.9 (Cardiac Arrest). Patient inclusion criteria included age range greater than or equal to 48 hours to less than 18 years, OHCA within 24 hours of admission, greater than or equal to 1 min of cardiopulmonary resuscitation, and return-of-spontaneous circulation for greater than or equal to 20 min. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-five children (65% male) with a median age of 3 years (interquartile range 0.6-11.8) met inclusion criteria. Overall, 63 of 135 patients (47%) died before hospital discharge, including 34 of 63 patients (54%) after WLST. Among these, 20 of 34 patients underwent WLST less than or equal to 3 days postarrest, including 10 of 34 patients who underwent WLST within 1 day. WLST occurred because of poor perceived neurologic prognosis in all cases, although 7 of 34 also had poor perceived systemic prognosis. Delayed neurologic recovery from coma on day 3 postarrest was observed in 7 of 72 children (10%) who ultimately survived to discharge. CONCLUSIONS: In our two centers between 2016 and 2020, more than half the deaths after pediatric OHCA occurred after WLST, and a majority of WLST occurred within 3 days postarrest. Additional research is warranted to determine optimal timing and predictors of neurologic prognosis after pediatric OHCA to better inform families during goals of care discussions.

Conditioning- and time-dependent increases in context fear and generalization.

A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2 mA, 2 sec) during contextual fear conditioning. Following a recent (1 d) or remote (28 d) retention interval all subjects were returned to the original training context to measure fear memory and/or to a novel context to measure the specificity of fear conditioning. Our results indicate rats that received two or five shocks show an "incubation"-like enhancement of fear between recent and remote retention intervals, while single-shocked animals show stable levels of context fear memory. Moreover, when fear was tested in a novel context, 1 and 2 shocked groups failed to freeze, whereas five shocked rats showed a time-dependent generalization of context memory. Stress enhancement of fear learning to a second round of conditioning was evident in all previously shocked animals. Based on these results, we conclude that the severity or number of foot shocks determines not only the level of fear memory, but also the time-dependent incubation of fear and its generalization across distinct contexts.

The Relationship Between Temperature and Temporal Patterns and Incidence of Abusive Head Trauma in a Midwest Region Hospital.

Background: Abusive head trauma (AHT) is a leading cause of death and disability in children and one of the most lethal forms of child abuse. Most known risk factors for AHT pertain to the infant's caregiver and limited research has assessed external influences beyond the familial or caregiver/infant dyad. Objective: Our primary objective was to determine if temperature patterns are associated with AHT events. Secondary outcomes included associations between AHT and specific days of the week, months, or seasons. Methods: This was a retrospective review of 198 patients under 24 months old who were diagnosed with AHT at Saint Louis Children's Hospital. Demographic information was obtained from the medical record for each patient. For each AHT incident, the date and zip code of the incident were recorded. Temperature on the date of incident was identified using the Midwestern Regional Climate Center (MRCC). Chi square tests were utilized to calculate differences in cases per year as well as temperature and seasonal variation. Results: Temperature was not associated with a statistically significant increase in cases of AHT. There was an increase in cases as temperatures rose, but no statistically significant associations between incidence of AHT and day of the week, month, or season. Conclusion: Our study suggests no significant association between AHT incidence and temperature or temporal patterns in this Midwest hospital.

Seizure Burden, EEG, and Outcome in Neonates With Acute Intracranial Infections: A Prospective Multicenter Cohort Study.

BACKGROUND: Limited data exist regarding seizure burden, electroencephalogram (EEG) background, and associated outcomes in neonates with acute intracranial infections. METHODS: This secondary analysis was from a prospective, multicenter study of neonates enrolled in the Neonatal Seizure Registry with seizures due to intracranial infection. Sites used continuous EEG monitoring per American Clinical Neurophysiology Society guidelines. High seizure burden was defined a priori as seven or more EEG-confirmed seizures. EEG background was categorized using standardized terminology. Primary outcome was neurodevelopment at 24-months corrected age using Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS). Secondary outcomes were postneonatal epilepsy and motor disability. RESULTS: Twenty-seven of 303 neonates (8.9%) had seizures due to intracranial infection, including 16 (59.3%) bacterial, 5 (18.5%) viral, and 6 (22.2%) unknown. Twenty-three neonates (85%) had at least one subclinical seizure. Among 23 children with 24-month follow-up, the WIDEA-FS score was, on average, 23 points lower in children with high compared with low seizure burden (95% confidence interval, [-48.4, 2.1]; P = 0.07). After adjusting for gestational age, infection etiology, and presence of an additional potential acute seizure etiology, the effect size remained unchanged (ß = -23.8, P = 0.09). EEG background was not significantly associated with WIDEA-FS score. All children with postneonatal epilepsy (n = 4) and motor disability (n = 5) had high seizure burden, although associations were not significant. CONCLUSION: High seizure burden may be associated with worse neurodevelopment in neonates with intracranial infection and seizures. EEG monitoring can provide useful management and prognostic information in this population.

NMNAT3 is protective against the effects of neonatal cerebral hypoxia-ischemia.

OBJECTIVE: To determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase-3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia-ischemia (H-I) and reducing glutamate receptor-mediated excitotoxic neurodegeneration of immature neurons. METHODS: Using NMNAT3-overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H-I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3-dependent neuroprotection. Using AAV8-mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor-mediated excitotoxicity. RESULTS: NMNAT3 mRNA and protein levels increased after neonatal H-I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase-3 activity and calpain-mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3. CONCLUSIONS: Our observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H-I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic-ischemic encephalopathy.

Amnesia for early life stress does not preclude the adult development of posttraumatic stress disorder symptoms in rats.

BACKGROUND: Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms. METHODS: Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors. RESULTS: Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks. CONCLUSIONS: These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma.