Impact of ABCC8 and TRPM4 genetic variation in central nervous system dysfunction associated with pediatric sepsis.

BACKGROUND: Sepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a non-selective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis. METHODS: 326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact. RESULTS: Pooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), p-value = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, p-value = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4. CONCLUSION: This study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. While exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants.

Effectiveness of Fosphenytoin and Levetiracetam to Prevent Posttraumatic Seizures in Young Children with Accidental or Abusive Traumatic Brain Injury.

BACKGROUND: Seizures occur frequently in pediatric patients with traumatic brain injury (TBI), particularly abusive head trauma (AHT). There are limited data on the effectiveness of fosphenytoin and levetiracetam to prevent posttraumatic seizures. METHODS: We performed a retrospective single center cohort study of children < 3 years old admitted with mild [Glasgow Coma Scale (GCS) score 13-15], moderate (GCS 9-12), and severe (GCS 3-8) TBI at a level I trauma center from 2011 to 2021. Antiseizure medications were used at the discretion of the treating physicians. Nonparametric tests were used to compare antiseizure medication prophylaxis and TBI etiology. RESULTS: A total of 717 patients (263 with AHT, 454 with accidental TBI) were included, of whom 135 (19%) received fosphenytoin, 152 (21%) received levetiracetam, and 430 (60%) did not receive any seizure prophylaxis. Over the study period, the use of fosphenytoin prophylaxis decreased (R2 = 0.67, p = 0.004), whereas the use of levetiracetam increased (R2 = 0.51, p = 0.008). Additionally, the occurrence of early posttraumatic seizures decreased (R2 = 0.58, p = 0.006). Children with AHT were more likely to receive any seizure prophylaxis than those with accidental TBI (52% vs. 27%; p < 0.001) and were more likely to have ≥ 1 seizure during hospitalization (22% vs. 4%; p < 0.001). Among children who received seizure prophylaxis, those who received fosphenytoin had a higher occurrence of seizures than those who received levetiracetam (33% vs.18%; p = 0.004). After controlling for age, admission year, TBI mechanism, and severity of injury, we observed no differences in seizure occurrence between groups. CONCLUSIONS: In children < 3 years old with TBI, no differences were observed in occurrence of seizures between patients who received fosphenytoin and patients who received levetiracetam prophylaxis after controlling for patient factors including severity of injury. Levetiracetam may be an equally effective alternative to fosphenytoin for seizure prophylaxis for early posttraumatic seizure prevention in this age group.

Association Between Persistent Hypothermia After Cardiopulmonary Bypass in Neonates and Odds of Serious Complications.

IMPORTANCE: Persistent hypothermia after cardiopulmonary bypass (CPB) in neonates with congenital heart defects (CHD) has been historically considered benign despite lack of evidence on its prognostic significance. OBJECTIVES: Examine associations between the magnitude and pattern of unintentional postoperative hypothermia and odds of complications in neonates with CHD undergoing CPB. DESIGN: Retrospective cohort study. SETTING: Single northeastern U.S., urban pediatric quaternary care center with an established cardiac surgery program. PARTICIPANTS: Population-based sample of neonates greater than or equal to 34 weeks gestation undergoing their first CPB between 2015 and 2019. INTERVENTIONS: None. MAIN OUTCOMES AND MEASUREMENTS: Hourly temperature measurements for the first 48 postoperative hours were extracted from inpatient medical records, and clinical characteristics and outcomes were accessed through the local patient registry. Group-based trajectory modeling (GBTM) identified latent temporal temperature trajectories. Associations of trajectories with outcomes were assessed using multivariable binary logistic regression. Outcomes (postoperative complications) were manually adjudicated by experts or were predefined by the patient registry. RESULTS: Four hundred fifty neonates met inclusion criteria. Their mean (sd) gestational age was 38 weeks (1.3), mean (sd) birth weight was 3.19 kilograms (0.55), median (interquartile range) surgical age was 4.7 days (3.3-7.0), 284 of 450 (63%) were male, and 272 of 450 (60%) were White. GBTM identified three distinct curvilinear temperature trajectories: persistent hypothermia (n = 38, 9%), resolving hypothermia (n = 233, 52%), and normothermia (n = 179, 40%). Compared with the normothermic group, those with persistent hypothermia had significantly higher odds of cardiac arrest, actionable arrhythmia, delayed first successful extubation, prolonged cardiac ICU length of stay, very poor weight gain, and 30-day hospital mortality. The persistent hypothermia group was characterized by greater odds of having a lower gestational age, more prevalent neurologic abnormalities, more unplanned reoperations, and a low surgical mortality risk assessment. CONCLUSIONS: Persistent postoperative hypothermia in neonates after CPB is independently associated with having greater odds of complications. Recovery patterns from postoperative hypothermia may be a clinically useful marker to identify patient instability in neonates. Additional research is needed for causal modeling and prospective validation before clinical adoption.

A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Retrospective Validation of a Computerized Physiologic Equation to Predict Minute Ventilation Needs in Critically Ill Children.

OBJECTIVES: Mechanical ventilation (MV) is pervasive among critically ill children. We sought to validate a computerized physiologic equation to predict minute ventilation requirements in children and test its performance against clinician actions in an in silico trial. DESIGN: Retrospective, electronic medical record linkage, cohort study. SETTING: Quaternary PICU. PATIENTS: Patients undergoing invasive MV, serial arterial blood gas (ABG) analysis within 1-6 hours, and pharmacologic neuromuscular blockade (NMB). MEASUREMENTS AND MAIN RESULTS: ABG values were filtered to those occurring during periods of NMB. Simultaneous ABG and minute ventilation data were linked to predict serial Pa co2 and pH values using previously published physiologic equations. There were 15,121 included ABGs across 500 encounters among 484 patients, with a median (interquartile range [IQR]) of 20 (10-43) ABGs per encounter at a duration of 3.6 (2.1-4.2) hours. The median (IQR) Pa co2 prediction error was 0.00 (-3.07 to 3.00) mm Hg. In Bland-Altman analysis, the mean error was -0.10 mm Hg (95% CI, -0.21 to 0.01 mm Hg). A nested, in silico trial of ABGs meeting criteria for weaning (respiratory alkalosis) or escalation (respiratory acidosis), compared the performance of recommended ventilator changes versus clinician decisions. There were 1,499 of 15,121 ABGs (9.9%) among 278 of 644 (43.2%) encounters included in the trial. Calculated predictions were favorable to clinician actions in 1124 of 1499 ABGs (75.0%), equivalent to clinician choices in 26 of 1499 ABGs (1.7%), and worse than clinician decisions in 349 of 1499 ABGs (23.3%). Calculated recommendations were favorable to clinician decisions in sensitivity analyses limiting respiratory rate, analyzing only when clinicians made changes, excluding asthma, and excluding acute respiratory distress syndrome. CONCLUSIONS: A computerized equation to predict minute ventilation requirements outperformed clinicians' ventilator adjustments in 75% of ABGs from critically ill children in this retrospective analysis. Prospective validation studies are needed.

Brain-Derived Neurotrophic Factor in Pediatric Acquired Brain Injury and Recovery.

We review emerging preclinical and clinical evidence regarding brain-derived neurotrophic factor (BDNF) protein, genotype, and DNA methylation (DNAm) as biomarkers of outcomes in three important etiologies of pediatric acquired brain injury (ABI), traumatic brain injury, global cerebral ischemia, and stroke. We also summarize evidence suggesting that BDNF is (1) involved in the biological embedding of the psychosocial environment, (2) responsive to rehabilitative therapies, and (3) potentially modifiable. BDNF's unique potential as a biomarker of neuroplasticity and neural repair that is reflective of and responsive to both pre- and post-injury environmental influences separates it from traditional protein biomarkers of structural brain injury with exciting potential to advance pediatric ABI management by increasing the accuracy of prognostic tools and informing clinical decision making through the monitoring of therapeutic effects.

Differential Effects of Targeted Temperature Management on Sex-Dependent Outcomes After Experimental Asphyxial Cardiac Arrest.

Asphyxial cardiac arrest (ACA) survivors face lasting neurological disability from hypoxic ischemic brain injury. Sex differences in long-term outcomes after cardiac arrest (CA) are grossly understudied and underreported. We used rigorous targeted temperature management (TTM) to understand its influence on survival and lasting sex-specific neurological and neuropathological outcomes in a rodent ACA model. Adult male and female rats underwent either sham or 5-minute no-flow ACA with 18 hours TTM at either ∼37°C (normothermia) or ∼36°C (mild hypothermia). Survival, temperature, and body weight (BW) were recorded over the 14-day study duration. All rats underwent neurological deficit score (NDS) assessment on days 1-3 and day 14. Hippocampal pathology was assessed for cell death, degenerating neurons, and microglia on day 14. Although ACA females were less likely to achieve return of spontaneous circulation (ROSC), post-ROSC physiology and biochemical profiles were similar between sexes. ACA females had significantly greater 14-day survival, NDS, and BW recovery than ACA males at normothermia (56% vs. 29%). TTM at 36°C versus 37°C improved 14-day survival in males, producing similar survival in male (63%) versus female (50%). There were no sex or temperature effects on CA1 histopathology. We conclude that at normothermic conditions, sex differences favoring females were observed after ACA in survival, NDS, and BW recovery. We achieved a clinically relevant ACA model using TTM at 36°C to improve long-term survival. This model can be used to more fully characterize sex differences in long-term outcomes and test novel acute and chronic therapies.

Gene knockout of RNA binding motif 5 in the brain alters RIMS2 protein homeostasis in the cerebellum and Hippocampus and exacerbates behavioral deficits after a TBI in mice.

RNA binding motif 5 (RBM5) is a tumor suppressor in cancer but its role in the brain is unclear. We used conditional gene knockout (KO) mice to test if RBM5 inhibition in the brain affects chronic cortical brain tissue survival or function after a controlled cortical impact (CCI) traumatic brain injury (TBI). RBM5 KO decreased baseline contralateral hemispheric volume (p < 0.0001) and exacerbated ipsilateral tissue loss at 21 d after CCI in male mice vs. wild type (WT) (p = 0.0019). CCI injury, but not RBM5 KO, impaired beam balance performance (0-5d post-injury) and swim speed on the Morris Water Maze (MWM) (19-20d) (p < 0.0001). RBM5 KO was associated with mild learning impairment in female mice (p = 0.0426), reflected as a modest increase in escape latency early in training (14-18d post-injury). However, KO did not affect spatial memory at 19d post-injury in male or in female mice but it was impaired by CCI in females (p = 0.0061). RBM5 KO was associated with impaired visual function in male mice on the visible platform test at 20d post-injury (p = 0.0256). To explore signaling disturbances in KOs related to behavior, we first cross-referenced known brain-specific RBM5-regulated gene targets with genes in the curated RetNet database that impact vision. We then performed a secondary literature search on RBM5-regulated genes with a putative role in hippocampal function. Regulating synaptic membrane exocytosis 2 (RIMS) 2 was identified as a gene of interest because it regulates both vision and hippocampal function. Immunoprecipitation and western blot confirmed protein expression of a novel ~170 kDa RIMS2 variant in the cerebellum, and in the hippocampus, it was significantly increased in KO vs WT (p < 0.0001), and in a sex-dependent manner (p = 0.0390). Furthermore, male KOs had decreased total canonical RIMS2 levels in the cerebellum (p = 0.0027) and hippocampus (p < 0.0001), whereas female KOs had increased total RIMS1 levels in the cerebellum (p = 0.0389). In summary, RBM5 modulates brain function in mammals. Future work is needed to test if RBM5 dependent regulation of RIMS2 splicing effects vision and cognition, and to verify potential sex differences on behavior in a larger cohort of mice.

New Functional Impairment After Hospital Discharge by Traumatic Brain Injury Mechanism in Younger Than 3 Years Old Admitted to the PICU in a Single Center Retrospective Study.

OBJECTIVES: Children who suffer traumatic brain injury (TBI) are at high risk of morbidity and mortality. We hypothesized that in patients with TBI, the abusive head trauma (AHT) mechanism vs. accidental TBI (aTBI) would be associated with higher frequency of new functional impairment between baseline and later follow-up. DESIGN: Retrospective single center cohort study. SETTING AND PATIENTS: Children younger than 3 years old admitted with TBI to the PICU at a level 1 trauma center between 2014 and 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, TBI mechanism, and Functional Status Scale (FSS) scores at baseline, hospital discharge, short-term (median, 10 mo [interquartile range 3-12 mo]), and long-term (median, 4 yr [3-6 yr]) postdischarge were abstracted from the electronic health record. New impairment was defined as an increase in FSS greater than 1 from baseline. Patients who died were assigned the highest score (30). Multivariable logistic regression was performed to determine the association between TBI mechanism with new impairment. Over 6 years, there were 460 TBI children (170 AHT, 290 aTBI), of which 13 with AHT and four with aTBI died. Frequency of new impairment by follow-up interval, in AHT vs. aTBI patients, were as follows: hospital discharge (42/157 [27%] vs. 27/286 [9%]; p < 0.001), short-term (42/153 [27%] vs. 26/259 [10%]; p < 0.001), and long-term (32/114 [28%] vs. 18/178 [10%]; p < 0.001). Sensory, communication, and motor domains were worse in AHT patients at the short- and long-term timepoint. On multivariable analysis, AHT mechanism was associated with greater odds (odds ratio [95% CI]) of poor outcome (death and new impairment) at hospital discharge (4.4 [2.2-8.9]), short-term (2.7 [1.5-4.9]), and long-term timepoints (2.4 [1.2-4.8]; p < 0.05). CONCLUSIONS: In patients younger than 3 years old admitted to the PICU after TBI, the AHT mechanism-vs. aTBI-is associated with greater odds of poor outcome in the follow-up period through to ~5 years postdischarge. New impairment occurred in multiple domains and only AHT patients further declined in FSS over time.

