Biomedical subjects

Patrick M Kochanek

Publications and source records attributed to Patrick M Kochanek.

At least 19 recordsLinked to original sources

PubMed2007

Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial.

OBJECTIVE: Emergency preservation and resuscitation (EPR) comprise a novel approach for resuscitation of exsanguination cardiac arrest victims. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass. Development of a rat EPR model would enable study of the molecular mechanisms of neuronal injury and the screening of novel agents for emergency preservation. DESIGN: A prospective, randomized study. SETTING: University research facility. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Isoflurane-anesthetized rats were subjected to lethal hemorrhage (12.5 mL for 5 mins), followed by KCl-induced cardiac arrest and 1 min of no flow. Three groups (n=6) were studied: hypothermic EPR (H-EPR; 0 degrees C flush; target temperature, 15 degrees C); normothermic EPR (N-EPR; 38 degrees C flush); and controls. After 20 mins of H-EPR or N-EPR, resuscitation was initiated with cardiopulmonary bypass for 60 mins and mechanical ventilation. Controls were subjected to complete experimental preparation and anesthesia without cardiac arrest, followed by 60 mins of cardiopulmonary bypass and mechanical ventilation. Surviving rats were extubated 2 hrs later. Survival, Overall Performance Category (1, normal; 5, death), Neurologic Deficit Score, Histologic Damage Score, and biochemistry were assessed in survivors on day 7. MEASUREMENTS AND MAIN RESULTS: All rats in H-EPR and control groups survived, whereas none of the rats in the N-EPR group had restoration of spontaneous circulation. All rats in the H-EPR and control groups achieved Overall Performance Category 1, normal Neurologic Damage Score, and normal or near normal Histologic Damage Score and biochemical markers of organ injury. CONCLUSIONS: We have established an EPR model in rats showing no neurologic injury, despite an exsanguination cardiac arrest, followed by 20 mins of EPR using miniaturized cardiopulmonary bypass. Establishment of this model should facilitate application of molecular tools to study the effects of hypothermic preservation and reperfusion and to screen novel pharmacologic adjuncts.

Animals↗

PubMed2006

Transgenic mice that overexpress the anti-apoptotic Bcl-2 protein have improved histological outcome but unchanged behavioral outcome after traumatic brain injury.

Increasing evidence suggests that apoptosis is a contributing factor to neuronal cell death in traumatic brain injury (TBI). There is increased expression, cleavage and activation of caspases as well as other proteins known to regulate apoptosis in neurons after TBI. These proteins include the proto-oncogene Bcl-2 which belongs to a family of proteins with both pro- and anti-apoptotic properties. To investigate the role of apoptosis in TBI and the importance of Bcl-2 protein on the severity and outcome of injury, Bcl-2 overexpressing transgenic and wild-type control mice were subjected to the controlled cortical impact model of TBI. There was no significant difference in the cleavage of caspase-3 or caspase-9 detected by Western blotting of hippocampal samples from transgenic or wild-type mice after TBI. Bcl-2 transgenic mice had smaller contusion volumes and increased numbers of surviving neurons in CA2 but not other regions of hippocampus compared to wild-type controls. By contrast, there was no difference in motor function determined by the round beam balance and wire grip tests between transgenic and wild-type mice after TBI. Cognitive function assessed by the Morris water maze was also not different between groups. These results suggest that overexpression of Bcl-2 is only partially neuroprotective and other members of this protein family may prove to be more important in protecting neurons from cell death.

Animals↗

PubMed2006

Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation.

BACKGROUND: Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. METHODS AND RESULTS: Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (n=9), mild hypothermia (34 degrees C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (n=8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (P=0.012). CONCLUSIONS: Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible.

Animals↗

PubMed2006

Oxidation and cytotoxicity of 6-OHDA are mediated by reactive intermediates of COX-2 overexpressed in PC12 cells.

