Azithromycin reduces inflammation-amplified hypoxic-ischemic brain injury in neonatal rats.

BACKGROUND: Systemic inflammation amplifies neonatal hypoxic-ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury. DESIGN/METHODS: Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or Pam3Cys-Ser-(Lys)4 (PAM) prior to right carotid ligation followed by 50 min (LPS + HI) or 60 min (PAM + HI) in 8% oxygen. Outcomes included contralateral forelimb function (forepaw placing; grip strength), survival, %Intact right hemisphere (brain damage), and a composite score incorporating these measures. We compared postnatal day 35 outcomes in controls and groups treated with three or five AZ doses. Then, we compared P21 outcomes when the first (of five) AZ doses were administered 1, 2, or 4 h after HI. RESULTS: In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay. CONCLUSIONS: Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection. IMPACT: AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats.

Electrographic Seizures and Brain Injury in Children Requiring Extracorporeal Membrane Oxygenation.

BACKGROUND: Single-center studies suggest that up to 30% of children undergoing extracorporeal membrane oxygenation have electrographic seizures. The aim of this study was to characterize seizure prevalence, seizure risk factors, and brain injury prevalence in the pediatric extracorporeal membrane oxygenation population at a tertiary care children's hospital. METHODS: We performed a retrospective systematic review of medical records for 86 consecutive children (neonates to age 21 years) who received Neurology consults and continuous video electroencephalography while undergoing extracorporeal membrane oxygenation from November 2015 to September 2018. RESULTS: Continuous video electroencephalography was initiated in 86 of 170 children who required extracorporeal membrane oxygenation (51%); median duration of continuous vodeo electroencephalography was four days. Nineteen of 86 had electroencephalography-confirmed seizures (22%). Sixteen of 19 had seizures within the first 48 hours on continuous video electroencephalography. Interictal epileptiform discharges were a significant risk factor for seizures; 89% of those with seizures versus 46% of those without had interictal epileptiform discharges (P < 0.001, Fisher's exact test). Children with seizures also had higher pericannulation lactate (median 6.7, interquartile range of 4.3 to 19.0 for those with, and median 4.0, interquartile range of 2.0 to 7.3 for those without; P = 0.02, Mann-Whitney U test). Seizures were associated with hemorrhage on neuroimaging (68% of children with seizures had intracranial hemorrhage versus 34% of those without, P = 0.01, chi-square test). CONCLUSION: Approximately half the children undergoing extracorporeal membrane oxygenation received continuous video electroencephalography during the study period, and 22% had seizures. Interictal epileptiform discharges and elevated pre-extracorporeal membrane oxygenation lactate levels were risk factors for seizures; seizures were associated with intracranial hemorrhage.

Repurposing azithromycin for neonatal neuroprotection.

BACKGROUND: Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model. METHODS: Seven-day-old rats underwent right carotid artery ligation followed by 90-min 8% oxygen exposure; this procedure elicits quantifiable left forepaw functional impairment and right cerebral hemisphere damage. Sensorimotor function (vibrissae-stimulated forepaw placing, grip strength) and brain damage were compared in azithromycin- and saline-treated littermates 2-4 weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15 to 45 mg/kg; treatment onset 15 min to 4 h post-hypoxia, and comparison of 1 vs. 3 injections). RESULTS: All azithromycin doses improved function and reduced brain damage; efficacy was dose dependent, and declined with increasing treatment delay. Three azithromycin injections, administered over 48 h, improved performance on both function measures and reduced brain damage more than a single dose. CONCLUSION: In this neonatal rodent model, azithromycin improved functional and neuropathology outcomes. If supported by confirmatory studies in complementary neonatal brain injury models, azithromycin could be an attractive candidate drug for repurposing and evaluation for neonatal neuroprotection in clinical trials.

Relationships between three and twelve month outcomes in children enrolled in the therapeutic hypothermia after pediatric cardiac arrest trials.