Multiorgan Dysfunction Syndrome in Abusive and Accidental Pediatric Traumatic Brain Injury.

BACKGROUND: Abusive head trauma (AHT) is a mechanism of pediatric traumatic brain injury (TBI) with high morbidity and mortality. Multiorgan dysfunction syndrome (MODS), defined as organ dysfunction in two or more organ systems, is also associated with morbidity and mortality in critically ill children. Our objective was to compare the frequency of MODS and evaluate its association with outcome between AHT and accidental TBI (aTBI). METHODS: This was a single center, retrospective cohort study including children under 3 years old admitted to the pediatric intensive care unit with nonpenetrating TBI between 2014 and 2021. Presence or absence of MODS on days 1, 3, and 7 using the Pediatric Logistic Organ Dysfunction-2 score and new impairment status (Functional Status Scale score change > 1 compared with preinjury) at hospital discharge (HD), short-term timepoint, and long-term timepoint were abstracted from the electronic health record. Multiple logistic regression was performed to examine the association between MODS and TBI mechanism with new impairment status. RESULTS: Among 576 children, 215 (37%) had AHT and 361 (63%) had aTBI. More children with AHT had MODS on days 1 (34% vs. 23%, p = 0.003), 3 (28% vs. 6%, p < 0.001), and 7 (17% vs. 3%, p < 0.001) compared with those with aTBI. The most common organ failures were cardiovascular ([AHT] 66% vs. [aTBI] 66%, p = 0.997), neurologic (33% vs. 16%, p < 0.001), and respiratory (34% vs. 15%, p < 0.001). MODS was associated with new impairment in multivariable logistic regression at HD (odds ratio 19.1 [95% confidence interval 9.8-38.6, p < 0.001]), short-term discharge (7.4 [3.7-15.2, p < 0.001]), and long-term discharge (4.3 [2.0-9.4, p < 0.001])]. AHT was also associated with new impairment at HD (3.4 [1.6-7.3, p = 0.001]), short-term discharge (2.5 [1.3-4.7, p = 0.005]), and long-term discharge (2.1 [1.1-4.1, p = 0.036]). CONCLUSIONS: Abusive head trauma as a mechanism was associated with MODS following TBI. Both AHT mechanism and MODS were associated with new impairment at all time points.

Neuronal RBM5 modulates cell signaling responses to traumatic and hypoxic-ischemic injury in a sex-dependent manner.

It is not clear if inhibiting the pro-death gene RNA binding motif 5 (RBM5) is neuroprotective in isolated primary neurons or if it regulates cell survival in a sex-dependent manner. Here we established sex-dichotomized primary cortical neuron cultures from transgenic mice harboring a floxed RBM5 gene-trap. Lentivirus-mediated expression of CRE was used to silence RBM5 expression. Male and female neurons were maintained in next-generation Neurobasal-Plus media and subjected to a mechanical stretch-injury (to model traumatic brain injury) or oxygen-glucose deprivation/OGD (to model ischemia). RBM5 KO did not affect 24 h post-injury survival as determined by lactate dehydrogenase (LDH) release, in either paradigm. In contrast, female KO neurons had increased spectrin breakdown products post-insult (in both models). Furthermore, in OGD, RBM5 KO in male neurons exacerbated injury-induced downregulation of pro-survival AKT activation (pAKT473) but conversely led to pAKT473 sparing in female neurons. Moreover, global proteomics identified 19 differentially expressed (DE) proteins in OGD-injured male neurons, and 102 DE proteins in injured female neurons. Two novel RBM5-regulated proteins (PIGQ and EST1C) were identified in injured male KO neurons, and 8 novel proteins identified in injured female KO neurons (S35A5, DHTK1, STX3, IF3M, RN167, K1C14, DYHS, and MED13). In summary, RBM5 inhibition does not modify neuronal survival in primary mouse neurons in 2 clinically relevant models of excitotoxic insult, but RBM5 does regulate intracellular responses to injury in a sex-dependent manner.

Characterization of Circulating Cold Shock Proteins FGF21 and RBM3 in a Multi-Center Study of Pediatric Cardiac Arrest.