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, likely associated with dysregulation of oxidation of catechols, such as dopamine (DA) and 6-hydroxydopamine (6-OHDA), and resulting in oxidative stress. The involvement of cyclooxygenase-2 (COX-2) in pathogenesis of Parkinson's disease has been suggested. However, specific COX-2 triggered mechanisms participating in catalysis of DA oxidation and enhanced catechol-induced cytotoxicity remain poorly characterized. Here, we demonstrate that in a model biochemical system, recombinant heme-reconstituted COX-2 induced oxidation of 6-OHDA in the course of its peroxidase (H(2)O(2)-dependent) and cyclooxygenase (arachidonic acid (AA)-dependent) catalytic half-cycles. Similarly, COX-2 was able to stimulate 6-OHDA oxidation during its peroxidase- and cyclooxygenase half-cycles and caused oxidative stress in homogenates of PC12 cells stably overexpressing the enzyme (but not in mock-transfected cells). In addition, the increased levels of COX-2 were associated with enhanced cytotoxicity of 6-OHDA in stably transfected PC12 cells. Finally, co-oxidation of 6-OHDA by COX-2 triggered production of superoxide radicals critical for both propagation of 6-OHDA oxidation and induction of oxidative stress in COX-2 overexpressing cells. Thus, we conclude that both peroxidase and cyclooxygenase half-cycles of COX-2-catalyzed reactions are essential for COX-2-dependent activation of 6-OHDA oxidation, oxygen radical production, oxidative stress, and cytotoxicity.

Animals↗

PubMed2006

boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats.

The pathobiology of traumatic brain injury (TBI) includes activation of multiple caspases followed by cell death with a spectrum of apoptotic phenotypes. There are initiator (e.g. caspase-2, -8, and -9) and effector (e.g. caspase-3 and -7) caspases. Recently, caspase-2 and -8 have been shown to regulate cell death via provoking cytochrome c release from the mitochondria upstream of caspase-9. Here, we show that an intracerebral injection of the pan-caspase inhibitor boc-Aspartyl(OMe)-fluoromethylketone (BAF; 1 micromol) 1 min after TBI in rats reduces caspase-3-like activity, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and tissue damage, and cytochrome c release in ipsilateral cortex at 24 h versus vehicle. To investigate whether either caspase-2 and/or caspase-8 activation may contribute to cytochrome release, the effect of BAF treatment on caspase-2 and caspase-8 proteolysis was also examined. boc-aspartyl(OMe)-fluoromethylketone treatment inhibited proteolysis of caspase-2 but not caspase-8 24 h after TBI in rats versus vehicle. However, BAF with or without nerve growth factor (12.5 ng/h x 14 days intracerebrally via osmotic pump) did not result in differences in motor function, Morris water maze performance, hippocampal neuron survival, nor contusion volume at 14 days. These data suggest that BAF treatment reduces acute cell death after TBI by inhibiting mitochondrial release of cytochrome c, possibly via a mechanism involving initiator caspases; however, BAF appears to delay cell death, rather than result in permanent protection.

Amino Acid Chloromethyl Ketones↗

PubMed2006

Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs.

BACKGROUND: Induction of profound hypothermia for emergency preservation and resuscitation (EPR) of trauma victims who experience exsanguination cardiac arrest may allow survival from otherwise-lethal injuries. Previously, we achieved intact survival of dogs from 2 hours of EPR after rapid hemorrhage. We tested the hypothesis that EPR would achieve good outcome if prolonged hemorrhage preceded cardiac arrest. METHODS AND RESULTS: Two minutes after cardiac arrest from prolonged hemorrhage and splenic transection, dogs were randomized into 3 groups (n=7 each): (1) the cardiopulmonary resuscitation (CPR) group, resuscitated with conventional CPR, and the (2) EPR-I and (3) EPR-II groups, both of which received 20 L of a 2 degrees C saline aortic flush to achieve a brain temperature of 10 degrees C to 15 degrees C. CPR or EPR lasted 60 minutes and was followed in all groups by a 2-hour resuscitation by cardiopulmonary bypass. Splenectomy was then performed. The CPR dogs were maintained at 38.0 degrees C. In the EPR groups, mild hypothermia (34 degrees C) was maintained for either 12 (EPR-I) or 36 (EPR-II) hours. Function and brain histology were evaluated 60 hours after rewarming in all dogs. Cardiac arrest occurred after 124+/-16 minutes of hemorrhage. In the CPR group, spontaneous circulation could not be restored without cardiopulmonary bypass; none survived. Twelve of 14 EPR dogs survived. Compared with the EPR-I group, the EPR-II group had better overall performance, final neurological deficit scores, and histological damage scores. CONCLUSIONS: EPR is superior to conventional CPR in facilitating normal recovery after cardiac arrest from trauma and prolonged hemorrhage. Prolonged mild hypothermia after EPR was critical for achieving intact neurological outcomes.