AIM: To inform design aspects of future trials by comparing 3 and 12-month neurobehavioural outcomes in children enrolled in Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-Of-Hospital and In-Hospital (THAPCA-OH, THAPCA-IH) trials. METHODS: The THAPCA trials evaluated two targeted temperature management interventions (hypothermia, 32.0-34.0 °C; normothermia, 36.0-37.5 °C). Children, aged 2 days to <18 years, were enrolled from 2009-2015. Three and 12-month post-cardiac arrest (CA) outcomes included the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) (population mean = 100, SD = 15) and the pediatric cerebral performance category (PCPC) scale. Children without significant pre-existing neurodevelopmental deficits were included in primary outcome analyses. Among survivors, favorable 12-month outcome was defined as VABS-II ≥ 70. RESULTS: VABS-II and PCPC were available at 3 and 12 months in 204 of 222 eligible survivors (THAPCA-OH, n = 82; THAPCA-IH, n = 122). Relative to THAPCA-IH, THAPCA-OH had significantly less pre-CA disability and significantly greater 12-month CA impairment, based on both VABS-II and PCPC. Correlations between 3 and 12-month VABS-II scores were strong for THAPCA-OH (r = 0.95) and THAPCA-IH (r = 0.72), and lower (p ≤ 0.001) in THAPCA-IH. Between time-points correlations were lower, but still significant in children <1 year at CA (p < 0.001). In both cohorts, 3-month VABS-II and PCPC categorical outcomes had high sensitivity (≥70%) for predicting favorable 12-month VABS-II outcomes, but specificity was lower for THAPCA-IH (68-89%) relative to THAPCA-OH (≥95%). Overall, 12-month diagnostic accuracy was ≥80% for both VABS-II and PCPC in both cohorts. CONCLUSIONS: In future paediatric cardiac arrest clinical trials that enroll similar cohorts, integration of 3-month neurobehavioral outcome measures should be considered.

One-year cognitive and neurologic outcomes in survivors of paediatric extracorporeal cardiopulmonary resuscitation.

OBJECTIVE: To describe one-year cognitive and neurologic outcomes among extracorporeal cardiopulmonary resuscitation (ECPR) survivors enrolled in the Therapeutic Hypothermia after Paediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial; and compare outcomes between survivors who received ECPR, later extracorporeal membrane oxygenation (ECMO), or no ECMO. METHODS: All children recruited to THAPCA-IH were comatose post-arrest. Neurobehavioral function was assessed by caregivers using the Vineland Adaptive Behaviour Scales, 2nd edition (VABS-II) at pre-arrest baseline and 12 months post-arrest. Age-appropriate cognitive performance measures (Mullen Scales of Early Learning or Wechsler Abbreviated Scale of Intelligence) and neurologic examinations were obtained 12 months post-arrest. VABS-II and cognitive performance measures were transformed to standard scores (mean = 100, SD = 15) with higher scores representing better performance. Only children with broadly normal pre-arrest function (VABS-II ≥70) were included in this analysis. RESULTS: One-year follow-up was attained for 127 survivors with pre-arrest VABS-II ≥70. Of these, 57 received ECPR, 14 received ECMO later in their course, and 56 did not receive ECMO. VABS-II assessments were completed at 12 months for 55 (96.5%) ECPR survivors, cognitive testing for 44 (77.2%) and neurologic examination for 47 (82.5%). At 12 months, 39 (70.9%) ECPR survivors had VABS-II scores ≥70. On cognitive testing, 24 (54.6%) had scores ≥70, and on neurologic examination, 28 (59.5%) had no/minimal to mild impairment. Cognitive and neurologic score distributions were similar between ECPR, later ECMO and no ECMO groups. CONCLUSIONS: Many ECPR survivors had favourable outcomes although impairments were common. ECPR survivors had similar outcomes to other survivors who were initially comatose post-arrest.

Cardiac Arrest Outcomes in Children With Preexisting Neurobehavioral Impairment.