Fibroblast Growth Factor 21 (FGF21) is a neuroprotective hormone induced by cold exposure that targets the ß-klotho co-receptor. ß-klotho is abundant in the newborn brain but decreases rapidly with age. RNA-Binding Motif 3 (RBM3) is a potent neuroprotectant upregulated by FGF21 in hypothermic conditions. We characterized serum FGF21 and RBM3 levels in patients enrolled in a prospective multi-center study of pediatric cardiac arrest (CA) via a secondary analysis of samples collected to evaluate brain injury biomarkers. Patients (n = 111) with remnant serum samples available from at least two of three available timepoints (0-24, 24-48 or 48-72 hours post-resuscitation) were included. Serum samples from 20 healthy controls were used for comparison. FGF21 was measured by Luminex and internally validated enzyme-linked immunoassay (ELISA). RBM3 was measured by internally validated ELISA. Of postarrest patients, 98 were managed with normothermia, while 13 were treated with therapeutic hypothermia (TH). FGF21 increased >20-fold in the first 24 hours postarrest versus controls (681 pg/mL [200-1864] vs. 29 pg/mL [15-51], n = 99 vs. 19, respectively, p < 0.0001, median [interquartile range]) with no difference in RBM3. FGF21 did not differ by sex, while RBM3 was increased in females versus males at 48-72 hours postarrest (1866 pg/mL [873-5176] vs. 1045 pg/mL [535-2728], n = 40 vs. 54, respectively, p < 0.05). Patients requiring extracorporeal membrane oxygenation (ECMO) postresuscitation had increased FGF21 versus those who did not at 48-72 hours (6550 pg/mL [1455-66,781] vs. 1213 pg/mL [480-3117], n = 7 vs 74, respectively, p < 0.05). FGF21 and RBM3 did not correlate (Spearman's rho = 0.004, p = 0.97). We conclude that in a multi-center study of pediatric CA patients where normothermic targeted temperature management was largely used, FGF21 was markedly increased postarrest versus control and highest in patients requiring ECMO postresuscitation. RBM3 was sex-dependent. We provide a framework for future studies examining the effect of TH on FGF21 or use of FGF21 therapy after pediatric CA.

N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.

N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.

Interoperable and explainable machine learning models to predict morbidity and mortality in acute neurological injury in the pediatric intensive care unit: secondary analysis of the TOPICC study.

Background: Acute neurological injury is a leading cause of permanent disability and death in the pediatric intensive care unit (PICU). No predictive model has been validated for critically ill children with acute neurological injury. Objectives: We hypothesized that PICU patients with concern for acute neurological injury are at higher risk for morbidity and mortality, and advanced analytics would derive robust, explainable subgroup models. Methods: We performed a secondary subgroup analysis of the Trichotomous Outcomes in Pediatric Critical Care (TOPICC) study (2011-2013), predicting mortality and morbidity from admission physiology (lab values and vital signs in 6 h surrounding admission). We analyzed patients with suspected acute neurological injury using standard machine learning algorithms. Feature importance was analyzed using SHapley Additive exPlanations (SHAP). We created a Fast Healthcare Interoperability Resources (FHIR) application to demonstrate potential for interoperability using pragmatic data. Results: 1,860 patients had suspected acute neurological injury at PICU admission, with higher morbidity (8.2 vs. 3.4%) and mortality (6.2 vs. 1.9%) than those without similar concern. The ensemble regressor (containing Random Forest, Gradient Boosting, and Support Vector Machine learners) produced the best model, with Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.91 [95% CI (0.88, 0.94)] and Average Precision (AP) of 0.59 [0.51, 0.69] for mortality, and decreased performance predicting simultaneous mortality and morbidity (0.83 [0.80, 0.86] and 0.59 [0.51, 0.64]); at a set specificity of 0.995, positive predictive value (PPV) was 0.79 for mortality, and 0.88 for mortality and morbidity. By comparison, for mortality, the TOPICC logistic regression had AUROC of 0.90 [0.84, 0.93], but substantially inferior AP of 0.49 [0.35, 0.56] and PPV of 0.60 at specificity 0.995. Feature importance analysis showed that pupillary non-reactivity, Glasgow Coma Scale, and temperature were the most contributory vital signs, and acidosis and coagulopathy the most important laboratory values. The FHIR application provided a simulated demonstration of real-time health record query and model deployment. Conclusions: PICU patients with suspected acute neurological injury have higher mortality and morbidity. Our machine learning approach independently identified previously-known causes of secondary brain injury. Advanced modeling achieves improved positive predictive value in this important population compared to published models, providing a stepping stone in the path to deploying explainable models as interoperable bedside decision-support tools.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.