Osmolar therapy in pediatric traumatic brain injury.

OBJECTIVES: To describe patterns of use for mannitol and hypertonic saline in children with traumatic brain injury, to evaluate any potential associations between hypertonic saline and mannitol use and patient demographic, injury, and treatment hospital characteristics, and to determine whether the 2003 guidelines for severe pediatric traumatic brain injury impacted clinical practice regarding osmolar therapy. DESIGN: Retrospective cohort study. SETTING: Pediatric Health Information System database, January, 2001 to December, 2008. PATIENTS: Children (age <18 yrs) with traumatic brain injury and head/neck Abbreviated Injury Scale score ≥ 3 who received mechanical ventilation and intensive care. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital billing for parenteral hypertonic saline and mannitol use, by day of service. Overall, 33% (2,069 of 6,238) of the patients received hypertonic saline, and 40% (2,500 of 6,238) received mannitol. Of the 1,854 patients who received hypertonic saline or mannitol for ≥ 2 days in the first week of therapy, 29% did not have intracranial pressure monitoring. After adjustment for hospital-level variation, primary insurance payer, and overall injury severity, use of both drugs was independently associated with older patient age, intracranial hemorrhage (other than epidural), skull fracture, and higher head/neck injury severity. Hypertonic saline use increased and mannitol use decreased with publication of the 2003 guidelines, and these trends continued through 2008. CONCLUSIONS: Hypertonic saline and mannitol are used less in infants than in older children. The patient-level and hospital-level variation in osmolar therapy use and the substantial amount of sustained osmolar therapy without intracranial pressure monitoring suggest opportunities to improve the quality of pediatric traumatic brain injury care. With limited high-quality evidence available, published expert guidelines appear to significantly impact clinical practice in this area.

Monitoring and prediction of intracranial hypertension in pediatric traumatic brain injury: clinical factors and initial head computed tomography.

BACKGROUND: Control of intracranial hypertension (ICH) in patients with traumatic brain injury (TBI) is standard care. However, predicting risk for ICH is essential to balance risks and benefits of intracranial pressure (ICP) monitoring. Current recommendations for ICP monitoring in pediatric trauma patients are extrapolated from adult studies. METHODS: This retrospective study evaluated 299 children admitted to Primary Children's Medical Center with moderate to severe TBI. ICP monitors were used in 120. Demographic, injury, and admission computed tomography (CT) scan characteristics were compared with determine factors associated with monitoring among those with less severe head CT findings. Among all monitored patients, clinical and radiographic features were compared for early ICH defined as any sustained ICP ≥20 mm Hg in the first 24 hours. RESULTS: Factors independently associated with monitoring children with Marshall I or II scores included presence of intraventricular hemorrhage (odds ratio [OR], 21.4; 95% confidence interval [CI], 4.0-114.7) and greater injury severity scores (ISS) (OR, 9.5 [95% CI, 2.9-31.1] for ISS 21 to 29 and OR, 14.3 [95% CI, 4.3-50.5] for ISS >29 compared with ISS <21). Among those with a normal head CT, 9 of 68 had an ICP monitor placed because of the inability to localize pain. Of these, 78% (7 of 9) had early ICH. Among monitored patients radiologic and clinical features of injury severity were not useful to distinguish risk for early ICH. CONCLUSIONS: Among children with severe TBI, a normal head CT does not exclude ICH. Need for ICP monitoring should be determined by depth of coma in addition to radiographic imaging.

Early post-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, and clinical features.