Animals↗

PubMed2006

Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia.

Cytochrome P450 metabolism of arachidonic acid produces the potent vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). Recent studies have implicated 20-HETE as a vasoconstrictive mediator in hemorrhagic stroke. The purpose of this study was to determine the effect of the 20-HETE inhibitor, HET0016, on lesion volume and cerebral blood flow (CBF) after temporary middle cerebral artery occlusion (MCAO) in rats. Plasma pharmacokinetics and tissue concentrations of HET0016 were determined after a 10 mg/kg intraperitoneal dose. Separate rats were treated with HET0016 or vehicle before 90 mins of MCAO. Lesion volume was assessed by 2,3,5-triphenyl-tetrazolium-chloride and cerebral flow was determined using laser Doppler flow. The effect of MCAO on in vitro microsomal formation of mono-oxygenated arachidonic acid metabolites was also determined. Results show that HET0016 has a short biologic half-life, distributes into the brain, and is associated with a 79.6% reduction in 20-HETE concentration in the cortex. Lesion volume was greatly reduced in HET0016-treated (9.1%+/-4.9%) versus vehicle-treated (57.4%+/-9.8%; n=6; P<0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%+/-6.2%; 240 mins 88.1%+/-5.7% of baseline flow) versus vehicle control (180 mins 57.6%+/-19.0%; 240 mins 53.8%+/-20.0% of baseline flow; n=6; P<0.05). Brain cortical microsomal formation rate of 20-HETE was also reduced at 24 h in the ipsilateral hemisphere after MCAO. These data support a significant role for 20-HETE in the pathogenesis of ischemic stroke.

Amidines↗

PubMed2006

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.

Anesthetics, Intravenous↗

PubMed2006

Immunohistochemical analysis of histone H3 acetylation and methylation--evidence for altered epigenetic signaling following traumatic brain injury in immature rats.

Posttranslational modifications (PTMs) of histone proteins may result in altered epigenetic signaling after pediatric traumatic brain injury (TBI). Hippocampal histone H3 acetylation and methylation in immature rats after moderate TBI were measured and decreased only in CA3 at 6 h and 24 h with persistent methylation decreases up to 72 h after injury. Decreased histone H3 acetylation and methylation suggest altered hippocampal CA3 epigenetic signaling during the first hours to days after TBI.

Acetylation↗

PubMed2006

Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury.

Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy--and inhibits progression to status epilepticus (SE). Seizures after traumatic brain injury (TBI) may contribute to pathophysiology. Thus, we hypothesized that endogenous adenosine, acting via A1 receptors, mediates antiepileptic benefit after experimental TBI. We subjected A1-receptor knockout (ko) mice, heterozygotes, and wild-type (wt) littermates (n=115) to controlled cortical impact (CCI). We used four outcome protocols in male mice: (1) observation for seizures, SE, and mortality in the initial 2 h, (2) assessment of seizure score (electroencephalogram (EEG)) in the initial 2 h, (3) assessment of mortality at 24 h across injury levels, and (4) serial assessment of arterial blood pressure, heart rate, blood gases, and hematocrit. Lastly, to assess the influence of gender on this observation, we observed female mice for seizures, SE, and mortality in the initial 2 h. Seizure activity was noted in 83% of male ko mice in the initial 2 h, but was seen in no heterozygotes and only 33% of wt (P<0.05). Seizures in wt were brief (1 to 2 secs). In contrast, SE involving lethal sustained (>1 h) tonic clonic activity was uniquely seen in ko mice after CCI (50% incidence in males), (P<0.05). Seizure score was twofold higher in ko mice after CCI versus either heterozygote or wt (P<0.05). An injury-intensity dose-response for 24 h mortality was seen in ko mice (P<0.05). Physiologic parameters were similar between genotypes. Seizures were seen in 100% of female ko mice after CCI versus 14% of heterozygotes and 25% wt (P<0.05) and SE was restricted to the ko mice (83% incidence). Our data suggest a critical endogenous anticonvulsant action of adenosine at A1 receptors early after experimental TBI.