OBJECTIVES: To describe survival and 3-month and 12-month neurobehavioral outcomes in children with preexisting neurobehavioral impairment enrolled in one of two parallel randomized clinical trials of targeted temperature management. DESIGN: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials data. SETTING: Forty-one PICUs in the United States, Canada, and United Kingdom. PATIENTS: Eighty-four participants (59 in-hospital cardiac arrest and 25 out-of-hospital cardiac arrest), 49 males, 35 females, mean age 4.6 years (SD, 5.36 yr), with precardiac arrest neurobehavioral impairment (Vineland Adaptive Behavior Scales, Second Edition composite score < 70). All required chest compressions for greater than or equal to 2 minutes, were comatose and required mechanical ventilation after return of circulation. INTERVENTIONS: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting precardiac arrest status), and at 3 and 12 months postcardiac arrest, followed by on-site cognitive evaluation. Vineland Adaptive Behavior Scales, Second Edition norms are 100 (mean) ± 15 (SD); higher scores indicate better function. Analyses evaluated survival, changes in Vineland Adaptive Behavior Scales, Second Edition, and cognitive functioning. MEASUREMENTS AND MAIN RESULTS: Twenty-eight of 84 (33%) survived to 12 months (in-hospital cardiac arrest, 19/59 (32%); out-of-hospital cardiac arrest, 9/25 [36%]). In-hospital cardiac arrest (but not out-of-hospital cardiac arrest) survival rate was significantly lower compared with the Therapeutic Hypothermia after Pediatric Cardiac Arrest group without precardiac arrest neurobehavioral impairment. Twenty-five survived with decrease in Vineland Adaptive Behavior Scales, Second Edition less than or equal to 15 (in-hospital cardiac arrest, 18/59 (31%); out-of-hospital cardiac arrest, 7/25 [28%]). At 3-months postcardiac arrest, mean Vineland Adaptive Behavior Scales, Second Edition scores declined significantly (-5; SD, 14; p < 0.05). At 12 months, Vineland Adaptive Behavior Scales, Second Edition declined after out-of-hospital cardiac arrest (-10; SD, 12; p < 0.05), but not in-hospital cardiac arrest (0; SD, 15); 43% (12/28) had unchanged or improved scores. CONCLUSIONS: This study demonstrates the feasibility, utility, and challenge of including this population in clinical neuroprotection trials. In children with preexisting neurobehavioral impairment, one-third survived to 12 months and their neurobehavioral outcomes varied broadly.

Pediatric out-of-hospital cardiac arrest: Time to goal target temperature and outcomes.

AIM: Although recent out-of-hospital cardiac arrest (CA) trials found no benefits of hypothermia versus normothermia targeted temperature management, preclinical models suggest earlier timing of hypothermia improves neuroprotective efficacy. This study investigated whether shorter time to goal temperature was associated with better one-year outcomes in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital Trial. METHODS: Patients were classified by tertiles of time to attain assigned goal temperature range (32-34°C or 36-37.5°C) following ROSC. Outcomes in the first tertile ("earlier") Group 1 were compared with second and third tertiles ("later") Group 2. Separate analyses were, additionally, completed for hypothermia and normothermia intervention groups. Three one-year outcomes were examined: survival; Vineland Adaptive Behavior Scale (VABS-II) score≥70; and decrease in VABS-II≤15 points from baseline. RESULTS: In the entire cohort (n=281), median time from ROSC to goal temperature was 7.4 [IQR 6.2-9.7] hours: Group 1, 5.8 [IQR 5.2, 6.2] and Group 2, 8.8 [IQR 7.4, 10.4] h. Outcomes did not differ between these groups. For hypothermia subgroup, survival was lower in Group 1 than 2, [10/49(20%) versus 47/99(47%), p<0.002], with a trend toward fewer with VABS-II scores≥70 and change in VABS-II≤15 points (p=0.07-0.08). For normothermia subgroup, there was a trend toward higher survival in Group 1 than 2 [18/42(43%) versus 21/83(25%), p=0.065], but no differences in VABS-II-related measures. In multivariable logistic regression models, no difference in earlier and later groups or temperature intervention was observed. CONCLUSION: We found no evidence that earlier time to goal temperature was associated with better outcomes.

Therapeutic hypothermia after paediatric cardiac arrest: Pooled randomized controlled trials.