We performed a retrospective, observational study at a level I pediatric trauma center of children with moderate-to-severe traumatic brain injury (TBI) from January 2002 to September 2006 to identify clinical and radiographic risk factors for early post-traumatic seizures (EPTS). Two hundred and ninety-nine children ages 0-15 years were evaluated, with 24 excluded because they died before the initial head computed tomography (CT) was obtained (n=20), or because their medical records were missing (n=4). Records were reviewed for accident characteristics, pre-hospital hypoxia or hypotension, initial non-contrast head CT characteristics, seizure occurrence, antiepileptic drug (AED) administration, and outcome. All care was at the discretion of the treating physicians, including the use of AEDs and continuous electroencephalogram (EEG) monitoring in patients receiving neuromuscular blocking agents. The primary outcome was seizure activity during the first 7 days as determined by clinician observation or EEG analysis. Of the 275 patients included in the study, 34 had identified EPTS (12%). Risk factors identified on bivariable analysis included pre-hospital hypoxia, young age, non-accidental trauma (NAT), severe TBI, impact seizure, and subdural hemorrhage, while receiving an AED was protective. Independent risk factors identified by multivariable analysis were age <2 years (OR 3.0 [95% CI 1.0,8.6]), Glasgow Coma Scale (GCS) score ≤8 (OR 8.7 [95% CI 1.1,67.6]), and NAT as a mechanism of injury (OR 3.4 [95% CI 1.0,11.3]). AED treatment was protective against EPTS (OR 0.2 [95% CI 0.07,0.5]). Twenty-three (68%) patients developed EPTS within the first 12 h post-injury. This early peak in EPTS activity and demonstrated protective effect of AED administration in this cohort suggests that to evaluate the maximal potential benefit among patients at increased risk for EPTS, future research should be randomized and prospective, and should intervene during pre-trauma center care with initiation of continuous EEG monitoring as soon as possible.

Pediatric stroke: clinical characteristics, acute care utilization patterns, and mortality.

PURPOSE: Acute care utilization patterns are not well described but may help inform care coordination and treatment for pediatric stroke. The Kids Inpatient Database was queried to describe demographics and clinical characteristics of children with stroke, compare acute care utilization for hemorrhagic vs. ischemic stroke and Children's vs. non-Children's Hospitals, and identify factors associated with aggressive care and in-hospital mortality. METHODS: Using a retrospective cohort of children hospitalized with stroke, demographics, predisposing conditions, and intensive (mechanical ventilation, advanced monitoring, and blood product administration) or aggressive (pharmacological therapy and/or invasive interventions) care were compared by stroke and hospital types. Factors associated with aggressive care or in-hospital mortality were explored using logistic regression. RESULTS: Hemorrhagic stroke comprised 43% of stroke discharges, was more common in younger children, and carried greater mortality. Ischemic stroke was more common in older children and more frequently associated with a predisposing condition. Rates of intensive and aggressive care were low (30% and 15%), similar by stroke type, and greater at Children's Hospitals. Older age, hemorrhagic stroke, predisposing condition, and treatment at a Children's Hospital were associated with aggressive care. Hemorrhagic stroke and aggressive care were associated with in-hospital mortality. CONCLUSIONS: Acute care utilization is similar by stroke type but both intensive and aggressive care are more common at Children's Hospitals. Mortality remains relatively high after pediatric stroke. Widespread implementation of treatment guidelines improved outcomes in adult stroke. Adoption of recently published treatment recommendations for pediatric stroke may help standardize care and improve outcomes.

Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality.

OBJECTIVE: The last multicentered analysis of extracorporeal membrane oxygenation in pediatric acute respiratory failure was completed in 1993. We reviewed recent international data to evaluate survival and predictors of mortality. DESIGN: Retrospective case series review. SETTING: The Extracorporeal Life Support Organization Registry, which includes data voluntarily submitted from over 115 centers worldwide, was queried. The work was completed at the Division of Pediatric Critical Care, Department of Pediatrics, Primary Children's Medical Center, University of Utah, Salt Lake City, UT. SUBJECTS: Patients aged 1 month to 18 yrs supported with extracorporeal membrane oxygenation for acute respiratory failure from 1993 to 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 3,213 children studied. Overall survival remained relatively unchanged over time at 57%. Considerable variability in survival was found based on pulmonary diagnosis, ranging from 83% for status asthmaticus to 39% for pertussis. Comorbidities significantly decreased survival to 33% for those with renal failure (n = 329), 16% with liver failure (n = 51), and 5% with hematopoietic stem cell transplantation (n = 22). The proportion of patients with comorbidities increased from 19% during 1993 to 47% in 2007. Clinical factors associated with mortality included precannulation ventilatory support longer than 2 wks and lower precannulation blood pH. CONCLUSIONS: Although the survival of pediatric patients with acute respiratory failure treated with extracorporeal membrane oxygenation has not changed, this treatment is currently offered to increasingly medically complex patients. Mechanical ventilation in excess of 2 wks before the initiation of extracorporeal membrane oxygenation is associated with decreased survival.

