Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Association of Postarrest Hypotension Burden With Unfavorable Neurologic Outcome After Pediatric Cardiac Arrest.

OBJECTIVE: Quantify hypotension burden using high-resolution continuous arterial blood pressure (ABP) data and determine its association with outcome after pediatric cardiac arrest. DESIGN: Retrospective observational study. SETTING: Academic PICU. PATIENTS: Children 18 years old or younger admitted with in-of-hospital or out-of-hospital cardiac arrest who had invasive ABP monitoring during postcardiac arrest care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-resolution continuous ABP was analyzed up to 24 hours after the return of circulation (ROC). Hypotension burden was the time-normalized integral area between mean arterial pressure (MAP) and fifth percentile MAP for age. The primary outcome was unfavorable neurologic status (pediatric cerebral performance category ≥ 3 with change from baseline) at hospital discharge. Mann-Whitney U tests compared hypotension burden, duration, and magnitude between favorable and unfavorable patients. Multivariable logistic regression determined the association of unfavorable outcomes with hypotension burden, duration, and magnitude at various percentile thresholds from the 5th through 50th percentile for age. Of 140 patients (median age 53 [interquartile range 11-146] mo, 61% male); 63% had unfavorable outcomes. Monitoring duration was 21 (7-24) hours. Using a MAP threshold at the fifth percentile for age, the median hypotension burden was 0.01 (0-0.11) mm Hg-hours per hour, greater for patients with unfavorable compared with favorable outcomes (0 [0-0.02] vs. 0.02 [0-0.27] mm Hg-hr per hour, p < 0.001). Hypotension duration and magnitude were greater for unfavorable compared with favorable patients (0.03 [0-0.77] vs. 0.71 [0-5.01]%, p = 0.003; and 0.16 [0-1.99] vs. 2 [0-4.02] mm Hg, p = 0.001). On logistic regression, a 1-point increase in hypotension burden below the fifth percentile for age (equivalent to 1 mm Hg-hr of burden per hour of recording) was associated with increased odds of unfavorable outcome (adjusted odds ratio [aOR] 14.8; 95% CI, 1.1-200; p = 0.040). At MAP thresholds of 10th-50th percentiles for age, MAP burden below the threshold was greater in unfavorable compared with favorable patients in a dose-dependent manner. CONCLUSIONS: High-resolution continuous ABP data can be used to quantify hypotension burden after pediatric cardiac arrest. The burden, duration, and magnitude of hypotension are associated with unfavorable neurologic outcomes.

Neuromonitoring after Pediatric Cardiac Arrest: Cerebral Physiology and Injury Stratification.

BACKGROUND: Significant long-term neurologic disability occurs in survivors of pediatric cardiac arrest, primarily due to hypoxic-ischemic brain injury. Postresuscitation care focuses on preventing secondary injury and the pathophysiologic cascade that leads to neuronal cell death. These injury processes include reperfusion injury, perturbations in cerebral blood flow, disturbed oxygen metabolism, impaired autoregulation, cerebral edema, and hyperthermia. Postresuscitation care also focuses on early injury stratification to allow clinicians to identify patients who could benefit from neuroprotective interventions in clinical trials and enable targeted therapeutics. METHODS: In this review, we provide an overview of postcardiac arrest pathophysiology, explore the role of neuromonitoring in understanding postcardiac arrest cerebral physiology, and summarize the evidence supporting the use of neuromonitoring devices to guide pediatric postcardiac arrest care. We provide an in-depth review of the neuromonitoring modalities that measure cerebral perfusion, oxygenation, and function, as well as neuroimaging, serum biomarkers, and the implications of targeted temperature management. RESULTS: For each modality, we provide an in-depth review of its impact on treatment, its ability to stratify hypoxic-ischemic brain injury severity, and its role in neuroprognostication. CONCLUSION: Potential therapeutic targets and future directions are discussed, with the hope that multimodality monitoring can shift postarrest care from a one-size-fits-all model to an individualized model that uses cerebrovascular physiology to reduce secondary brain injury, increase accuracy of neuroprognostication, and improve outcomes.

Co-administration of Ketamine in Pediatric Patients with Neurologic Conditions at Risk for Intracranial Hypertension.