BACKGROUND: Separate trials to evaluate therapeutic hypothermia after paediatric cardiac arrest for out-of-hospital and in-hospital settings reported no statistically significant differences in survival with favourable neurobehavioral outcome or safety compared to therapeutic normothermia. However, larger sample sizes might detect smaller clinical effects. Our aim was to pool data from identically conducted trials to approximately double the sample size of the individual trials yielding greater statistical power to compare outcomes. METHODS: Combine individual patient data from two clinical trials set in forty-one paediatric intensive care units in USA, Canada and UK. Children aged at least 48 h up to 18 years old, who remained comatose after resuscitation, were randomized within 6 h of return of circulation to hypothermia or normothermia (target 33.0 °C or 36.8 °C). The primary outcome, survival 12 months post-arrest with Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score at least 70 (scored from 20 to 160, higher scores reflecting better function, population mean = 100, SD = 15), was evaluated among patients with pre-arrest scores ≥70. RESULTS: 624 patients were randomized. Among 517 with pre-arrest VABS-II scores ≥70, the primary outcome did not significantly differ between hypothermia and normothermia groups (28% [75/271] and 26% [63/246], respectively; relative risk, 1.08; 95% confidence interval [CI], 0.81 to 1.42; p = 0.61). Among 602 evaluable patients, the change in VABS-II score from baseline to 12 months did not differ significantly between groups (p = 0.20), nor did, proportion of cases with declines no more than 15 points or improvement from baseline [22% (hypothermia) and 21% (normothermia)]. One-year survival did not differ significantly between hypothermia and normothermia groups (44% [138/317] and 38% [113/ 297], respectively; relative risk, 1.15; 95% CI, 0.95 to 1.38; p = 0.15). Incidences of blood-product use, infection, and serious cardiac arrhythmia adverse events, and 28-day mortality, did not differ between groups. CONCLUSIONS: Analysis of combined data from two paediatric cardiac arrest targeted temperature management trials including both in-hospital and out-of-hospital cases revealed that hypothermia, as compared with normothermia, did not confer a significant benefit in survival with favourable functional outcome at one year.

Targeted Temperature Management in Pediatric Neurocritical Care.

Targeted temperature management encompasses a range of clinical interventions to regulate systemic temperature, and includes both induction of varying degrees of hypothermia and fever prevention ("targeted normothermia"). Targeted temperature management plays a key role in the contemporary management of critically ill neonates and children with acute brain injury. Yet, many unanswered questions remain regarding optimal temperature management in pediatric neurocritical care. The introduction highlights experimental studies that have evaluated the neuroprotective efficacy of therapeutic hypothermia and explored possible mechanisms of action in several brain injury models. The next section focuses on three major clinical conditions in which therapeutic hypothermia has been evaluated in randomized controlled trials in pediatric populations: neonatal hypoxic-ischemic encephalopathy, postcardiac arrest encephalopathy, and traumatic brain injury. Clinical implications of targeted temperature management in pediatric neurocritical care are also discussed. The final section examines some of the factors that may underlie the limited neuroprotective efficacy of hypothermia that has been observed in several major pediatric clinical trials, and outlines important directions for future research.

Neuropsychological Outcomes of Children 1 Year After Pediatric Cardiac Arrest: Secondary Analysis of 2 Randomized Clinical Trials.