Animals↗

PubMed2006

Proteolysis consistent with activation of caspase-7 after severe traumatic brain injury in humans.

The expression and proteolysis of caspase family proteins are involved in the initiation and execution of apoptosis, which has been reported to occur in human and experimental traumatic brain injury (TBI). Caspase-3, -6, and -7 belong to the group of executioner caspases, which are cleaved and activated at the late, irreversible stage of apoptosis. Our previous studies demonstrated roles for caspase-1, -3, and -8 in humans after severe TBI. Here we report expression of caspase-7 mRNA and protein in humans after TBI (n = 16) and control brain-bank tissue (n = 6). Semiquantitative reverse transcription polymerase chain reaction showed no differences between caspase-7 mRNA in TBI patients versus controls (73 +/- 24 vs. 85 +/- 56 relative optical density [ROD], respectively). In contrast, Western blot analysis showed increased pro-caspase-7 in TBI patients versus controls (214 +/- 30 vs. 1 +/- 1 ROD, respectively), as well as an increase in the approximately 20 kD proteolytic fragment in TBI patients versus controls (86 +/- 13 vs. 22 +/- 12 ROD, respectively), consistent with activation of caspase-7 after TBI in humans. Immunohistochemical analysis showed that cells expressing caspase-7 included astrocytes and neurons and possibly other glial cell types and infiltrated inflammatory cells. These data show that caspase-7 and its cleavage product are increased in human brain after TBI in many central nervous system, as well as noncentral nervous system, cell types. Thus, caspase-7 may play a role in the glial and inflammatory responses, and possibly neuronal death, after TBI in humans.

Apoptosis↗

PubMed2006

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.

Anesthetics↗

PubMed2006

Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model.

OBJECTIVES: Therapeutic hypothermia has demonstrated considerable benefit in patients experiencing cardiac arrest. Despite increasing clinical use, there is a paucity of information regarding the effect of hypothermia on the disposition of medications, specifically cytochrome P450-mediated drug metabolism. The objective was to determine the effect of hypothermia after cardiac arrest on the in vivo kinetics of a cytochrome P450 (CYP2E1) probe drug, chlorzoxazone, and to investigate the mechanism of these alterations. DESIGN: Laboratory investigation. SETTING: University pharmacy school and animal research facility. SUBJECTS: Sixteen male Sprague-Dawley rats. INTERVENTIONS: An asphyxial arrest rat model was used and moderate hypothermia was induced immediately postinsult via surface cooling. Chlorzoxazone was administered as an intravenous bolus, and plasma concentrations were analyzed using high-performance liquid chromatography methods. Protein binding was analyzed using rat control plasma, and Michaelis-Menten enzyme kinetic analysis was performed at 37 degrees C and 30 degrees C using control rat microsomes at varying concentrations of chlorzoxazone. MEASUREMENTS AND MAIN RESULTS: Moderate hypothermia after cardiac arrest in rats markedly decreased the systemic clearance of the CYP2E1 substrate, chlorzoxazone, when compared with normothermia after cardiac arrest, 1.26+/-0.34 mL/min vs. 0.580+/-0.37 mL/min (p<.001). No changes in chlorzoxazone protein binding were observed at 37 degrees C and 30 degrees C, and CYP2E1 enzyme capacity (maximum velocity) was not altered at these different incubation temperatures. However, Michaelis-Menten constant was significantly increased at 30 degrees C (551+/-150 microM) compared with incubations at 37 degrees C (255+/-52 microM, p<.01). CONCLUSIONS: Moderate hypothermia markedly reduces the systemic clearance of chlorzoxazone in cardiac arrest rats. This results from hypothermia-induced decreases in the CYP2E1 enzyme affinity for the substrate chlorzoxazone. This is the first systematic mechanistic investigation of the effect of hypothermia on CYP2E1-mediated metabolism.