Early and sustained increase in the expression of hippocampal IGF-1, but not EPO, in a developmental rodent model of traumatic brain injury.

Pediatric traumatic brain injury (pTBI) is the leading cause of traumatic death and disability in children in the United States. Impaired learning and memory in these young survivors imposes a heavy toll on society. In adult TBI (aTBI) models, cognitive outcome improved after administration of erythropoietin (EPO) or insulin-like growth factor-1 (IGF-1). Little is known about the production of these agents in the hippocampus, a brain region critical for learning and memory, after pTBI. Our objective was to describe hippocampal expression of EPO and IGF-1, together with their receptors (EPOR and IGF-1R, respectively), over time after pTBI in 17-day-old rats. We used the controlled cortical impact (CCI) model and measured hippocampal mRNA levels of EPO, IGF-1, EPOR, IGF-1R, and markers of caspase-dependent apoptosis (bcl2, bax, and p53) at post-injury days (PID) 1, 2, 3, 7, and 14. CCI rats performed poorly on Morris water maze testing of spatial working memory, a hippocampally-based cognitive function. Apoptotic markers were present early and persisted for the duration of the study. EPO in our pTBI model increased much later (PID7) than in aTBI models (12 h), while EPOR and IGF-1 increased at PID1 and PID2, respectively, similar to data from aTBI models. Our data indicate that EPO expression showed a delayed upregulation post-pTBI, while EPOR increased early. We speculate that administration of EPO in the first 1-2 days after pTBI would increase hippocampal neuronal survival and function.

Traumatic brain injury: preferred methods and targets for resuscitation.

PURPOSE OF REVIEW: Severe traumatic brain injury (TBI) is the most common cause of death and disability in pediatric trauma. This review looks at the strategies to treat TBI in a temporal fashion. We examine the targets for resuscitation from field triage to definitive care in the pediatric ICU. RECENT FINDINGS: Guidelines for the management of pediatric TBI exist. The themes of contemporary clinical research have been compliance with these guidelines and refinement of treatment recommendations developing a more sophisticated understanding of the pathophysiology of the injured brain. In the field, the aim has been to achieve routine compliance with the resuscitation goals. In the hospital, efforts have been directed at improving our ability to monitor the injured brain, developing techniques that limit brain swelling, and customizing brain perfusion. SUMMARY: As our understanding of pediatric TBI evolves, the ambition is that age-specific and perhaps individual brain injury strategies based upon feedback from continuous monitors will be defined. In addition, vogue methods such as hypothermia, hypertonic saline, and aggressive surgical decompression may prove to impact brain swelling and outcomes.

Traumatic brain injury during development reduces minimal clonic seizure thresholds at maturity.