Importance: Little is known about neuropsychological outcomes of children who survived pediatric cardiac arrest (CA). Objective: To describe the neuropsychological outcomes of CA survivors enrolled in the Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) and Out-of-Hospital (THAPCA-OH) trials and compare the results with the primary outcome measure for these trials. Design, Setting, and Participants: Secondary analysis of 222 CA survivors aged 1 to 18 years who received chest compressions for 2 minutes or more, remained comatose and required mechanical ventilation after return of circulation, and were enrolled in targeted temperature-management trials from 41 pediatric intensive care units. Data were collected from September 3, 2009, to February 3, 2016, and analyzed from March 10, 2017, to April 20, 2018. Main Outcomes and Measures: The Vineland Adaptive Behavior Scales, Second Edition (VABS-II), a standardized measure of neurobehavioral functioning based on caregiver report (age-corrected mean [SD] scores = 100 [15]), was used to evaluate pre-CA functioning within 24 hours after enrollment; VABS-II<70 indicated significant developmental delays; VABS-II and neuropsychological testing were completed 1 year after CA. Neuropsychological testing included the Mullen Scales of Early Learning (Mullen) for children younger than 6 years and the Wechsler Abbreviated Scale of Intelligence (WASI) and neuropsychological measures of attention, memory, processing speed, and executive functioning for older children. Results: Of 160 participants who completed neuropsychological testing, 96 (60.0%) were male; the median (interquartile range [IQR]) age was 2.5 years (1.3-6.1 years). Ninety-six (60.0%) were white, 41 (25.6%) were black, and 23 (14.4%) were of other/unknown race; 343 (21.2%) were Hispanic or Latino; 119 (74.4%) were non-Hispanic or Latino; and 7 (4.4%) were of unknown ethnicity. One hundred fourteen participants (71.2%) were classified as having favorable outcomes (VABS-II ≥70). Impairments (>2 SD below the mean for age) across neuropsychological measures ranged from 7% to 61%. Correlations between global cognitive and VABS-II scores were strong for younger children (Mullen, r = 0.69-0.87) but moderate for older children (r = 0.21-0.54 for the WASI). Of 111 children with favorable outcomes on VABS-II, 25.2% had global cognitive impairment and 30 of 35 older children (85.7%) had selective neuropsychological deficits. Conclusions and Relevance: In this prospectively evaluated cohort of pediatric CA survivors who were initially comatose, although 71.2% were classified as having favorable outcomes, significant neuropsychological deficits were identified in pediatric CA survivors who were classified as having favorable outcomes. The findings provide clinicians with a greater understanding of the spectrum of neuropsychological outcomes of pediatric CA survivors and the complex relationship between standardized caregiver-reported functional outcome measures incorporated in clinical trials and performance-based neuropsychological assessments.

Sedation and Analgesia Influence Electroencephalography Monitoring in Pediatric Neurocritical Care.

OBJECTIVES: We assessed neuroactive medication use in critically ill children who require neurological consultation and evaluated the associations between administration of these medications and continuous electroencephalography (cEEG) utilization and seizure frequency. METHODS: We evaluated exposure to sedatives, analgesics, anesthetics, and paralytics in consecutive patients (0 days to 18 years) for whom neurological consultation was requested in three intensive care units (ICUs) [neonatal (NICU), pediatric (PICU), and cardiothoracic (PCTU)]) at one children's hospital. We assessed cEEG usage and seizure incidence in relation to drug exposure. RESULTS: From November 2015 to November 2016, 300 consecutive patients were evaluated (93 NICU, 139 PICU, and 68 PCTU). Ninety-seven (32%) were receiving ≥1 sedative infusion at the time of consultation [NICU 7 (8%), PICU 50(36%), PCTU 40 (58%%]; 91 (30%) received ≥1 paralytic agent within the preceding 24 hours. Continuous electroencephalography was performed more often for patients treated with sedative infusions (81 of 97 versus 133 of 203, P = 0.001) and paralytic medications (80 of 91 versus 134 of 209, P < 0.001) within 24 hours preceding consultation than those who were not. Sixty-eight of 214 (32%) had electrographic seizures (65 of 68 within initial 24 hours of monitoring); seizures were less common among patients who had received sedative infusions (18 of 81 versus 51 of 133, P = 0.014). In multivariable analysis of seizure likelihood, only younger age was associated with increased risk (P = 0.037). CONCLUSIONS: Critically ill infants and children are frequently treated with sedatives, anesthetics, analgesics, and paralytics. Neuroactive medications limit bedside neurological assessments and, in this cohort, were associated with increased cEEG usage. Our data underscore the need to study the effect of these medications on clinical care and long-term outcomes.

Neurologic outcomes in pediatric cardiac arrest survivors enrolled in the THAPCA trials.

