Alicia K. Au

Cerebrospinal fluid mitochondrial DNA: a novel DAMP in pediatric traumatic brain injury.

ABSTRACT Danger-associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to the release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Cerebrospinal fluid was collected from children with severe TBI who required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores of 8 or less via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis who demonstrated no leukocytes in the diagnostic lumbar puncture. The median age for patients with TBI was 6.3 years, and 62% were male. The common mechanisms of injury included motor vehicle collision (35.8%), followed by falls (21.5%) and inflicted TBI (19%); six children (14.2%) died during their intensive care unit course. The mean CSF mtDNA concentration was 1.10E+05 ± 2.07E+05 and 1.63E+03 ± 1.80E+03 copies/&mgr;L in the pediatric TBI and control populations, respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E+05 ± 2.77E+05 vs. 5.05E+04 ± 6.21E+04 copies/&mgr;L) (P < 0.0001). We found a significant correlation between CSF mtDNA and high mobility group box 1, another prototypical DAMP, concentrations (&rgr; = 0.574, P < 0.05), supporting the notion that both DAMPs are increased in the CSF after TBI. Our data suggest that CSF mtDNA is a novel DAMP in TBI and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI.

Brain injuries and neurological system failure are the most common proximate causes of death in children admitted to a pediatric intensive care unit

Objective: Mortality rates from critical illness in children have declined over the past several decades, now averaging between 2% and 5% in most pediatric intensive care units. Although these rates, and mortality rates from specific disorders, are widely understood, the impact of acute neurologic injuries in such children who die and the role of these injuries in the cause of death are not well understood. We hypothesized that neurologic injuries are an important cause of death in children. Design: Retrospective review. Setting: Pediatric intensive care unit at Childrens Hospital of Pittsburgh, an academic tertiary care center. Patients: Seventy-eight children who died within the pediatric intensive care unit from April 2006 to February 2008. Interventions: None. Measurements and Main Results: Data regarding admission diagnosis, presence of chronic illness, diagnosis of brain injury, and cause of death were collected. Mortality was attributed to brain injury in 65.4% (51 of 78) of deaths. Ninety-six percent (28 of 29) of previously healthy children died with brain injuries compared with 46.9% (23 of 49) of chronically ill children (p < .05). The diagnosed brain injury was the proximate cause of death in 89.3% of previously healthy children and 91.3% with chronic illnesses. Pediatric intensive care unit and hospital length of stay was longer in those with chronic illnesses (38.8 ± 7.0 days vs. 8.9 ± 3.7 days and 49.2 ± 8.3 days vs. 9.0 ± 3.8 days, p < .05 and p < .001, respectively). Conclusion: Brain injury was exceedingly common in children who died in our pediatric intensive care unit and was the proximate cause of death in a large majority of cases. Neuroprotective measures for a wide variety of admission diagnoses and initiatives directed to prevention or treatment of brain injury are likely to attain further improvements in mortality in previously healthy children in the modern pediatric intensive care unit.

Evaluation of autophagy using mouse models of brain injury

Autophagy is a homeostatic, carefully regulated, and dynamic process for intracellular recycling of bulk proteins, aging organelles, and lipids. Autophagy occurs in all tissues and cell types, including the brain and neurons. Alteration in the dynamics of autophagy has been observed in many diseases of the central nervous system. Disruption of autophagy for an extended period of time results in accumulation of unwanted proteins and neurodegeneration. However, the role of enhanced autophagy after acute brain injury remains undefined. Established mouse models of brain injury will be valuable in clarifying the role of autophagy after brain injury and are the topic of discussion in this review.

ABCB1 genotype is associated with fentanyl requirements in critically Ill children

BackgroundThe gene ABCB1 encodes p-glycoprotein, a xenobiotic efflux pump capable of transporting certain opioids, including fentanyl. ABCB1 genotype has been previously associated with patient opioid requirements and may influence fentanyl dosing requirements in critically ill children.MethodsA diagnostically diverse cohort of 61 children who received a fentanyl infusion while admitted to the pediatric intensive care unit (PICU) were included in this study. We examined associations between fentanyl requirements, pain and sedation scores, serum fentanyl levels, and ABCB1 genotype.ResultsPatients with the AA allele at ABCB1 locus rs1045642 received less fentanyl compared with patients with the AG or GG allele. A multivariable model demonstrated that patients with the AA allele received 18.6 mcg/kg/day less fentanyl than patients with either the AG or GG allele (95% confidence interval −33.4 to −3.8 mcg/kg/day; P=0.014). Incorporating race in this model demonstrated a similar association, but did not reach the threshold for multiple testing.ConclusionABCB1 genotype rs1045642 AA is associated with fentanyl administration in this cohort of children admitted to the PICU, likely because of decreased expression and activity of p-glycoprotein. Prospective evaluation of the influence of ABCB1 in sedative–analgesia administration in critically ill children is warranted.

Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children

Background There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. Methods IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1–96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. Results There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. Conclusions Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. Trial registration ClinicalTrials.gov NCT01322009

Feasibility Study Evaluating Therapeutic Hypothermia for Refractory Status Epilepticus in Children

Pediatric refractory status epilepticus (RSE) is a neurological emergency with significant morbidity and mortality, which lacks consensus regarding diagnosis and treatment(s). Therapeutic hypothermia (TH) is an effective treatment for RSE in preclinical models and small series. In addition, TH is a standard care for adults after cardiac arrest and neonates with hypoxic-ischemic encephalopathy. The purpose of this study was to identify the feasibility of a study of pediatric RSE within a research group (Pediatric Neurocritical Care Research Group [PNCRG]). Pediatric intensive care unit (PICU) admissions at seven centers were prospectively screened from October 2012 to July 2013 for RSE. Experts within the PNCRG estimated that clinicians would be unwilling to enroll a child, unless the child required at least two different antiepileptic medications and a continuous infusion of another antiepileptic medication with ongoing electrographic seizure activity for ≥2 hours after continuous infusion initiation. Data for children meeting the above inclusion criteria were collected, including the etiology of RSE, history of epilepsy, and maximum dose of continuous antiepileptic infusions. There were 8113 PICU admissions over a cumulative 52 months (October 2012-July 2013) at seven centers. Of these, 69 (0.85%) children met inclusion criteria. Twenty children were excluded due to acute diagnoses affected by TH, contraindications to TH, or lack of commitment to aggressive therapies. Sixteen patients had seizure cessation within 2 hours, resulting in 33 patients who had inadequate seizure control after 2 hours and a continuous antiepileptic infusion. Midazolam (21/33, 64%) and pentobarbital (5/33, 15%) were the most common infusions with a wide maximum dose range. More than one infusion was required for seizure control in four patients. There are substantial numbers of subjects at clinical sites within the PNCRG with RSE that would meet the proposed inclusion criteria for a study of TH. The true feasibility of such a study depends on the sample size necessary to achieve therapeutic effects on justifiable clinical outcomes.

Presenting predictors and temporal trends of treatment-related outcomes in diabetic ketoacidosis

This study examines temporal trends in treatment‐related outcomes surrounding a diabetic ketoacidosis (DKA) performance improvement intervention consisting of mandated intensive care unit admission and implementation of a standardized management pathway, and identifies physical and biochemical characteristics associated with outcomes in this population.

Paediatric traumatic brain injury: prognostic insights and outlooks

PURPOSE OF REVIEW Traumatic brain injury (TBI) is a leading cause of death and disability in children. Prognostication of outcome following TBI is challenging in this population and likely requires complex, multimodal models to achieve clinically relevant accuracy. This review highlights injury characteristics, physiological indicators, biomarkers and neuromonitoring modalities predictive of outcome that may be integrated for future development of sensitive and specific prognostic models. RECENT FINDINGS Paediatric TBI is responsible for physical, psychosocial and neurocognitive deficits that may significantly impact quality of life. Outcome prognostication can be difficult in the immature brain, but is aided by the identification of novel biomarkers (neuronal, astroglial, myelin, inflammatory, apoptotic and autophagic) and neuromonitoring techniques (electroencephalogram and MRI). Investigation in the future may focus on assessing the prognostic ability of combinations of biochemical, protein, neuroimaging and functional biomarkers and the use of mathematical models to develop multivariable predication tools to improve the prognostic ability following childhood TBI. SUMMARY Prognostication of outcome following paediatric TBI is multidimensional, influenced by injury severity, age, physiological factors, biomarkers, electroencephalogram and neuroimaging. Further development, integration and validation of combinatorial prognostic algorithms are necessary to improve the accuracy and timeliness of prognosis in a meaningful fashion.

Chapter 11 – Autophagy in Critical Illness

Autophagy or cellular self-digestion is an important homeostatic function that occurs at low basal levels in all eukaryotic cells and is upregulated during pathophysiological conditions. In this chapter we review the principal components of the autophagic process and the mechanisms and regulation of autophagy relating to critical illness.

Severe postoperative hyponatremia after pediatric intracranial tumor surgery--is this preventable?*.

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