Post-traumatic seizures affect 12-35% of children after traumatic brain injury (TBI) and are associated with worse cognitive and functional outcome, even after adjustment for severity of injury. Unfortunately, experimental models of pediatric post-traumatic epilepsy are lacking, and pathogenesis remains poorly understood. We have applied a standard model of TBI in immature rats to determine the effect of TBI on electroconvulsive seizure thresholds later in life. Male rats underwent controlled cortical impact to left parietal cortex on post-natal day (PND) 16-18. Hindbrain, forebrain, and limbic seizure thresholds were assessed, respectively, by tonic hindlimb extension (THE), minimal clonic, and partial psychomotor seizure responses during adolescence (PND 34-40) and at maturity (PND 60-63). Post-traumatic seizure thresholds were compared to those obtained in age- and litter-matched sham craniotomy and naïve controls. TBI during immaturity had no clear effect on THE seizure thresholds. In contrast, TBI lowered minimal clonic seizure thresholds at maturity (p<0.05 vs. sham or naïve rats), but not during adolescence. Consequently, minimal clonic seizure thresholds increased with age for sham and naïve rats but remained similar for TBI rats during adolescence and at maturity. TBI also tended to lower partial psychomotor seizure thresholds, which were determined only during adolescence (p<0.1 vs. naïve). Controlled cortical impact causes both focal cortical injury at the site of impact and ipsilateral hippocampal neuronal death. Since minimal clonic seizures are mediated by the forebrain, partial psychomotor seizures by the limbic system, and THE seizures by the brainstem, the observed pattern of changes in post-traumatic seizure thresholds is not surprising. The apparent age-dependent effects of TBI, however, are unexpected and likely due to a combination of attenuated maturational increases and progressive epileptogenesis. Additional study is needed to delineate the relative contributions of these processes. Given the sustained reduction in post-traumatic minimal clonic seizure thresholds, controlled cortical impact may hold promise as an experimental model of pediatric post-traumatic epilepsy.

Lower hospital mortality and complications after pediatric hematopoietic stem cell transplantation.

OBJECTIVE: To assess protective and risk factors for mortality among pediatric patients during initial care after hematopoietic stem cell transplantation (HSCT) and to evaluate changes in hospital mortality. DESIGN: Retrospective cohort using the 1997, 2000, and 2003 Kids Inpatient Database, a probabilistic sample of children hospitalized in the United States with a procedure code for HSCT. SETTING: Hospitalized patients in the United States submitted to the database. PATIENTS: Age, <19 yrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hospital mortality significantly decreased from 12% in 1997 to 6% in 2003. Source of stem cells changed with increased use of cord blood. Rates of sepsis, graft versus host disease, and mechanical ventilation significantly decreased. Compared with autologous HSCT, patients who received an allogenic HSCT without T-cell depletion were more likely to die (adjusted odds ratio, 2.4; 95% confidence interval, 1.5, 3.9), while children who received cord blood HSCT were at the greatest risk of hospital death (adjusted odds ratio, 4.8; 95% confidence interval, 2.6, 9.1). Mechanical ventilation (adjusted odds ratio, 26.32; 95% confidence interval, 16.3-42.2), dialysis (adjusted odds ratio, 12.9; 95% confidence interval, 4.7-35.4), and sepsis (adjusted odds ratio, 3.9; 95% confidence interval, 2.5-6.1) were all independently associated with death, while care in 2003 was associated with decreased risk (adjusted odds ratio, 0.4; 95% confidence interval, 0.2-0.7) of death. CONCLUSIONS: Hospital mortality after HSCT in children decreased over time as did complications including need for mechanical ventilation, graft versus host disease, and sepsis. Prevention of complications is essential as the need for invasive support continues to be associated with high mortality risk.

Strain and age affect electroconvulsive seizure testing in rats.

Electroconvulsive seizure thresholds were compared between adolescent and mature Sprague--Dawley, Wistar, and Fischer rats. All strains had similar hindbrain or forebrain seizure thresholds as adolescents. As adults, hindbrain or forebrain seizure thresholds were highest for Sprague--Dawley and lowest for Fischer rats. Conversely, limbic seizure thresholds during adolescence were highest for Fischer rats. Additional study is needed to better delineate strain and maturational effects on electroconvulsive seizure testing.

Pediatric posttraumatic seizures: epidemiology, putative mechanisms of epileptogenesis and promising investigational progress.