OBJECTIVE: To implement a standardized approach to characterize neurologic outcomes among 12-month survivors in the Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) trials. METHODS: Two multicenter trials enrolled children age 48 hours to 18 years who remained comatose after cardiac arrest (CA) occurring out-of-hospital (THAPCA-OH, NCT00878644) or in-hospital (THAPCA-IH, NCT00880087); patients were randomized to therapeutic hypothermia or therapeutic normothermia. The primary outcome, survival with favorable 12-month neurobehavioral outcome (Vineland Adaptive Behavior Scales [VABS-II]), did not differ between treatment groups in either trial. Neurologists examined 181 12-month survivors, described findings using the novel semi-quantitative Pediatric Resuscitation after Cardiac Arrest (PRCA) form, and rated findings in 6 domains; scores ranged from 0 (no deficits) to 21 (maximal deficits). PRCA scores were compared with 12-month VABS-II scores and cognitive scores. RESULTS: Neurologic outcome PRCA scores were classified as no/minimal impairment, PRCA 0-3, 81/179 (45%); mild impairment, PRCA 4-7, 24/179 (13%); moderate impairment, PRCA 8-11, 15/179 (8%); severe impairment, PRCA 12-16, 20/179 (11%); profound impairment, PRCA 17-21, 39/179 (21%) (2/181 incomplete). VABS-II scores correlated strongly with PRCA category (r = -0.88, p < 0.0001, Pearson correlation coefficient) and cognitive scores (r = -0.72, p < 0.0001). Factors associated with poor outcomes included out-of-hospital CA, seizure recognition in the early postarrest period, and poor neurologic status at hospital discharge. CONCLUSION: The PRCA provides a robust method for depicting neurologic outcomes after acute encephalopathy caused by CA in children. It provides a global semiquantitative rating of neurologic impairment and domain-specific impairment. The strong correlation with well-established neurobehavioral outcome measures supports its validity over a broad age range and wide spectrum of outcomes.

Neurobehavioural outcomes in children after In-Hospital cardiac arrest.

AIM: Children who remain comatose after in-hospital cardiac arrest (IH-CA) resuscitation are at risk for poor neurological outcome. We report results of detailed neurobehavioural testing in paediatric IH-CA survivors, initially comatose after return of circulation, and enrolled in THAPCA-IH, a clinical trial that evaluated two targeted temperature management interventions (hypothermia, 33.0 °C or normothermia, 36.8 °C; NCT00880087). METHODS: Children, aged 2 days to <18 years, were enrolled in THAPCA-IH from 2009 to 2015; primary trial outcome (survival with favorable neurobehavioural outcome) did not differ between groups. Pre-IH-CA neurobehavioural functioning, measured with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) was evaluated soon after enrollment; this report includes only children with broadly normal pre-IH-CA scores (VABS-II composite scores ≥70; 269 enrolled). VABS-II was re-administered 3 and 12 months later. Cognitive testing was completed at 12 months. RESULTS: Follow-ups were obtained on 125 of 135 eligible one-year survivors. Seventy-seven percent (96/125) had VABS-II scores ≥70 at 12 months; cognitive composites were ≥2SD of mean in 59%. VABS-II composite, domain, and most subdomain scores declined between pre-IH-CA and 3-month, and pre-IH-CA and 12-month assessments (composite means declined about 1 SD at 3 and 12 months, p < 0.005); 3 and 12-month scores were strongly correlated (r = 0.72, p < 0.001). CONCLUSIONS: In paediatric IH-CA survivors at high risk for unfavorable outcomes, the majority demonstrated significant declines in neurobehavioural functioning, across multiple functional domains, with similar functioning at 3 and 12 months. About three-quarters attained VABS-II functional performance composite scores within the broadly normal range.

Drug Treatment of Seizures and Epilepsy in Newborns and Children.

The mainstay of treatment of childhood epilepsy is to administer antiepileptic drugs (AEDs). This article provides an overview of the clinical approach to drug treatment of childhood epilepsy, focusing on general principles of therapy and properties of recently introduced medications. Initiation and cessation of therapy, adverse medication effects, drug interactions, indications for the various AEDs, and off-label use of AEDs are reviewed. The distinct challenges in treatment of epileptic spasms and neonatal seizures are addressed. Finally, ideas for the future of drug treatment of childhood epilepsy are presented, with particular attention to precision medicine.