Analysis of Variance↗

PubMed2006

Reliability and validity of the Pediatric Intensity Level of Therapy (PILOT) scale: a measure of the use of intracranial pressure-directed therapies.

OBJECTIVE: To test the reliability and validity of the Pediatric Intensity Level of Therapy (PILOT) scale, a novel measure of overall therapeutic effort directed at controlling intracranial pressure (ICP) in the setting of severe (Glasgow Coma Scale of <or= 8) pediatric traumatic brain injury (TBI). DESIGN: Case-control study via retrospective review of medical records. SETTING: Tertiary-care, university-based children's hospital intensive care unit. PATIENTS: Randomly selected patients <or=18 yrs old admitted to the intensive care unit in 2002-2003 with severe TBI (cases: group 1, n = 27), mild-moderate TBI (control: group 2, n = 30), extracranial trauma (control: group 3, n = 29), or nontraumatic illnesses (control: group 4, n = 27). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A 38-point scale was developed to quantify daily ICP-directed therapeutic effort. All currently recommended therapies are represented. Demographic and physiologic data were collected on all patients. A total of 24 of 27 patients with severe TBI received ICP-directed therapy; three did not because of judgments of futility. No control patients received ICP-directed therapy. The PILOT scale score was assessed for the first 7 days posttrauma or postadmission. Interrater reliability was 0.91 (intraclass correlation coefficient) and intrarater reliability was 0.94. The highest PILOT scale scores were in patients with severe TBI (11.7 +/- 5.6 vs. 1.3 +/- 1.7 vs. 2.0 +/- 2.1 vs. 1.9 +/- 1.8 for groups 1, 2, 3 and 4, respectively [mean +/- sd]; p < .001 by analysis of variance/Bonferroni). Patients with severe TBI who received ICP-directed therapy had higher PILOT scale scores (12.6 +/- 5.3 vs. 5.0 +/- 3.0, p = .001) than those who did not. Pearson's correlation coefficients of mean PILOT scale scores with measures of injury severity, outcome, and ICP were as follows: Glasgow Coma Scales score, -0.73 (p < .001); overall Injury Severity Score, 0.37 (p < .001); Injury Severity Score (head component only), 0.53 (p < .001); 6-month Glasgow Outcome Scale, -0.26 (p = .006); ICP burden (hours per day with ICP above treatment threshold), 0.59 (p = .002); and mean ICP, 0.41 (p = .044). CONCLUSIONS: The PILOT scale score can be obtained retrospectively and has good reliability. It can discriminate patients receiving ICP-directed therapy, even among patients with severe TBI, and correlates with measures of injury severity, outcome, and ICP in an expected way. Thus, it seems to be a valid measure of the use of ICP-directed therapy, although prospective, multiple-center validation is recommended.

Brain Injuries↗

PubMed2006

Urinary S100B concentrations are increased after brain injury in children: A preliminary study.

