Jimmy W. Huh

Reference Range for Cerebrospinal Fluid Opening Pressure in Children

To the Editor: A reference range for cerebrospinal fluid (CSF) opening pressure in children undergoing diagnostic lumbar puncture has not been established.1 The influence of age, body-mass index (B...

S-100β protein-serum levels in healthy children and its association with outcome in pediatric traumatic brain injury

ObjectiveTo describe normal serum levels of S-100&bgr; in healthy children and determine whether serum S-100&bgr; levels after traumatic brain injury are associated with outcome. DesignProspective cohort study. SettingUrban, tertiary care, children’s teaching hospital. PatientsA total of 136 healthy children and 27 children with traumatic brain injury. MethodsSerum S-100&bgr; levels were measured in 136 healthy children. A total of 27 children with traumatic brain injury had S-100&bgr; levels collected within 12 hrs of injury. Other indices of severity of injury measured were admission Glasgow Coma Scale score, and Pediatric Risk of Mortality score at 24 hrs (PRISM 24). Outcome was measured by the Pediatric Cerebral Performance Category (PCPC) score at hospital discharge and 6 months postinjury or at death. Measurements and Main ResultsS-100&bgr; levels in healthy children had a mean of 0.3 &mgr;g/L (90% confidence interval, 0.03–1.47) and inversely correlated with age, (r = −.32, p < .001). In children with traumatic brain injury, 6-month postinjury outcome inversely correlated with Glasgow Coma Scale score (r = −.47, p = .01) and correlated with PRISM 24 score (r = .83, p < .001) and S-100&bgr; levels (r = .75, p < .001). Six months postinjury, comparing good outcome (PCPC ≤ 3, n = 20) vs. poor outcome (PCPC ≥ 4, n = 7), median admission Glasgow Coma Scale scores were 8 (range, 3–15) and 3 (range, 3–7, p = .01), median PRISM 24 scores were 7 (range, 0–19) and 30 (range, 18–35, p < .001), and median S-100&bgr; levels were 0.85 &mgr;g/L (range, 0.08–4.8 &mgr;g/L) and 3.6 &mgr;g/L (range, 1.4–20 &mgr;g/L, p < .001), respectively. A serum S-100&bgr; level of ≥2.0 &mgr;g/L is associated with poor outcome, with a sensitivity of 86% and a specificity of 95%. The area under the receiver operating curve for S-100&bgr; was 0.94 (±0.05). ConclusionsSerum S-100&bgr; levels in healthy children have a moderate inverse correlation with age. After traumatic brain injury in children, the acute assessment of serum S-100&bgr; levels seems to be associated with outcome.

Impaired axonal transport and neurofilament compaction occur in separate populations of injured axons following diffuse brain injury in the immature rat

Diffuse brain injury is a leading cause of mortality in infants and children under 4 years of age and results in cognitive deficits in survivors. The anatomic basis for these behavioral deficits may be traumatic axonal injury (TAI), which manifests as impaired axonal transport (IAT) and neurofilament compaction (NFC), and may occur as a result of glutamate receptor activation. The extent of IAT and NFC was evaluated at 6, 24 and 72 h following non-contusive brain trauma in the 17 day-old rat to examine the causal relationship between these two pathologic entities; in addition, the effect of antagonists to the ionotropic glutamate receptors on TAI was evaluated. At 6 h post-injury, NFC was observed primarily in the cingulum, and appeared as swollen axons and terminal bulbs. By 24 h, swollen axons were additionally present in the corpus callosum and lateral white matter tracts, and appeared to increase in diameter. At 72 h, the extent of axonal swellings exhibiting compacted neurofilaments appeared to decrease, and was accompanied by punctate immunoreactivity within axon tracts suggestive of axonal degeneration. Although NFC was present in the same anatomical locations where axonal accumulation of amyloid precursor protein (APP) has been observed, double-label immunohistochemistry revealed no evidence of colocalization of compacted neurofilament and APP. Pre-injury treatment with either the NMDA receptor antagonist, ifenprodil, or the AMPA receptor antagonist, NBQX, had no significant effect on the extent of TAI, suggesting that excitotoxicity may not be a primary mechanism underlying TAI. Importantly, these data are indicative of the heterogeneity of mechanisms underlying TAI in the traumatically-injured immature brain.

Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration

Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3-15 s), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury (p<0.0005), and, significant learning (p<0.005) and memory deficits (p<0.05) in the third post-injury week. Between 6 and 72 h, blood-brain barrier breakdown, extensive traumatic axonal injury in the subcortical white matter and thalamus, and focal areas of neurodegeneration in the cortex and hippocampus were observed in both hemispheres of the injured brain. At 8 to 18 days post-injury, reactive astrocytosis in the cortex, axonal degeneration in the subcortical white matter tracts, and degeneration of neuronal cell bodies and processes in the thalamus of both hemispheres were observed; however, cortical volumes were not different between un-injured and injured rat brains. These data suggest that diffuse TBI in the immature rat can lead to ongoing degeneration of both cell soma and axonal compartments of neurons, which may contribute, in part, to the observed sustained cognitive deficits.

Use of recombinant factor VIIa for refractory hemorrhage during extracorporeal membrane oxygenation.

Objective: To describe the outcome and treatment of two patients with recombinant factor VIIa (rFVIIa) for severe hemorrhage associated with extracorporeal membrane oxygenation (ECMO). Design: Case report. Setting: A 38-bed pediatric intensive care unit and 20-bed pediatric cardiac intensive care unit at a tertiary care children’s hospital. Patient: Two patients with life-threatening hemorrhagic complications associated with ECMO requiring massive transfusion of blood products. Interventions: Administration of repeated doses of rFVIIa at 90 &mgr;g/kg/dose. Measurement and Main Results: Patient 1 was an 11-yr-old male with a dilated cardiomyopathy who had undergone an orthotopic heart transplant treated with venoarterial ECMO postoperatively for right ventricular dysfunction. Patient 2 was a 13-yr-old male treated with venoarterial ECMO for cardiopulmonary failure from necrotizing staphylococcal pneumonia. Both patients had severe hemorrhage from the cannulation sites and thoracostomy tubes requiring massive transfusion to maintain intravascular blood volume and replace clotting factors. Both patients were treated with rFVIIa every 2–4 hrs and attained hemostasis. Patient 1 was administered three doses and Patient 2 was administered ten doses. No evidence of abnormal thrombus formation was noted in their respective ECMO circuits. Conclusions: The efficacy of rFVIIa in reducing intractable bleeding postcardiac surgery and in other coagulopathic states is being investigated. Despite theoretical concerns of thrombosis, these cases illustrate that there may be a role for the cautious use of rFVIIa in treating severe and intractable hemorrhage associated with ECMO.

New Concepts in Treatment of Pediatric Traumatic Brain Injury

Emerging evidence suggests unique age-dependent responses following pediatric traumatic brain injury. The anesthesiologist plays a pivotal role in the acute treatment of the head-injured pediatric patient. This review provides important updates on the pathophysiology, diagnosis, and age-appropriate acute management of infants and children with severe traumatic brain injury. Areas of important clinical and basic science investigations germane to the anesthesiologist, such as the role of anesthetics and apoptosis in the developing brain, are discussed.

CSF opening pressure in children with optic nerve head edema.

Background: We previously reported that an abnormal CSF opening pressure (OP) in children was greater than 28 cm H2O. Since elevated intracranial pressure can cause optic nerve head edema (ONHE), we would expect that most patients with ONHE would have an OP greater than 28 cm H2O. This study describes the range of OP for children with ONHE and compared them to age-matched controls without ONHE. Methods: Case subjects were children (1–18 years of age) enrolled in a prospective study of CSF OP that demonstrated ONHE at time of lumbar puncture and that the ONHE later resolved. Patients with ONHE secondary to infectious, inflammatory, or ischemic conditions were excluded. Control subjects from the same study, but without ONHE, were matched to cases. Results: Of the 472 subjects enrolled in the study, 41 OP measurements were obtained from 33 patients with ONHE who did not have any exclusionary criteria and matched to 41 control subjects without ONHE. Case subjects had a significantly higher OP (mean, 41.4 cm H20; range, 22–56) than control subjects (mean, 18.9 cm H2O; range, 9–29; p < 0.01). Forty of 41 (97.6%) case subjects and 2 of 41 (4.8%) control subjects had OP measures >28 cm H2O. Conclusions: Children with ONHE not related to infectious, inflammatory, or ischemic causes typically have an OP >28 cm H2O, significantly higher than age-matched controls without ONHE. This study provides further support to our previously published findings that suggests an abnormal OP in children is typically above 28 cm H2O.