Pediatric cardiac arrest due to drowning and other respiratory etiologies: Neurobehavioral outcomes in initially comatose children.

AIM: To describe the 1-year neurobehavioral outcome of survivors of cardiac arrest secondary to drowning, compared with other respiratory etiologies, in children enrolled in the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) trial. METHODS: Exploratory analysis of survivors (ages 1-18 years) who received chest compressions for ≥2min, were comatose, and required mechanical ventilation after return of circulation (ROC). Participants recruited from 27 pediatric intensive care units in North America received targeted temperature management [therapeutic hypothermia (33°C) or therapeutic normothermia (36.8°C)] within 6h of ROC. Neurobehavioral outcomes included 1-year Vineland Adaptive Behavior Scales, Second Edition (VABS-II) total and domain scores and age-appropriate cognitive performance measures (Mullen Scales of Early Learning or Wechsler Abbreviated Scale of Intelligence). RESULTS: Sixty-six children with a respiratory etiology of cardiac arrest survived for 1-year; 60/66 had broadly normal premorbid functioning (VABS-II≥70). Follow up was obtained on 59/60 (30 with drowning etiology). VABS-II composite and domain scores declined significantly from premorbid scores in drowning and non-drowning groups (p<0.001), although declines were less pronounced for the drowning group. Seventy-two percent of children had well below average cognitive functioning at 1-year. Younger age, fewer doses of epinephrine, and drowning etiology were associated with better VABS-II composite scores. Demographic variables and treatment with hypothermia did not influence neurobehavioral outcomes. CONCLUSIONS: Risks for poor neurobehavioral outcomes were high for children who were comatose after out-of-hospital cardiac arrest due to respiratory etiologies; survivors of drowning had better outcomes than those with other respiratory etiologies.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

Maternal high-fat diet influences outcomes after neonatal hypoxic-ischemic brain injury in rodents.

The typical US diet has >30% calories from fat; yet, typical laboratory diets contain 17% calories from fat. This disparity could confound the clinical relevance of findings in cerebral ischemia models. We compared outcomes after neonatal brain injury in offspring of rat dams fed standard low-fat chow (17% fat calories) or a higher fat diet (34% fat calories) from day 7 of pregnancy. On postnatal day 7, hypoxic-ischemic injury was induced by right carotid ligation, followed by 60, 75 or 90 min 8% oxygen exposure. Sensorimotor function, brain damage, and serum and brain fatty acid content were compared 1 to 4 weeks later. All lesioned animals developed left forepaw placing deficits; scores were worse in the high-fat groups (p < 0.0001, ANOVA). Similarly, reductions in left forepaw grip strength were more pronounced in the high-fat groups. Severity of right hemisphere damage increased with hypoxia-ischemia duration but did not differ between diet groups. Serum and brain docosahexaenoic acid fatty acid fractions were lower in high-fat progeny (p < 0.05, ANOVA). We speculate that the high-fat diet disrupted docosahexaenoic acid-dependent recovery mechanisms. These findings have significant implications both for refinement of neonatal brain injury models and for understanding the impact of maternal diet on neonatal neuroplasticity.

Functional Outcome Trajectories After Out-of-Hospital Pediatric Cardiac Arrest.