OBJECTIVE: S100B is a renally excreted protein concentrated in glial cells of the nervous system. Increases in serum S100B concentrations reflect brain injury. However, increases in serum are rapid and transient and therefore may be of limited use in certain patients. Urinary S100B concentrations may be able to provide information about brain injury in this subgroup of patients. DESIGN: Prospective, descriptive study. SETTING: Level I trauma center. PATIENTS: Fifteen children with acute traumatic or hypoxemic brain injury (subjects) and 14 healthy controls. INTERVENTIONS: Urine and serum samples were collected from subjects and controls. Serial samples were collected in brain injury subjects up to every 12 hrs for 3 days. S100B concentrations were measured by enzyme-linked immunosorbent assay (Nanogen, San Diego CA). Outcome was assessed by Glasgow Outcome Scale score. MEASUREMENTS AND MAIN RESULTS: Urinary S100B concentrations were detectable in 80% of subjects with increased serum S100B concentrations and 0% of controls. Peak urinary S100B concentrations occurred significantly later than peak serum S100B concentrations: 55.3 (29.8) (mean [sd]) vs. 14.6 (11.8) hrs after injury (p = .002). All subjects with an undetectable urinary S100B had a good outcome vs. only 20% of subjects with a detectable urinary S100B. Subjects with increased serum S100B were more likely to have a poor outcome than those with normal S100B (p = .01). CONCLUSIONS: Increases in urinary S100B are found in the majority of children with acute brain injury and an increased serum S100B. Urinary S100B concentrations peak later than serum concentrations, suggesting that measurement of urinary S100B may be helpful in subjects in whom early serum S100B is unavailable. Urinary and/or serum S100B concentrations may be useful to assist in the prediction of outcome after pediatric brain injury.

Adolescent↗

PubMed2006

Pediatric traumatic brain injury: quo vadis?

In this review, five questions serve as the framework to discuss the importance of age-related differences in the pathophysiology and therapy of traumatic brain injury (TBI). The following questions are included: (1) Is diffuse cerebral swelling an important feature of pediatric TBI and what is its etiology? (2) Is the developing brain more vulnerable than the adult brain to apoptotic neuronal death after TBI and, if so, what are the clinical implications? (3) If the developing brain has enhanced plasticity versus the adult brain, why are outcomes so poor in infants and young children with severe TBI? (4) What contributes to the poor outcomes in the special case of inflicted childhood neurotrauma and how do we limit it? (5) Should both therapeutic targets and treatments of pediatric TBI be unique? Strong support is presented for the existence of unique biochemical, molecular, cellular and physiological facets of TBI in infants and children versus adults. Unique therapeutic targets and enhanced therapeutic opportunities, both in the acute phase after injury and in rehabilitation and regeneration, are suggested.

Aging↗

PubMed2006

Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury.

Inflicted traumatic brain injury (iTBI) involves a combination of mechanical trauma and hypoxemia. Serum biomarker concentrations may provide objective information about their relative importance to the pathophysiology of iTBI. We compared the time course of neuron-specific enolase (NSE), S100B and myelin basic protein after pediatric hypoxic-ischemic brain injury, iTBI and noninflicted TBI (nTBI). The time to reach peak concentrations of all three biomarkers was shorter after nTBI. Initial and peak S100B, initial and peak myelin basic protein and peak NSE concentrations were no different between the three groups. Initial NSE concentration was highest after nTBI. These results suggest that the biochemical response of the brain to iTBI is distinct from the response to nTBI and shares temporal similarities with hypoxic-ischemic brain injury. This may have important implications for the treatment and prognosis of children with iTBI.

Age Factors↗

PubMed2006

Mitochondrial heat shock protein 60 is increased in cerebrospinal fluid following pediatric traumatic brain injury.

Mitochondrial dysfunction occurs after traumatic brain injury (TBI) and contributes significantly to subsequent cell death. Heat shock protein 60 (hsp60) is a predominantly mitochondrial protein with important homeostatic functions. Induction of hsp60 has been demonstrated in cerebral ischemia models, possibly reflecting mitochondrial stress. We measured hsp60 concentration in the cerebrospinal fluid (CSF) of 34 infants and children after severe TBI and of 7 control patients by ELISA. Peak CSF hsp60 concentration was increased in TBI patients versus controls (0.84 ng/ml, range 0-44.59, vs. 0.0 ng/ml, range 0-0.48; p<0.05). Induction of hsp60 occurred early after the injury. Peak hsp60 concentration was independently associated with the severity of injury, defined as the admission Glasgow Coma Scale score. These data suggest that increased hsp60 in CSF might reflect the severity of early mitochondrial stress or damage after TBI.

Biomarkers↗