Transient loss of microtubule-associated protein 2 immunoreactivity after moderate brain injury in mice.

Microtubule-associated protein 2 (MAP2) is important for microtubule stability and neural plasticity and appears to be among the most vulnerable of the cytoskeletal proteins under conditions of neuronal injury. To evaluate the acute effects of moderate severity traumatic brain injury on MAP2, anesthetized, adult male C57BL/6 mice were subjected to controlled cortical impact brain injury. At 5 min, 15 min, 90 min, 4 h, and 24 h following brain injury (n = 4 injured and n = 1 sham-injured per time point), mice were sacrificed and immunohistochemistry was performed on coronal brain sections. Profound decreases in MAP2 immunolabeling were observed in the ipsilateral cortex and hippocampal dentate hilus at 5 min postinjury and in the ipsilateral hippocampal CA3 area by 4 h postinjury. Decreases in MAP2 labeling occurred prior to notable neuronal cell loss. Interestingly, cortical MAP2 immunoreactivity returned by 90 min postinjury, but the recovery was short-lived within the core in comparison to the periphery of the impact site. Partial restoration of MAP2 immunoreactivity was also observed in the ipsilateral CA3 and dentate hilus by 24 h postinjury. Our data corroborate that MAP2 is an early and sensitive marker for neuronal damage following traumatic brain injury. Acute MAP2 loss, however, may not necessarily presage neuronal death, even following moderate severity traumatic brain injury. Rather, to the best of our knowledge, our data are the first to suggest an intrinsic ability of the traumatized brain for MAP2 recovery after injury of moderate severity.

Nonconvulsive Electrographic Seizures are Common in Children With Abusive Head Trauma

Objective: To determine the prevalence of nonconvulsive seizures in children with abusive head trauma. Design: Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring. Setting: PICU of a tertiary care hospital. Subjects: Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team. Interventions: None. Measurements and Main Results: Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p = 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p = 0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10). Conclusions: Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome.

Regionally Distinct Patterns of Calpain Activation and Traumatic Axonal Injury following Contusive Brain Injury in Immature Rats

Impact-induced head injury in infants results in acute focal contusions and traumatic axonal injury (TAI) that are associated with chronic holohemispheric cortical and white matter atrophy and may contribute to poor outcome in brain-injured children less than 4 years of age. Contusive brain trauma in postnatal day (PND) 11 or PND 17 rat pups, ages neurologically equivalent to a human infant and toddler, respectively, leads to cortical tissue loss and white matter atrophy which are associated with cognitive deficits. In adult models of brain trauma and in brain-injured humans, acute and sustained activation of the calpain family of calcium-activated neutral proteases has been implicated in neuronal death and TAI. PND 11 or PND 17 rat pups were subjected to closed head injury over the left hemisphere using the controlled cortical impact device and sacrificed at 6 h, 24 h or 3 days. Hemorrhagic contusions and tissue tears in the cortex and white matter were visible at 6 h, and neuronal loss was evident by 3 days. Calpain activation was observed in cell soma and dendrites of injured neurons at 6 h, and in degenerating dendrites and atrophic neurons at 24 h after injury at both ages. Axonal accumulation of amyloid precursor protein, indicative of TAI, was observed in the corpus callosum and lateral aspects of the white matter below the site of impact, and in the thalamus in PND 11 rats only. Intra-axonal calpain activation was observed to a limited extent in the corpus callosum and subcortical white matter tracts in both brain-injured PND 11 and PND 17 rats. Collectively, these results provide evidence that calpain activation may participate in neuronal loss in the injured cortex, but may not contribute to the pathogenesis of TAI following contusive brain trauma in the immature rat.