OBJECTIVES: To analyze functional performance measures collected prospectively during the conduct of a clinical trial that enrolled children (up to age 18 yr old), resuscitated after out-of-hospital cardiac arrest, who were at high risk of poor outcomes. DESIGN: Children with Glasgow Motor Scale score less than 5, within 6 hours of resuscitation, were enrolled in a clinical trial that compared two targeted temperature management interventions (THAPCA-OH, NCT00878644). The primary outcome, 12-month survival with Vineland Adaptive Behavior Scale, second edition, score greater or equal to 70, did not differ between groups. SETTING: Thirty-eight North American PICUs. PARTICIPANTS: Two hundred ninety-five children were enrolled; 270 of 295 had baseline Vineland Adaptive Behavior Scale, second edition, scores greater or equal to 70; 87 of 270 survived 1 year. INTERVENTIONS: Targeted temperatures were 33.0°C and 36.8°C for hypothermia and normothermia groups. MEASUREMENTS AND MAIN RESULTS: Baseline measures included Vineland Adaptive Behavior Scale, second edition, Pediatric Cerebral Performance Category, and Pediatric Overall Performance Category. Pediatric Cerebral Performance Category and Pediatric Overall Performance Category were rescored at hospital discharges; all three were scored at 3 and 12 months. In survivors with baseline Vineland Adaptive Behavior Scale, second edition scores greater or equal to 70, we evaluated relationships of hospital discharge Pediatric Cerebral Performance Category with 3- and 12-month scores and between 3- and 12-month Vineland Adaptive Behavior Scale, second edition, scores. Hospital discharge Pediatric Cerebral Performance Category scores strongly predicted 3- and 12-month Pediatric Cerebral Performance Category (r = 0.82 and 0.79; p < 0.0001) and Vineland Adaptive Behavior Scale, second edition, scores (r = -0.81 and -0.77; p < 0.0001). Three-month Vineland Adaptive Behavior Scale, second edition, scores strongly predicted 12-month performance (r = 0.95; p < 0.0001). Hypothermia treatment did not alter these relationships. CONCLUSIONS: In comatose children, with Glasgow Motor Scale score less than 5 in the initial hours after out-of-hospital cardiac arrest resuscitation, function scores at hospital discharge and at 3 months predicted 12-month performance well in the majority of survivors.

Targeted Temperature Management After Pediatric Cardiac Arrest Due To Drowning: Outcomes and Complications.

OBJECTIVE: To describe outcomes and complications in the drowning subgroup from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial. DESIGN: Exploratory post hoc cohort analysis. SETTING: Twenty-four PICUs. PATIENTS: Pediatric drowning cases. INTERVENTIONS: Therapeutic hypothermia versus therapeutic normothermia. MEASUREMENTS AND MAIN RESULTS: An exploratory study of pediatric drowning from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial was conducted. Comatose patients aged more than 2 days and less than 18 years were randomized up to 6 hours following return-of-circulation to hypothermia (n = 46) or normothermia (n = 28). Outcomes assessed included 12-month survival with a Vineland Adaptive Behavior Scale score of greater than or equal to 70, 1-year survival rate, change in Vineland Adaptive Behavior Scale-II score from prearrest to 12 months, and select safety measures. Seventy-four drowning cases were randomized. In patients with prearrest Vineland Adaptive Behavior Scale-II greater than or equal to 70 (n = 65), there was no difference in 12-month survival with Vineland Adaptive Behavior Scale-II score of greater than or equal to 70 between hypothermia and normothermia groups (29% vs 17%; relative risk, 1.74; 95% CI, 0.61-4.95; p = 0.27). Among all evaluable patients (n = 68), the Vineland Adaptive Behavior Scale-II score change from baseline to 12 months did not differ (p = 0.46), and 1-year survival was similar (49% hypothermia vs 42%, normothermia; relative risk, 1.16; 95% CI, 0.68-1.99; p = 0.58). Hypothermia was associated with a higher prevalence of positive bacterial culture (any blood, urine, or respiratory sample; 67% vs 43%; p = 0.04); however, the rate per 100 days at risk did not differ (11.1 vs 8.4; p = 0.46). Cumulative incidence of blood product use, serious arrhythmias, and 28-day mortality were not different. Among patients with cardiopulmonary resuscitation durations more than 30 minutes or epinephrine doses greater than 4, none had favorable Pediatric Cerebral Performance Category outcomes (≤ 3). CONCLUSIONS: In comatose survivors of out-of-hospital pediatric cardiac arrest due to drowning, hypothermia did not result in a statistically significant benefit in survival with good functional outcome or mortality at 1 year, as compared with normothermia. High risk of culture-proven bacterial infection was observed in both groups.