BACKGROUND: Ketamine has traditionally been avoided as an induction agent for tracheal intubation in patients with neurologic conditions at risk for intracranial hypertension due to conflicting data in the literature. The objective of this study was to evaluate and compare the effects of ketamine versus other medications as the primary induction agent on peri-intubation neurologic, hemodynamic and respiratory associated events in pediatric patients with neurologic conditions at risk for intracranial hypertension. METHODS: This retrospective observational study enrolled patients < 18 years of age at risk for intracranial hypertension who were admitted to a quaternary children's hospital between 2015 and 2020. Associated events included neurologic, hemodynamic and respiratory outcomes comparing primary induction agents of ketamine versus non-ketamine for tracheal intubation. RESULTS: Of 143 children, 70 received ketamine as the primary induction agent prior to tracheal intubation. Subsequently after tracheal intubation, all the patients received adjunct analgesic and sedative medications (fentanyl, midazolam, and/or propofol) at doses that were inadequate to induce general anesthesia but would keep them comfortable for further diagnostic workup. There were no significant differences between associated neurologic events in the ketamine versus non-ketamine groups (p = 0.42). This included obtaining an emergent computed tomography scan (p = 0.28), an emergent trip to the operating room within 5 h of tracheal intubation (p = 0.6), and the need for hypertonic saline administration within 15 min of induction drug administration for tracheal intubation (p = 0.51). There were two patients who had clinical and imaging evidence of herniation, which was not more adversely affected by ketamine compared with other medications (p = 0.49). Of the 143 patients, 23 had pre-intubation and post-intubation intracranial pressure values recorded; 11 received ketamine, and 3 of these patients had intracranial hypertension that resolved or improved, whereas the remaining 8 children had intracranial pressure within the normal range that was not exacerbated by ketamine. There were no significant differences in overall associated hemodynamic or respiratory events during tracheal intubation and no 24-h mortality in either group. CONCLUSIONS: The administration of ketamine as the primary induction agent prior to tracheal intubation in combination with other agents after tracheal intubation in children at risk for intracranial hypertension was not associated with an increased risk of peri-intubation associated neurologic, hemodynamic or respiratory events compared with those who received other induction agents.

Deviations from NIRS-derived optimal blood pressure are associated with worse outcomes after pediatric cardiac arrest.

AIM: Evaluate cerebrovascular autoregulation (CAR) using near-infrared spectroscopy (NIRS) after pediatric cardiac arrest and determine if deviations from CAR-derived optimal mean arterial pressure (MAPopt) are associated with outcomes. METHODS: CAR was quantified by a moving, linear correlation between time-synchronized mean arterial pressure (MAP) and regional cerebral oxygenation, called cerebral oximetry index (COx). MAPopt was calculated using a multi-window weighted algorithm. We calculated burden (magnitude and duration) of MAP less than 5 mmHg below MAPopt (MAPopt - 5), as the area between MAP and MAPopt - 5 curves using numerical integration and normalized as percentage of monitoring duration. Unfavorable outcome was defined as death or pediatric cerebral performance category (PCPC) at hospital discharge ≥3 with ≥1 change from baseline. Univariate logistic regression tested association between burden of MAP less than MAPopt - 5 and outcome. RESULTS: Thirty-four children (median age 2.9 [IQR 1.5,13.4] years) were evaluated. Median COx in the first 24 h post-cardiac arrest was 0.06 [0,0.20]; patients spent 27% [19,43] of monitored time with COx ≥ 0.3. Patients with an unfavorable outcome (n = 24) had a greater difference between MAP and MAPopt - 5 (13 [11,19] vs. 9 [8,10] mmHg, p = 0.01) and spent more time with MAP below MAPopt - 5 (38% [26,61] vs. 24% [14,28], p = 0.03). Patients with unfavorable outcome had a higher burden of MAP less than MAPopt - 5 than patients with favorable outcome in the first 24 h post-arrest (187 [107,316] vs. 62 [43,102] mmHg × Min/Hr; OR 4.93 [95% CI 1.16-51.78]). CONCLUSIONS: Greater burden of MAP below NIRS-derived MAPopt - 5 during the first 24 h after cardiac arrest was associated with unfavorable outcomes.

"Your Child Has Cerebral Palsy": Parental Understanding and Misconceptions.

IMPORTANCE: Caregivers of children with cerebral palsy can best help their child if they understand the disorder and the correct terminology. OBJECTIVE: To assess caregiver understanding of cerebral palsy. DESIGN: This was a cross-sectional study from a large tertiary medical center in Boston, to assess understanding of the term cerebral palsy by primary caregivers of children and adolescents with cerebral palsy. All cases were obtained from hospital electronic medical records. Telephone surveys were conducted. Caregiver understanding of cerebral palsy was assessed by open-ended responses (50%) and success in answering true/false questions about cerebral palsy (50%). PARTICIPANTS: Primary caregivers of children 18 years and younger with cerebral palsy. RESULTS: Thirty-three percent of caregivers denied ever being told that their child had cerebral palsy. Most caregivers identified cerebral palsy as a brain problem (79%), lifelong condition (73%), often caused by a perinatal (60%) or gestational (40%) insult. Fifty-two percent knew that cerebral palsy was nonprogressive. Sixty-two percent of caregivers believed they had a good, very good, or excellent understanding of cerebral palsy, whereas the investigators found 69% of caregivers had a good, very good, or excellent understanding of cerebral palsy (P = .006). Most caregivers rated very good or excellent the setting where cerebral palsy was discussed (58%), the explanations provided (55%), and the amount of time spent (45%), yet using a Pearson correlation coefficient, most important was the time spent (r = 0.53). CONCLUSIONS: Following discussion with their child's physician, most primary caregivers of children with cerebral palsy have a good, very good, or excellent understanding of cerebral palsy. Most critical to a good understanding of cerebral palsy was the time spent in explaining the diagnosis.

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years.

OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = -0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.