Posttraumatic seizures and epilepsy are common in children experiencing traumatic brain injury and portend worse functional outcome. Unfortunately, the pathogenesis of pediatric posttraumatic seizures and epilepsy remains poorly understood, and no efficacious preventive therapy for post-traumatic epilepsy has been identified. This article reviews the epidemiology of pediatric posttraumatic seizures, discusses prominent putative mechanisms of posttraumatic epileptogenesis and highlights recent promising progress in experimental investigations of posttraumatic seizures and epilepsy.

Isoflurane exerts neuroprotective actions at or near the time of severe traumatic brain injury.

Isoflurane improves outcome vs. fentanyl anesthesia, in experimental traumatic brain injury (TBI). We assessed the temporal profile of isoflurane neuroprotection and tested whether isoflurane confers benefit at the time of TBI. Adult, male rats were randomized to isoflurane (1%) or fentanyl (10 mcg/kg iv bolus then 50 mcg/kg/h) for 30 min pre-TBI. Anesthesia was discontinued, rats recovered to tail pinch, and TBI was delivered by controlled cortical impact. Immediately post-TBI, rats were randomized to 1 h of isoflurane, fentanyl, or no additional anesthesia, creating 6 anesthetic groups (isoflurane:isoflurane, isoflurane:fentanyl, isoflurane:none, fentanyl:isoflurane, fentanyl:fentanyl, fentanyl:none). Beam balance, beam walking, and Morris water maze (MWM) performances were assessed over post-trauma d1-20. Contusion volume and hippocampal survival were assessed on d21. Rats receiving isoflurane pre- and post-TBI exhibited better beam walking and MWM performances than rats treated with fentanyl pre- and any treatment post-TBI. All rats pretreated with isoflurane had better CA3 neuronal survival than rats receiving fentanyl pre- and post-TBI. In rats pretreated with fentanyl, post-traumatic isoflurane failed to affect function but improved CA3 neuronal survival vs. rats given fentanyl pre- and post-TBI. Post-traumatic isoflurane did not alter histopathological outcomes in rats pretreated with isoflurane. Rats receiving fentanyl pre- and post-TBI had the worst CA1 neuronal survival of all groups. Our data support isoflurane neuroprotection, even when used at the lowest feasible level before TBI (i.e., when discontinued with recovery to tail pinch immediately before injury). Investigators using isoflurane must consider its beneficial effects in the design and interpretation of experimental TBI research.

Comparison of seven anesthetic agents on outcome after experimental traumatic brain injury in adult, male rats.

Isoflurane is commonly used in experimental traumatic brain injury (TBI), both before and early after injury, yet it is rarely used clinically. Narcotics and benzodiazepines are frequently used after injury in clinical TBI. We compared seven anesthetic/sedative agents applied after injury in the controlled cortical impact model: diazepam, fentanyl, isoflurane, ketamine, morphine, pentobarbital, and propofol. Our objective was to provide insight into the relative degrees of neuroprotection provided by these agents in a standard model of TBI. We hypothesized that the choice of anesthetic/sedative early after experimental TBI critically impacts outcome and that the agents most commonly used clinically may be less neuroprotective than isoflurane. Rats treated with isoflurane had the best cognitive recovery (p < 0.05) and hippocampal neuronal survival (p < 0.05). Conversely, rats treated with ketamine had the most hippocampal neuronal death (p < 0.05). Morphine or propofol, two agents commonly used clinically, were associated with the poorest motor function on post-trauma day 1-5 (p < 0.05). Our data support beneficial effects of isoflurane early after experimental TBI. Our data suggest that the early post-TBI use of isoflurane, despite practical logistical issues, could potentially provide clinical benefits in TBI--versus other commonly used sedatives or analgesics. Furthermore, the choice of post-injury sedation and analgesia could have important implications on attempts to translate novel therapies from bench to field or bedside.